Pyrrolo-pyridazine inhibitors of JAK2

Abstract

The present disclosure provides pyrrolo-pyridazinc 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, wherein R1, R2, R3, and R4 are as defined in classes and subclasses herein, both singly and in combination.

Description

Attorney Docket No.: 2013518-0095PYRROLO-PYRIDAZINE INHIBITORS OF JAK2CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to and benefit of Indian Appl. No. 202411067506, filed September 6, 2024, and U.S. Appl. No. 63 / 831,517, filed June 27, 2025, the entire contents of each of which are hereby incorporated 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 l of 83712954319vlAttorney Docket No.: 2013518-0095SUMMARY

[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, R3, and R4are as defined in classes and subclasses herein, both singly and in combination.

[0007] In some embodiments, the present disclosure provides a compound represented by formula II- 1 or II-2:II- 1 II-2 or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3a, and R4arc as defined in classes and subclasses herein, both singly and in combination.

[0008] In some embodiments, the present disclosure provides a compound represented by formula II- 1 :Page 2 of 83712954319vlAttorney Docket No.: 2013518-009511- 1 or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3a, and R4arc as defined in classes and subclasses herein, both singly and in combination.

[0009] In some embodiments, the present disclosure provides a compound represented by formula II-2:or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3a, and R4are as defined in classes and subclasses herein, both singly and in combination.

[0010] In some embodiments, the present disclosure provides a compound represented by formula II- 3:or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3a, and R4are as defined in classes and subclasses herein, both singly and in combination.

[0011] In some embodiments, the present disclosure provides a compound represented by formula II- 1, II-2, or II-3 , or a pharmaceutically acceptable salt thereof.

[0012] In some embodiments, the present disclosure provides a compound represented by formula III:Page 3 of 83712954319vlAttorney Docket No.: 2013518-0095Ill or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, and R4aarc as defined in classes and subclasses herein, both singly and in combination.

[0013] In some embodiments, the present disclosure provides a compound represented by formula IV- 1 or IV-2:IV- 1 IV-2 or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3a, and R4aare as defined in classes and subclasses herein, both singly and in combination.

[0014] In some embodiments, the present disclosure provides a compound represented by formula IV- 1:or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3a, and R4aare as defined in classes and subclasses herein, both singly and in combination.

[0015] In some embodiments, the present disclosure provides a compound represented by formula IV-2:Page 4 of 83712954319vlAttorney Docket No.: 2013518-0095IV-2 or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3a, and R4aarc as defined in classes and subclasses herein, both singly and in combination.

[0016] In some embodiments, the present disclosure provides a compound represented by formula IV-3:or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3a, and R4aare as defined in classes and subclasses herein, both singly and in combination.

[0017] In some embodiments, the present disclosure provides a compound represented by formula IV-1, IV-2, or IV-3, or a pharmaceutically acceptable salt thereof.

[0018] In some embodiments, the present disclosure provides a compound represented by formula V-l:or a pharmaceutically acceptable salt thereof, wherein R1, L, R5, R3, and R4are as defined in classes and subclasses herein, both singly and in combination.

[0019] In some embodiments, the present disclosure provides a compound represented by formula V-2:Page 5 of 83712954319vlAttorney Docket No.: 2013518-0095or a pharmaceutically acceptable salt thereof, wherein R1, L, R5, R3, and R4are as defined in classes and subclasses herein, both singly and in combination.

[0020] In some embodiments, the present disclosure provides a compound represented by formula VI- 1:or a pharmaceutically acceptable salt thereof, wherein R1, L, R5, R3, and R4aare as defined in classes and subclasses herein, both singly and in combination.

[0021] In some embodiments, the present disclosure provides a compound represented by formula VI-2:or a pharmaceutically acceptable salt thereof, wherein R1, L, R5, R3, and R4aare as defined in classes and subclasses herein, both singly and in combination.

[0022] In some embodiments, the present disclosure provides a compound represented by formula VII- 1 or VII-2:Page 6 of 83712954319vlAttorney Docket No.: 2013518-0095or a pharmaceutically acceptable salt thereof, wherein R1, L, R5, R3a, and R4aare as defined in classes and subclasses herein, both singly and in combination.

[0023] In some embodiments, the present disclosure provides a compound represented by formula VTI-1 :VII- 1 or a pharmaceutically acceptable salt thereof, wherein R1, L, R5, R3a, and R4aare as defined in classes and subclasses herein, both singly and in combination.

[0024] In some embodiments, the present disclosure provides a compound represented by formula VII-2:Page 7 of 83712954319vlAttorney Docket No.: 2013518-0095VIT-2 or a pharmaceutically acceptable salt thereof, wherein R1, L, R5, R3a, and R4aarc as defined in classes and subclasses herein, both singly and in combination.

[0025] In some embodiments, the present disclosure provides a compound represented by formula VII-3:or a pharmaceutically acceptable salt thereof, wherein R1, L, R5, R3a, and R4aare as defined in classes and subclasses herein, both singly and in combination.

[0026] In some embodiments, the present disclosure provides a compound represented by formula VII-4:or a pharmaceutically acceptable salt thereof, wherein R1, L, R5, R3a, and R4aare as defined in classes and subclasses herein, both singly and in combination.

[0027] In some embodiments, the present disclosure provides a compound represented by formula VII-5:Page 8 of 83712954319vlAttorney Docket No.: 2013518-0095VII-5 or a pharmaceutically acceptable salt thereof, wherein R1, L, R5, R3a, and R4aare as defined in classes and subclasses herein, both singly and in combination.

[0028] In some embodiments, the present disclosure provides a compound represented by formula VTI-1 , VII-2, VII-3, VII-4, or VII-5, or a pharmaceutically acceptable salt thereof.

[0029] In some embodiments, the present disclosure provides a compound represented by formula VIII:or a pharmaceutically acceptable salt thereof, wherein R1, R2, La, R6, Lb, R3, and R4are as defined in classes and subclasses herein, both singly and in combination.

[0030] 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 VIII) or a pharmaceutical composition comprising a compound described herein.

[0031] In some embodiments, the present disclosure provides a method of treating a disease, disorder, or condition associated with JAK2, comprising administering to the subject a compound described herein (e.g., a compound of any one of Formula I to VIII) or a pharmaceutical composition comprising a compound described herein.Page 9 of 83712954319vlAttorney Docket No.: 2013518-0095

[0032] In some embodiments, the present disclosure provides a method of treating cancer, comprising administering to a subject in need thereof a compound described herein (c.g., a compound of any one of Formula I to VIII) or a pharmaceutical composition comprising a compound described herein.

[0033] 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 VIII) or a pharmaceutical composition comprising a compound described herein.

[0034] 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 VIII) or a pharmaceutical composition comprising a compound described herein.DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS

[0035] 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 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 mutation to the JH2 domain of JAK2.

[0036] In some embodiments, the present disclosure provides a compound represented by Formula I:Page 10 of 83712954319vlAttorney Docket No.: 2013518-0095or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, and R4are as defined in classes and subclasses herein, both singly and in combination.Compounds and Definitions

[0037] Compounds of this disclosure include those described generally above and arc 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.

[0038] 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 stereochemical isomers, as well as enantiomeric, diastcrcomic, and geometric (or conformational) mixtures of provided compounds are within the scope of the disclosure. For example, in some case, Tables 1A-1C show 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.

[0039] 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 orPage 11 of 83712954319vlAttorney Docket No.: 2013518-0095 tritium, or replacement of a carbon by13C- or14C-enriched carbon are within the scope of this disclosure.

[0040] 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.

[0041] 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, 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, afterPage 12 of 83712954319vlAttorney Docket No.: 2013518-0095 an interval of time, administration of a second or subsequent dose of a pharmaceutical composition (c.g., an immunogenic composition, c.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.

[0042] 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., CM). 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., C ). 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 (e.g., is multivalent).

[0043] 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 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, C , CM, CM, or CM). Exemplary alkyl groups include methyl, ethyl, propyl, butyl, pentyl, hexyl, and heptyl.

[0044] 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 appreciatedPage 13 of 83712954319vlAttorney Docket No.: 2013518-0095 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-mcmbcrcd 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, e.g.,.

[0045] Alkenyl: The term “alkenyl”, used alone or as part of a larger moiety, refers to 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 carboncarbon double bond and having about 3 to about 10 carbon atoms. Exemplary monocyclic cycloalkenyl rings include cyclopentenyl, cyclohexenyl, and cycloheptenyl.

[0046] 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.

[0047] 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 arc fusedPage 14 of 83712954319vlAttorney Docket No.: 2013518-0095

[0048] Bicyclic: The term “bicyclic ring” 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 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 bridged bicyclics include:Page 15 of 83712954319vlAttorney Docket No.: 2013518-0095

[0049] Biological sample: As used herein, the term “biological sample” typically 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 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 arc 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 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, filteringPage 16 of 83712954319vlAttorney Docket No.: 2013518-0095 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.

[0050] 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.

[0051] 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.

[0052] 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 atoms. Exemplary monocyclic cycloalkyl rings include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.

[0053] 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).

[0054] 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.

[0055] 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,Page 17 of 83712954319vlAttorney Docket No.: 2013518-0095 starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostcaratc, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol and the like.

[0056] Halogen: The term “halogen” or “halo” means F, Cl, Br, or I.

[0057] 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 quatemized 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 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.

[0058] Heteroaryh 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 % 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[l,2-a]pyrimidinyl, imidazo[l,2-a]pyridinyl, thienopyrimidinyl, triazolopyridinyl, and benzoisoxazolyl. The terms “heteroaryl” and “heteroar-”, as used herein, also include groups in which a heteroaromatic ringPage 18 of 83712954319vlAttorney Docket No.: 2013518-0095 is fused to one or more aryl, cycloaliphatic, or heterocyclyl rings (i.e., a bicyclic heteroaryl ring having 1 to 3 hctcroatoms). Nonlimiting examples include indolyl, isoindolyl, bcnzothicnyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzothiazolyl, benzo thiadiazolyl, benzoxazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 477- quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, pyrido[2,3-b]-l,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.

[0059] Heteroatom: The term “heteroatom” as used herein refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quatemized form of a basic nitrogen.

[0060] 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. 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, inPage 19 of 83712954319vlAttorney Docket No.: 2013518-0095 addition to carbon atoms, one or more heteroatoms as defined above (e.g., one, two, three or four hctcroatoms)). 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.

[0061] 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.

[0062] Parenteral: The phrases “parenteral administration” and “administered parenterally” as used herein have their art-understood meaning referring to modes of 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.

[0063] 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.

[0064] 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.

[0065] 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. InPage 20 of 83712954319vlAttorney Docket No.: 2013518-0095 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 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 intrarec tally, for example, as a pessary, cream, or foam; sublingually; ocularly; transdermally; or nasally, pulmonary, and to other mucosal surfaces.

[0066] 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.

[0067] 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 / or 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,Page 21 of 83712954319vlAttorney Docket No.: 2013518-0095 methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phcnylpropionatc, phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like.

[0068] Further, acids which are generally considered suitable for the formation of pharmaceutically useful salts from basic pharmaceutical compounds are discussed, for example, 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 etal., 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.

[0069] Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N+(C7 alky 1)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.

[0070] 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 implicit from the structure (e.g.,refers to at leastrefers to at leastUnless otherwise indicated, an “optionally substituted” group may have a suitable substituent at each substitutable position of the 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 orPage 22 of 83712954319vlAttorney Docket No.: 2013518-0095 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 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.

[0071] Suitable monovalent substituents on a substitutable carbon atom of an “optionally substituted” group are independently halogen; -(CH2)o4RC; -(CH2)CMOR°; -0(CH2)O-4R°; -O- (CH2)OHC(0)OR°; -(CH2)OHCH(OR°)2; -(CH2)OHSR°; -(CH2)O-4Ph. which may be substituted with R°; -(CH2)o40(CH2)o iPh which may be substituted with R°; -CH=CHPh, which may be substituted with R°; -(CH2)OHO(CH2)O-I -pyridyl which may be substituted with R°; -NO2; -CN; -N3; -(CH2)O4N( RO)2; -(CH2)OHN(R°)C(0)R0; -N(R°)C(S)R°; -(CH2)O-4N(R°)C(O)NRO2; -N(RO)C(S)NR°2; -(CH2)(MN(R°)C(0)0R°;N(R°)N(R°)C(O)R0; -N(R°)N(R°)C(O)NR°2; -N(R°)N(R°)C(O)OR°; -(CH2J0 4C(O)R°; - C(S)R°; -(CH2)OHC(0)OR°; -(CH2)O 4C(O)SRO; -(CH2)(wC(O)OSiR°3; -(CH2)o-4OC(O)R°; - OC(O)(CH2)0 4SR°; (CH2)O4SC(O)RO; (CH2)O 4C(O)NRO2; C(S)NRO2; C(S)SR°;SC(S)SR°, -(CH2)(MOC(O)NR°2; -C(O)N(OR°)R°; -C(O)C(O)R°; -C(O)CH2C(O)RO; - C(NOR°)R°; -(CH2)O4SSR°; -(CH2)O 4S(OJ2R°; -(CH2)O-4S(O)2ORO; -(CH2)O4OS(O)2RO; - S(O)2NR°2; -(CH2)OHS(0)(NH)R°; -(CH2)onS(0)R°; -N(R°)S(O)2NR°2; -N(R°)S(O)2RO; - N(OR°)R°; -C(NH)NR°2; -P(O)2RO; -P(O)RO2; -OP(O)RO2; -OP(O)(ORO)2; -SiR°3; -(CM straight or branched alkylene)O-N(R°)2; or -(CH straight or branched alkylene)C(O)O-N(R°)2, wherein each R° may be substituted as defined below and is independently hydrogen, Ci- 6 aliphatic, -CH2Ph, -0(CH2)o-iPh, -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 heteroatomsPage 23 of 83712954319vlAttorney Docket No.: 2013518-0095 independently selected from nitrogen, oxygen, or sulfur, which may be substituted as defined below.

[0072] 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)o2R*. -(haloR*), -(CH2)O 2OH, -(CH2)O-20R*, -(CH2)O2CH(OR*)2, -O(haloR’), -CN, -N3, -(CH2)o2C(O)R*, -(CH2)O2C(O)OH, -(CH2)O2C(O)OR*, -(CH2)^2SR*, -(CH2)O -2SH, -(CH2)O -2NH2, - (CH2)0 2NHR*, -(CH2)O-2NR*2, -NO2, -SiR*3, -OsiR*3, -C(O)SR* -(CM 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 CIM aliphatic, - CH2Ph, -0(CH2)o iPh, 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 =0 and =S.

[0073] Suitable divalent substituents on a saturated carbon atom of an “optionally substituted” group include the following: =0 (“oxo”), =S, =NNR*2, =NNHC(O)R*, =NNHC(O)OR*, =NNHS(O)2R*, =NR*, =NOR*, -O(C(R*2))23O-, or -S(C(R*2))2-3S-, wherein each independent occurrence of R* is selected from hydrogen, C1-6 aliphatic 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, C1-6 aliphatic 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.

[0074] 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 CIM aliphatic, -CH2Ph, -0(CH2)o iPh, or a 3- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 hctcroatoms independently selected from nitrogen, oxygen, or sulfur.

[0075] Suitable substituents on a substitutable nitrogen of an “optionally substituted” group include -R:, -NR2, -C(O)Rf, -C(O)ORf, -C(O)C(O)Rf,Page 24 of 83712954319vlAttorney Docket No.: 2013518-0095C(O)CH2C(O)Rt, -8(0)^, -S(O)2NRt2, -C(S)NRf2, -C(NH)NRf2, or -N^S^R1; wherein each R is independently hydrogen, Ci-6 aliphatic 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 definition above, two independent occurrences of Rf, 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.

[0076] 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%, or -NO2, wherein each R* is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently CH aliphatic, -CH2Ph, -0(CH2)o iPh, or a 3- to 6- membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0077] 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.

[0078] 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.

[0079] 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. InPage 25 of 83712954319vlAttorney Docket No.: 2013518-0095 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.

[0080] 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 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.

[0081] 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.

[0082] 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.

[0083] Those of skill in the art will appreciate that certain small molecule compounds have structures that pennit isotopic substitution (e.g.,2H or3H for H;nC,13C or14C for12C;13N or15N for14N;17O or18O for16O;36C1 for35C1 or37C1;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.

[0084] 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.

[0085] 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 moleculePage 26 of 83712954319vlAttorney Docket No.: 2013518-0095 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 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 (E)) 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.

[0086] Those skilled in the art will further appreciate that, in small molecule structures, the symbol , as used herein, 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. Those skilled in the art will further appreciate, in small molecule structures, the symbol, as used herein, represents a single or double bond between two atoms in a ring structure. For example:H is intended to encompass both: H and H .

[0087] Treat: As used herein, the term “treat” (also “treatment” or “treating”) refers to any administration of a therapy that partially or completely alleviates, ameliorates, relieves, 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 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.Page 27 of 83712954319vlAttorney Docket No.: 2013518-0095

[0088] As used herein, a “floating” substituent drawn on a ring indicates that a substituent may exist at any position of the ring. For example, for a ring suchsubstituent may exist at any position and may replace a hydrogen atom of any substitutable carbon or nitrogen atom. In some embodiments, a “floating” substituent drawn on one ring of a polycyclic moiety, indicates that a substituent may exist on any ring of the polycyclic moiety (e.g.,is equivalent tProvided Compounds

[0089] In some embodiments, the present disclosure provides a compound of Formula I:or a pharmaceutically acceptable salt thereof, wherein:R1is hydrogen or optionally substituted Ci-Ce aliphatic;R2is C3-C12 cycloaliphatic, Ci-Ce aliphatic, 2- to 10-membered hetero aliphatic, 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 Ce-Cio aryl, wherein R2is optionally substituted with one or more instances of -L-R5or R7; each L is independently selected from the group consisting of a bond, N(Ra)C(O)N(Ra)-, -N(Ra)C(O)O-, -OC(O)N(Ra)-, -C(O)N(Ra)-, -N(Ra)C(O)-, -N(Ra)-, -O-, -Page 28 of 83712954319vlAttorney Docket No.: 2013518-0095C(0)-, -C(0)0-, -0C(0)-, -N(Ra)C(S)O-, -OC(S)N(Ra)-, -C(S)N(Ra)-, -N(Ra)C(S)-, -C(S)-, - C(S)O-, and -OC(S)-; each R5is independently selected from the group consisting of optionally substituted Ci-C6aliphatic, optionally substituted 2- to 10-membered 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 Ce-Cioaryl; each R7is independently selected from the group consisting of halogen, -OH, -SH, and -NH2;R3is 5- to 12-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, 4- to 12-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S, C6-C12 aryl, C3-C12 cycloaliphatic, or Ci-Ce aliphatic, wherein R3is optionally substituted with one or more instances of R3a; orR2and R3are connected by *-La-R6-Lb-**, wherein * represents a point of attachment to R2, and ** represents a point of attachment to R3;Lais a bond, -N(Ra)C(O)N(Ra)-, -N(Ra)C(O)O-, -OC(O)N(Ra)-, -C(O)N(Ra)-, - N(Ra)C(O)-, -N(Ra)-, -O-, -C(O)-, -C(O)O-, -OC(O)-, -N(Ra)C(S)O-, -OC(S)N(Ra)-, -C(S)N(Ra)- , -N(Ra)C(S)-, -C(S)-, -C(S)O-, or -OC(S)-;Lbis a bond, -N(Ra)C(O)N(Ra)-, -N(Ra)C(O)O-, -OC(O)N(Ra)-, -C(O)N(Ra)-, - N(Ra)C(O)-, -N(Ra)-, -O-, -C(O)-, -C(O)O-, -OC(O)-, -N(Ra)C(S)O-, -OC(S)N(Ra)-, -C(S)N(Ra)- , -N(Ra)C(S)-, -C(S)-, -C(S)O-, or -OC(S)-;R6is optionally substituted Ci-Ce aliphatic, optionally substituted 2- to 10-membered 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, or optionally substituted Ce-Cio aryl;R4is Ci-Ce aliphatic, -CN, 2- to 10-membered 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 Ce-Cio aryl, wherein R4is optionally substituted with one or more instances of R4a;Page 29 of 83712954319vlAttorney Docket No.: 2013518-0095 each R3ais independently selected from the group consisting of optionally substituted Ci-Ce aliphatic, optionally substituted 2- to 10-mcmbcrcd hctcroaliphatic, 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, optionally substituted C6-C10 aryl, 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, and -ORa; each R4ais independently selected from the group consisting of optionally substituted Ci-Ce aliphatic, optionally substituted 2- to 10-membered 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, optionally substituted Ce-Cio aryl, halogen, oxo, -CN, -NO2, -C(O)Ra, -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; and each Rais independently selected from hydrogen, optionally substituted Ci-Ce aliphatic, optionally substituted 2- to 10-membered 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.

[0090] In some embodiments, the present disclosure provides a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein:R1is hydrogen or optionally substituted Ci-Ce aliphatic;R2is C3-C12 cycloaliphatic, Ci-Ce aliphatic, 2- to 10-membered heteroaliphatic, 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 Ce-Cio aryl, wherein R2is optionally substituted with one or more instances of -L-R5or R7; each L is independently selected from the group consisting of a bond, - N(Ra)C(O)N(Ra)-, -N(Ra)C(O)O-, -OC(O)N(Ra)-, -C(O)N(Ra)-, -N(Ra)C(O)-, -N(Ra)-, -O-, - C(O)-, -C(O)O-, -OC(O)-, -N(Ra)C(S)O-, -OC(S)N(Ra)-, -C(S)N(Ra)-, -N(Ra)C(S)-, -C(S)-, - C(S)O-, and -OC(S)-;Page 30 of 83712954319vlAttorney Docket No.: 2013518-0095 each R5is independently selected from the group consisting of optionally substituted Ci-Ce aliphatic, optionally substituted 2- to 10-mcmbcrcd hctcroaliphatic, 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-Cioaryl; each R7is independently selected from the group consisting of halogen, -OH, -SH, and -NH2;R3is 5- to 12-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, 4- to 12-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S, C6-C12 aryl, C3-C12 cycloaliphatic, or Ci-Ce aliphatic, wherein R3is optionally substituted with one or more instances of R3a; orR2and R3are connected by *-La-R6-Lb-**, wherein * represents a point of attachment to R2, and ** represents a point of attachment to R3;Lais a bond, -N(Ra)C(O)N(Ra)-, -N(Ra)C(O)O-, -OC(O)N(Ra)-, -C(O)N(Ra)-, - N(Ra)C(O)-, -N(Ra)-, -O-, -C(O)-, -C(O)O-, -OC(O)-, -N(Ra)C(S)O-, -OC(S)N(Ra)-, -C(S)N(Ra)- , -N(Ra)C(S)-, -C(S)-, -C(S)O-, or -OC(S)-;Lbis a bond, -N(Ra)C(O)N(Ra)-, -N(Ra)C(O)O-, -OC(O)N(Ra)-, -C(O)N(Ra)-, - N(Ra)C(O)-, -N(Ra)-, -O-, -C(O)-, -C(O)O-, -OC(O)-, -N(Ra)C(S)O-, -OC(S)N(Ra)-, -C(S)N(Ra)- , -N(Ra)C(S)-, -C(S)-, -C(S)O-, or -OC(S)-;R6is optionally substituted Ci-Ce aliphatic, optionally substituted 2- to 10-membered 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, or optionally substituted Ce-Cio aryl;R4is Ci-Ce aliphatic, 2- to 10-membered 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 Ce-Cio aryl, wherein R4is optionally substituted with one or more instances of R4a; each R3ais independently selected from the group consisting of optionally substituted C1-C6 aliphatic, optionally substituted 2- to 10-membered heteroaliphatic, optionally substituted C3-C12 cycloaliphatic, optionally substituted 4- to 10-membered heterocycle comprising 1 to 4Page 31 of 83712954319vlAttorney Docket No.: 2013518-0095 heteroatoms selected from N, O, and S, optionally substituted 5- to 10-membered heteroaryl comprising 1 to 4 hctcroatoms selected from N, O, and S, optionally substituted Ce-Cio aryl, 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, and -ORa; each R4ais independently selected from the group consisting of optionally substituted Ci-Ce aliphatic, optionally substituted 2- to 10-membered heteroaliphatic, optionally substituted C3-Ci2cycloaliphatic, 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, optionally substituted Ce-Cio aryl, 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, and -ORa; and each Rais independently selected from hydrogen, optionally substituted Ci-Ce aliphatic, optionally substituted 2- to 10-membered 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.

[0091] In some embodiments, the present disclosure provides a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein:R1is hydrogen or optionally substituted Ci-Ce aliphatic;R2is C3-C12 cycloaliphatic, Ci-Ce aliphatic, 2- to 10-membered heteroaliphatic, 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 Ce-Cio aryl, wherein R2is optionally substituted with one or more instances of -L-R5; each L is independently selected from the group consisting of a bond, - N(Ra)C(O)N(Ra)-, -N(Ra)C(O)O-, -OC(O)N(Ra)-, -C(O)N(Ra)-, -N(Ra)C(O)-, -N(Ra)-, -O-, - C(O)-, -C(O)O-, -OC(O)-, -N(Ra)C(S)O-, -OC(S)N(Ra)-, -C(S)N(Ra)-, -N(Ra)C(S)-, -C(S)-, - C(S)O-, and -OC(S)-; each R5is independently selected from the group consisting of optionally substituted Ci-Ce aliphatic, optionally substituted 2- to 10-membered heteroaliphatic, optionally substituted C3-C12 cycloaliphatic, optionally substituted 4- to 10-membered heterocycle comprising 1 to 4Page 32 of 83712954319vlAttorney Docket No.: 2013518-0095 heteroatoms selected from N, O, and S, optionally substituted 5- to 10-membered heteroaryl comprising 1 to 4 hctcroatoms selected from N, O, and S, and optionally substituted Ce-Cioaryl;R3is 5- to 12-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, 4- to 12-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S, C6-C12 aryl, C3-C12 cycloaliphatic, or Ci-Ce aliphatic, wherein R3is optionally substituted with one or more instances of R3a; orR2and R3are connected by *-La-R6-Lb-**, where * represents a point of attachment to R2, and ** represents a point of attachment to R3;Lais a bond, -N(Ra)C(O)N(Ra)-, -N(Ra)C(O)O-, -OC(O)N(Ra)-, -C(O)N(Ra)-, - N(Ra)C(O)-, -N(Ra)-, -O-, -C(O)-, -C(O)O-, -OC(O)-, -N(Ra)C(S)O-, -OC(S)N(Ra)-, -C(S)N(Ra)- , -N(Ra)C(S)-, -C(S)-, -C(S)O-, or -OC(S)-;Lbis a bond, -N(Ra)C(O)N(Ra)-, -N(Ra)C(O)O-, -OC(O)N(Ra)-, -C(O)N(Ra)-, - N(Ra)C(O)-, -N(Ra)-, -O-, -C(O)-, -C(O)O-, -OC(O)-, -N(Ra)C(S)O-, -OC(S)N(Ra)-, -C(S)N(Ra)- , -N(Ra)C(S)-, -C(S)-, -C(S)O-, or -OC(S)-;R6is optionally substituted Ci-Ce aliphatic, optionally substituted 2- to 10-membered 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, or optionally substituted Ce-Cio aryl;R4is Ci-Ce aliphatic, 2- to 10-membered 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 Ce-Cio aryl, wherein R4is optionally substituted with one or more instances of R4a; each R3ais independently selected from the group consisting of optionally substituted Ci-Ce aliphatic, optionally substituted 2- to 10-membered 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, optionally substituted Ce-Cio aryl, 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, and -ORa;Page 33 of 83712954319vlAttorney Docket No.: 2013518-0095 each R4ais independently selected from the group consisting of optionally substituted Ci-Ce aliphatic, optionally substituted 2- to 10-mcmbcrcd hctcroaliphatic, 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, optionally substituted C6-C10 aryl, 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, and -ORa; and each Rais independently selected from hydrogen, optionally substituted Ci-Ce aliphatic, optionally substituted 2- to 10-membered 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.

[0092] In some embodiments, a compound of Formula I is a compound represented byFormula II- 1 or II-2:II- 1 II-2 or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3a, and R4arc as defined in classes and subclasses herein, both singly and in combination.

[0093] In some embodiments, the present disclosure provides a compound represented by formula II- 3:Page 34 of 83712954319vlAttorney Docket No.: 2013518-0095 or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3a, and R4are as defined in classes and subclasses herein, both singly and in combination.

[0094] In some embodiments, a compound of Formula I is a compound represented by Formula III:or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, and R4aare as defined in classes and subclasses herein, both singly and in combination.

[0095] In some embodiments, a compound of Formula I is a compound represented by Formula IV- 1 or IV-2:IV- 1 IV-2 or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3a, and R4aare as defined in classes and subclasses herein, both singly and in combination.

[0096] In some embodiments, the present disclosure provides a compound represented by formula IV-3:Page 35 of 83712954319vlAttorney Docket No.: 2013518-0095IV-3 or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3a, and R4aarc as defined in classes and subclasses herein, both singly and in combination.

[0097] In some embodiments, a compound of Formula I is a compound represented by Formula V-l:or a pharmaceutically acceptable salt thereof, wherein R1, L, R5, R3, and R4are as defined in classes and subclasses herein, both singly and in combination.

[0098] In some embodiments, the present disclosure provides a compound represented by formula V-2:or a pharmaceutically acceptable salt thereof, wherein R1, L, R5, R3, and R4are as defined in classes and subclasses herein, both singly and in combination.

