[go: up one dir, main page]

WO2025245175A1 - Inhibiteurs hétéroaromatiques macrocycliques de jak2 - Google Patents

Inhibiteurs hétéroaromatiques macrocycliques de jak2

Info

Publication number
WO2025245175A1
WO2025245175A1 PCT/US2025/030295 US2025030295W WO2025245175A1 WO 2025245175 A1 WO2025245175 A1 WO 2025245175A1 US 2025030295 W US2025030295 W US 2025030295W WO 2025245175 A1 WO2025245175 A1 WO 2025245175A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
optionally substituted
equiv
mmol
heteroatoms selected
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/US2025/030295
Other languages
English (en)
Inventor
Craig E. Masse
Jiayi Xu
Phani GHANAKOTA
Kevin Robert DEMARCO
Susanta HALDAR
Alice HOOPER
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Ajax Therapeutics Inc
Original Assignee
Ajax Therapeutics Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Ajax Therapeutics Inc filed Critical Ajax Therapeutics Inc
Publication of WO2025245175A1 publication Critical patent/WO2025245175A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Definitions

  • 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.
  • JAK proteins also contain a pseudokinase domain (JH2).
  • 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.
  • 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.
  • 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.
  • a modulator of JAK2 kinase activity 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.
  • the present disclosure provides compounds useful for inhibiting JAK2.
  • provided compounds are useful for, among other things, treating and/or preventing diseases, disorders, or conditions associated with JAK2.
  • the present disclosure provides a compound of Formula I: or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , Q, L, and Z are as defined in classes and subclasses herein, both singly and in combination.
  • the present disclosure provides a compound of Formula I- A: or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , and L are as defined in classes and subclasses herein, both singly and in combination.
  • the present disclosure provides a compound of Formula I- B: Page 2 of 196 12746579v1 Attorney Docket No.: 2013518-0088 or a pharmaceutically acceptable salt thereof, wherein Q, L 2 , and Z are as defined in classes and subclasses herein, both singly and in combination.
  • the present disclosure provides a compound of Formula I- C: or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 and L 2 are as defined in classes and subclasses herein, both singly and in combination.
  • the present disclosure provides a compound of Formula I- D: Page 3 of 196 12746579v1 Attorney Docket No.: 2013518-0088 or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , Q, Z, and L 2 are as defined in classes and subclasses herein, both singly and in combination.
  • the present disclosure provides a compound of Formula I- E: L 2 are as defined in classes and subclasses herein, both singly and in combination.
  • the present disclosure provides a compound of Formula I- F: Page 4 of 196 12746579v1 Attorney Docket No.: 2013518-0088 or a pharmaceutically acceptable salt thereof, wherein and L are as defined in classes and subclasses herein, both singly and in combination.
  • the present disclosure provides a compound of Formula I- G: or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , Q, Z, and L 2 are as defined in classes and subclasses herein, both singly and in combination.
  • the present disclosure provides a compound of Formula I- H: Page 5 of 196 12746579v1 Attorney Docket No.: 2013518-0088 or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , and L 2 are as defined in classes and subclasses herein, both singly and in combination.
  • the present disclosure provides a compound of Formula I-J: or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , Q, and L are as defined in classes and subclasses herein, both singly and in combination.
  • the present disclosure provides a compound of Formula I- K: Page 6 of 196 12746579v1 Attorney Docket No.: 2013518-0088 or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , Z, and L are as defined in classes and subclasses herein, both singly and in combination.
  • the present disclosure provides a compound of Formula I- L: R 2 , Q, Z, and L are as defined in classes and subclasses herein, both singly and in combination.
  • the present disclosure provides a compound of Formula II: or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2a , Q, L, and Z are as defined in classes and subclasses herein, both singly and in combination.
  • the present disclosure provides a compound of Formula II- A: Page 7 of 196 12746579v1 Attorney Docket No.: 2013518-0088 or a pharmaceutically L are as defined in classes and subclasses herein, both singly and in combination.
  • the present disclosure provides a compound of Formula II- B: or a pharmaceutically L 2 , and Z are as defined in classes and subclasses herein, both singly and in combination.
  • the present disclosure provides a compound of Formula II- C: Page 8 of 196 12746579v1 Attorney Docket No.: 2013518-0088 or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2a and L 2 are as defined in classes and subclasses herein, both singly and in combination.
  • the present disclosure provides a compound of Formula II- D: or a pharmaceutically 2a 2 or -CD3, and R , Q, Z, and L are as defined in classes and subclasses herein, both singly and in combination..
  • the present disclosure provides a compound of Formula II- E: or a pharmaceutically acceptable salt thereof, wherein R 1 is -CH 3 or -CD 3, and R 2a and L 2 are as defined in classes and subclasses herein, both singly and in combination.
  • Page 9 of 196 12746579v1 Attorney Docket No.: 2013518-0088
  • the present disclosure provides a compound of Formula II- F: or a pharmaceutically or -CD 3 2a , and R and L are as defined in classes and subclasses herein, both singly and in combination.
  • the present disclosure provides a compound of Formula II- G: or a pharmaceutically acceptable salt thereof, wherein R 1 is -CH3 or -CD3, and R 2a , Q, Z, and L 2 are as defined in classes and subclasses herein, both singly and in combination.
  • the present disclosure provides a compound of Formula II- H: Page 10 of 196 12746579v1 Attorney Docket No.: 2013518-0088 or a pharmaceutically acceptable salt thereof, wherein R 1 is -CH 3 or -CD 3, and R 2a and L 2 are as defined in classes and subclasses herein, both singly and in combination.
  • the present disclosure provides a compound of Formula II- J: or a pharmaceutically acceptable salt thereof, wherein R 1 is -CH3 or -CD3, and R 2a , Q, and L are as defined in classes and subclasses herein, both singly and in combination.
  • the present disclosure provides a compound of Formula II- K: Page 11 of 196 12746579v1 Attorney Docket No.: 2013518-0088 or a pharmaceutically or -CD3, and R 2a , Z, and L are as defined in classes and subclasses herein, both singly and in combination.
  • the present disclosure provides a compound of Formula III- A: or a pharmaceutically acceptable salt thereof, wherein R 1 , Q, Z, and L are as defined in classes and subclasses herein, both singly and in combination.
  • the present disclosure provides a compound of Formula III- B: Page 12 of 196 12746579v1 Attorney Docket No.: 2013518-0088 or a pharmaceutically acceptable salt thereof, wherein R 1 is -CH 3 or -CD 3, and L is as defined in classes and subclasses herein, both singly and in combination.
  • the present disclosure provides a compound of Formula III- C: or a pharmaceutically acceptable salt thereof, wherein R 1 is -CH 3 or -CD 3, and Q, Z, and L 2 are as defined in classes and subclasses herein, both singly and in combination.
  • the present disclosure provides a compound of Formula III- D: or a pharmaceutically acceptable salt thereof, wherein R 1 is -CH 3 or -CD 3, and L 2 is as defined in classes and subclasses herein, both singly and in combination.
  • the present disclosure provides a compound of Formula IV- A: Page 13 of 196 12746579v1 Attorney Docket No.: 2013518-0088 or a pharmaceutically acceptable Z, and L are as defined in classes and subclasses herein, both singly and in combination.
  • the present disclosure provides a compound of Formula IV- B: or a pharmaceutically acceptable salt thereof, wherein R 1 and L are as defined in classes and subclasses herein, both singly and in combination.
  • the present disclosure provides a compound of Formula IV- C: Page 14 of 196 12746579v1 Attorney Docket No.: 2013518-0088 IV-C or a pharmaceutically acceptable salt thereof, wherein R 1 , Q, Z, and L 2 are as defined in classes and subclasses herein, both singly and in combination.
  • the present disclosure provides a compound of Formula IV- D: or a pharmaceutically acceptable salt thereof, wherein R 1 and L 2 are as defined in classes and subclasses herein, both singly and in combination.
  • the present disclosure provides a compound of Formula V- A: or a pharmaceutically acceptable salt thereof, wherein R 1 , Q, Z, and L are as defined in classes and subclasses herein, both singly and in combination.
  • the present disclosure provides a compound of Formula V- B: Page 15 of 196 12746579v1 Attorney Docket No.: 2013518-0088 or a pharmaceutically L are as defined in classes and subclasses herein, both singly and in combination.
  • the present disclosure provides a compound of Formula V- C: or a pharmaceutically Z, and L 2 are as defined in classes and subclasses herein, both singly and in combination.
  • the present disclosure provides a compound of Formula V- D: Page 16 of 196 12746579v1 Attorney Docket No.: 2013518-0088 V-D or a pharmaceutically acceptable salt thereof, wherein R 1 and L 2 are as defined in classes and subclasses herein, both singly and in combination.
  • the present disclosure provides a method of inhibiting JAK2 in a subject, comprising administering to the subject a compound described herein (e.g., a compound of any one of Formula I to V-D) or a pharmaceutical composition comprising a compound described herein.
  • the present disclosure provides a method of treating a disease, disorder, or condition associated with JAK2, comprising administering to a subject in need thereof the compound of any one of claims 1-38 or the pharmaceutical composition of claim 39.
  • the present disclosure provides a method of treating cancer, comprising administering to a subject in need thereof a compound described herein (e.g., a compound of any one of Formula I to V-D) or a pharmaceutical composition comprising a compound described herein.
  • the present disclosure provides a method of treating a hematological malignancy, comprising administering to a subject in need thereof a compound described herein (e.g., a compound of any one of Formula I to V-D) or a pharmaceutical composition comprising a compound described herein.
  • a compound described herein e.g., a compound of any one of Formula I to V-D
  • a pharmaceutical composition comprising a compound described herein.
  • the present disclosure provides, among other things, compounds useful for inhibiting JAK2.
  • provided compounds are useful for, among other things, treating and/or preventing diseases, disorders, or conditions associated with JAK2.
  • the present disclosure encompasses the insight that compounds that bind to the JH2 domain of JAK proteins are particularly useful as inhibitors of JAK2.
  • Such compounds are useful Page 17 of 196 12746579v1 Attorney Docket No.: 2013518-0088 for treating diseases, disorders, and conditions associated with mutations of the JH2 domain that may lead to hyperactivity.
  • the V617F mutation is a mutation that leads to hyperactivity of JAK2.
  • the discovery of new compounds described herein provides inhibitors that are useful as therapy for diseases and disorders associated with, for example, a V617F to the JH2 domain of JAK2.
  • the present disclosure provides a compound represented by Formula I: or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , Q, L, and Z are as defined in classes and subclasses herein, both singly and in combination.
  • R 1 , R 2 , Q, L, and Z are as defined in classes and subclasses herein, both singly and in combination.
  • Compounds and Definitions [0048] Compounds of this disclosure include those described generally above and are further illustrated by the classes, subclasses, and species disclosed herein. As used herein, the following definitions shall apply unless otherwise indicated.
  • each stereocenter the R and S configurations of each stereocenter are contemplated as part of the disclosure. Therefore, single Page 18 of 196 12746579v1 Attorney Docket No.: 2013518-0088 stereochemical isomers, as well as enantiomeric, diastereomic, and geometric (or conformational) mixtures of provided compounds are within the scope of the disclosure.
  • Table 1 shows one or more stereoisomers of a compound, and unless otherwise indicated, represents each stereoisomer alone and/or as a mixture. Unless otherwise stated, all tautomeric forms of provided compounds are within the scope of the disclosure.
  • structures depicted herein are meant to include compounds that differ only in the presence of one or more isotopically enriched atoms.
  • compounds having the present structures including replacement of hydrogen by deuterium or tritium, or replacement of a carbon by 13 C- or 14 C-enriched carbon are within the scope of this disclosure.
  • 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.
  • 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.
  • Administering 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.
  • administration may be ocular, oral, parenteral, topical, etc.
  • 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.
  • bronchial e.g., by bronchial instillation
  • buccal which may be or comprise, for example, one or more of topical to the dermis, intradermal, interdermal, transdermal, etc.
  • enteral intra-arterial, intradermal, intragas
  • administration may be parenteral. In some embodiments, administration may be oral. In some particular embodiments, Page 19 of 196 12746579v1 Attorney Docket No.: 2013518-0088 administration may be intravenous. In some particular embodiments, administration may be subcutaneous. In some embodiments, administration may involve only a single dose. In some embodiments, administration may involve application of a fixed number of doses. In some embodiments, administration may involve dosing that is intermittent (e.g., a plurality of doses separated in time) and/or periodic (e.g., individual doses separated by a common period of time) dosing. In some embodiments, administration may involve continuous dosing (e.g., perfusion) for at least a selected period of time.
  • intermittent e.g., a plurality of doses separated in time
  • periodic e.g., individual doses separated by a common period of time
  • administration may involve continuous dosing (e.g., perfusion) for at least a selected period of time.
  • administration may comprise a prime- and-boost protocol.
  • a prime-and-boost protocol can include administration of a first dose of a pharmaceutical composition (e.g., an immunogenic composition, e.g., a vaccine) followed by, after an interval of time, administration of a second or subsequent dose of a pharmaceutical composition (e.g., an immunogenic composition, e.g., a vaccine).
  • a prime-and-boost protocol can result in an increased immune response in a patient.
  • 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.
  • aliphatic groups contain 1-12 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-6 aliphatic carbon atoms (e.g., C1-6).
  • aliphatic groups contain 1-5 aliphatic carbon atoms (e.g., C1-5). In other embodiments, aliphatic groups contain 1-4 aliphatic carbon atoms (e.g., C1-4). In still other embodiments, aliphatic groups contain 1-3 aliphatic carbon atoms (e.g., C1-3), and in yet other embodiments, aliphatic groups contain 1-2 aliphatic carbon atoms (e.g., C1-2). Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups and hybrids thereof.
  • 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.
  • Alkyl refers to a saturated, optionally substituted straight or branched hydrocarbon group having (unless otherwise Page 20 of 196 12746579v1 Attorney Docket No.: 2013518-0088 specified) 1-12, 1-10, 1-8, 1-6, 1-4, 1-3, or 1-2 carbon atoms (e.g., C 1-12 , C 1-10 , C 1-8 , C 1-6 , C 1-4 , C 1- 3, or C1-2).
