Combination of a car-t therapy and a chromene derivative TCR inhibitor

Abstract

Provided herein are methods and compositions involving chromene derivatives acting as TCR or TCR-Nck inhibitors, and CAR-T therapies. The provided methods include the use of a chromene derivative in combination with a CAR-T therapy for treating a disease or disorder, for preventing or reducing an autoimmune reaction associated with a CAR-T therapy, and for increasing or improving a CAR-T therapy effectiveness.

Description

397743-013WO (218530) COMBINATION OF A CAR-T THERAPY AND A CHROMENE DERIVATIVE TCR INHIBITOR CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of and priority to United States Provisional PatentApplication serial number 63 / 655,482, filed June 3, 2024, the entire contents of which are hereby incorporated by reference. TECHNICAL FIELD OF THE DISCLOSURE

[0002] The present disclosure relates to chromene derivatives, compositions thereof, and useof a chromene derivative in combination with a CAR-T therapy for treating diseases, disorders, or conditions as described herein. BACKGROUND OF THE DISCLOSURE

[0003] The TCR is composed of the antigen / MHC binding clonotypic subunits TCRα andTCRβ and the signal-transducing subunits CD3γ, CD3δ, CD3ε and CD3ζ. The CD3 subunits contain relatively long cytoplasmic tails and mediate signal transduction by connecting antigen / MHC binding in the extracellular domains of TCRα and TCRβ with the intracellular signaling machinery.

[0004] Key to the signal transduction mechanism of the TCR is the presence of tyrosineresidues in a motif called immunoreceptor tyrosine activation motif (ITAM). ITAMs are present in one dose in each of the CD3γ, CD3δ and CD3ε subunits and in three doses in the tail of CD3ζ (Journal of Biological Chemistry 295, 914–925 (2020)). Upon TCR triggering, the tyrosine residues of the ITAMs become phosphorylated by the Src-family kinase Lck and those phosphotyrosines become docking sites for the tyrosine kinase ZAP70 which becomes recruited to the TCR and activated. Subsequently, ZAP70 carries out a number of phosphorylations in downstream intracellular substrates that result in T cell activation. The multiplicity of ITAMs in CD3ζ is the reason why the so-called “Chimeric Antigen Receptors (CARs)” created to target tumor-associated antigens contain just the cytoplasmic tail of CD3ζ in addition to signaling cytoplasmic tails of costimulatory receptors (usually 4-1BB or CD28) (Am J Hematol.94, S3–S9 (2019)). BUSINESS.32999895.1 1397743-013WO (218530)

[0005] However, the TCR contains motifs additional to the ITAMs and recruit intracellularsignaling proteins other than Lck and ZAP70. One of such motifs is the proline-rich sequence (PRS) present in the cytoplasmic tail of CD3ε just upstream of its ITAM. This PRS is responsible for the recruitment of the cytoplasmic adaptor protein Nck through the N-terminal SH3 domain of the latter (Cell 109, 901–12. (2002)). Interestingly, the PRS is not competent to recruit Nck if the TCR is in the resting conformation, but it is if the TCR is triggered by binding to its cognate antigen / MHC complexes of by stimulatory anti-TCR or anti-CD3 antibodies. A direct inhibitor of the recruitment of Nck to the PRS of CD3ε has been generated and this inhibitor has been shown to have immunomodulatory properties in different models of autoimmune diseases in mice in addition to impair T cell activation to weak but not to strong antigen / MHC ligands (Science Translational Medicine 8, 370ra184-370ra184 (2016)). SUMMARY OF THE DISCLOSURE

[0006] In has been found that a chromene derivative as described herein can inhibit TCR-Nckinteractions and human T cell alloresponses, and increase or improve CAR-T therapy effectiveness. Accordingly, provided herein are methods for treating a disease or disorder in apatient, comprising administering to the patient a chromene derivative as described herein, incombination with a CAR-T therapy.

[0007] In one aspect, the present disclosure provides a method for treating a disease or disorderin a patient, comprising administering a therapeutically effective amount of a chromene derivativeas described herein, and a therapeutically effective amount of a CAR-T therapy to the patient.

[0008] In another aspect, the present disclosure provides a method for preventing or reducingan autoimmune reaction associated with a CAR-T therapy in a patient, comprising administeringto the patient a therapeutically effective amount of a chromene derivative as described herein, incombination with the CAR-T therapy.