[0099] In some embodiments, the present disclosure provides a compound represented by formula VI:Page 36 of 83712954319vlAttorney Docket No.: 2013518-0095or a pharmaceutically acceptable salt thereof, wherein R1, L, R5, R3, and R4aare as defined in classes and subclasses herein, both singly and in combination.

[0100] In some embodiments, the present disclosure provides a compound represented by formula VII- 1 or VII-2:or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3a, and R4aarc as defined in classes and subclasses herein, both singly and in combination.

[0101] In some embodiments, the present disclosure provides a compound represented by formula VII-3:Page 37 of 83712954319vlAttorney Docket No.: 2013518-0095 or a pharmaceutically acceptable salt thereof, wherein R1, L, R5, R3a, and R4aare as defined in classes and subclasses herein, both singly and in combination.

[0102] In some embodiments, the present disclosure provides a compound represented by formula VII-4 or VII- 5:or a pharmaceutically acceptable salt thereof, wherein R1, L, R5, R3a, and R4aare as defined in classes and subclasses herein, both singly and in combination.

[0103] In some embodiments, the present disclosure provides a compound represented by formula VIII:or a pharmaceutically acceptable salt thereof, wherein R1, R2, La, R6, Lb, R3, and R4are as defined in classes and subclasses herein, both singly and in combination.

[0104] In some embodiments, the present disclosure provides a compound represented by formula IX:Page 38 of 83712954319vlAttorney Docket No.: 2013518-0095or a pharmaceutically acceptable salt thereof, wherein R5is optionally substituted cyclopropyl; and R1, R3, and R4are as defined in classes and subclasses herein, both singly and in combination. In some embodiments, R5is cyclopropyl optionally substituted with one or more halogen, -(CH2)o- 4R0, or -CN. In some embodiments, R5is cyclopropyl optionally substituted with one or more fluoro, a 3- to 6-membered aryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur optionally substituted with Ci^ aliphatic, or -CN. In some embodiments, R5is cyclopropyl optionally substituted with one or more halogen (e.g., fluoro). In some embodiments,

[0105] As described herein, with respect to any formula provided herein (e.g., any of Formulae I-IX), R1is hydrogen or optionally substituted Ci-Ce aliphatic. In some embodiments, R1is hydrogen. In some embodiments, R1is optionally substituted Ci-Ce aliphatic. In some embodiments, R1is optionally substituted C1-C3 aliphatic. In some embodiments, R1is Ci-Ce aliphatic. In some embodiments, R1is methyl (-CH3) or deuterated methyl (e.g., one or more H atoms of methyl have been replaced with deuterium, i.e., -CH2D, -CHD2, or -CD3). In some embodiments, R1is -CH3 or -CD3. In some embodiments, R1is -CH3. In some embodiments, R1is -CD3.

[0106] As described herein, with respect to any formula provided herein (e.g., any of Formulae I-IX), R2is C3-C12 cycloaliphatic, Ci-Ce aliphatic, 2- to 10-membered heteroaliphatic, 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 Ce-Cio aryl, wherein R2is optionally substituted with one or more instances of -L-R5or R7. In somePage 39 of 83712954319vlAttorney Docket No.: 2013518-0095 embodiments, R2is C3-C12 cycloaliphatic, Ci-Ce aliphatic, 2- to 10-membered heteroaliphatic, 4- to 10-mcmbcrcd hctcrocyclc comprising 1 to 4 hctcroatoms selected from N, O, and S, 5- to 10- membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, or Ce-Cio aryl, wherein R2is substituted with one or more instances of -L-R5or R7. In some embodiments, R2is C3-C12 cycloaliphatic, Ci-Ce aliphatic, 2- to 10-membered heteroaliphatic, 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 Ce-Cio aryl, wherein R2is substituted with 1-2 instances of -L-R5and with 0-2 instances of R7. In some embodiments, R2is C3-C12 cycloaliphatic, Ci-Ce aliphatic, 2- to 10-membered heteroaliphatic, 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 Ce-Cio aryl, wherein R2is substituted with 0-2 instances of -L-R5and with 1-2 instances of R7.

[0107] In some embodiments, R2is Ci-Ce aliphatic, C3-C12 cycloaliphatic, or 4- to 10- membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S, wherein R2is optionally substituted with one or more instances of -L-R5or R7. In some embodiments, R2is Ci- Ce aliphatic, C3-C12 cycloaliphatic, or 4- to 10-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S, wherein R2is substituted with 0-2 instances of -L-R5or R7. In some embodiments, R2is Ci-Ce aliphatic, C3-C12 cycloaliphatic, or 4- to 10-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S, wherein R2is optionally substituted with one instance of -L-R5or R7. In some embodiments, R2is C3-C12 cycloaliphatic or 4- to 10-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S; and wherein R2is substituted with 0-2 instances of -L-R5or R7. In some embodiments, R2is C3-C12 cycloaliphatic or 4- to 10-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S; and wherein R2is substituted with 1-2 instances of -L-R5or R7. In some embodiments, R2is C3-C12 cycloaliphatic or 4- to 10-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S; and wherein R2is substituted with one instance of -L-R5or R7. In some embodiments, R2is C3-C7 monocyclic cycloaliphatic or 4- to 6-membered monocyclic heterocycle comprising 1 to 2 heteroatoms selected from N, O, and S; and wherein R2is substituted with 0-2 instances of -L-R5or R7. In some embodiments, R2is C3-C7 monocyclic cycloaliphatic or 4- to 6- membered monocyclic heterocycle comprising 1 to 2 heteroatoms selected from N, O, and S; and wherein R2is substituted with 1-2 instances of -L-R5or R7. In some embodiments, R2is C3-C7Page 40 of 83712954319vlAttorney Docket No.: 2013518-0095 monocyclic cycloaliphatic or 4- to 6-membered monocyclic heterocycle comprising 1 to 2 hctcroatoms selected from N, O, and S; and wherein R2is substituted with one instance of -L-R5or R7.

[0108] In some embodiments, R2is C3-C12 cycloaliphatic, Ci-Ce aliphatic, 2- to 10-membered heteroaliphatic, 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 Ce-Cioaryl, wherein R2is optionally substituted with one or more instances of -L-R5. In some embodiments, R2is C3-C12 cycloaliphatic, C1-C6 aliphatic, 2- to 10-membered hetero aliphatic, 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 Ce-Cio aryl, wherein R2is substituted with one or more instances of -L-R5. In some embodiments, R2is Ci-Ce aliphatic, C3-C12 cycloaliphatic, or 4- to 10-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S, wherein R2is optionally substituted with one or more instances of -L- R5. In some embodiments, R2is Ci-Ce aliphatic, C3-C12 cycloaliphatic, or 4- to 10-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S, wherein R2is substituted with 1-2 instances of -L-R5. In some embodiments, R2is Ci-Ce aliphatic, C3-C12 cycloaliphatic, or 4- to 10-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S, wherein R2is optionally substituted with one instance of -L-R5. In some embodiments, R2is C3- C12 cycloaliphatic or 4- to 10-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S; and wherein R2is substituted with one instance of -L-R5. In some embodiments, R2is C3-C7 monocyclic cycloaliphatic or 4- to 6-membered monocyclic heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S; and wherein R2is substituted with one instance of -L- R5.

[0109] In some embodiments, R2is Ci-Ce aliphatic, and wherein R2is optionally substituted with one or more instances of -L-R5or R7. In some embodiments, R2is Ci-Ce aliphatic, and wherein R2is optionally substituted with one or more instances of -L-R5. In some embodiments, R2is C1-C6 aliphatic, and wherein R2is optionally substituted with one instance of -L-R5. In some embodiments, R2is 2- to 10-membered heteroaliphatic, and wherein R2is optionally substituted with one or more instances of -L-R5or R7. In some embodiments, R2is 2- to 10-membered heteroaliphatic, and wherein R2is optionally substituted with one or more instances of -L-R5. InPage 41 of 83712954319vlAttorney Docket No.: 2013518-0095 some embodiments, R2is 2- to 10-membered heteroaliphatic, and wherein R2is optionally substituted with one instance of -L-R5.

[0110] In some embodiments, R2is C3-C12 cycloaliphatic, and wherein R2is optionally substituted with one or more instances of -L-R5or R7. In some embodiments, R2is C3-C12 cycloaliphatic, and wherein R2is substituted with 1-2 instances of -L-R5or R7. In some embodiments, R2is C3-C6 cycloaliphatic, and wherein R2is optionally substituted with one or more instances of -L-R5or R7. In some embodiments, R2is C3-C6 cycloaliphatic, and wherein R2is substituted with 1-2 instances of -L-R5or R7. In some embodiments, R2is C4-C6 cycloaliphatic, and wherein R2is optionally substituted with one or more instances of -L-R5or R7. In some embodiments, R2is C4-C6 cycloaliphatic, and wherein R2is substituted with 1-2 instances of -L- R5or R7. In some embodiments, R2is C3-C6 cycloaliphatic selected from cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, and wherein R2is optionally substituted with one or more instances of -L-R5or R7. In some embodiments, R2is C3-C6 cycloaliphatic selected from cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, and wherein R2is substituted with 1-2 instances of -L-R5or R7. hr some embodiments, R2is cyclopropyl, and wherein R2is optionally substituted with one or more instances of -L-R5or R7. In some embodiments, R2is cyclopropyl, and wherein R2is substituted with 1-2 instances of -L-R5or R7. In some embodiments, R2is cyclobutyl, and wherein R2is optionally substituted with one or more instances of -L-R5or R7. In some embodiments, R2is cyclobutyl, and wherein R2is substituted with 1-2 instances of -L-R5or R7. hi some embodiments, R2is cyclopentyl, and wherein R2is optionally substituted with one or more instances of -L-R5or R7. In some embodiments, R2is cyclopentyl, and wherein R2is substituted with 1-2 instances of -L-R5or R7. In some embodiments, R2is cyclohexyl, and wherein R2is optionally substituted with one or more instances of -L-R5or R7. In some embodiments, R2is cyclohexyl, and wherein R2is substituted with 1-2 instances of -L-R5or R7.

[0111] In some embodiments, R2is C3-C12 cycloaliphatic, and wherein R2is optionally substituted with one or more instances of -L-R5. In some embodiments, R2is C3-C12 cycloaliphatic, and wherein R2is optionally substituted with one instance of -L-R5. hi some embodiments, R2is C3-C12 cycloaliphatic. In some embodiments, R2is C3-C6 cycloaliphatic, and wherein R2is optionally substituted with one or more instances of -L-R5. In some embodiments, R2is C3-C6 cycloaliphatic, and wherein R2is optionally substituted with one instance of -L-R5. In some embodiments, R2is C4-C6 cycloaliphatic, and wherein R2is optionally substituted with onePage 42 of 83712954319vlAttorney Docket No.: 2013518-0095 or more instances of -L-R5. In some embodiments, R2is C3-C6 cycloaliphatic selected from cyclopropyl, cyclobutyl, cyclopcntyl, and cyclohcxyl, and wherein R2is optionally substituted with one or more instances of -L-R5. In some embodiments, R2is C3-C6 cycloaliphatic selected from cyclopropyl, cyclobutyl, and cyclopentyl, and wherein R2is optionally substituted with one or more instances of -L-R5. In some embodiments, R2is cyclopropyl, and wherein R2is optionally substituted with one or more instances of -L-R5. In some embodiments, R2is cyclobutyl, and wherein R2is optionally substituted with one or more instances of -L-R5. In some embodiments, R2is cyclopentyl, and wherein R2is optionally substituted with one or more instances of -L-R5. In some embodiments, R2is cyclohexyl, and wherein R2is optionally substituted with one or more instances of -L-R5.

[0112] In some embodiments, R2is. In somePage 43 of 83712954319vlAttorney Docket No.: 2013518-0095Page 44 of 83712954319vlAttorney Docket No.: 2013518-0095Page 45 of 83712954319vlAttorney Docket No.: 2013518-0095

[0115] In some embodiments, R2is 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 -L-R5or R7. In some embodiments, R2is 4- to 10-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S, and wherein R2is substituted with 1-2 instances of -L-R5or R7. hi some embodiments, R2is 4- to 6-membered heterocycle comprising 1 to 2 heteroatoms selected from N, O, and S, and wherein R2is optionally substituted with one or more instances of -L-R5or R7. hi some embodiments, R2is 4- to 6-membered heterocycle comprising 1 to 2 heteroatoms selected from N, O, and S, and wherein R2is substituted with 1-2 instances of-L-R5or R7. In some embodiments, R2is oxetane, tetrahydrofuran, or pyran, and wherein R2is optionally substituted with one or more instances of -L-R5or R7. hi some embodiments, R2is oxetane, tetrahydrofuran, or pyran, and wherein R2is substituted with 1-2 instances of -L-R5or R7.

[0116] In some embodiments, R2is 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 -L-R5. In some embodiments, R2is 4- to 10-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S, and wherein R2is optionally substituted with one instance of -L-R5. hi some embodiments, R2is 4- to 10-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, R2is 4- to 6-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S, and wherein R2is optionally substituted with one or more instances of -L-R5. In some embodiments, R2is 4- to 6-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S, and wherein R2is optionally substituted with one instance of -L-R5. In some embodiments, R2is 4- to 6-membered heterocycle comprising 1 to 2 heteroatoms selected from N, O, and S, and wherein R2is optionally substituted with one or more instances of -L-R5. In some embodiments, R2is oxetane, tetrahydrofuran, or pyran, and wherein R2is optionally substituted with one or more instances of -L-R5.Page 46 of 83712954319vlAttorney Docket No.: 2013518-0095

[0120] In some embodiments,Page 47 of 83712954319vlAttorney Docket No.: 2013518-0095Page 48 of 83712954319vlAttorney Docket No.: 2013518-0095Page 49 of 83712954319vlAttorney Docket No.: 2013518-0095

[0123] In some embodiments, 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 -L-R5or R7. In some embodiments, R2is 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, and wherein R2is substituted with 1-2 instances of-L-R5or R7. In some embodiments, R2is 5- to 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, and wherein R2is optionally substituted with one or more instances of -L-R5or R7. In some embodiments, R2is 5- to 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, and wherein R2is substituted with 1-2 instances of - L-R5or R7.

[0124] In some embodiments, 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 -L-R5. In some embodiments, R2is 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, and wherein R2is optionally substituted with one instancePage 50 of 83712954319vlAttorney Docket No.: 2013518-0095 of -L-R5. In some embodiments, R2is 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, R2is 5- to 6-mcmbcrcd hctcroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, and wherein R2is optionally substituted with one or more instances of -L-R5. In some embodiments, R2is 5- to 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, and wherein R2is optionally substituted with one instance of -L-R5.

[0125] In some embodiments, R2is Ce-Cio aryl, and wherein R2is optionally substituted with one or more instances of -L-R5or R7. In some embodiments, R2is Ce-Cio aryl, and wherein R2is substituted with 1-2 instances of -L-R5or R7. In some embodiments, R2is phenyl, and wherein R2is optionally substituted with one or more instances of -L-R5or R7. In some embodiments, R2is phenyl, and wherein R2is substituted with 1-2 instances of -L-R5or R7. In some embodiments, R2is naphthyl, and wherein R2is optionally substituted with one or more instances of -L-R5or R7. In some embodiments, R2is naphthyl, and wherein R2is substituted with 1-2 instances of -L-R5or R7.

[0126] In some embodiments, R2is Ce-Cio aryl, and wherein R2is optionally substituted with one or more instances of -L-R5. In some embodiments, R2is Ce-Cio aryl, and wherein R2is optionally substituted with one instance of -L-R5. In some embodiments, R2is phenyl, and wherein R2is optionally substituted with one or more instances of -L-R5. In some embodiments, R2is naphthyl, and wherein R2is optionally substituted with one or more instances of -L-R5.

[0127] As described herein, with respect to any formula provided herein, each L is independently selected from a bond, -N(Ra)C(O)N(Ra)-, -N(Ra)C(O)O-, -OC(O)N(Ra)-, - C(O)N(Ra)-, -N(Ra)C(O)-, -N(Ra)-, -O-, -C(O)-, -C(O)O-, -OC(O)-, -N(Ra)C(S)O-, -OC(S)N(Ra)- , -C(S)N(Ra)-, -N(Ra)C(S)-, -C(S)-, -C(S)O-, and -OC(S)-. In some embodiments, each L is independently selected from a bond, -N(Ra)C(O)O-, -OC(O)N(Ra)-, -C(O)N(Ra)-, -N(Ra)C(O)-, - O-, and -C(O)-. In some embodiments, each L is independently selected from a bond, - N(Ra)C(O)O-, -OC(O)N(Ra)-, -C(O)N(Ra)-, -N(Ra)C(O)-, -O-, and -C(O)-, wherein each Raof L is independently hydrogen or C1-2 alkyl. In some embodiments, each L is independently selected from -N(Ra)C(O)O-, -C(O)N(Ra)-, and -C(O)-. In some embodiments, each L is independently selected from -N(H)C(O)O-, -C(O)NH-, -C(O)N(CH3)-, and -C(O)-. In some embodiments, each L is independently selected from a bond, -N(Ra)C(O)O-, and -N(Ra)C(O)-. In some embodiments, each L is independently selected from a bond, -N(Ra)C(O)O-, and -N(Ra)C(O)-, wherein each RaPage 51 of 83712954319vlAttorney Docket No.: 2013518-0095 of L is independently hydrogen or C1-2 alkyl. In some embodiments, each L is independently selected from a bond, -N(Ra)C(O)O-, -OC(O)N(Ra)-, -C(O)N(Ra)-, -N(Ra)C(O)-, -N(Ra)-, -O-, - C(O)-, and -OC(O)-. In some embodiments, each L is independently selected from a bond, - N(Ra)C(O)O-, -OC(O)N(Ra)-, -C(O)N(Ra)-, -N(Ra)C(O)-, -N(Ra)-, -O-, -C(O)-, and -OC(O)-, wherein each Raof L is independently hydrogen or C1-2 alkyl. In some embodiments, each L is independently selected from -N(Ra)C(O)O-, -C(O)N(Ra)-, -N(Ra)C(O)-, -N(Ra)-, -C(O)-, and - OC(O)-. In some embodiments, each L is independently selected -N(H)C(O)O-, -N(CH3)C(O)O- , -C(O)N(H)-, -C(O)N(CH3)-, -N(H)C(O)-, -N(H)-, -C(O)-, and -OC(O)-.

[0128] In some embodiments, L is a bond.

[0129] In some embodiments, L is -N(Ra)C(O)N(Ra)-. In some embodiments, L is - NHC(O)NH-.

[0130] In some embodiments, L is -N(Ra)C(O)O-. In some embodiments, L is -N(H)C(O)O-. In some embodiments, L is -N(CH3)C(O)O-.

[0131] In some embodiments, L is -OC(O)N(Ra)-. In some embodiments, L is -OC(O)NH-.

[0132] In some embodiments, L is -C(O)N(Ra)-. In some embodiments, L is -C(O)NH-. In some embodiments, L is -C(O)N(CH3)-.

[0133] In some embodiments, L is -N(Ra)C(O)-. In some embodiments, L is -NHC(O)-. In some embodiments, L is -N(CI-3 alkyl)C(O)-. In some embodiments, L is -N(CH3)C(O)-.

[0134] In some embodiments, L is -N(Ra)-. In some embodiments, L is -NH-.

[0135] In some embodiments, L is -O-.

[0136] In some embodiments, L is -C(O)-.

[0137] In some embodiments, L is -C(O)O-.

[0138] In some embodiments, L is -OC(O)-.

[0139] In some embodiments, L is -N(Ra)C(S)O-. In some embodiments, L is -NHC(S)O-.

[0140] In some embodiments, L is -OC(S)N(Ra)-. In some embodiments, L is -OC(S)NH-.

[0141] In some embodiments, L is -C(S)N(Ra)-. In some embodiments, L is -C(S)NH-.

[0142] In some embodiments, L is -N(Ra)C(S)-. In some embodiments, L is -NHC(S)-.

[0143] In some embodiments, L is -C(S)-.

[0144] In some embodiments, L is -C(S)O-.

[0145] In some embodiments, L is -OC(S)-.Page 52 of 83712954319vlAttorney Docket No.: 2013518-0095

[0146] As described herein, with respect to any formula provided herein (e.g., any of Formulae I-IX), each R5is independently selected from the group consisting of optionally substituted Ci-Ce aliphatic, optionally substituted 2- to 10-membered 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 Ce-Cio aryl. In some embodiments, each R5is independently selected from optionally substituted Ci-Ce aliphatic, optionally substituted 2- to 10-membered heteroaliphatic, optionally substituted 4- to 10- membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S, and optionally substituted 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, each R5is independently selected from optionally substituted Ci-Ce aliphatic, optionally substituted C3-C12 cycloaliphatic, optionally substituted 4- to 10-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S, and optionally substituted 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, each R5is independently selected from optionally substituted Ci-Ce aliphatic, optionally substituted C3-C6 cycloaliphatic, optionally substituted 4- to 6-membered heterocycle comprising 1 to 2 heteroatoms selected from N, O, and S, and optionally substituted 5- to 6- membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S.

[0147] In some embodiments, R5is optionally substituted Ci-Ce aliphatic. In some embodiments, R5is optionally substituted C1-C3 aliphatic. In some embodiments, R5is Ci-Ce aliphatic (e.g., -CH3 or -CH2CH3). In some embodiments, R5is C1-C3 aliphatic (e.g., -CH3 or - CH2CH3). In some embodiments, R5is -CH3. In some embodiments, R5is -CH2CH3. In some embodiments, R5is Ci-Ce aliphatic optionally substituted with two occurrences of -(CfFjo 4R0. wherein the 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. In some embodiments, R5is Ci-Ce aliphatic optionally substituted with two occurrences of -(CHTJO 40. wherein the 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 with halogen, - (CH2)O 2R*, -(haloR*), -(CH2)o 2OH, or =0 (“oxo”), and wherein each R* is unsubstituted orPage 53 of 83712954319vlAttorney Docket No.: 2013518-0095 where preceded by “halo” is substituted only with one or more halogens, and is independently selected from CM aliphatic. In some embodiments, R5is optionally substituted C2-C6 alkenyl. In some embodiments, R5is -CH=CH2. In some embodiments, R5is Ci-Ce aliphatic, optionally substituted with -CN, -OR°, halogen, or -(Cfkjo MN(R°)C(O)R°. In some embodiments, R5is Ci- Ce aliphatic, optionally substituted with -CN, -OH, halogen, or -CH2-N(H)C(O)(CI-C6 aliphatic). In some embodiments, R5is Ci-Ce aliphatic, optionally substituted with -CN, -OH, halogen, or - N(H)C(O)(Ci-Ce aliphatic). In some embodiments, R5is Ci-Ce aliphatic, optionally substituted with -CN, -OH, halogen, -N(H)C(O)(Ci-Ce aliphatic), -N(CH3)C(O)(CI-C6 aliphatic), - N(CH3)C(O)(3-membered cycloaliphatic), -N(CH3)C(O)(Ci-Ce aliphatic)(4-membered heterocycle), or -N(CH3)C(O)(Ci-Ce aliphatic)(5-membered heteroaryl). In some embodiments, R5is Ci-Ce aliphatic, optionally substituted with R°, -CN, -OR°, or -N(R°)C(O)R°. In some embodiments, R5is C1-C6 aliphatic, optionally substituted with R°, -CN, -OR°, or -N(R°)C(O)R°, wherein each R° is independently hydrogen, Ci-6 aliphatic, or a 3- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 hctcroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R5is C1-C6 aliphatic, optionally substituted with -CN, - OH, -O(Ci-3 alkyl), -N(H)C(O)(CI-3 alkyl), -N(CI-3 alkyl)C(O)(Ci-3 alkyl), or a 5- to 6-membered heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R5is Ci-Ce aliphatic, optionally substituted with -CN, -OH, -O(Ci-3 alkyl), - N(H)C(O)(CI-3alkyl), -N(CI-3alkyl)C(O)(Ci-3alkyl), -N(CI-3alkyl)C(O)(Ci-3aliphatic), -N(CI-3alkyl)C(O)(3-membered cycloaliphatic), -N(CI-3 alkyl)C(O)(Ci-3 aliphatic)(4-membered heterocycle), -N(CI-3 alkyl)C(O)(Ci-3 aliphatic)(5 -membered heteroaryl), or two occurrences of - (CI 12)0 4R0. wherein the 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 with halogen, -(CH2)o-2R*, -(haloR*), -(CH2)o 2OH, or =0 (“oxo”), and wherein each R* is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently selected from CIM aliphatic.Page 54 of 83712954319vlAttorney Docket No.: 2013518-0095

[0151] In some embodiments, R5is optionally substituted 2- to 10-membered heteroaliphatic.In some embodiments, R5is 2- to 10-membered heteroaliphatic optionally substituted with two occurrences of -(CH2)CMRO, wherein the 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. In some embodiments, R5is 2- to 10-membered heteroaliphatic optionally substituted with one orPage 55 of 83712954319vlAttorney Docket No.: 2013518-0095 more -(CHiJo 4R0or =0 (“oxo”), wherein each R° is independently hydrogen, C1-6 aliphatic, or a 3- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or two occurrences of-(CH2)o^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,

[0152] In some embodiments, R5is optionally substituted C3-C12 cycloaliphatic. In some embodiments, R5is optionally substituted C3-C6 cycloaliphatic. In some embodiments, R5is optionally substituted C3-C6 cycloaliphatic selected from cyclopropyl and cyclobutyl. In some embodiments, R5is optionally substituted C3-C6 cycloaliphatic selected from cyclopropyl, cyclobutyl, and cyclohexyl. In some embodiments, R5is C3-C6 cycloaliphatic optionally substituted with -(CI bJo 4N(RO)C(O)OR°, wherein the first instance of R° is hydrogen and the second instance of R° is -(CH2)o-2R*, wherein R* is Ci^ aliphatic. In some embodiments, R5isC3-C6 cycloaliphatic optionally substituted with -(CHiJo ^N(R°)C(O)OR°, wherein the first instance of R° is hydrogen and the second instance of R° is Ci-6 aliphatic. In some embodiments,OA A / N OR5is C3-C6 cycloaliphatic optionally substituted with H . In some embodiments, R5is C3-C6 cycloaliphatic optionally substituted with one or more halogen or -N(R°)C(O)R°. In some embodiments, R5is C3-C6 cycloaliphatic optionally substituted with one or more halogen or - N(R°)C(O)R°, wherein each R° is independently hydrogen or C1-6 aliphatic. In some embodiments, R5is cyclopropyl optionally substituted with 1-2 fluoro. In some embodiments, R5is C3-C6 cycloaliphatic optionally substituted with one or more halogen, -(CHTJO ^N( R°)C(O)OR°, -N(R°)C(O)R°, -CN, -(CH 2 Jo -R°, or -(CH2)CMORO. In some embodiments, R5is C3-C6Page 56 of 83712954319vlAttorney Docket No.: 2013518-0095 cycloaliphatic optionally substituted with one or more halogen, -(CHiJo ^N(R°)C(O)OR°, - N(R°)C(O)R°, -CN, -(CHoJo 4R0, or -(CHiJo -OR°. wherein each R° is independently selected from hydrogen, Ci-6 aliphatic or an optionally substituted 5-membered aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein the 5-membered aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur is optionally substituted with -(CH2)o 2R*, wherein R* is CH aliphatic. In some embodiments, R5is

[0153] In some embodiments, R5is optionally substituted 4- to 10-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, R5is optionally substituted monocyclic 4- to 10-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, R5is optionally substituted monocyclic 4- to 6- membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, R5is optionally substituted monocyclic 4- to 6-membered heterocycle comprising 1 to 2 heteroatoms selected from N, O, and S. In some embodiments, R5is monocyclic 4- to 6- membered heterocycle comprising 1 to 2 heteroatoms selected from N, O, and S, wherein the heterocycle is optionally substituted with one or more oxo or -OR°, wherein each R° is independently hydrogen or C1-6 aliphatic. In some embodiments, R5is monocyclic 4- to 6- membered heterocycle comprising 1 to 2 heteroatoms selected from N, O, and S, wherein thePage 57 of 83712954319vlAttorney Docket No.: 2013518-0095 heterocycle is optionally substituted with one or more oxo or -(CH2J0 4OR0, wherein each R° is independently hydrogen or Ci-6 aliphatic. In some embodiments, R5is optionally substituted spirocyclic 7- to 10-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, R5is optionally substituted bicyclic 7- to 10-membered heterocycle

[0154] In some embodiments, R5is optionally substituted 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, R5is optionally substituted bicyclic 8- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, R5is optionally substituted monocyclic 5- to 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, R5is monocyclic 5- to 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, andPage 58 of 83712954319vlAttorney Docket No.: 2013518-0095

[0155] In some embodiments, R5is optionally substituted Ce-Cio aryl. In some embodiments, R5is optionally substituted phenyl. In some embodiments, R5is optionally substituted naphthyl.Page 59 of 83712954319vlAttorney Docket No.: 2013518-009512954319vl Page 60 of 837Attorney Docket No.: 2013518-0095

[0158] In some embodiments, each -L-R5is independently selected from: -CH3, -CH2OH, -Page 61 of 83712954319vlAtorney Docket No.: 2013518-0095

[0159] In some embodiments, each -L-R5is independently selected from: -CH3, -CH2OH, -Page 62 of 83712954319vlAttorney Docket No.: 2013518-0095Page 63 of 83712954319vlAttorney Docket No.: 2013518-0095Page 64 of 83712954319vlAttorney Docket No.: 2013518-0095Page 65 of 83712954319vlAttorney Docket No.: 2013518-0095Page 66 of 83712954319vlAtorney Docket No.: 2013518-009512954319vl Page 67 of 837Attorney Docket No.: 2013518-0095

[0161] In some embodiments, each -L-R5is O . In some embodiments, each -L-R5is O . in some embodiments, each -L-R5is O

[0162] As described herein, with respect to any formula provided herein (e.g., any of Formulae LIX), each R7is independently selected from the group consisting of halogen, -OH, -SH, and - NH2. In some embodiments, each R7is independently selected from the group consisting of -OH, -SH, and -NH2.