  • Exemplary alkyl groups include methyl, ethyl, propyl, butyl, pentyl, hexyl, and heptyl.
  • Alkylene 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.
  • two substituents of the alkylene group may be taken together to form a ring system.
  • two substituents can be taken together to form a 3- to 7-membered ring.
  • the substituents can be on the same or different atoms.
  • the suffix “-ene” or “-enyl” when appended to certain groups herein are intended to refer to a bifunctional moiety of said group.
  • “-ene” or “-enyl” when appended to “cyclopropyl” becomes “cyclopropylene” or “cyclopropylenyl” and is intended to refer to a bifunctional cyclopropyl group, .
  • Alkenyl The term “alkenyl”, used alone or as part of a larger 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., C 2-12 , C 2-10 , C 2-8 , C 2-6 , C 2-4 , or C 2-3 ).
  • alkenyl groups include ethenyl, propenyl, butenyl, pentenyl, hexenyl, and heptenyl.
  • cycloalkenyl refers to an optionally substituted non-aromatic monocyclic or multicyclic ring system containing at least one carbon-carbon double bond and having about 3 to about 10 carbon atoms.
  • exemplary monocyclic cycloalkenyl rings include cyclopentenyl, cyclohexenyl, and cycloheptenyl.
  • Alkynyl 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.
  • 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., C 6 -C 12 ). The term “aryl” may be used interchangeably with the term “aryl ring”.
  • aryl refers to an aromatic ring system which includes, but not limited to, phenyl, biphenyl, naphthyl, anthracyl and the like, which may bear one or more substituents. Unless otherwise specified, “aryl” groups are hydrocarbons. In some embodiments, an “aryl” ring system is an aromatic ring (e.g., phenyl) that is fused to a non-aromatic ring (e.g., cycloalkyl). Examples of aryl rings include that are fused .
  • 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.
  • the term includes any permissible ring fusion, such as ortho-fused or spirocyclic.
  • heterocyclic 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.
  • a bicyclic group has 7-12 ring members and 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • the term “bridged bicyclic” refers to any bicyclic ring system, i.e., carbocyclic or heterocyclic, saturated or partially unsaturated, having at least one bridge.
  • 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).
  • 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.
  • a bridged bicyclic group is optionally substituted with one or more Page 22 of 196 12746579v1 Attorney Docket No.: 2013518-0088 substituents as set forth for aliphatic groups. Additionally or alternatively, any substitutable nitrogen of a bridged bicyclic group is optionally substituted.
  • Exemplary bicyclic rings include: Exemplary bridged NH NH .
  • term refers to a sample obtained or derived from a biological source (e.g., a tissue or organism or cell culture) of interest, as described herein.
  • a source of interest comprises an organism, such as an animal or human.
  • a biological sample is or comprises biological tissue or fluid.
  • a biological sample may be or comprise bone marrow; blood; blood cells; ascites; tissue or fine needle biopsy samples; cell-containing body fluids; free Page 23 of 196 12746579v1 Attorney Docket No.: 2013518-0088 floating nucleic acids; sputum; saliva; urine; cerebrospinal fluid, peritoneal fluid; pleural fluid; feces; lymph; gynecological fluids; skin swabs; vaginal swabs; oral swabs; nasal swabs; washings or lavages such as a ductal lavages or broncheoalveolar lavages; aspirates; scrapings; bone marrow specimens; tissue biopsy specimens; surgical specimens; feces, other body fluids, secretions, and/or excretions; and/or cells therefrom, etc.
  • a biological sample is or comprises cells obtained from an individual.
  • obtained cells are or include cells from an individual from whom the sample is obtained.
  • a sample is a “primary sample” obtained directly from a source of interest by any appropriate means.
  • a primary biological sample is obtained by methods selected from the group consisting of biopsy (e.g., fine needle aspiration 24ncubae biopsy), surgery, collection of body fluid (e.g., blood, lymph, feces etc.), etc.
  • sample refers to a preparation that is obtained by processing (e.g., by removing one or more components of and/or by adding one or more agents to) a primary sample. For example, filtering using a semi-permeable membrane.
  • 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.
  • composition may be used to refer to a discrete physical entity that comprises one or more specified components.
  • a composition may be of any form – e.g., gas, gel, liquid, solid, etc.
  • 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.
  • a cycloaliphatic ring can be attached in a spirocyclic manner, .
  • Cycloalkyl refers to an optionally substituted saturated ring monocyclic or polycyclic system of about 3 to about 10 ring carbon Page 24 of 196 12746579v1 Attorney Docket No.: 2013518-0088 atoms.
  • Exemplary monocyclic cycloalkyl rings include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.
  • Dosage form or unit 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.
  • an active agent e.g., a therapeutic or diagnostic agent
  • each such unit contains a predetermined quantity of active agent.
  • 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).
  • 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.
  • Excipient refers to a non-therapeutic agent that may be included in a pharmaceutical composition, for example, to provide or contribute to a desired consistency or stabilizing effect.
  • Suitable pharmaceutical excipients include, for example, starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol and the like.
  • Halogen The term “halogen” or “halo” means F, Cl, Br, or I.
  • Heteroaliphatic 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.
  • heteroatom refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternized form of a basic nitrogen.
  • nitrogen also includes a substituted nitrogen.
  • 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.
  • 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.
  • 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.
  • a 1- to 10 atom heteroaliphatic group includes the following exemplary groups: -O-CH 3 , -CH 2 -O-CH 3 , -O-CH 2 - CH2-O-CH2-CH2-O-CH3, and the like.
  • Heteroaryl The terms “heteroaryl” and “heteroar—”, used alone or as part of a larger moiety, e.g., “heteroaralkyl”, or “heteroaralkoxy”, refer to monocyclic or bicyclic ring groups having 5 to 10 ring atoms (e.g., 5- to 6-membered monocyclic heteroaryl or 9- to 10- membered bicyclic heteroaryl); having 6, 10, or 14 ⁇ electrons shared in a cyclic array; and having, in addition to carbon atoms, from one to five heteroatoms.
  • 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
  • heteroaryl groups include, without limitation, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridonyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, pteridinyl, imidazo[1,2-a]pyrimidinyl, imidazo[1,2-a]pyridinyl, thienopyrimidinyl, triazolopyridinyl, and benzoisoxazolyl.
  • heteroaryl and “heteroar—”, as used herein, also include groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclyl rings (i.e., a bicyclic heteroaryl ring having 1 to 3 heteroatoms).
  • Nonlimiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzothiazolyl, benzothiadiazolyl, benzoxazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H– quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, pyrido[2,3–b]–1,4–oxazin–3(4H)–one, and benzoisoxazolyl.
  • heteroaryl may be used interchangeably with the terms “heteroaryl ring”, “heteroaryl group”, or “heteroaromatic”, any of which terms include rings that are optionally substituted.
  • Heteroatom refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternized form of a basic nitrogen.
  • 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.
  • nitrogen includes a substituted 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.
  • saturated or partially unsaturated heterocyclic radicals include, without limitation, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and thiamorpholinyl.
  • a heterocycle can be attached in a spirocyclic manner, e.g., or .
  • a heterocyclyl group may be mono-, bi-, tri-, or polycyclic, preferably mono-, bi-, or tricyclic, more preferably mono- or bicyclic.
  • a bicyclic heterocyclic ring also includes groups in which the heterocyclic ring is fused to one or more aryl, heteroaryl, or cycloaliphatic rings.
  • Exemplary bicyclic heterocyclic groups include indolinyl, isoindolinyl, benzodioxolyl, 1,3- dihydroisobenzofuranyl, 2,3-dihydrobenzofuranyl, and tetrahydroquinolinyl.
  • a bicyclic heterocyclic ring can also be a spirocyclic ring system (e.g., 6- to 11-membered spirocyclic fused heterocyclic ring having, in addition to carbon atoms, one or more heteroatoms as defined above (e.g., one, two, three or four heteroatoms)).
  • a bicyclic heterocyclic ring can also be a bridged ring system (e.g., 7- to 11-membered bridged heterocyclic ring having one, two, or three bridging atoms.
  • Parenteral The phrases “parenteral administration” and “administered parenterally” as used herein have their art-understood meaning referring to modes of Page 27 of 196 12746579v1 Attorney Docket No.: 2013518-0088 administration other than enteral and topical administration, usually by injection, and include, without limitation, intravenous, intramuscular, intra-arterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticulare, subcapsular, subarachnoid, intraspinal, and intrasternal injection and infusion.
  • 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.
  • 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).
  • a patient is a human.
  • a patient or a subject is suffering from or susceptible to one or more disorders or conditions.
  • a patient or subject displays one or more symptoms of a disorder or condition.
  • a patient or subject has been diagnosed with one or more disorders or conditions.
  • a patient or a subject is receiving or has received certain therapy to diagnose and/or to treat a disease, disorder, or condition.
  • Pharmaceutical composition refers to an active agent, formulated together with one or more pharmaceutically acceptable carriers.
  • 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.
  • pharmaceutical compositions may be specially formulated for administration in solid or liquid form, including those adapted for the following: oral administration, for example, drenches (aqueous or non-aqueous solutions or suspensions), tablets, e.g., those targeted for buccal, sublingual, and systemic absorption, boluses, powders, granules, pastes for application to the tongue; parenteral administration, for example, by subcutaneous, intramuscular, intravenous or epidural injection as, for example, a sterile solution Page 28 of 196 12746579v1 Attorney Docket No.: 2013518-0088 or suspension, or sustained-release formulation; topical application, for example, as a cream, ointment, or a controlled-release patch or spray applied to the skin, lungs, or oral
  • oral administration for example,
  • 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.
  • compositions that are appropriate for use in pharmaceutical contexts, i.e., salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge, et al. describes pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66: 1-19 (1977).
  • Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid
  • 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.
  • salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2– hydroxy–ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2–naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pec
  • Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N + (C1–4alkyl)4 salts.
  • Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
  • Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and aryl sulfonate.
  • Substituted or optionally substituted As described herein, compounds of this disclosure may contain “optionally substituted” moieties.
  • 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 a n 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 or different at every position. Combinations of substituents envisioned by this invention are preferably those that result in the formation of stable or chemically feasible compounds.
  • stable refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain embodiments, their recovery, purification, and use Page 30 of 196 12746579v1 Attorney Docket No.: 2013518-0088 for one or more of the purposes provided herein.
  • Groups described as being “substituted” preferably have between 1 and 4 substituents, more preferably 1 or 2 substituents.
  • Groups described as being “optionally substituted” may be unsubstituted or be “substituted” as described above.
  • Suitable monovalent substituents on R° are independently halogen, –(CH 2 ) 0–2 R ⁇ , –(haloR ⁇ ), –(CH 2 ) 0–2 OH, –(CH 2 ) 0–2 OR ⁇ , –(CH 2 ) 0–2 CH(OR ⁇ ) 2 , -O(haloR ⁇ ), –CN, – Page 31 of 196 12746579v1 Attorney Docket No.: 2013518-0088 N 3 , –(CH 2 ) 0–2 C(O)R ⁇ , –(CH 2 ) 0–2 C(O)OH, –(CH 2 ) 0–2 C(O)OR ⁇ , –(CH 2 ) 0–2 SR ⁇ , –(CH 2 ) 0–2 SH,
  • Suitable divalent substituents that are bound to vicinal substitutable carbons of an “optionally substituted” group include: –O(CR * 2 ) 2–3 O–, wherein each independent occurrence of R * is selected from hydrogen, C 1–6 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.
  • 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 – NO 2 , wherein each R ⁇ is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C 1–4 aliphatic, –CH 2 Ph, –O(CH 2 ) 0–1 Ph, or a 3- to 6- membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • Suitable substituents on a substitutable nitrogen of an “optionally substituted” group include –R ⁇ , –NR ⁇ 2, –C(O)R ⁇ , –C(O)OR ⁇ , –C(O)C(O)R ⁇ , – C(O)CH2C(O)R ⁇ , -S(O)2R ⁇ , -S(O)2NR ⁇ 2, –C(S)NR ⁇ 2, –C(NH)NR ⁇ 2, or –N(R ⁇ )S(O)2R ⁇ ; wherein each R ⁇ is independently hydrogen, C 1–6 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 Page 32 of 196 12746579v1 Attorney Docket No.: 2013518-0088 definition above
  • Suitable substituents on the aliphatic group of R ⁇ are independently halogen, – R ⁇ , -(haloR ⁇ ), –OH, –OR ⁇ , –O(haloR ⁇ ), –CN, –C(O)OH, –C(O)OR ⁇ , –NH2, –NHR ⁇ , –NR ⁇ 2, or -NO2, wherein each R ⁇ is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C 1–4 aliphatic, –CH 2 Ph, –O(CH 2 ) 0–1 Ph, or a 3- to 6- membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • Small molecule means a low molecular weight organic and/or inorganic compound.
  • a “small molecule” is a molecule that is less than about 5 kilodaltons (kD) in size.
  • a small molecule is less than about 4 kD, 3 kD, about 2 kD, or about 1 kD.
  • 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.
  • a small molecule is less than about 2000 g/mol, less than about 1500 g/mol, less than about 1000 g/mol, less than about 800 g/mol, or less than about 500 g/mol. In some embodiments, a small molecule is not a polymer. [0089] In some embodiments, a small molecule does not include a polymeric moiety. In some embodiments, a small molecule is not and/or does not comprise a protein or polypeptide (e.g., is not an oligopeptide or peptide). In some embodiments, a small molecule is not and/or does not comprise a polynucleotide (e.g., is not an oligonucleotide).
  • a small molecule is not and/or does not comprise a polysaccharide; for example, in some embodiments, a small molecule is not a glycoprotein, proteoglycan, glycolipid, etc.). In some embodiments, a small molecule is not a lipid. [0090] In some embodiments, a small molecule is a modulating agent (e.g., is an inhibiting agent or an activating agent). In some embodiments, a small molecule is biologically active. In some embodiments, a small molecule is detectable (e.g., comprises at least one detectable moiety). In some embodiments, a small molecule is a therapeutic agent.
  • a modulating agent e.g., is an inhibiting agent or an activating agent.
  • a small molecule is biologically active.
  • a small molecule is detectable (e.g., comprises at least one detectable moiety). In some embodiments, a small molecule is a therapeutic agent.
  • 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.
  • 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.
