2-cyclopropyl-3,3,9-trifluoro-l,2,3,4-tetrahydro- [1,4|oxazepino[2,3-ciouinolin-6(7H)-one BCL6 modulators

Abstract

This disclosure provides compounds of Formula (I), or pharmaceutically acceptable salts thereof, that inhibit a BCL6 protein. These compounds are useful, for example, for treating a cancer or an autoimmune disease or condition in a subject (e.g., a human). This disclosure also provides compositions containing compounds of Formula (I), or pharmaceutically acceptable salts thereof, as well as methods of using and making the same.

Description

[0001] Docket No. TRLN-013-034W01 / TLS-072WO

[0002] 2-CYCLOPROPYL-3,3,9-TRIFLUORO-1,2,3,4-TETRAHYDRO-[1,4]OXAZEPINO[2,3-C]QUINOLIN-6(7H)-ONE BCL6 MODULATORS

[0003]

[0004] CROSS-REFERENCE TO RELATED APPLICATION

[0005] This application claims priority to U. S. Provisional Application Serial No. 63 / 765,065, filed February 28, 2025, which is incorporated by reference in its entirety herein.

[0006] SEQUENCE LISTING

[0007] This application contains a Sequence Listing that has been submitted electronically as an XML file named “TRLN-013-034W01_Sequence_Listing, XML.” The XML file, created on January 27, 2026, is 3 KB in size. The material in the XML file is hereby incorporated by reference in its entirety.

[0008] TECHNICAL FIELD

[0009] This disclosure provides compounds of Formula (I), or pharmaceutically acceptable salts thereof, that modulate a BCL6 protein. These compounds are useful, for example, for treating cancer or an autoimmune disease or condition in a subject (e.g., a human). This disclosure also provides compositions containing compounds of Formula (I), or pharmaceutically acceptable salts thereof, as well as methods of using and making the same.

[0010] BACKGROUND

[0011] B-cell lymphoma 6 (BCL6) protein is a transcriptional repressor involved in the formation and maintenance of germinal centers (GCs) within lymphoid follicles. It controls the functions of the GC and coordinates the activities of signaling mediators in the maturation of GC B cells. There are over 1000 known or putative BCL6 target genes, including MYC, BCL2, genes related to DNA damage response (e.g., ATR, TP53 and cell cycle checkpoint control (e.g., CDKN1A, CDKN1B). BCL6 is expressed in the dark zone cells of GCs, where somatic hypermutation is allowed to occur to generate high-affinity B-cell receptors. Overexpression or loss of control of BCL6, for example by translocation, can permit maintenance of the prohypermutation functions and abrogation of the antitumor functions of BCL6.

[0012] SUMMARY

[0013] Provided herein are compounds of Formula (I):Docket No. TRLN-013-034W01 / TLS-072WO

[0014]

[0015] Formula (I)

[0016] or pharmaceutically acceptable salts thereof, wherein:

[0017] R1, R2, R3, R4, and X1are each as defined herein.

[0018] Also provided herein are pharmaceutical compositions comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0019] Provided herein are methods for treating cancer in a subj ect in need thereof, the methods comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein.

[0020] Also provided herein are methods for treating or preventing an autoimmune condition in a subject in need thereof, the methods comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein.

[0021] To facilitate understanding of the disclosure set forth herein, a number of additional terms are provided. Generally, the nomenclature used herein and the laboratory procedures in organic chemistry, medicinal chemistry, and pharmacology described are those well-known and commonly employed in the art. Unless defined otherwise, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Each of the patents, applications, published applications, and other publications that are mentioned throughout the specification and the attached appendices are incorporated herein by reference in their entireties. In the case of conflict between the present disclosure and any content incorporated by reference, the present disclosure controls.

[0022] The details of one or more embodiments of the invention are set forth in the accompanying drawings and the description below. Other features and advantages of the invention will be apparent from the description and drawings, and from the claims.Docket No. TRLN-013-034W01 / TLS-072WO

[0023] DETAILED DESCRI PTION

[0024] This disclosure provides compounds of Formula (I), or pharmaceutically acceptable salts thereof, that modulate a BCL6 protein. For example, compounds of Formula (I) can inhibit the interaction between BCL6 and a corepressor peptide (e.g., BCOR) and / or the compounds of Formula (I) can induce the degradation of a BCL6 protein (e.g., via a polymerization mechanism). These compounds are useful, e.g., for treating a cancer or an autoimmune disease or condition. This disclosure also provides compositions containing compounds of Formula (I), or pharmaceutically acceptable salts thereof, as well as methods of using and making the same.

[0025] Upon antigen challenge, germinal centers (GCs) are formed in lymphoid follicles, and B-cells in the dark zone of GCs undergo rapid proliferation and somatic hypermutation, both of their immunoglobin variable genes to generate high-affinity B-cell receptors, as well as of other genes including BCL6. BCL6 is often considered to be a ‘master regulator’ of the GC reaction. The BCL6 protein has multiple domains, including a BTB domain, an RD2 domain, and a DNA binding domain. The N-terminal BTB domain is the site of homodimerization of BCL6, and the interface of the monomers forms the “lateral groove”, which is a binding site for endogenous co-repressors of BCL6, such as SMRT, NCOR, and BCOR. See, e.g., Cardenas, Mariano G., et al. Clinical Cancer Research 23.4 (2017): 885-893, doi: 10.1158 / 1078- 0432. CCR- 16-2071.

[0026] Compound Embodiments

[0027] Provided herein are compounds of Formula (I):

[0028]

[0029] Formula (I)

[0030] or pharmaceutically acceptable salts thereof, wherein:

[0031] R1is a Ci-3 alkyl optionally substituted with 1-3 -F;

[0032] X1is selected from the group consisting of: N and CH;Docket No. TRLN-013-034W01 / TLS-072WO

[0033] R2is selected from the group consisting of:

[0034] (a) 4-10 membered heterocyclyl optionally substituted with 1-3 R5;

[0035] (b) -H; and

[0036] (c) halo;

[0037] R3and R4are each independently selected from the group consisting of: -H, halo, -CN, and Ci-3 alkyl optionally substituted with 1-3 -F;

[0038] each R5is independently selected from the group consisting of:

[0039] (a) Ci-3 alkyl optionally substituted with 1-3 R6;

[0040] (b) -OH;

[0041] (c) -C(=O)H;

[0042] (d) -C(=O)OH;

[0043] (e) -CN;

[0044] (f) Ci-3 alkoxy optionally substituted with 1-3 R6;

[0045] (g) 4-6 membered heterocyclyl; and

[0046] (h) oxo; and

[0047] each R6is independently selected from the group consisting of: -F and -OH.

[0048] In some embodiments of Formula (I), R1is C1-3 alkyl. For example, R1can be methyl.

[0049] In some embodiments of Formula (I), R2is a 4-10 membered heterocyclyl optionally substituted with 1-3 R5. In some embodiments, R2is selected from the group consisting of: piperidinyl; piperazinyl; morpholinyl; pyrrolidinyl; azetidinyl; azepanyl; 2-oxa-6-azaspiro[3.3]heptan-6-yl; 8-azabicyclo[3.2.1]octan-8-yl; 8-oxa-3-azabicyclo[3.2.1]octan-3-yl; and 1,1-dioxidothiomorpholinyl, each of which is optionally substituted with 1-3 R5.

[0050] In some embodiments of Formula (I), each R5is independently selected from the group consisting of:

[0051] (a) C1-3 alkyl optionally substituted with 1-3 R6;

[0052] (b) -OH;

[0053] (c) -CN;

[0054] (d) C1-3 alkoxy optionally substituted with 1-3 R6; andDocket No. TRLN-013-034W01 / TLS-072WO

[0055] (e) oxo.

[0056] In some embodiments of Formula (I), R2is selected from the group consisting of piperidinyl; piperazinyl; morpholinyl; pyrrolidinyl; azetidinyl; azepanyl; 2-oxa-6- azaspiro[3.3]heptan-6-yl; 8-azabicyclo[3.2.1]octan-8-yl; 8-oxa-3-azabicyclo[3.2.1]octan-3-yl; and 1,1-dioxidothiomorpholinyl, each of which is optionally substituted with 1-3 R5; and each R5is independently selected from the group consisting of

[0057] (a) Ci-3 alkyl optionally substituted with 1-3 R6;

[0058] (b) -OH;

[0059] (c) -CN;

[0060] (d) Ci-3 alkoxy optionally substituted with 1-3 R6; and

[0061] (e) oxo.

[0062] In some embodiments of Formula (I), R3is halo. In some embodiments, R3is -F or - Cl. For example, R3can be -F. For example, R3can be -Cl.

[0063] In some embodiments of Formula (I), R3is -CN.

[0064] In some embodiments of Formula (I), R3is -H.

[0065] In some embodiments of Formula (I), R4is -H or methyl. In some embodiments, R4is -H.

[0066] In some embodiments of Formula (I), X1is N.

[0067] In some embodiments of Formula (I), X1is CH.

[0068] In some embodiments, the compounds of Formula (I) are selected from the group consisting of the compounds depicted in Table Cl, or pharmaceutically acceptable salts thereof.Docket No. TRLN-013-034W01 / TLS-072WO

[0069] Table Cl

[0070]

[0071] Docket No. TRLN-013-034W01 / TLS-072WO

[0072]

[0073] Docket No. TRLN-013-034W01 / TLS-072WO

[0074]

[0075] Docket No. TRLN-013-034W01 / TLS-072WO

[0076]

[0077] Docket No. TRLN-013-034W01 / TLS-072WO

[0078]

[0079] Docket No. TRLN-013-034W01 / TLS-072WO

[0080]

[0081] Docket No. TRLN-013-034W01 / TLS-072WO

[0082]

[0083] Docket No. TRLN-013-034W01 / TLS-072WO

[0084]

[0085] Docket No. TRLN-013-034W01 / TLS-072WO

[0086]

[0087] In some embodiments, the compounds of Formula (I), or pharmaceutically acceptable salts thereof inhibit the interaction of a BCL6 protein with a corepressor peptide with an ICso of less than I pM (e.g., less than 750 nM, less than 500 nM, or less than 200 nM). In some embodiments, the compounds of Formula (I), or pharmaceutically acceptable salts thereof, inhibit the interaction of a BCL.6 protein with a corepressor peptide with an ICso of less than 200 nM (e.g., less than 150 nM, less than 100 nM, less than 10 nM, less than 1 nM). For example, the compounds can inhibit the interaction of a BCL6 protein with a corepressor peptide with an ICso of about 0.1 nM to about 100 nM, about 0.1 nM to about 50 nM, about 1 nM to about 50 nM, about 1 nM to about 20 nM, or about 0.1 nM to about 1 nMl

[0088] Chemical definitions

[0089] The term “halo” refers to fluoro (F), chloro (Cl), bromo (Br), or iodo (I).

[0090] The term “oxo” refers to a divalent doubly bonded oxygen atom (i.e., “=O”). As used herein, oxo groups are attached to carbon atoms to form carbonyls.

[0091] The term “alkyl” refers to a saturated acyclic hydrocarbon radical that may be a straight chain or branched chain, containing the indicated number of carbon atoms. For example, Ci-io indicates that the group may have from 1 to 10 (inclusive) carbon atoms in it. Alkyl groups can either be unsubstituted or substituted with one or more substituents. Non-limiting examples include methyl, ethyl, z o-propyl, tert-butyl, zz-hexyl. The term “saturated” as used in thisDocket No. TRLN-013-034W01 / TLS-072WO

[0092] context means only single bonds present between constituent carbon atoms and other available valences occupied by hydrogen and / or other substituents as defined herein.

[0093] The term “haloalkyl” refers to an alkyl, in which one or more hydrogen atoms is / are replaced with an independently selected halo (e.g., -CF3, -CHF2, or -CH2F).

[0094] The term “alkoxy” refers to an -O-alkyl radical (e.g., -OCH3).

[0095] The term “alkylene” refers to a divalent alkyl (e.g,, -CH2-). Similarly, terms such as “cycloalkylene” and “heterocyclylene” refer to divalent cycloalkyl and heterocyclyl respectively. For avoidance of doubt, in “cycloalkylene” and “heterocyclylene”, the two

[0096] radicals can be on the same ring carbon atom (e.g., a geminal diradical such

[0097]

[0098] as or

[0099] ^

[0100]

[0101] ^0^ ) or on different ring atoms (e.g., ring carbon and / or nitrogen atoms (e.g., vicinal ring

[0102] carbon and / or nitrogen atoms))

[0103]

[0104] (e.g.,3)• The term “alkenyl” refers to an acyclic hydrocarbon chain that may be a straight chain or branched chain having one or more carbon-carbon double bonds. The alkenyl moiety contains the indicated number of carbon atoms. For example, C2-6 indicates that the group may have from 2 to 6 (inclusive) carbon atoms in it. Alkenyl groups can either be unsubstituted or substituted with one or more substituents.

[0105] The term “alkynyl” refers to an acyclic hydrocarbon chain that may be a straight chain or branched chain having one or more carbon-carbon triple bonds. The alkynyl moiety contains the indicated number of carbon atoms. For example, C2-6 indicates that the group may have from 2 to 6 (inclusive) carbon atoms in it. Alkynyl groups can either be unsubstituted or substituted with one or more substituents.

[0106] The term “aryl” refers to a 6-20 carbon mono-, bi-, tri- or polycyclic group wherein at least one ring in the system is aromatic (e.g., 6-carbon monocyclic, 10-carbon bicyclic, or 14-carbon tricyclic aromatic ring system); and wherein 0, 1, 2, 3, or 4 atoms of each ring may be substituted by a substituent. Examples of aryl groups include phenyl, naphthyl, tetrahydronaphthyl, and the like.

[0107] The term “cycloalkyl” as used herein refers to mono-, bi-, tri-, or polycyclic saturated or partially unsaturated hydrocarbon groups having, e.g., 3 to 20 ring carbons, preferably 3 toDocket No. TRLN-013-034W01 / TLS-072WO

[0108] 15 ring carbons, and more preferably 3 to 12 ring carbons or 3-10 ring carbons or 3-6 ring carbons, wherein the cycloalkyl group may be optionally substituted. The term “saturated” as used in this context means only single bonds present between constituent carbon atoms. Examples of saturated cycloalkyl groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Partially unsaturated cycloalkyl may have any degree of unsaturation provided that one or more double bonds is present in the cycloalkyl, none of the rings in the ring system are aromatic, and the partially unsaturated cycloalkyl group is not fully saturated overall. Examples of partially unsaturated cycloalkyl include, without limitation, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Cycloalkyl may include multiple fused and / or bridged rings. Non-limiting examples of fused / bridged cycloalkyl includes: bicyclofl.1.0]butyl, bicyclo[2.1,0]pentyl, bicyclo[l.l.l]pentyl, bicyclo[3.1.0]hexyl, bicyclo[2.1.1]hexyl, bicyclo[3.2.0]heptyl, bicyclo[4.1. Ojheptyl, bicyclo[2.2.1]heptyl, bicyclop.1. Ijheptyl, bicyclo[4.2.0]octyl, bicyclo[3.2. l]octyl, bicyclo[2.2.2]octyl, and the like. Cycloalkyl also includes spirocyclic rings (e.g., spirocyclic bicycle wherein two rings are connected through just one atom). Non-limiting examples of spirocyclic cycloalkyls include spiro[2.2]pentyl, spiro[2.5]octyl, spiro[3.5]nonyl, spiro[3.5]nonyl, spiro[3.5]nonyl, spiro[4.4]nonyl, spiro[2.6]nonyl, spiro[4.5]decyl, spiro[3.6]decyl, spiro[5.5]undecyl, and the like.

[0109] The term “heteroaryl”, as used herein, means a mono-, bi-, tri- or polycyclic group having 5 to 20 ring atoms, alternatively 5, 6, 9, 10, or 15 ring atoms; wherein at least one ring in the system contains one or more heteroatoms independently selected from the group o..o o consisting of N, O, and S (inclusive of oxidized forms such as:

[0110]

[0111] ) and at least one ring in the system is aromatic (but does not have to be a ring which contains a heteroatom, e.g. tetrahydroisoquinolinyl, e.g., tetrahydroquinolinyl). In some embodiments, heteroaryl groups contain 1-4 (e.g., 1, 2, or 3) ring heteroatoms each independently selected from the

[0112] group consisting of N, O, and S (inclusive of oxidized forms such as:

[0113]

[0114] Heteroaryl groups can either be unsubstituted or substituted with one or more substituents. Examples of heteroaryl include thienyl, pyridinyl, furyl, oxazolyl, oxadiazolyl, pyrrolyl, imidazolyl, triazolyl, thiodiazolyl, pyrazolyl, isoxazolyl, thiadiazolyl, pyranyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, thiazolyl benzothienyl, benzoxadiazolyl, benzofuranyl, benzimidazolyl, benzotri azolyl, cinnolinyl, indazolyl, indolyl, isoquinolinyl, isothiazolyl,Docket No. TRLN-013-034W01 / TLS-072WO

[0115] naphthyridinyl, purinyl, thienopyridinyl, pyrido[2,3-d]pyrimidinyl, pyrrolo[2,3-£>]pyridinyl, quinazolinyl, quinolinyl, thieno[2,3-c]pyridinyl, pyrazolo[3,4-Z>]pyridinyl, pyrazolo[3,4- c]pyridinyl, pyrazolo[4,3-c]pyridinyl, pyrazolo[4,3-Z>]pyridinyl, tetrazolyl, chromanyl, 2,3-dihydrobenzo[Z>] [ 1,4]dioxinyl, benzo[<f] [ 1,3 ]dioxoly 1, 2,3 -dihydrobenzofuranyl, tetrahydroquinolinyl, 2,3-dihydrobenzo[Z>][l,4]oxathiinyl, isoindolinyl, and others. In some embodiments, the heteroaryl is selected from thienyl, pyridinyl, furyl, pyrazolyl, imidazolyl, isoindolinyl, pyranyl, pyrazinyl, and pyrimidinyl. For purposes of clarification, heteroaryl also includes aromatic lactams, aromatic cyclic ureas, or vinylogous analogs thereof, in which each ring nitrogen adjacent to a carbonyl is tertiary (i.e., all three valences are occupied by non-

[0116] hydrogen substituents), such as one or more of pyridone (e.g.,

[0117]

[0118]

[0119]

[0120] ), wherein each ring nitrogen adjacent to a carbonyl is tertiary (i.e., the oxo group (i.e., “=O”) herein is a constituent part of the heteroaryl ring).

[0121] The term “heterocyclyl” refers to a mono-, bi-, tri-, or polycyclic saturated or partially unsaturated ring system with 3-15 ring atoms (e.g., 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-15 membered tricyclic ring system) having 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic or polycyclic, said heteroatoms selected o..o o

[0122] from O, N, and S (inclusive of oxidized forms such as:

[0123]

[0124] g., carbon atoms and 1-3, 1-6, or 1-9 heteroatoms of N, O, S, or P if monocyclic, bicyclic, or tricyclic, respectively), wherein 0, 1, 2 or 3 atoms of each ring may be substituted by a substituent. The term “saturated” as used in this context means only single bonds present between constituent ring atoms and other available valences occupied by hydrogen and / or other substituents as defined herein. Examples of saturated heterocyclyl groups include piperazinyl, pyrrolidinyl, dioxanyl, morpholinyl, tetrahydrofuranyl, and the like. Partially unsaturated heterocyclylDocket No. TRLN-013-034W01 / TLS-072WO

[0125] groups may have any degree of unsaturation provided that one or more double bonds is present in the heterocyclyl, none of the rings in the ring system are aromatic, and the partially unsaturated heterocyclyl group is not fully saturated overall. Examples of partially unsaturated heterocyclyl groups include, without limitation, tetrahydropyridyl, dihydropyrazinyl, dihydropyridyl, dihydropyrrolyl, dihydrofuranyl, dihydrothiophenyl.