[0163] In some embodiments, R7is halogen.

[0164] In some embodiments, R7is -OH.

[0165] In some embodiments, R7is -SH.

[0166] In some embodiments, R7is -NH2.

[0167] In some embodiments, R2that is substituted with one or more -L-R5is:Page 68 of 83712954319vlAttorney Docket No.: 2013518-0095Page 69 of 83712954319vlAttorney Docket No.: 2013518-0095Page 70 of 83712954319vlAttorney Docket No.: 2013518-0095Page 71 of 83712954319vlAttorney Docket No.: 2013518-0095Page 72 of 83712954319vl12954319vi12954319vlAttorney Docket No.: 2013518-0095

[0169] In some embodiments, R2that is substituted with one or more -L-R5or R7is selected from:Page 75 of 83712954319vlAttorney Docket No.: 2013518-0095Page 76 of 83712954319vlAttorney Docket No.: 2013518-0095Page 77 of 83712954319vlAttorney Docket No.: 2013518-0095Page 78 of 83712954319vlAtorney Docket No.: 2013518-0095Page 79 of 83712954319vlAttorney Docket No.: 2013518-0095Page 80 of 83712954319vl319vlAtorney Docket No.: 2013518-009512954319vl Page 82 of 837Attorney Docket No.: 2013518-0095Page 83 of 83712954319vlAttorney Docket No.: 2013518-009512954319vl Page 84 of 837Atorney Docket No.: 2013518-0095Page 85 of 83712954319vlAtorney Docket No.: 2013518-0095Page 86 of 83712954319vlAttorney Docket No.: 2013518-0095

[0171] As described herein, with respect to any formula provided herein (e.g., any of FormulaeI-IX), R3is 5- to 12-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, 4- to 12-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S, Ce- C12 aryl, C3-C12 cycloaliphatic, or Ci-Ce aliphatic, wherein R3is optionally substituted with one or more instances of R3a. In some embodiments, R3is 5- to 12-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, 4- to 12-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S, C6-C12 aryl, C3-C12 cycloaliphatic, or Ci-Ce aliphatic, wherein R3is optionally substituted with 0-3 instances of R3a. In some embodiments, R3is 5- toPage 87 of 83712954319vlAttorney Docket No.: 2013518-009512-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, 4- to 12- mcmbcrcd hctcrocyclc comprising 1 to 4 hctcroatoms selected from N, O, and S, or Ce-Cn aryl, wherein R3is optionally substituted with one or more instances (e.g., 0-3 instances) of R3a. In some embodiments, R3is 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, 9- to 10-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S, or phenyl, wherein R3is optionally substituted with one or more instances (e.g., 0-3 instances) of R3a. In some embodiments, R3is 5- to 12-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S or C6-C12 aryl, wherein R3is optionally substituted with one or more instances of R3a. In some embodiments, R3is 5- to 12-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S or Ce-Cn aryl, wherein R3is optionally substituted with 0- 3 instances of R3a.

[0172] In some embodiments, R3is 5- to 12-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, and wherein R3is optionally substituted with one or more instances of R3a. In some embodiments, R3is 5- to 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S, optionally substituted with one or more instances of R3a. In some embodiments, R3is a 5-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, optionally substituted with one or more instances of R3il. In some embodiments, R3is a pyrazole optionally substituted with one or more instances of R3a. In some embodiments, R3is a 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, optionally substituted with one or more instances of R3a. In some embodiments, R3is a pyridine or pyridazone optionally substituted with one or more instances of R3a.

[0173] In some embodiments, R3is bicyclic 7- to 12-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, and wherein R3is optionally substituted with one or more instances of R3a. In some embodiments, R3is bicyclic 8- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, and wherein R3is optionally substituted with one or more instances of R3a. In some embodiments, R3is bicyclic 9-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S, and wherein R3is optionally substituted with one or more instances of R3a. In some embodiments, R3is an indazole, thienopyridine, benzoxazole, pyrazolopyridine, or imidazopyridine, optionally substituted with one or more instances of R3a. In some embodiments, R3is indole, indazole, thienopyridine, benzothiophene, or pyrrolopyridine, optionally substituted with one or more instances of R3a. In some embodiments, R3is bicyclic 7-Page 88 of 83712954319vlAttorney Docket No.: 2013518-0095 to 12-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, optionally substituted with one or more instances of R3a, and wherein R3ais optionally substituted Ci-Ce aliphatic, optionally substituted C3-C12 cycloaliphatic, or optionally substituted 4- to 6-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S.

[0174] In some embodiments, R3isIn some embodiments, R3is

[0175] In some embodiments, R3is 4- to 12-mcmbcrcd heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S, wherein R3is optionally substituted with one or more instances of R3a. In some embodiments, R3is an optionally substituted 6- to 10-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, R3is bicyclic 6- to 12-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S, and wherein R3is optionally substituted with one or more instances of R3a. In some embodiments, R3is bicyclic 6- to 12-membered heterocycle comprising 1 to 4 heteroatomsPage 89 of 83712954319vlAttorney Docket No.: 2013518-0095 selected from N, O, and S, and wherein R3is optionally substituted with one or more instances of R3a, and wherein R3ais optionally substituted Ci-Ce aliphatic. In some embodiments, R3is bicyclic 6- to 12-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S, and wherein R3is optionally substituted with one or more instances of R3a, and wherein each R3ais independently Ci-Ce aliphatic or oxo. In some embodiments, R3is bicyclic 6- to 12-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S, and wherein R3is optionally substituted with one or more instances of R3a, and wherein R3ais -CH3. In some embodiments, R3is bicyclic 6- to 12-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S, and wherein R3is optionally substituted with one or more instances of R3a, and wherein each R3ais independently -CH3 or oxo. In some embodiments, R3is a bicyclic 9- to 10-membered heterocycle comprising 1 to 3 heteroatoms selected from N, O, and S, and wherein R3is optionally substituted with one or more instances of R3a.

[0176] In some embodiments, R3is C6-C12 aryl, and wherein R3is optionally substituted with one or more instances of R3a. In some embodiments, R3is phenyl optionally substituted with one or more instances or R3a. In some embodiments, R3is phenyl optionally substituted with one or more instances of R3a, and wherein R3ais optionally substituted Ci-Ce aliphatic, optionally substituted 2- to 10-membered heteroaliphatic, or optionally substituted 4- to 10-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, R3Page 90 of 83712954319vlAttorney Docket No.: 2013518-0095

[0177] In some embodiments, R3is C3-C12 cycloaliphatic, and wherein R3is optionally substituted with one or more instances of R3a. In some embodiments, R3is a C3-C7 monocyclic cycloaliphatic, and wherein R3is optionally substituted with one or more instances of R3a. In some embodiments, R3is a C3-C7 monocyclic cycloalkyl, and wherein R is optionally substituted with one or more instances of R3a. In some embodiments, R3is a C5-C12 bicyclic cycloaliphatic, and wherein R3is optionally substituted with one or more instances of R3a. In some embodiments, R3is a C5-C12 bicyclic cycloalkyl, and wherein R3is optionally substituted with one or more instances of R3a.

[0178] In some embodiments, R3is Ci-Ce aliphatic, wherein R3is optionally substituted with one or more instances of R3a. In some embodiments, R3is Ci-Ce alkyl, wherein R3is optionally substituted with one or more instances of R3a.

[0179] In some embodiments, R3is substituted with 0 to 4 instances of R3a. In some embodiments, R3is substituted with 0 to 3 instances of R3a. In some embodiments, R3is substituted with 0 to 2 instances of R3a. In some embodiments, R3is unsubstituted. In some embodiments, R3is substituted with 1 to 3 instances of R3a. In some embodiments, R3is substituted with 1 to 2 instances of R3a. In some embodiments, R3is substituted with 1 instance of R3a. In some embodiments, R3is substituted with 2 instances of R3a. hi some embodiments, R3is substituted with 3 instances of R3a. In some embodiments, R3is substituted with 4 instances of R3a.

[0180] In some embodiments, R3is selected from:embodiments, R3is selected from:In somePage 91 of 83712954319vlAttorney Docket No.: 2013518-0095 embodiments, R3is selected from

[0181] In some embodiments, R3is selected fromPage 92 of 83712954319vlAttorney Docket No.: 2013518-0095Page 93 of 83712954319vlAttorney Docket No.: 2013518-0095Page 94 of 83712954319vlAttorney Docket No.: 2013518-0095Page 95 of 83712954319vlAttorney Docket No.: 2013518-0095Page 96 of 83712954319vlAttorney Docket No.: 2013518-0095Page 97 of 83712954319vlAttorney Docket No.: 2013518-0095

[0188] In some embodiments, R3optionally substituted with one or more instances of R3ais:Page 98 of 83712954319vlAttorney Docket No.: 2013518-0095

[0189] In some embodiments, R3optionally substituted with one or more instances of R3ais:Page 99 of 83712954319vlAttorney Docket No.: 2013518-0095Page 100 of 83712954319vlAttorney Docket No.: 2013518-0095

[0190] In some embodiments, R3optionally substituted with one or more instances of R3ais:Page 101 of 83712954319vlAttorney Docket No.: 2013518-0095

[0191] As described herein, with respect to any formula provided herein (e.g., any of Formulae I-IX), each R3ais independently selected from the group consisting of optionally substituted Ci- Ce aliphatic, optionally substituted 2- to 10-membered 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, optionally substituted C6-C10 aryl, 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, and -ORa. In some embodiments, each R3ais independently selected from the group consisting of optionally substituted Ci-Ce aliphatic, optionally substituted C3-C6 cycloaliphatic, optionally substituted 4- to 6-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, optionally substituted Ce-Cio aryl, halogen, oxo, -CN, -C(O)N(Ra)2, -N(Ra)C(O)Ra, - S(O)2N(Ra)2, -N(Ra)S(O)2Ra, S(O)2Ra, and -ORa. In some embodiments, each R3ais independently selected from optionally substituted Ci-Ce aliphatic, optionally substituted 2- to 10- membered heteroaliphatic, optionally substituted C3-C12 cycloaliphatic, and optionally substituted 4- to 10-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, each R3ais independently selected from optionally substituted Ci-Ce aliphatic, optionally substituted 2- to 10-membered heteroaliphatic, optionally substituted C3-C12 cycloaliphatic, optionally substituted 4- to 10-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S, halogen, and oxo. In some embodiments, each R3ais independently selected from optionally substituted Ci-Ce aliphatic, optionally substituted C3-C6 cycloaliphatic, halogen, -C(O)N(Ra)2, and -ORa. In some embodiments, each R3ais independently selected from optionally substituted Ci-Ce aliphatic, optionally substituted C3-C6 cycloaliphatic,Page 102 of 83712954319vlAttorney Docket No.: 2013518-0095 halogen, oxo, -C(O)N(Ra)2, and -ORa. In some embodiments, each R3ais independently selected from Ci-Ce aliphatic optionally substituted with one or more -OR0or halogen, C3-C6 cycloaliphatic, halogen, -C(O)N(Ra)2, and -ORa. In some embodiments, each R3ais independently selected from Ci-Ce aliphatic optionally substituted with one or more -OR° or halogen, C3-C6 cycloaliphatic, halogen, oxo, -C(O)N(Ra)2, and -ORa.

[0192] In some embodiments, R3ais optionally substituted Ci-Ce aliphatic. In some embodiments, R3ais optionally substituted Ci-Ce alkyl. In some embodiments, R3ais Ci-Ce aliphatic optionally substituted with one or more -OR° or halogen. In some embodiments, R3ais Ci-Ce alkyl optionally substituted with one or more -OR° or halogen. In some embodiments, R3ais methyl or deuterated methyl (e.g., one or more H atoms of methyl have been replaced with deuterium). In some embodiments, R3ais a branched Ci-Ce aliphatic. In some embodiments, R3ais Ci-Ce aliphatic optionally substituted with -(CH2)o 4OR0, wherein R° is hydrogen or Ci-Ce aliphatic. In some embodiments, R3ais -CH3, -CD3, -CF3, -CH2CH3, or -C(CH3)2OH. In some embodiments, R3ais -CH3, -CD3, -CF3, -CH2CH3, -CH2OH, or -C(CH3)2OH.

[0193] In some embodiments, R3ais optionally substituted C1-C3 aliphatic.

[0194] In some embodiments, R3ais optionally substituted C3-C12 cycloaliphatic. In some embodiments, R3ais optionally substituted C3-C6 cycloaliphatic. In some embodiments, R3ais C3- Ce cycloaliphatic. In some embodiments, R3ais optionally substituted C3-C6 cycloaliphatic wherein the C3-C6 cycloaliphatic is selected from cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0195] In some embodiments, R3ais optionally substituted 2- to 10-membered heteroaliphatic. In some embodiments, R3ais methoxy. In some embodiments, R3ais ethoxy.

[0196] In some embodiments, R3ais optionally substituted 4- to 10-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, R3ais 4- to 10- membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, R3ais optionally substituted 4- to 10-membered heterocycle comprising 1 to 2 heteroatoms selected from N, O, and S. In some embodiments, R3ais optionally substituted 4- to 6-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, R3ais a 4- to 6-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, R3ais optionally substituted 4- to 6-membered heterocycle comprising 1 to 2 heteroatoms selected from N, O, and S.Page 103 of 83712954319vlAttorney Docket No.: 2013518-0095

[0197] In some embodiments, R3ais optionally substituted 5- to 10-membered heteroaryl comprising 1 to 4 hctcroatoms selected from N, O, and S. In some embodiments, R3ais optionally substituted 5- to 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S.

[0198] In some embodiments, R3ais optionally substituted Ce-Cio aryl. In some embodiments, R3ais optionally substituted phenyl. In some embodiments, R3ais optionally substituted naphthyl.

[0199] In some embodiments, R3ais halogen. In some embodiments, R3ais fluoro. In some embodiments, R3ais chloro.

[0200] In some embodiments, R3ais oxo. In some embodiments, R3ais -CN. In some embodiments, R3ais -NO2. In some embodiments, R3ais -C(O)N(Ra)2. In some embodiments, R3ais -C(O)NH2. In some embodiments, R3ais -C(O)N(H)CH3. In some embodiments, R3ais - C(O)N(CH3)2. In some embodiments, R3ais -OC(O)Ra. In some embodiments, R3ais -OC(O)CH3. In some embodiments, R3ais -OC(O)N(Ra)2. In some embodiments, R3ais -OC(O)NH2. In some embodiments, R3ais -OC(O)N(CH3)2. In some embodiments, R3ais -N(Ra)C(O)Ra. In some embodiments, R3ais -NHC(O)CH3. In some embodiments, R3ais -N(CH3)C(O)CH3. In some embodiments, R3ais -N(Ra)C(O)ORa. In some embodiments, R3ais -NHC(O)OH. In some embodiments, R3ais -NHC(O)OCH3. In some embodiments, R3ais -N(Ra)C(O)N(Ra)2. In someembodiments, R3ais -NHS(O)2CH3. In some embodiments, R3ais -S(O)2Ra. In some embodiments, R3ais -ORa. In some embodiments, R3ais -O(Ci-3 alkyl), e.g., -OCH3. In some embodiments, R3ais -OH. In some embodiments, R3ais -CH3. In some embodiments, R3ais -CD3.Page 104 of 83712954319vlAttorney Docket No.: 2013518-0095

[0202] In some embodiments, each R3ais independently -CH3, -CD3, -CF3, -CH2CH3,Page 105 of 83712954319vlAttorney Docket No.: 2013518-0095

[0204] In some embodiments, R2and R3are connected by *-La-R6-Lb-**, where * represents a point of attachment to R2, and ** represents a point of attachment to R3.

[0205] As described herein, with respect to any formula provided herein (e.g., any of Formulae I-IX), Lais a bond, -N(Ra)C(O)N(Ra)-, -N(Ra)C(O)O-, -OC(O)N(Ra)-, -C(O)N(Ra)-, -N(Ra)C(O)- , -N(Ra)-, -O-, -C(O)-, -C(O)O-, -OC(O)-, -N(Ra)C(S)O-, -OC(S)N(Ra)-, -C(S)N(Ra)-, - N(Ra)C(S)-, -C(S)-, -C(S)O-, or -OC(S)-. In some embodiments, Lais a bond, -N(Ra)C(O)O-, - OC(O)N(Ra)-, -C(O)N(Ra)-, -N(Ra)C(O)-, -N(Ra)-, -O-, -C(O)-, or -C(O)O-. In some embodiments, Lais a bond, -N(H)C(O)O-, -OC(O)N(H)-, -C(O)N(H)-, or -N(H)C(O)-.

[0206] In some embodiments, Lais a bond. In some embodiments, Lais -N(Ra)C(O)N(Ra)-. In some embodiments, Lais -NHC(O)NH-. In some embodiments, Lais -N(Ra)C(O)O-. In some embodiments, Lais -NHC(O)O-. In some embodiments, Lais -OC(O)N(Ra)-. In some embodiments, Lais -OC(O)NH-. In some embodiments, Lais -C(O)N(Ra)-. In some embodiments, Lais -C(O)NH-. In some embodiments, Lais -N(Ra)C(O)-. In some embodiments, Lais -NHC(O)-. In some embodiments, Lais -N(Ra)-. In some embodiments, Lais -NH-. In some embodiments, Lais -O-. In some embodiments, Lais -C(O)-. In some embodiments, Lais -C(O)O- . In some embodiments, Lais -OC(O)-. In some embodiments, Lais -N(Ra)C(S)O-. In some embodiments, Lais -NHC(S)O-. In some embodiments, Lais -OC(S)N(Ra)-. In some embodiments, Lais -OC(S)NH-. In some embodiments, Lais -C(S)N(Ra)-. In some embodiments, Lais -C(S)NH-. In some embodiments, Lais -N(Ra)C(S)-. In some embodiments, Lais -NHC(S)- . In some embodiments, Lais -C(S)-. In some embodiments, Lais -C(S)O-. In some embodiments, Lais -OC(S)-.Page 106 of 83712954319vlAttorney Docket No.: 2013518-0095

[0207] As described herein, with respect to any formula provided herein (e.g., any of Formulae I-IX), Lbis a bend, -N(Ra)C(O)N(Ra)-, -N(Ra)C(O)O-, -OC(O)N(Ra)-, -C(O)N(Ra)-, -N(Ra)C(O)- , -N(Ra)-, -O-, -C(O)-, -C(O)O-, -OC(O)-, -N(Ra)C(S)O-, -OC(S)N(Ra)-, -C(S)N(Ra)-, - N(Ra)C(S)-, -C(S)-, -C(S)O-, or -OC(S)-. In some embodiments, Lbis a bond, -N(Ra)-, -O-, -C(O)- , -C(O)O-, or -OC(O)-.

[0208] In some embodiments, Lbis a bond. In some embodiments, Lbis -N(Ra)C(O)N(Ra)-. In some embodiments, Lbis -NHC(O)NH-. In some embodiments, Lbis -N(Ra)C(O)O-. In some embodiments, Lbis -NHC(O)O-. In some embodiments, Lbis -OC(O)N(Ra)-. In some embodiments, Lbis -OC(O)NH-. In some embodiments, Lbis -C(O)N(Ra)-. In some embodiments, Lbis -C(O)NH-. In some embodiments, Lbis -N(Ra)C(O)-. In some embodiments, Lbis -NHC(O)-. In some embodiments, Lbis -N(Ra)-. In some embodiments, Lbis -NH-. In some embodiments, Lbis -O-. In some embodiments, Lbis -C(O)-. In some embodiments, Lbis -C(O)O- . In some embodiments, Lbis -OC(O)-. In some embodiments, Lbis -N(Ra)C(S)O-. In some embodiments, Lbis -NHC(S)O-. In some embodiments, Lbis -OC(S)N(Ra)-. In some embodiments, Lbis -OC(S)NH-. In some embodiments, Lbis -C(S)N(Ra)-. In some embodiments, Lbis -C(S)NH-. In some embodiments, Lbis -N(Ra)C(S)-. In some embodiments, Lbis -NHC(S)- . In some embodiments, Lbis -C(S)-. In some embodiments, Lbis -C(S)O-. In some embodiments, Lbis -OC(S)-.

[0209] In some embodiments, Lais -N(Ra)C(O)O- or -C(O)N(Ra)-, and Lbis a bond. In some embodiments, Lais -N(H)C(O)O- and Lbis a bond. In some embodiments, Lais -N(Ra)C(O)O-, - C(O)N(Ra)-, or -O- and Lbis a bond. In some embodiments, Lais -N(H)C(O)O- or -O- and Lbis a bond. In some embodiments, Lais -O- and Lbis a bond

[0210] As described herein, with respect to any formula provided herein (e.g., any of Formulae I-IX), R6is optionally substituted Ci-Ce aliphatic, optionally substituted 2- to 10-membered 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, or optionally substituted Ce-Cio aryl. In some embodiments, R6is optionally substituted Ci-Ce aliphatic, optionally substituted 2- to 10-membered heteroaliphatic, optionally substituted C3-C12 cycloaliphatic, or optionally substituted 4- to 10-membered heterocycle comprising 1 to 4Page 107 of 83712954319vlAttorney Docket No.: 2013518-0095 heteroatoms selected from N, O, and S. In some embodiments, R6is optionally substituted Ci-Ce aliphatic or optionally substituted 2- to 10-mcmbcrcd hctcroaliphatic.

[0211] In some embodiments, R6is optionally substituted Ci-Ce aliphatic. In some embodiments, R6is optionally substituted C1-C3 aliphatic. In some embodiments, R6is a branched C1-C6 aliphatic. In some embodiments, R6is methyl, ethyl, propyl, butyl, pentyl, or hexyl.

[0212] In some embodiments, R6is optionally substituted C3-C12 cycloaliphatic. In some embodiments, R6is optionally substituted C3-C6 cycloaliphatic. In some embodiments, R6is optionally substituted C3-C6 cycloaliphatic, wherein the C3-C6 cycloaliphatic is selected from cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0213] In some embodiments, R6is optionally substituted 2- to 10-membered heteroaliphatic. In some embodiments, R6is optionally substituted C1-C3 heteroaliphatic. In some embodiments, R6is methoxy. In some embodiments, R6is ethoxy.

[0214] In some embodiments, R6is optionally substituted 4- to 10-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, R6is 4- to 10- membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, R6is optionally substituted 4- to 6-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, R6is a 4- to 6-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, R6is optionally substituted 4- to 6-membered heterocycle comprising 1 to 2 heteroatoms selected from N, O, and S. In some embodiments, R6is a 4- to 6-membered heterocycle comprising 1 to 2 heteroatoms selected from N, O, and S.

[0215] In some embodiments, R6is optionally substituted 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, R6is optionally substituted 5- to 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S.

[0216] In some embodiments, R6is optionally substituted Ce-Cio aryl. In some embodiments, R6is optionally substituted phenyl. In some embodiments, R6is optionally substituted naphthyl.Page 108 of 83712954319vlAttorney Docket No.: 2013518-0095

[0217] In some embodiments, a moietyIn some embodiments, a moietyIn some embodiments, a moiety

[0218] It will be appreciated that R6is bivalent (i.e., R6has two points of attachment to the rest of the molecule) and, therefore, any definitions of R6throughout this disclosure refer to a bivalent chemical moiety.Page 109 of 83712954319vlAttorney Docket No.: 2013518-0095

[0219] As described with respect to any formula provided herein (e.g., any of Formulae I-IX), R4is selected fromCi-Ce aliphatic, -CN, 2- to 10-mcmbcrcdhctcroaliphatic, 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, Ce-Cio aryl, and wherein R4is optionally substituted with one or more instances of R4a. In some embodiments, R4is selected from Ci-Ce aliphatic, 2- to 10-membered 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 R4is optionally substituted with one or more instances of R4a. In some embodiments, R4is selected from Ci-Ce aliphatic, 2- to 10-membered 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, Ce-Cio aryl, and wherein R4is optionally substituted with 0-3 instances of R4a. In some embodiments, R4is selected from Ci-Ce aliphatic, -CN, 2- to 10-membered 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, Ce-Cio aryl, and wherein R4is optionally substituted with 0-3 instances of R4a. In some embodiments, R4is 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S or 4- to 10- membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S, and wherein R4is optionally substituted with one or more instances of R4a. In some embodiments, R4is 5- to 10- membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S or 4- to 10- membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S, and wherein R4is optionally substituted with 0-3 instances of R4a.

[0220] In some embodiments, R4is Ci-Ce aliphatic optionally substituted with one or more instances of R4a. In some embodiments, R4is C1-C3 aliphatic optionally substituted with one or more instances of R4a. In some embodiments, R4is Ci-Ce aliphatic optionally substituted with one or two instances of R4a.

[0221] In some embodiments, R4is -CN.

[0222] In some embodiments, R4is 2- to 10-membered heteroaliphatic optionally substituted with one or more instances of R4a.Page 110 of 83712954319vlAttorney Docket No.: 2013518-0095

[0223] In some embodiments, R4is C3-C12 cycloaliphatic optionally substituted with one or more instances of R4a. In some embodiments, R4is C3-C6 cycloaliphatic. In some embodiments, R4is monocyclic 3- to 7-membered cycloaliphatic optionally substituted with one or more instances of R4a. In some embodiments, R4is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl. In some embodiments, R4is cyclopropyl.

[0224] In some embodiments, R4is 4- to 10-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S optionally substituted with one or more instances of R4a. In some embodiments, R4is 4- to 6-membered monocyclic heterocycle comprising 1 to 3 heteroatoms selected from N, O, and S. In some embodiments, R4is 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 R4a. In some embodiments, R4is 4- to 6-membered monocyclic heterocycle comprising 1 to 3 heteroatoms selected from N, O, and S substituted with one or more instances of R4a, wherein each R4ais independently halogen, -CH3, or -CD3. In some embodiments, R4is piperidine or pyran optionally substituted with one or more instances of R4a. In some embodiments, R4is piperidine or pyran. In some embodiments, R4is a tetrahydropyran or dihydropyran optionally substituted with 0-3 instances of R4a. In some embodiments, R4is a tetrahydropyran or dihydropyran.

[0225] In some embodiments, R4is 6- to 10-membered bicyclic heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, R4is 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 R4a. hi some embodiments, R4is 8- to 10-membered bicyclic heterocycle comprising 1 to 4 heteroatoms selected from N and O, optionally substituted with one or more instances of R4a.

[0226] In some embodiments, R4is 6- to 10-membered spirocyclic heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, R4is 6- to 10-membered spirocyclic heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S optionally substituted with one or more instances of R4a. In some embodiments, R4is 6- to 10-membered spirocyclic heterocycle comprising 1 to 2 heteroatoms selected from N and O, optionally substituted with one or more instances of R4a.

[0227] In some embodiments, R4is 5- to 10-membered hctcroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, and is optionally substituted with one or more instances ofPage 111 of 83712954319vlAttorney Docket No.: 2013518-0095R4a. In some embodiments, R4is monocyclic 5- to 6-membered heteroaryl comprising 1 to 3 hctcroatoms selected from N, O, and S, and is optionally substituted with one or more instances of R4a. In some embodiments, R4is monocyclic 5-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S, and is optionally substituted with one or more instances of R4a. In some embodiments, R4is monocyclic 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S, and is optionally substituted with one or more instances of R4a. In some embodiments, R4is 5- to 6-membered monocyclic heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S and is substituted with one instance of R4a. In some embodiments, R4is 5- to 6-membered monocyclic heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S, and wherein R4is optionally substituted with one or more instances of R4a, wherein R4ais selected from optionally substituted Ci-Ce aliphatic, -ORa, and halogen. In some embodiments, R4is 5- to 6-membered monocyclic heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S, and wherein R4is optionally substituted with one or more instances of R4a, wherein each R4ais independently selected from optionally substituted Ci-Ce aliphatic, optionally substituted 2- to 10-membered heteroaliphatic, -ORa, , -C(O)Ra, and halogen. In some embodiments, R4is 5- to 6-membered monocyclic heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S, and wherein R4is optionally substituted with R4a, wherein R4ais selected from optionally substituted CI-C aliphatic and halogen. In some embodiments, R4is 5- to 6-membered monocyclic heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S, and wherein R4is substituted with one or more instances of R4a, wherein R4ais selected from optionally substituted Ci-Ce aliphatic and halogen. In some embodiments, R4is 5- to 6-membered monocyclic heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S, and wherein R4is optionally substituted with R4a, wherein R4ais selected from -CH3 or -CD3. In some embodiments, R4is a pyrazole, triazole, thiazole, thiadiazole, oxazole, pyridazine, pyrimidine, or pyrazine, and wherein R4is optionally substituted with one or more instances of R4a. In some embodiments, R4is pyrrole, pyrazole, imidazole, triazole, or thiazole, optionally substituted with R4a. In some embodiments, R4is pyrazole optionally substituted with R4a. In some embodiments, R4is pyrazole optionally substituted with R4a, and wherein R4ais -CH3, or -CD3.Page 112 of 83712954319vlAttorney Docket No.: 2013518-0095Page 113 of 83712954319vlAttorney Docket No.: 2013518-0095

[0230] In some embodiments, R4is bicyclic 7- 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 R4a. hi some embodiments, R4is bicyclic 7- to 10-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S. In some embodiments, R4is bicyclic 7- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, and is optionally substituted with R4a. In some embodiments, R4is 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 R4a. In some embodiments, R4is 8- to 10-membered bicyclic heteroaryl having 1 to 4 heteroatoms selected from N, O, and S and is optionally substituted with one or more instances of R4a. In some embodiments, R4is 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 R4a. In some embodiments, R4is 8- to 10-membered bicyclic heteroaryl having 1 to 3 heteroatoms selected from N and O. In some embodiments, R4is 8- to 10- membered bicyclic heteroaryl having 1 to 3 heteroatomsPage 114 of 83712954319vlAttorney Docket No.: 2013518-0095 selected from N and O. In some embodiments, R4is

[0231] In some embodiments, R4is Ce-Cio aryl, and wherein R4is optionally substituted with one or more instances of R4a. hi some embodiments, R4is Ce-Cio aryl. In some embodiments, R4is phenyl optionally substituted with one or more instances of R4a. In some embodiments, R4is phenyl. In some embodiments, R4is naphthyl.