  • small molecule compounds have structures that permit isotopic substitution (e.g., 2 H or 3 H for H; 11 C, 13 C or 14 C for 12 C; 13 N or 15 N for 14 N; 17 O or 18 O for 16 O; 36 Cl for 35 Cl or 37 Cl; 18 F for 19 F; 131 I for 127 I; etc.).
  • such a small molecule may be utilized in accordance with the present disclosure in one or more isotopically modified forms, or mixtures thereof.
  • reference to a particular small molecule compound may relate to a specific form of that compound.
  • 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.
  • 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.
  • a preparation of a particular small molecule compound that contains an absolute or relative amount of the compound, or of a particular form thereof, that is different from the absolute or relative (with respect to another component of the preparation including, for example, another form of the compound) amount of Page 34 of 196 12746579v1 Attorney Docket No.: 2013518-0088 the compound or form that is present in a reference preparation of interest (e.g., in a primary sample from a source of interest such as a biological or environmental source) is distinct from the compound as it exists in the reference preparation or source.
  • a reference preparation of interest e.g., in a primary sample from a source of interest such as a biological or environmental source
  • a preparation of a single stereoisomer of a small molecule compound may be considered to be a different form of the compound than a racemic mixture of the compound; a particular salt of a small molecule compound may be considered to be a different form from another salt form of the compound; a preparation that contains only a form of the compound that contains one conformational isomer ((Z) or I) of a double bond may be considered to be a different form of the compound from one that contains the other conformational isomer (E) or (Z)) of the double bond; a preparation in which one or more atoms is a different isotope than is present in a reference preparation may be considered to be a different form; etc.
  • the symbol refers to a point of attachment between two atoms. Additionally or alternatively, the symbol refers to a point of attachment ring in a spirocyclic manner. Alternatively, the symbol , when drawn adjacent to a double bond, is intended to encompass both a cis alkene and a trans alkene, e.g.: . in small molecule structures, the symbol , as used herein, represents a single or double bond between two atoms in a ring structure. For .
  • treat refers to any administration of a therapy that partially or completely alleviates, ameliorates, relives, inhibits, delays onset of, reduces severity of, and/or reduces incidence of one or more symptoms, features, and/or causes of a particular disease, disorder, and/or condition.
  • treatment may be of a subject who does not exhibit signs of the relevant disease, disorder and/or condition and/or of a subject who exhibits only early signs of the disease, disorder, and/or Page 35 of 196 12746579v1 Attorney Docket No.: 2013518-0088 condition.
  • the present disclosure provides a compound of Formula I: or a pharmaceutically acceptable salt thereof, wherein: R 1 is hydrogen or optionally substituted C1-C6 aliphatic; R 2 is C1-C6 aliphatic, C1-C6 heteroaliphatic, C3-C12 cycloaliphatic, 4- to 10-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S, 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, or C6-C10 aryl, wherein R 2 is optionally substituted with one or more instances of R 2a ; each R 2a is independently selected from the group consisting of optionally substituted C1-C
  • the present disclosure provides a compound of Formula I- A: Page 37 of 196 12746579v1 Attorney Docket No.: 2013518-0088 I-A or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , and L are as defined above for Formula I and described in classes and subclasses herein, both singly and in combination.
  • the present disclosure provides a compound of Formula I- B: or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , Q, Z, and L 2 are as defined above for Formula I and described in classes and subclasses herein, both singly and in combination.
  • the present disclosure provides a compound of Formula I- C: or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , and L 2 are as defined above for Formula I and described in classes and subclasses herein, both singly and in combination.
  • the present disclosure provides a compound of Formula I- D: Page 38 of 196 12746579v1 Attorney Docket No.: 2013518-0088 or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , Q, Z, and L 2 are as defined above for Formula I and described in classes and subclasses herein, both singly and in combination.
  • the present disclosure provides a compound of Formula I- E: L 2 are as defined above for Formula I and described in classes and subclasses herein, both singly and in combination.
  • the present disclosure provides a compound of Formula I- F: Page 39 of 196 12746579v1 Attorney Docket No.: 2013518-0088 or a pharmaceutically acceptable salt thereof, wherein and L are as defined above for Formula I and described in classes and subclasses herein, both singly and in combination.
  • the present disclosure provides a compound of Formula I- G: or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , Q, Z, and L 2 are as defined above for Formula I and described in classes and subclasses herein, both singly and in combination.
  • the present disclosure provides a compound of Formula I- H: Page 40 of 196 12746579v1 Attorney Docket No.: 2013518-0088 or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , and L 2 are as defined above for Formula I and described in classes and subclasses herein, both singly and in combination.
  • the present disclosure provides a compound of Formula I-J: or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , Q, and L are as defined above for Formula I and described in classes and subclasses herein, both singly and in combination.
  • the present disclosure provides a compound of Formula I- K: Page 41 of 196 12746579v1 Attorney Docket No.: 2013518-0088 or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , Z, and L are as defined above for Formula I and described in classes and subclasses herein, both singly and in combination.
  • the present disclosure provides a compound of Formula I- L: R 2 , Q, Z, and L are as defined above for Formula I and described in classes and subclasses herein, both singly and in combination.
  • the present disclosure provides a compound of Formula II: or a pharmaceutically or -CD3, and R 2a , Q, Z, and L are as defined above for Formula I and described in classes and subclasses herein, both singly and in combination.
  • the present disclosure provides a compound of Formula II- A: Page 42 of 196 12746579v1 Attorney Docket No.: 2013518-0088 or a pharmaceutically or -CD3, and R 2a and L are as defined above for Formula I and described in classes and subclasses herein, both singly and in combination.
  • the present disclosure provides a compound of Formula II- B: or a pharmaceutically acceptable salt thereof, wherein R 1 is -CH3 or -CD3, and R 2a , Q, Z, and L 2 are as defined above for Formula I and described in classes and subclasses herein, both singly and in combination.
  • the present disclosure provides a compound of Formula II- C: Page 43 of 196 12746579v1 Attorney Docket No.: 2013518-0088 or a pharmaceutically or -CD3, and R 2a and L 2 are as defined above for Formula I and described in classes and subclasses herein, both singly and in combination.
  • the present disclosure provides a compound of Formula II- D: or a pharmaceutically acceptable salt thereof, wherein R 1 is -CH 3 or -CD 3, and R 2a , Q, Z, and L 2 are as defined above for Formula I and described in classes and subclasses herein, both singly and in combination.
  • the present disclosure provides a compound of Formula II- E: Page 44 of 196 12746579v1 Attorney Docket No.: 2013518-0088 or a pharmaceutically or -CD 3, and R 2a 2 and L are as defined above for Formula I and described in classes and subclasses herein, both singly and in combination.
  • the present disclosure provides a compound of Formula II- F: or a pharmaceutically acceptable salt thereof, wherein R 1 is -CH3 or -CD3, and R 2a and L are as defined above for Formula I and described in classes and subclasses herein, both singly and in combination.
  • the present disclosure provides a compound of Formula II- G: Page 45 of 196 12746579v1 Attorney Docket No.: 2013518-0088 or a pharmaceutically or -CD3, and R 2a , Q, Z, and L 2 are as defined above for Formula I and described in classes and subclasses herein, both singly and in combination.
  • the present disclosure provides a compound of Formula II- H: or a pharmaceutically acceptable salt thereof, wherein R 1 is -CH 3 or -CD 3, and R 2a and L 2 are as defined above for Formula I and described in classes and subclasses herein, both singly and in combination.
  • the present disclosure provides a compound of Formula II- J: Page 46 of 196 12746579v1 Attorney Docket No.: 2013518-0088 Or a pharmaceutically or -CD3, and R 2a , Q, and L are as defined above for Formula I and described in classes and subclasses herein, both singly and in combination.
  • the present disclosure provides a compound of Formula II- K: Or a pharmaceutically acceptable salt thereof, wherein R 1 is -CH 3 or -CD 3, and R 2a , Z, and L are as defined above for Formula I and described in classes and subclasses herein, both singly and in combination.
  • the present disclosure provides a compound of Formula III- A: Page 47 of 196 12746579v1 Attorney Docket No.: 2013518-0088 or a pharmaceutically acceptable salt thereof, wherein R 1 , Q, Z, and L are as defined above for Formula I and described in classes and subclasses herein, both singly and in combination.
  • the present disclosure provides a compound of Formula III- B: or a pharmaceutically acceptable salt thereof, wherein R 1 is -CH 3 or -CD 3, and L is as defined above for Formula I and described in classes and subclasses herein, both singly and in combination.
  • the present disclosure provides a compound of Formula III- C: or a pharmaceutically acceptable salt thereof, wherein R 1 is -CH 3 or -CD 3, and Q, Z, and L 2 are as defined above for Formula I and described in classes and subclasses herein, both singly and in combination.
  • the present disclosure provides a compound of Formula III- D: Page 48 of 196 12746579v1 Attorney Docket No.: 2013518-0088 or a pharmaceutically acceptable salt thereof, wherein R 1 is -CH 3 or -CD 3, and L 2 is as defined above for Formula I and described in classes and subclasses herein, both singly and in combination.
  • the present disclosure provides a compound of Formula IV- A: or a pharmaceutically acceptable salt thereof, wherein R 1 , Q, Z, and L are as defined above for Formula I and described in classes and subclasses herein, both singly and in combination.
  • the present disclosure provides a compound of Formula IV- B: Page 49 of 196 12746579v1 Attorney Docket No.: 2013518-0088 or a pharmaceutically acceptable salt thereof, wherein and L are as defined above for Formula I and described in classes and subclasses herein, both singly and in combination.
  • the present disclosure provides a compound of Formula IV- C: or a pharmaceutically acceptable salt thereof, wherein R 1 , Q, Z, and L 2 are as defined above for Formula I and described in classes and subclasses herein, both singly and in combination.
  • the present disclosure provides a compound of Formula IV- D: Page 50 of 196 12746579v1 Attorney Docket No.: 2013518-0088 or a pharmaceutically acceptable salt thereof, wherein R 1 and L 2 are as defined above for Formula I and described in classes and subclasses herein, both singly and in combination.
  • the present disclosure provides a compound of Formula V- A: or a pharmaceutically acceptable salt thereof, wherein R 1 , Q, Z, and L are as defined above for Formula I and described in classes and subclasses herein, both singly and in combination.
  • the present disclosure provides a compound of Formula V- B: Page 51 of 196 12746579v1 Attorney Docket No.: 2013518-0088 V-B or a pharmaceutically acceptable salt thereof, wherein R 1 and L are as defined above for Formula I and described in classes and subclasses herein, both singly and in combination.
  • the present disclosure provides a compound of Formula V- C: or a pharmaceutically Z, and L 2 are as defined above for Formula I and described in classes and subclasses herein, both singly and in combination.
  • the present disclosure provides a compound of Formula V- D: or a pharmaceutically L 2 are as defined above for Formula I and described in classes and subclasses herein, both singly and in combination.
  • R 1 is hydrogen or optionally substituted C 1 -C 6 aliphatic. In some embodiments, R 1 is hydrogen. In some embodiments, R 1 is optionally substituted C 1 -C 6 aliphatic.
  • R 1 is optionally Page 52 of 196 12746579v1 Attorney Docket No.: 2013518-0088 substituted C 1 -C 3 aliphatic.
  • R 1 is C 1 -C 6 aliphatic.
  • R 1 is methyl or deuterated methyl (e.g., one or more H atoms of methyl have been replaced with deuterium).
  • R 1 is -CH3 or -CD3.
  • R 1 is -CH3.
  • R 1 is -CD 3 .
  • R 2 is selected from C1- C6 aliphatic, C1-C6 heteroaliphatic, C3-C12 cycloaliphatic, 4- to 10-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S, 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, C6-C10 aryl, and wherein R 2 is optionally substituted with one or more instance of R 2a .
  • R 2 is C 1 -C 6 aliphatic optionally substituted with one or more instances of R 2a .
  • R 2 is methyl, ethyl, propyl, butyl, pentyl, or hexyl, wherein R 2 is optionally substituted with one or more instances of R 2a .
  • R 2 is C1-C6 aliphatic optionally substituted with one to three instances of R 2a .
  • R 2 is C 1 -C 6 aliphatic optionally substituted with two instances of R 2a , wherein one R 2a is -OR a and one R 2a is -L a -R b , wherein L a is a bond and R b is optionally substituted C3-C12 cycloaliphatic.
  • R 2 is C1-C6 aliphatic optionally substituted with one instance of R 2a wherein R 2a is -OR a .
  • R 2 is C 1 -C 6 aliphatic optionally substituted with two instances of R 2a , wherein one R 2a is L a -R b , wherein L a is a bond, and R b is C3 cycloaliphatic, and one R 2a is -OH.
  • R 2 is methyl substituted with two instances of R 2a , wherein one R 2a is -OH, and one R 2a is cyclopropyl.
  • R 2 is C 1 -C 6 heteroaliphatic optionally substituted with one or more instances of R 2a .
  • R 2 is 4- to 10-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S optionally substituted with one or more instances of R 2a .
  • R 2 is 4- to 6-membered monocyclic heterocycle comprising 1 to 3 heteroatoms selected from N, O, and S.
  • R 2 is 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 R 2a .
  • R 2 is 4- to 6-membered monocyclic heterocycle comprising 1 to 3 heteroatoms selected from N, O, and S substituted with one or more instances of R 2a , wherein R 2a is -CH 3 or -CD 3 .
  • R 2 is piperidine or pyran Page 53 of 196 12746579v1 Attorney Docket No.: 2013518-0088 optionally substituted with one or more instances of R 2a .
  • R 2 is piperidine or pyran.
  • R 2 is 6-membered heterocycle comprising an oxygen atom.
  • R 2 is .
  • R is 6- to 10-membered bicyclic heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S.
  • R 2 is 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 R 2a .
  • R 2 is 8- to 10-membered bicyclic heterocycle comprising 1 to 4 heteroatoms selected from N and O, optionally substituted with one or more instances of R 2a .
  • R 2 is 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, and is optionally substituted with one or more instances of R 2a .
  • R 2 is monocyclic 5- to 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S, and is optionally substituted with one or more instances of R 2a .
  • R 2 is 5- to 6-membered monocyclic heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S, and is substituted with one instance of R 2a .
  • R 2 is 5- to 6-membered monocyclic heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S, and is substituted with two instances of R 2a .
  • R 2 is 5- to 6-membered monocyclic heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S, and wherein R 2 is optionally substituted with R 2a wherein R 2a is selected from optionally substituted C 1 -C 6 aliphatic and -OR a .