[0009] In another aspect, the present disclosure provides a method for increasing or improvinga CAR-T therapy effectiveness in a patient, comprising administering to the patient atherapeutically effective amount of a chromene derivative as described herein, in combination withthe CAR-T therapy. BUSINESS.32999895.1 2397743-013WO (218530)

[0010] In another aspect, the present disclosure provides a method for preparing a CAR-Ttherapy, comprising adding a therapeutically effective amount of a chromene derivative as described herein in the CAR-T therapy.

[0011] In another aspect, the present disclosure provides a composition comprising atherapeutically effective amount of a chromene derivative as described herein and a CAR-T therapy.

[0012] In some embodiments, a chromene derivative is selected from the chromene derivativesas described herein. In some embodiments, a disease or disorder is selected from the proliferative diseases and cancers as described herein. In some embodiments, a CAR-T therapy is selected from those as described herein. In some embodiments, a CAR-T therapy is an allogeneic CAR-T therapy. BRIEF DESCRIPTION OF FIGURES

[0013] FIG.1 depicts the effect of compound A-68 on cytokine release by CAR-bearing T cellsin response to CAR and TCR triggering.

[0014] FIG. 2 depicts the effect of compound A-68 on CAR-triggered T cell proliferation andtarget cell killing.

[0015] FIG. 3 depicts the effect of compound A-68 on TCR-mediated allogeneic responses.

[0016] FIG. 4 depicts the effect of compound A-68 on early CAR and TCR signaling.DETAILED DESCRIPTION OF THE DISCLOSURE 1. General Description of Certain Embodiments of the Disclosure

[0017] The use of T cells expressing CARs to B cell-specific membrane proteins CD19 andCD20 has been demonstrated to be an effective therapy against B cell leukemias and lymphomas in the clinic. Those CAR-expressing T cells (called CAR-Ts) are currently used in an autologous setting, i.e. T cells are isolated from the patient and expanded ex vivo in order to be transduced with the CAR construct and after a few weeks they are reintroduced into the same patient that donated the cells. This approach is time-consuming and not all cancer patients are able to donate sufficient T cells or T cells of sufficient quality, this is critical for blood-borne cancers, as to be subjects of CAR-T therapies. An approximation in which off-the-shelf T cells already expressing the CAR constructs generated from healthy donors offers the advantages of reproducibility, BUSINESS.32999895.1 3397743-013WO (218530) immediate availability and tested efficacy. However, the infusion of CAR-T cells generated from a HLA unmatched donor is confronted with severe graft-versus-host (GvHD) effect in which the donor’s T cells recognize the HLA haplotypes of the patient’s organs and attack them resulting in a fatal disease (Br J Haematol.195, 660–668 (2021)). This reaction is mediated by the recognition of alloantigens by the TCR expressed by the CAR-T cells, not by the CAR itself. Therefore, an approach to reduce GvHD during CAR-T therapies using mismatched blood donors is to genetically downregulate the expression of the endogenous TCR of the donor’s CAR-T cells. However, such approach is confronted with the technical difficulty of targeting the TCR of every CAR-T cell and also with the incapacity to resolve a second problem of CAR-T therapies with allogeneic T cells: the fact that the patient’s T cells can also recognize the donor’s T cells as foreign and destroy them, making the therapy less effective.

[0018] It has been found that the chromene derivatives as described herein can inhibit TCR-Nck interactions and human T cell alloresponses, without affecting the activity of the CAR in CAR-T cells. As shown in the example, compound A-68 inhibits TCR-mediated T cell activation, both in response to anti-CD3 antibodies and in response to human cells with unmatched HLA, and did not affect the activity of a CD19-specific CAR construct expressed in primary human T cells in terms of inducing cytokine production, T cell proliferation and target cell killing. Accordingly, the chromene derivatives as described herein may prevent or reduce autoimmune reactions associated with CAR-T therapies (e.g., an alloresponse associated with an allogeneic CAR-T therapy) in a patient, and increase or improve CAR-T therapy effectiveness.

[0019] In one aspect, the present disclosure provides a method for treating a disease or disorderin a patient, comprising administering a therapeutically effective amount of a chromene derivativeas described herein, and a therapeutically effective amount of a CAR-T therapy to the patient.