[0232] In some embodiments, R4is substituted with 0 to 4 instances of R4a. In some embodiments, R4is substituted with 0 to 3 instances of R4a. In some embodiments, R4is substituted with 0 to 2 instances of R4a. In some embodiments, R4is substituted with 1 to 3 instances of R4a. In some embodiments, R4is substituted with 1 to 2 instances of R4a. In some embodiments, R4is substituted with 1 instance of R4a. In some embodiments, R4is substituted with 2 instances of R4a. In some embodiments, R4is substituted with 3 instances of R4a. In some embodiments, R4is substituted with 4 instances of R4a.

[0233] In some embodiments, R4is selected from:Page 115 of 83712954319vlAttorney Docket No.: 2013518-0095

[0234] In some embodiments, R4is selected from:Z (R4a)o-2 v-VN r N-R4a

[0235] In some embodiments, R4is N orIn some embodiments,,< (R4a)o-2 r N- R4a

[0236] In some embodiments, R4is selected from: N

[0237] In some embodiments, R4optionally substituted with one or more instances of R4ais selected from:Page 116 of 83712954319vlAttorney Docket No.: 2013518-0095

[0238] In some embodiments, R4optionally substituted with one or more instances R4ais

[0239] In some embodiments, R4optionally substituted with one or more instances R4aisPage 117 of 83712954319vlAttorney Docket No.: 2013518-0095

[0240] As described with respect to any formula provided herein, each R4ais independently selected from optionally substituted Ci-Ce aliphatic, optionally substituted 2- to 10-membered 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, optionally substituted Ce-Cio aryl, halogen, oxo, -CN, -NO2, -C(O)Ra, -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, each R4ais independently selected from optionally substituted Ci-Ce aliphatic, optionally substituted 2- to 10-membered 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, optionally substituted Ce-Cio aryl, 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, and -ORa. In some embodiments, each R4ais independently selected from optionally substituted Ci-Ce aliphatic, -ORa, and halogen. In some embodiments, each R4ais independently selected from optionally substituted C1-C6 aliphatic, optionally substituted 2- to 10-membered heteroaliphatic, -ORa, halogen, and -C(O)Ra. In some embodiments, each R4ais independently selected from optionally substituted Ci-Ce aliphatic and halogen. In some embodiments, each R4aPage 118 of 83712954319vlAttorney Docket No.: 2013518-0095 is independently selected from optionally substituted Ci-Ce aliphatic, optionally substituted 2- to 10-mcmbcrcd hetero aliphatic, halogen, -C(O)Ra, and -ORa.

[0241] In some embodiments, R4ais optionally substituted Ci-Ce aliphatic. In some embodiments, R4ais optionally substituted Ci-Ce alkyl. In some embodiments, R4ais methyl or deuterated methyl (e.g., one or more H atoms of methyl have been replaced with deuterium). In some embodiments, R4ais a branched Ci-Ce aliphatic. In some embodiments, R4ais Ci-Ce aliphatic optionally substituted with halogen. In some embodiments, R4ais Ci-Ce aliphatic optionally substituted with one or more halogen or -OR°. In some embodiments, R4ais Ci-Ce aliphatic optionally substituted with one or more halogen, -CN, -OR°, or -(CHojo iR0. In some embodiments, R4ais Ci-Ce aliphatic optionally substituted with one or more halogen or -OR°, wherein each R° is independently Ci-Ce alkyl or hydrogen. In some embodiments, R4ais Ci-Ce aliphatic optionally substituted with one or more halogen, -CN, -OR°, or (CH2)o 4R0. wherein each R° is independently hydrogen, C1-6 aliphatic, or 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. In some embodiments, R4ais -CH3, -CD3, -CH2C(CH3)2OH, or -(CH2)2OCH3. In some embodiments, R4ais -CH3, -CD3, -CH2CN, -CH2C(CH3)2OH, -(CH2)2OH, -(CH2)2OCH3,

[0242] In some embodiments, R4ais optionally substituted C1-C3 aliphatic.

[0243] In some embodiments, R4ais optionally substituted 2- to 10-membered heteroaliphatic. In some embodiments, R4ais methoxy. In some embodiments, R4ais ethoxy. In some embodiments, R4ais -CH2N(CH3)2.

[0244] In some embodiments, R4ais optionally substituted C3-C12 cycloaliphatic. In some embodiments, R4ais optionally substituted C3-C6 cycloaliphatic. In some embodiments, R4ais cyclopropyl.

[0245] In some embodiments, R4ais optionally substituted 4- to 10-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, R4ais 4- to 10- membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, R4ais optionally substituted 4- to 6-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, R4ais a 4- to 6-memberedPage 119 of 83712954319vlAttorney Docket No.: 2013518-0095 heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, R4ais optionally substituted 4- to 6-mcmbcrcd heterocycle comprising 1 to 2 hctcroatoms selected from N, O, and S. In some embodiments, R4ais a 4- to 6-membered heterocycle comprising 1 to 2 heteroatoms selected from N, O, and S.

[0246] In some embodiments, R4ais optionally substituted 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, R4ais optionally substituted 5- to 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S.

[0247] In some embodiments, R4ais optionally substituted Ce-Cio aryl. In some embodiments, R4ais optionally substituted phenyl. In some embodiments, R4ais optionally substituted naphthyl.

[0248] In some embodiments, R4ais halogen. In some embodiments, R4ais fluoro. In some embodiments, R4ais chloro.

[0249] In some embodiments, R4ais oxo. In some embodiments, R4ais -CN. In some embodiments, R4ais -NO2. In some embodiments, R4ais -C(O)Ra. In some embodiments, R4ais - C(O)(morpholinyl). In some embodiments, R4ais -C(O)(CH3). In some embodiments, R4ais - C(O)(oxetanyl). In some embodiments, R4ais -C(O)N(Ra)2. In some embodiments, R4ais - C(O)NH2. In some embodiments, R4ais -C(O)N(CH3)2. hi some embodiments, R4ais -OC(O)Ra. In some embodiments, R4ais -OC(O)CH3. In some embodiments, R4ais -OC(O)N(Ra)2. In some embodiments, R4ais -OC(O)NH2. In some embodiments, R4ais -OC(O)N(CH3)2. In some embodiments, R4ais -N(Ra)C(O)Ra. hi some embodiments, R4ais -NHC(O)CH3. hi some embodiments, R4ais -N(CH3)C(O)CH3. In some embodiments, R4ais -N(Ra)C(O)ORa. In some embodiments, R4ais -NHC(O)OH. In some embodiments, R4ais -NHC(O)OCH3. In some embodiments, R4ais -N(Ra)C(O)N(Ra)2. In some embodiments, R4ais -NHC(O)NH2. In some embodiments, R4ais -NHC(O)N(CH3)2. hi some embodiments, R4ais -S(O)2N(Ra)2. In some embodiments, R4ais -S(O)2NH2. hi some embodiments, R4ais -S(O)2N(CH3)2. In some embodiments, R4ais -N(Ra)S(O)2Ra. In some embodiments, R4ais -NHS(O)2CH3. In some embodiments, R4ais-S(O)2Ra. In some embodiments, R4ais -ORa. In some embodiments, R4ais - OH. In some embodiments, R4ais -OCH3. In some embodiments, R4ais -CH3. In some embodiments, R4ais -CD3.

[0250] In some embodiments, each R4ais independently selected from -CH3, -CD3, - CH2C(CH3)2OH, -(CH2)2OCH3, -OCH3, and fluoro. In some embodiments, each R4ais independently selected from -CH3, -CD3, -CH2CN, -CH2C(CH3)2OH, -(CH2)2OH, -(CH2)2OCH3,Page 120 of 83712954319vlAttorney Docket No.: 2013518-0095fluoro, -C(O)(CH3), -C(O)(oxetanyl), and - C(O)(morpholinyl) .

[0251] As described with respect to any formula provided herein (e.g., any of Formulae I-IX), each Rais independently selected from hydrogen, optionally substituted C1-C6 aliphatic, optionally substituted 2- to 10-membered hetero aliphatic, 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 independently selected from hydrogen and optionally substituted Ci-Ce aliphatic (e.g., optionally substituted Ci-Ce alkyl). In some embodiments, each Rais independently selected from hydrogen and Ci-Ce aliphatic. In some embodiments, each Rais independently selected from hydrogen and Ci-Ce alkyl. In some embodiments, each Rais independently selected from hydrogen, optionally substituted Ci-Ce aliphatic (e.g., optionally substituted Ci-Ce alkyl), and an optionally substituted 4- to 12-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, each Rais independently selected from hydrogen, Ci-Ce aliphatic, and a 4- to 6-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, each Rais independently selected from hydrogen, C1-C6 alkyl, oxetanyl, and morpholinyl.

[0252] In some embodiments, Rais hydrogen.

[0253] In some embodiments, Rais optionally substituted Ci-Ce aliphatic. In some embodiments, Rais Ci-Ce aliphatic. In some embodiments, Rais optionally substituted C1-C6 alkyl. In some embodiments, Rais Ci-Ce alkyl. In some embodiments, Rais methyl or ethyl.

[0254] In some embodiments, Rais optionally substituted 2- to 10-membered heteroaliphatic.

[0255] In some embodiments, Rais optionally substituted 5- to 12-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, Rais optionally substituted 5- to 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S.

[0256] 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 optionally substituted 4- to 6-membered heterocycle comprising 1 to 2 heteroatoms selected from N, O, and S. In some embodiments, Rais a 4- to 6-membered heterocycle comprising 1 to 2 heteroatomsPage 121 of 83712954319vlAttorney Docket No.: 2013518-0095 selected from N, O, and S. In some embodiments, Rais oxetanyl. In some embodiments, Rais morpholinyl.

[0257] In some embodiments, the present disclosure provides a compound of Formula I:or a pharmaceutically acceptable salt thereof, wherein:R1is hydrogen or optionally substituted Ci-Ce aliphatic;R2is C3-C12 cycloaliphatic, Ci-Ce aliphatic, 2- to 10-membered hetero aliphatic, 4- to 10-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S, 5- to 10- mcmbcrcd hctcroaryl comprising 1 to 4 hctcroatoms selected from N, O, and S, or Ce-Cio aryl, wherein R2is optionally substituted with one or more instances of -L-R5; each L is independently selected from the group consisting of a bond, - N(Ra)C(O)N(Ra)-, -N(Ra)C(O)O-, -OC(O)N(Ra)-, -C(O)N(Ra)-, -N(Ra)C(O)-, -N(Ra)-, -O-, - C(O)-, -C(O)O-, -OC(O)-, -N(Ra)C(S)O-, -OC(S)N(Ra)-, -C(S)N(Ra)-, -N(Ra)C(S)-, -C(S)-, - C(S)O-, and -OC(S)-; each R5is independently selected from the group consisting of optionally substituted Ci-Ce aliphatic, optionally substituted 2- to 10-membered 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 Ce-Cioaryl;R3is 5- to 12-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, 4- to 12-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S, C6-C12 aryl, C3-C12 cycloaliphatic, or Ci-Ce aliphatic, wherein R3is optionally substituted with one or more instances of R3a;R4is Ci-Ce aliphatic, 2- to 10-membered heteroaliphatic, C3-C12 cycloaliphatic, 4- to 10-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S, 5- to 10-Page 122 of 83712954319vlAttorney Docket No.: 2013518-0095 membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, or Ce-Cio aryl, wherein R4is optionally substituted with one or more instances of R4a; each R3ais independently selected from the group consisting of optionally substituted Ci-C6aliphatic, optionally substituted 2- to 10-membered 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, optionally substituted C6-C10 aryl, 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, and -ORa; each R4ais independently selected from the group consisting of optionally substituted C1-C6 aliphatic, optionally substituted 2- to 10-membered 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, optionally substituted C6-C10 aryl, 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, and -ORa; and each Rais independently selected from hydrogen, optionally substituted C1-C6 aliphatic, optionally substituted 2- to 10-membered 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.

[0258] In some embodiments, the present disclosure provides a compound of Formula I:or a pharmaceutically acceptable salt thereof, wherein:R1is hydrogen or optionally substituted Ci-Ce aliphatic;Page 123 of 83712954319vlAttorney Docket No.: 2013518-0095R2is C3-C12 cycloaliphatic, Ci-Ce aliphatic, 2- to 10-membered heteroaliphatic, 4- to 10-mcmbcrcd heterocycle comprising 1 to 4 hctcroatoms selected from N, O, and S, 5- to 10- membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, or Ce-Cio aryl, wherein R2is optionally substituted with one or more instances of -L-R5; each L is independently selected from the group consisting of a bond, - N(Ra)C(O)N(Ra)-, -N(Ra)C(O)O-, -OC(O)N(Ra)-, -C(O)N(Ra)-, -N(Ra)C(O)-, -N(Ra)-, -O-, - C(O)-, -C(O)O-, -OC(O)-, -N(Ra)C(S)O-, -OC(S)N(Ra)-, -C(S)N(Ra)-, -N(Ra)C(S)-, -C(S)-, - C(S)O-, and -OC(S)-; each R5is independently selected from the group consisting of optionally substituted Ci-Ce aliphatic, optionally substituted 2- to 10-membered 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 Ce-Cioaryl;R3is 5- to 12-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, 4- to 12-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S, C6-C12 aryl, C3-C12 cycloaliphatic, or Ci-Ce aliphatic, wherein R3is optionally substituted with one or more instances of R3a;R4is Ci-Ce aliphatic, -CN, 2- to 10-membered 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 Ce-Cio aryl, wherein R4is optionally substituted with one or more instances of R4a; each R3ais independently selected from the group consisting of optionally substituted Ci-Ce aliphatic, optionally substituted 2- to 10-membered 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, optionally substituted C6-C10 aryl, 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, and -ORa; each R4ais independently selected from the group consisting of optionally substituted C1-C6 aliphatic, optionally substituted 2- to 10-membered heteroaliphatic, optionally substituted C3-C12 cycloaliphatic, optionally substituted 4- to 10-membered heterocycle comprising 1 to 4Page 124 of 83712954319vlAttorney Docket No.: 2013518-0095 heteroatoms selected from N, O, and S, optionally substituted 5- to 10-membered heteroaryl comprising 1 to 4 hctcroatoms selected from N, O, and S, optionally substituted Ce-Cio aryl, halogen, oxo, -CN, -NO2, -C(O)Ra, -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; and each Rais independently selected from hydrogen, optionally substituted Ci-Ce aliphatic, optionally substituted 2- to 10-membered 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.

[0259] In some embodiments, the present disclosure provides a compound of Formula I:or a pharmaceutically acceptable salt thereof, wherein:R1is hydrogen or optionally substituted Ci-Ce aliphatic;R2is C3-C12cycloaliphatic, Ci-Ce aliphatic, 2- to 10-membered heteroaliphatic, 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 Ce-Cio aryl, wherein R2is optionally substituted with one or more instances of -L-R5or R7; each L is independently selected from the group consisting of a bond, - N(Ra)C(O)N(Ra)-, -N(Ra)C(O)O-, -OC(O)N(Ra)-, -C(O)N(Ra)-, -N(Ra)C(O)-, -N(Ra)-, -O-, - C(O)-, -C(O)O-, -OC(O)-, -N(Ra)C(S)O-, -OC(S)N(Ra)-, -C(S)N(Ra)-, -N(Ra)C(S)-, -C(S)-, - C(S)O-, and -OC(S)-; each R5is independently selected from the group consisting of optionally substituted C1-C6 aliphatic, optionally substituted 2- to 10-membered heteroaliphatic, optionally substituted C3-Ci2 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 Ce-Ci 0 aryl;Page 125 of 83712954319vlAttorney Docket No.: 2013518-0095 each R7is independently selected from the group consisting of halogen, -OH, -SH, and -NH2;R3is 5- to 12-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, 4- to 12-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S, C6-C12 aryl, C3-C12 cycloaliphatic, or Ci-Ce aliphatic, wherein R3is optionally substituted with one or more instances of R3a;R4is Ci-Ce aliphatic, 2- to 10-membered 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 Ce-Cio aryl, wherein R4is optionally substituted with one or more instances of R4a; each R3ais independently selected from the group consisting of optionally substituted Ci-Ce aliphatic, optionally substituted 2- to 10-membered 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, optionally substituted Ce-Cio aryl, 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, and -ORa; each R4ais independently selected from the group consisting of optionally substituted C1-C6 aliphatic, optionally substituted 2- to 10-membered heteroaliphatic, optionally substituted C3-Ci2cycloaliphatic, 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, optionally substituted C6-C10 aryl, 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, and -ORa; and

[0260] each Rais independently selected from hydrogen, optionally substituted Ci-Ce aliphatic, optionally substituted 2- to 10-membered 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.In some embodiments, the present disclosure provides a compound of Formula I:Page 126 of 83712954319vlAttorney Docket No.: 2013518-0095or a pharmaceutically acceptable salt thereof, wherein:R1is hydrogen or optionally substituted Ci-Ce aliphatic;R2is C3-C12 cycloaliphatic, C1-C6 aliphatic, 2- to 10-membered hetero aliphatic, 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 Ce-Cio aryl, wherein R2is optionally substituted with one or more instances of -L-R5or R7; each L is independently selected from the group consisting of a bond, - N(Ra)C(O)N(Ra)-, -N(Ra)C(O)O-, -OC(O)N(Ra)-, -C(O)N(Ra)-, -N(Ra)C(O)-, -N(Ra)-, -O-, - C(O)-, -C(O)O-, -OC(O)-, -N(Ra)C(S)O-, -OC(S)N(Ra)-, -C(S)N(Ra)-, -N(Ra)C(S)-, -C(S)-, - C(S)O-, and -OC(S)-; each R5is independently selected from the group consisting of optionally substituted Ci-Ce aliphatic, optionally substituted 2- to 10-membered 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 Ce-Cioaryl; each R7is independently selected from the group consisting of halogen, -OH, -SH, and -NH2;R3is 5- to 12-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, 4- to 12-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S, C6-C12 aryl, C3-C12 cycloaliphatic, or Ci-Ce aliphatic, wherein R3is optionally substituted with one or more instances of R3a;R4is Ci-Ce aliphatic, -CN, 2- to 10-membered 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 Ce-Cio aryl, wherein R4is optionally substituted with one or more instances of R4a;Page 127 of 83712954319vlAttorney Docket No.: 2013518-0095 each R3ais independently selected from the group consisting of optionally substituted Ci-Ce aliphatic, optionally substituted 2- to 10-mcmbcrcd hctcroaliphatic, 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, optionally substituted C6-C10 aryl, 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, and -ORa; each R4ais independently selected from the group consisting of optionally substituted Ci-Ce aliphatic, optionally substituted 2- to 10-membered 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, optionally substituted Ce-Cio aryl, halogen, oxo, -CN, -NO2, -C(O)Ra, -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; and each Rais independently selected from hydrogen, optionally substituted Ci-Ce aliphatic, optionally substituted 2- to 10-membered 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.

[0261] In some embodiments, the present disclosure provides a compound of Formula VIII:or a pharmaceutically acceptable salt thereof, wherein:R1is hydrogen or optionally substituted Ci-Ce aliphatic;Page 128 of 83712954319vlAttorney Docket No.: 2013518-0095R2is C3-C12 cycloaliphatic, Ci-Ce aliphatic, 2- to 10-membered heteroaliphatic, 4- to 10-mcmbcrcd heterocycle comprising 1 to 4 hctcroatoms selected from N, O, and S, 5- to 10- membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, or Ce-Cio aryl;R3is 5- to 12-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, 4- to 12-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S, C6-C12 aryl, C3-C12 cycloaliphatic, or Ci-Ce aliphatic, wherein R3is optionally substituted with one or more instances of R3a;Lais a bond, -N(Ra)C(O)N(Ra)-, -N(Ra)C(O)O-, -OC(O)N(Ra)-, -C(O)N(Ra)-, - N(Ra)C(O)-, -N(Ra)-, -O-, -C(O)-, -C(O)O-, -OC(O)-, -N(Ra)C(S)O-, -OC(S)N(Ra)-, -C(S)N(Ra)- , -N(Ra)C(S)-, -C(S)-, -C(S)O-, or -OC(S)-;Lbis a bond, -N(Ra)C(O)N(Ra)-, -N(Ra)C(O)O-, -OC(O)N(Ra)-, -C(O)N(Ra)-, - N(Ra)C(O)-, -N(Ra)-, -O-, -C(O)-, -C(O)O-, -OC(O)-, -N(Ra)C(S)O-, -OC(S)N(Ra)-, -C(S)N(Ra)- , -N(Ra)C(S)-, -C(S)-, -C(S)O-, or -OC(S)-;R6is optionally substituted Ci-Ce aliphatic, optionally substituted 2- to 10-membered 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, or optionally substituted C6-C10 aryl;R4is Ci-Ce aliphatic, 2- to 10-membered hetero aliphatic, 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 Ce-Cio aryl, wherein R4is optionally substituted with one or more instances of R4a; each R3ais independently selected from the group consisting of optionally substituted Ci-Ce aliphatic, optionally substituted 2- to 10-membered 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, optionally substituted Ce-Cio aryl, 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, and -ORa; each R4ais independently selected from the group consisting of optionally substituted Ci-Ce aliphatic, optionally substituted 2- to 10-membered heteroaliphatic, optionally substitutedPage 129 of 83712954319vlAttorney Docket No.: 2013518-0095C3-C12 cycloaliphatic, optionally substituted 4- to 10-membered heterocycle comprising 1 to 4 hctcroatoms selected from N, O, and S, optionally substituted 5- to 10-mcmbcrcd hctcroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, optionally substituted C6-C10 aryl, 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, and -ORa; and each Rais independently selected from hydrogen, optionally substituted Ci-Ce aliphatic, optionally substituted 2- to 10-membered 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.

[0262] In some embodiments, the present disclosure provides a compound of Formula VIII:or a pharmaceutically acceptable salt thereof, wherein:R1is hydrogen or optionally substituted Ci-Ce aliphatic;R2is C3-C12 cycloaliphatic, Ci-Ce aliphatic, 2- to 10-membered heteroaliphatic, 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 Ce-Cioaryl;R3is 5- to 12-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, 4- to 12-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S, C6-C12 aryl, C3-C12 cycloaliphatic, or Ci-Ce aliphatic, wherein R3is optionally substituted with one or more instances of R3a;Lais a bond, -N(Ra)C(O)N(Ra)-, -N(Ra)C(O)O-, -OC(O)N(Ra)-, -C(O)N(Ra)-, - N(Ra)C(O)-, -N(Ra)-, -O-, -C(O)-, -C(O)O-, -OC(O)-, -N(Ra)C(S)O-, -OC(S)N(Ra)-, -C(S)N(Ra)- , -N(Ra)C(S)-, -C(S)-, -C(S)O-, or -OC(S)-;Page 130 of 83712954319vlAttorney Docket No.: 2013518-0095Lbis a bond, -N(Ra)C(O)N(Ra)-, -N(Ra)C(O)O-, -OC(O)N(Ra)-, -C(O)N(Ra)-, - N(Ra)C(O)-, -N(Ra)-, -O-, -C(O)-, -C(O)O-, -OC(O)-, -N(Ra)C(S)O-, -OC(S)N(Ra)-, -C(S)N(Ra)- , -N(Ra)C(S)-, -C(S)-, -C(S)O-, or -OC(S)-;R6is optionally substituted Ci-Ce aliphatic, optionally substituted 2- to 10-membered 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, or optionally substituted Ce-Cio aryl;R4is Ci-Ce aliphatic, -CN, 2- to 10-membered 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 Ce-Cio aryl, wherein R4is optionally substituted with one or more instances of R4a; each R3ais independently selected from the group consisting of optionally substituted C1-C6 aliphatic, optionally substituted 2- to 10-membered 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, optionally substituted C6-C10 aryl, 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, and -ORa; each R4ais independently selected from the group consisting of optionally substituted Ci-Ce aliphatic, optionally substituted 2- to 10-membered 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, optionally substituted Ce-Cio aryl, halogen, oxo, -CN, -NO2, -C(O)Ra, -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; and each Rais independently selected from hydrogen, optionally substituted Ci-Ce aliphatic, optionally substituted 2- to 10-membered 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.Page 131 of 83712954319vlAttorney Docket No.: 2013518-0095

[0263] In some embodiments, the present disclosure provides a compound of Formula I:I or a pharmaceutically acceptable salt thereof, wherein:R1is hydrogen or optionally substituted Ci-Ce aliphatic;R2is C3-C 12 cycloaliphatic, Ci-Ce aliphatic, 2- to 10-membered heteroaliphatic, 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 Ce-Cio aryl, wherein R2is substituted with one or more instances of -L-R5or R7; each L is independently selected from the group consisting of a bond, - N(Ra)C(O)N(Ra)-, -N(Ra)C(O)O-, -OC(O)N(Ra)-, -C(O)N(Ra)-, -N(Ra)C(O)-, -N(Ra)-, -O-, - C(O)-, -C(O)O-, -OC(O)-, -N(Ra)C(S)O-, -OC(S)N(Ra)-, -C(S)N(Ra)-, -N(Ra)C(S)-, -C(S)-, - C(S)O-, and -OC(S)-; each R5is independently selected from the group consisting of optionally substituted Ci-C6aliphatic, optionally substituted 2- to 10-membered 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 Ce-Cioaryl; each R7is independently selected from the group consisting of halogen, -OH, -SH, and -NH2;R3is 5- to 12-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, 4- to 12-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S, C6-C12 aryl, C3-C12 cycloaliphatic, or Ci-Ce aliphatic, wherein R3is optionally substituted with one or more instances of R3a; orR2and R3are connected by *-La-R6-Lb-**, wherein * represents a point of attachment to R2, and ** represents a point of attachment to R3;Page 132 of 83712954319vlAttorney Docket No.: 2013518-0095Lais a bond, -N(Ra)C(O)N(Ra)-, -N(Ra)C(O)O-, -OC(O)N(Ra)-, -C(O)N(Ra)-, - N(Ra)C(O)-, -N(Ra)-, -O-, -C(O)-, -C(O)O-, -OC(O)-, -N(Ra)C(S)O-, -OC(S)N(Ra)-, -C(S)N(Ra)- , -N(Ra)C(S)-, -C(S)-, -C(S)O-, or -OC(S)-;Lbis a bond, -N(Ra)C(O)N(Ra)-, -N(Ra)C(O)O-, -OC(O)N(Ra)-, -C(O)N(Ra)-, - N(Ra)C(O)-, -N(Ra)-, -O-, -C(O)-, -C(O)O-, -OC(O)-, -N(Ra)C(S)O-, -OC(S)N(Ra)-, -C(S)N(Ra)- , -N(Ra)C(S)-, -C(S)-, -C(S)O-, or -OC(S)-;R6is optionally substituted Ci-Ce aliphatic, optionally substituted 2- to 10-membered 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, or optionally substituted Ce-Cio aryl;R4is Ci-Ce aliphatic, 2- to 10-membered 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 Ce-Cio aryl, wherein R4is optionally substituted with one or more instances of R4a; each R3ais independently selected from the group consisting of optionally substituted C1-C6 aliphatic, optionally substituted 2- to 10-membered 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, optionally substituted Ce-Cio aryl, 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, and -ORa; each R4ais independently selected from the group consisting of optionally substituted Ci-Ce aliphatic, optionally substituted 2- to 10-membered 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, optionally substituted C6-C10 aryl, 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, and -ORa; and each Rais independently selected from hydrogen, optionally substituted Ci-Ce aliphatic, optionally substituted 2- to 10-membered heteroaliphatic, optionally substituted 5- to 12-Page 133 of 83712954319vlAttorney Docket No.: 2013518-0095 membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, and optionally substituted 4- to 12-mcmbcrcd hctcrocyclc comprising 1 to 4 hctcroatoms selected from N, O, and S.