  • R 2 is 5- to 6-membered monocyclic heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S, and wherein R 2 is substituted with one or more instances of R 2a wherein R 2a is selected from optionally substituted C1-C6 aliphatic and -OR a .
  • R 2 is 5- to 6-membered monocyclic heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S, and wherein R 2 is optionally substituted with R 2a wherein R 2a is selected from -CH3 or -CD3.
  • R 2 is 5- to 6-membered monocyclic heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S, and wherein R 2 is optionally substituted with R 2a wherein R 2a is selected from -CD 3 , and halogen.
  • R 2 is 5- to 6-membered monocyclic heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S, and wherein R 2 is optionally substituted with R 2a wherein R 2a is selected from -CD 3 , and -F.
  • R 2 is pyrrole, pyrazole, imidazole, triazole, thiazole, Page 54 of 196 12746579v1 Attorney Docket No.: 2013518-0088 optionally substituted with R 2a .
  • R 2 is pyrazole optionally substituted with R 2a .
  • R 2 is pyrazole optionally substituted with R 2a , and wherein R 2a is - CH3 or -CD3. In some embodiments, R 2 is pyrazole substituted with two instances of R 2a , and wherein R 2a is -CD 3 and halogen. In some embodiments, R 2 is pyrazole substituted with two instances of R 2a , and wherein R 2a is -CD3 and -F. In some embodiments, R 2 is pyrazole or thiazole, optionally substituted with R 2a . , substituted with one or more instances of In some embodiments, is bicyclic 7- to 10- membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S.
  • R 2 is bicyclic 7- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, and is optionally substituted with R 2a .
  • R 2 is 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 R 2a .
  • R 2 is 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 R 2a .
  • R 2 is 8- to 10- membered bicyclic heteroaryl having 1 to 3 heteroatoms selected from N and O.
  • R 2 is 8- to 10- membered bicyclic heteroaryl having 1 to 3 heteroatoms selected from N and O. In some . [0143] C 10 aryl, and wherein R 2 is optionally substituted with one or more instances of R 2a . In some embodiments, R 2 is C 6 -C 10 aryl. In some embodiments, R 2 is phenyl optionally substituted with one or more instances of R 2a . In some embodiments, R 2 is phenyl. In some embodiments, R 2 is naphthyl.
  • R 2 is phenyl, and wherein R 2 is optionally substituted with one or more instances of R 2a selected from -L a -R b and -OR a .
  • R 2 is C6-C10 aryl optionally substituted with one or more instances of R 2a , and Page 55 of 196 12746579v1 Attorney Docket No.: 2013518-0088 wherein R 2a is -L a -R b , wherein L a is C 1 -C 6 aliphatic and R b is 4- to 10-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S, and optionally substituted with (CH2)0– 4S(O)2R°, wherein R° is C1–6 aliphatic.
  • R 2 is C3-C12 cycloaliphatic optionally substituted with one or more instances of R 2a .
  • R 2 is C 3 -C 6 cycloaliphatic.
  • R 2 is monocyclic 3- to 7-membered cycloaliphatic optionally substituted with one or more instances of R 2a .
  • R 2 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl.
  • R 2 is cyclopropyl.
  • R 2 is substituted with 0 to 4 instances of R 2a .
  • R 2 is substituted with 0 to 3 instances of R 2a . In some embodiments, R 2 is substituted with 1 to 3 instances of R 2a . In some embodiments, R 2 is substituted with 1 to 2 instances of R 2a . In some embodiments, R 2 is substituted with 1 instance of R 2a . In some embodiments, R 2 is substituted with 2 instances of R 2a . In some embodiments, R 2 is substituted with 3 instances of R 2a . In some embodiments, R 2 is substituted with 4 instances of R 2a . [0146] In some embodiments, R 2 is selected , , wherein each Y is independently CH, CH2, O, N, NH, and S, as valency permits.
  • R 2 is selected , and . [0149] In some embodiments, R 2 is selected .
  • R 2a is selected from optionally substituted C 1 -C 6 aliphatic, optionally substituted C 1 -C 6 heteroaliphatic, halogen, oxo, -CN, -NO2, -C(O)N(R a )2, -OC(O)R a , -OC(O)N(R a )2, -N(R a )C(O)R a , -N(R a )C(O)OR a , - N(R a )C(O)N(R a ) 2 , -S(O) 2 N(R a ) 2 , -N(R a )S(O) 2 R
  • R 2a is selected from oxo, -CN, -NO 2 , -C(O)N(R a ) 2 , - OC(O)R a , -OC(O)N(R a )2, -N(R a )C(O)R a , -N(R a )C(O)OR a , -N(R a )C(O)N(R a )2, -S(O)2N(R a )2, - N(R a )S(O) 2 R a , -S(O) 2 R a , and -OR a .
  • R 2a is selected from oxo, -C(O)N(R a ) 2 , -OC(O)R a , -S(O) 2 R a , and -OR a .
  • R 2a is selected from optionally substituted C1-C6 aliphatic and halogen.
  • R 2a is selected from -CD3 and -F.
  • R 2a is optionally substituted C1-C6 aliphatic.
  • R 2a is methyl or deuterated methyl (e.g., one or more H atoms of methyl have been replaced with deuterium).
  • R 2a is a branched C1-C6 aliphatic. In some embodiments, R 2a is C1-C6 aliphatic optionally substituted with –(CH2)0–4OR°, wherein R° is hydrogen or C1-C6 aliphatic. [0153] In some embodiments, R 2a is optionally substituted C 1 -C 3 aliphatic. In some embodiments, R 2a is optionally substituted C 3 -C 12 cycloaliphatic. In some embodiments, R 2a is optionally substituted C3-C6 cycloaliphatic. [0154] In some embodiments, R 2a is optionally substituted C1-C6 heteroaliphatic.
  • R 2a is methoxy. In some embodiments, R 2a is ethoxy. Page 57 of 196 12746579v1 Attorney Docket No.: 2013518-0088 [0155] In some embodiments, R 2a is halogen. In some embodiments, R 2a is fluoro. In some embodiments, R 2a is chloro. [0156] In some embodiments, R 2a is oxo. In some embodiments, R 2a is -CN. In some embodiments, R 2a is -NO 2 . In some embodiments, R 2a is -C(O)N(R a ) 2 . In some embodiments, R 2a is -C(O)NH2.
  • R 2a is -C(O)N(CH3)2. In some embodiments, R 2a is - OC(O)R a . In some embodiments, R 2a is -OC(O)CH3. In some embodiments, R 2a is -OC(O)N(R a )2. In some embodiments, R 2a is -OC(O)NH 2 . In some embodiments, R 2a is -OC(O)N(CH 3 ) 2 . In some embodiments, R 2a is -N(R a )C(O)R a . In some embodiments, R 2a is -NHC(O)CH3. In some embodiments, R 2a is -N(CH3)C(O)CH3.
  • R 2a is -N(R a )C(O)OR a . In some embodiments, R 2a is -NHC(O)OH. In some embodiments, R 2a is -NHC(O)OCH 3 . In some embodiments, R 2a is -N(R a )C(O)N(R a ) 2 . In some embodiments, R 2a is -NHC(O)NH 2 . In some embodiments, R 2a is -NHC(O)N(CH3)2. In some embodiments, R 2a is -S(O)2N(R a )2. In some embodiments, R 2a is -S(O)2NH2.
  • R 2a is -S(O)2N(CH3)2. In some embodiments, R 2a is -N(R a )S(O) 2 R a . In some embodiments, R 2a is -NHS(O) 2 CH 3 . In some embodiments, R 2a is-S(O)2R a . In some embodiments, R 2a is -OR a . In some embodiments, R 2a is - OH. In some embodiments, R 2a is -CH3. In some embodiments, R 2a is -CD3. [0157] In some embodiments, R 2a is -L a -R b .
  • L a is selected from a bond and optionally substituted C1-C6 aliphatic. In some embodiments, L a is a bond. In some embodiments, L a is optionally substituted C 1 -C 6 aliphatic. In some embodiments, L a is C 1 -C 3 aliphatic. In some embodiments, L a is methylene or ethylene. In some embodiments, L a is methylene.
  • R b is selected from optionally substituted C 3 -C 12 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- C 10 aryl.
  • R b is optionally substituted C3-C12 cycloaliphatic.
  • R b is optionally substituted C3-C6 cycloaliphatic.
  • R b is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
  • Page 58 of 196 12746579v1 Attorney Docket No.: 2013518-0088 [0161]
  • R b is optionally substituted 4- to 10-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S.
  • R b is optionally substituted monocyclic 5- to 6-membered heterocycle comprising 1 to 3 heteroatoms selected from N, O, and S.
  • R b is optionally substituted pyran.
  • R b is optionally substituted piperidine.
  • R b is optionally substituted morpholine.
  • R b is monocyclic 5- to 6-membered heterocycle comprising 1 to 3 heteroatoms selected from N, O, and S, and optionally substituted with (CH 2 ) 0–4 S(O) 2 R°, wherein R° is C 1–6 aliphatic.
  • R b is optionally substituted 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S.
  • R b is optionally substituted 5- to 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S.
  • R b is optionally substituted pyrazole, pyrrole, imidazole, triazole, oxazole, isoxazole, oxadiazole, isothiazole, thiazole, or thiadiazole.
  • R b is optionally substituted pyridine, pyridazine, pyrazine, or pyrimidine.
  • R b is optionally substituted C6-C10 aryl.
  • R b is optionally substituted phenyl.
  • R b is optionally substituted naphthyl.
  • R 2a is .
  • R 2a is . In some embodiments, R 2a .
  • R 2a is independently selected from hydrogen, optionally substituted C 1 -C 6 aliphatic, optionally substituted C 1 -C 6 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.
  • each R a is Page 59 of 196 12746579v1 Attorney Docket No.: 2013518-0088 independently selected from optionally substituted 5- to 12-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, optionally substituted 4- to 12-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S, optionally substituted C6-C12 aryl, optionally substituted C 3 -C 12 cycloaliphatic, or optionally substituted C 1 -C 6 aliphatic.
  • R a is hydrogen.
  • R a is optionally substituted C1-C6 aliphatic.
  • R a is -CH3. In some embodiments, R a is -CD3. In some embodiments, R a is optionally substituted 4- to 12-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, R a is a 4- to 6-membered heterocycle comprising at least 1 oxygen. In some embodiments, R a is tetrahydrofuran. In some embodiments, R a is pyran. In some embodiments, R a is optionally substituted 5- to 12-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S.
  • Q is selected from optionally substituted C1-C6 aliphatic, optionally substituted C1-C6 heteroaliphatic, optionally substituted C 3 -C 12 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- C 10 aryl.
  • Q is optionally substituted C 3 -C 6 cycloaliphatic, optionally substituted C6-C12 aryl, or optionally substituted 4- to 6-membered heterocycle comprising 1 to 3 heteroatoms selected from N, O, and S.
  • Q is optionally substituted C 1 -C 6 aliphatic.
  • Q is optionally substituted C 1 -C 3 aliphatic.
  • Q is - C(H)(CH3)-.
  • Q is optionally substituted C2-C6 alkynylene.
  • Q is C2-C4 alkynylene.
  • Q is a C2 alkynyl group.
  • Q is optionally substituted C 1 -C 6 heteroaliphatic.
  • Q is optionally substituted C3-C12 cycloaliphatic.
  • Q is optionally substituted C3-C7 cycloaliphatic.
  • Q is optionally substituted C 3 -C 6 cycloaliphatic.
  • Q is optionally substituted cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl.
  • Q is optionally substituted cyclopentyl or cyclobutyl.
  • Q is unsubstituted cyclopentyl or cyclobutyl. Page 60 of 196 12746579v1 Attorney Docket No.: 2013518-0088 or [0171]
  • Q is selected * represents a point of attachment to L 1 .
  • Q is optionally substituted 4- to 10-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S.
  • Q is optionally substituted 4- to 8-membered monocyclic heterocycle comprising 1 to 2 heteroatoms selected from N, O, and S.
  • Q is optionally substituted pyran, piperidine, or morpholine.
  • Q is optionally substituted pyran. In some embodiments, Q is optionally substituted piperidine. In some embodiments, Q is optionally substituted morpholine. [0173] In some embodiments, Q is optionally substituted 6- to 8-membered bridged or bicyclic heterocycle comprising 1 to 2 heteroatoms selected from N, O, and S. In some embodiments, Q is optionally substituted 6- to 8-membered monocyclic heterocycle comprising 1 to 2 heteroatoms selected from N and O. In some or represents a point of attachment to L 1 . embodiments, Q is optionally substituted 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S.
  • Q is optionally substituted 5- to 6-membered monocyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S.
  • Q is optionally substituted and selected from pyrazole, pyrrole, Page 61 of 196 12746579v1 Attorney Docket No.: 2013518-0088 imidazole, triazole, oxazole, isoxazole, oxadiazole, isothiazole, thiazole, and thiadiazole.
  • Q is optionally substituted pyrazole or thiazole.
  • * represents a point of attachment to L 1 .
  • Q is optionally substituted bicyclic 8- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, Q is optionally substituted bicyclic 8- to 10-membered heteroaryl comprising 1 to 2 heteroatoms selected from N and S. In some or , where * represents a point of attachment to L 1 . In some embodiments, Q is optionally substituted C6-C10 aryl. In some embodiments, Q is optionally substituted phenyl. In some embodiments, Q is optionally substituted naphthyl. , or represents a point of attachment to L 1 .
  • Z is selected from optionally substituted C1-C6 aliphatic, optionally substituted C1-C6 heteroaliphatic, optionally substituted C3-C12 cycloaliphatic, optionally substituted 4- to 10-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S, optionally substituted 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, and optionally substituted C6- C10 aryl.
  • Z is optionally substituted C1-C6 aliphatic, optionally substituted C 1 -C 6 heteroaliphatic, optionally substituted C 3 -C 12 cycloaliphatic, and optionally substituted C 6 - C10 aryl.
  • Z is optionally substituted C1-C6 aliphatic.
  • Z is optionally substituted C 1 -C 3 aliphatic.
  • Z is -C(H)(CH 3 )-.
  • Z is optionally substituted C 2 -C 6 alkynylene.
  • Z is C2-C4 alkynylene.
  • Z is a C2 alkynyl group. In some embodiments, Z is optionally substituted C1-C6 heteroaliphatic. [0180] In some embodiments, Z is optionally substituted C 3 -C 12 cycloaliphatic. In some embodiments, Z is optionally substituted C3-C7 cycloaliphatic. In some embodiments, Z is optionally substituted C3-C6 cycloaliphatic. In some embodiments, Z is optionally substituted cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl. [0181] In some embodiments, Z is or represents a point of attachment to L 3 .
  • Z is optionally substituted 4- to 10-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, Z is optionally substituted 4- to 8-membered monocyclic heterocycle comprising 1 to 2 heteroatoms selected from N, O, and S. In some embodiments, Z is optionally substituted pyran, piperidine, or morpholine. In some embodiments, Z is optionally substituted pyran. In some embodiments, Z is optionally substituted piperidine. In some embodiments, Z is optionally substituted morpholine.
  • Z is optionally substituted 6- to 8-membered bridged or bicyclic heterocycle comprising 1 to 2 heteroatoms selected from N, O, and S.
  • Z is optionally substituted 6- to 8-membered monocyclic heterocycle comprising 1 to 2 heteroatoms selected from N and O.
  • Z is optionally substituted 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S.
  • Z is optionally substituted 5- to 6-membered monocyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S.
  • Z is optionally substituted and selected from pyrazole, pyrrole, imidazole, triazole, oxazole, isoxazole, oxadiazole, isothiazole, thiazole, and thiadiazole.
  • Z is optionally substituted pyrazole or thiazole.
  • Z is unsubstituted pyrazolyl or thiazolyl.
  • ** represents a point of attachment to L3.
  • ** represents a point of attachment to L 3 .
  • Z is optionally substituted bicyclic 8- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S.
  • Z is optionally substituted bicyclic 8- to 10-membered heteroaryl comprising 1 to 2 heteroatoms selected from N and S.
  • Z is optionally substituted indazolyl.
  • Page 64 of 196 12746579v1 Attorney Docket No.: 2013518-0088 embodiments Z is unsubstituted indazolyl.
  • In some ** represents a point of attachment to L 3 .
  • Page 65 of 196 12746579v1 Attorney Docket No.: 2013518-0088
  • Z is optionally substituted C 6 -C 10 aryl.
  • Z is optionally substituted phenyl. In some embodiments, Z is optionally substituted naphthyl. In some embodiments, Z is unsubstituted phenyl. In some . , * * [0189] In some embodiments, Z is phenyl, alkynyl, pyrazolyl, thiazolyl, or indazolyl, [0190] In some embodiments, Z is selected , ** represents a point of attachment to L 3 . e mbodiments, Z is selected , represents a point of attachment to L 3 .
  • L 1 is a bond, a 4- to 6- membered heterocycle having 1 to 2 heteroatoms independently selected from N, O, and S, - C(O)N(R a )-, -OC(O)-, -OC(O)N(R a )-, -N(R a )C(O)-, -N(R a )C(O)O-, -N(R a )C(O)N(R a )-, - S(O)2N(R a )-, -N(R a )S(O)2-, -S(O)2-, -C(R a )2O-, -N(Ra)-, -S-, or -O-.