[0126] Heterocyclyl may include multiple fused and bridged rings. Non-limiting examples of fused / bridged heterocyclyl includes: 2-azabicyclo[1.1.0]butyl, 2-azabicyclo[2.1.0]pentyl, 2- azabicyclof 1.1.1 Jpentyl, 3-azabicyclo[3. l. OJhexyl, 5-azabicyclo[2.1.1 Jhexyl, 3-azabicyclo[3.2.0]heptyl, octahydrocyclopenta[c]pyrrolyl, 3-azabicyclo[4.1. OJheptyl,

[0127]

[0128] azabicyclo[2.2.1 Jheptyl, 6-azabicyclo[3.1.1 Jheptyl, 7-azabicyclo[4.2.0]octyl,

[0129]

[0130] azabicyclo[2.2.2]octyl, 3-azabicyclo[3.2. l]octyl, 2-oxabicyclo[l.1 OJbutyl, 2- oxabicyclo[2.1,0]pentyl, 2-oxabicyclo[ 1.1.1 Jpentyl, 3 -oxabicy clo[3.1. OJhexyl,

[0131]

[0132] oxabicyclo[2, 1.1 Jhexyl, 3-oxabicyclo[3.2.0Jheptyl, 3-oxabicyclo[4.1. OJheptyl, 7- oxabicy clo[2.2.1 Jheptyl, 6-oxabicyclo[3.1.1 Jheptyl, 7-oxabicyclo[4.2.0]octyl,

[0133]

[0134] oxabicyclo[2.2.2]octyl, 3-oxabicyclo[3.2.1Joctyl, and the like. Heterocyclyl also includes spirocyclic rings (e.g., spirocyclic bicycle wherein two rings are connected through just one atom). Non-limiting examples of spirocyclic heterocyclyls include 2-azaspiro[2.2]pentyl, 4-azaspiro[2.5Joctyl, l-azaspiro[3.5]nonyl, 2-azaspiro[3.5]nonyl, 7-azaspiro[3.5]nonyl, 2-azaspiro[4.4]nonyl, 6-azaspiro[2.6]nonyl, l,7-diazaspiro[4.5]decyl, 7-azaspiro[4.5]decyl 2,5-diazaspiro[3,6]decyl 3-azaspiro[5.5]undecyl, 2-oxaspiro[2.2]pentyl, 4-oxaspiro[2.5]octyl, 1-oxaspiro[3.5]nonyl, 2-oxaspiro[3.5Jnonyl, 7-oxaspiro[3.5]nonyl, 2-oxaspiro[4.4]nonyl, 6-oxaspiro[2.6]nonyl, l,7-dioxaspiro[4.5]decyl, 2,5-dioxaspiro[3.6Jdecyl, 1-oxaspiro[5.5]undecyl, 3-oxaspiro[5.5]undecyl, 3-oxa-9-azaspiro[5.5]undecyl and the like.

[0135] A nitrogen-containing heterocyclyl as used herein refers to a heterocyclyl having 1-2 ring nitrogen atoms and 0-2 additional ring heteroatoms selected from the group consisting of 0 0 o

[0136] is

[0137] O and S (inclusive of oxidized such as:

[0138]

[0139] ' ' or ' ' The nitrogen-containing heterocyclyl can be monocyclic, bicyclic, or polycyclic as defined elsewhere herein. Examples of monocyclic nitrogen-containing heterocyclyl include azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, and the like. Examples of bicyclic nitrogen-containing heterocyclyl include 7-azaspiro[3.5]nonyl, l,7-diazaspiro[4.5]decyl, 3-oxa-7,9-diazabicyclo[3.3. IJnonanyl, 2,6-diazaspiro[3.3]heptanyl, and the like.Docket No. TRLN-013-034W01 / TLS-072WO

[0140] As used herein, when a ring is described as being ‘"partially unsaturated”, it means said ring has one or more additional degrees of unsaturation (in addition to the degree of unsaturation attributed to the ring itself; e.g., one or more double or triple bonds between constituent ring atoms), provided that the ring is not aromatic. Examples of such rings include: cyclopentene, cyclohexene, cycloheptene, dihydropyridine, tetrahydropyridine, dihydropyrrole, dihydrofuran, dihydrothiophene, and the like.

[0141] For the avoidance of doubt, and unless otherwise specified, for rings and cyclic groups (e.g., and, heteroaryl, heterocyclyl, heterocycloalkenyl, cycloalkenyl, cycloalkyl, and the like described herein) containing a sufficient number of ring atoms to form bicyclic or higher order ring systems (e.g., tricyclic, polycyclic ring systems), it is understood that such rings and cyclic groups encompass those having fused rings, including those in which the points of fusion are located (i) on adjacent ring atoms (e.g., [x.x. O] ring systems, in which 0 represents a zero atom

[0142] bridge (e.g., (ii)asingle ring atom (spiro-fused ring systems) (e.g.,

[0143]

[0144]

[0145] or 0^^ ),or(iii) a contiguous array of ring atoms (bridged ring systems

[0146]

[0147] In addition, atoms making up the compounds of the present embodiments are intended to include all isotopic forms of such atoms. Isotopes, as used herein, include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include tritium and deuterium, and isotopes of carbon include13C and14C.

[0148] In addition, the compounds generically or specifically disclosed herein are intended to include all tautomeric forms. Thus, by way of example, a compound containing the moiety:

[0149]

[0150] HO N encompasses the tautomeric form containing the moiety:

[0151]

[0152] Similarly, a pyridinyl or pyrimidinyl moiety that is described to be optionally substituted with hydroxyl encompasses pyridone or pyrimidone tautomeric forms.

[0153] The compounds provided herein may encompass various stereochemical forms. The compounds also encompass diastereomers as well as optical isomers, e.g., mixtures ofDocket No. TRLN-013-034W01 / TLS-072WO

[0154] enantiomers including racemic mixtures, as well as individual enantiomers and diastereomers, which arise as a consequence of structural asymmetry in certain compounds. Unless otherwise indicated, when a disclosed compound is named or depicted by a structure without specifying the stereochemistry and has one or more chiral centers, it is understood to represent all possible stereoisomers of the compound.

[0155] Methods of Treatment

[0156] Indications

[0157] Provided herein are methods for inhibiting a BCL6 protein. For example, provided herein are compounds capable of inhibiting a BCL6 protein useful for treating or preventing cancers or treating or preventing an autoimmune disease or condition. Exemplary compounds that bind to BCL6 are described in, e.g., Cerchietti, Leandro C., et al. Cancer Cell 17.4 (2010): 400-411, doi: 10.1016 / j.ccr.2009.12.050; Cardenas, Mariano G., et al. The Journal of Clinical Investigation 126(9) (2016): 3351-3362, doi: 10.1172 / JCI85795; Kerres, Nina, et al., Cell Reports 20.12 (2017): 2860-2875, doi: 10.1016 / j.celrep.2017.08.081; Yasui, Takeshi, et al., Bioorganic & Medicinal Chemistry 25.17 (2017): 4876-4886, doi: 10.1016 / j.bmc.2017.07.037; Kamada, Yusuke, et al., Journal of Medicinal Chemistry 60.10 (2017): 4358-4368, doi: 10.1021 / acs.jmedchem.7b00313; McCoull, William, et al., ACS Chemical Biology 13.11 (2018): 3131-3141, doi: 10.1021 / acschembio.8b00698; Guo, Weikai, et al. Journal of Medicinal Chemistry 63.2 (2020): 676-695, doi: 10.1021 / acs.jmedchem.9b01618; Teng, Mingxing, et al., ACS Medicinal Chemistry Letters 11.6 (2020): 1269-1273, doi: 10.1021 / acsmedchemlett.0c00111; Pearce, Andrew C., et al.. Journal of Biological Chemistry 297.2 (2021): 100928, doi: 10.1016 / j.jbc.2021.100928; Ding, Shu, Yu Rao, and Qianjin Lu, Cellular & Molecular Immunology (2022): 1-3, doi: 10.1038 / s41423-022-00882-l; Xing, Y, et al., Cancer Letters (2022), doi: 10.1016 / j.canlet.2021.12.035; Huckvale, R. et al., Journal of Medicinal Chemistry (2022), doi: 10.1021 / acs.jmedchem.lc02175; Davis, O. et al., Journal of Medicinal Chemistry (2022), doi: 10.1021 / acs.jmedchem.lc02174; International Publication Nos. WO 2008 / 066887; WO 2010 / 008436; WO 2014 / 204859; WO 2018 / 215798; WO 2018 / 215801; WO 2018 / 219281; WO 2019 / 119138; WO 2019 / 119144; WO 2019 / 119145; WO 2019 / 153080; WO 2019 / 197842; WO 2020 / 104820; WO 2021 / 074620; WO 2021 / 077010; WO 2022 / 221673; WO 2023 / 212147; WO 2023 / 114460; WO 2023 / 240038; WO 2023 / 244918; WO 2023 / 015164; WO 2024 / 086094; WO 2024 / 035688; WO 2024 / 019995; WO 2025 / 050016; WO 2025 / 049968; WO 2025 / 049964; and WO 2025 / 195363.

[0158] The term “compound(s) provided herein” refers to compound(s) of Formula (I) asDocket No. TRLN-013-034W01 / TLS-072WO

[0159] disclosed herein.

[0160] The compounds provided herein are modulators of BCL6. In some embodiments, a compound provided herein inhibits the interaction between a BCL6 protein and a corepressor peptide (e.g., BCOR); in such embodiments, the compound provided herein can also be termed a “BCL6 inhibitor” or “inhibitor of BCL6”. In some embodiments, a compound provided herein can induce degradation of a BCL6 protein; in such embodiments, the compound provided herein can also be termed a “BCL6 degrader”. For example, a compound provided herein can act as a “monovalent degrader” or “polymerizer” as described in, e.g., Bellenie, Benjamin R., et al. Journal of Medicinal Chemistry 63.8 (2020): 4047-4068, doi: 10.1021 / acs.jmedchem.9b02076 or Slabicki, Mikolaj, et al. Nature 588.7836 (2020): 164-168, doi: 10.1038 / s41586-020-2925-1. In some embodiments, a compound provided herein is both a BCL6 inhibitor and a BCL6 degrader. In some embodiments, a compound provided herein is a BCL6 inhibitor, but not a BCL6 degrader.

[0161] Binding affinity of a compound provided herein, or a pharmaceutically acceptable salt thereof, to BCL6 can be determined by, for example, a binding ICso or Ki value (e.g., using a competition assay), or by a KD value (e.g., using a biophysical assay). A compound with a lower binding ICso value, as determined under substantially similar conditions, is a more potent binder relative to a compound with a higher binding ICso value. A compound with a lower binding Ki value, as determined under substantially similar conditions, is a more potent binder relative to a compound with a higher binding Ki value. Similarly, a compound with a lower KD value, as determined under substantially similar conditions, is a more potent binder relative to a compound with a higher KD value. A KD value can be determined by surface plasmon resonance (SPR) or biolayer interferometry; see, e.g., Guo, Weikai, et al., Journal of Medicinal Chemistry 63.2 (2020): 676-695, doi: 10.1021 / acs.jmedchem.9b01618; Lloyd, Matthew G., et al., Journal of Medicinal Chemistry 64.23 (2021): 17079-17097, doi: 10.1021 / acs.jmedchem.1c00946, and International Publication Nos. WO 2019 / 153080; WO 2019 / 119144; and WO 2019 / 119145.

[0162] The ability of a compound provided herein, or a pharmaceutically acceptable salt thereof, to inhibit BCL6 can be determined using an IC50 value. A compound with a lower ICso value, as determined under substantially similar conditions, is a more potent inhibitor relative to a compound with a higher IC50 value. For example, an IC50 value can be calculated using a FRET (e.g., Homogeneous Time Resolved Fluorescence (HTRF)) assay, where a tagged (e.g., His-tagged) BCL6 protein and tagged (e.g., fluorophore-tagged (e.g., Alexa-Fluor633)) corepressor peptide (e.g., BCOR) are incubated in the presence of compoundsDocket No. TRLN-013-034W01 / TLS-072WO

[0163] provided herein, or pharmaceutically acceptable salts thereof, and subsequently, the FRET ratio (relative to appropriate controls) can be measured using an appropriate FRET pair (e.g., with an antibody that recognizes the tagged BCL6 protein (e.g., anti-His-Terbium cryptate)). An exemplary BCL6 inhibition assay is described in Example B2. See also, e.g., International Publication Nos. WO 2018 / 108704; WO 2018 / 215798; WO 2019 / 197842; WO 2020 / 104820; WO 2021 / 074620. As another example, an ICso value can be calculated using an enzyme-linked immunosorbent assay (ELISA) using a tagged (e.g., biotinylated) corepressor peptide (e.g., BCOR) immobilized on a substrate and a tagged (e.g., FLAG-tagged) BCL6 (e.g., a domain, such as the BTB domain, thereof), where compounds provided herein, or pharmaceutically acceptable salts thereof, can be used to prevent the interaction between the corepressor peptide and BCL6, and the interaction between the corepressor peptide and BCL6 can be measured using an antibody to the BCL6 construct (e.g., anti-FLAG antibody). See, e.g., Kamada, Yusuke, et al,, Journal of Medicinal Chemistry 60.10 (2017): 4358-4368, doi: 10.1021 / acs.jmedchem.7b00313. As yet another example, an ICso value can be calculated using a fluorescence polarization assay with a fluorescently-tagged corepressor peptide (e.g., SMRT) where compounds provided herein, or pharmaceutically acceptable salts thereof, can be used to prevent the interaction between the corepressor peptide and BCL6. See, e.g., International Publication No. WO 2019 / 119144. As another example, a cellular ICso value can be calculated using a BRET (Bioluminescence Resonance Energy Transfer) assay, where vectors encoding BCL6 and a corepressor peptide (e.g., SMRT), complementarily fused with NanoLuc or HaloTag, can be inserted into cells. The cells can be treated with compounds provided herein, or pharmaceutically acceptable salts thereof, to determine the effect of the compounds on inhibiting the BCL6-corepressor interaction. See, e.g., International Publication Nos. WO 2018 / 215798 and WO 2019 / 197842. In another example, an IC50 value for the inhibition of BCL6 repressor function can be calculated using a luciferase assay, where cells are engineered to express luciferase under the control of one or more BCL6 repressor sites, and the cells can be incubated with compounds provided herein, or pharmaceutically acceptable salts thereof, to determine the effect of the compounds on the function of the BCL6 repressor. See, e.g., International Publication Nos. WO 2019 / 119144; WO 2019 / 119145; WO 2019 / 153080.

[0164] Potency of degradation by a compound provided herein, or a pharmaceutically acceptable salt thereof, can be determined by DCso value. As used herein, DCso refers to the concentration of the compound provided herein, or a pharmaceutically acceptable salt thereof, that results in a 50% decrease in the concentration of a protein (e.g., BCL6 protein) in a cell compared to the concentration of the protein before the cell is contacted with the compoundDocket No. TRLN-013-034W01 / TLS-072WO

[0165] provided herein, or a pharmaceutically acceptable salt thereof, or compared to the concentration of the protein in a cell not contacted with the compound provided herein, or a pharmaceutically acceptable salt thereof. A compound with a lower DCso value, as determined under substantially similar conditions, is a more potent inducer of degradation relative to a compound with a higher DCso value. In some embodiments, a DCso value can be determined (e.g., using HiBiT detection) in vitro or in vivo (e.g., in tumor cells expressing a BCL6 protein (e.g., cell lines such as A3 / KAW, A4 / FUK, DB, DOHH2, Farage, HT, Karpas 422, KML1, MHHPREB1, NUDHL1, OCI-Lyl, OCI-Ly3, OCI-Ly7, OCI-Lyl 8, OCI-Lyl 9, Pfeiffer, RI1, RL, SU-DHL-4, SU-DHL-5, SU-DHL-6, SU-DHL-8, SU-DHL-10, VAL, or WSU-DLCL2; see also those disclosed in, e.g., Cardenas, Mariano G., et al. Clinical Cancer Research 23.4 (2017): 885-893, doi: 10.1158 / 1078-0432. CCR-16-2071 and International Publication Nos. WO 2021 / 080950, WO 2021 / 077010, and WO 2022 / 221673)). In some embodiments, a cell line that is not dependent on BCL6 and / or that does not have significant expression of BCL6 can be used as a control (e.g., Toledo, H929, MM. IS, or OPM2).

[0166] Potency of degradation by a compound provided herein, or a pharmaceutically acceptable salt thereof, can be determined by ECso value. As used herein, ECso refers to the concentration of the compound provided herein, or a pharmaceutically acceptable salt thereof, that results in a 50% decrease in the concentration of a protein (e.g., BCL6 protein) relative to the trough concentration of the protein in a cell, when compared to the concentration of the protein before the cell is contacted with the compound provided herein, or a pharmaceutically acceptable salt thereof, or compared to the concentration of the protein in a cell not contacted with the compound provided herein, or a pharmaceutically acceptable salt thereof. A compound with a lower ECso value, as determined under substantially similar conditions, is a more potent inducer of degradati on rel ative to a compound with a higher ECso value. In some embodiments, an ECso value can be determined (e.g., using HiBiT detection) in vitro or in vivo (e.g., in tumor cells expressing a BCL6 protein (e.g., cell lines such as A3 / KAW, A4 / FUK, DB, D0HH2, Farage, HT, Karpas 422, KML1, MHHPREB1, NUDHL1, OCI-Ly1, OCI-Ly3, OCI-Ly7, OCI-Ly18, OCI-Ly19, Pfeiffer, RI1, RL, SU-DHL-4, SU-DHL-5, SU-DHL-6, SU-DHL-8, SU-DHL-10, VAL, or WSU-DLCL2; see also those disclosed in, e.g., Cardenas, Mariano G., et al. Clinical Cancer Research 23.4 (2017): 885-893, doi: 10.1158 / 1078-0432. CCR-16-2071 and International Publication Nos. WO 2021 / 080950, WO 2021 / 077010, and WO 2022 / 221673)). In some embodiments, a cell line that is not dependent on BCL6 and / or that does not have significant expression of BCL6 can be used as a control (e g., Toledo, H929, MM. IS, or OPM2).Docket No. TRLN-013-034W01 / TLS-072WO

[0167] Potency of degradation by a compound provided herein, or a pharmaceutically acceptable salt thereof, can be determined by a Ymin value. As used herein, Ymin refers to the ratio of trough concentration of a protein (e.g., BCL6 protein) in a cell compared to the concentration of the protein before the cell is contacted with the compound provided herein, or a pharmaceutically acceptable salt thereof, or compared to the concentration of the protein in a cell not contacted with the compound provided herein, or a pharmaceutically acceptable salt thereof, expressed as a percentage. As used herein, Dmax is 1-Ymin. Ymin can be measured by a HiBiT assay (e.g., as described in Example B3). A compound with a lower Ymin value, as determined under substantially similar conditions, is a more potent inducer of degradation relative to a compound with a higher Ymin value. In some embodiments, a Ymin value can determined (e.g., using HiBiT detection), in vitro or in vivo (e.g., in tumor cells expressing a BCL6 protein (e.g., cell lines such as A3 / KAW, A4 / FUK, DB, D0HH2, Farage, HT, Karpas 422, KML1, MHHPREB1, NUDHL1, OCI-Ly1, OCI-Ly3, OCI-Ly7, OCI-Ly18, OCI-Ly19, Pfeiffer, RI1, RL, SU-DHL-4, SU-DHL-5, SU-DHL-6, SU-DHL-8, SU-DHL-10, VAL, or WSU-DLCL2; see also those disclosed in, e.g., Cardenas, Mariano G., et al. Clinical Cancer Research 23.4 (2017): 885-893, doi: 10.1158 / 1078-0432. CCR-16-2071 and International Publication Nos. WO 2021 / 080950, WO 2021 / 077010, and WO 2022 / 221673)). In some embodiments, a cell line that is not dependent on BCL6 and / or that does not have significant expression of BCL6 can be used as a control (e.g., Toledo, H929, MM. IS, or OPM2).