[0020] In another aspect, the present disclosure provides a use of a therapeutically effectiveamount of a chromene derivative as described herein, and a therapeutically effective amount of aCAR-T therapy, for treating a disease or disorder in a patient.

[0021] In another aspect, the present disclosure provides a use of a therapeutically effectiveamount of a chromene derivative as described herein for the manufacture of a medicament for treating a disease or disorder in a patient, in combination with a therapeutically effective amount of a CAR-T therapy. BUSINESS.32999895.1 4397743-013WO (218530)

[0022] In some embodiments, a chromene derivative as described herein prevents or reducesan autoimmune reaction associated with a CAR-T therapy in a patient. In some embodiments, a chromene derivative as described herein prevents or reduces a patient’s autoimmune reaction to a CAR-T therapy. In some embodiments, a chromene derivative as described herein prevents or reduces a CAR-T therapy’s autoimmune reaction to a patient.

[0023] In some embodiments, a chromene derivative as described herein inhibits T cellactivation mediated by TCR in a patient, wherein the patient receives a CAR-T therapy. In some embodiments, a chromene derivative as described herein inhibits T cell activation mediated by TCR in a patient, wherein the patient receives a CAR-T therapy, without substantially affecting T cell activation mediated by the CAR of the CAR-T therapy.

[0024] In some embodiments, a chromene derivative as described herein inhibits cytokine (e.g.,IFNγ, IL-2, etc.) release mediated by TCR in a patient, wherein the patient receives a CAR-T therapy. In some embodiments, a chromene derivative as described herein inhibits cytokine (e.g., IFNγ, IL-2, etc.) release mediated by TCR in a patient, wherein the patient receives a CAR-T therapy, without substantially affecting cytokine (e.g., IFNγ, IL-2, etc.) release mediated by the CAR of the CAR-T therapy.

[0025] In some embodiments, a chromene derivative as described herein inhibits T cellproliferation and / or T cell efficiency in killing target cells mediated by TCR in a patient, wherein the patient receives a CAR-T therapy. In some embodiments, a chromene derivative as described herein inhibits T cell proliferation and / or T cell efficiency in killing target cells mediated by TCR in a patient, wherein the patient receives a CAR-T therapy, without substantially affecting T cell proliferation and / or T cell efficiency in killing target cells mediated by the CAR of the CAR-T therapy.

[0026] In some embodiments, a chromene derivative as described herein inhibitsphosphorylation of CD3ζ and / or ERK kinase mediated by TCR in a patient, wherein the patient receives a CAR-T therapy. In some embodiments, a chromene derivative as described herein inhibits phosphorylation of CD3ζ and / or ERK kinase mediated by TCR in a patient, wherein the patient receives a CAR-T therapy, without substantially affecting phosphorylation of CD3ζ and / or ERK kinase mediated by the CAR of the CAR-T therapy.

[0027] In another aspect, the present disclosure provides a method for preparing a CAR-Ttherapy, comprising adding a therapeutically effective amount of a chromene derivative as BUSINESS.32999895.1 5397743-013WO (218530) described herein in the CAR-T therapy. Without being bound by any specific theory, a chromene derivative as described herein inhibits TCR mediated T cell activation, differentiation, exhaustion and apoptosis, and may increase or improves CAR-T cell product quality, yield, and potency.

[0028] In another aspect, the present disclosure provides a composition comprising atherapeutically effective amount of a chromene derivative as described herein and a CAR-T therapy. 2. Definitions

[0029] Compounds of the present invention include those described generally herein, and arefurther illustrated by the classes, subclasses, and species disclosed herein. As used herein, the following definitions shall apply unless otherwise indicated. For purposes of this invention, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75thEd. Additionally, general principles of organic chemistry are described in Organic Chemistry, Thomas Sorrell, University Science Books, Sausalito: 1999, and March’s Advanced Organic Chemistry, 5thEd., Ed.: Smith, M.B. and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are hereby incorporated by reference.