[0264] In some embodiments, the present disclosure provides a compound of Formula I:I or a pharmaceutically acceptable salt thereof, wherein:R1is hydrogen or optionally substituted Ci-Ce aliphatic;R2is C3-C12 cycloaliphatic, Ci-Ce aliphatic, 2- to 10-membered heteroaliphatic, 4- to 10-mcmbcrcd hctcrocyclc comprising 1 to 4 hctcroatoms selected from N, O, and S, 5- to 10- membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, or Ce-Cio aryl, wherein R2is substituted with one or more instances of -L-R5or R7; each L is independently selected from the group consisting of a bond, - N(Ra)C(O)N(Ra)-, -N(Ra)C(O)O-, -OC(O)N(Ra)-, -C(O)N(Ra)-, -N(Ra)C(O)-, -N(Ra)-, -O-, - C(O)-, -C(O)O-, -OC(O)-, -N(Ra)C(S)O-, -OC(S)N(Ra)-, -C(S)N(Ra)-, -N(Ra)C(S)-, -C(S)-, - C(S)O-, and -OC(S)-; each R5is independently selected from the group consisting of optionally substituted Ci-Ce aliphatic, optionally substituted 2- to 10-membered 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 Ce-Cioaryl; each R7is independently selected from the group consisting of halogen, -OH, -SH, and -NH2;R3is 5- to 12-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, 4- to 12-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S, C6-C12 aryl, C3-C12 cycloaliphatic, or Ci-Ce aliphatic, wherein R3is optionally substituted with one or more instances of R3a; orPage 134 of 83712954319vlAttorney Docket No.: 2013518-0095R2and R3are connected by *-La-R6-Lb-**, wherein * represents a point of attachment to R2, and ** represents a point of attachment to R3;Lais a bond, -N(Ra)C(O)N(Ra)-, -N(Ra)C(O)O-, -OC(O)N(Ra)-, -C(O)N(Ra)-, - N(Ra)C(O)-, -N(Ra)-, -O-, -C(O)-, -C(O)O-, -OC(O)-, -N(Ra)C(S)O-, -OC(S)N(Ra)-, -C(S)N(Ra)- , -N(Ra)C(S)-, -C(S)-, -C(S)O-, or -OC(S)-;Lbis a bond, -N(Ra)C(O)N(Ra)-, -N(Ra)C(O)O-, -OC(O)N(Ra)-, -C(O)N(Ra)-, - N(Ra)C(O)-, -N(Ra)-, -O-, -C(O)-, -C(O)O-, -OC(O)-, -N(Ra)C(S)O-, -OC(S)N(Ra)-, -C(S)N(Ra)- , -N(Ra)C(S)-, -C(S)-, -C(S)O-, or -OC(S)-;R6is optionally substituted Ci-Ce aliphatic, optionally substituted 2- to 10-membered 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, or optionally substituted Ce-Cio aryl;R4is Ci-Ce aliphatic, -CN, 2- to 10-membered 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 Ce-Cio aryl, wherein R4is optionally substituted with one or more instances of R4a; each R3ais independently selected from the group consisting of optionally substituted C1-C6 aliphatic, optionally substituted 2- to 10-membered 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, optionally substituted C6-C10 aryl, 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, and -ORa; each R4ais independently selected from the group consisting of optionally substituted C1-C6 aliphatic, optionally substituted 2- to 10-membered 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, optionally substituted CG-C IO aryl, halogen, oxo, -CN, -NO2, -C(O)Ra, -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; andPage 135 of 83712954319vlAttorney Docket No.: 2013518-0095 each Rais independently selected from hydrogen, optionally substituted Ci-Ce aliphatic, optionally substituted 2- to 10-mcmbcrcd hctcroaliphatic, 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.

[0265] In some embodiments, the present disclosure provides a compound of Formula I:or a pharmaceutically acceptable salt thereof, wherein:R1is hydrogen or optionally substituted Ci-Ce aliphatic;R2is C3-C12 cycloaliphatic, Ci-Ce aliphatic, 2- to 10-membered heteroaliphatic, 4- to 10-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S, or 5- to 10- membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, wherein R2is optionally substituted with one instance of -L-R5; each L is independently selected from the group consisting of a bond, - N(Ra)C(O)N(Ra)-, -N(Ra)C(O)O-, -OC(O)N(Ra)-, -C(O)N(Ra)-, -N(Ra)C(O)-, -N(Ra)-, -O-, - C(O)-, -C(O)O-, -OC(O)-, -N(Ra)C(S)O-, -OC(S)N(Ra)-, -C(S)N(Ra)-, -N(Ra)C(S)-, -C(S)-, - C(S)O-, and -OC(S)-; each R5is independently selected from the group consisting of optionally substituted Ci-Ce aliphatic, optionally substituted 2- to 10-membered 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 Ce-Ci 0 aryl;R3is 5- to 12-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, 4- to 12-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S,Page 136 of 83712954319vlAttorney Docket No.: 2013518-0095Ce-Cn aryl, or C3-C12 cycloaliphatic, wherein R3is optionally substituted with one or more instances of R3a; orR2and R3are connected by *-La-R6-Lb-**, where * represents a point of attachment to R2, and ** represents a point of attachment to R3;Lais a bond, -N(Ra)C(O)N(Ra)-, -N(Ra)C(O)O-, -OC(O)N(Ra)-, -C(O)N(Ra)-, - N(Ra)C(O)-, -N(Ra)-, -O-, -C(O)-, -C(O)O-, -OC(O)-, -N(Ra)C(S)O-, -OC(S)N(Ra)-, -C(S)N(Ra)- , -N(Ra)C(S)-, -C(S)-, -C(S)O-, or -OC(S)-;Lbis a bond, -C(O)N(Ra)-, -N(Ra)C(O)-, -N(Ra)-, -O-, -C(O)-, -C(O)O-, -OC(O)-, - C(S)N(Ra)-, -N(Ra)C(S)-, -C(S)-, -C(S)O-, or -OC(S)-;R6is optionally substituted Ci-Ce aliphatic, optionally substituted 2- to 10-membered heteroaliphatic, optionally substituted C3-C12 cycloaliphatic, optionally substituted 4- to 10- membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S, or optionally substituted 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S;R4is 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 R4is optionally substituted with one or more instances of R4a; each R3ais independently selected from the group consisting of optionally substituted Ci-Ce aliphatic, optionally substituted 2- to 10-membered 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, halogen, oxo, -CN, -NO2, -C(0)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; each R4ais independently selected from the group consisting of optionally substituted C1-C6 aliphatic, optionally substituted 2- to 10-membered 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, optionally substituted C6-C10 aryl, halogen, oxo, -CN, -NO2, and -ORa; andPage 137 of 83712954319vlAttorney Docket No.: 2013518-0095 each Rais independently selected from hydrogen, optionally substituted Ci-Ce aliphatic, optionally substituted 2- to 10-mcmbcrcd hctcroaliphatic, 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.

[0266] In some embodiments, the present disclosure provides a compound of Formula I:or a pharmaceutically acceptable salt thereof, wherein:R1is hydrogen or optionally substituted Ci-Ce aliphatic;R2is C3-C12 cycloaliphatic, Ci-Ce aliphatic, 2- to 10-membered heteroaliphatic, 4- to 10-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S, or 5- to 10- membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, wherein R2is optionally substituted with one instance of -L-R5; each L is independently selected from the group consisting of a bond, - N(Ra)C(O)N(Ra)-, -N(Ra)C(O)O-, -OC(O)N(Ra)-, -C(O)N(Ra)-, -N(Ra)C(O)-, -N(Ra)-, -O-, - C(O)-, -C(O)O-, -OC(O)-, -N(Ra)C(S)O-, -OC(S)N(Ra)-, -C(S)N(Ra)-, -N(Ra)C(S)-, -C(S)-, - C(S)O-, and -OC(S)-; each R5is independently selected from the group consisting of optionally substituted Ci-Ce aliphatic, optionally substituted 2- to 10-membered 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 Ce-Ci 0 aryl;R3is 5- to 12-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, 4- to 12-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S,Page 138 of 83712954319vlAttorney Docket No.: 2013518-0095Ce-Cn aryl, or C3-C12 cycloaliphatic, wherein R3is optionally substituted with one or more instances of R3a; orR2and R3are connected by *-La-R6-Lb-**, where * represents a point of attachment to R2, and ** represents a point of attachment to R3;Lais a bond, -N(Ra)C(O)N(Ra)-, -N(Ra)C(O)O-, -OC(O)N(Ra)-, -C(O)N(Ra)-, - N(Ra)C(O)-, -N(Ra)-, -O-, -C(O)-, -C(O)O-, -OC(O)-, -N(Ra)C(S)O-, -OC(S)N(Ra)-, -C(S)N(Ra)- , -N(Ra)C(S)-, -C(S)-, -C(S)O-, or -OC(S)-;Lbis a bond, -C(O)N(Ra)-, -N(Ra)C(O)-, -N(Ra)-, -O-, -C(O)-, -C(O)O-, -OC(O)-, - C(S)N(Ra)-, -N(Ra)C(S)-, -C(S)-, -C(S)O-, or -OC(S)-;R6is optionally substituted Ci-Ce aliphatic, optionally substituted 2- to 10-membered heteroaliphatic, optionally substituted C3-C12 cycloaliphatic, optionally substituted 4- to 10- membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S, or optionally substituted 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S;R4is -CN, 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 R4is optionally substituted with one or more instances of R4a; each R3ais independently selected from the group consisting of optionally substituted Ci-Ce aliphatic, optionally substituted 2- to 10-membered 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, halogen, oxo, -CN, -NO2, -C(0)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; each R4ais independently selected from the group consisting of optionally substituted C1-C6 aliphatic, optionally substituted 2- to 10-membered 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, optionally substituted C6-C10 aryl, halogen, oxo, -CN, -NO2, -C(O)Ra, and -ORa; andPage 139 of 83712954319vlAttorney Docket No.: 2013518-0095 each Rais independently selected from hydrogen, optionally substituted Ci-Ce aliphatic, optionally substituted 2- to 10-mcmbcrcd hctcroaliphatic, 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.

[0267] In some embodiments, the present disclosure provides a compound of Formula I:or a pharmaceutically acceptable salt thereof, wherein:R1is hydrogen or optionally substituted Ci-Ce aliphatic;R2is C3-C12 cycloaliphatic, Ci-Ce aliphatic, or 4- to 10-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S, wherein R2is optionally substituted with one instance of -L-R5; each L is independently selected from the group consisting of a bond, - N(Ra)C(O)N(Ra)-, -N(Ra)C(O)O-, -OC(O)N(Ra)-, -C(O)N(Ra)-, -N(Ra)C(O)-, -N(Ra)-, -O-, - C(O)-, -C(O)O-, and -OC(O)-; each R5is independently selected from the group consisting of optionally substituted Ci-Ce aliphatic, optionally substituted 2- to 10-membered heteroaliphatic, optionally substituted C3-C12 cycloaliphatic, and optionally substituted 4- to 10-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S;R3is 5- to 12-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, 4- to 12-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S, C6-C12 aryl, C3-C12 cycloaliphatic, or Ci-Ce aliphatic, wherein R3is optionally substituted with one or more instances of R3a; orR2and R3are connected by *-La-R6-Lb-**, where * represents a point of attachment to R2, and ** represents a point of attachment to R3;Page 140 of 83712954319vlAttorney Docket No.: 2013518-0095Lais a bond, -N(Ra)C(O)N(Ra)-, -N(Ra)C(O)O-, -OC(O)N(Ra)-, -C(O)N(Ra)-, - N(Ra)C(O)-, -N(Ra)-, -O-, -C(O)-, -C(O)O-, or -OC(O)-;Lbis a bond, -N(Ra)C(O)N(Ra)-, -N(Ra)C(O)O-, -OC(O)N(Ra)-, -C(O)N(Ra)-, - N(Ra)C(O)-, -N(Ra)-, -O-, -C(O)-, -C(O)O-, or -OC(O)-;R6is optionally substituted C1-C6 aliphatic, optionally substituted 2- to 10-membered heteroaliphatic, optionally substituted C3-C12 cycloaliphatic, or optionally substituted 4- to 10- membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S ;R4is 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 Ce-Cio aryl, wherein R4is optionally substituted with one or more instances of R4a; each R3ais independently selected from the group consisting of optionally substituted Ci-Ce aliphatic, optionally substituted 2- to 10-membered heteroaliphatic, optionally substituted C3-C12 cycloaliphatic, halogen, oxo, -CN, -NO2, -C(0)N(Ra)2, -OC(O)Ra, 0C(0)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; each R4ais independently selected from the group consisting of optionally substituted C1-C6 aliphatic, optionally substituted 2- to 10-membered heteroaliphatic, optionally substituted C3-C12 cycloaliphatic, optionally substituted 4- to 10-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S, halogen, oxo, -CN, -NO2, -C(0)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; and each Rais independently selected from hydrogen, optionally substituted Ci-Ce aliphatic, optionally substituted 2- to 10-membered 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.

[0268] In some embodiments, the present disclosure provides a compound of Formula I:Page 141 of 83712954319vlAttorney Docket No.: 2013518-0095I or a pharmaceutically acceptable salt thereof, wherein:R1is hydrogen or optionally substituted Ci-Ce aliphatic;R2is C3-C12 cycloaliphatic, Ci-Ce aliphatic, or 4- to 10-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S, wherein R2is optionally substituted with one instance of -L-R5; each L is independently selected from the group consisting of a bond, - N(Ra)C(O)N(Ra)-, -N(Ra)C(O)O-, -OC(O)N(Ra)-, -C(O)N(Ra)-, -N(Ra)C(O)-, -N(Ra)-, -O-, - C(O)-, -C(O)O-, and -OC(O)-; each R5is independently selected from the group consisting of optionally substituted Ci-Ce aliphatic, optionally substituted 2- to 10-membered heteroaliphatic, optionally substituted C3-C12 cycloaliphatic, and optionally substituted 4- to 10-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S;R3is 5- to 12-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, 4- to 12-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S, C6-C12 aryl, C3-C12 cycloaliphatic, or Ci-Ce aliphatic, wherein R3is optionally substituted with one or more instances of R3a; orR2and R3are connected by *-La-R6-Lb-**, where * represents a point of attachment to R2, and ** represents a point of attachment to R3;Lais a bond, -N(Ra)C(O)N(Ra)-, -N(Ra)C(O)O-, -OC(O)N(Ra)-, -C(O)N(Ra)-, - N(Ra)C(O)-, -N(Ra)-, -O-, -C(O)-, -C(O)O-, or -OC(O)-;Lbis a bond, -N(Ra)C(O)N(Ra)-, -N(Ra)C(O)O-, -OC(O)N(Ra)-, -C(O)N(Ra)-, - N(Ra)C(O)-, -N(Ra)-, -O-, -C(O)-, -C(O)O-, or -OC(O)-;R6is optionally substituted Ci-Ce aliphatic, optionally substituted 2- to 10-membered heteroaliphatic, optionally substituted C3-C12 cycloaliphatic, or optionally substituted 4- to 10- membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S;Page 142 of 83712954319vlAttorney Docket No.: 2013518-0095R4is -CN, C3-C12 cycloaliphatic, 4- to 10-membered heterocycle comprising 1 to 4 hctcroatoms selected from N, O, and S, 5- to 10-mcmbcrcd hctcroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, or C6-C10 aryl, wherein R4is optionally substituted with one or more instances of R4a; each R3ais independently selected from the group consisting of optionally substituted Ci-Ce aliphatic, optionally substituted 2- to 10-membered heteroaliphatic, optionally substituted C3-C12 cycloaliphatic, halogen, oxo, -CN, -NO2, -C(0)N(Ra)2, -OC(O)Ra, 0C(0)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; each R4ais independently selected from the group consisting of optionally substituted C1-C6 aliphatic, optionally substituted 2- to 10-membered heteroaliphatic, optionally substituted C3-C12 cycloaliphatic, optionally substituted 4- to 10-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S, halogen, oxo, -CN, -NO2, -C(O)Ra, -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; and each Rais independently selected from hydrogen, optionally substituted Ci-Ce aliphatic, optionally substituted 2- to 10-membered 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.

[0269] In some embodiments, the present disclosure provides a compound selected from Table 1A, or a pharmaceutically acceptable salt thereof.[REMAINDER OF THIS PAGE INTENTIONALLY LEFT BLANK]Page 143 of 83712954319vlAttorney Docket No.: 2013518-0095Table 1APage 144 of 83712933262v 1Attorney Docket No.: 2013518-0095Page 145 of 83712933262v 1Attorney Docket No.: 2013518-0095Page 146 of 83712933262v 1Attorney Docket No.: 2013518-0095Page 147 of 83712933262v 1Attorney Docket No.: 2013518-0095Page 148 of 83712933262v 1Attorney Docket No.: 2013518-0095Page 149 of 83712933262v 1Attorney Docket No.: 2013518-0095Page 150 of 83712933262v 1Attorney Docket No.: 2013518-0095Page 151 of 83712933262v 1Attorney Docket No.: 2013518-0095Page 152 of 83712933262v 1Attorney Docket No.: 2013518-0095Page 153 of 83712933262v 1Attorney Docket No.: 2013518-0095Page 154 of 83712933262v 1Attorney Docket No.: 2013518-0095Page 155 of 83712933262v 1Attorney Docket No.: 2013518-0095Page 156 of 83712933262v 1Attorney 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[0270] In some embodiments, the present disclosure provides a compound selected from Table IB, or a pharmaceutically acceptable salt thereof.Table IBPage 252 of 83712933262v 1Attorney Docket No.: 2013518-0095

[0271] In some embodiments, the present disclosure provides a compound selected from Table 1C, or a pharmaceutically acceptable salt thereof.Table 1CPage 253 of 83712933262v 1Attorney Docket No.: 2013518-0095Page 254 of 83712933262v 1Attorney Docket No.: 2013518-0095Page 255 of 83712933262v 1Attorney Docket No.: 2013518-0095Page 256 of 83712933262v 1Attorney Docket No.: 2013518-0095Page 257 of 83712933262v 1Attorney Docket No.: 2013518-0095Page 258 of 83712933262v 1Attorney Docket No.: 2013518-0095Page 259 of 83712933262v 1Attorney Docket No.: 2013518-0095Page 260 of 83712933262v 1Attorney Docket No.: 2013518-0095Page 261 of 83712933262v 1Attorney Docket No.: 2013518-0095Page 262 of 83712933262v 1Attorney Docket No.: 2013518-0095Page 263 of 83712933262v 1Attorney Docket No.: 2013518-0095Page 264 of 83712933262v 1Attorney Docket No.: 2013518-0095Page 265 of 83712933262v 1Attorney Docket No.: 2013518-0095Page 266 of 83712933262v 1Attorney Docket No.: 2013518-0095

[0272] 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 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 cases, Tables 1A-1C show one or more stereoisomers of a compound, and unless otherwise indicated, represent each stereoisomer alonePage 267 of 83712933262v 1Attorney Docket No.: 2013518-0095 and / or as a mixture. Unless otherwise stated, all tautomeric forms of provided compounds are within the scope of the disclosure.

[0273] 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.

[0274] 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).

[0275] It will be appreciated that throughout the present disclosure, unless otherwise indicated, reference to a compound of Formula I is intended to also include II- 1, II-2, II-3, III, IV- 1, IV-2, IV-3, V-l, V-2, VI-1, VI-2, VII-1, VII-2, VII-3, VII-4, VII-5, VIII, and IX, and compound species of such formulas disclosed herein.Compositions

[0276] The present disclosure also provides compositions comprising a compound provided herein with one or more other components. In some embodiments, provided compositionsPage 268 of 83712933262v 1Attorney Docket No.: 2013518-0095 comprise and / or deliver a compound described herein (e.g., compounds of Formulae I, II- 1 , II-2, II-3, III, IV-1, IV-2, IV-3, V-l, V-2, VI-1, VI-2, VII-1, VII-2, VII-3, VII-4, VII-5, VIII, and IX).

[0277] 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, II- 1, II-2, II-3, III, IV-1, IV-2, IV-3, V-l, V-2, VI-1, VI-2, VII-1, VII-2, VII-3, VII-4, VII-5, VIII, and IX) 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.

[0278] 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 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.

[0279] 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.Page 269 of 83712933262v 1Attorney Docket No.: 2013518-0095Uses

[0280] 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.

[0281] 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.

[0282] 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.

[0283] In some embodiments, the present disclosure provides methods of treating a disease, disorder, or condition associated with JAK2. JAK (e.g., JAK2) has been implicated in various diseases, disorders, and conditions, such as myeloproliferative neoplasms (Vainchenker, W. et al., FlOOOResearch 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 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.

[0284] In some embodiments, the present disclosure provides a method of treating a disease, disorder, or condition associated with JAK2, wherein the disease, disorder, or condition is a cancer, a proliferative disease, a hematological malignancy, or an inflammatory disease, disorder, or condition.

[0285] In some embodiments, the present disclosure provides methods of treating cancer, comprising administering a provided compound or composition to a subject in need thereof. InPage 270 of 83712933262v 1Attorney Docket No.: 2013518-0095 some embodiments, the present disclosure provides methods of treating proliferative diseases, comprising administering a provided compound or composition to a subject in need thereof.

[0286] 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 nonHodgkin’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.

[0287] 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.

[0288] 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 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 compositionPage 271 of 83712933262v 1Attorney Docket No.: 2013518-0095(or even necessarily at the same time), although in some embodiments, two or more agents, or active moictics thereof, may be administered together in a combination composition.

[0289] 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 LSD 1 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