[0168] In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, exhibits a Ymin of less than 70% (e.g., less than 50% or less than 30%) in a HiBiT based degradation assay (e.g., an assay as described in Example B3). In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, exhibits a Ymin of less than 50% (e.g., less than 30%) in a HiBiT based degradation assay. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, exhibits a Ymin of less than 30% in a HiBiT based degradation assay.

[0169] The effect of protein degradation typically increases over time, though the appearance of degradation (e.g., as expressed by the percentage degradation compared to a control, or the parameters Ymin, DCso, EC 50, and / or Dmax) is affected by the resynthesis rate of the protein. Accordingly, degradation can be examined after a specified period of time, such as 6 hours, 12 hours, 18 hours, 1 day, 2 days, 3 days, 5 days, 10 days, or more. For example, degradation can be expressed as the percent degradation after 24 hours.

[0170] Exemplary assays for validating the degradation-inducing mechanism of a compound as provided herein are known in the art and are described, for example, in Wu, et al. NatureDocket No. TRLN-013-034W01 / TLS-072WO

[0171] Structural & Molecular Biology 22.1 (2020): 605-614, doi: 10.1038 / s41594-020-0438-0.

[0172] Another exemplary way of evaluating the effect of a compound provided herein, or a pharmaceutically acceptable salt thereof, is to measure the induction (e.g., fold induction) of genes that are typically repressed by BCL6 (e.g., p53, ATR, CXCR3, CD69, and CDKNIA using a method such as RT-PCR. See, e.g., Guo, Weikai, et al., Journal of Medicinal Chemistry 63.2 (2020): 676-695, doi: 10.1021 / acs.jmedchem.9b01618.

[0173] An exemplary assay for determining the potency of a compound provided herein, or a pharmaceutically acceptable salt thereof, includes measuring the effect of the compound provided herein, or a pharmaceutically acceptable salt thereof, on cell proliferation and / or viability. Cell proliferation assays can be performed in a number of formats, including 2D and 3D. Similarly, a cell proliferation assay can be performed with any appropriate cell line, including, for example, A3 / KAW, A4 / FUK, DB, D0HH2, Farage, HT, Karpas 422, KML1, MHHPREB1, NUDHL1, OCI-Lyl, OCI-Ly3, OCI-Ly7, OCI-Ly18, OCI-Ly19, Pfeiffer, RI1, RL, SU-DHL-4, SU-DHL-5, SU-DHL-6, SU-DHL-8, SU-DHL-10, VAL, orWSU-DLCL2. In some embodiments, a cell line that is not dependent on BCL6 and / or that does not have significant expression of BCL6 can be used as a control (e.g., Toledo, H929, MM. IS, or OPM2).

[0174] A cell viability assay can be used to measure the effect of a compound provided herein, or a pharmaceutically acceptable salt thereof, on cell death. For example, cells expressing BCL6 protein (e.g., A3 / KAW, A4 / FUK, DB, DOHH2, Farage, HT, Karpas 422, KML1, MHHPREB1, NUDHL1, OCI-Lyl, OCI-Ly3, OCI-Ly7, OCI-Lyl 8, OCI-Lyl 9, Pfeiffer, RI1, RL, SU-DHL-4, SU-DHL-5, SU-DHL-6, SU-DHL-8, SU-DHL-10, VAL, or WSU-DLCL2 cells) can be incubated with various concentrations of a compound provided herein, or a pharmaceutically acceptable salt thereof, and then exposed to a detection reagent (e.g., using a CELLTITER-GLO® Cell Viability Assay kit) to determine cell viability. In some embodiments, the effect on ceil viability can be compared to a ceil line that is not dependent on BCL6 and / or that does not have significant expression of BCL6 (e.g., Toledo, H929, MM. IS, or OPM2).

[0175] As another example, the potency and / or efficacy of a compound provided herein, or a pharmaceutically acceptable salt thereof, can be evaluated in an animal model, for example, a cell line-derived (CDX) xenograft model (e.g., using an established cancer cell line such as DB, DoHH2, OCI-Lyl, OCI-Ly7, RL, Pfeiffer, SU-DHL-5, SU-DHL-6, WSU-DLCL2, REH, BALL-1, RS4;11, SEMK2, KOPN8, NALM-6, KASUMI-2, RCH-ACV, SUP-B15, BV-173, TOM-1, NALM-20, NALM-21, MUTZ-5, or MHH-CALL-4 (e.g., OCI-Lyl, OCI-Ly7, SU-Docket No. TRLN-013-034W01 / TLS-072WO

[0176] DHL-5, SU-DHL-6, WSU-DLCL2, DB, RL, Pfeiffer, or DoHH2)), a genetically engineered mouse model (GEMM), or a patient-derived xenograft (PDX) model.

[0177] In some embodiments, a compound provided herein, or pharmaceutically acceptable salt thereof can be assessed for its ability to modulate (e.g., decrease) Ig antibody production (e.g., IgA antibody production, IgE antibody production, and / or IgG antibody production), modulate (e.g., decrease) Ig antibody affinity (e.g., IgA antibody affinity, IgE antibody affinity, and / or IgG antibody affinity), and / or modulate (e.g., decrease) germinal center formation in an animal (e.g., a mouse) following challenge with a T cell -depend ent antigen (e.g., keyhole limpet haemocyanin (KLH) or sheep red blood cells (SRBC)). For example, KLH can be administered to mice (e.g., C57BL / 6 mice), followed by administration of the compound provided herein, or a pharmaceutically acceptable salt thereof, for a period of time (e.g., 14 days). Following sacrifice, serum samples from the mice can be analyzed for IgG specific for KLH, for example, by ELISA. Similarly, germinal centers can be detected using immunohistological staining using, e.g., peanut agglutinin (PNA). See, e.g., Example 1 of WO 2020 / 014599.

[0178] In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, can be assessed for its ability to modulate (e.g., decrease) the number of germinal center B cells in an animal (e.g., mouse) following immunization with an antigen. For example, animals (e g., mice) can be immunized with specific antigens formulated in adjuvant such as Complete Freund's Adjuvant (CFA) or / Mum, and after a period of time (e.g., 8 days), the animals can be sacrificed and the spleens harvested. The spleens can be processed into a suspension and cultured in the presence of a compound provided herein, or pharmaceutically acceptable salt thereof. The cells can then be analyzed, for example, for the number of germinal center B cells (e.g., by flow cytometry' using the lineage markers GL7 and CD95). See, e.g., WO 2021 / 074620.

[0179] Also provided herein are methods of treating a cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof.

[0180] In some embodiments of any of the methods or uses described herein, the cancer is breast cancer (e.g., breast invasive carcinoma, breast invasive ductal carcinoma), central or peripheral nervous system tissue cancer (e.g., brain cancer (e.g., astrocytoma, glioblastoma, glioma, oligoastrocytoma)), endocrine or neuroendocrine cancer (e.g., adrenal cancer (e.g., adrenocortical carcinoma, pheochromocytoma, paraganglioma), multiple neuroendocrine typeDocket No. TRLN-013-034W01 / TLS-072WO

[0181] I and type II tumors, parathyroid cancer, pituitary tumors, thyroid cancer (e.g., papillary thyroid cancer)), eye cancer (e.g., uveal cancer (e.g., uveal melanoma)), gastrointestinal cancer (e.g., anal cancer, bile duct cancer (e.g., cholangiocarcinoma), colorectal cancer (e.g., colon adenocarcinom, rectal adenocarcinoma, mucinous adenocarcinoma, mucinous carcinoma), esophageal cancer (e.g., esophageal adenocarcinoma), gallbladder cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor, liver cancer (e.g., hepatocellular carcinoma, intrahepatic bile duct cancer), pancreatic cancer (e.g., pancreatic adenocarcinoma, pancreatic islet cell cancer), small intestine cancer, or stomach cancer (e.g., stomach adenocarcinoma, signet ring cell carcinoma of the stomach)), genitourinary cancer (e.g., bladder cancer (e.g., bladder urothelial carcinoma), kidney cancer (e.g., renal clear cell carcinoma, renal papillary cell carcinoma, kidney chromophobe), prostate cancer (e g., prostate adenocarcinoma), testicular cancer (e.g., testicular germ cell tumors), or ureter cancer), gynecologic cancer (e.g., cervical cancer (e.g., cervical squamous cell carcinoma, endocervical adenocarcinoma, mucinous carcinoma), ovarian cancer (e.g., serous ovarian cancer, ovarian serous cystadenocarcinoma), uterine cancer (e.g., uterine carcinosarcoma, uterine endometrioid carcinoma, uterine serous carcinoma, uterine papillary serous carcinoma, uterine corpus endometrial carcinoma), or vulvar cancer), head and neck cancer (e.g., ear cancer (e.g., middle ear cancer), head and neck squamous cell carcinoma, nasal cavity cancer, oral cancer, pharynx cancer (e.g., hypopharynx cancer, nasopharynx cancer, oropharyngeal cancer), hematological cancer (e.g., leukemia (e.g., acute lymphocytic leukemia (ALL) (e.g., Philadelphia chromosome positive ALL, Philadelphia chromosome negative ALL), acute myeloid leukemia (AML) (e.g., acute promyelocytic leukemia (APL)), chronic myeloid leukemia (CML), or early T-precursor lymphoblastic leukemia, or myelodysplastic syndrome), lymphoma (e.g., Hodgkin lymphoma (e.g., nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) or classic Hodgkin lymphoma), non-Hodgkin lymphoma (e.g., B cell lymphoid proliferations and lymphomas (e.g., tumor-like lesions with B-cell predominance (e.g., IgG4-related disease), precursor B cell neoplasms (e.g., B lymphoblastic lymphomas), mature B cell neoplasms (e.g., chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), marginal zone lymphoma, Burkitt lymphoma (BL), large B cell lymphoma (e.g., diffuse large B-cell lymphoma not otherwise specified (DLBCL-NOS), T-cell / histiocyte-rich large B-cell lymphoma, diffuse large B-cell lymphoma / high grade B cell lymphoma (HGBCL) (e.g., HGBCL with MYC and / or BCL2 rearrangements (HGBCL-MYC / BCL-2)), ALK-positive large B-cell lymphoma, large B cell lymphoma with IRF4 rearrangements, high-grade B cell lymphoma with llq aberration, lymphomatoid granulomatosis, Epstein-Barr virus (EBV)-Docket No. TRLN-013-034W01 / TLS-072WO

[0182] positive large B-cell lymphoma, diffuse large B-cell lymphoma associated with chronic inflammation, fibrin-associated large B-cell lymphoma, fluid-overload large B-cell lymphoma, plasmablastic lymphoma, primary large B cell lymphoma of immune-privileged sites (primary LBCL of immune-privileged sites), primary cutaneous large B-cell lymphoma leg type, intravascular large B-cell lymphoma (IVLBCL), primary mediastinal large B cell lymphoma (primary mediastinal LBCL), mediastinal grey zone lymphoma, or high grade B-cell lymphoma NOS), follicular lymphoma (FL), transformations of indolent B cell lymphomas, mantle cell lymphoma (MCL), or plasma cell neoplasms (e.g., multiple myeloma))), T-cell and NK-cell lymphoid proliferations and lymphomas (e.g., tumor-like lesions with T-cell predominance (e.g., autoimmune lymphoproliferative syndrome), precursor T-cell neoplasms (e.g., early T-precursor lymphoblastic leukemia / lymphoma or T-lymphoblastic leukemia / lymphoma NOS), mature T-cell and NK-cell neoplasms (e.g., mature T-cell and NK- cell leukemias (e.g., T-prolymphocytic leukemia, T-large granular lymphocytic leukemia, NK-large granular lymphocytic leukemia, adult T-cell leukemia / lymphoma, or aggressive NK-cell leukemia), primary cutaneous T-cell lymphoid proliferations and lymphomas (cutaneous T-cell lymphoma (CTCL)) (e.g., primary cutaneous CD4-positive small or medium T-cell lymphoproliferative disorder, primary cutaneous acral CD8-positive T-cell lymphoproliferative disorder, mycosis fungoides, Sezary syndrome, primary cutaneous CD30- positive T-cell lymphoproliferative disorder: lymphomatoid papulosis, primary cutaneous CD30-positive T-cell lymphoproliferative disorder: primary cutaneous anaplastic large cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, primary cutaneous gamma-delta T-cell lymphoma, primary' cutaneous CD8-positive aggressive epidermotropic cytotoxic T-cell lymphoma, or primary cutaneous peripheral T-cell lymphoma NOS), peripheral T-cell lymphoma (PTCL) (e.g., intestinal T-cell and NK-cell lymphoid proliferations and lymphomas (e.g., indolent T-cell lymphoma of the gastrointestinal tract, indolent NK-cell lymphoproliferative disorder of the gastrointestinal tract, enteropathy-associated T-cell lymphoma, monomorphic epitheliotropic intestinal T-cell lymphoma, or intestinal T-cell lymphoma NOS)),hepatosplenic T-cell lymphoma, anaplastic large cell lymphoma (ALCL) (e.g., ALK-positive anaplastic large cell lymphoma, ALK-negative anaplastic large cell lymphoma, or breast implant-associated anaplastic large cell lymphoma), nodal T follicular helper cell lymphoma (e.g., nodal T follicular helper cell lymphoma angioimmunoblastic type (also known as angioimmunoblastic T-cell lymphoma (AITL) or follicular helper T-cell lymphoma, angioimmunoblastic type), nodal T follicular helper cell lymphoma follicular type (also known as follicular helper T-cell lymphoma, follicular type), or nodal T follicular helperDocket No. TRLN-013-034W01 / TLS-072WO

[0183] cell lymphoma NOS (also known as follicular helper T-cell lymphoma, NOS)), other peripheral T-cell lymphomas (e.g., peripheral T-cell lymphoma NOS), or EBV-positive T-cell and NK- cell lymphomas (e.g., EBV-positive nodal T- and NK-cell lymphoma or extranodal NK / T-cell lymphoma)))))), Li-Fraumeni tumors, mesentery cancer (e.g., omentum cancer, peritoneal cancer), pleural cancer, respiratory cancer (e.g., larynx cancer, lung cancer (e.g., lung squamous cell carcinoma, lung adenocarcinoma, mesothelioma, non-small cell lung cancer (NSCLC)), tracheal cancer), sarcoma (e.g., bone cancer (e.g., osteosarcoma, chondrosarcoma) or soft tissue sarcoma (Ewing sarcoma, leiomyosarcoma, myxofibrosarcoma, rhabdomyosarcoma)), skin cancer (e.g., melanoma), thymus cancer (e.g., thymoma), or a combination thereof.

[0184] Also provided herein are methods of treating a hematological malignancy (e.g., a relapsed or refractory hematological malignancy or a lymphoma) in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof.

[0185] In some embodiments, the hematological malignancy is a lymphoma. In some embodiments, the lymphoma is a non-Hodgkin lymphoma.

[0186] In some embodiments, the non-Hodgkin lymphoma is a B-cell lymphoma. In some embodiments, the B-cell lymphoma is a large B-cell lymphoma (DLBCL). For example, the large B-cell lymphoma can be DLBCL-NOS In some embodiments, the B-cell lymphoma is selected from the group consisting of follicular lymphoma (FL) and transformed FL.

[0187] In some embodiments, the non-Hodgkin lymphoma is a T-cell lymphoma. In some embodiments, the T-cell lymphoma is peripheral T-cell lymphoma (PTCL). For example, the PTCL can be PTCL-NOS. In some embodiments, the PTCL is a nodal T follicular helper cell lymphoma. For example, the nodal T follicular helper cell lymphoma is selected from the group consisting of AITL, nodal T follicular helper cell lymphoma follicular type, and nodal T follicular helper cell lymphoma-NOS. In some embodiments, the T-cell lymphoma is CTCL.

[0188] In some embodiments, the hematological malignancy (e.g., the lymphoma) is relapsed or refractory.

[0189] In some embodiments, the cancer in the subject is positive for BCL6 expression. In some embodiments, the cancer in the subject is negative for BCL6 expression. Accordingly, also provided herein is a method of treating cancer in a subject in need thereof, the method comprising (a) determining the BCL6 expression status of the cancer (e.g., by performing an assay or a test, or consulting the subject’s medical record); and (b) administering to the subject a therapeutically effective amount of a compound provided herein, or a pharmaceuticallyDocket No. TRLN-013-034W01 / TLS-072WO

[0190] acceptable salt thereof.

[0191] As used herein, “determining BCL6 expression status,” means assessing whether BCL6 is expressed, e.g., at the mRNA or protein level. In some embodiments, the assessment includes the level of BCL6 expression (e.g., BCL6 expression above or below a threshold value). BCL6 expression status can be assessed by a variety of methods (e.g., measuring protein levels, mRNA levels, or both) and can be assessed quantitatively or qualitatively, e.g., using a scale or threshold accepted by, e.g., a regulatory agency or by a pathologist. In some embodiments, the assessment includes consulting the medical record of a subject. In some embodiments, the BCL6 expression status is positive (e.g., the sample from the subject is positive for BCL6 expression).

[0192] In some embodiments, a BCL6 expression status can be determined for a sample from a subject. In some embodiments, the BCL6 expression status can be determined by expression profiling (e.g., mRNA expression profiling) (e.g., of a sample of the cancer or from a blood sample). In some embodiments, the BCL6 expression status can be determined by an mRNA-based test, such as RNA sequencing (RNA-seq), reverse transcription polymerase chain reaction (RT-PCR), digital PCR (dPCR), or in-situ hybridization (ISH). In some embodiments, the BCL6 expression status can be determined by an IHC test, using any appropriate IHC method and reagents. In some cases, a diagnosis of a mature B-cell neoplasm (e g., FL or a large B-cell lymphoma (e.g., DLBCL-NOS)) is made by pathologists using a diagnostic algorithm that includes IHC markers like BCL6, CD20, CD10, BCL2, MUM1 and / or Ki-67, such as the Hans algorithm. The Hans algorithm includes BCL6 as a determinant of germinal center cell of origin and defines BCL6-positivity as 30% nuclear staining in tumor cells. See, e.g., Hans, Christine P., et al. Blood 103.1 (2004): 275-282, doi: 10.1182 / blood-2003-05- 1545 and Choi, William WL, et al. Clinical Cancer Research ] 5 Al (2009): 5494-5502, doi: 10.1158 / 1078-0432. CCR-09-0113.

[0193] Also provided herein is a method of treating cancer, the method comprising administering to a subject who has a record (e.g., a medical record) that indicates that the cancer in the subject is positive for BCL6 expression (e.g., a subject previously identified as having a cancer that is positive for BCL6 expression by an IHC test) a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof.

[0194] As used herein, methods of treating a cancer can include treatment of a primary tumor (i.e., non-metastatic cancer) (e.g., as first, second, third, or later line of therapy, including, but not limited to, the relapsed / refractory setting), treatment of a metastatic (or secondary) tumor, neoadjuvant therapy (e.g., before treatment with an additional therapy or therapeutic agent,Docket No. TRLN-013-034W01 / TLS-072WO

[0195] such as surgery, radiation, chemotherapy, or a line of therapy), adjuvant therapy (e.g., following treatment with an additional therapy or therapeutic agent, such as surgery, radiation, chemotherapy, or a line of therapy), or maintenance therapy (e.g., treatment following response to an additional therapy or therapeutic agent, such as surgery, radiation, chemotherapy, or a line of therapy).

[0196] Also provided herein are methods for treating or preventing an autoimmune condition in a subject in need thereof, the methods comprising administering to the subject a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof.