[0030] The term “aliphatic” or “aliphatic group”, as used herein, means a straight-chain (i.e.unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation, or a monocyclic hydrocarbon or bicyclic hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic (also referred to herein as "carbocycle," “cycloaliphatic” or “cycloalkyl”), that has a single point of attachment to the rest of the molecule. Unless otherwise specified, aliphatic groups contain 1-6 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-5 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-4 aliphatic carbon atoms. In still other embodiments, aliphatic groups contain 1-3 aliphatic carbon atoms, and in yet other embodiments, aliphatic groups contain 1-2 aliphatic carbon atoms. In some embodiments, “cycloaliphatic” (or “carbocycle” or “cycloalkyl”) refers to a monocyclic C3-C6 hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, that has a single point of attachment to the rest of the molecule. Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted BUSINESS.32999895.1 6397743-013WO (218530) alkyl, alkenyl, alkynyl groups and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.

[0031] As used herein, the term “bicyclic ring” or “bicyclic ring system” refers to any bicyclicring system, i.e. carbocyclic or heterocyclic, saturated or having one or more units of unsaturation, having one or more atoms in common between the two rings of the ring system. Thus, the term includes any permissible ring fusion, such as ortho-fused or spirocyclic. As used herein, the term “heterobicyclic” is a subset of “bicyclic” that requires that one or more heteroatoms are present in one or both rings of the bicycle. Such heteroatoms may be present at ring junctions and are optionally substituted, and may be selected from nitrogen (including N-oxides), oxygen, sulfur (including oxidized forms such as sulfones and sulfonates), phosphorus (including oxidized forms such as phosphates), boron, etc. In some embodiments, a bicyclic group has 7-12 ring members and 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. As used herein, the term “bridged bicyclic” refers to any bicyclic ring system, i.e. carbocyclic or heterocyclic, saturated or partially unsaturated, having at least one bridge. As defined by IUPAC, a “bridge” is an unbranched chain of atoms or an atom or a valence bond connecting two bridgeheads, where a “bridgehead” is any skeletal atom of the ring system which is bonded to three or more skeletal atoms (excluding hydrogen). In some embodiments, a bridged bicyclic group has 7-12 ring members and 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Such bridged bicyclic groups are well-known in the art and include those groups set forth below where each group is attached to the rest of the molecule at any substitutable carbon or nitrogen atom. Unless otherwise specified, a bridged bicyclic group is optionally substituted with one or more substituents as set forth for aliphatic groups. Additionally or alternatively, any substitutable nitrogen of a bridged bicyclic group is optionally substituted. Exemplary bicyclic rings include:BUSINESS.32999895.1 7397743-013WO (218530)[ larylower alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl.

[0033] The term “lower haloalkyl” refers to a C1-4 straight or branched alkyl group that issubstituted with one or more halogen atoms.

[0034] The term “heteroatom” means one or more of oxygen, sulfur, nitrogen, phosphorus, orsilicon (including, any oxidized form of nitrogen, sulfur, phosphorus, or silicon; the quaternized form of any basic nitrogen or; a substitutable nitrogen of a heterocyclic ring, for example N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR+(as in N-substituted pyrrolidinyl)).

[0035] The term "unsaturated," as used herein, means that a moiety has one or more units ofunsaturation.

[0036] As used herein, the term “bivalent C1-4 (or C1-6) saturated or unsaturated, straight orbranched, hydrocarbon chain”, refers to bivalent alkylene, alkenylene, and alkynylene chains that are straight or branched as defined herein.

[0037] The term “alkylene” refers to a bivalent alkyl group. An “alkylene chain” is apolymethylene group, i.e., –(CH2)n–, wherein n is a positive integer, preferably from 1 to 6, from 1 to 4, from 1 to 3, from 1 to 2, or from 2 to 3. A substituted alkylene chain is a polymethylene group in which one or more methylene hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for a substituted aliphatic group.

[0038] The term “alkenylene” refers to a bivalent alkenyl group. A substituted alkenylenechain is a polymethylene group containing at least one double bond in which one or more hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for a substituted aliphatic group. BUSINESS.32999895.1 8397743-013WO (218530)

[0039] As used herein, the term “cyclopropylenyl” refers to a bivalent cyclopropyl group of thefollowing structure: .

[0040] The term n” means F, Cl, Br, or I.