  • L 1 is -N(R a )C(O)-, -N(R a )C(O)O-, -N(R a )C(O)N(R a )-, or -O-. In some embodiments, L 1 is -OC(O)-, - OC(O)N(R a )-, -C(R a )2O-, -N(Ra)-, -S-, or -O-. In some embodiments, L 1 is -N(R a )C(O)O- or - N(R a )C(O)N(R a )-.
  • L 1 is -C(R a )2O- or -O-. [0194] In some embodiments, L 1 is a bond. [0195] In some embodiments, L 1 is a 4- to 6-membered heterocycle having 1 to 2 heteroatoms independently selected from N, O, and S. In some embodiments, L 1 is azetidine. In some embodiments, L 1 is -C(O)N(R a )-. In some embodiments, L 1 is -C(O)NH-. In some embodiments, L 1 is -OC(O)-. In some embodiments, L 1 is -OC(O)N(R a )-. In some embodiments, L 1 is -OC(O)NH-.
  • L 1 is -N(R a )C(O)-. In some embodiments, L 1 is - NHC(O)-. In some embodiments, L 1 is -N(R a )C(O)O-. In some embodiments, L 1 is -NHC(O)O-. In some embodiments, L 1 is -N(R a )C(O)N(R a )-. In some embodiments, L 1 is -NHC(O)NH-. In some embodiments, L 1 is -S(O)2N(R a )-. In some embodiments, L 1 is -S(O)2NH-.
  • L 1 is -N(R a )S(O)2-. In some embodiments, L 1 is -NHS(O)2-. In some embodiments, L 1 is -S(O) 2 -. In some embodiments, L 1 is -C(R a ) 2 O-. In some embodiments, L 1 is -CH 2 O-. In some embodiments, L 1 is -N(R a )-. In some embodiments, L 1 is -NH-. In some embodiments, L 1 is -S-. In some embodiments, L 1 is -O-. In some embodiments, L 1 is -N(CH3)-.
  • L 1 is -OC(O)N(R a )- or -N(R a )C(O)O-. In some embodiments, L 1 is -OC(O)NH- or -NHC(O)O-.
  • L 3 is a bond, a 4- to 6- membered heterocycle having 1 to 2 heteroatoms independently selected from N, O, and S, - C(O)N(R a )-, -OC(O)-, -OC(O)N(R a )-, -N(R a )C(O)-, -N(R a )C(O)O-, -N(R a )C(O)N(R a )-, - S(O)2N(R a )-, -N(R a )S(O)2-, -S(O)2-, -C(R a )2O-, -N(Ra)-, -S-, or -O-.
  • L 3 is -N(R a )C(O)-, -N(R a )C(O)O-, -N(R a )C(O)N(R a )-, or -O-. In some embodiments, L 3 is -OC(O)-, - OC(O)N(R a )-, -C(R a ) 2 O-, -N(R a )-, -S-, or -O-.
  • L 3 is -N(R a )C(O)O- or - Page 67 of 196 12746579v1 Attorney Docket No.: 2013518-0088 N(R a )C(O)N(R a )-.
  • L 3 is -C(R a ) 2 O- or -O-.
  • L 3 is a bond, a 4- to 6-membered heterocycle having 1 to 2 heteroatoms independently selected from N, O, and S, -C(R a )2O-, -N(Ra)-, or -O-.
  • L 3 is a bond, azetidinyl, -CH2O-, - N(CH 3 )-, or -O-. [0197] In some embodiments, L 3 is a bond. In some embodiments, L 3 is a 4- to 6- membered heterocycle having 1 to 2 heteroatoms independently selected from N, O, and S. In some embodiments, L 3 is azetidinyl. In some embodiments, L 3 is -C(O)N(R a )-. In some embodiments, L 3 is -C(O)NH-. In some embodiments, L 3 is -OC(O)-. In some embodiments, L 3 is -OC(O)N(R a )-.
  • L 3 is -OC(O)NH-. In some embodiments, L 3 is - N(R a )C(O)-. In some embodiments, L 3 is -NHC(O)-. In some embodiments, L 3 is -N(R a )C(O)O-. In some embodiments, L 3 is -NHC(O)O-. In some embodiments, L 3 is -N(R a )C(O)N(R a )-. In some embodiments, L 3 is -NHC(O)NH-. In some embodiments, L 3 is -S(O)2N(R a )-. In some embodiments, L 3 is -S(O)2NH-.
  • L 3 is -N(R a )S(O)2-. In some embodiments, L 3 is -NHS(O) 2 -. In some embodiments, L 3 is -S(O) 2 -. In some embodiments, L 3 is -C(R a ) 2 O-. In some embodiments, L 3 is -CH2O-. In some embodiments, L 3 is -N(Ra)-. In some embodiments, L 3 is -NH-. In some embodiments, L 3 is -N(CH3)-. In some embodiments, L 3 is -S-. In some embodiments, L 3 is -O-. In some embodiments, L 3 is -N(CH 3 )-.
  • L 1 is -N(R a )C(O)O- or -N(R a )C(O)N(R a )-, and L 3 is - C(R a )2O- or -O-.
  • L 1 is -N(R a )C(O)O- and L 3 is -O-.
  • L 1 is -NHC(O)O- and L 3 is -O-.
  • L 1 is -NHC(O)O- and L 3 is -CH 2 O-.
  • L 1 is -NHC(O)O- and L 3 is a bond.
  • L 2 is optionally substituted C1-C6 aliphatic, optionally substituted 2- to 6-membered heteroaliphatic, optionally substituted 4- to 10-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S, or optionally substituted C3-C10 cycloaliphatic.
  • L 2 is optionally substituted C1-C6 aliphatic or optionally substituted 2- to 6-membered heteroaliphatic.
  • L 2 is optionally substituted C 1 -C 6 aliphatic.
  • L 2 is optionally substituted C1-C4 aliphatic.
  • L 2 is unsubstituted C1-C4 aliphatic. In some embodiments, L 2 is an optionally substituted methyl, ethyl, propyl, butyl, or pentyl group. In some embodiments, L 2 is optionally substituted ethylene, propylene, butylene, or pentylene. In some Page 68 of 196 12746579v1 Attorney Docket No.: 2013518-0088 embodiments, L 2 is optionally substituted C 1 -C 6 aliphatic, optionally substituted 2- to 6-membered heteroaliphatic, or optionally substituted 4- to 10-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S.
  • L 2 is unsubstituted C1-C6 aliphatic, unsubstituted 2- to 6-membered heteroaliphatic, or unsubstituted 4- to 10-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S.
  • L 2 is optionally substituted 2- to 6-membered heteroaliphatic.
  • L 2 is optionally substituted 2- to 6-membered heteroaliphatic selected from -CH2-O-CH2-, -CH2-CH2-O-CH2-, -CH2-CH2-O-CH2-CH2-, or - CH2-CH2-CH2-O-CH2-CH2-CH2-.
  • L 2 is optionally substituted -CH2-CH2- O-CH 2 -CH 2 -. In some embodiments, L 2 is optionally substituted 5-membered heteroaliphatic. In some embodiments, L 2 is unsubstituted 5-membered heteroaliphatic. In some embodiments, L 2 is -CH2-CH2-O-CH2-CH2-. [0201] In some embodiments, L 2 is an optionally substituted 4- to 10-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, L 2 is an optionally substituted 4- to 6-membered heterocycle comprising 1 to 2 heteroatoms selected from N, O, and S.
  • L 2 is an optionally substituted tetrahydrofuran. In some embodiments, L 2 is an optionally substituted pyran. In some embodiments, L 2 is an optionally substituted oxetane. In some embodiments, L 2 is an optionally substituted 4- to 10- membered heterocycle comprising 1 to 2 heteroatoms selected from N, O, and S, and is attached in a spirocyclic manner. In some embodiments, L 2 is an optionally substituted 4- to 7-membered heterocycle comprising 1 to 2 heteroatoms selected from N, O, and S, and is attached in a spirocyclic manner. In some In some embodiments, L 2 is . In some embodiments, L 2 is .
  • L 2 is an optionally substituted 4- to 6-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, L 2 is tetrahydrofuran. In some . Page 69 of 196 12746579v1 Attorney Docket No.: 2013518-0088 [0202] In some embodiments, L 2 is an optionally substituted C 3 to C 10 cycloaliphatic. In some embodiments, L 2 is an optionally substituted monocyclic C3 to C7 cycloaliphatic. In some embodiments, L 2 is optionally substituted and selected from cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • L 2 is an optionally substituted C 3 to C 10 cycloaliphatic that is attached in a spirocyclic manner. In some embodiments, L 2 is an optionally substituted monocyclic C3 to C7 cycloaliphatic that is attached in a spirocyclic manner.
  • a compound represented by formula I wherein: R 1 is optionally substituted C 1 -C 6 aliphatic; R 2 is selected from C3-C12 cycloaliphatic, 4- to 10-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S, 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, or C 6 -C 10 aryl, wherein R 2 is optionally substituted with one or more instances of R 2a ; each R 2a is independently selected from the group consisting of optionally substituted C 1 -C 6 aliphatic, halogen, -S(O) 2 R a , -OR a , and -L a -R b ; Page 70 of 196 12746579v1 Attorney Docket No.: 2013518-0088 each L a is independently selected from a bond and optionally substituted C 1 -C 6 aliphatic;
  • R 2 is 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, or C6-C10 aryl, wherein R 2 is optionally substituted with one or more instances of R 2a ; and each R 2a is independently selected from the group consisting of optionally substituted C1-C6 aliphatic, -OR a , and -L a -R b .
  • R 1 is -CD3 and R 2 is 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S optionally substituted with one or more instances of R 2a .
  • Q is selected from optionally substituted C 1 -C 6 aliphatic, optionally substituted C3-C12 cycloaliphatic, and optionally substituted C6-C10 aryl
  • Z is selected from optionally substituted C1-C6 aliphatic, optionally substituted C1-C6 heteroaliphatic, optionally substituted C 3 -C 12 cycloaliphatic, and optionally substituted C 6 -C 10 aryl.
  • Q is optionally substituted C3-C12 cycloaliphatic and Z is optionally substituted C6- C10 aryl.
  • L 1 is N(R a )C(O)O-, -N(R a )-, or -O-;
  • L 2 is optionally substituted C1-C6 aliphatic, and
  • L 3 is N(R a )C(O)O-, -N(Ra)-, or -O-.
  • L 1 is N(R a )C(O)O- or -N(Ra)-;
  • L 2 is optionally substituted C1-C6 aliphatic or optionally substituted 2- to 6-membered heteroaliphatic, and
  • L 3 is -C(R a ) 2 O- or -O-.
  • a compound is of formula I, wherein R 1 is optionally substituted C1-C6 aliphatic; R 2 is 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, wherein R 2 is optionally substituted with one or more instances of R 2a ; each R 2a is independently selected from the group consisting of optionally substituted C1-C6 aliphatic, halogen, and -OR a ; each R a is independently selected from hydrogen and optionally substituted C 1 -C 6 aliphatic; Q is selected from optionally substituted C3-C12 cycloaliphatic, optionally substituted 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, and optionally substituted C 6 -C 10 aryl; Z is selected from optionally substituted C1-C6 aliphatic, optionally substituted 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from
  • the present disclosure provides a compound selected from Table 1, or a pharmaceutically acceptable salt thereof.
  • Table 1 Compoun Compoun d Structure d Structure Page 73 of 196 12746579v1 Attorney Docket No.: 2013518-0088 Page 74 of 196 12746579v1 Attorney Docket No.: 2013518-0088 3 Page 75 of 196 12746579v1 Attorney Docket No.: 2013518-0088 F H N N N 3 3 Page 76 of 196 12746579v1 Attorney Docket No.: 2013518-0088 3 Page 77 of 196 12746579v1 Attorney Docket No.: 2013518-0088 Page 78 of 196 12746579v1 Attorney Docket No.: 2013518-0088 Page 79 of 196 12746579v1 Attorney Docket No.: 2013518-0088 [0211]
  • Table 1 Compoun Compoun d Structure d Structure Page 73 of 196 12746579v1 Attorney Docke
  • 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.
  • biochemical or cellular assays e.g., the JAK2 Binding Assay or SET2-pSTAT5 Cellular Assay described herein
  • ADME
  • provided compounds display certain desirable characteristics in one or more assays described herein, e.g., compared to other known compounds.
  • provided compounds are provided and/or utilized in a salt form (e.g., a pharmaceutically acceptable salt form).
  • 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.
  • compositions [0214] The present disclosure also provides compositions comprising a compound provided herein with one or more other components.
  • provided compositions comprise and/or deliver a compound described herein (e.g., compounds of Formulae I-A–I-L, II-A–II-K, III-A–III-D, IV-A–IV-D, and V-A–V-D).
  • a provided composition is a pharmaceutical composition that comprises and/or delivers a compound provided herein (e.g., compounds of Formulae I-A–I- L, II-A–II-K, III-A–III-D, IV-A–IV-D, and V-A–V-D), and further comprises a pharmaceutically acceptable carrier.
  • 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.
  • 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.
  • provided compounds are formulated in a unit dosage form for ease of administration and uniformity of dosage.
  • unit dosage form 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.
  • a unit dosage form contains an entire single dose of the agent. In some embodiments, more than one unit dosage form is administered to achieve a total single dose. In some embodiments, administration of multiple unit dosage forms is required, or expected to be required, in order to achieve an intended effect.
  • a unit dosage form may be, for example, a liquid pharmaceutical composition containing a predetermined quantity of one or more active Page 81 of 196 12746579v1 Attorney Docket No.: 2013518-0088 agents, a solid pharmaceutical composition (e.g., a tablet, a capsule, or the like) containing a predetermined amount of one or more active agents, a sustained release formulation containing a predetermined quantity of one or more active agents, or a drug delivery device containing a predetermined amount of one or more active agents, etc.
  • Provided compositions may be administered using any amount and any route of administration effective for treating or lessening the severity of any disease or disorder described herein. Uses [0218] The present disclosure provides uses for compounds and compositions described herein.
  • provided compounds and compositions are useful in medicine (e.g., as therapy). In some embodiments, provided compounds and compositions are useful in research as, for example, analytical tools and/or control compounds in biological assays. [0219] In some embodiments, the present disclosure provides methods of administering provided compounds or compositions to a subject in need thereof. In some embodiments, the present disclosure provides methods of administering provided compounds or compositions to a subject suffering from or susceptible to a disease, disorder, or condition associated with JAK2. [0220] In some embodiments, provided compounds are useful as JAK2 inhibitors. In some embodiments, provided compounds are useful as JAK2 inhibitors that bind the pseudokinase (JH2) domain of JAK2.
  • JH2 pseudokinase
  • 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.
  • JAK e.g., JAK2
  • JAK2 has been implicated in various diseases, disorders, and conditions, such as myeloproliferative neoplasms (Vainchenker, W. et al., F1000Research 2018, 7(F1000 Faculty Rev):82), atopic dermatitis (Rodrigues, M. A. and Torres, T. J. Derm. Treat.
  • the present disclosure provides methods of treating a disease, disorder or condition Page 82 of 196 12746579v1 Attorney Docket No.: 2013518-0088 associated with JAK2 in a subject in need thereof comprising administering to the subject a provided compound or composition.
  • a disease, disorder, or condition is associated with overexpression of JAK2.
  • the present disclosure provides methods of treating cancer, comprising administering a provided compound or composition to a subject in need thereof.
  • the present disclosure provides methods of treating proliferative diseases, comprising administering a provided compound or composition to a subject in need thereof.
  • the present disclosure provides methods of treating a hematological malignancy, comprising administering a provided compound or composition to a subject in need thereof.
  • 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).
  • a hematological malignancy is lymphoma (e.g., Burkitt’s lymphoma, Hodgkin’s lymphoma, or non-Hodgkin’s lymphoma).
  • a non- Hodgkin’s lymphoma is a B-cell lymphoma.
  • a non-Hodgkin’s lymphoma is a NK/T-cell lymphoma (e.g., cutaneous T-cell lymphoma).
  • a hematological malignancy is myeloma (e.g., multiple myeloma).
  • a hematological malignancy is myeloproliferative neoplasm (e.g., polycythemia vera, essential thrombocytopenia, or myelofibrosis). In some embodiments, a hematological malignancy is myelodysplastic syndrome.
  • 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.
  • a provided compound or composition is administered as part of a combination therapy.
  • 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).
  • the two or more regimens may be administered simultaneously; in some embodiments, such regimens may be Page 83 of 196 12746579v1 Attorney Docket No.: 2013518-0088 administered sequentially (e.g., all “doses” of a first regimen are administered prior to administration of any doses of a second regimen); in some embodiments, such agents are administered in overlapping dosing regimens.
  • “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.
  • combination therapy does not require that individual agents be administered together in a single composition (or even necessarily at the same time), although in some embodiments, two or more agents, or active moieties thereof, may be administered together in a combination composition.
  • 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.
  • 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
  • CXCR2 inhibitors CXCR2 inhibitors.