[0197] In some embodiments, the autoimmune disease or condition is an anti-drug or antitherapy antibody. In some embodiments, the autoimmune disease or condition is an anti-drug antibody. In some embodiments, the anti-drug antibody is an antibody against an antibody drug (e g., an anti-TNFa antibody drug). In some embodiments, the autoimmune disease or condition is an anti-therapy antibody. In some embodiments, the anti-therapy antibody is an antibody against an enzyme replacement therapy (e.g., Factor VII replacement therapy, a-galactosidase replacement therapy, or alpha-glucosidase replacement therapy). In some embodiments, the anti-therapy antibody is an antibody against a gene therapy (e.g., AAV-based gene therapy). See, e.g., Vaisman-Mentesh, Anna, et al. Frontiers in Immunology 11 (2020): 1951, doi: 10.3389 / fimmu.2020.01951; Lenders, Malte, and Eva Brand. Drugs 81.17 (2021): 1969-1981, doi: 10.1007 / s40265-021-01621-y; Rana, Jyoti, Maite Melero Munoz, and Moanaro Biswas. Cellular Immunology (2022): 104641, doi: 10.1016 / j.cellimm.2022.104641; and Butterfield, John SS, et al. Cellular Immunology (2023): 104742, doi: 10.1016 / j. cellimm.2023.104742.

[0198] In some embodiments, the autoimmune disease or condition is anti-synthetase syndrome. In some embodiments, the autoimmune disease or condition is arthritis (e.g., rheumatoid arthritis or inflammatory arthritis). In some embodiments, the autoimmune disease or condition is graft-versus-host disease (e.g., chronic graft-versus-host disease). In some embodiments, the autoimmune disease or condition is IgG4-related disease (IgG4-RD). In some embodiments, the autoimmune disease or condition is lupus (e.g., lupus erythematosus). In some embodiments, the autoimmune disease or condition is myasthenia gravis (e.g., muscle¬ specific tyrosine kinase (MuSK) positive myasthenia gravis). In some embodiments, the autoimmune disease or condition is multiple sclerosis (MS). In some embodiments, the MS is clinically isolated syndrome (CIS), relapsing-remitting MS (RRMS), primary progressive MS (PPMS), or secondary progressive MS (SPMS). In some embodiments, the autoimmuneDocket No. TRLN-013-034W01 / TLS-072WO

[0199] disease or condition is neuromyelitis optica (NMO). In some embodiments, the autoimmune disease or condition is pemphigus (e.g., pemphigus vulgaris). In some embodiments, the autoimmune disease or condition is Sjogren’s syndrome.

[0200] In some embodiments of any of the methods provided herein, the compound provided herein, or a pharmaceutically acceptable salt thereof, is dosed q.d. (once daily) to the subject. In some embodiments of any of the methods provided herein, the compound provided herein, or a pharmaceutically acceptable salt thereof, is dosed b.i.d. (twice daily) to the subject. In some embodiments of any of the methods provided herein, the compound provided herein, or a pharmaceutically acceptable salt thereof, is dosed t.i.d. (three times daily) to the subject. In some embodiments of any of the methods provided herein, the compound provided herein, or a pharmaceutically acceptable salt thereof, is dosed q.i.d. (four times daily) to the subject. In some embodiments of any of the provided herein, the compound provided herein, or a pharmaceutically acceptable salt thereof, is dosed q.o.d. (every other day) to the subject. In some embodiments of any of the methods provided herein, the compound provided herein, or a pharmaceutically acceptable salt thereof, is dosed q.week (once weekly) to the subject. In some embodiments of any of the methods provided herein, the compound provided herein, or a pharmaceutically acceptable salt thereof, is dosed b.i.w. (twice weekly) to the subject. In some embodiments of any of the methods provided herein, the compound provided herein, or a pharmaceutically acceptable salt thereof, is dosed t.i.w. (three times weekly) to the subject.

[0201] Also provided is a method for modulating (e.g., decreasing) BCL6 protein activity in a cell, comprising contacting the cell with a compound provided herein, or a pharmaceutically acceptable salt thereof. In some embodiments, the contacting is in vitro. In some embodiments, the contacting is in vivo. In some embodiments, the contacting is ex vivo. In some embodiments, the contacting is in vivo, wherein the method comprises administering an effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof, to a subject. In some embodiments, the cell is a cancer cell. In some embodiments, the cell is a mammalian cell. In some embodiments, the cell is a mammalian cancer cell. In some embodiments, the cancer cell is any cancer as described herein.

[0202] As used herein, the term “contacting” refers to the bringing together of indicated moieties in an in vitro system, an in vivo system, or an ex vivo system. For example, “contacting” a cell with a compound provided herein includes the administration of a compound provided herein to the cell, in vitro or in vivo, including, for example, introducing a compound provided herein into a sample containing cells (e.g., grown in culture or derivedDocket No. TRLN-013-034W01 / TLS-072WO

[0203] from a subject), an organoid, or an organism (e.g., an animal (e.g., an animal bearing a tumor), or a human).

[0204] Also provided herein is a method of inhibiting cell proliferation, in vitro or in vivo, the method comprising contacting a cell with an effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof as defined herein.

[0205] Further provided herein is a method of increasing cell death, in vitro or in vivo, the method comprising contacting a cell with an effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof as defined herein. Also provided herein is a method of increasing tumor cell death in a subject, the method comprising administering to the subject a compound provided herein, or a pharmaceutically acceptable salt thereof, in an amount effective to increase tumor cell death.

[0206] When employed as pharmaceuticals, the compounds provided herein, or pharmaceutically acceptable salts thereof, can be administered in the form of pharmaceutical compositions as described herein.

[0207] Combinations

[0208] In any of the indications described herein, a compound provided herein, or a pharmaceutically acceptable salt thereof, can be used as a monotherapy. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, can be used prior to administration of an additional therapeutic agent or additional therapy. For example, a subject in need thereof can be administered one or more doses of a compound provided herein, or a pharmaceutically acceptable salt thereof, for a period of time and then undergo at least partial resection of the tumor. In some embodiments, the treatment with one or more doses of a compound provided herein, or a pharmaceutically acceptable salt thereof, reduces the size of the tumor (e.g., the tumor burden) prior to the at least partial resection of the tumor.

[0209] In some embodiments, a subject in need thereof can be administered one or more doses of a compound provided herein, or a pharmaceutically acceptable salt thereof, for a period of time and undergo one or more rounds of radiation therapy. In some embodiments, the treatment with one or more doses of a compound provided herein, or a pharmaceutically acceptable salt thereof, reduces the size of the tumor (e.g., the tumor burden) prior to the one or more rounds of radiation therapy.

[0210] In some embodiments of any the methods described herein, the compound provided herein, or a pharmaceutically acceptable salt thereof, is administered in combination with aDocket No. TRLN-013-034W01 / TLS-072WO

[0211] therapeutically effective amount of at least one additional therapeutic (e.g., chemotherapeutic) agent.

[0212] Non-limiting examples of additional therapeutic agents include: RAS pathway targeted therapeutic agents (e.g., Ras / RAF / MEK / PI3K pathway inhibitors, (e.g., Ras inhibitors, KRas-targeted therapeutic agents, S0S1 inhibitors, SOSl / Ras protein-protein interaction inhibitors, SHP2 inhibitors, PI3K-AKT-mTOR pathway inhibitors)), kinase-targeted therapeutics (e.g., MEK inhibitors, ERK inhibitors, Raf inhibitors (e.g., BRaf inhibitors), PI3K inhibitors, AKT inhibitors, BTK inhibitors, mTOR inhibitors, CDK4 / 5 inhibitors, CDK4 / 6 inhibitors, MET inhibitors, JAK inhibitors (e.g., JAK2 inhibitors), FAK inhibitors, ErbB family inhibitors (e.g., EGFR inhibitors, Her2 inhibitors), Src inhibitors), menin inhibitors, mTORCl inhibitors, YAP inhibitors, proteasome inhibitors, farnesyl transferase inhibitors, HSP90 inhibitors, PTEN inhibitors, inhibitors of the polycomb repressive complex 2 (PRC2) (e.g., EZH1 / 2 or EZH2 inhibitors), signal transduction pathway inhibitors, checkpoint inhibitors, modulators of the apoptosis pathway (e.g., BCL-2 inhibitors, BCL-XLinhibitors), XPO1 inhibitors, steroids, chemotherapeutics, angiogenesis-targeted therapies, immune-targeted agents including immunomodulatory imide drugs (sometimes called “IMiDs” or “CELMoDs”), immunotherapy (e.g., anti-PDl, anti-PD-Ll, anti-CD19, anti-CD20, anti-CD22, anti-CD3, anti-CD30, anti-CD79B, or anti-CD47 therapies, including antibodies (e.g., single-targeted antibodies targeting one or more of PD1, PD-L1, CD19, CD20, CD22, CD3, CD30, CD79B, or CD47, bispecific antibodies (including bispecific T cell engagers (BiTEs)) targeting one or more of PD1, PD- Ll, CD19, CD20, CD22, CD3, CD30, CD79B, or CD47, and antibody-drug conjugates (ADCs) incorporating one or more of PD1, PD-L1, CD19, CD20, CD22, CD3, CD30, CD79B, or CD47 antibodies ) or antigen -binding fragments thereof, a PD-1 inhibitor, or a PD-L1 inhibitor), cell-based therapeutics (e.g., adoptive cell therapy (e.g., CAR T therapy, cytokine-induced killer cells (CIKs), natural killer cells (e.g., CAR-modified NK cells)) or antibody¬ armed ceil therapy), and radiotherapy.

[0213] These additional therapeutic agents can be administered with one or more doses of the compound provided herein, or a pharmaceutically acceptable salt thereof, or pharmaceutical composition comprising a compound provided herein, or a pharmaceutically acceptable salt thereof, as part of the same or separate dosage forms, via the same or different routes of administration, and / or on the same or different administration schedules according to standard pharmaceutical practice known to one skilled in the art. In some embodiments, the compound provided herein, or a pharmaceutically acceptable salt thereof, and the additional therapeutic agent are administered simultaneously as separate dosages. In some embodiments, a compoundDocket No. TRLN-013-034W01 / TLS-072WO

[0214] provided herein, or a pharmaceutically acceptable salt thereof’ and the additional therapeutic agent are administered as separate dosages simultaneously, separately, or sequentially in any order, in jointly therapeutically effective amounts, e.g., in daily or intermittent dosages. In some embodiments, the compound provided herein, or a pharmaceutically acceptable salt thereof, and the additional therapeutic agent are administered simultaneously as a combined dosage. When administered simultaneously, the two agents can be administered as a single dosage form (e.g., a fixed dosage form) or as separate dosages (e.g., non-fixed dosage forms).

[0215] As used herein, the terms “treat” or “treatment” refer to therapeutic or palliative measures. Beneficial or desired clinical results include, but are not limited to, alleviation, in whole or in part, of symptoms associated with a disease or disorder or condition, diminishment of the extent of disease, stabilized (i.e., not worsening) state of disease, delay or slowing of disease progression, amelioration or palliation of the disease state (e.g., one or more symptoms of the disease), and remission (whether partial or total), whether detectable or undetectable. “Treatment” can also mean prolonging survival as compared to expected survival if not receiving treatment.

[0216] As used herein, the terms “prevent” or “prevention” refer to prophylactic measures. Beneficial or desired clinical results include, but are not limited to, the delay, arrest, or preclusion of the onset, recurrence or spread, in whole or in part, of a disease or condition, or a symptom thereof, such as any of those provided herein.

[0217] As used herein, the terms “subject,” “individual,” or “patient,” are used interchangeably, and refer to any animal, including mammals such as mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, primates, and humans. In some embodiments, the subject is a human. In some embodiments, the subject has experienced and / or exhibited at least one symptom of the disease, disorder, or condition to be treated and / or prevented.

[0218] In some embodiments, the subject is a pediatric subject.

[0219] The term “pediatric subject” as used herein refers to a subject under the age of 17 years at the time of diagnosis or treatment. The term “pediatric” can be further be divided into various subpopulations including: neonates (from birth through the first 27 days of life); infants (28 days up to 23 months); children (two years of age to 11 years of age); and adolescents (12 years of age to younger than 17 years (up to, but not including, the seventeenth birthday)). See 21 C. F. R. 201.57(c)(9)(iv)(A); Regulatory Considerations Guidance at FN 1; and Guidance -Pediatric Drug Development: Regulator}' Considerations — Complying With the Pediatric Research Equity Act and Qualifying for Pediatric Exclusivity Under the Best Pharmaceuticals for Children Act, U. S. Food & Drug Administration (May 17, 2023). In some embodiments, aDocket No. TRLN-013-034W01 / TLS-072WO

[0220] pediatric subject is from birth through the first 28 days of life, from 29 days of age to less than two years of age, from two years of age to less than 12 years of age, or 12 years of age through 16 years of age (up to, but not including, the seventeenth birthday). In some embodiments, a pediatric subject is from birth through the first 28 days of life, from 29 days of age to less than 1 year of age, from one month of age to less than four months of age, from three months of age to less than seven months of age, from six months of age to less than 1 year of age, from 1 year of age to less than 2 years of age, from 2 years of age to less than 3 years of age, from 2 years of age to less than seven years of age, from 3 years of age to less than 5 years of age, from 5 years of age to less than 10 years of age, from 6 years of age to less than 13 years of age, from 10 years of age to less than 15 years of age, or from 15 years of age to less than 17 years of age.

[0221] In some embodiments, the subject is a geriatric subject.

[0222] The term “geriatric subject” as used herein refers to a subject 65 years of age or older. See 21 C. F. R. 201.57(c)(9)(v)(A). In some embodiments, a geriatric subject is 70 years of age or older. In some embodiments, a geriatric subject is 75 years of age or older.

[0223] The term “regulatory agency” refers to a country's agency for the approval of the medical use of pharmaceutical agents with the country. For example, a non-limiting example of a regulatory agency is the U. S. Food and Drug Administration (FDA).

[0224] The phrase “therapeutically effective amount” means an amount of a compound that, when administered to a subject in need thereof is sufficient to (i) treat a disease, disorder, or condition, (ii) attenuate, ameliorate, or eliminate one or more symptoms of the particular disease, disorder, or condition, or (iii) delay the onset of one or more symptoms of the particular disease, disorder, or condition as described herein. The amount of the compound that will correspond to such an amount may vary depending upon factors such as the particular compound, disease condition and its severity, the identity (e.g., weight) of the subject in need of treatment, the use or identity of prior treatments, as well as whether the compound is administered in combination with another agent (e.g., another therapeutic agent or a supportive care agent).

[0225] The phrase “effective amount” means an amount of a compound that, when administered to a cell, in vitro or in vivo, is sufficient to reduce proliferation of the cell or to kill the cell. The amount of the compound that will correspond to such an amount will vary depending upon factors such as the particular compound and genetics of the cell to be treated, as well as whether the compound is administered in combination with another agent (e.g., another therapeutic agent or a supportive care agent).Docket No. TRLN-013-034W01 / TLS-072WO

[0226] Pharmaceutical Compositions and Administration

[0227] General

[0228] In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, is administered as a pharmaceutical composition that includes the compound, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients, and optionally one or more additional therapeutic agents as described herein.

[0229] In some embodiments, the compounds can be administered in combination with one or more conventional pharmaceutical excipients. Pharmaceutically acceptable excipients include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifving drug delivery systems (SEDDS) such as d-a-tocopherol polyethylene glycol 1000 succinate, surfactants used in pharmaceutical dosage forms such as Tweens, poloxamers or other similar polymeric delivery matrices, serum proteins, such as human serum albumin, buffer substances such as phosphates, tris, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium-chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene- polyoxypropylene-block polymers, and wool fat. Cyclodextrins such as a-, p-, and y- cyclodextrin, or chemically modified derivatives such as hydroxyalkylcyclodextrins, including 2- and 3-hydroxypropyl-P-cyclodextrins, or other solubilized derivatives can also be used to enhance delivery of compounds described herein. Dosage forms or compositions containing a compound as described herein in the range of 0.005% to 100% with the balance made up from non-toxic excipient can be prepared. The contemplated compositions can contain 0.001%-100% of a compound provided herein, in one embodiment 0.1-95%, in another embodiment 75-85%, in a further embodiment 20-80%. Actual methods of preparing such dosage forms are known, or will be apparent, to those skilled in this art; for example, see Remington: The Science and Practice of Pharmacy, 22ndEdition (Pharmaceutical Press, London, UK. 2012).

[0230] Routes of Administration and Composition Components

[0231] In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, as described herein, or a pharmaceutical composition thereof, can be administered to a subject in need thereof by any accepted route of administration. Acceptable routes of administration include, but are not limited to, buccal, cutaneous, endocervical, endosinusial,Docket No. TRLN-013-034W01 / TLS-072WO

[0232] endotracheal, enteral, epidural, interstitial, intra-abdominal, intra-arterial, intrabronchial, intrabursal, intracerebral, intraci sternal, intracoronary, intradermal, intraductal, intraduodenal, intradural, intraepidermal, intraesophageal, intragastric, intragingival, intraileal, intralymphatic, intramedullary, intrameningeal, intramuscular, intraovarian, intraperitoneal, intraprostatic, intrapulmonary, intrasinal, intraspinal, intrasynovial, intratesticular, intrathecal, intratubular, intratumoral, intrauterine, intravascular, intravenous, nasal, nasogastric, oral, parenteral, percutaneous, peridural, rectal, respiratory (inhalation), subcutaneous, sublingual, submucosal, topical, transdermal, transmucosal, transtracheal, ureteral, urethral and vaginal. In certain embodiments, a preferred route of administration is parenteral (e.g., intratumoral).

[0233] In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, as described herein, or a pharmaceutical composition thereof, can be administered orally to a subject in need thereof. Without being bound by any particular theory, it is believed that oral dosing (e.g., versus IV dosing) can be preferred by subjects for convenience, perception of efficacy, and / or past experience.

[0234] Compositions can be formulated for parenteral administration, e.g., formulated for injection via the intravenous, intramuscular, sub-cutaneous, or even intraperitoneal routes. Typically, such compositions can be prepared as injectables, either as liquid solutions or suspensions; solid forms suitable for use to prepare solutions or suspensions upon the addition of a liquid prior to injection can also be prepared; and the preparations can also be emulsified. The preparation of such formulations will be known to those of skill in the art in light of the present disclosure.

[0235] The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions; formulations including sesame oil, peanut oil, or aqueous propylene glycol; and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases the form must be sterile and must be fluid to the extent that it can be easily injected. It also should be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms, such as bacteria and fungi.

[0236] The carrier also can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oils. The proper fluidity can be maintained, for example, by the use of a coating, such as lecithin, by the maintenance of the required particle size in the case of dispersion, and by the use of surfactants. The prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, forDocket No. TRLN-013-034W01 / TLS-072WO

[0237] example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars or sodium chloride. Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin.

[0238] Sterile injectable solutions are prepared by incorporating the active compounds in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum-drying and freeze-drying techniques, which yield a powder of the active ingredient, plus any additional desired ingredient from a previously sterile-filtered solution thereof.

[0239] Intratumoral injections are discussed, e.g., in Lammers, et al., “Effect of Intratumoral Injection on the Biodistribution and the Therapeutic Potential of HPMA Copolymer-Based Drug Delivery Systems” Neoplasia. 2006, 10. 788-795.

[0240] Pharmacologically acceptable excipients usable in the rectal composition as a gel, cream, enema, or rectal suppository, include, without limitation, any one or more of cocoa butter glycerides, synthetic polymers such as polyvinylpyrrolidone, PEG (like PEG ointments), glycerine, glycerinated gelatin, hydrogenated vegetable oils, poloxamers, mixtures of polyethylene glycols of various molecular weights and fatty acid esters of polyethylene glycol Vaseline, anhydrous lanolin, shark liver oil, sodium saccharinate, menthol, sweet almond oil, sorbitol, sodium benzoate, anoxid SBN, vanilla essential oil, aerosol, parabens in phenoxyethanol, sodium methyl p-oxybenzoate, sodium propyl p-oxybenzoate, di ethylamine, carbomers, carbopol, methyloxybenzoate, macrogol cetostearyl ether, cocoyl capryl ocaprate, isopropyl alcohol, propylene glycol, liquid paraffin, xanthan gum, carboxy-metabisulfite, sodium edetate, sodium benzoate, potassium metabisulfite, grapefruit seed extract, methyl sulfonyl methane (MSM), lactic acid, glycine, vitamins, such as vitamin A and E and potassium acetate.