[0290] The following numbered embodiments, while non-limiting, are exemplary of certain aspects of the present disclosure:1. A compound represented by formula I:or a pharmaceu tic ally acceptable salt thereof, wherein:R1is hydrogen or optionally substituted Ci-Ce aliphatic;R2is C3-C12 cycloaliphatic, Ci-Ce aliphatic, 2- to 10-membered heteroaliphatic, 4- to 10-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S, 5- to 10-memberedPage 272 of 83712933262v 1Attorney Docket No.: 2013518-0095 heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, or Ce-Cio aryl, wherein R2is optionally substituted with one or more instances of -L-R5; each L is independently selected from the group consisting of a bond, -N(Ra)C(O)N(Ra)-, - N(Ra)C(O)O-, -OC(O)N(Ra)-, -C(O)N(Ra)-, -N(Ra)C(O)-, -N(Ra)-, -O-, -C(O)-, -C(O)O-, - OC(O)-, -N(Ra)C(S)O-, -OC(S)N(Ra)-, -C(S)N(Ra)-, -N(Ra)C(S)-, -C(S)-, -C(S)O-, and - OC(S)-; each R5is independently selected from the group consisting of optionally substituted Ci-Ce aliphatic, optionally substituted 2- to 10-membered 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;R3is 5- to 12-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, 4- to 12-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S, C6-C12 aryl, C3-C12 cycloaliphatic, or Ci-Ce aliphatic, wherein R3is optionally substituted with one or more instances of R3a; orR2and R3are connected by *-La-R6-Lb-**, where * represents a point of attachment to R2, and ** represents a point of attachment to R3;Lais a bond, -N(Ra)C(O)N(Ra)-, -N(Ra)C(O)O-, -OC(O)N(Ra)-, -C(O)N(Ra)-, -N(Ra)C(O)-, - N(Ra)-, -O-, -C(O)-, -C(O)O-, -OC(O)-, -N(Ra)C(S)O-, -OC(S)N(Ra)-, -C(S)N(Ra)-, - N(Ra)C(S)-, -C(S)-, -C(S)O-, or -OC(S)-;Lbis a bond, -N(Ra)C(O)N(Ra)-, -N(Ra)C(O)O-, -OC(O)N(Ra)-, -C(O)N(Ra)-, -N(Ra)C(O)-, - N(Ra)-, -O-, -C(O)-, -C(O)O-, -OC(O)-, -N(Ra)C(S)O-, -OC(S)N(Ra)-, -C(S)N(Ra)-, - N(Ra)C(S)-, -C(S)-, -C(S)O-, or -OC(S)-;R6is optionally substituted Ci-Ce aliphatic, optionally substituted 2- to 10-membered 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, or optionally substituted Ce-Cio aryl;R4is Ci-Ce aliphatic, 2- to 10-membered heteroaliphatic, C3-C12 cycloaliphatic, 4- to 10-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S, 5- to 10-memberedPage 273 of 83712933262v 1Attorney Docket No.: 2013518-0095 heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, or Ce-Cio aryl, wherein R4is optionally substituted with one or more instances of R4a; each R3ais independently selected from the group consisting of optionally substituted Ci-Ce aliphatic, optionally substituted 2- to 10-membered 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, optionally substituted Ce-Cio aryl, 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, and -ORa; each R4ais independently selected from the group consisting of optionally substituted Ci-Ce aliphatic, optionally substituted 2- to 10-membered heteroaliphatic, optionally substituted C3- Ci2cycloaliphatic, 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, optionally substituted Ce-Cio aryl, 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, and -ORa; and each Rais independently selected from hydrogen, optionally substituted C1-C6 aliphatic, optionally substituted 2- to 10-membered 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.2. The compound of embodiment 1, wherein R1is optionally substituted Ci-Ce aliphatic.3. The compound of embodiment 1 or 2, wherein R1is -CH3 or -CD3.4. The compound of any one of embodiments 1-3, wherein R2is Ci-Ce aliphatic, C3-Ci2cycloaliphatic, or 4- to 10-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S, wherein R2is optionally substituted with one or more instances of -L-R5.5. The compound of embodiment 4, wherein R2is C3-C12 cycloaliphatic, wherein R2is optionally substituted with -L-R5.6. The compound of embodiment 4, wherein R2is monocyclic C3-C6 cycloaliphatic, wherein R2is optionally substituted with -L-R5.7. The compound of embodiment 4, wherein R2is 4- to 10-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S, wherein R2is optionally substituted with -L-R5.Page 274 of 83712933262v 1Attorney Docket No.: 2013518-00958. The compound of any one of embodiments 1-3, wherein R2is:9. The compound of any one of embodiments 1-3, wherein R2is:10. The compound of any one of embodiments 1-9, wherein L is selected from -N(Ra)C(O)O- , -C(O)N(Ra)-, and -C(O)-.11. The compound of any one of embodiments 1-9, wherein L is selected from -N(H)C(O)O-, -C(O)NH-, -C(O)NCH2-, and -C(O)-.12. The compound of any one of embodiments 1-11, wherein R5is selected from optionally substituted Ci-Ce aliphatic, optionally substituted 2- to 10-membered heteroaliphatic, and optionally substituted 4- to 10-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S, and optionally substituted 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S.13. The compound of any one of embodiments 1-9, wherein L is selected from -N(Ra)C(O)O- and -C(O)N(Ra)-, and wherein R5is optionally substituted Ci-Ce aliphatic.14. The compound of any one of embodiments 1 -9, wherein -L-R5is selected from:Page 275 of 83712933262v 1Attorney Docket No.: 2013518-0095Page 276 of 83712933262v 1Attorney Docket No.: 2013518-0095Page 277 of 83712933262v 1Attorney Docket No.: 2013518-009516. The compound of any one of embodiments 1-15, wherein R3is 5- to 12-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, and R3is optionally substituted with one or more instances of R3a.17. The compound of any one of embodiments 1-15, wherein R3is bicyclic 7- to 12-membered hctcroaryl comprising 1 to 4 hctcroatoms selected from N, O, and S, and R3is optionally substituted with one or more instances of R3a.18. The compound of any one of embodiments 1-15, wherein R3is:Page 278 of 83712933262v 1Attorney Docket No.: 2013518-009519. The compound of any one of embodiments 1-15, wherein R3is C6-C12 aryl, and R3is optionally substituted with one or more instances of R3a.(R3a)o-220. The compound of any one of embodiments 1-15, wherein R ’ is:21. The compound of any one of embodiments 1-15, wherein22. The compound of any one of embodiments 1-21 , wherein each R3ais independently selected from optionally substituted Ci-Ce aliphatic, optionally substituted 2- to 10-membered heteroaliphatic, optionally substituted C3-C12 cycloaliphatic, and optionally substituted 4- to 10- membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S.23. The compound any one of embodiments 1-21, wherein R3ais -CH3, -CD3,Page 279 of 83712933262v 1Attorney Docket No.: 2013518-009525. The compound of any one of embodiments 1-15, wherein R2and R3are connected by *-La-R6-Lb-**, where * represents a point of attachment to R2, and ** represents a point of attachment to R3.26. The compound of embodiment 25, wherein Lais a bond, -N(Ra)C(O)O-, -OC(O)N(Ra)-, - C(O)N(Ra)-, -N(Ra)C(O)-, -N(Ra)-, -O-, -C(O)-, or -C(O)O-.27. The compound of embodiment 25 or 26, wherein Lais a bond, -N(H)C(O)O-, -OC(O)N(H)- , -C(O)N(H)-, or -N(H)C(O)-.28. The compound of any one of embodiments 25-27, wherein Lbis a bond, -N(Ra)-, -O-, - C(O)-, -C(O)O-, or -OC(O)-.29. The compound of any one of embodiments 25-28, wherein Lais -N(Ra)C(O)O- or - C(O)N(Ra)-, and Lbis a bond.30. The compound of any one of embodiments 25-29, wherein R6is optionally substituted Ci- Ce aliphatic, optionally substituted 2- to 10-membered heteroaliphatic, optionally substituted C3- C12 cycloaliphatic, or optionally substituted 4- to 10-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S.Page 280 of 83712933262v 1Attorney Docket No.: 2013518-009531 . The compound of any one of embodiments 25-29, wherein R6is optionally substituted Ci- Ce aliphatic or optionally substituted 2- to 10-mcmbcrcd hctcroaliphatic.32. The compound of any one of embodiments 25-29, wherein R6is optionally substituted Ci- Ce aliphatic.33. The compound of any one of embodiments 25-30, wherein moiety:34. The compound of any one of embodiments 25-33, wherein moiety:35. The compound of embodiment 34, wherein moiety:36. The compound of any one of embodiments 1-35, wherein R4is 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, or 4- to 10-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S, and wherein R4is optionally substituted with one or more instances of R4a.37. The compound of any one of embodiments 1-35, wherein R4is 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, and wherein R4is optionally substituted with one or more instances of R4a.Page 281 of 83712933262v 1Attorney Docket No.: 2013518-009538. The compound of any one of embodiments 1 -35, wherein R4is 7- to 10-membered bicyclic hctcroaryl comprising 1 to 4 hctcroatoms selected from N, O, and S, and wherein R4is optionally substituted with one or more instances of R4a.39. The compound of any one of embodiments 1-35, wherein R4is 5- to 6-membered monocyclic heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S, and wherein R4is optionally substituted with one or more instance of R4a.40. The compound of any one of embodiments 1-35, wherein R4is 5- to 6-membered monocyclic heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S, and wherein R4is substituted with one or more instances of R4a, wherein R4ais selected from optionally substituted Ci-Ce aliphatic and halogen.41. The compound of any one of embodiments 1-35, wherein R4is 4- to 10-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S, and wherein R4is optionally substituted with one or more instances of R4a.42. The compound of any one of embodiments 1-41, wherein each instance of R4ais selected from optionally substituted Ci-Ce aliphatic and halogen.43. The compound of any one of embodiments 1-35, wherein R4is selected from:44. The compound of any one of embodiments 1-35, wherein R4is selected from:Page 282 of 83712933262v 1Attorney Docket No.: 2013518-009545. The compound of embodiment 1, wherein R2is C3-C12 cycloaliphatic or 4- to 10-mcmbcrcd heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S; and wherein R2is substituted with one instance of -L-R5.46. The compound of any one of embodiments 1-45, wherein the compound is represented by formula II- 1 or II-2:or a pharmaceutically acceptable salt thereof.47. The compound of any one of embodiments 1-46, wherein the compound is represented by formula III:or a pharmaceu tic ally acceptable salt thereof.48. The compound of any one of embodiments 1-47, wherein the compound is represented by formula IV- 1 or IV-2:Page 283 of 83712933262v 1Attorney Docket No.: 2013518-0095or a pharmaceu tic ally acceptable salt thereof.49. The compound of any one of embodiments 1-48, wherein the compound is represented by formula V :or a pharmaceutically acceptable salt thereof.50. The compound of any one of embodiments 1-49, wherein the compound is represented by formula VI:or a pharmaceutically acceptable salt thereof.51. The compound of any one of embodiments 1-50, wherein the compound is represented by formula VII- 1 or VII-2:Page 284 of 83712933262v 1Attorney Docket No.: 2013518-009552. The compound of any one of embodiments 1-51, wherein the compound is represented by formula VIII:or a pharmaceu tic ally acceptable salt thereof.53. The compound of embodiment 1, wherein the compound is selected from Table 1C, or a pharmaceutically acceptable salt thereof.54. A pharmaceutical composition comprising a compound of any one of embodiments 1-53, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.55. A method of inhibiting JAK2 in a subject, comprising administering to the subject the compound of any one of embodiments 1-53 or the pharmaceutical composition of embodiment 54.56. 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 1-53 or the pharmaceutical composition of embodiment 54.57. A method of treating cancer, comprising administering to a subject in need thereof the compound of any one of embodiments 1-53 or the pharmaceutical composition of embodiment 54.Page 285 of 83712933262v 1Attorney Docket No.: 2013518-009558. A method of treating a hematological malignancy, comprising administering to a subject in need thereof the compound of any one of embodiments 1-53 or the pharmaceutical composition of embodiment 54.59. The method of embodiment 58, wherein the hematological malignancy is leukemia or lymphoma.60. A method of treating a myeloproliferative neoplasm, comprising administering to a subject in need thereof the compound of any one of embodiments 1-53 or the pharmaceutical composition of embodiment 54.61. The method of embodiment 60, wherein the myeloproliferative neoplasm is polycythemia vera, essential thrombocytopenia, or myelofibrosis.62. A compound of formula I:or a pharmaceutically acceptable salt thereof, wherein:R1is hydrogen or optionally substituted Ci-Ce aliphatic;R2is C3-C12 cycloaliphatic, C1-C6 aliphatic, 2- to 10-membered heteroaliphatic, 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 Ce-Cio aryl, wherein R2is optionally substituted with one or more instances of -L-R5or R7; each L is independently selected from the group consisting of a bond, -N(Ra)C(O)N(Ra)-, - N(Ra)C(O)O-, -OC(O)N(Ra)-, -C(O)N(Ra)-, -N(Ra)C(O)-, -N(Ra)-, -O-, -C(O)-, -C(O)O-, - OC(O)-, -N(Ra)C(S)O-, -OC(S)N(Ra)-, -C(S)N(Ra)-, -N(Ra)C(S)-, -C(S)-, -C(S)O-, and - OC(S)-; each R5is independently selected from the group consisting of optionally substituted Ci-Ce aliphatic, optionally substituted 2- to 10-membered 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 heteroarylPage 286 of 83712933262v 1Attorney Docket No.: 2013518-0095 comprising 1 to 4 heteroatoms selected from N, O, and S, and optionally substituted Ce-Cio aryl; each R7is independently selected from the group consisting of halogen, -OH, -SH, and -NH2;R3is 5- to 12-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, 4- to 12-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S, C6-C12 aryl, C3-C12 cycloaliphatic, or Ci-Ce aliphatic, wherein R3is optionally substituted with one or more instances of R3a; orR2and R3are connected by *-La-R6-Lb-**, wherein * represents a point of attachment to R2, and ** represents a point of attachment to R3;Lais a bond, -N(Ra)C(O)N(Ra)-, -N(Ra)C(O)O-, -OC(O)N(Ra)-, -C(O)N(Ra)-, -N(Ra)C(O)-, - N(Ra)-, -O-, -C(O)-, -C(O)O-, -OC(O)-, -N(Ra)C(S)O-, -OC(S)N(Ra)-, -C(S)N(Ra)-, - N(Ra)C(S)-, -C(S)-, -C(S)O-, or -OC(S)-;Lbis a bond, -N(Ra)C(O)N(Ra)-, -N(Ra)C(O)O-, -OC(O)N(Ra)-, -C(O)N(Ra)-, -N(Ra)C(O)-, - N(Ra)-, -O-, -C(O)-, -C(O)O-, -OC(O)-, -N(Ra)C(S)O-, -OC(S)N(Ra)-, -C(S)N(Ra)-, - N(Ra)C(S)-, -C(S)-, -C(S)O-, or -OC(S)-;R6is optionally substituted Ci-Ce aliphatic, optionally substituted 2- to 10-membered 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, or optionally substituted Ce-Cio aryl;R4is Ci-Ce aliphatic, 2- to 10-membered 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 Ce-Cio aryl, wherein R4is optionally substituted with one or more instances of R4a; each R3ais independently selected from the group consisting of optionally substituted Ci-Ce aliphatic, optionally substituted 2- to 10-membered 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, optionally substituted Ce-Cio aryl, 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, and -ORa;Page 287 of 83712933262v 1Attorney Docket No.: 2013518-0095 each R4ais independently selected from the group consisting of optionally substituted Ci-Ce aliphatic, optionally substituted 2- to 10-mcmbcrcd hctcroaliphatic, 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, optionally substituted Ce-Cio aryl, 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, and -ORa; and each Rais independently selected from hydrogen, optionally substituted Ci-Ce aliphatic, optionally substituted 2- to 10-membered 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.63. A compound of formula I:or a pharmaceutically acceptable salt thereof, wherein:R1is hydrogen or optionally substituted Ci-Ce aliphatic;R2is C3-C12 cycloaliphatic, Ci-Ce aliphatic, 2- to 10-membered heteroaliphatic, 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 Ce-Cio aryl, wherein R2is optionally substituted with one or more instances of -L-R5or R7; each L is independently selected from the group consisting of a bond, -N(Ra)C(O)N(Ra)-, - N(Ra)C(O)O-, -OC(O)N(Ra)-, -C(O)N(Ra)-, -N(Ra)C(O)-, -N(Ra)-, -O-, -C(O)-, -C(O)O-, - OC(O)-, -N(Ra)C(S)O-, -OC(S)N(Ra)-, -C(S)N(Ra)-, -N(Ra)C(S)-, -C(S)-, -C(S)O-, and - OC(S)-; each R5is independently selected from the group consisting of optionally substituted Ci-Ce aliphatic, optionally substituted 2- to 10-membered heteroaliphatic, optionally substituted C3- C12 cycloaliphatic, optionally substituted 4- to 10-membered heterocycle comprising 1 to 4Page 288 of 83712933262v 1Attorney Docket No.: 2013518-0095 heteroatoms selected from N, O, and S, optionally substituted 5- to 10-membered heteroaryl comprising 1 to 4 hctcroatoms selected from N, O, and S, and optionally substituted Ce-Cio aryl; each R7is independently selected from the group consisting of halogen, -OH, -SH, and -NH2;R3is 5- to 12-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, 4- to 12-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S, C6-C12 aryl, C3-C12 cycloaliphatic, or Ci-Ce aliphatic, wherein R3is optionally substituted with one or more instances of R3a;R4is Ci-Ce aliphatic, 2- to 10-membered 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 Ce-Cio aryl, wherein R4is optionally substituted with one or more instances of R4a; each R3ais independently selected from the group consisting of optionally substituted Ci-Ce aliphatic, optionally substituted 2- to 10-membered 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, optionally substituted C6-C10 aryl, 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, and -ORa; each R4ais independently selected from the group consisting of optionally substituted Ci-Ce aliphatic, optionally substituted 2- to 10-membered 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, optionally substituted Ce-Cio aryl, 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, and -ORa; and each Rais independently selected from hydrogen, optionally substituted Ci-Ce aliphatic, optionally substituted 2- to 10-membered 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.Page 289 of 83712933262v 1Attorney Docket No.: 2013518-009564. The compound of embodiment 62 or 63, wherein R1is optionally substituted Ci-Ce aliphatic.65. The compound of any one of embodiments 62-64, wherein R1is -CH3 or -CD3.66. The compound of any one of embodiments 62-65, wherein R2is C3-C12 cycloaliphatic or 4- to 10-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S; and wherein R2is substituted with one instance of -L-R5.67. The compound of any one of embodiments 62-66, wherein R2is C3-C7 monocyclic cycloaliphatic or 4- to 6-membered monocyclic heterocycle comprising 1 to 2 heteroatoms selected from N, O, and S; and wherein R2is substituted with 0-2 instances of -L-R5or R7.68. The compound of any one of embodiments 62-67, wherein R2is substituted with 1-2 instances of -L-R5or R7.69. The compound of embodiment 67 or 68, wherein R2is C3-C6 monocyclic cycloaliphatic, and wherein R2is substituted with 1-2 instances of -L-R5or R7.70. The compound of embodiment 67 or 68, wherein R2is 4- to 6-membered heterocycle comprising 1 to 2 heteroatoms selected from N, O, and S, and wherein R2is substituted with 1-2 instances of -L-R5or R7.71. The compound of any one of embodiments 62-65, wherein R2is:72. The compound of any one of embodiments 62-65, wherein R2is:Page 290 of 83712933262v 1Attorney Docket No.: 2013518-009573. The compound of any one of embodiments 62-72, wherein each L is independently selected from a bond, -N(Ra)C(O)O-, -OC(O)N(Ra)-, -C(O)N(Ra)-, -N(Ra)C(O)-, -O-, and -C(O)-.74. The compound of embodiment 73, wherein each L is independently selected from a bond, -N(Ra)C(O)O-, and -N(Ra)C(O)-.75. The compound of any one of embodiments 62-74, wherein each R5is independently selected from optionally substituted Ci-Ce aliphatic, optionally substituted C3-C6 cycloaliphatic, optionally substituted 4- to 6-membered heterocycle comprising 1 to 2 heteroatoms selected from N, O, and S, and optionally substituted 5- to 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S.76. The compound of any one of embodiments 62-72, wherein each -L-R5is independently77. The compound of any one of embodiments 62-76, wherein each R7is independently selected from the group consisting of -OH, -SH, and -NH2.78. The compound of any one of embodiments 62-65, wherein R2optionally substituted with one or more -L-R5or R7is selected from:Page 291 of 83712933262v 1Attorney Docket No.: 2013518-0095Page 292 of 83712933262v 1Attorney Docket No.: 2013518-009579. The compound of any one of embodiments 62-78, wherein R3is 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, 9- to 10-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S, or phenyl, wherein R3is optionally substituted with 0-3 instances of R3a.80. The compound of any one of embodiments 62-78, wherein R3is monocyclic 5- to 6- membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S, and wherein R3is optionally substituted with 0-3 instances of R3a.81. The compound of any one of embodiments 62-78, wherein R3is bicyclic 8- to 10- mcmbcrcd hctcroaryl comprising 1 to 4 hctcroatoms selected from N, O, and S, and wherein R3is optionally substituted with 0-3 instances of R3a.82. The compound of embodiment 81, wherein R3is:83. The compound of any one of embodiments 62-78, wherein R3is 9- to 10-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S, and wherein R3is optionally substituted with 0-3 instances of R3a.84. The compound of any one of embodiments 62-78, wherein R3is phenyl, and R3is optionally substituted with 0-3 instances of R3a.Page 293 of 83712933262v 1Attorney Docket No.: 2013518-009585. The compound of any one of embodiments 62-84, wherein each R3ais independently selected from optionally substituted Ci-Ce aliphatic, optionally substituted C3-C6 cycloaliphatic, halogen, -C(O)N(Ra)2, and -ORa.86. The compound of any one of embodiments 62-78, wherein R3optionally substituted withPage 294 of 83712933262v 1Attorney Docket No.: 2013518-009587. The compound of any one of embodiments 62 or 64-86, wherein R2and R3are connected by *-La-R6-Lb-**, wherein * represents a point of attachment to R2, and ** represents a point of attachment to R3.88. The compound of embodiment 87, wherein Lais a bond, -N(Ra)C(O)O-, -OC(O)N(Ra)-, - C(O)N(Ra)-, -N(Ra)C(O)-, -N(Ra)-, -O-, -C(O)-, or -C(O)O-.89. The compound of embodiment 87 or 88, wherein Lbis a bond, -N(Ra)-, -O-, -C(O)-, - C(O)O-, or -OC(O)-.90. The compound of any one of embodiments 87-89, wherein R6is optionally substituted Ci- Ce aliphatic, optionally substituted 2- to 10-membered heteroaliphatic, optionally substituted C3- C12 cycloaliphatic, or optionally substituted 4- to 10-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S.91. The compound of embodiment 90, wherein R6is optionally substituted Ci-Ce aliphatic.92. The compound of any one of embodiments 87-91, wherein a moiety:93. The compound of any one of embodiments 62-92, wherein R4is 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S or 4- to 10-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S, and wherein R4is optionally substituted with 0-3 instances of R4a.94. The compound of any one of embodiments 62-92, wherein R4is monocyclic 5- to 6- membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S, and is optionally substituted with 0-3 instances of R4a.95. The compound of any one of embodiments 62-92, wherein R4is 8- to 10-membered bicyclic heteroaryl having 1 to 4 heteroatoms selected from N, O, and S and is optionally substituted with 0-3 instances of R4a.Page 295 of 83712933262v 1Attorney Docket No.: 2013518-009596. The compound of any one of embodiments 62-92, wherein R4is 4- to 6-membered monocyclic heterocycle comprising 1 to 3 hctcroatoms selected from N, O, and S and is optionally substituted with 0-3 instances of R4a.97. The compound of any one of embodiments 62-96, wherein each R4ais independently selected from optionally substituted Ci-Ce aliphatic, -ORa, and halogen.98. The compound of any one of embodiments 62-92, wherein R4optionally substituted with99. The compound of any one of embodiments 62-98, wherein the compound is represented by formula 11-1, 11-2, or 11-3:Page 296 of 83712933262v 1Attorney Docket No.: 2013518-0095or a pharmaceutically acceptable salt thereof.100. The compound of any one of embodiments 62-98, wherein the compound is represented by formula III:or a pharmaceutically acceptable salt thereof.101. The compound of any one of embodiments 62-98, wherein the compound is represented by formula IV- 1, IV-2, or TV-3:Page 297 of 83712933262v 1Attorney Docket No.: 2013518-0095or a pharmaceutically acceptable salt thereof.102. The compound of any one of embodiments 62-98, wherein the compound is represented by formula V-l or V-2:or a pharmaceutically acceptable salt thereof.103. The compound of any one of embodiments 62-98, wherein the compound is represented by formula VI:or a pharmaceutically acceptable salt thereof.104. The compound of any one of embodiments 62-98, wherein the compound is represented by formula VII- 1, VII-2, VII-3, VIM, or VII-5:Page 298 of 83712933262v 1Attorney Docket No.: 2013518-0095VII-5 or a pharmaceutically acceptable salt thereof.105. The compound of any one of embodiments 62 or 64-98, wherein the compound is represented by formula VIII:Page 299 of 83712933262v 1Attorney Docket No.: 2013518-0095or a pharmaceutically acceptable salt thereof.106. A compound selected from Table 1A, Table IB, or Table 1C, or a pharmaceutically acceptable salt thereof.107. A pharmaceutical composition comprising a compound of any one of embodiments 62-106, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.108. A method of inhibiting JAK2 in a subject, comprising administering to the subject the compound of any one of embodiments 62-106 or the pharmaceutical composition of embodiment107.109. 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 62-106 or the pharmaceutical composition of embodiment 107.110. A method of treating cancer, comprising administering to a subject in need thereof the compound of any one of embodiments 62-106 or the pharmaceutical composition of embodiment 107.111. A method of treating a hematological malignancy, comprising administering to a subject in need thereof the compound of any one of embodiments 62-106 or the pharmaceutical composition of embodiment 107.112. The method of embodiment 111, wherein the hematological malignancy is leukemia or lymphoma.113. A method of treating a myeloproliferative neoplasm, comprising administering to a subject in need thereof the compound of any one of embodiments 62-106 or the pharmaceutical composition of embodiment 107.114. The method of embodiment 113, wherein the myeloproliferative neoplasm is polycythemia vera, essential thrombocytopenia, or myelofibrosis.Page 300 of 83712933262v 1Attorney Docket No.: 2013518-0095EXAMPLES

[0291] 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 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.

[0292] Certain abbreviations are utilized in the Examples below:EA=ethyl acetate;DMF=N,N-dimethylformamide;DCM=Dichloromethane ;THF=T etrahy drofuran ;LAH=Lithium aluminium hydride;DME=1,2-Dimethoxyethane;TEA=Triethylamine;EIPEA=Ethyldiisopropylamine; h=hour(s); min=minute(s); g=gram(s); mg=milligram(s); mol=mole(s); mmol=millimole(s) ; equiv=equivalents ;L=liters; mL=milliliters;M-molarity / molar;N=normal; pm=micrometer(s ) ;HATU=2-(7 -Aza- 1 H-benzotriazole- 1 -yl)- 1 , 1 ,3,3-tetramethyluronium hexafluorophosphate; EDCI=N-(3-dimethylaminopropyl)-N’-ethylcarbodiimide hydrochloride;HOBt= 1 -Hydroxybenzotriazole;Page 301 of 83712938777vlAttorney Docket No.: 2013518-0095HPLC=high performance liquid chromatography;SFC=supcrcritical fluid chromatography;DIBAL-H=Diisobutylaluminium hydride;Bn=Benzyl;DMSO=Dimethyl sulfoxide; rt=room temperature;DBU=l,8-Diazabicyclo[5.4.0]undec-7-ene;NCS=N-Chlorosuccinimide;LiHMDS=Lithium bis(trimethylsilyl)amide;DMAP=4-Dimethylaminopyridine; n-BuLi=n-Butyllithium;CAN or MeCN=acetonitrile;TCFH=Chloro-N,N,N',N'-tetramethylformamidinium Hexafluorophosphate;NMI= 1 -Methylimidazole;°C=degrees Celsius; bp=boiling point;DEA=diethanolamine .Preparation of Provided CompoundsExample 1-1: methyl (( \R, 37?)-3-(3-methyl-9-(l -methyl- 177-indazol-5-yl)-8-(l -methyl- 1 / 7- pyrazol-4-yl)-2-oxo-2,3-dihydro- 1 H- i m idazo[ 4,5 -6?]pyrrolo[ 1 ,2-&]pyridazin- 1 - yl)cyclopentyl)carbamatePage 302 of 83712938777vlAttorney Docket No.: 2013518-0095

[0293] Synthesis of compound 1.1. To a solution of methyl 3-bromo- lH-pyrrole-2- carboxylate (20.0 g, 98.03 mmol, 1.0 equiv) in DCM (200 mL) was added 4- dimethylaminopyridine (1.19 g, 9.80 mmol, 0.1 equiv), triethylamine (29.70 g, 294 mmol, 3.0 equiv) and di-terz-butyldicarbonate (32.05 g, 110 mmol, 3.0 equiv) at 0 °C. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture 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. The residue was purified by flash column chromatography on silica gel (10% ethyl acetate in hexane) to afford 1.1 (21.8 g, 73 %). MS(ES) : m z 304 [M+H]+.Page 303 of 83712938777vlAttorney Docket No.: 2013518-0095

[0294] Synthesis of compound 1.2. A mixture of 1.1 (21.8 g, 71.7 mmol, 1.0 equiv), (1 - mcthyl-177-indazol-5-yl)boronic acid (25.3 g, 143.8 mmol, 2.0 equiv), sodium carbonate (22.8 g, 215.8 mmol, 3.0 equiv) in 1,4-dioxane (440 mL) and water (60 mL) was degassed by bubbling through a stream of argon for 10 min. [l,l'-Bis(diphenylphosphino)ferrocene] dichloropalladium(II), complex with dichloromethane (5.87 g, 7.17 mmol, 0.1 equiv) was added, and degassed for 5 min. The reaction mixture was stirred at 100 ° C for 2 h. It was cooled to room temperature, filtered through a pad of Celite®, and rinsed with ethyl acetate. 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 (15% ethyl acetate in hexane) to afford 1.2 (14.8 g, 58%). MS(ES): m / z 356.1 [M+H]+.

[0295] Synthesis of compound 1.3. To a solution of 1.2 (14.8 g, 41.62 mmol, 1.0 equiv) in DCM (150 mL) was added trifluoroacetic acid (50 mL) at 0 °C for dropwise. The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was t ran s ferrod into a saturated sodium bicarbonate solution and extracted with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford 1.3 (10.4 g, 98%). It was used in the next step without purification. MS(ES): m / z 256.10 [M+H]+.

[0296] Synthesis of compound 1.4. To a solution of 1.3 (10.4 g, 40.78 mmol, 1.0 equiv) in THE (166 mL) and water (41.6 mL) was added N-bromo succinimide (7.25 g, 40.78 mmol, 1.0 equiv) at 0 °C in portions. The reaction mixture was stirred at 0 °C for 30 min. The reaction mixture was quenched with a saturated solution of sodium thiosulphate 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 (25% ethyl acetate in hexane) to afford 1.4 (10.8 g, 79%). MS(ES): m z 335.1 [M+H]+.

[0297] Synthesis of compound 1.5. To a solution of 1.4 (10.8 g, 32.4 mmol, 1.0 equiv) in DME was added sodium hydride (60% dispersion in mineral oil, 1.94 g, 48.6 mmol, 1.5 equiv) in portions at 0 °C. It was stirred for 30 min and added O-(2,4-dinitrophenyl) hydroxylamine (9.68 g, 48.6 mmol, 1.5 equiv). The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was transferred into ice-water and extracted with ethyl acetate. The combinedPage 304 of 83712938777vlAttorney Docket No.: 2013518-0095 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 (30% ethyl acetate in hexane) to afford 1.5 (10.5 g, 93%). MS(ES): m / z 350.3 [M+H]+.

[0298] Synthesis of compound 1.6. To a solution of 1.5 (10.5 g, 3.01 mmol, 1.0 equiv) in methanol (1000 mL) was added ethyl propiolate (36.9 g, 362.0 mmol, 12.0 equiv) at room temperature. The reaction mixture was stirred at 70 °C for 16 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (40% ethyl acetate in hexane) to afford 1.6 (8.9 g, 66%). MS(ES): m / z 448.2 [M+H]+.

[0299] Synthesis of compound 1.7. To a solution of 1.6 (8.9 g, 19.9 mmol, 1.0 equiv) in ethanol (150 mL) was added potassium tert-butoxide (4.47 g, 39.9 mmol, 2.0 equiv) at room temperature. The reaction mixture was stirred at 100 °C for 2 h. It was concentrated under reduced pressure. The residue was poured into ice-water. The solid precipitates were filtered, washed with water and dried under reduced pressure to afford 1.7 (5.2 g, 63%). MS(ES): m / z 416. 5 [M+H]+.

[0300] Synthesis of compound 1.8. To a solution of 1.7 (5.2 g, 12.5 mmol, 1.0 equiv) in POCh (104 mL, 20v) at 0 ° C was added DIPEA (49.55 g, 125 mmol, 10.0 equiv) dropwise and the mixture was allowed to stir at 100 °C for 16 h. The reaction mixture was poured into ice- water and quenched with a saturated solution of sodium bicarbonate. It was 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 (30% ethyl acetate in hexane) to afford 1.8 (2.8 g, 64%). MS(ES) : m / z 434.1 [M+H]+.

[0301] Synthesis of compound 1.9. A solution of 1.8 (2.8 g, 6.48 mmol, 1.0 equiv), tert-butyl ((17?,37?)-3-aminocyclopentyl)carbamate (1.5 g, 7.7 mmol, 1.2 equiv) and triethylamine (2.7 mL, 19.4 mmol, 3.0 equiv) in THF (74 mL) was stirred at 70 °C for 1 h. The reaction mixture 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®, 50% ethyl acetate in hexane) to afford 1.9 (2.6 g, 68%). MS(ES) : m / z 598.1 [M+H]+.

[0302] Synthesis of compound 1.10. To a solution of 1.9 (2.6 g, 4.6 mmol, 1.0 equiv) in 33 mL mixture of THF: MeOH: H2O (2:2:1) was added lithium hydroxide hydrate (3.66 g, 92 mmol, 20.0 equiv) at room temperature and stirred for 3 h. It was transferred into ice- water and adjustedPage 305 of 83712938777vlAttorney Docket No.: 2013518-0095 pH ~ 5 to 6 with 1 N HC1 and extracted with 10% methanol in DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was triturated with pentane to afford 1.10 (1.9 g, 77%). MS(ES): m / z 570.4 [M+H]+.

[0303] Synthesis of compound 1.11. To a solution of 1.10 (1.9 g, 3.3 mmol, 1.0 equiv) in toluene (30 mL) was added diphenyl phosphoryl azide (1.1 g, 4.0 mmol, 1.2 equiv) and triethylamine (7.4 mL, 53.5 mmol, 1.6 equiv) at room temperature. The reaction mixture was stirred at 120 °C for 3 h. The reaction mixture 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®, 1.8% methanol in DCM) to afford 1.11 (0.850 g, 45%). MS(ES): m / z 567.5 [M+H]+.

[0304] Synthesis of compound 1.12. To a solution of 1.11 (0.850 g, 1.50 mmol, 1.0 equiv) in DMF (10 mL) was added cesium carbonate (0.730 g, 2.0 mmol, 1.5 equiv) and methyl iodide (0.256 g, 1.8 mmol, 1.2 equiv) at 0 °C. The reaction mixture was stirred at room temperature for 15 min. 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 (1.4% methanol in DCM) to afford 1.12 (0.690 g, 79%). MS(ES): m / z 581.2 [M+H]+.

[0305] Synthesis of compound 1.13. A mixture of 1.12 (0.250 g, 0.424 mmol, 1.0 equiv), 1- methyl-4-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)- 177-pyrazolc (0.176 g, 0.848 mmol, 2.0 equiv) and sodium carbonate (0.135 g, 1.272 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. [1,1'- bis(diphenylphosphino)ferrocene] dichloropalladium(II) dichloromethane (0.035 g, 0.042 mmol, 0.1 equiv) was added and degassed for 5 min. The mixture was stirred at 100 °C 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 (0-2.3% methanol in DCM) to afford 1.13 (0.083 g, 33%). MS(ES): m / z 582.3 [M+H]+.Page 306 of 83712938777vlAttorney Docket No.: 2013518-0095

[0306] Synthesis of compound 1.14. To a solution of 1.13 (0.083 g, 0.14 mmol, 1 .0 equiv) in DCM (4.0 mL) was added trifluoroacctic acid (1.5 mL) at 0 °C dropwisc. The reaction mixture was stirred for 15 minutes at room temperature. Most solvent was removed under reduced pressure. The residue was triturated with n-pentane and the solids were dried under reduced pressure to afford 1.14 (0.061 g). It was used in next step without purification. MS(ES): 482.4 m / z [M+H]+.

[0307] Synthesis of 1-1. To a solution of 1.14 (0.061 g, 0.126 mmol, 1.0 equiv) in DCM (4.0 mL) was added aqueous solution (2 mL) of sodium carbonate (0.040 g, 0.38 mmol, 3.0 equiv) at 0 °C and stirred reaction mixture for 10 min. Methyl chloroformate (0.024 g, 0.25 mmol, 2.0 equiv) was added dropwise and the reaction mixture was stirred at room temperature for 10 min. The reaction mixture was quenched in water and product 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®, 0-2.6% methanol in DCM) to afford 1-1 (0.040 g, 59%). MS(ES): 540.3 m / z [M+H]+;NMR (DMSO-d6, 400 MHz): 8 8.39 (s, 1H), 8 8.39 (s, 1H), 8.15 (d, 1H), 8.08 (d, 1H), 7.78 (d, 2H), 7.42 (dd, 1H), 7.27 (d, 1H), 7.04 (s, 0.6H), 6.93 (s, 0.4H), 6.68 (m, 1H), 4.15 (s, 3H), 3.89-3.88 (m, 1H), 3.86-3.84 (m, 1H), 3.75 (s, 3H), 3.54 (s, 3H), 3.45 (s, 3H), 2.03 (m, 1H), 1.81 (m, 1H), 1.52 (m, 1H), 1.16-l. l l(m, 1H), 0.90-0.75 (m, 1H), 0.48-0.41 (m, 0.4H), - 0.13-0.17 (m, 0.6H).Example 1-2: methyl (( 17?,37?)-3-(8-(3-fluoro-l-methyl- lH-pyrazol-4-yl)-3-methyl-9-( 1-methyl- 17 / -indazol-5-yl)-2-oxo-2,3-dihydro-lH-imidazo[4,5-<7]pyrrolo[l,2-Z>]pyridazin-l- yl)cyclopentyl)carbamatePage 307 of 83712938777vlAttorney Docket No.: 2013518-0095

[0308] Synthesis of compound 2.1. A mixture of 1.12 (0.225 g, 0.38 mmol, 1.0 equiv) and 3- fluoro-l-methyl-4-(tributylstannyl)-177-pyrazole (0.606 g, 1.55 mmol, 4.0 equiv) in 1,4-dioxane (10 mL) was degassed under argon atmosphere for 10 min. Tetrakis (Pd PPfi3)4) (0.045 g, 0.038 mmol, 0.1 equiv) was added to the reaction mixture and purged for 10 min. The mixture was stirred at 140 °C for 3 h. The reaction mixture 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®, 0-3.2% methanol in DCM) to afford 2.1 (0.082 g, 35%). MS(ES): m / z 600.3 [M+H]+.