  • a combination of a JAK2 inhibitor with a LSD1 inhibitor demonstrated good efficacy in a mouse model of myeloproliferative neoplasms (Jutzi, J.S., et al., HemaSphere 2018, 2(3), http://dx.doi.org/10.1097/HS9.0000000000000054).
  • CXCR2 activity has been shown to modulate signaling pathways involved in tumor growth, angiogenesis, and/or metastasis, including the JAK-STAT3 pathway (Jaffer, T., Ma, D. Transl. Cancer Res.2016, 5(Suppl.4), S616-S628).
  • Embodiment 1 A compound represented by formula I: Page 84 of 196 12746579v1 Attorney Docket No.: 2013518-0088 or a pharmaceutically acceptable salt thereof, wherein: R 1 is hydrogen or optionally substituted C1-C6 aliphatic; R 2 is C1-C6 aliphatic, C1-C6 heteroaliphatic, C3-C12 cycloaliphatic, 4- to 10-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S, 5- to 10- membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, or C 6 - C10 aryl, wherein R 2 is optionally substituted with one or more instances of R 2a ; each R 2a is independently selected from the group consisting of optionally substituted C 1 - C 6 aliphatic, optionally substituted C 1 -C 6
  • Embodiment 2 The compound of Embodiment 1, wherein R 1 is optionally substituted C1- C 6 aliphatic.
  • Embodiment 3. The compound of Embodiments 1 or 2, wherein R 1 is -CH3 or -CD3.
  • Embodiment 4. The compound of any one of Embodiments 1-3, wherein R 2 is 5- to 10- membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, C3-C6 cycloaliphatic, or C 6 -C 10 aryl, and wherein R 2 is optionally substituted with one or more instances of R 2a .
  • Page 86 of 196 12746579v1 Attorney Docket No.: 2013518-0088 Embodiment 5.
  • Embodiment 1 wherein R 2 is 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, C3-C6 cycloaliphatic, or 4- to 10-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S, and wherein R 2 is optionally substituted with one or more instances of R 2a .
  • Embodiment 6 The compound of any one of Embodiments 1-5, wherein R 2 is 5- to 10- membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, and wherein R 2 is optionally substituted with one or more instances of R 2a .
  • Embodiment 6 wherein R 2 is 5- to 6-membered monocyclic heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S, and wherein R 2 is optionally substituted with one or more instance of R 2a .
  • Embodiment 8 The compound of Embodiment 7, wherein R 2 is 5- to 6-membered monocyclic heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S, and wherein R 2 is substituted with one or more instances of R 2a , wherein R 2a is selected from optionally substituted C1-C6 aliphatic and -OR a .
  • Embodiment 8 wherein R 2 is 5- to 6-membered monocyclic heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S, and wherein R 2 is substituted with one or more instances of R 2a , wherein R 2a is selected from optionally substituted C1-C6 aliphatic and halogen.
  • Embodiment 10. The compound of any one of Embodiments 1-4, wherein R 2 is C6-C10 aryl, and wherein R 2 is optionally substituted with one or more instances of R 2a .
  • Embodiment 11 The compound of any one of Embodiments 1-4, wherein R 2 is C6 aryl, and wherein R 2 is optionally substituted with one or more instances of R 2a .
  • Embodiment 12 The compound Embodiment 11 wherein R 2 is optionally substituted with one or more instances of R 2a , wherein R 2a is selected from -L a -R b and -OR a .
  • Embodiment 13 The compound of any one of Embodiments 1-3, wherein R 2 is selected from: , Embodiment 14.
  • Embodiment 16 wherein Q is optionally substituted C 3 - C6 cycloaliphatic.
  • Embodiment 20 The compound of any one of Embodiments 1-15, wherein Q is: , Embodiment 21. The compound of Embodiment 20, wherein Q is: , of attachment to L 1 .
  • Embodiment 22 The compound of any one of Embodiments 1-21, wherein Z is optionally substituted C1-C6 aliphatic, optionally substituted C1-C6 heteroaliphatic, optionally substituted C3- C 12 cycloaliphatic, and optionally substituted C 6 -C 10 aryl.
  • Embodiment 23 The compound of any one of Embodiments 1-21, wherein Z is optionally substituted C1-C6 aliphatic, optionally substituted 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, and optionally substituted C6-C10 aryl.
  • Embodiment 24 The compound of Embodiment 23, wherein Z is: , Embodiment 25.
  • Embodiment 27 The compound of any one of Embodiments 1-24, wherein Z is optionally substituted C 6 -C 10 aryl.
  • Embodiment 28 The compound of any one of Embodiments 1-21, wherein Z is: , Page 90 of 196 12746579v1 Attorney Docket No.: 2013518-0088 Embodiment 29.
  • Embodiment 30 The compound of Embodiment 29, wherein L 1 is -OC(O)N(R a )- or - N(R a )C(O)O-.
  • Embodiment 31 The compound of Embodiment 30, wherein L 1 is -OC(O)NH- or - NHC(O)O-.
  • Embodiment 32 The compound of any one of Embodiments 1-28, wherein L 1 is -N(R a )C(O)- , -N(R a )C(O)O-, -N(R a )C(O)N(R a )-, or -O-.
  • Embodiment 30 The compound of Embodiment 29, wherein L 1 is -OC(O)N(R a )- or - N(R a )C(O)O-.
  • Embodiment 31 The compound of Embodiment 30, wherein L 1 is -OC(O)NH- or
  • Embodiment 33 The compound of any one of Embodiments 1-31, wherein L 3 is -OC(O)-, - OC(O)N(R a )-, -C(R a ) 2 O-, -N(R a )-, -S-, or -O-.
  • Embodiment 33 The compound of any one of Embodiments 1-31, wherein L 3 is a bond, a 4- to 6-membered heterocycle having 1 to 2 heteroatoms independently selected from N, O, and S, - C(R a )2O-, -N(Ra)-, or -O-.
  • Embodiment 34 Embodiment 34.
  • Embodiment 33 wherein L 3 is a bond, azetidinyl, -CH 2 O- , -N(CH3)-, or -O-.
  • Embodiment 35 The compound of any one of Embodiments 1-34, wherein L 1 is - N(R a )C(O)O- or -N(R a )C(O)N(R a )-, and L 3 is -C(R a ) 2 O- or -O-.
  • Embodiment 36 The compound of any one of Embodiments 1-35, wherein L 1 is - N(R a )C(O)O- and L 3 is -O-.
  • Embodiment 37 The compound of any one of Embodiments 1-35, wherein L 1 is - N(R a )C(O)O- and L 3 is -O-.
  • Embodiment 40 The compound of any one of Embodiments 1-36, wherein L 2 is an optionally substituted C 1 -C 6 aliphatic.
  • Embodiment 38 The compound of Embodiment 37, wherein L 2 is C1-C6 alkylene or C2-C6 alkenylene. Page 91 of 196 12746579v1 Attorney Docket No.: 2013518-0088 Embodiment 39.
  • L 2 is an optionally substituted 4- to 10-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S.
  • Embodiment 40 The compound of any one of Embodiments 1-36, wherein L 2 is an optionally substituted 4- to 10-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S.
  • Embodiment 41 The compound of any one of Embodiments 1-36, wherein L 2 is an optionally substituted 4- to 6-membered heterocycle comprising 1 to 2 heteroatoms selected from N, O, and S.
  • Embodiment 41 The compound of any one of Embodiments 1-36, wherein L 2 is an optionally substituted 4- to 7-membered heterocycle comprising 1 to 2 heteroatoms selected from N, O, and S, and is attached in a spirocyclic manner.
  • Embodiment 42 The compound of any one of Embodiments 1-36, wherein L 2 is an optionally substituted monocyclic C 3 to C 7 cycloaliphatic.
  • Embodiment 43 The compound of any one of Embodiments 1-36, wherein L 2 is an optionally substituted monocyclic C 3 to C 7 cycloaliphatic.
  • Embodiment 44 The compound of any one of Embodiments 1-36, wherein L 2 is optionally substituted C 1 -C 6 aliphatic, optionally substituted 2- to 6-membered heteroaliphatic, or optionally substituted 4- to 10-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S.
  • Embodiment 44 The compound of any one of Embodiments 1-36, wherein L 2 is: *-CH 2 -**, , where * represents a point of attachment to L 1 and ** represents a point of attachment to L 3 .
  • Page 92 of 196 12746579v1 Attorney Docket No.: 2013518-0088 Embodiment 45.
  • Embodiment 43 wherein L 2 is: *-CH 2 - , Embodiment 46.
  • the compound of Embodiment 1, wherein the compound is represented by formula I-A–I-L or a pharmaceutically acceptable salt thereof.
  • Embodiment 47 The compound of Embodiment 1, wherein the compound is represented by formula II-A–II-K or a pharmaceutically acceptable salt thereof.
  • Embodiment 48 The compound of Embodiment 1, wherein the compound is represented by formula III-A–III-D or a pharmaceutically acceptable salt thereof.
  • Embodiment 49 The compound of Embodiment 1, wherein the compound is represented by formula IV-A–IV-D or a pharmaceutically acceptable salt thereof.
  • Embodiment 50 The compound of Embodiment 50.
  • Embodiment 51 A compound selected from Table 1, or a pharmaceutically acceptable salt thereof.
  • Embodiment 52 A pharmaceutical composition comprising a compound of any one of Embodiments 1-51, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • Page 93 of 196 12746579v1 Attorney Docket No.: 2013518-0088 Embodiment 53.
  • a method of inhibiting JAK2 in a subject comprising administering to the subject the compound of any one of Embodiments 1-51 or the pharmaceutical composition of Embodiment 52.
  • Embodiment 54 A method of inhibiting JAK2 in a subject, comprising administering to the subject the compound of any one of Embodiments 1-51 or the pharmaceutical composition of Embodiment 52.
  • Embodiment 55. A method of treating cancer, comprising administering to a subject in need thereof the compound of any one of Embodiments 1-51 or the pharmaceutical composition of Embodiment 52.
  • Embodiment 56. A method of treating a hematological malignancy, comprising administering to a subject in need thereof the compound of any one of Embodiments 1-51 or the pharmaceutical composition of Embodiment 52.
  • Embodiment 57 The method of Embodiment 56, wherein the hematological malignancy is leukemia or lymphoma.
  • Embodiment 58 A method of treating a myeloproliferative neoplasm, comprising administering to a subject in need thereof the compound of any one of Embodiments 1-51 or the pharmaceutical composition of Embodiment 52.
  • Example 1 Synthesis of (3 1 R,3 3 R)-2 7 -(3-fluoro-1-(methyl-d 3 )-1H-pyrazol-4-yl)-2 3 -(methyl- d 3 )-21 ,2 2 ,2 3 ,2 6 -tetrahydro-6,11-dioxa-4-aza-2(8,1)-imidazo[4,5-d]pyrrolo[2,3-b]pyridina- 1(1,4)-benzena-3(1,3)-cyclopentanacycloundecaphane-2 2 ,5-dione (Compound I-1A) Page 96 of 196 12746579v1 Attorney Docket No.: 2013518-0088 mol, 1.0 equiv) in THF ( 1 L) at 0 o C was added sodium hydride (60% in mineral oil, 123.2 g, 3.08 mol, 1.5 equiv) in portions and stirred for 45 min.
  • Compound I-1A Page 96 of 196 12
  • N-fluorobenzenesulfonimide (170 g, 541.51 mmol, 1.5 equiv) in THF (500 mL) was added slowly at -78 °C and stirred for 45 min. It was transferred into saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 1% ethyl acetate in hexane) to afford 1.2 (12.5 g, Yield: 12%).
  • Triisopropylborate (9.5 g, 50.8 mmol, 1.2 equiv) was added dropwise at -78 °C and stirred for 45 min.
  • 2,3-Dimethylbutane- 2,3-diol (6.49 g, 55.04 mmol, 1.3 equiv) at -78°C and stirred for 45 min. It was transferred into saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure.
  • Example 2 Synthesis of (3 1 R,3 3 R)-2 7 -(3-fluoro-1-(methyl-d 3 )-1H-pyrazol-4-yl)-2 3 -(methyl- d 3 )-21 ,2 2 ,2 3 ,2 6 -tetrahydro-6,11-dioxa-4-aza-2(8,1)-imidazo[4,5-d]pyrrolo[2,3-b]pyridina- 1(1,4)-benzena-3(1,3)-cyclopentanacycloundecaphane-2 2 ,5-dione (Compound I-1A) Page 102 of 196 12746579v1 Attorney Docket No.: 2013518-0088
  • Example 3 Synthesis of (3 1 s,3 3 s)-2 7 -(3-fluoro-1-(methyl-d 3 )-1H-pyrazol-4-yl)-2 3 -(methyl- d 3 )-21 ,2 2 ,2 3 ,2 6 -
  • Example 4 Synthesis of (3 1 s,3 3 s)-2 7 -(3-fluoro-1-(methyl-d 3 )-1H-pyrazol-4-yl)-2 3 -(methyl- d 3 )-21 ,2 2 ,2 3 ,2 6 -tetrahydro-6,11-dioxa-4-aza-2(8,1)-imidazo[4,5-d]pyrrolo[2,3-b]pyridina- 1(1,4)-benzena-3(1,3)-cyclobutanacycloundecaphane-2 2 ,5-dione (Compound I-2A) Page 108 of 196 12746579v1 Attorney Docket No.: 2013518-0088 d 3 )-21 ,2 2 ,2 3 ,2 6 -tetrahydro-6,11-dioxa-4-aza-2(8,1)-imidazo[4,5-d]pyrrolo[2,3-b]pyridina- 1(1,4)-benzena
  • Example 6 Synthesis of (3 1 s,3 3 s)-2 7 -(3-fluoro-1-(methyl-d 3 )-1H-pyrazol-4-yl)-2 3 -(methyl- d 3 )-21 ,2 2 ,2 3 ,2 6 -tetrahydro-6,11-dioxa-4-aza-2(8,1)-imidazo[4,5-d]pyrrolo[2,3-b]pyridina- 1(1,4)-benzena-3(1,3)-cyclobutanacycloundecaphan-8-ene-2 2 ,5-dione (Compound I-3AC)
  • Example 7 Synthesis of (3 1 s,3 3 s)-2 7 -(3-fluoro-1-(methyl-d 3 )-1H-pyrazol-4-yl)-2 3 -(methyl- d 3 )-21 ,2 2 ,2 3 ,2 6 -tetrahydro-6,9,12-trioxa-4-aza-2(
  • reaction mixture was stirred at 0 o C for 10 min.
  • a solution of tosyl chloride (0.043 g, 0.227 mmol, 1.0 equiv) in DMF dropwise at 0 °C.
  • the reaction mixture was stirred for 1 h. It was poured into crushed ice and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 3.5% methanol in DCM) to afford 4.5 (0.040 g, Yield: 25%).
  • Example 8 Synthesis of (3 1 s,3 3 s)-2 7 -(3-fluoro-1-(methyl-d 3 )-1H-pyrazol-4-yl)-2 3 -(methyl- d 3 )-21 ,2 2 ,2 3 ,2 6 -tetrahydro-6,9,12-trioxa-4-aza-2(8,1)-imidazo[4,5-d]pyrrolo[2,3-b]pyridina- 1(1,4)-benzena-3(1,3)-cyclobutanacyclododecaphane-2 2 ,5-dione (Compound I-4A) B(OH) PhO S Bn F SO Ph F SO Ph F N O N N N N CD Page 113 of 196 12746579v1 Attorney Docket No.: 2013518-0088
  • Example 9 Synthesis of (3 1 s,3 3 s)-2 7 -(3-fluoro-1-(methyl-d 3 )-1H-pyrazol-4-yl)
  • Example 11 Synthesis of Compound I-6A Page 117 of 196 12746579v1 Attorney Docket No.: 2013518-0088
  • Example 12 Synthesis of Compound I-7A Page 118 of 196 12746579v1 Attorney Docket No.: 2013518-0088 [0280] Synthesis of compound 7.1. To a solution of 2-((tert- butyldimethylsilyl)oxy)ethan-1-ol (5 g, 28.36 mmol, 1.0 equiv) in DMF (50 mL) was added sodium hydride (60%wt in mineral oil, 1.70 g, 42.53 mmol, 1.5 equiv) was added at 0 o C.
  • Tetrakis(triphenylphosphine)palladium (0) (0.340 g, 0.294 mmol, 0.1 equiv) was added and degassed by argon for 10 min. The reaction mixture was stirred at 100 oC for 12 h. It was diluted with water and extracted with ethyl acetate. The organic extract was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduce pressure.
  • Example 13 Synthesis of Compound I-7A Page 120 of 196 12746579v1 Attorney Docket No.: 2013518-0088 PhO F 2 S F N N H OTBDPS SO 2 Ph N N N N N N CuI, Pd(PPh 3 ) 4 , TEA D 3 C TFA C D3
  • Example 14 Synthesis of (3 1 s,3 3 s,Z)-2 7 -(3-fluoro-1-(methyl-d 3 )-1H-pyrazol-4-yl)-2 3 - (methyl-d 3 )-2 1 ,2 2 ,2 3 ,2 6 -tetrahydro-1 1 H-6,9-dioxa-4-aza-2(8,1)-imidazo[4,5-d]pyrrolo[2,3- b]pyridina-1(4,1)-pyrazola-3(1,3)-cyclobutanacycloundecaphane-2 2 ,5-dione (Compound I- 8A) Page 121 of 196 12
  • Example 15 Synthesis of (3 1 s,3 3 s,Z)-2 7 -(3-fluoro-1-(methyl-d 3 )-1H-pyrazol-4-yl)-2 3 - (methyl-d 3 )-2 1 ,2 2 ,2 3 ,2 6 -tetrahydro-1 1 H-6,9-dioxa-4-aza-2(8,1)-imidazo[4,5-d]pyrrolo[2,3- b]pyridina-1 3(1,3)-cyclobutanacycloundecaphane-2 2 ,5-dione (Compound I- 8A) Page 124 of 196 12746579v1 Attorney Docket No.: 2013518-0088
  • Example 16 Synthesis of (3 1 s,3 3 s)-2 7 -(3-fluoro-1-(methyl-d 3 )-1H-pyrazol-4-yl)-10-methyl- 2 3 -(methyl-d 3 )-2 1 ,2 2 ,2 3
  • Example 17 Synthesis of (3 1 s,3 3 s)-2 7 -(3-fluoro-1-(methyl-d 3 )-1H-pyrazol-4-yl)-10-methyl- 2 3 -(methyl-d 3 )-2 1 ,2 2 ,2 3 ,2 6 -tetrahydro-6-oxa-4,10-diaza-1(5,2)-thiazola-2(8,1)-imidazo[4,5- d]pyrrolo[2,3-b]pyridina-3(1,3)-cyclobutanacyclodecaphane-2 2 ,5-dione (Compound I-9A) Page 129 of 196 12746579v1 Attorney Docket No.: 2013518-0088 Page 130 of 196 12746579v1 Attorney Docket No.: 2013518-0088
  • Example 18 Synthesis of (3 1 s,3 3 s)-2 7 -(3-fluoro-1-(methyl-d 3 )-1H-pyrazol-4-
  • Example 19 Synthesis of (3 1 s,3 3 s)-2 7 -(3-fluoro-1-(methyl-d 3 )-1H-pyrazol-4-yl)-2 3 -(methyl- d 3 )-21 ,2 2 ,2 3 ,2 6 -tetrahydro-6,10-dioxa-4-aza-1(5,2)-thiazola-2(8,1)-imidazo[4,5- d]pyrrolo[2,3-b]pyridina-3(1,3)-cyclobutanacyclodecaphane-2 2 ,5-dione (Compound I-10A) Page 133 of 196 12746579v1 Attorney Docket No.: 2013518-0088
  • Example 20 Synthesis of (3 1 s,3 3 s)-2 7 -(3-fluoro-1-(methyl-d 3 )-1H-pyrazol-4-yl)-2 3 -(methyl- d 3 )-21 ,2 2 ,2 3 ,2 6
  • the reaction mixture was allowed to warm to room temperature and stirred for 1 h. It was poured into water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure 11.1 (1.3 g, Yield: 67%). The product was used without purification.
  • Example 21 Synthesis of (3 1 s,3 3 s)-2 7 -(3-fluoro-1-(methyl-d 3 )-1H-pyrazol-4-yl)-2 3 -(methyl- d 3 )-21 ,2 2 ,2 3 ,2 6 -tetrahydro-1 1 H-6-oxa-4-aza-2(8,1)-imidazo[4,5-d]pyrrolo[2,3-b]pyridina- 1(5,1)-indazola-3(1,3)-cyclobutanacyclononaphane-2 2 ,5-dione (Compound I-11A) Page 137 of 196 12746579v1 Attorney Docket No.: 2013518-0088 Page 138 of 196 12746579v1 Attorney Docket No.: 2013518-0088
  • Example 22 Synthesis of Compounds I-12-Isomer 1 and I-12-Isomer 2 3,4-diol (6.0 g, 57.69 mmol, 1.0