[0241] In certain embodiments, suppositories can be prepared by mixing the compound described herein with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum and release the active compound. In other embodiments, compositions for rectal administration are in the form of an enema.Docket No. TRLN-013-034W01 / TLS-072WO

[0242] In other embodiments, the compounds described herein, or a pharmaceutical composition thereof, are suitable for local delivery to the digestive or GI tract by way of oral administration (e.g., solid or liquid dosage forms.).

[0243] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the compound is mixed with one or more pharmaceutically acceptable excipients, such as sodium citrate or dicalcium phosphate and / or: a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof In the case of capsules, tablets and pills, the dosage form can also comprise buffering agents. Solid compositions of a similar type can also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.

[0244] In one embodiment, the compositions will take the form of a unit dosage form such as a pill or tablet and thus the composition can contain, along with a compound, or pharmaceutically acceptable salt thereof, as provided herein, a diluent such as lactose, sucrose, dicalcium phosphate, or the like; a lubricant such as magnesium stearate or the like; and a binder such as starch, gum acacia, polyvinylpyrrolidine, gelatin, cellulose, cellulose derivatives, or the like. In another solid dosage form, a powder, marume, solution or suspension (e.g., in propylene carbonate, vegetable oils, PEGs, poloxamer 124 or triglycerides) is encapsulated in a capsule (gelatin or cellulose base capsule). Unit dosage forms in which one or more compounds provided herein or additional active agents are physically separated are also contemplated; e.g., capsules with granules (or tablets in a capsule) of each drug; two-layer tablets; two-compartment gel caps, etc. Enteric coated or delayed release oral dosage forms are also contemplated.

[0245] Other physiologically acceptable compounds include wetting agents, emulsifying agents, dispersing agents or preservatives that are particularly useful for preventing the growth or action of microorganisms. Various preservatives are well known and include, for example, phenol and ascorbic acid.Docket No. TRLN-013-034W01 / TLS-072WO

[0246] In certain embodiments the excipients are sterile and generally free of undesirable matter. These compositions can be sterilized by conventional, well-known sterilization techniques. For various oral dosage form excipients such as tablets and capsules sterility is not required. The USP / NF standard is usually sufficient.

[0247] In certain embodiments, solid oral dosage forms can include one or more components that chemically and / or structurally predispose the composition for delivery of the compounds to the stomach or the lower GI; e.g., the ascending colon and / or transverse colon and / or distal colon and / or small bowel. Exemplary formulation techniques are described in, e.g., Filipski, K. J., et al., Current Topics in Medicinal Chemistry, 2013, 13, 776-802.

[0248] Examples include upper-GI targeting techniques, e.g., Accordion Pill (Intec Pharma), floating capsules, and materials capable of adhering to mucosal walls.

[0249] Other examples include lower-GI targeting techniques. For targeting various regions in the intestinal tract, several enteric / pH-responsive coatings and excipients are available. These materials are typically polymers that are designed to dissolve or erode at specific pH ranges, selected based upon the GI region of desired drug release. These materials also function to protect acid labile drugs from gastric fluid or limit exposure in cases where the active ingredient can be irritating to the upper GI (e.g., hydroxypropyl methylcellulose phthalate series, Coateric (polyvinyl acetate phthalate), cellulose acetate phthalate, hydroxypropyl methylcellulose acetate succinate, Eudragit series (methacrylic acid-methyl methacrylate copolymers), and Marcoat). Other techniques include dosage forms that respond to local flora in the GI tract, Pressure-controlled colon delivery capsule, and Pulsincap.

[0250] Ocular compositions can include, without limitation, one or more of any of the following: viscogens (e.g., Carboxymethylcellulose, Glycerin, Polyvinylpyrrolidone, Polyethylene glycol); Stabilizers (e.g., Plutonic (triblock copolymers), Cyclodextrins); Preservatives (e.g., Benzalkonium chloride, ETDA, SofZia (boric acid, propylene glycol, sorbitol, and zinc chloride; Alcon Laboratories, Inc.), Purite (stabilized oxychloro complex; Allergan, Inc.)).

[0251] Topical compositions can include ointments and creams. Ointments are semisolid preparations that are typically based on petrolatum or other petroleum derivatives. Creams containing the selected active agent are typically viscous liquid or semisolid emulsions, often either oil-in-water or water-in-oil. Cream bases are typically water-washable, and contain an oil phase, an emulsifier, and an aqueous phase. The oil phase, also sometimes called the “internal” phase, is generally comprised of petrolatum and a fatty alcohol such as cetyl or stearyl alcohol; the aqueous phase usually, although not necessarily, exceeds the oil phase inDocket No. TRLN-013-034W01 / TLS-072WO

[0252] volume, and generally contains a humectant. The emulsifier in a cream formulation is generally a nonionic, anionic, cationic, or amphoteric surfactant. As with other carriers or vehicles, an ointment base should be inert, stable, nonirritating, and non-sensitizing.

[0253] In any of the foregoing embodiments, pharmaceutical compositions described herein can include one or more one or more of the following: lipids, interbilayer crosslinked multilamell ar vesicles, biodegradable poly(D, L-lactic-co-glycolic acid) [PLGA]-based or poly anhydride-based nanoparticles or microparticles, and nanoporous particle-supported lipid bilayers.

[0254] Dosages

[0255] The dosages can be varied depending on the requirement of the subject, the severity of the condition being treated, and the particular compound being employed. Determination of the proper dosage for a particular situation can be determined by one skilled in the medical arts. The total daily dosage can be divided and administered in portions throughout the day or by means providing continuous delivery.

[0256] In some embodiments, the compounds described herein are administered at a dosage of from about 0.001 mg / kg to about 500 mg / kg (e.g., from about 0.001 mg / kg to about 200 mg / kg; from about 0.01 mg / kg to about 200 mg / kg; from about 0.01 mg / kg to about 150 mg / kg; from about 0.01 mg / kg to about 100 mg / kg; from about 0.01 mg / kg to about 50 mg / kg; from about 0.01 mg / kg to about 10 mg / kg; from about 0.01 mg / kg to about 5 mg / kg; from about 0.01 mg / kg to about 1 mg / kg; from about 0.01 mg / kg to about 0.5 mg / kg; from about 0.01 mg / kg to about 0.1 mg / kg; from about 0.1 mg / kg to about 200 mg / kg; from about 0.1 mg / kg to about 150 mg / kg; from about 0.1 mg / kg to about 100 mg / kg; from about 0.1 mg / kg to about 50 mg / kg; from about 0.1 mg / kg to about 10 mg / kg; from about 0,1 mg / kg to about 5 mg / kg; from about 0.1 mg / kg to about 1 mg / kg; from about 0.1 mg / kg to about 0.5 mg / kg).

[0257] Regimens

[0258] The foregoing dosages can be administered on a daily basis (e.g., as a single dose or as two or more divided doses) or non-daily basis (e.g., every other day, every two days, every three days, once weekly, twice weeks, once every two weeks, once a month).

[0259] In some embodiments, the period of administration of a compound described herein is for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10Docket No. TRLN-013-034W01 / TLS-072WO

[0260] months, 11 months, 12 months, or more. In a further embodiment, a period during which administration is stopped is for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or more. In an embodiment, a therapeutic compound is administered to an individual for a period of time followed by a separate period of time. In another embodiment, a therapeutic compound is administered for a first period and a second period following the first period, with administration stopped during the second period, followed by a third period where administration of the therapeutic compound is started and then a fourth period following the third period where administration is stopped. In an aspect of this embodiment, the period of administration of a therapeutic compound followed by a period where administration is stopped is repeated for a determined or undetermined period of time. In a further embodiment, a period of administration is for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or more. In a further embodiment, a period during which administration is stopped is for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or more.

[0261] The term “acceptable” with respect to a formulation, composition, or ingredient, as used herein, means having no persistent detrimental effect on the general health of the subject being treated.

[0262] “API” refers to an active pharmaceutical ingredient.

[0263] The term “excipient” or “pharmaceutically acceptable excipient” means a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, carrier, solvent, or encapsulating material. In one embodiment, each component is “pharmaceutically acceptable” in the sense of being compatible with the other ingredients of a pharmaceutical formulation, and suitable for use in contact with the tissue or organ of humans and animals without excessive toxicity, irritation, allergic response, immunogenicity, or other problems or complications, commensurate with a reasonable benefit / risk ratio. See, e.g., Remington: The Science and Practice of Pharmacy, 21st ed. Lippincott Williams & Wilkins: Philadelphia, PA, 2005; Handbook of Pharmaceutical Excipients, 6th ed.; Rowe et al., Eds.;Docket No. TRLN-013-034W01 / TLS-072WO

[0264] The Pharmaceutical Press and the American Pharmaceutical Association: 2009; Handbook of Pharmaceutical Additives, 3rd ed. Ash and Ash Eds.; Gower Publishing Company: 2007; Pharmaceutical Preformulation and Formulation, 2nd ed. Gibson Ed.; CRC Press LLC: Boca Raton, FL, 2009.

[0265] The term “pharmaceutically acceptable salt” refers to a formulation of a compound that does not cause significant irritation to an organism to which it is administered and does not abrogate the biological activity and properties of the compound. In certain instances, pharmaceutically acceptable salts are obtained by reacting a compound described herein, with acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. In some instances, pharmaceutically acceptable salts are obtained by reacting a compound having acidic group described herein with a base to form a salt such as an ammonium salt, an alkali metal salt, such as a sodium or a potassium salt, an alkaline earth metal salt, such as a calcium or a magnesium salt, a salt of organic bases such as dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, and salts with amino acids such as arginine, lysine, and the like, or by other methods previously determined. The term “pharmacologically acceptable salts” is not specifically limited as far as it can be used in medicaments. Examples of a salt that the compounds described herein form with a base include the following: salts thereof with inorganic bases such as sodium, potassium, magnesium, calcium, and aluminum; salts thereof with organic bases such as methylamine, ethylamine, and ethanolamine; salts thereof with basic amino acids such as lysine and ornithine; and ammonium salt. The salts can be acid addition salts, which are specifically exemplified by acid addition salts with the following: mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid; organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, and ethanesulfonic acid; acidic amino acids such as aspartic acid and glutamic acid.

[0266] In some embodiments, a pharmaceutically acceptable salt is an anion salt selected from the group consisting of: a mesylate salt, a besylate salt, an acetate salt, a benzenesulfonate salt, a benzoate salt, a bicarbonate salt, a bitartrate salt, a bromide salt, a calcium edetate salt, a camsylate salt, a carbonate salt, a chloride salt, a citrate salt, a dihydrochloride salt, an edetate salt, an edisylate salt, an estolate salt, an esylate salt, a fumarate salt, a gluceptate salt, a gluconate salt, a glucuronate salt, a glutamate salt, a glycollylarsanilate salt, a hexylresorcinol salt, a hydramine salt, a hydrobromide salt, a hydrochloride salt, a hydroxynaphthoate salt, anDocket No. TRLN-013-034W01 / TLS-072WO

[0267] iodide salt, an isethionate salt, a lactate salt, a lactobionate salt, a malate salt, a maleate salt, a mandelate salt, a methylbromide salt, a methylnitrate salt, a methylsulfate salt, a mucate salt, a napsylate salt, a nitrate salt, a pamoate (embonate) salt, a pantothenate salt, a phosphate / diphosphate salt, a polygalacturonate salt, a salicylate salt, a stearate salt, a subacetate salt, a succinate salt, a sulfate salt, an oleate salt, a tannate salt, a tartrate salt, a teoclate salt, and atriethiodide salt.

[0268] In some embodiments, a pharmaceutically acceptable salt is a cation salt selected from the group consisting of: a benzathine salt, a chloroprocaine salt, a choline salt, a tromethamine salt, a diethanolamine salt, an ethylenediamine salt, a meglumine salt, a procaine salt, an aluminum salt, a calcium salt, a lithium salt, a magnesium salt, a potassium salt, a sodium salt, and a zinc salt.

[0269] Examples of pharmaceutically acceptable salts also include those disclosed in e.g., Berge, Stephen M., Lyle D. Bighley, and Donald C. Monkhouse. " Pharmaceutical salts." Journal of pharmaceutical sciences 66.1 (1977): 1-19 doi: 10.1002 / jps.2600660104, Bharate, Sonali S. " Recent developments in pharmaceutical salts: FDA approvals from 2015 to 2019." Drug Discovery Today 26.2 (2021): 384-398 doi: 10.1016 / j.drudis.2020.11.016, and Bharate, Sonali S. " Modulation of biopharmaceutical properties of drugs using sulfonate counterions: A critical analysis of FDA-approved pharmaceutical salts." Journal of Drug Delivery Science and Technology 66 (2021): 102913 doi: 10.1016 / j.jddst.2021.102913.

[0270] The term “pharmaceutical composition” refers to a mixture of a compound described herein with other chemical components (referred to collectively herein as “excipients”), such as carriers, stabilizers, diluents, dispersing agents, suspending agents, and / or thickening agents. The pharmaceutical composition facilitates administration of the compound to a subject. Multiple techniques of administering a compound exist in the art including, but not limited to: rectal, oral, intravenous, aerosol, parenteral, ophthalmic, pulmonary, and topical administration.

[0271] Compound Preparation

[0272] The compounds disclosed herein can be prepared in a variety of ways using commercially available starting materials, compounds known in the literature, or from readily prepared intermediates, by employing standard synthetic methods and procedures either known to those skilled in the art, or in light of the teachings herein.

[0273] Standard synthetic methods and procedures for the preparation of organic molecules and functional group transformations and manipulations can be obtained from the relevantDocket No. TRLN-013-034W01 / TLS-072WO

[0274] scientific literature or from standard textbooks in the field. Although not limited to any one or several sources, classic texts such as R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); Smith, M. B., March, J., March' s Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5th edition, John Wiley & Sons: New York, 2001; and Greene, T. W., Wuts, P. G. M., Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons: New York, 1999, are useful and recognized reference textbooks of organic synthesis known to those in the art. The following descriptions of synthetic methods are designed to illustrate, but not to limit, general procedures for the preparation of compounds of the present disclosure.

[0275] The synthetic processes disclosed herein can tolerate a wide variety of functional groups; therefore, various substituted starting materials can be used. The processes generally provide the desired final compound at or near the end of the overall process, although it may be desirable in certain instances to further convert the compound to a pharmaceutically acceptable salt thereof.

[0276] EXAMPLES

[0277] Example 1: (S)-2-cyclopropyl-10-((2,5-dichloropyrimidin-4-yl)amino)-3,3,9-trifluoro-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinolin-6(7H)-one (Compound 101a)

[0278]

[0279] Step 1: 6-bromo-7-fluoro-lH-3,l-benzoxazine-2, 4-dione

[0280] To a solution of 2-amino-5-bromo-4-fluoro-benzoic acid (90 g, 384.58 mmol, 1 equiv.) in THF (900 mL) was added bis(trichloromethyl)carbonate (39.94 g, 134.60 mmol, 0.35 equiv. ) at 0 °C under N2. The mixture was stirred at 70 °C for 2 hours. The reaction mixture was filtered and washed with THF. The filtrate was concentrated under reduced pressure to give 6-bromo-7-fluoro-lH-3,l-benzoxazine-2, 4-dione (81.2 g) as a white solid.Docket No. TRLN-013-034W01 / TLS-072WO

[0281] XH NMR (400 MHz, DMSO-tfc) 8 = 11.98 (s, 1H), 8.19 (d, J = 7.6 Hz, 1H), 7.03 (d, J = 9.2 Hz, 1H)

[0282] Step 2: 6-bromo-7-fluoro-1-methyl-3,1-benzoxazine-2,4-dione

[0283] To a solution of 6-bromo-7-fluoro-1H-3,1-benzoxazine-2,4-dione (81.2 g, 312.29 mmol, 1 equiv.) in dimethylacetamide (90 mL) was added MeI (132.98 g, 936.86 mmol, 58.32 mL, 3 equiv.) and DIEA (80.72 g, 624.58 mmol, 108.79 mL, 2 equiv.). The mixture was stirred at 25 °C for 2 hours. The reaction mixture was diluted with water (100 mL) and filtered to obtain 6-bromo-7-fluoro-l-methyl-3,l-benzoxazine-2, 4-dione (80 g) as a white solid.

[0284] LC-MS (ESI): m / z = 273.9 [M+Hp

[0285] Step 3: ethyl 6-bromo-7-fluoro-4-hydroxy-1-methyl-2-oxo-quinoline-3-carboxylate

[0286] A mixture of 6-bromo-7-fluoro-1-methyl-3,1-benzoxazine-2,4-dione (80 g, 291.92 mmol, 1 equiv.), diethyl propanedioate (140.27 g, 875.77 mmol, 132.96 mL, 3 equiv.), and NaH (23.35 g, 583.85 mmol, 60% purity, 2 equiv.) in DMF (1000 mL) was degassed and purged with N2 three times. The mixture was stirred at 25 °C for 2 hours under N2 atmosphere. The reaction mixture was diluted with saturated ammonium chloride (1500 mL), filtered, and concentrated under reduced pressure to give a residue, which was triturated with ethyl acetate at 25 °C for 30 minutes to obtain ethyl 6-bromo-7-fluoro-4-hydroxy-l-methyl-2-oxo-quinoline-3 -carboxylate (37 g) as a white solid.

[0287] LC-MS (ESI): m / z = 343.9 [M+Hp

[0288] Step 4: ethyl 6-bromo-4-chloro-7-fluoro-1-methyl-2-oxo-quinoline-3-carboxylate To a solution of ethyl 6-bromo-7-fluoro-4-hydroxy-l-methyl-2-oxo-quinoline-3-carboxylate (15 g, 43.59 mmol, 1 equiv.) in DMF (150mL)was added dropwise (COCl)₂ (16.60 g, 130.76 mmol, 11.45 mL, 3 equiv.). The mixture was stirred at 70 °C for 0.5 hours. The reaction mixture was quenched by water (500 mL), filtered, and concentrated under reduced pressure to give a residue, which was triturated with petroleum ether at 25 °C for 10 minutes to obtain ethyl 6-bromo-4-chloro-7-fluoro-l -methyl-2-oxo-quinoline-3-carboxylate (11.2 g) as a white solid.

[0289] LC-MS (ESI): m / z = 362.0 [M+Hp

[0290] Step 5: 6-bromo-4-[[(1S)-1-cyclopropyl-2,2-difluoro-3-hydroxy-propyl]amino]-7-fluoro-1-methyl-quinolin-2-one

[0291] Ethyl 6-bromo-4-chloro-7-fluoro-1-methyl-2-oxo-quinoline-3-carboxylate (700 mg, 1.93 mmol, 1 equiv.), (3S)-3-amino-3-cyclopropyl-2,2-difluoro-propan-1-ol (398.43 mg, 2.12 mmol, 1.1 equiv., HC1) and DIEA (748.56 nig, 5.79 mmol, 1.01 mL, 3 equiv.) were taken upDocket No. TRLN-013-034W01 / TLS-072WO

[0292] into a microwave tube with NMP (15 mL). The sealed tube was heated at 200 °C for 2 hours in a microwave reactor. The reaction mixture was diluted with water (120 mL) and extracted with ethyl acetate (360 mL). The combined organic layers were washed with brine (2400 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue, which was purified by flash silica gel chromatography (60% ethyl acetate / petroleum ether) to afford 6-bromo-4-[[(l S)-l-cyclopropyl-2,2-difluoro-3-hydroxy-propyl]amino]-7-fluoro-1-methyl-quinolin-2-one as a yellow solid.