[0309] Synthesis of compound 2.2. To a solution of 2.1 (0.082 g, 0.136 mmol, 1.0 equiv) in DCM (5.0 mL) at 0 °C was dropwise added trifluoroacetic acid (1.5 mL) and stirred for 15 minutes at room temperature. Most solvent was removed under reduced pressure. The residue was triturated with pentane and the solids were dried under reduced pressure to afford 2.2 (0.059 g). It was used in next step without purification. MS(ES): 500.2 m z [M+H]+.

[0310] Synthesis of 1-2. Compound 1-2 was prepared from 2.2 following the procedure described in the synthesis of compound 1-1. The product was purified by flash column chromatography on silica gel (Combiflash®, 0-2.6% methanol in DCM). MS(ES): 558.3 m / z [M+H]+, ’H NMR (DMSO-d6, 400 MHz); 8 8.43 (s, 1H), 8.06 (d, 1H), 7.97 (m, 1H), 7.74 (m, 2H), 7.39-7.35 (m, 1H), 6.71 (s, 1H), 6.66 (s, 0.5H), 6.34 (s, 0.5H), 4.13 (s, 3H), 3.89-3.88 (m, 1H), 3.86-3.84 (m, 1H), 3.74 (s, 3H), 3.52 (s, 3H), 3.44 (s, 3H), 2.03-1.97 (m, 1H), 1.81 -1.79 (m, 1H), 1.53 (m, 1H), 1.24-(m, 1H), 0.85-0.73 (m, 1H), 0.32 (s, 0.5H), -0.19 (s, 0.5H).Example 1-3: methyl ((Ly,3 )-3-(8-(3-fluoro-1 -(methyl-d3)-l H-pyrazol-4-yl)-3-methyl-9-(1 - (methyl-d3)-l / / -indazol-5-yl)-2-oxo-2,3-dihydro-lH-imidazo[4,5-d]pyrrolo[l,2-Z>]pyridazin-l- yl)cyclobutyl)carbamatePage 308 of 83712938777vlAttorney Docket No.: 2013518-0095Page 309 of 83712938777vlAttorney Docket No.: 2013518-0095

[0311] Synthesis of compound 3.1. Compound 3.1 was prepared from 1.1 and (l-(methyl- 6?3)- 17 -indazol-5-yl)boronic acid following the procedure described in the synthesis of compound 1.2. The product was purified by flash column chromatography on silica gel (15% ethyl acetate in hexane). MS(ES): m / z 359.2 [M+H]+.

[0312] Synthesis of compound 3.2. Compound 3.2 was prepared from 3.1 following the procedure described in the synthesis of compound 1.3. The product was used in the next step without purification. MS(ES): m / z 259.1 [M+H]+.

[0313] Synthesis of compound 3.3. Compound 3.3 was prepared from 3.2 following the procedure described in the synthesis of compound 1.4. The product was purified by flash column chromatography on silica gel (10-30% ethyl acetate in hexane). MS(ES): m / z 338.2 [M+H]+.

[0314] Synthesis of compound 3.4. Compound 3.4 was prepared from 3.3 following the procedure described in the synthesis of compound 1.5. The product was purified by flash column chromatography on silica gel (30% ethyl acetate in hexane). MS(ES): m / z 353. 1 [M+H]+.

[0315] Synthesis of compound 3.5. Compound 3.5 was prepared from 3.4 following the procedure described in the synthesis of compound 1.6. The product was purified by flash column chromatography on silica gel (40% ethyl acetate in hexane). MS(ES): m / z 451.4 [M+H]+.

[0316] Synthesis of compound 3.6. Compound 3.6 was prepared from 3.5 following the procedure described in the synthesis of compound 1.7. The product was used in next step without further purification. MS(ES): m / z 419.4 [M+H]+.

[0317] Synthesis of compound 3.7. Compound 3.7 was prepared from 3.6 following the procedure described in the synthesis of compound 1.8. The product was purified by flash column chromatography on silica gel (30% ethyl acetate in hexane). MS(ES): m / z 437.5 [M+H]+.

[0318] Synthesis of compound 3.8. Compound 3.8 was prepared from 3.7 and tert-butyl ((ls,3s)-3-aminocyclobutyl)carbamate following the procedure described in the synthesis ofPage 310 of 83712938777vlAttorney Docket No.: 2013518-0095 compound 1.9. The product was purified by flash column chromatography on silica gel (Combiflash®, 0-40% ethyl acetate in hexane). MS(ES): m z 587.3 [M+H]+.

[0319] Synthesis of compound 3.9. Compound 3.9 was prepared from 3.8 following the procedure described in the synthesis of compound 1.10. The product was purified by trituration with pentane. MS(ES): m / z 559.1 [M+H]+.

[0320] Synthesis of compound 3.10. Compound 3.10 was prepared from 3.9 following the procedure described in the synthesis of compound 1.11. The product was purified by flash column chromatography on silica gel (Combiflash®, 0-3% methanol in DCM). MS(ES): m / z 556.2 [M+H]+.

[0321] Synthesis of compound 3.11. Compound 3.11 was prepared from 3.10 following the procedure described in the synthesis of compound 1.12. The product was purified by flash column chromatography on silica gel (0-3% methanol in DCM). MS(ES): m / z 570.2 [M+H]+.

[0322] Synthesis of compound 3.12. A mixture of 3.11 (0.250 g, 0.43 mmol, 1.0 equiv) and 3-fluoro- l-(methyl- ?3)-4-(tributylstannyl)- l / 7-pyrazolc (0.860 g, 21.94 mmol, 5.0 equiv) in 1,4- dioxane (10 mL) was degassed by bubbling through a stream of argon for 10 min. Tetrakis(Pd(PPh3)4) (0.051 g, 0.043 mmol, 0.1 equiv) was added and purged for 10 min. The reaction mixture was stirred at 140 °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®, 2.2% methanol in DCM). MS(ES): m / z 592.1 [M+H]+.

[0323] Synthesis of compound 3.13. Compound 3.13 was prepared from 3.12 following the procedure described in the synthesis of compound 1.14. The product was triturated with n-pcntanc and dried under reduced pressure. It was used in next step without further purification. MS(ES): 492.2 m / z [M+H]+.

[0324] Synthesis of 1-3. Compound 1-3 was prepared from 3.13 following the procedure described in the synthesis of compound 1-1. The product was purified by flash column chromatography on silica gel (Combiflash®, 3.2% methanol in DCM). MS(ES): 550.4 m / z [M+H]+; ‘ H NMR (DMSO-d6, 400 MHz) : 8 8.44 (s, 1H), 8.09 (s, 1H), 8.19 (s, 1H), 7.97 (s, 1H), 7.83 (d, J = 8.8 Hz, 1H), 7.75 (s, 1H), 7.28-7.26 (m, 1H), 6.80 (s, 1H), 3.56 (s, 3H), 3.43 (s, 3H),Page 311 of 83712938777vlAttorney Docket No.: 2013518-00953.05-3.01 (m, 1H), 2.66-2.58 (m, 1H), 2.16-2.14 (m, 1H), 1.76 (s, 1H), 1.35-1.33 (m, 1H), 1.28- 1.14 (m, 1H).Example I-4-a and I-4-b: methyl ((15,25)-2-(8-(3-fluoro-l-(methyl-d3)-lH-pyrazol-4-yl)-3- mcthyl-9-(l-(mcthyl-t / 3)-lH-indazol-5-yl)-2-oxo-2,3-dihydro-177-imidazo[4,5-<5?]pyrrolo[l,2- Z>]pyridazin-l-yl)cyclopropyl)carbamate and methyl ((17?,27?)-2-(8-(3-fluoro-l-(methyl-d3)-177- pyrazol-4-yl)-3-methyl-9-(l-(methyl-t / 3)-lH-indazol-5-yl)-2-oxo-2,3-dihydro-lH-imidazo[4,5- rf]pyrrolo[l,2-&]pyridazin-l-yl)cyclopropyl)carbamatePage 312 of 83712938777vlAttorney Docket No.: 2013518-0095

[0325] Synthesis of compound (±)-4.1. To a solution of Zrans-cyclopropane-l,2-dicarboxylic acid (20 g, 153.73 mmol, 1.0 equiv) in DCM (300 mL) at 0 °C was added oxalyl chloride (48.75 g, 384.61 mmol, 2.5 equiv) dropwise followed by catalytic amount of DMF. The reaction mixture was stirred at room temperature for 1 h. It was concentrated under reduced pressure to afford (±)- 4.1 (20 g). The residue was used in the next step without purification.

[0326] Synthesis of compound (±)-4.2. To a solution of (±)-4.1 (20 g, 119.77 mmol, 1.0 equiv) in acetone (100 mL) at -40 °C was added drop wise aqueous solution (200 mL) of sodium azide (27.24 g, 419.16 mmol, 3.5 equiv). The reaction mixture was stirred at room temperature for 45 min. It was transferred into water and extracted with diethyl ether. The organic layer was washed with water, brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to half of the volume under reduced pressure. The residue was diluted with toluene (100 mL), and again partially concentrated under reduced pressure to remove traces of diethyl ether. The product was used in the next step without purification.

[0327] Synthesis of compound (±)-4.3. The solution of (±)-4.2 in toluene (100 mL) was stirred at 80 °C for 2 h until the evolution of nitrogen gas ceased completely. (Caution: the reaction was highly exothermic.) Tert-butanol (80.0 mL) was added dropwise to the reaction mixture at 80 °C and stirred for 2 h. It was cooled to ambient temperature and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (35% ethyl acetate in hexane) to afford (±)-4.3 (15.00 g, 51%). MS(ES): m / z 273.3 [M+H]+Page 313 of 83712938777vlAttorney Docket No.: 2013518-0095

[0328] Synthesis of compound (±)-4.4. To a solution of (±)-4.3 (15.0 g, 55.14 mmol, 1.0 cquiv) in diethyl ether (200 mL) at 0 °C was added trifluoroacctic acid (84.38 mL, 1102.94 mmol, 20.0 equiv). The reaction mixture was stirred at room temperature for 16 h. Most solvent was removed under reduced pressure to afford (±)-4.4 (4.60 g). It was used in the next step without purification.

[0329] Synthesis of compound 4.5. To a solution of methyl 4-bromo-lH-pyrrole-2- carboxylate (25 g, 122.54 mmol, 1.0 equiv) in DMF (1.25 L) was added sodium hydride (60% dispersion in oil, 3.52 g, 147.05 mmol, 1.2 equiv) at 0 °C and allowed to stir for 30 min. To the mixture was added O-(2,4-dinitrophenyl) hydroxylamine (29.26 g, 147.05 mmol, 1.2 equiv) and stirred at room temperature 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 purified by flash column chromatography on silica gel (23% ethyl acetate in hexane) to afford 4.5 (20 g, 74%). MS(ES): m / z 220.6 [M+H]+.

[0330] Synthesis of compound 4.6. To a solution of 4.5 (20.0 g, 91.32 mmol, 1.0 equiv) in methanol (1 L) was added ethyl propionate (107.39 g, 1095.89 mmol, 12.0 equiv) at room temperature. The mixture was heated to reflux for 16 h. Most solvent was removed under reduced pressure. The residue was purified by flash column chromatography on silica gel (25% ethyl acetate in hexane) to afford 4.6 (13 g, 45%). MS(ES): m / z 318.3 [M+H]+.

[0331] Synthesis of compound 4.7. To a solution of 4.6 (13.0 g, 41.00 mmol, 1.0 equiv) in ethanol (160 mL) was added potassium tert-butoxide (9.18 g, 82.01 mmol, 2.0 equiv) at room temperature. The reaction mixture was stirred at 90 °C for 3 h. It was poured on to ice-water and stirred for 15 min. The precipitated solids were collected by filtration and dried under vacuum to afford 4.7 (9.2 g, 79 %). MS(ES): m / z 286.3 [M+H]+.

[0332] Synthesis of compound 4.8. To a solution of 4.7 (9.2 g, 32.28 mmol, 1.0 equiv) in phosphorus oxychloride (78.5 mL) at 0 °C was added N,N-diisopropylethylamine (7.1 mL). The mixture was stirred at 90 °C for 3 h. It was transferred into ice-water, basified with saturated sodium bicarbonate solution and extracted with dichloromethane. 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 (10% ethyl acetate in hexane) to afford 4.8 (6.0 g, 61%). MS(ES): m / z 303.5 [M+H]+, 305.2 [M+H]+.Page 314 of 83712938777vlAttorney Docket No.: 2013518-0095

[0333] Synthesis of compound (±)-4.9. To a solution of 4.8 (5.2 g, 17.16 mmol, 1 .0 equiv) in acetonitrile (60 mL) was added (±)-4.4 (4.4 g, 25.70 mmol, 1.5 equiv) followed by tricthylaminc (5.19 g, 51.48 mmol, 3.0 equiv). The reaction mixture was stirred at 70 °C for 2h. 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 (7% ethyl acetate in hexane) to afford (±)-4.9 (4.30 g, 57%). MS(ES): m / z 439.1 [M+H]+, 441.1 [M+H]+.

[0334] Synthesis of compound (±)-4.10. To a solution of (±)-4.9 (4.30 g, 9.79 mmol, 1.0 equiv) in ethanol (45 mL) and THF (22 mL) was added lithium hydroxide monohydrate (8.2 g, 195.8 mmol, 20 equiv) in H2O (20 mL). The reaction mixture was stirred at 60 °C for 2 h. It was concentrated under reduced pressure. The residue was acidified with IN HC1 and solids were precipitated. The solids were collected by filtration, rinsed with water and dried under reduce pressure to afford (±)-4.10 (3.7 g, 92%) MS(ES): m / z 411.1 [M+H]+, 413.1 [M+H]+.

[0335] Synthesis of compound (±)-4.11. To a solution of (±)-4.10 (3.70 g, 9.00 mmol, 1.0 equiv) in toluene was added triethylamine (1.45 g, 14.40 mmol, 1.6 equiv) followed by diphenylphosphoryl azide (2.97 g, 10.80 mmol, 1.2 equiv) at 0 °C. The reaction mixture was stirred at 120 °C for 2 h. The 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 (2.5% methanol in DCM) to afford (±)-4.11 (2.8 g, 76%) MS(ES): m / z 408.2 [M+H]+, 410.2 [M+H]+.

[0336] Synthesis of compound (±)-4.12. To a solution of (±)-4.11 (2.80 g, 6.86 mmol, 1.0 equiv) in DMF (40 mL) was slowly added cesium carbonate (3.3 g, 1.02 mmol, 1.5 equiv) at 0 °C followed by methyl iodide (1.16 g, 8.02 mmol, 1.2 equiv). The reaction mixture was stirred at room temperature for 1 h. It was poured into ice-water and solids were precipitated. The solids were collected by filtration, rinsed with water and dried under vacuum to afford (±)-4.12 (2.10 g, 73%). MS(ES): m / z 422.1 [M+H]+, 424.1 [M+H]+.

[0337] Synthesis of compound (±)-4.13. A mixture of (±)-4.12 (2.1 g, 4.97 mmol, 1.0 equiv) and 3-fluoro-l-(methyl-6?3)-4-(tributylstannyl)-lH-pyrazole (9.75 g, 24.86 mmol, 5.0 equiv) in 1,4-dioxane (35 mL) was degassed by bubbling through a stream of argon for 10 min. Tetrakis(triphenylphosphine) palladium (0) (0.574 g, 0.497 mmol, 0.1 equiv) was added to thePage 315 of 83712938777vlAttorney Docket No.: 2013518-0095 reaction mixture and again purged for 10 min. The mixture was stirred at 140 °C for 1 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 (1.8% methanol in DCM) to afford (±)-4.13 (0.48 g, 22%). MS(ES): m z 445.2 [M+H]+.

[0338] Synthesis of compound (±)-4.14. To a solution of (±)-4.13 (0.48 g, 1.08 mmol, 1.0 equiv) in chloroform (20 mL) was added pyridine (0.512 g, 6.486 mmol, 6.0 equiv) at -10 °C. A solution of bromine (0.171 g, 2.162 mmol, 2.0 equiv) in chloroform was added dropwise. The reaction mixture was stirred at -10 °C for 5 min. It was transferred into a saturated sodium bicarbonate solution and extracted with dichloromethane. 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®, 2.0% methanol in DCM) to afford (±)-4.14 (0.370 g, 60%). MS(ES): m / z 601.3 [M+H]+, m / z 603.3 [M+H]+.

[0339] Synthesis of compound (±)-4.15. To a solution of (±)-4.14 (0.370 g, 0.614 mmol, 1.0 equiv) in THF (8 mL) at -10 °C was added a solution of isopropylmagnesium chloride (2 M in THF, 1.84 g, 3.68 mmol, 6.0 equiv). The mixture was stirred at -10 °C for 15 min. It was transferred into saturated ammonium chloride solution and product 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 (±)-4.15 (0.310 g, 96%). MS(ES): m / z 523.2 [M+H]+, 525.2 [M+H]+.

[0340] Synthesis of compound (±)-4.16. A mixture of (±)-4.15 (0.310 g, 0.592 mmol, 1.0 equiv), l-(methyl-t / 3)-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-177-indazole (0.159 g, 0.888 mmol, 1.5 equiv) and cesium carbonate (0.578 g, 1.778 mmol, 3.0 equiv) in 1,2- dimethoxyethane (6 mL) and water (1.5 mL) was degassed by bubbling through a stream of argon for 10 min. Bis|di- / c / 7-butyl (4-dimethylaminophenyl) phosphine] dichloropalladium(II) (0.042 g, 0.059 mmol, 0.1 equiv) was added and degassed for 5 min. The reaction mixture was stirred at 110 °C for 1 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 gelPage 316 of 83712938777vlAttorney Docket No.: 2013518-0095(Combi fl ash®, 2.8% methanol in DCM) to afford (±)-4.16 (0.115 g, 34%). MS(ES): m / z 578.4 [M+H]+.

[0341] Synthesis of compound (±)-4.17. To a solution of (±)-4.16 (0.115 g, 0.199 mmol, 1.0 equiv) in DCM (5.0 mL) at 0 °C was added trifluoroacetic acid (1 mL) and stirred for 15 min at room temperature. Most solvent was removed under reduced pressure to afford (±)-4.17 (0.110 g). MS(ES): 478.3 m / z [M+H]+. The product was used in the next step without purification.

[0342] Synthesis of compound (±)-I-4. To a solution of (±)-4.17 (0.110 g, 0.175 mmol, 1.0 equiv) in DCM (3.0 mL) was added aqueous solution of sodium carbonate (2 mL) and stirred reaction mixture at 0 °C for 10 min. Methyl chloroformate (0.054 g, 0.575 mmol, 2.5 equiv) was added dropwise and the reaction mixture stirred at same temperature for 10 min. 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®, 3.2% methanol in DCM) to afford (±)-I-4 (0.062 g, 50%). MS(ES) : 536.4 m / z [M+H]+.

[0343] Synthesis of I-4-a and I-4-b. The racemate was separated by SFC (column: CHIRALPAK AD-H (250 * 30 mm), 5 pm; mobile phase: (A) Liquid CO2. (B) 0.1% NH3 in propane-2-ol: ACN (50:50); flow rate: 80 mL / min) to afford first eluting fraction (I-4-a) and second eluting fraction (I-4-b). *The absolute configuration of the chiral center is not determined. I-4-a: MS(ES) : m / z : 536.35400 MHz) : 8 8.43 (s, 1H), 8.03-8.01 (d, J = 9.6 Hz 1H), 7.94 (s, 1H), 7.71-7.69 (d, J = 6.8 Hz, 1H), 7.62-7.57 (d, J = 8 Hz, 1H), 7.37 (s, 1H), 7.16 (bs, 1H), 6.98 (s, 1H), 3.37 (s, 3H), 3.34 (s, 3H), 2.83 (bs, 0.5H), 2.67 (bs, 0.5H), 2.23 (bs, 0.5H), 2.14 (bs, 0.5H), 0.79 (bs, 0.5H), 0.71 (bs, 0.5H), -0.48 (bs, 0.5H), -0.58 (bs, 0.5H). I-4-b: MS(ES): m / z : 536.32 [M+H]+, ’ H NMR (DMSO-d6, 400 MHz): 8 8.43 (s, 1H), 8.01 (d, J = 9.6 Hz 1H), 7.94 (s, 1H), 7.71-7.69 (d, J= 6.8 Hz, 1H), 7.62-7.57 (d, J= 8 Hz, 1H), 7.37 (s, 1H), 7.16 (bs, 1H), 6.98 (s, 1H), 3.39 (s, 3H), 3.36 (s, 3H), 2.84 (bs, 0.5H), 2.66 (bs, 0.5H), 2.22 (bs, 0.5H), 2.14 (bs, 0.5H), 0.79 (bs, 0.5H), 0.70 (bs, 0.5H), -0.48 (bs, 0.5H), -0.59 (bs, 0.5H).Example 1-5: ( lR,35)-A,A-dimethyl-3-(3-methyl-9-( 1 -methyl- lH-indazol-5-yl)-8-( 1 -methyl- 1H- pyrazol-4-yl)-2-oxo-2,3-dihydro-lW-imidazo[4,5-t / ]pyrrolo[l,2-&]pyridazin-l-yl)cyclopentane- 1 -carboxamidePage 317 of 83712938777vlAttorney Docket No.: 2013518-0095

[0344] Synthesis of compound 5.1. To a solution of (1 / ?,3S)-3-((tert butoxycarbonyl)amino)cyclopentane-l-carboxylic acid (2.00 g, 8.73 mmol, 1.0 equiv) in DMF (20 mL) was added HATU (4.97 g, 13.1 mmol, 1.5 equiv) at 0 °C and stirred for 30 min. Diisopropylethylamine (3.38 g, 26.2 mmol, 3.0 equiv) and dimethylamine hydrochloride (1.06 g, 13.1 mmol, 1.5 equiv) were added. The reaction mixture was stirred at room temperature for 2 h and 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. The residue was purified by flash column chromatography on silica gel (50% ethyl acetate in hexane) to afford 5.1 (1.60 g, 72%). MS(ES): m / z 257.35 [M+H]+.

[0345] Synthesis of compound 5.2. To a solution of 5.1 (1.6 g, 6.250 mmol, 1.0 equiv) in DCM (18 mL) was added trifluoroacetic acid (3.4 mL) at 0 °C drop wise. The reaction mixture was stirred at room temperature for 1 h. It was concentrated under reduced pressure. The residue was triturated with n-pentane and dried under reduced pressure to afford 5.2 (0.98 g, 62%). It was used in the next step without purification. MS(ES): m / z 157.25 [M+H]+.

[0346] Synthesis of compound 5.3. Compound 5.3 was prepared from compound 5.2 and 1.8 following the procedure described in the synthesis of compound 1.9. The product was purified byPage 318 of 83712938777vlAttorney Docket No.: 2013518-0095 flash column chromatography on silica gel (Combiflash®, 50% ethyl acetate in hexane). MS(ES): m / z 553.5 and 555.4 [M+H]+.

[0347] Synthesis of compound 5.4. Compound 5.4 was prepared from compound 5.3 following the procedure described in the synthesis of compound 1.10. The product was triturated with pentane, dried under reduced pressure and used in the next step without purification. MS(ES): m / z. tl / 5TlA\ [M+H]+.

[0348] Synthesis of compound 5.5. Compound 5.5 was prepared from compound 5.4 following the procedure described in the synthesis of compound 1.11. The product was purified by flash column chromatography on silica gel (Combiflash®, 2.0% methanol in DCM). MS(ES): m / z 5T1A\ and 524.5 [M+H]+.

[0349] Synthesis of compound 5.6. Compound 5.6 was prepared from compound 5.5 following the procedure described in the synthesis of compound 1.12. The product was purified by flash column chromatography on silica gel (2.0% methanol in DCM). MS(ES): m / z 536.43 and 538.7 [M+H]+.

[0350] Synthesis of compound 1-5. Compound 1-5 was prepared from compound 5.6 and 1- methyl-4-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)- 177-pyrazole following the procedure described in the synthesis of compound 1.13. The product was purified by flash column chromatography on silica gel (50% ethyl acetate in hexane). MS(ES): m / z 538.63 [M+H]+. ’H NMR (DMSO-d6, 400 MHz): 5 8.40 (s, 1H), 8.16 (s, 1H), 8.12 (d, J = 5.2 Hz, 1H), 7.83 (s, 1H), 7.80 (s, 1H), 7.41 (s, 1H), 7.24 (d, 1H), 6.97 (s, 1H), 4.16 (s, 3H), 3.65 (s, 3H), 3.65-3.50 (m, 1H), 2.71 (s, 6H), 2.29-2.24 (m, 1H), 2.11-2.00 (m, 1H), 1.52 (s, 1H), 1.33 (m, 1H), 1.23 (s, 3H), 1.23- 1.14(m, 2H), 0.91 (m, 1H).Example 1-6: methyl (( I / ?,3.S')-3-(3-mcthyl-9-( I -methyl- 17 / -indazol-5-yl)-8-( I -methyl- 1 H- pyrazol-4-yl)-2-oxo-2,3-dihydro- 177-imidazo[4,5 -<7| py rrolo| 1 ,2-&]pyridazin- 1 - yl)cyclopentyl)carbamatePage 319 of 83712938777vlAttorney Docket No.: 2013518-0095

[0351] Synthesis of compound 6.1. Compound 6.1 was prepared from compound 1.8 and tert- butyl ((ll?,35)-3-aminocyclopentyl)carbamate following the procedure described in the synthesis of compound 1.9. The product was purified by flash column chromatography on silica gel (Combiflash®, 52% ethyl acetate in hexane). MS(ES): m / z 598.2 [M+H]+.

[0352] Synthesis of compound 6.2. Compound 6.2 was prepared from compound 6.1 following the procedure described in the synthesis of compound 1.10. The product was triturated with pentane, dried under reduced pressure and used in the next step without purification. MS(ES): m / z 570.1 [M+H]+.

[0353] Synthesis of compound 6.3. Compound 6.3 was prepared from compound 6.2 following the procedure described in the synthesis of compound 1.11. The product was purified by flash column chromatography on silica gel (Combiflash®, 1.6% methanol in DCM). MS(ES): m / z 567.4 [M+H]+.

[0354] Synthesis of compound 6.4. Compound 6.4 was prepared from compound 6.3 following the procedure described in the synthesis of compound 1.12. The product was purified by flash column chromatography on silica gel (1.3% methanol in DCM). MS(ES): m / z 581.3 [M+H]+.

[0355] Synthesis of compound 6.5. Compound 6.5 was prepared from compound 6.4 and 1- methyl-4-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)- 1 H-pyrazole following the procedure described in the synthesis of compound 1.13. The product was purified by flash column chromatography on silica gel (Combiflash®, 0-3.1% methanol in DCM). MS(ES): m / z 582.2 [M+H]+.Page 320 of 83712938777vlAttorney Docket No.: 2013518-0095

[0356] Synthesis of compound 6.6. Compound 6.6 was prepared from compound 6.5 following the procedure described in the synthesis of compound 1.14. The product was triturated with pentane and dried under reduced pressure. It was used in the next step without purification. MS(ES): m / z 482.4 [M+H]+.