  • Triethylamine (1.48 g, 14.7 mmol, 5.0 equiv), tetrakis (triphenylphosphine)palladium (0.340 g, 0.29 mmol, 0.1 equiv) and ( ⁇ )-12.2 (2.31 g, 8.82 mmol, 3.0 equiv) were added and degassed for 5 min.
  • the reaction mixture was stirred at 50 °C for 16 h. It was concentrated under reduced pressure. The residue was purified by column chromatography (25% ethyl acetate in hexane) to afford ( ⁇ )-12.3 (0.750 g, Yield: 30%).
  • the racemate was purified by SFC (Column: CHIRALPAK IB-N (250 * 30 mm, 5 ⁇ m); Mobile Phase: (A) liquid CO2 (B) 0.1% NH3 in isopropanol: MeCN (50: 50); Flow rate: 100 mL/min) to afford first eluting fraction (0.012 g, Yield: 21%) and second eluting fraction (0.010 g, Yield: 21%).
  • Example 23 Synthesis of Compounds I-12-Isomer 1 and I-12-Isomer 2 Page 141 of 196 12746579v1 Attorney Docket No.: 2013518-0088 Page 142 of 196 12746579v1 Attorney Docket No.: 2013518-0088
  • Example 24 Synthesis of Compounds I-12 Isomer 3 and I-12 Isomer 4 Page 143 of 196 12746579v1 Attorney Docket No.: 2013518-0088
  • Example 25 Synthesis of (4 1 s,4 3 s)-3 7 -(3-fluoro-1-(methyl-d 3 )-1H-pyrazol-4-yl)-3 3 -(methyl- d 3 )-31 ,3 2 ,3 3 ,3 6 -tetrahydro-7-oxa-5-aza-2(2,5)-thiazola-3(8,1)-imidazo[4,5-d]pyrrolo[2,3- b]pyridina-1(1,3)-azeti
  • Example 26 Synthesis of (4 1 s,4 3 s)-3 7 -(3-fluoro-1-(methyl-d 3 )-1H-pyrazol-4-yl)-3 3 -(methyl- d 3 )-31 ,3 2 ,3 3 ,3 6 -tetrahydro-7-oxa-5-aza-2(2,5)-thiazola-3(8,1)-imidazo[4,5-d]pyrrolo[2,3- b]pyridina-1(1,3)-azetidina-4(1,3)-cyclobutanacyclooctaphane-3 2 ,6-dione (Compound I- 13A) Page 147 of 196 12746579v1 Attorney Docket No.: 2013518-0088
  • Example 27 Synthesis of (3 1 s,3 3 s)-2 7 -(3-fluoro-1-(methyl-d 3 )-1H-pyrazol-4-yl)-2 3 -(methyl- d 3 )-21
  • Example 28 Synthesis of (3 1 s,3 3 s)-2 7 -(3-fluoro-1-(methyl-d 3 )-1H-pyrazol-4-yl)-10-methyl- 2 3 -(methyl-d 3 )-2 1 ,2 2 ,2 3 ,2 6 -tetrahydro-6-oxa-4,10-diaza-2(8,1)-imidazo[4,5-d]pyrrolo[2,3- b]pyridina-1(1,4)-benzena-3(1,3)-cyclobutanacyclodecaphane-2 2 ,5-dione (Compound I- 15A) Page 151 of 196 12746579v1 Attorney Docket No.: 2013518-0088 B r NH Oxalyl Chloride Pd(dppf)Cl 2.
  • Example 29 Synthesis of (3 1 s,3 3 s)-2 7 -(3-fluoro-1-(methyl-d 3 )-1H-pyrazol-4-yl)-2 3 -(methyl- d 3 )-21 ,2 2 ,2 3 ,2 6 -tetrahydro-6,9-dioxa-4-aza-2(8,1)-imidazo[4,5-d]pyrrolo[2,3-b]pyridina- 1(1,4)-benzena-3(1,3)-cyclobutanacyclononaphane-2 2 ,5-dione
  • Compound I-16A dioxaborolan-2-yl)phenol (0.8 g, 4.87 mmol, 1.0 equiv), ((2-bromoethoxy)methyl)benzene (1.0 g, 5.85 mmol, 1.2 equiv) and cesium carbonate (2.0 g, 9.74 mmol, 2.0 equiv) in DMF (20 mL) was stirred at 80
  • Example 30 Synthesis of (3 1 s,3 3 s)-2 7 -(3-fluoro-1-(methyl-d 3 )-1H-pyrazol-4-yl)-2 3 -(methyl- d 3 )-21 ,2 2 ,2 3 ,2 6 -tetrahydro-1 1 H-6-oxa-4-aza-2(8,1)-imidazo[4,5-d]pyrrolo[2,3-b]pyridina- 1(5,1)-indazola-3(1,3)-cyclobutanacyclooctaphane-2 2 ,5-dione (Compound I-17A) dioxaborolan-2-yl)-1H-indazole (1.5 g, 6.14 mmol, 1.0 equiv), potassium carbonate (1.69 g,12.2 mmol,2.0 equiv) and ((2-bromoethoxy)methyl)benzene (2.62 g,12.2 mmol, 2.0 equiv) in DMF (10
  • Example 32 Synthesis of (3 1 s,3 3 s)-2 3 -(methyl-d 3 )-2 7 -(thiazol-5-yl)-2 1 ,2 2 ,2 3 ,2 6 -tetrahydro- 6,10-dioxa-4-aza-2(8,1)-imidazo[4,5-d]pyrrolo[2,3-b]pyridina-1(1,4)-benzena-3(1,3)- cyclobutanacyclodecaphane-2 2 ,5-dione (Compound I-19A) Page 162 of 196 12746579v1 Attorney Docket No.: 2013518-0088 dioxaborolan-2-yl)phenol (2.0 g, 9.09 mmol, 1.0 equiv) in DMF (50 mL) was added sodium hydride (60%wt in mineral oil, 0.545 g, 13.6 mmol, 1.5 equiv) at 0 o C and stirred for 30 min.
  • Example 33 Synthesis of (3 1 s,3 3 s)-2 7 -(3-fluoro-1-(methyl-d 3 )-1H-pyrazol-4-yl)-9-methyl- 2 3 -(methyl-d 3 )-2 1 ,2 2 ,2 3 ,2 6 -tetrahydro-6-oxa-4,9-diaza-2(8,1)-imidazo[4,5-d]pyrrolo[2,3- b]pyridina-1(1,4)-benzena-3(1,3)-cyclobutanacyclononaphane-2 2 ,5-dione (Compound I- 20A) [0371] a g, 19.98 mmol, 1.0 equiv) in 1,2-dichloroethane (50 mL) at 0 °C was added 4-bromo-N-methylaniline Page 165 of 196 12746579v1 Attorney Docket No.: 2013518-0088 (4.46 g, 23.97 mmol
  • Example 35 Synthesis of (3 1 s,3 3 s)-2 7 -cyclopropyl-2 3 -(methyl-d 3 )-2 1 ,2 2 ,2 3 ,2 6 -tetrahydro- 1 1 H-6-oxa-4-aza-2(8,1)-imidazo[4,5-d]pyrrolo[2,3-b]pyridina-1(5,1)-indazola-3(1,3)- cyclobutanacyclooctaphane-2 2 ,5-dione (Compound I-22A) Page 170 of 196 12746579v1 Attorney Docket No.: 2013518-0088 , (1.0 g, 2.6 mmol, 1.5 equiv) and cesium carbonate (1.73 g, 5.2 mmol, 3.0 equiv) in 1,4-dioxane (10 mL) and water (1 mL) was degassed by bubbling through a stream of argon 15 min.
  • Example 36 Synthesis of (31s,33s)-27-(3,6-dihydro-2H-pyran-4-yl)-23-(methyl-d3)- 21,22,23,26-tetrahydro-11H-6-oxa-4-aza-2(8,1)-imidazo[4,5-d]pyrrolo[2,3-b]pyridina- 1(5,1)-indazola-3(1,3)-cyclobutanacyclooctaphane-22,5-dione (Compound I-23A) Page 172 of 196 12746579v1 Attorney Docket No.: 2013518-0088 P hO 2 S PhOS PhO 2 S PhO 2 S H2N 2 NHBoc N N N N N N N NBS N N TEA Fe, NH4Cl CD3 Page 173 of 196 12746579v1 Attorney Docket No.: 2013518-0088 [0390] Synthesis of compound 23.1.
  • JAK2 JH2 Domain Binding Assay [0403] JAK2 (JH2domain-pseudokinase, NP_004963.1, partial length construct with AA start/stop at R513/N824) was produced in HEK-293 cells and subsequently tagged with DNA for qPCR detection. Streptavidin-coated magnetic beads were treated with biotinylated small molecule ligands for 30 minutes at room temperature to generate affinity resins for kinase assays.
  • Binding reactions were assembled by combining kinases, liganded affinity beads, and test compounds in 1x binding buffer (20% SeaBlock, 0.17x PBS, 0.05% Tween 20, 6 mM DTT). Test compounds were prepared as 111x stocks in 100% DMSO. Kd values were determined using an 11-point 3-fold compound dilution series with three DMSO control points.
  • Example 38 JAK Family Selectivity Assays Page 178 of 196 12746579v1 Attorney Docket No.: 2013518-0088 [0405] Provided compounds are evaluated for selectivity by comparing their JAK2 binding affinity (Kd) in the above JAK2 Binding Assay with their binding affinity (Kd) for one or more other kinases. Binding affinity for other kinases is determined as follows: Kinase-tagged T7 phage strains are prepared in an E. coli host derived from the BL21 strain. E. coli are grown to log-phase and infected with T7 phage and incubated with shaking at 32 °C until lysis.
  • the lysates are centrifuged and filtered to remove cell debris.
  • the remaining kinases are produced in HEK-293 cells and subsequently tagged with DNA for qPCR detection.
  • Streptavidin-coated magnetic beads are treated with biotinylated small molecule ligands for 30 minutes at room temperature to generate affinity resins for kinase assays.
  • the liganded beads are blocked with excess biotin and washed with blocking buffer (SeaBlock (Pierce), 1% BSA, 0.05% Tween 20, 1 mM DTT) to remove unbound ligand and to reduce non-specific binding.
  • Binding reactions are assembled by combining kinases, liganded affinity beads, and test compounds in 1x binding buffer (20% SeaBlock, 0.17x PBS, 0.05% Tween 20, 6 mM DTT).
  • Test compounds are prepared as 111X stocks in 100% DMSO.
  • K d values are determined using an 11-point 3-fold compound dilution series with three DMSO control points. All compounds for Kd measurements are distributed by acoustic transfer (non-contact dispensing) in 100% DMSO. The compounds are then diluted directly into the assays such that the final concentration of DMSO is 0.9%. All reactions are performed in polypropylene 384-well plate. Each has a final volume of 0.02 ml.
  • the assay plates are incubated at room temperature with shaking for 1 hour and the affinity beads are washed with wash buffer (1x PBS, 0.05% Tween 20). The beads are then re-suspended in elution buffer (1x PBS, 0.05% Tween 20, 0.5 ⁇ M non-biotinylated affinity ligand) and incubated at room temperature with shaking for 30 minutes.
  • the kinase concentration in the eluates is measured by qPCR. Compounds that exhibit a better binding affinity for JAK2 compared to one or more other kinases are considered to be JAK2- selective compounds.
  • provided compounds may be JAK2-selective over one or more of the following kinases: JAK1, JAK3, and Tyk2.
  • test compound A solution of test compound is added to the assay plate.
  • the plates are covered with a lid and placed in a 37 °C 5% CO2 incubator for 4 hours. After 4 hours, the cells are spun, and the cell pellets are re-suspended with 100 ⁇ L cold PBS. Then, the cells are spun again at 4 °C and 4000 rpm for 5 min. PBS is aspirated, and 25 ⁇ L lysis buffer (with protease and phosphatase inhibitor cocktail) is added to each cell pellet. The cell lysate is shaken at 4 °C for 20 min to fully lyse the cells.
  • MSD Meso-scale discovery
  • the MSD plate is washed three times with 150 ⁇ L/well of 1x MSD Wash Buffer (TBST). Sample lysates are then added to MSD plates (25 ⁇ L/well) and shaken for 1 h at room temperature and 600 rpm. The MSD plate is washed three times with 150 ⁇ L/well of 1x MSD Wash Buffer (TBST). Detection antibody (prepared in Antibody Detection buffer, 1% BSA in 1xTBST) is then added to the MSD plates, and they are shaken for 1 h at room temperature and 600 rpm. The MSD plate is washed three times with 150 ⁇ L/well of 1x MSD Wash Buffer (TBST).
  • a secondary detection antibody (prepared in Antibody Detection buffer, 1% BSA in 1xTBST) is then added to the MSD plates, and they are shaken for 1 h at room temperature and 600 rpm.
  • the MSD plate is washed three times with 150 ⁇ L/well of 1x MSD Wash Buffer (TBST).
  • MSD reading buffer (1x) is added to the plates (150 ⁇ L/well), and they are diluted from 4x with water.
  • the plates are imaged using an MSD imaging instrument according to the manufacturer’s instructions.
  • Example 40 Caco2 Permeability Assay [0407] Preparation of Caco-2 Cells: 50 ⁇ L and 25 mL of cell culture medium are added to each well of a Transwell® insert and reservoir, respectively.
  • HTS Transwell® plates are incubated at 37 °C, 5% CO2 for 1 hour before cell seeding.
  • Caco-2 cell cells are diluted to 6.86 ⁇ 105 cells/mL with culture medium, and 50 ⁇ L of cell suspension are dispensed into the filter well of the 96-well HTS Transwell® plate.
  • Cells are cultivated for 14-18 days in a cell culture Page 180 of 196 12746579v1 Attorney Docket No.: 2013518-0088 incubator at 37 °C, 5% CO 2 , 95% relative humidity. Cell culture medium is replaced every other day, beginning no later than 24 hours after initial plating.
  • Preparation of Stock Solutions 10 mM stock solutions of test compounds are prepared in DMSO.
  • a TEER value greater than 230 ohm•cm 2 indicates a well-qualified Caco-2 monolayer.
  • Assay Procedure The Caco-2 plate is removed from the incubator and washed twice with pre-warmed HBSS (10 mM HEPES, pH 7.4), and then incubated at 37 °C for 30 minutes. The stock solutions of control compounds are diluted in DMSO to get 1 mM solutions and then diluted with HBSS (10 mM HEPES, pH 7.4) to get 5 ⁇ M working solutions. The stock solutions of the test compounds are diluted in DMSO to get 1 mM solutions and then diluted with HBSS (10 mM HEPES and 4% BSA, pH 7.4) to get 5 ⁇ M working solutions.
  • the final concentration of DMSO in the incubation system is 0.5%.
  • 75 ⁇ L of 5 ⁇ M working solutions of test compounds are added to the Transwell® insert (apical compartment) and the wells in the receiver plate (basolateral compartment) are filled with 235 ⁇ L of HBSS (10 mM HEPES and 4% BSA, pH 7.4).
  • 235 ⁇ L of 5 ⁇ M working solutions of test compounds are added to the receiver plate wells (basolateral compartment) and then the Transwell® inserts (apical compartment) are filled with 75 ⁇ L of HBSS (10 mM HEPES and 4% BSA, pH 7.4).
  • Time 0 samples are prepared by transferring 50 ⁇ L of 5 ⁇ M working solution to wells of the 96-deepwell plate, followed by the addition of 200 ⁇ L cold methanol containing appropriate internal standards (IS). The plates are incubated at 37 °C for 2 hours.
  • HEK293T cells are harvested from flask into cell culture medium, and then the cells are counted. The cells are diluted with culture medium to the desired density, and 40 ⁇ L of cell suspension is added into each well of a 384-well cell culture plate.
  • the plates are covered with a lid and spun at room temperature at 1,000 RPM for 1 minute and then transferred into 37 °C 5% CO 2 incubator overnight.
  • Test compounds are dissolved at 10 mM DMSO stock solution.45 ⁇ L of stock solution is then transferred to a 384 PP-plate.
  • a 3-fold, 10-point dilution is performed via transferring 15 ⁇ L compound into 30 ⁇ L DMSO by using TECAN (EVO200) liquid handler.
  • the plates are spun at room temperature at 1,000 RPM for 1 minute and shaken on a plate shaker for 2 minutes. 40 nL of diluted compound is transferred from compound source plate into the cell plate by using liquid handler Echo550.
  • IC 50 values are calculated using XLFit (equation 201).
  • Example 42 Hepatocyte Stability Assay [0412] 10 mM stock solutions of test compound and positive control are prepared in DMSO. Stock solutions are diluted to 100 ⁇ M by combining 198 ⁇ L of 50% acetonitrile/50% water and 2 ⁇ L of 10 mM stock solution. Verapamil is used as positive control in the assay. Vials of cryopreserved hepatocytes are thawed in a 37 °C water bath with gently shaking. The contents are poured into the 50 mL thawing medium conical tube. Vials are centrifuged at 100 g for 10 minutes at room temperature.
  • Thawing medium is aspirated and hepatocytes are re-suspended with serum-free incubation medium to yield ⁇ 1.5 ⁇ 106 cells/mL.
  • Cell viability and density are counted using a Trypan Blue exclusion, and then cells are diluted with serum-free incubation medium to a working cell density of 0.5 ⁇ 106 viable cells/mL.
  • a portion of the hepatocytes at 0.5 ⁇ 106 viable cells/mL are boiled for 5 min prior to adding to the plate as negative control to eliminate the enzymatic activity so that little or no substrate turnover should be observed.
  • Aliquots of 198 ⁇ L hepatocytes are dispensed into each well of a 96-well non-coated plate. The plate is placed in the incubator for approximately 10 minutes.
  • Example 43 Kinetic Solubility Assay [0413] Stock solutions of test compounds are prepared in DMSO at the concentration of 10 mM, and a stock solution of control compound is prepared in DMSO at the concentration of 30 mM. Diclofenac is used as positive control in the assay.
  • test compounds are filtered by vacuum manifold. The filtered samples are diluted with methanol. Samples are analyzed by LC-MS/MS and quantified against a standard of known concentration in DMSO using LC coupled with Mass spectral peak identification and quantitation. The solubility values of the test compounds are calculated as follows, wherein INJ VOL is injection volume, DF is dilution factor, and STD is standard: Example 44: Plasma Protein Binding Assay [0414] Working solutions of test compounds and control compound are prepared in DMSO at the concentration of 200 ⁇ M, and then the working solutions are spiked into plasma. The final concentration of compound is 1 ⁇ M. The final concentration of DMSO is 0.5%. Ketoconazole is used as positive control in the assay.
  • Dialysis membranes are soaked in ultrapure water for 60 minutes to separate strips, then in 20% ethanol for 20 minutes, finally in dialysis buffer for 20 minutes.
  • the dialysis set up is assembled according to the manufacturer’s instruction.
  • Each Cell is with 150 ⁇ L of plasma sample and dialyzed against equal volume of dialysis buffer (PBS).
  • PBS dialysis buffer
  • the assay is performed in duplicate.
  • the dialysis plate is sealed and incubated in an incubator at 37 °C with 5% CO2 at 100 rpm for 6 hours. At the end of incubation, 50 ⁇ L of samples from both buffer and plasma chambers are transferred to wells of a 96-well plate. 50 ⁇ L of plasma is added to each buffer samples and an equal volume of PBS is supplemented to the collected plasma sample.
  • Page 184 of 196 12746579v1 Attorney Docket No.: 2013518-0088 [0415] While we have described a number of embodiments of this invention, it is apparent that our basic examples may be altered to provide other embodiments that utilize the compounds and methods of this invention. Therefore, it will be appreciated that the scope of this invention is to be defined by the appended claims rather than by the specific embodiments that have been represented by way of example. Page 185 of 196 12746579v1