[0293] LC-MS (ESI): m / z = 404.9 [M+H]+

[0294] Step 6: 3,6-dibromo-4-[[(1S)-1-cyclopropyl-2,2-difluoro-3-hydroxy-propyl]amino]-7-fluoro-1-methyl-quinolin-2-one

[0295] To a solution of 6-bromo-4-[[(l S)-l-cyclopropyl-2,2-difluoro-3-hydroxy-propyl]amino]-7-fluoro-l-methyl-quinolin-2-one (3.6 g, 8.47 mmol, 1 equiv.) inDMF (36 mL) was added NBS (1.36 g, 7.62 mmol, 0.9 equiv.) at 0 °C. The mixture was stirred at 0 °C for 20 minutes. The reaction mixture was diluted with water (40 mL) and extracted with ethyl acetate (150 mL). The combined organic layers were washed with brine (150 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue, which was purified by flash silica gel chromatography (25% ethyl acetate / petroleum ether) to afford 3,6-dibromo-4-[[(l S)-l-cyclopropyl-2,2-difluoro-3-hydroxy-propyl]amino]-7-fluoro-1-methyl-quinolin-2-one (2.7 g) as a yellow solid.

[0296] LC-MS (ESI): m / z = 484.9 [M+H]+

[0297] Step 7: (2S)-10-bromo-2-cyclopropyl-3,3,9-trifluoro-7-methyl-2,4-dihydro-1H-[1,4]oxazepino[2,3-c]quinolin-6-one

[0298] To a solution of 3,6-dibromo-4-[[(lS)-l-cyclopropyl-2,2-difluoro-3-hydroxy-propyl]amino]-7-fluoro- 1-methyl-quinolin-2-one (2.7 g, 5.58 mmol, 1 equiv.) in THF (10 mL) was added t-BuOK (1 M, 2.79 mL, 0.5 equiv.). The mixture was stirred at 60 °C for 1 hour followed by the addition of t-BuOK (1 M, 2.79 mL, 0.5 equiv.). The resulting mixture was stirred at 60 °C for 0.1 hours. The reaction mixture was concentrated under reduced pressure to give a residue, which was purified by flash silica gel chromatography (40% ethyl acetate / petroleum ether) to afford (2S)-10-bromo-2-cyclopropyl-3,3,9-trifluoro-7-methyl-2,4-dihydro-lH-[l,4]oxazepino[2,3-c]quinolin-6-one (2.2 g) as a white solid.

[0299] LC-MS (ESI): m / z = 402.9 [M+H]+

[0300] Step 8: (2S)-10-(benzhydrylideneamino)-2-cyclopropyl-3,3,9-trifluoro-7-methyl-2,4-dihydro-1H-[1,4]oxazepino[2,3-c]quinolin-6-one

[0301] A mixture of (2S)-10-bromo-2-cyclopropyl-3,3,9-trifluoro-7-methyl-2,4-dihydro-lH-Docket No. TRLN-013-034W01 / TLS-072WO

[0302] [1.4]oxazepino[2,3-c]quinolin-6-one (2.2 g, 5.46 mmol, 1 equiv), diphenylmethanimine (1.19 g, 6.55 mmol, 1.10 mL, 1.2 equiv.), Pd2(dba)s (499.66 mg, 545.64 pmol, 0.1 equiv.), XantPhos (631.44 mg, 1.09 mmol, 0.2 equiv), and cesium carbonate (4.44 g, 13.64 mmol, 2.5 equiv) in toluene (25 mL) was degassed and purged with N2 three times. The mixture was stirred at 100 °C for 12 hours under N2 atmosphere. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (90 mL). The combined organic layers were washed with brine (90 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue, which was purified by flash silica gel chromatography (50% ethyl acetate / petroleum ether) to afford (2S)-10-(benzhydrylideneamino)-2-cyclopropyl-3,3,9-trifluoro-7-methyl-2,4-dihydro-lH-[l,4]oxazepino[2,3-c]quinolin-6-one (2.07 g) as a yellow' solid.

[0303] LC-MS (ESI): m / z = 504.1 [M+H]+

[0304] Step 9: (2S)-10-amino-2-cyclopropyl-3,3,9-trifluoro-7-methyl-2,4-dihydro-1H-[1,4]oxazepino[2,3-c]quinolin-6-one

[0305] To a solution of (2S)-10-(benzhydrylideneamino)-2-cyclopropyl-3,3,9-trifluoro-7-methyl-2,4-dihydro-lH-[l,4]oxazepino[2,3-c]quinolin-6-one (2.07 g, 4.12 mmol, 1 equiv.) in 1.4-dioxane (7 mL) was added HC1 in 1,4-dioxane (14 mL). The mixture was stirred at 25 °C for 1 hour. The reaction mixture was concentrated under reduced pressure to give a residue, which was purified by prep-HPLC to afford (2S)-10-amino-2-cyclopropyl-3,3,9-trifluoro-7-methyl-2,4-dihydro-lH-[l,4]oxazepino[2,3-c]quinolin-6-one (931 mg) as a pink solid.

[0306] LC-MS (ESI): m / z = 340.1 [M+H]+

[0307] ¹H NMR (400 MHz, DMSO-d₆ 8 = 7.40 - 7.27 (m, 1H), 7.25 - 7.15 (m, 1H), 6.04 (d, J = 3.2 Hz, 1H), 5.02 (s, 2H), 4.48 - 4.24 (m, 2H), 3.46 (s, 3H), 3.26 - 3.13 (m, 1H), 1.37 - 1.24 (m, 1H), 0.75 - 0.64 (m, 1H), 0.56 - 0.46 (m, 2H), 0.37 - 0.27 (m, 1H)

[0308] Step 10: (S)-2-cyclopropyl-10-((2,5-dichloropyrimidin-4-yl)amino)-3,3,9-trifluoro-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinolin-6(7H)-one

[0309] 2,4,5-trichloropyrimidine (398.2 mg, 0.25 mL, 1.015 equiv., 2.171 mmol) was dissolved in DCM (1.00 mL) and then added through a 0.45 μm filter into a stirring solution of (2S)-10-amino-2-cyclopropyl-3,3,9-trifluoro-7-methyl-2,4-dihydro-1H- [1.4]oxazepino[2,3-c]quinolin-6-one (725.8 mg, 1.000 equiv, 2.139 mmol) and DIEA (1.659 g, 2.24 mL, 6.00 equiv, 12.83 mmol) in DMSO (5.00 mL). The reaction mixture was stirred to 70 °C for 16 hours. The resulting mixture was filtered and purified via C18 flash column using a gradient 10-100% (A: water + 0.1% formic acid; B: MeCN + 0.1% formic acid) to afford (5’)-2-cyclopropyl-l 0-((2,5-dichloropyrimidin-4-yl)amino)-3,3,9-trifluoro-7-methyl- 1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinolin-6(7H)-one (888.3 mg).Docket No. TRLN-013-034W01 / TLS-072WO

[0310] LC-MS (ESI): m / z = 486.4 [M+H]+

[0311]

[0312] NMR (400 MHz, DMSO-d₆) 8 = 9.79 (s, 1H), 8.42 (s, 1H), 8.21 (d, J= 8.1 Hz, 1H), 7.48 (d, J= 12.4 Hz, 1H), 6.56 - 6.32 (m, IH), 4.46 (br d, J= 13.6 Hz, 2H), 3.56 (s, 3H), 3.29 - 3.17 (m, IH), 1.34 - 1.24 (m, IH), 0.80 - 0.65 (m, IH), 0.52 (br t, J = 5.8 Hz, 2H), 0.32 (br d,.7= 5.3 Hz, IH)

[0313] Example 2: (S)-1-(5-chloro-4-((2-cyclopropyl-3,3,9-trifluoro-7-methyl-6-oxo-1,2,3,4,6,7-hexahydro-[1,4]oxazepino[2,3-c]quinolin-10-yl)amino)pyrimidin-2-yl)piperidine-4-carboxylic acid (Compound 103a)

[0314]

[0315] Step 1: tert-butyl (S)-1-(5-chloro-4-((2-cyclopropyl-3,3,9-trifluoro-7-methyl-6-oxo-1,2,3,4,6,7-hexahydro-[1,4]oxazepino[2,3-c]quinolin-10-yl)amino)pyrimidin-2-yl)piperidine-4-carboxylate

[0316] A solution of (S)-2-cyclopropyl-10-((2,5-dichloropyrimidin-4-yl)amino)-3,3,9-trifluoro-7-methyl-l,2,3,4-tetrahydro-[l,4]oxazepino[2,3-c]quinolin-6(7H)-one (93.0 mg, 191 pmol) and tert-butyl piperidine-4-carboxylate hydrochloride (87.7 nig, 396 pmol) in DMSO (1.20 mL) was treated with DIEA (167 pL, 956 pmol ) and warmed to 80 °C for 17 hours. The reaction mixture was cooled to room temperature, filtered, and purified by prep-HPLC to afford tert-butyl (S)-l-(5-chloro-4-((2-cyclopropyl-3,3,9-trifluoro-7-methyl-6-oxo-l,2,3,4,6,7-hexahydro-[l,4]oxazepino[2,3-c]quinolin-10-yl)amino)pyrimidin-2-yl)piperidine-4-carb oxy 1 ate (78.5 mg).

[0317] ¹H NMR (400 MHz, DMSO-d₆) 8 = 8.85 (s, IH), 8.22 (d, J= 8.0 Hz, IH), 8.03 (s, IH), 7.42 (d, J = 12.5 Hz, 1H), 6.46 - 6.41 (m, IH), 4.51 - 4.30 (m, IH), 4.18 (d, J = 12.6 Hz, 2H) 3.55 (s, 3H), 3.31 - 3.19 (m, 2H), 2.83 (t, J= 12.4 Hz, 2H), 2.46 - 2.36 (m, IH), 1.70 (d, J = 13.1 Hz, 2H), 1.38 (s, 9H), 1.36 - 1.25 (m, 3H), 0.76 - 0.66 (m, IH), 0.56 - 0.45 (m, 2H), 0.39 - 0.26 (m, IH)

[0318] LC-MS (ESI): m / z = 635.3 [M+H]+Docket No. TRLN-013-034W01 / TLS-072WO

[0319] Step 2: (5)-l-(5-chloro-4-((2-cyclopropyI-3,3,9-trifluoro-7-methyl-6-oxo-l,2,3,4,6,7-hexahydro-[l,4]oxazepmo[2 -c]quinolin-10-yI)amino)pyrimidin-2-yl)piperidine-4-carboxylic acid

[0320] A solution of tert-butyl (S)-l-(5-chloro-4-((2-cyclopropyl-3,3,9-trifluoro-7-methyl-6-oxo-1, 2, 3,4,6, 7-hexahydro-[l, 4]oxazepino[2,3-c]quinolin-10-yl)amino)pyrimidin-2-yl)piperidine-4-carboxylate (77.3 mg, 122 umol) in DCM (1.00 mL.) was treated with TFA (1.00 mL, 13.0 mmol) in DCM (1.00 L) and stirred at room temperature for 5 hours. The volatiles were removed under reduced pressure, and the residue was dissolved in DMSO, filtered, and purified by prep-HPLC to afford (S)-l-(5-chloro-4-((2-cyclopropyl-3,3,9-trifluoro-7-methyl-6-oxo- 1,2, 3,4,6,7-hexahy dro-[ 1,4]oxazepino[2, 3 -c]quinolin- 10-yl)amino)pyrimidin-2-yl)piperidine-4-carboxylic acid (37 mg).

[0321] 1H NMR (400 MHz, DMSO-d6) 5 = 12.12 (s, 1H), 8.79 (s, 1H), 8.12 (d, J= 8.0 Hz, 1H), 7.95 (s, 1H), 7.34 (d, J = 12.5 Hz, 1H), 6.40 - 6.34 (m, 1H), 4.44 - 4.22 (m, 2H), 4.10 (d, J = 12.9 Hz, 2H), 3.47 (s, 3H), 3.21 - 3.11 (m, 1H), 2.76 (t, J= 12.8 Hz, 2H), 2.40 - 2.28 (m, 1H), 1.65 (d, J = 12.9 Hz, 2H), 1.43 - 1.15 (m, 3H), 0.68 - 0.57 (m, 1H), 0.50 - 0.38 (m, 2H) 0.29 - 0.20 (m, 1H)

[0322] LC-MS (ESI): m / z = 579.2 [M+H]+

[0323] Example 3: (5)-l-(5-chIoro-4-((2-cyclopropyl-3,3,9-trifluoro-7-methyl-6-oxo-l,2,3,4,6,7-hexahydro-[l,4]oxazepino[2 -f]quinoIin-10-yI)amino)pyrimidin-2-yl)piperidine-4-carbaldehyde (Compound 102a)

[0324]

[0325] Step 1: (S)-10-((2-(4-(1,3-dioxolan-2-yl)piperidin-1-yl)-5-chloropyrimidin-4-yl)amino)-2-cyclopropyl-3,3,9-trifluoro-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinolin-6(7H)-one

[0326] A solution of (S)-2-cyclopropyl-10-((2,5-dichloropyrimidin-4-yl)amino)-3,3,9-trifiuoro-7-methyl-l,2,3,4-tetrahydro-[l,4]oxazepino[2,3-c]quinolin-6(7H)-one (155 mg, 319Docket No. TRLN-013-034W01 / TLS-072WO

[0327] pniol) and 4-(l,3-dioxolan-2-yl)piperidine hydrochloride (129 mg, 666 pmol) in DMSO (2.00 mL) was treated with DIEA (278 pL, 1.59 mmol) and warmed to 80 °C for 17 hours. The reaction mixture was cooled to room temperature, filtered, and purified by prep-HPLC to afford (S)-10-((2-(4-(l,3-dioxolan-2-yl)piperidin-l-yl)-5-chloropyrimidin-4-yl)amino)-2-cyclopropyl-3,3,9-trifluoro-7-methyl-l,2,3,4-tetrahydro-[l,4]oxazepino[2,3-c]quinolin-6(7H)-one (139 mg).

[0328]

[0329] NMR (400 MHz, DMSO-d₆) 6 = 8.83 (s, IH), 8.18 (d,.7 = 8.0 Hz, 1H), 8.01 (s, 1H), 7.40 (d, J = 12.5 Hz, IH), 6.43 (s, IH), 4.53 (d, J = 4.8 Hz, IH), 4.50 - 4.38 (m, 2H), 4.38 -4.26 (m, IH), 3.87 -3.77 (m, 2H), 3.77 - 3.68 (m, 2H), 3.54 (s, 3H), 3.30 - 3.08 (m, 2H), 2.65 (d, J = 12.6 Hz, 2H), 1.75 - 1.63 (m, IH), 1.57 (d, J= 12.9 Hz, 2H), 1.36 - 1.25 (m, IH), 1.11 (q,.7= 12.5 Hz, 2H), 0.69 (p, 7 = 6.3 Hz, IH), 0.56 - 0.44 (m, 2H), 0.31 (q,.7= 6.5 Hz, IH) LC-MS (ESI): m / z = 607.3 [M+H]+

[0330] Step 2: (S)-1-(5-chloro-4-((2-cyclopropyl-3,3,9-trifluoro-7-methyl-6-oxo-1,2,3,4,6,7-hexahydro-[1,4]oxazepino[2,3-c]quinolin-10-yl)amino)pyrimidin-2-yl)piperidine-4-carbaldehyde

[0331] A solution of (S)-10-((2-(4-(l,3-dioxolan-2-yl)piperidin-l-yl)-5-chloropyrimidin-4-yl)amino)-2-cyclopropyl-3,3,9-trifluoro-7-methyl-l,2,3,4-tetrahydro-[l,4]oxazepino[2,3-c]quinolin-6(7H)-one (137.5 mg, 226.5 pmol) in formic acid (2.00 mL, 53.0 mmol) was warmed to 80 °C for 5 hours. The reaction mixture was cooled to room temperature, and the volatiles were removed under reduced pressure. The crude residue was dissolved in DMSO, filtered, and purified by prep-HPLC to afford (S)-l-(5-chloro-4-((2-cyclopropyl-3,3,9-trifluoro-7-methyl-6-oxo- 1,2,3, 4,6, 7-hexahydro-[l,4]oxazepino[2, 3-c]quinolin-10-yl)amino)pyrimidin-2-yl)piperidine-4-carbaldehyde (56 mg).

[0332] 1H NMR (400 MHz, DMSO-d6) δ = 9.48 (s, IH), 8.79 (s, IH), 8.12 (d, J = 8.0 Hz, IH), 7.96 (s, IH), 7.34 (d, J= 12.5 Hz, IH), 6.39 - 6.34 (m, IH), 4.45 - 4.31 (m, IH), 4.31 - 4.21 (m, IH), 4.04 (d, J= 13.0 Hz, 2H), 3.47 (s, 3H), 3.22 - 3.10 (m, IH), 2.86 (t, J = 12.0 Hz, 2H), 1.68 (d,.7= 13.1 Hz, 2H), 1.36 - 1.10 (m, 4H), 0.68 - 0.59 (m, IH), 0.44 (t, J= 6.0 Hz, 2H), 0.24 (q, J = 6.3 Hz, IH)

[0333] LC-MS (ESI): m / z = 563.2 [M+H]+

[0334] Example 4: (S)-10-((5-chloro-2-(4-(hydroxymethyl)piperidin-1-yl)pyrimidin-4-yl)amino)-2-cyclopropyl-3,3,9-trifluoro-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinolin-6(7H)-one (Compound 104a)Docket No. TRLN-013-034W01 / TLS-072WO

[0335]

[0336] Step 1: (S)-10-((5-chloro-2-(4-(hydroxymethyl)piperidin-1-yl)pyrimidin-4-yl)amino)-2-cyclopropyl-3,3,9-trifluoro-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinolin-6(7H)-one

[0337] A solution of (S)-l-(5-chloro-4-((2-cyclopropyl-3,3,9-trifluoro-7-methyl-6-oxo- 1,2, 3,4,6, 7-hexahydro-[l, 4]oxazepino[2, 3-c]quinolin-l 0-yl)amino)pyrimidin-2-yl)piperidine-4-carbaldehyde (34.8 mg, 61.8 pmol) in MeOH (0.600 mL) was treated with NaBH4 (6.90 mg, 182 pmol) and stirred at room temperature for 3 hours. The reaction was quenched by the addition of water (0.5 mL), stirred for 5 minutes, then diluted with DMSO (0.500 mL). The volatiles were removed under reduced pressure, and the solution was filtered and purified by prep-HPLC to afford (S)-10-((5-chloro-2-(4-(hydroxymethyl)piperidin-l-yl)pyrimidin-4-yl)amino)-2-cyclopropyl-3,3,9-trifluoro-7-methyl-l,2,3,4-tetrahydro-[l,4]oxazepino[2,3-c]quinolin-6(7H)-one (27.5 mg).

[0338]

[0339] NMR (400 MHz, DMSO-d6) δ = 8.81 (s, 1H), 8.18 (d, J = 8.0 Hz, 1H), 8.00 (s, 1H), 7.40 (d, J = 12.5 Hz, 1H), 6.50 - 6.39 (m, 1H), 4.52 - 4.23 (m, 4H), 3.54 (s, 3H), 3.30 - 3.22 (m, 1H), 3.20 (t, J = 5.3 Hz, 3H), 2.71 - 2.58 (m, 2H), 1.53

[0340]

[0341] (d, 18.8 Hz, 3H), 1.37 - 1.22 (m, 1H), 1.00 - 0.86 (m, 2H), 0.75 - 0.65 (m, 1H), 0.51 (t, J= 6.0 Hz, 2H), 0.31 (q, J= 6.7 Hz, 1H)

[0342] LC-MS (ESI): m / z = 565.2 [M+H]

[0343] Example 5: (S)-10-((3-chloro-2-fluoropyridin-4-yl)amino)-2-cyclopropyl-3,3,9-trifluoro-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinolin-6(7H)-one (Compound 111a)Docket No. TRLN-013-034W01 / TLS-072WO

[0344]

[0345] Step 1: (S)-10-((3-chloro-2-fluoropyridin-4-yl)amino)-2-cyclopropyl-3,3,9-trifluoro-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinolin-6(7H)-one

[0346] A mixture of (2S)-10-amino-2-cyclopropyl-3,3,9-trifluoro-7-methyl-2,4-dihydro-lH-[l,4]oxazepino[2,3-c]quinolin-6-one (75 mg, 0.22 mmol, 1 equiv., 4-bromo-3-chloro-2-fluoropyridine (56 mg, 0.27 mmol, 1.2 equiv.), cesium carbonate (0.11 g, 0.33 mmol, 1.5 equiv.), and 1,4-di oxane (10 mL) was degassed and purged with N2 three times. XantPhos-Pd-G2 (20 nig, 22 pmol, 0.1 equiv.) was added, and the mixture was heated to 90 °C for 2 hours. The reaction mixture was concentrated under reduced pressure, adsorbed onto silica, and purified by flash silica gel chromatography followed by reverse-phase chromatography to give (S)-10-((3-chloro-2-fluoropyridin-4-yl)amino)-2-cyclopropyl-3,3,9-trif1uoro-7-methyl-1,2,3,4-tetrahy dro- [ 1,4] oxazepino[2,3 -c] quinolin-6(7H)-one (33.2 mg).