[0357] Synthesis of compound 1-6. Compound 1-6 was prepared from compound 6.6 following the procedure described in the synthesis of compound 1-1. The product was purified by flash column chromatography on silica gel (Combiflash®, 0-2.6% methanol in DCM). MS(ES): m / z 540.4 [M+H]+. 'H NMR (DMSO-d6, 400 MHz): 8 8.41 (d, J= 3.6 Hz, 1H), 8.17-8.08 (m, 2H), 7.79-7.77 (m, 2H), 7.41-7.39 (m, 1H), 7.26 (s, 1H), 7.16-7.04 (m, 2H), 4.14 (s, 3H), 3.67 (s, 3H), 3.46 (s, 3H), 3.41 (s, 3H), 2.87-2.56 (m, 1H), 1.99-1.86 (m, 2H), 1.49-1.44 (m, 1H), 1.34-1.30 (m, 1H), 1.05-1.02 (m, 1H), 0.89-0.87 (m, 1H), 0.44-0.39 (m, 1H).Example 1-7: cyanomethyl ((U?,3R)-3-(3-methyl-9-(l-methyl-177-indazol-5-yl)-8-(l-methyl-177- pyrazol-4-yl)-2-oxo-2,3-dihydro- 177- i m idazo| 4,5 -<7| py rrolo| 1 ,2-&]pyridazin- 1 - yl)cyclopentyl)carbamate

[0358] Synthesis of 1-7. To a solution of 1.14 (0.075 g, 1.31 mmol, 1.0 equiv) and triethylamine (0.91 mL, 6.57 mmol, 5.0 equiv) in DCM (3 mL) at 0 °C was added a solution of triphosgene (0.136 g, 0.46 mmol, 0.35 equiv) in DCM. The reaction mixture was stirred at 0 °C for 20 min. It was 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 silica gel flash column chromatography on silica gel (5.8% methanol in DCM) to afford 1-7 (0.018 g, 18.6%). MS(ES): m / z 565.45 [M+H]+. ^-NMR (400 MHz, DMSO-d6): 8 8.32 (d, J = 2.0 Hz, 1H), 8.08 (d, 7= 2.4 Hz, 1H), 8.04 (s, 1H), 7.75-7.72 (m, 2H), 7.41-7.39 (m, 1H), 7.23 (s, 1H), 7.01 (s, 1H), 6.89 (m, 0.5H), 6.59 (m, 0.5H), 4.80 (s, 2H), 4.13 (s, 3H), 3.97-3.75 (m, 1H), 3.61 (s, 3H), 3.36 (s, 3H), 2.07-2.05 (m, 1H), 1.83- 1 .64 (m, 2H), 0.83-1 .64 (m, 2H), 0.46-0.08 (m, 1H).Page 321 of 83712938777vlAttorney Docket No.: 2013518-0095Example 1-8: methyl ((l.y,3s)-3-(3-methyl-9-(l -(methyl-^)-! H-indazol-5-yl)-8-(1 -(methyl-dg)- l / / -pyrazol-4-yl)-2-oxo-2,3-dihydro-lH-imidazo[4,5-rf]pyiTolo[l,2-&]pyridazin-l- yl)cyclobutyl)carbamate

[0359] Synthesis of compound 8.1. Compound 8.1 was prepared from compound 3.11 and 1- (methyl-t / 3)-4-(4,4,5,5-tetramelhyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole following the procedure described in the synthesis of compound 1.13. The product was purified by flash column chromatography on silica gel (Combiflash®, 2.2% methanol in DCM). MS(ES): m / z 574 [M+H]+.

[0360] Synthesis of compound 8.2. Compound 8.2 was prepared from compound 8.1 following the procedure described in the synthesis of compound 1.14. The product was triturated with H-pcntanc and dried under reduced pressure. It was used in the next step without purification. MS(ES): m / z 474 [M+H]+.

[0361] Synthesis of 1-8. Compound 1-8 was prepared from compound 8.2 following the procedure described in the synthesis of compound 1-1. The product was purified by flash column chromatography on silica gel (Combiflash®, 3.2% methanol in DCM). MS(ES): zn / z 532.1 [M+H]+, ‘ H NMR (DMSO-d6, 400 MHz): 6 8.39 (s, 1H), 8.15 (s, 1H), 8.09 (s, 1H), 7.83 (d, J = 8.8 Hz, 1H), 7.76 (s, 1H), 7.42-7.40 (m, 1H), 7.28 (m, 2H), 7.09 (s, 1H), 3.43 (s, 3H), 3.16-3.11 (m, 2H), 2.66-2.59 (m, 2H), 2.47 (s, 3H), 1.76-1.74 (m, 1H), 1.36-1.33 (m, 1H).Example 1-9: 3-(( 15,35)-3-(3-methyl-9-( 1 -methyl- lH-indazol-5-yl)-8-( l-methyl-lH-pyrazol-4- yl)-2-oxo-2,3-dihydro-1 H-imidazo[4,5-<7]pyrrolo[1 ,2-Z>]pyridazin-l-yl)cyclopentyl)oxazolidin-2- onePage 322 of 83712938777vlAttorney Docket No.: 2013518-0095

[0362] Synthesis of compound 9.1. Compound 9.1 was prepared from compound 1.8 and tert- butyl ((15,35)-3-aminocyclopentyl)carbamate following the procedure described in the synthesis of compound 1.9. The product was purified by flash column chromatography on silica gel (Combiflash®, 50% ethyl acetate in hexane). MS(ES): m / z 597.1 and 599.1 [M+H]+.

[0363] Synthesis of compound 9.2. Compound 9.2 was prepared from compound 9.1 following the procedure described in the synthesis of compound 1.10. The product was triturated with pentane, dried under reduced pressure and used in the next step without purification. MS(ES): m / z 569.4 and 571.4 [M+H]+.

[0364] Synthesis of compound 9.3. Compound 9.3 was prepared from compound 9.2 following the procedure described in the synthesis of compound 1.11. The product was purified by flash column chromatography on silica gel (Combiflash®, 1.8% methanol in DCM). MS(ES): m / z 566.5 and 568.5 [M+H]+.

[0365] Synthesis of compound 9.4. Compound 9.4 was prepared from compound 9.3 following the procedure described in the synthesis of compound 1.12. The product was purified by flash column chromatography on silica gel (1.4% methanol in DCM). MS(ES): m / z 580.2 and 582.2 [M+H]+.Page 323 of 83712938777vlAttorney Docket No.: 2013518-0095

[0366] Synthesis of compound 9.5. Compound 9.5 was prepared from compound 9.4 and 1 - mcthyl-4-(4,4,5,5-tctramcthyl-l,3,2-dioxaborolan-2-yl)-17 -pyrazolc following the procedure described in the synthesis of compound 1.13. The product was purified by flash column chromatography on silica gel (2.7% methanol in DCM). MS(ES): m z 582.2 [M+H]+.

[0367] Synthesis of compound 9.6. Compound 9.6 was prepared from compound 9.5 following the procedure described in the synthesis of compound 1.14. The product was used without purification. MS(ES): m / z 482.30 [M+H]+.

[0368] Synthesis of compound 9.7. To a solution of 9.6 (0.16 g, 0.332 mmol, 1.0 equiv) and triethylamine (0.14 mL, 0.997 mmol, 3.0 equiv) in THF (4 mL) at 0 °C was added 2-chloroethyl carbonochloridate (0.095 g, 0.664 mmol, 2.0 equiv) dropwise and stirred at the same temperature for 10 min. It was transferred in 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). MS(ES): m / z 589.3 [M+H]+.

[0369] Synthesis of 1-9. A solution of 9.7 (0.11 g, 0.18 mmol, 1.0 equiv) and potassium carbonate (0.077 g, 0.56 mmol, 3 equiv) in dimethyl sulfoxide (3 mL) was stirred at 75 °C 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®, 4.1% methanol in DCM) to afford 1-9 (0.034 g, 33%). MS(ES): m / z 552.4 [M+H]+. ^-NMR (400 MHz, DMSO-d6): 8 8.34 (d, J = 2.4 Hz, 1H), 8.09 (d, J = 2.8 Hz, 2H), 7.80-7.78 (m, 2H), 7.43 (bs, 1H), 7.24 (s, 1H), 7.02 (s, 1H), 4.19-4.15 (m, 6H), 3.67 (s, 3H), 3.32 (s, 3H), 2.54-2.50 (m, 2H), 2.08-1.89 (m, 3H), 1.61 (bs, 1H), 1.47-1.32 (m, 2H), 0.72-0.15 (m, 1H).Example 1-10: 3-(( 17?,35)-3-(3-methyl-9-( 1 -methyl- l / / -indazol-5-yl)-8-( 1-methyL l / / -pyrazol-4- yl)-2-oxo-2,3-dihydro-lH-imidazo[4,5-ri]pyrrolo[l,2-Z?]pyridazin-l-yl)cyclopentyl)oxazolidin-2- onePage 324 of 83712938777vlAttorney Docket No.: 2013518-0095

[0370] Synthesis of compound 10.1. Compound 10.1 was prepared from compound 1.8 and teri-butyl (( 17?,3S)-3-aminocyclopentyl)carbamate following the procedure described in the synthesis of compound 1.9. The product was purified by flash column chromatography on silica gel (Combiflash®, 50% ethyl acetate in hexane). MS(ES): m / z 598.1 and 600.1 [M+H]+.

[0371] Synthesis of compound 10.2. Compound 10.2 was prepared from compound 10.1 following the procedure described in the synthesis of compound 1.10. The product was triturated with pentane, dried under reduced pressure and used in the next step without purification. MS(ES): m / z 570.4 572.4 [M+H]+.

[0372] Synthesis of compound 10.3. Compound 10.3 was prepared from compound 10.2 following the procedure described in the synthesis of compound 1.11. The product was purified by flash column chromatography on silica gel (Combiflash®, 1.8% methanol in DCM). MS(ES): m / z 567.5 and 569.5 [M+H]+.

[0373] Synthesis of compound 10.4. Compound 10.4 was prepared from compound 10.3 following the procedure described in the synthesis of compound 1.12. The product was purified by flash column chromatography on silica gel (1.4% methanol in DCM). MS(ES): m / z 582.2 and 584.2 [M+H]+.

[0374] Synthesis of compound 10.5. Compound 10.5 was prepared from compound 10.4 and l-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole following the procedure described in the synthesis of compound 1.13. The product was purified by flash column chromatography on silica gel (70% ethyl acetate in hexane). MS(ES): m / z 582 [M+H]+.Page 325 of 83712938777vlAttorney Docket No.: 2013518-0095

[0375] Synthesis of compound 10.6. Compound 10.6 was prepared from compound 10.5 following the procedure described in the synthesis of compound 1.14. The product was used without purification. MS(ES): m / z 482.30 [M+H]+.

[0376] Synthesis of compound 10.7. Compound 10.7 was prepared from compound 10.6 following the procedure described in the synthesis of compound 9.7. The product was purified by flash column chromatography on silica gel (Combiflash®, 3.2% methanol in DCM). MS(ES): m / z 588.3 [M+H]+.

[0377] Synthesis of 1-10. Compound 1-10 was prepared from compound 10.7 following the procedure described in the synthesis of compound 1-9. The product was purified by flash column chromatography on silica gel (Combiflash®, 4.1% methanol in DCM). MS(ES): m / z 552.4 [M+H]+,1H NMR (DMSO-d6, 400 MHz): 6 8.33 (d, J = 2.8 Hz, 1H), 8.09 (s, 1H), 8.06 (s, 1H), 7.78-7.74 (m, 2H), 7.42-7.40 (m, 1H), 7.24 (s, 1H), 7.05 (s, 1H), 4.17- 4.14 (m, 6H), 3.67 (s, 3H), 3.36-3.35 (m, 6H), 2.01 (m, 1H), 1.57 (m, 1H), 1.43 (m, 3H), 1.38 (m, 1H).Example 1-11: tetrahydro-2H-pyran-4-yl ((17?,35)-3-(3-methyl-9-(l-methyl-lH-indazol-5-yl)-8- ( 1 -methyl- 1 H-py razol-4-yl)-2-oxo-2,3-dihydro- 1 H- i m i dazo [4,5-ri]pyrrolo [ 1 ,2-b]pyridazin- 1 - yl)cyclopentyl)carbamate

[0378] Synthesis of compound 1-11. To a solution of tetrahydro-2H-pyran-4-ol (0.100 g, 0.980 mmol, 1.0 equiv) in DCM (5 mL) was added l,T-carbonyldiimidazol (0.238 g, 1.47 mmol, 1.5 equiv) and triethylamine (0.148 g, 1.47 mmol, 1.0 equiv) at 0 °C. The reaction mixture was stirred at room temperature for 2 h. It was quenched with 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 added to a solution of 10.6 (0.100 g, 0.207 mmol, 1.0 equiv), DIPEA (0.200 g, 0.621 mmol, 3.0 equiv) and DMAP (2.5 g, 0.020 mmol, 0.1 equiv) in DMF. The reaction mixture was stirred at 65 °C for 16 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 materialPage 326 of 83712938777vlAttorney Docket No.: 2013518-0095 purified by flash column chromatography on silica gel (0-3.2% DCM in Methanol) to afford 1-11 (21 mg, 17%). MS(ES): m / z 610 [M+H]+, ’H NMR (DMSO-d6, 400 MHz): 8 8.41-8.40 (d, J= 8.8 Hz, 1H), 8.16 (s, 1H), 8.075 (s, 1H), 17.78 (m, 2H), 7.40-7.38 (d, J = 8.8 Hz, 1H), 7.24 (s, 1H), 7.12-7.10 (m, 1H), 7.05-7.02 (m, 1H) 4.63 (bs, 1H), 4.14-4.12 (m, 4H), 3.76-3.70 (m, 3H), 3.65 (s, 3H), 3.32 (s, 3H), 1.93-1.90 (m, 1H), 1.88-1.81 (m, 3H), 1.53-1.45 (m, 4H), 1.33-1.23 (m, 3H), 1.28-1.14 (m, 1H).Example 1-12: methyl methyl((17?,3S)-3-(3-methyl-9-(l-methyl-177-indazol-5-yl)-8-(l-methyl- l / / -pyrazol-4-yl)-2-oxo-2,3-dihydro-lH-imidazo[4,5-tZ]pyrrolo[l,2-&]pyridazin-l- yl)cyclopentyl)carbamate

[0379] Synthesis of 1-12. To a solution of 1-6 (0.035 g, 0.065 mmol, 1.0 equiv) in DMF (4.0 mL) was added sodium hydride (60% dispersion in mineral oil, 0.013 g, 0.032 mmol, 5.0 equiv) at 0 °C in portions. The mixture was stirred for 15 min. To the mixture was added methyl iodide (0.018 g, 0.129 mmol, 2.0 equiv) at same temperature. The reaction mixture was stirred at room temperature for 15 min. It was quenched in 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®, 0-2.2% methanol in DCM) to afford 1-12 (0.018 g, 50%). MS(ES): / z 554.4 [M+H]+, ’H NMR (DMSO-d6, 400 MHz): 8 8.39 (s, 1H), 8.16 (d, J= 3.2 Hz, 1H), 8.09 (s, 1H), 7.82-7.78 (m, 2H), 7.42-7.39 (m, 1H), 7.25 (s, 1H), 7.06-7.01 (m, 1H), 4.17 (m, 3H), 3.66 (s, 3H), 3.54 (s, 3H), 3.38 (s, 3H), 2.59 (s, 3H), 2.33-2.27 (m, 1H), 2.20-2.18 (m, 1H), 2.18-1.99 (m, 2H), 1.51-1.48 (m, 1H), 1.33-1.29 (m, 1H), 1.01-0.99 (m, 1H), 0.48-0.4...

Claims

Attorney Docket No.: 2013518-0095CLAIMS1. A compound of formula I:I or a pharmaceu tic ally acceptable salt thereof, wherein;R1is hydrogen or optionally substituted Ci-Ce aliphatic;R2is C3-C12 cycloaliphatic, Ci-Ce aliphatic, 2- to 10-membered heteroaliphatic, 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 Ce-Cio aryl, wherein R2is optionally substituted with one or more instances of -L-R5or R7; each L is independently selected from the group consisting of a bond, -N(Ra)C(O)N(Ra)-, - N(Ra)C(O)O-, -OC(O)N(Ra)-, -C(O)N(Ra)-, -N(Ra)C(O)-, -N(Ra)-, -O-, -C(O)-, -C(O)O-, - OC(O)-, -N(Ra)C(S)O-, -OC(S)N(Ra)-, -C(S)N(Ra)-, -N(Ra)C(S)-, -C(S)-, -C(S)O-, and - OC(S)-; each R5is independently selected from the group consisting of optionally substituted Ci-Ce aliphatic, optionally substituted 2- to 10-membered 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; each R7is independently selected from the group consisting of halogen, -OH, -SH, and -NH2;R3is 5- to 12-membered hctcroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, 4- to 12-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S, C6-C12 aryl, C3-C12 cycloaliphatic, or Ci-Ce aliphatic, wherein R3is optionally substituted with one or more instances of R3a; orR2and R are connected by *-La-R6-Lb-**, wherein * represents a point of attachment to R2, and ** represents a point of attachment to R3;Page 808 of 83712933266V 1Attorney Docket No.: 2013518-0095Lais a bond, -N(Ra)C(O)N(Ra)-, -N(Ra)C(O)O-, -OC(O)N(Ra)-, -C(O)N(Ra)-, -N(Ra)C(O)-, - N(Ra)-, -O-, -C(O)-, -C(O)O-, -OC(O)-, -N(Ra)C(S)O-, -OC(S)N(Ra)-, -C(S)N(Ra)-, - N(Ra)C(S)-, -C(S)-, -C(S)O-, or -OC(S)-;Lbis a bond, -N(Ra)C(O)N(Ra)-, -N(Ra)C(O)O-, -OC(O)N(Ra)-, -C(O)N(Ra)-, -N(Ra)C(O)-, - N(Ra)-, -O-, -C(O)-, -C(O)O-, -OC(O)-, -N(Ra)C(S)O-, -OC(S)N(Ra)-, -C(S)N(Ra)-, - N(Ra)C(S)-, -C(S)-, -C(S)O-, or -OC(S)-;R6is optionally substituted Ci-Ce aliphatic, optionally substituted 2- to 10-membered 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, or optionally substituted Ce-Cio aryl;R4is Ci-Ce aliphatic, -CN, 2- to 10-membered 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 Ce-Cio aryl, wherein R4is optionally substituted with one or more instances of R4a; each R3ais independently selected from the group consisting of optionally substituted Ci-Ce aliphatic, optionally substituted 2- to 10-membered 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, optionally substituted Ce-Cio aryl, 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, and -ORa; each R4ais independently selected from the group consisting of optionally substituted Ci-Ce aliphatic, optionally substituted 2- to 10-membered 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, optionally substituted Ce-Cio aryl, halogen, oxo, -CN, -NO2, -C(O)Ra, -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; and each Rais independently selected from hydrogen, optionally substituted Ci-Ce aliphatic, optionally substituted 2- to 10-membered heteroaliphatic, optionally substituted 5- to 12-memberedPage 809 of 83712933266V 1Attorney Docket No.: 2013518-0095 heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, and optionally substituted4- to 12-mcmbcrcd heterocycle comprising 1 to 4 hctcroatoms selected from N, O, and S.

2. A compound of formula I:I or a pharmaceutically acceptable salt thereof, wherein:R1is hydrogen or optionally substituted Ci-Ce aliphatic;R2is C3-C12 cycloaliphatic, Ci-Ce aliphatic, 2- to 10-membered heteroaliphatic, 4- to 10-membered heterocycle comprising 1 to 4 hctcroatoms selected from N, O, and S, 5- to 10-mcmbcrcd heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, or Ce-Cio aryl, wherein R2is optionally substituted with one or more instances of -L-R5or R7; each L is independently selected from the group consisting of a bond, -N(Ra)C(O)N(Ra)-, - N(Ra)C(O)O-, -OC(O)N(Ra)-, -C(O)N(Ra)-, -N(Ra)C(O)-, -N(Ra)-, -O-, -C(O)-, -C(O)O-, - OC(O)-, -N(Ra)C(S)O-, -OC(S)N(Ra)-, -C(S)N(Ra)-, -N(Ra)C(S)-, -C(S)-, -C(S)O-, and - OC(S)-; each R5is independently selected from the group consisting of optionally substituted Ci-Ce aliphatic, optionally substituted 2- to 10-membered 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 Ce-Cio aryl; each R7is independently selected from the group consisting of halogen, -OH, -SH, and -NH2;R3is 5- to 12-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, 4- to 12-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S, C6-C12 aryl, C3-C12 cycloaliphatic, or Ci-Ce aliphatic, wherein R3is optionally substituted with one or more instances of R3a;Page 810 of 83712933266V 1Attorney Docket No.: 2013518-0095R4is Ci-C6aliphatic, -CN, 2- to 10-membered heteroaliphatic, C3-C12 cycloaliphatic, 4- to 10- mcmbcrcd hctcrocyclc comprising 1 to 4 hctcroatoms selected from N, O, and S, 5- to 10- membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, or Ce-Cio aryl, wherein R4is optionally substituted with one or more instances of R4a; each R3ais independently selected from the group consisting of optionally substituted Ci-Ce aliphatic, optionally substituted 2- to 10-membered 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, optionally substituted Ce-Cio aryl, 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, and -ORa; each R4ais independently selected from the group consisting of optionally substituted Ci-Ce aliphatic, optionally substituted 2- to 10-membered 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, optionally substituted Ce-Cio aryl, halogen, oxo, -CN, -NO2, -C(O)Ra, -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; and each Rais independently selected from hydrogen, optionally substituted Ci-Ce aliphatic, optionally substituted 2- to 10-membered 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.

3. The compound of claim 1 or 2, wherein R1is optionally substituted Ci-Ce aliphatic.

4. The compound of any one of claims 1-3, wherein R1is -CH3 or -CD3.

5. The compound of any one of claims 1-4, wherein R2is C3-C12 cycloaliphatic or 4- to 10- membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S; and wherein R2is substituted with one or more instances of -L-R5.Page 811 of 83712933266V 1Attorney Docket No.: 2013518-00956. The compound of any one of claims 1 -5, wherein R2is C3-C7 monocyclic cycloaliphatic or 4- to 6-mcmbcrcd monocyclic heterocycle comprising 1 to 2 hctcroatoms selected from N, O, and S; and wherein R2is substituted with 1-2 instances of -L-R5or R7.

7. The compound of any one of claims 1-6, wherein R2is substituted with 2 instances of -L- R5or R7.

8. The compound of claim 6 or 7, wherein R2is C3-C6 monocyclic cycloaliphatic, and wherein R2is substituted with 2 instances of -L-R5or R7.

9. The compound of claim 6 or 7, wherein R2is 4- to 6-membered monocyclic heterocycle comprising 1 to 2 heteroatoms selected from N, O, and S, and wherein R2is substituted with 2 instances of -L-R5or R7.

10. The compound of any one of claims 1-4, wherein R2is:Page 812 of 83712933266V 1Attorney Docket No.: 2013518-009512. The compound of any one of claims 1-11, wherein each L is independently selected from a bond, -N(Ra)C(O)O-, -OC(O)N(Ra)-, -C(O)N(Ra)-, -N(Ra)C(O)-, -O-, and -C(O)-.

13. The compound of claim 12, wherein each L is independently selected from a bond, - N(Ra)C(O)O-, and -N(Ra)C(O)-.

14. The compound of any one of claims 1-13, wherein each R5is independently selected from optionally substituted Ci-Ce aliphatic, optionally substituted C3-C6 cycloaliphatic, optionally substituted 4- to 6-membered heterocycle comprising 1 to 2 heteroatoms selected from N, O, and S, and optionally substituted 5- to 6-membered hctcroaryl comprising 1 to 4 heteroatoms selected from N, O, and S.

15. The compound of any one of claims 1-11, wherein each -L-R5is independently selectedPage 813 of 83712933266V 1Attorney Docket No.: 2013518-0095Page 814 of 83712933266V 1Attorney Docket No.: 2013518-009516. The compound of any one of claims 1-15, wherein each R7is independently selected from the group consisting of -OH, -SH, and -NH2.Page 815 of 83712933266V 1Attorney Docket No.: 2013518-0095Page 816 of 83712933266V 1Attorney Docket No.: 2013518-0095Page 817 of 83712933266V 1Attorney Docket No.: 2013518 0095Page 818 of 83712933266V 1Attorney Docket No.: 2013518-0095Page 819 of 83712933266V 1Atorney Docket No.: 2013518-0095Page 821 of 83712933266vlAttorney Docket No.: 2013518-0095Page 822 of 83712933266V 1Attorney Docket No.: 2013518-009512933266v 1 Page 823 of 837Attorney Docket No.: 2013518-0095Page 824 of 83712933266V 1Attorney Docket No.: 2013518-0095Page 825 of 83712933266V 1Attorney Docket No.: 2013518-009518. The compound of any one of claims 1-17, wherein R3is 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, 9- to 10-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S, or phenyl, wherein R3is optionally substituted with 0-3 instances of R3a.

19. The compound of any one of claims 1-17, wherein R3is monocyclic 5- to 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S, and wherein R3is optionally substituted with 0-3 instances of R3a.Page 826 of 83712933266V 1Attorney Docket No.: 2013518-009520. The compound of any one of claims 1-17, wherein R3is bicyclic 8- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, and wherein R3is optionally substituted with 0-3 instances of R3a.

21. The compound of claim 20, wherein R3is:

22. The compound of any one of claims 1-17, wherein R3is a bicyclic 9- to 10- membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S, and wherein R3is optionally substituted with 0-3 instances of R3a.

23. The compound of claim 20, wherein R3is:

24. The compound of any one of claims 1-17, wherein R3is phenyl, and R3is optionally substituted with 0-3 instances of R3a.

25. The compound of any one of claims 1-24, wherein each R3ais independently selected from optionally substituted Ci-Ce aliphatic, optionally substituted C3-C6 cycloaliphatic, halogen, - C(O)N(Ra)2, and -ORa.Page 827 of 83712933266V 1Attorney Docket No.: 2013518-009526. The compound of any one of claims 1-17, wherein R3optionally substituted with one orPage 828 of 83712933266V 1Attorney Docket No.: 2013518-009527. The compound of any one of claims 1 or 3-26, wherein R2and R3are connected by *-La- R6-Lb-**, wherein * represents a point of attachment to R2, and ** represents a point of attachment to R3.

28. The compound of claim 27, wherein Lais a bond, -N(Ra)C(O)O-, -OC(O)N(Ra)-, - C(O)N(Ra)-, -N(Ra)C(O)-, -N(Ra)-, -O-, -C(O)-, or -C(O)O-.

29. The compound of claim 27 or 28, wherein Lbis a bond, -N(Ra)-, -O-, -C(O)-, -C(O)O-, or -OC(O)-.

30. The compound of any one of claims 27-29, wherein R6is optionally substituted Ci-Ce aliphatic, optionally substituted 2- to 10-mcmbcrcd hctcroaliphatic, optionally substituted C3-C12 cycloaliphatic, or optionally substituted 4- to 10-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S.

31. The compound of claim 30, wherein R6is optionally substituted Ci-Ce aliphatic.

32. The compound of any one of claims 27-31, wherein a moiety;Page 829 of 83712933266V 1Attorney Docket No.: 2013518-009533. The compound of any one of claims 1-32, wherein R4is 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S or 4- to 10-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S, and wherein R4is optionally substituted with 0-3 instances of R4a.

34. The compound of any one of claims 1-32, wherein R4is monocyclic 5- to 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S, and is optionally substituted with 0-3 instances of R4a.

35. The compound of any one of claims 1-32, wherein R4is 8- to 10-membered bicyclic heteroaryl having 1 to 4 heteroatoms selected from N, O, and S, and is optionally substituted with 0-3 instances of R4a.

36. The compound of any one of claims 1-32, wherein R4is 4- to 6-membered monocyclic heterocycle comprising 1 to 3 heteroatoms selected from N, O, and S, and is optionally substituted with 0-3 instances of R4a.

37. The compound of any one of claims 1-36, wherein each R4ais independently selected from optionally substituted Ci-Ce aliphatic, -ORa, and halogen.Page 830 of 83712933266V 1Attorney Docket No.: 2013518-009538. The compound of any one of claims 1-32, wherein R4optionally substituted with one or more instances R4ais selected from:

39. The compound of any one of claims 1-38, wherein the compound is represented by formula II- 1, II-2, or II-3:Page 831 of 83712933266V 1Attorney Docket No.: 2013518-0095or a pharmaceutically acceptable salt thereof.

40. The compound of any one of claims 1-38, wherein the compound is represented by formulaIII:or a pharmaceutically acceptable salt thereof.

41. The compound of any one of claims 1-38, wherein the compound is represented by formulaIV-l, IV-2, or IV-3:Page 832 of 83712933266V 1Attorney Docket No.: 2013518-009542. The compound of any one of claims 1-38, wherein the compound is represented by formulaV-l or V-2:or a pharmaceutically acceptable salt thereof.

43. The compound of any one of claims 1-38, wherein the compound is represented by formulaVI:Page 833 of 83712933266V 1Attorney Docket No.: 2013518-0095or a pharmaceu tic ally acceptable salt thereof.

44. The compound of any one of claims 1-38, wherein the compound is represented by formulaVII- 1, VII-2, VII-3, VII-4, or VII-5:Page 834 of 83712933266V 1Attorney Docket No.: 2013518-009545. The compound of any one of claims 1 or 3-38, wherein the compound is represented by formula VIII:or a pharmaceutically acceptable salt thereof.

46. The compound of any one of claims 1-38, wherein the compound is represented by formulaPage 835 of 83712933266V 1Attorney Docket No.: 2013518-0095 or a pharmaceutically acceptable salt thereof, wherein R5is optionally substituted cyclopropyl.

47. A compound selected from Table 1A, Table IB, or Table 1C, or a pharmaceutically acceptable salt thereof.

48. A pharmaceutical composition comprising a compound of any one of claims 1-47, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

49. A method of inhibiting JAK2 in a subject, comprising administering to the subject the compound of any one of claims 1-47 or the pharmaceutical composition of claim 48.

50. 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 1-47 or the pharmaceutical composition of claim 48.

51. A method of treating cancer, comprising administering to a subject in need thereof the compound of any one of claims 1-47 or the pharmaceutical composition of claim 48.

52. A method of treating a hematological malignancy, comprising administering to a subject in need thereof the compound of any one of claims 1-47 or the pharmaceutical composition of claim 48.

53. The method of claim 52, wherein the hematological malignancy is leukemia or lymphoma.

54. A method of treating a myeloproliferative neoplasm, comprising administering to a subject in need thereof the compound of any one of claims 1-47 or the pharmaceutical composition of claim 48.

55. The method of claim 54, wherein the myeloproliferative neoplasm is polycythemia vera, essential thrombocytopenia, or myelofibrosis.Page 836 of 83712933266V 1

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