Landscapes

  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente divulgation concerne des composés hétéroaromatiques macrocycliques et des compositions de ceux-ci utiles pour inhiber JAK2. Dans certains modes de réalisation, la présente divulgation concerne un composé de formule I : ou un sel pharmaceutiquement acceptable de celui-ci.
PCT/US2025/030295 2024-05-22 2025-05-21 Inhibiteurs hétéroaromatiques macrocycliques de jak2 Pending WO2025245175A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US202463650506P 2024-05-22 2024-05-22
US63/650,506 2024-05-22
US202463736937P 2024-12-20 2024-12-20
US63/736,937 2024-12-20

Publications (1)

Publication Number Publication Date
WO2025245175A1 true WO2025245175A1 (fr) 2025-11-27

Family

ID=97796152

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2025/030295 Pending WO2025245175A1 (fr) 2024-05-22 2025-05-21 Inhibiteurs hétéroaromatiques macrocycliques de jak2

Country Status (1)

Country Link
WO (1) WO2025245175A1 (fr)

Similar Documents

Publication Publication Date Title
JP7716110B2 (ja) ピリミジン－４（３ｈ）－オンヘテロ環式化合物、その調製方法、およびその医薬的使用
TWI675833B (zh) 布魯頓氏（ｂｒｕｔｏｎ’ｓ）酪胺酸激酶之聯芳基抑制劑
JP2024513554A (ja) ユビキチン特異的プロテアーゼ１（ｕｓｐ１）阻害剤
EP3921319B1 (fr) Dérivés imidazo [2, 1-f] [1, 2, 4] triazin-4-amine en tant qu'agonistes de tlr7
EP3919483A1 (fr) Composé de benzopyridone hétérocyclique et son utilisation
JP7617005B2 (ja) Ａｋｔ阻害剤
EP3444251A1 (fr) Composés biaryles utiles dans le traitement de maladies humaines en oncologie, neurologie et immunologie
CN104910137A (zh) Cdk激酶抑制剂
WO2021190615A1 (fr) Composés utilisés en tant qu'inhibiteurs de la caséine kinase
EP3072893B1 (fr) Dérivés cétone d'imidazoles, combinaisons pharmaceutiques desdits dérivés et leur utilisation
JP2020506957A (ja) イミダゾピラジン類化合物、その製造方法及び応用
JP2020516659A (ja) ブルトン型チロシンキナーゼの阻害剤としてのベンゾアゼピン類似体
AU2019296085A1 (en) Heterocyclic compound as TRK inhibitor
US20240034743A9 (en) Tricyclic compounds as egfr inhibitors
TW202003496A (zh) 一種新穎磷酸肌醇3 - 激酶抑制劑及其製備方法和用途
US20250171444A1 (en) PI3Ka INHIBITORS
WO2025245175A1 (fr) Inhibiteurs hétéroaromatiques macrocycliques de jak2
CN114075196B (zh) 一类芳香环并内酰胺类化合物、其制备方法和用途
JP6900406B2 (ja) Ａｋｔ阻害剤としてのジヒドロピラゾロアゼピン系化合物
WO2025230890A1 (fr) Inhibiteurs de jak2 hétéroaromatiques 5,6 bicycliques
EP4353721A1 (fr) Composé hétérocyclique contenant de l'azote
RU2815022C1 (ru) Трициклические соединения в качестве ингибиторов egfr
WO2023009709A1 (fr) Pyrazolo pipérazines en tant qu'inhibiteurs de jak2
WO2023009712A1 (fr) Hétéroaryloxy thiazolo azines en tant qu'inhibiteurs de jak2
HK40094745A (en) Aromatic ring-lactam compound, preparation method therefor and use thereof