[0347]

[0348] NMR (400 MHz, DMSO-d6) δ = 8.78 (s, 1H), 8.24 (d, J = 8.3 Hz, 1 H), 7.72 (d, J = 5.8 Hz, 1H), 7.53 (d, J= 12.4 Hz, 1H), 6.47 (d,.7= 4.4 Hz, 1H), 6.29 (dd, J= 5.8, 1.6 Hz, 1H), 4.52 -4.29 (m, 2H), 3.56 (s, 3H), 3.24 (ddt, J = 19.5, 10.0, 5.0 Hz, 1H), 1.34 - 1.21 (m, 1H), 0.70 (q,.7 = 6.3 Hz, 1H), 0.51 (q, J= 6.7 Hz, 2H), 0.30 (q, J= 6.2 Hz, 1H)

[0349] LC-MS (ESI): m / z = 469.2 [M+H]+

[0350] Example 23. (2S)-10-[(2-chloro-5-fluoro-pyrimidin-4-yl)amino]-2-cyclopropyl- 3,9-trifluoro-7-methyI-2,4-dihydro-lH-[l,4]oxazepino[2,3-c]quinolin-6-one (Compound 119a)Docket No. TRLN-013-034W01 / TLS-072WO

[0351]

[0352] Step 1: (2S)-10-[(2-chloro-5-fluoro-pyrimidin-4-yl)amino]-2-cyclopropyl-3,3,9-trifluoro-7-methyl-2,4-dihydro-1H-[1,4]oxazepino[2,3-c]quinolin-6-one

[0353] A solution of (2S)-10-amino-2-cyclopropyl-3,3,9-trifluoro-7-methyl-2,4-dihydro-lH-[l,4]oxazepino[2,3-c]quinolin-6-one (1 g, 2.95 mmol, 1 equiv.), 2,4-dichloro-5-fluoro- pyrimidine (984.16 mg, 5.89 mmol, 2 equiv.) and DIPEA (1.52 g, 11.79 mmol, 2.05 mL, 4 equivi) in NMP (10 mL) was heated at 140 °C for 3 hours under microwave. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (60 mL). The combined organic layers were washed with aqueous sodium chloride (60 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue, which was purified by flash silica gel chromatography (50% ethyl acetate / petroleum ether) to give (2S)-10-[(2-chloro-5-fluoro-pyrimidin-4-yl)amino]-2-cyclopropyl-3,3,9-trifluoro-7-methyl-2,4-dihydro-lH-[l,4]oxazepino[2,3-c]quinolin-6-one (223.88 mg) as a yellow solid.

[0354] LC-MS (ESI): m / z = 470.1 [M+H]+

[0355] 1H NMR (400 MHz, DMSO-rfc) 5 = 10.22 - 9.98 (m, 1H), 8.30 - 8.29 (m, 1H), 8.29 - 8.28 (m, 1H), 8.37 (d, 3.2 Hz, 1H), 8.22 (d, 8.0 Hz, 1H), 7.50 (d, J= 12.4 Hz, 1H), 6.46 - 6.30 (m, 1H), 4.66 - 4.24 (m, 2H), 3.56 (s, 3H), 3.26 - 3.16 (m, 1H), 1.37 - 1.22 (m, 1H), 1.22 - 1.19 (m, 1H), 0.77 - 0.62 (m, 1H), 0.59 - 0.42 (m, 2H), 0.36 - 0.26 (m, 1H)

[0356] Example 24. (2S)-10-[[5-chloro-2-[4-(1,3-dioxolan-2-yl)-1-piperidyl]-4-pyridyl]amino]-2-cyclopropyl-3,3,9-trifluoro-7-methyl-2,4-dihydro-1H-[1,4]oxazepino[2,3-c]quinolin-6-one (Compound 120a)Docket No. TRLN-013-034W01 / TLS-072WO

[0357]

[0358] O

[0359] Step 1: 5-chloro-2-[4-(1,3-dioxolan-2-yl)-1-piperidyl]-4-iodo-pyridine

[0360] To a solution of 5-chloro-2-fluoro-4-iodo-pyridine (2 g, 7.77 mmol, 1 equiv.) in NMP (20 mL) was added triethylamine (2.36 g, 23.31 mmol, 3.24 mL, 3 equiv.). Then 4-(1,3-dioxolan-2-yl)piperidine (1.47 g, 9.32 mmol, 1.2 equiv.) was added. The mixture was stirred at 140 °C for 1 hour. The reaction mixture was partitioned between water (50 mL) and ethyl acetate (150 mL). The organic phase was separated, washed with brine (150 mL), filtered, and concentrated under reduced pressure to give a residue, which was purified by flash silica gel chromatography (0~3% ethyl acetate / petroleum ether) to give 5-chloro-2-[4-(l,3-dioxolan-2-yl)-l-piperidyl]-4-iodo-pyridine (3.5 g) as a brown liquid.

[0361] LC-MS (ESI): m / z = 395.0 [M+H]+

[0362] Step 2: (2S)-10-[[5-chloro-2-[4-(1,3-dioxolan-2-yl)-1-piperidyl]-4-pyridyl]amino]-2-cyclopropyl-3,3,9-trifluoro-7-methyl-2,4-dihydro-1H-[1,4]oxazepino[2,3-c]quinolin-6-one

[0363] A mixture of 5-chloro-2-[4-(l,3-dioxolan-2-yl)-l-piperidyl]-4-iodo-pyridine (1.74 g, 4.42 mmol, 388.32 piL, 1.5 equiv.'), (2S)-10-amino-2-cyclopropyl-3,3,9-trifluoro-7-methyl-2,4-dihydro-1H-[1,4]oxazepino[2,3-c]quinolin-6-one (1 g, 2.95 mmol, 1 equiv.), t-BuONa (566.46 mg, 5.89 mmol, 2 equiv.), BINAP (367.02 mg, 589.43 μmol, 0.2 equiv.) and Pd2(dba)3 (269.87 mg, 294.71 pmol, 0.1 equiv. ) in dioxane (50 mL) was degassed and purged with N2 three times. The mixture was then stirred at 95 °C for 12 hours under a N2 atmosphere. The reaction mixture was partitioned between water (50 mL) and ethyl acetate (150 mL). The organic phase was separated, washed with brine (450 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue, which was purified by prep-HPLC to give (2S)-10-[[5-chloro-2-[4-(l,3-dioxolan-2-yl)-l-piperidyl]-4-pyridyl]amino]-2-cyclopropyl-3,3,9-trifluoro-7-methyl-2,4-dihydro-lH-[l,4]oxazepino[2,3-c]quinolin-6-one (450 mg) as a brown oil.

[0364] LC-MS (ESI): m / z = 606.1 [M+H]+Docket No. TRLN-013-034W01 / TLS-072WO

[0365] 1H NMR (400 MHz, DMSO-d6) δ = 8.27 - 8.08 (m, 1H), 7.98 - 7.77 (m, 2H), 7.58 - 7.41 (m, 1H), 6.54 - 6.36 (m, 1H), 5.76 - 5.63 (m, 1H), 5.50 - 5.48 (m, 1H), 4.56 - 4.26 (m, 4H), 4.06 - 3.91 (m, 2H), 3.84 - 3.68 (m, 4H), 3.54 (d, J= 6.4 Hz, 3H), 1.70 - 1.54 (m, 3H), 1.32 - 1.11 (m, 4H), 1.04 (d, J = 7.2 Hz, 2H), 0.70 (d, J = 6.4 Hz, 1H), 0.55 - 0.43 (m, 2H), 0.29 (dd,.7= 3.2, 8.0 Hz, 1H)

[0366] General SxAr procedure

[0367] A mixture of (S)-2-cyclopropyl-10-((2,5-dichloropyrimidin-4-yl)amino)-3,3,9-trifluoro-7-methyl-l,2,3,4-tetrahydro-[l,4]oxazepino[2,3-c]quinolin-6(7H)-one (75 mg, 0.15 mmol, 1 equiv.). an appropriate nucleophile (0.22 mmol, 1.5 equiv.), diisopropylethylamine (60 mg, 81 pL, 0.46 mmol, 3 equiv. ), and cesium fluoride (35 mg, 0.23 mmol, 1.5 equiv.) in DMSO (3 mL) was heated at 80 °C for 20 hours. The reaction was filtered and purified via reverse phase chromatography to yield the following compounds:

[0368] LC-MS

[0369] Example Compound 'll NMR

[0370] (ESI):

[0371] 1H NMR (400 MHz, DMSO-d6) δ = 8.80 (s, 1H), 8.16 - 8.07 (m, 1H), m / z = 7.96 (s, 1H), 7.34 (d, J = 12.5 Hz, 1H), 6.42 - 6.36 (m, 1H), 4.45 - 6 105a 550.3 4.21 (m, 2H), 3.47 (s, 3H), 3.39 (d, J = 6.2 Hz, 4H), 3.23 - 3.09 (m,

[0372] [M+H]+1H), 2.15 (t, J = 5.0 Hz, 4H), 2.06 (s, 3H). 1.27 - 1.19 (m, 1H), 0.63

[0373] (p, J = 6.5 Hz, 1H), 0.45 (q, J = 6.7 Hz, 2H), 0.24 (q, J = 6.5 Hz, 1H). ‘H NMR (400 MHz, DMSO-d6) 5 - 8.92 (s, 1H), 8.20 (d, J - 8.1 Hz, 1H), 8.06 (s, 1H), 7.41 (d, J- 12.4 Hz, 1H), 6.46 (dd, J- 4.8, 2.0 Hz, m / z - 1H), 4.51 - 4.28 (m, 2H), 3.56 - 3.49 (m, 7H). 3.42 (d, J- 4.9 Hz, 7 106a 537.3

[0374] 4H), 3.23 (ddt, J = 16.3, 10.3, 5.3 Hz, 1H), 1.31 (d, J = 6.2 Hz, 1H), [M+H]+

[0375] 0.75 - 0.64 (m, 1H), 0.52 (q, J = 6.7 Hz, 2H), 0.31 (q, J = 6.3 Hz,

[0376] 1H).

[0377] ‘H NMR (400 MHz, DMSO-d6) 8 = 8.73 (s, 1H), 8.22 (d,.7= 8.1 Hz, m / z = 1H), 8.00 (s, 1H), 7.40 (d, J= 12.5 Hz, 1H), 6.49 - 6.43 (m, 1H), 4.51 8 107a 521.2 - 4.27 (m, 2H), 3.54 (s, 3H), 3.31 - 3.17 (m, 6H), 1.79 (s, 4H), 1.30

[0378] [M+H]+(q, J = 8.4 Hz, 1H), 0.75 - 0.64 (m, 1H), 0.50 (dq, J = 8.2, 4.2 Hz,

[0379] 2H), 0.31 (p, J = 5.7 Hz, 1H).

[0380] ’H NMR (400 MHz, DMSO-fifc) 5 = 8.81 (s, 1H). 8.19 (d,.7 = 8.0 Hz, m / z =

[0381] 1H), 8.00 (s, 1H), 7.40 (d, J= 12.4 Hz, 1H), 6.49 - 6.43 (m, 1H), 4.50 9 108a 535.3

[0382] - 4.27 (m, 2H), 3.53 (s, 3H), 3.45 (d, J = 5.6 Hz, 4H), 3.23 (ddt, J = [M+H]+

[0383] 16.9, 10.2, 5.2 Hz, 1H), 1.51 (q, J = 6.1 Hz, 2H), 1.42 - 1.24 (m, 5H),

[0384]

[0385] Docket No. TRLN-013-034W01 / TLS-072WO

[0386] LC-MS

[0387] Example Compound1H NMR

[0388] (ESI):

[0389] 0.75 - 0.64 (m, 1H), 0.56 - 0.47 (m, 2H). 0.31 (ft, J = 8.6, 4.3 Hz.

[0390] 1H).

[0391] ’H NMR (400 MHz, DMSO-t / e) § = 8.90 (s, 1H), 8.15 (d, J= 8.0 Hz, 1H), 8.00 (s, 1H), 7.40 (d, J= 12.5 Hz, 1H), 6.49 - 6.43 (m, 1H), 4.79 m / z = (d, J = 4.4 Hz, 1H), 4.51 - 4.29 (m, 3H), 4.16 (s, 1H), 3.54 (s, 3H), 10 109a 565.3 3.24 (ddq, J= 16.8, 10.4, 5.0 Hz, 2H), 2.24 (t, J = 11.4 Hz, 1H), 2.12

[0392] [M+H]+- 2.02 (m, 1H), 1.88 (d, J = 12.3 Hz, 1H), 1.47 - 1.25 (m, 2H), 0.90

[0393] (q, J = 11.8 Hz, 1H), 0.79 - 0.64 (m, 4H), 0.54 - 0.47 (m, 2H), 0.31

[0394] (dt, J= 8.7, 4.7 Hz, 1H).

[0395] 1H NMR (400 MHz, DMSO-d6) δ = 8.87 (s, 1H), 8.18 (d, J = 8.0 Hz, 1H), 8.00 (s, 1H), 7.40 (d, J = 12.5 Hz, 1H), 6.46 (dd, J = 4.7, 2.1 Hz, m / z =

[0396] 1H), 4.49 - 4.12 (m, 4H), 3.53 (s, 3H), 3.23 (ddt, J= 16.2, 10.3, 5.3 11 110a 563.3

[0397] Hz, 1H), 2.10 (dd, J= 19.9, 8.6 Hz, 2H), 1.69 (d. J= 12.7 Hz, 1H), [M+H]+

[0398] 1.45 - 1.24 (m, 3H). 0.77 - 0.62 (m, 8H), 0.54 - 0.47 (m, 2H), 0.30

[0399] (q, J = 5.9 Hz, 1H).

[0400] ’H NMR (400 MHz, DMSO-A) 5 = 8.83 (s, 1H), 8.19 id. J = 8.0 Hz, 1H), 8.00 (s, 1H), 7.41 (d. J = 12.4 Hz. 1H), 6.46 (s, 1H), 4.51 - 4.27 m / z = (m. 2H), 4.16 (s, 2H), 3.53 (s. 3H), 3.23 (ddt. J = 16.4, 10.5, 5.5 Hz, 12 112a 549.3 1H). 2.65 (t, J= 11.8 Hz. 1H), 2.40 - 2.29 (m, 1H), 1.69 (d,.7 = 12.6

[0401] [M+H]+Hz, 1H), 1.51 (d, J = 13.3 Hz, 1H), 1.40 (dt, J = 7.1, 3.9 Hz, 1H), 1.33

[0402] - 1.20 (m, 2H), 1.04 (qd, J= 12.2, 3.7 Hz, 1H), 0.72 (dd, J= 16.2. 7.0 Hz, 4H). 0.50 (t, J= 6.0 Hz, 2H), 0.31 (q, J= 5.8 Hz, 1H). ’H NMR (400 MHz, DMSO-c / 6) 8 = 8.84 (s, 1H), 8.18 (d, 7 = 8.0 Hz, 1H), 8.00 (s, 1H), 7.40 (d, J = 12.5 Hz, 1H), 6.45 (dd, J = 5.0, 2.0 Hz, m / z ~ 1H), 4.51 - 4.28 (m, 2H), 4.17 (s, 2H), 3.53 (s, 3H), 3.23 (ddt, J = 13 1121) 549.3 16.0, 10.2, 5.3 Hz, 1H), 2.65 (t, J = 12.1 Hz, 1H), 2.32 (t, 7 = 11.7 Hz,

[0403] [M+H]+1H), 1.69 (d, 7 = 12.7 Hz, 1H), 1.51 (d, 7 = 13.0 Hz, 1H), 1.45 - 1.35

[0404] (m, 1H), 1.27 (d, 7 = 14.3 Hz, 2H), 1.11 - 0.97 (m, 1H), 0.73 (dd, 7 = 20.8, 7.0 Hz, 4H), 0.54 - 0.47 (m, 2H), 0.30 (q, 7= 6.0 Hz. 1H). ’H NMR (400 MHz, DMSO-408 = 8.86 (s, 1H), 8.21 (d, J= 8.0 Hz, 1H), 8.02 (s, 1H), 7.41 (d, J= 12.5 Hz, 1H), 6.46 (d, J= 4.6 Hz, 1H), m / z =

[0405] 4.50 - 4.28 (m, 2H), 4.17 (ddd, J= 10.2, 6.3, 4.0 Hz, 1H), 3.99 (s, 14 113a 537.4

[0406] 2H), 3.63 (s, 2H), 3.54 (s, 3H), 3.30 - 3.19 (m, 1H), 3.17 (s, 3H), 1.30 [M+H]+

[0407] (d, J = 5.2 Hz, 1H), 0.70 (t, J = 7.4 Hz, 1H), 0.55 - 0.48 (m, 2H), 0.31

[0408] (q, J = 6.2 Hz, 1H).

[0409] m / z =1H NMR (400 MHz, DMSO-d6) δ = 8.77 (s, 1H), 8.19 (d, J = 8.1 Hz, 15 114a 549.3 1H), 7.99 (s, 1H), 7.39 (d, J = 12.5 Hz, 1H), 6.44 (s, 1H), 4.50 - 4.27

[0410] [M+H]+(m, 2H), 3.53 (s, 5H), 3.23 (d, J = 27.6 Hz, 4H), 1.61 (s, 2H), 1.39 (s,

[0411]

[0412] Docket No. TRLN-013-034W01 / TLS-072WO

[0413] LC-MS

[0414] Example Compound1H NMR

[0415] (ESI):

[0416] 6H), 1.30 (d, 7 = 6.2 Hz. IH), 0.69 (p.7 = 6.8 Hz, IH), 0.54 - 0.46 (m, 2H), 0.30 (q, 7 = 6.0 Hz, IH).

[0417] ’H NMR (400 MHz, DMSO-t / e) § = 8.88 (s, 1H), 8.18 (d, J= 8.0 Hz, m / z = 1H), 8.01 (s, 1H), 7.41 (d, J= 12.4 Hz, 1H), 6.45 (dd, J= 4.7, 2.0 Hz, 16 115a 549.3 1H), 4.62 (s, 4H), 4.52 - 4.29 (m, 2H), 3.96 (s, 4H), 3.55 (s, 3H), 3.25

[0418] [M+H]+(ddd, J= 22.7, 10.1, 5.1 Hz, 1H), 1.31 (s, 1H), 0.70 (dt, J= 12.0, 6.5

[0419] Hz, 1H), 0.55 - 0.48 (m, 2H), 0.32 (q, J= 6.0 Hz, 1H).

[0420] 1H NMR (400 MHz, DMSO-d6) δ = 9.03 (s, 1H), 8.20 (d, J = 7.9 Hz, 1H), 8.14 (s, 1H), 7.42 (d, J = 12.5 Hz, 1H), 6.41 (s, 1H), 4.52 - 4.28 m / z =

[0421] (m, 2H), 3.54 (s, 3H), 3.32 - 3.18 (m, 2H), 2.57 (ddd, J = 19.6, 9.4, 17 116a 575.3

[0422] 5.0 Hz, 2H), 2.16 (d, J= 15.6 Hz, 2H), 1.95 (s, 2H), 1.56 (d,.7= 7.6 [M+H]+

[0423] Hz, 2H), 1.25 (d, J= 16.8 Hz, 1H), 0.75 - 0.65 (m, 1H), 0.50 (t, J =

[0424] 6.0 Hz, 2H), 0.30 (q, J= 6.2 Hz, IH).

[0425] ’H NMR (400 MHz, DMSO-Jg) 8 = 8.87 (s, 1H), 8.22 (d, 7 = 8.0 Hz, 1H), 8.03 (s, IH), 7.41 (d,7= 12.5 Hz, 1H), 6.45 (s, 1H), 4.49 - 4.31 m / z =

[0426] (m, 2H), 4.26 (s, 2H), 3.85 (s, 2H). 3.54 (s, 3H), 3.23 (ddt, 7= 16.2, 18 117a 563.3

[0427] 10.3, 5.3 Hz, IH). 2.87 (d, 7= 13.0 Hz, 2H). 1.72 (d, 7= 7.0 Hz, 2H), [M+H]+

[0428] 1.56 (d, 7= 7.4 Hz, 2H), 1.29 (d, 7= 5.0 Hz. Ill), 0.70 (p, 7= 6.4 Hz, IH), 0.50 (q, 7= 6.7 Hz, 2H), 0.31 (q, 7= 6.2 Hz, IH).

[0429] ’H NMR (400 MHz, DMSO-A) 8 = 9.09 (s, IH), 8.23 (d, 7= 8.0 Hz, m / z = IH), 8.13 (s, IH), 7.41 (d.7= 12.5 Hz, IH), 6.37 (t, 7 = 3.3 Hz, IH), 19 118a 585.2 4.51 - 4.32 (m, 2H), 3.91 (s, 4H), 3.54 (s, 3H), 3.31 - 3.17 (m, IH),

[0430] [M+H]+3.04 (qd, 7 = 14.0, 6.4 Hz, 4H), 1.35 - 1.22 (m, IH), 0.77 - 0.65 (m,

[0431] IH), 0.55 - 0.48 (m, 2H), 0.31 (q, 7= 5.6 Hz, IH).

[0432]

[0433] General Cross-coupling

[0434] A mixture of (2S)-10-amino-2-cyclopropyl-3,3,9-trifluoro-7-methyl-2,4-dihydro-lH-[l,4]oxazepino[2,3-c]quinolin-6-one (75 mg, 0.22 mmol, 1 equiv.), cesium carbonate (0.22 g, 0.66 mmol, 3 equiv.), and bromopyridine (0.28 mmol, 1.25 equiv.) in 1,4-dioxane (10 mL) was purged with N2 three times. To this mixture was added RuPhos-Pd-G3 (9.2 mg, 11 pmol, 0.05 equiv), and the reaction was heated at 90 °C for 20 hours. The reaction mixture was concentrated under reduced pressure and loaded onto silica. The residue was purified by flash silica gel chromatography followed by reverse-phase chromatography to yield the following compounds:Docket No. TRLN-013-034W01 / TLS-072WO

[0435] LC-MS

[0436] Example Compound ‘H NMR

[0437] (ESI):

[0438] 1H NMR (400 MHz, DMSO-d6) δ = 8.25 - 8.13 (m, 2H), 7.92 (d, J = m / z = 5.6 Hz, 1H), 7.50 (d, J = 12.4 Hz, 1H), 6.49 - 6.43 (m, 1H), 6.19 (dd, 20 121a 465.2 J = 5.6, 1.8 Hz, 1H), 4.53 - 4.29 (m, 2H), 3.55 (s, 3H), 3.24 (ddt, J =

[0439] [M+H]+20.1, 10.2, 5.5 Hz, 1H), 2.51 (s, 3H), 1.31 - 1.21 (m, 1H), 0.69 (h, J =

[0440] 6.0 Hz, 1H), 0.55 - 0.46 (m, 2H), 0.30 (t, J = 6.0 Hz, 1H).

[0441] 1H NMR (400 MHz, DMSO-d6) δ = 9.51 (s, 1H), 8.19 (s, 1H), 8.02 m / z = (s, 1H), 7.51 (d, J = 12.5 Hz, 1H), 6.49 - 6.39 (m, 2H), 4.53 - 4.29 21 122a 475.9 (m, 2H), 3.55 (s, 3H), 3.23 (dq, J = 15.1, 5.1 Hz, 1H), 2.51 (s, 3H),

[0442] [M+H]+1.31 - 1.22 (m, 1H), 0.70 (p, J = 6.4 Hz, 1H), 0.55 - 0.47 (m, 2H),

[0443] 0.30 (q, J = 6.5 Hz, 1H).

[0444] ’H NMR (400 MHz, DMSO-Je,) 8 = 8.99 (s, 1H), 8.20 (d, J= 8.4 Hz.

[0445] 1H). 7.97 (d, J= 5.8 Hz, 1H), 7.50 (d, J= 12.7 Hz, 1H), 6.67 (dd, J = m / z =

[0446] 5.8, 2.1 Hz, 1H), 6.59 (d, J = 2.0 Hz, 1H), 6.46 (dd, J= 4.8, 2.1 Hz, 22 123a 451.2

[0447] 1H), 4.53 - 4.30 (m. 2H), 3.54 (s, 3H), 3.32 - 3.15 (m, 1H). 1.32 - [M+H]+

[0448] 1.21 (m, 1H), 0.70 (p, J = 6.5 Hz, 1H), 0.56 - 0.47 (m, 2H), 0.31 (q, J = 6.1 Hz, 1H).

[0449]

[0450] Example Bl

[0451] Expression and Purification of Recombinant BCL6 protein

[0452] The gene fragment encoding human BCL6 BTB domain encompassing residues 5-129 with mutations C8Q, C67R, and C84N was synthesized by integrated DNA Technologies (IDT). This was assembled into a pET28 vector with an N-temiinal His-SUMO tag and a C-terminal GS-Avi tag by Gibson Assembly (NEB). Next, the plasmid was transformed into an E. coli expression cell line BL21(DE3)star (Invitrogen). The cells were grown in TB complete media supplemented with selective antibiotics to an OD at 600 nm of ~0.8 at 37 °C, at which point expression was induced by the addition of 200 pM IPTG. The cultures were expressed for 4 hours at 37 °C. After the expression, the cultures were harvested by centrifugation at 5,000 x g for 15 min. The cell pellet was stored at -20 °C until purification.

[0453] The cell pellet was resuspended in lysis buffer (40 mM Tris pH 7.5, 500 mM NaCl, 5 mM imidazole) with EDTA-free protease inhibitor tablets add to the resuspension (Roche). Next, the cells were lysed using a microfluidizer (Microfluidics, M-l lOp). The lysate was clarified by centrifugation at 30kxg for 1 hour. The protein was captured from the clarified lysate by affinity chromatography over a HisTrapFF column(Cytiva). The protein was eluted over an imidazole gradient from 5 to 500 mM. Fractions of eluted protein were then pooled.Docket No. TRLN-013-034W01 / TLS-072WO

[0454] ULP1 protease was added at a 1:15 ratio nig of ULP1 to mg of BCL6 to cleave the N-terminal tag, and the mixture was dialyzed overnight to remove imidazole in dialysis buffer (25 mM Tris PH 7.5, 500 mM NaCl). Cleaved protein (SEQ ID NO: 1) was then separated from the N-terminal tag and the ULP1 protease by a subtractive affinity purification using Ni-NTA resin (Qiagen). The protein was then biotinylated using a BirA ligation kit (Avidity LLC). The final polishing step for BCL6 was size exclusion chromatography (SEC) over a Hiload 16 / 600 Superdex 75 pg column (Cytiva) into assay buffer (25 mM HEPES pH 7.5, 125 mM NaCl, 0.5 mM TCEP). The protein was aliquoted, and flash frozen in liquid nitrogen. The protein was then stored at -80 °C.

[0455] SEQ ID NO: 1 ADSQIQFTRHASDVLLNLNRLRSRDILTDVVIVVSREQFRAHKTVLMACSGLFYSIFT DQLKRNLSVINLDPEINPEGFNILLDFMYTSRLNLREGNIMAVMATAMYLQMEHVV DTCRKFIKASEGSGLNDIFEAQKIEWHE

[0456] Example B2

[0457] BCL6 Peptide Displacement Assay

[0458] Fresh assay buffer (25 mM HEPES pH 7.5, 125 mM NaCl, 0.5 mM TCEP) was prepared and used to dilute all reagents used in the assay. First, a mixture of recombinantly expressed and biotinylated BCL6 (5-129-C8Q-C67R-C84N) and a-Strep-Tb cryptate (Revvity ) was made. The concentration of BCL6 was 15 nM in this mixture. Next, 5 pl of the mixture was dispensed into each well of 384 shallow-well black plates (Corning 4514) pre-spotted with a 10 point, 1:3 compound titration and normalized with 1% DMSO. The plate was sealed with foil, placed on a shaker and incubated at room temperature for 30 minutes. During the incubation, a second mixture was prepared. This mixture contained a synthesized peptide known to bind to the BTB domain of BCL6. The peptide had a C-terminal HA tag (Thermo Fisher, LVATVKEAGRSIWEIPRGSYPYDVPDYAGS (SEQ ID NO:2)) and was diluted to 97.5 nM and mixed with a-HA XL665 cryptate (Revvity). After incubation of BCL6 protein mixture with the compounds, 10 pL of the second mixture was dispensed into all compound containing wells and high signal control wells. Low signal control wells contained BCL6, a-Strep-Tb cryptate, and a-HA XL655 cryptate. The total reaction volume was 15 µl with the final concentration of BCL6 at 5 nM and the peptide at 65 nM. The plate was resealed and incubated at room temperature for 1 hour. Following incubation, the seal was removed, andDocket No. TRLN-013-034W01 / TLS-072WO

[0459] the fluorescence was read on a PHERAstar FSX Plate Reader (BMG) with the TR-FRET module.

[0460] Background fluorescence was determined by the average of the low signal control wells and subtracted from the data. Then the data was normalized with the average of the high signal control wells. Compound inhibition curves were fit using a four-parameter logistics module, and IC50values were determined. The IC50values are reported in Table B1.

[0461] Table Bl.

[0462] Compound No. ICso (nM)

[0463] 103a < 2.5

[0464] 104a < 2.5

[0465] 105a < 2.5

[0466] 106a < 2.5

[0467] 107a 5.9

[0468] 108a 2.8

[0469] 109a < 2.5

[0470] 110a 4.3

[0471] 111a < 2.5

[0472] 112a 7.3

[0473] 112b 4.1

[0474] 113a 2.5

[0475] 114a 14

[0476] 115a < 2.5

[0477] 116a < 2.5

[0478] 117a < 2.5

[0479] 118a < 2.5

[0480] 121a 3.8

[0481] 122a < 2.5

[0482]

[0483] 123a 32

[0484] Example B3

[0485] HiBiT Based Degradation Assay

[0486] Human BCL6 protein coding open reading frame fused with N-terminal HiBiT coding sequence was synthesized from Integrated DNA Technologies (IDT). Next, the N-HiBiT-BCL6 sequence was cloned into pLV-UBC-PGK-Puro, a lentivirus plasmid purchased from Vectorbuilder, to generate pLV-UBC-N-HiBiT-BCL6-PGK-puro. Lentiviral particles were generated from Lenti-X™ 293T cells (Clontech) by co-transfection of pLV-UBC-N-HiBiT-BCL6-PGK-puro plasmids and lentiviral packaging plasmid mix (Cellecta). HT1080 [HT1080]Docket No. TRLN-013-034W01 / TLS-072WO

[0487] (ATCC CCL-121™) cells were infected with the lentivirus, and HT1080 cells stably integrated with the lentiviral vectors were established by incubation with 1 pg / mL puromycin (ThermoFisher).

[0488] HT1080 cells expressing N-terminal HiBiT tagged BCL6 were dispensed into a 384-well plate pre-spotted with compounds at varying concentrations. Five thousand cells were seeded into each well in 40 pL of RPMI 1640 media plus 10% Fetal Bovine Serum (10082-147, ThermoFisher). After 5 hours of incubation at 37 °C with 5% CO2, 30 pL of the NANO-GLO® HiBiT Lytic Detection System working solution (Promega) was added to each well and incubated at room temperature for 15 min. After incubation, luminescence was read on a PHERAstar FSX Plate Reader (BMG). BCL6 degradation at each indicated concentration was normalized with DMSO control. The BCL6 degradation curves were plotted using a four- parameter logistic model.

[0489] Table B2 provides the Ymin and ECso values for certain compounds of this disclosure as the arithmetic mean (Ymin) or the geometric mean (EC50) of multiple runs, if applicable. Only compounds with a Ymin less than 70% are reported.

[0490] Table B2.

[0491] Compound No. ECso (5 h) Ymin (5 h)

[0492] 106a +++ +

[0493] 109a +++ ++

[0494] 110a ++ +

[0495]

[0496] 112b ++ +

[0497] Notes:

[0498] Ymin <

[0499]

[0500] 50%: “+++”; 50% < Ymin< 60%: 60% < Ymm< 70%:

[0501] ECso < 25 nM: “+++”; 25 nM < ECso< 100 n

[0502]

[0503] M: 100 nM < EC.so< 1000 nM: “+”

Claims

Docket No. TRLN-013-034W01 / TLS-072WOWHAT IS CLAIMED IS:

1. A compound of Formula (I):Formula (I)or a pharmaceutically acceptable salt thereof, wherein:R1is a C1-3 alkyl optionally substituted with 1-3 -F;X1is selected from the group consisting of: N and CH;R2is selected from the group consisting of:(a) 4-10 membered heterocyclyl optionally substituted with 1-3 R5;(b) -H; and(c) halo;R3and R4are each independently selected from the group consisting of: -H, halo, -CN, and C1-3 alkyl optionally substituted with 1-3 -F;each R5is independently selected from the group consisting of:(a) C1-3 alkyl optionally substituted with 1-3 R6;(b) -OH;(c) -C(=O)H;(d) -C(=O)OH;(e) -CN;(f) C1-3 alkoxy optionally substituted with 1-3 R6;(g) 4-6 membered heterocyclyl; and(h) oxo; andeach R6is independently selected from the group consisting of: -F and -OH.

2. The compound of claim 1, wherein R1is C1-3 alkyl.Docket No. TRLN-013-034W01 / TLS-072WO3. The compound of claim 1 or 2, wherein R1is methyl.

4. The compound of any one of claims 1-3, wherein R2is a 4-10 membered heterocyclyl optionally substituted with 1-3 R55. The compound of any one of claims 1-4, wherein R2is selected from the group consisting of: piperidinyl; piperazinyl; morpholinyl; pyrrolidinyl; azetidinyl; azepanyl; 2-oxa- 6-azaspiro[3.3]heptan-6-yl; 8-azabicyclo[3.2.1]octan-8-yl; 8-oxa-3-azabicyclo[3.2.1]octan-3-yl; and 1,1-dioxidothiomorpholinyl, each of which is optionally substituted with 1-3 R56. The compound of any one of claims 1-5, wherein each R5is independently selected from the group consisting of.(a) Ci-3 alkyl optionally substituted with 1-3 R6;(b) -OH;(c) -CN;(d) Ci-3 alkoxy optionally substituted with 1-3 R6; and(e) oxo.

7. The compound of any one of claims 1-6, wherein R3is halo.

8. The compound of any one of claims 1-7, wherein R3is -F or -Cl.

9. The compound of any one of claims 1-6, wherein R3is -CN.

10. The compound of any one of claims 1-6, wherein R3is -H.

11. The compound of any one of claims 1-10, wherein R4is -H or methyl.

12. The compound of any one of claims 1-10, wherein R4is -H.

13. The compound of any one of claims 1-12, wherein X1is N,Docket No. TRLN-013-034W01 / TLS-072WO14. The compound of any one of claims 1-12, wherein X1is CH.

15. The compound of claim 1, wherein the compound of Formula (I) is selected from the group consisting of the compounds depicted in Table Cl, or a pharmaceutically acceptable salt thereof.

16. A pharmaceutical composition comprising a compound of any one of claims 1-15, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

17. A method for treating a cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1-15, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 16.

18. The method of claim 17, wherein the cancer is a hematological cancer (e.g., lymphoma (e.g., Hodgkin lymphoma (e.g., nodular lymphocyte predominant Hodgkin lymphoma (NLPHL)), non-Hodgkin lymphoma (e g., B cell lymphoid proliferations and lymphomas (e.g., mature B cell neoplasms (e.g., Burkitt lymphoma (BL), large B cell lymphoma (e.g., diffuse large B-cell lymphoma not otherwise specified (DLBCL-NOS), T-cell / histiocyte-rich large B-cell lymphoma, diffuse large B-cell lymphoma / high grade B cell lymphoma (HGBCL) (e.g., HGBCL with MYC and / or BCL2 rearrangements (HGBCL-MYC / BCL-2)), primary large B cell lymphoma of immune-privileged sites (primary LBCL of immune-privileged sites), primary mediastinal large B cell lymphoma (primary mediastinal LBCL), or high grade B-cell lymphoma NOS), follicular lymphoma (FL), or transformations of indolent B cell lymphomas)), T-cell and NK-cell lymphoid proliferations and lymphomas (e.g., mature T-cell and NK-cell neoplasms (e.g., mature T-cell and NK-cell leukemias (e.g., adult T-cell leukemia / lymphoma), primary cutaneous T-cell lymphoid proliferations and lymphomas (cutaneous T-cell lymphoma (CTCL)) (e.g., primary cutaneous CD4-positive small or medium T-cell lymphoproliferative disorder, mycosis fungoides, Sezary syndrome, primary cutaneous CD30-positive T-cell lymphoproliferative disorder: lymphomatoid papulosis, primary cutaneous CD30-positive T-cell lymphoproliferative disorder: primary cutaneous anaplastic large cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, primary cutaneous gamma-delta T-cell lymphoma, or primary cutaneous peripheral T-cell lymphoma NOS), peripheral T-cell lymphoma (PTCL) (e.g., anaplastic large cell lymphomaDocket No. TRLN-013-034W01 / TLS-072WO(ALCL) (e.g., ALK-positive anaplastic large cell lymphoma, or ALK-negative anaplastic large cell lymphoma), nodal T follicular helper cell lymphoma (e.g., nodal T follicular helper cell lymphoma angioimmunoblastic type (also known as angioimmunoblastic T-cell lymphoma (AITL) or follicular helper T-cell lymphoma, angioimmunoblastic type), nodal T follicular helper cell lymphoma follicular type (also known as follicular helper T-cell lymphoma, follicular type), or nodal T follicular helper cell lymphoma NOS (also known as follicular helper T-cell lymphoma, NOS)), or other peripheral T-cell lymphomas (e.g., peripheral T-cell lymphoma NOS)))))).

19. The method of claim 17 or 18, comprising administering an additional therapy or therapeutic agent to the subject.

20. The method of claim 19, wherein the additional therapy or therapeutic agent is a PI3K inhibitor, an Abl inhibitor (e.g., a BCR-Abl inhibitor), a BTK inhibitor, a JAK inhibitor, a BRaf inhibitor, a MEK inhibitor, a BCL-2 inhibitor, a BC1-XL inhibitor, an XPOl inhibitor, an inhibitor of the polycomb repressive complex 2 (PRC2), an immunomodulatory imide drug, anti-CD19 therapy, anti-CD20 therapy, anti-CD3 therapy, chemotherapy, or a combination thereof.

21. A method for treating or preventing an autoimmune condition in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1-15, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 16.

22. A method for inhibiting a BCL6 protein in a mammalian cell, the method comprising contacting the mammalian cell with an effective amount of a compound of any one of claims 1-15, or a pharmaceutically acceptable salt thereof.

23. The method of claim 22, wherein the contacting occurs in vivo.

24. The method of claim 22, wherein the contacting occurs in vitro.

25. The method of claim 22, wherein the contacting occurs ex vivo.Docket No. TRLN-013-034W01 / TLS-072WO26. The method of anv one of claims 22-25, wherein the mammalian cell is a mammalian cancer cell.

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