[0041] The term “aryl” used alone or as part of a larger moiety as in “aralkyl,” “aralkoxy,” or“aryloxyalkyl,” refers to monocyclic or bicyclic ring systems having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic and wherein each ring in the system contains 3 to 7 ring members. The term “aryl” may be used interchangeably with the term “aryl ring.” In certain embodiments of the present invention, “aryl” refers to an aromatic ring system which includes, but not limited to, phenyl, biphenyl, naphthyl, anthracyl and the like, which may bear one or more substituents. Also included within the scope of the term “aryl,” as it is used herein, is a group in which an aromatic ring is fused to one or more non–aromatic rings, such as indanyl, phthalimidyl, naphthimidyl, phenanthridinyl, or tetrahydronaphthyl, and the like.

[0042] The terms “heteroaryl” and “heteroar–,” used alone or as part of a larger moiety, e.g.,“heteroaralkyl,” or “heteroaralkoxy,” refer to groups having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms; having 6, 10, or 14 ^ electrons shared in a cyclic array; and having, in addition to carbon atoms, from one to five heteroatoms. The term “heteroatom” refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternized form of a basic nitrogen. Heteroaryl groups include, without limitation, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl. The terms “heteroaryl” and “heteroar–”, as used herein, also include groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclyl rings, where the radical or point of attachment is on the heteroaromatic ring. Nonlimiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H–quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido[2,3–b]–1,4–oxazin–3(4H)–one. A heteroaryl group may be mono– or bicyclic. The term “heteroaryl” may be used interchangeably with the terms “heteroaryl ring,” “heteroaryl group,” or “heteroaromatic,” any of which terms include rings that are optionally BUSINESS.32999895.1 9397743-013WO (218530) substituted. The term “heteroaralkyl” refers to an alkyl group substituted by a heteroaryl, wherein the alkyl and heteroaryl portions independently are optionally substituted.

[0043] As used herein, the terms “heterocycle,” “heterocyclyl,” “heterocyclic radical,” and“heterocyclic ring” are used interchangeably and refer to a stable 5– to 7–membered monocyclic or 7–10–membered bicyclic heterocyclic moiety that is either saturated or partially unsaturated, and having, in addition to carbon atoms, one or more, preferably one to four, heteroatoms, as defined above. When used in reference to a ring atom of a heterocycle, the term "nitrogen" includes a substituted nitrogen. As an example, in a saturated or partially unsaturated ring having 0–3 heteroatoms selected from oxygen, sulfur or nitrogen, the nitrogen may be N (as in 3,4– dihydro–2H–pyrrolyl), NH (as in pyrrolidinyl), or+NR (as in N–substituted pyrrolidinyl).

[0044] A heterocyclic ring can be attached to its pendant group at any heteroatom or carbonatom that results in a stable structure and any of the ring atoms can be optionally substituted. Examples of such saturated or partially unsaturated heterocyclic radicals include, without limitation, tetrahydrofuranyl, tetrahydrothiophenyl pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl. The terms “heterocycle,” “heterocyclyl,” “heterocyclyl ring,” “heterocyclic group,” “heterocyclic moiety,” and “heterocyclic radical,” are used interchangeably herein, and also include groups in which a heterocyclyl ring is fused to one or more aryl, heteroaryl, or cycloaliphatic rings, such as indolinyl, 3H–indolyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl. A heterocyclyl group may be mono– or bicyclic. The term “heterocyclylalkyl” refers to an alkyl group substituted by a heterocyclyl, wherein the alkyl and heterocyclyl portions independently are optionally substituted.

[0045] As used herein, the term “partially unsaturated” refers to a ring moiety that includes atleast one double or triple bond. The term “partially unsaturated” is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aryl or heteroaryl moieties, as herein defined.

[0046] As described herein, compounds of the invention may contain “optionally substituted”moieties. In general, the term “substituted,” whether preceded by the term “optionally” or not, means that one or more hydrogens of the designated moiety are replaced with a suitable substituent. Unless otherwise indicated, an “optionally substituted” group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure BUSINESS.32999895.1 10397743-013WO (218530) may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position. Combinations of substituents envisioned by this invention are preferably those that result in the formation of stable or chemically feasible compounds. The term “stable,” as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.

[0047] Suitable monovalent substituents on a substitutable carbon atom of an “optionallysubstituted” group are independently halogen; -(CH2)0–4R^; -(CH2)0–4OR^; -O(CH2)0-4Ro, -O- (CH2)0–4C(O)OR°; -(CH2)0–4CH(OR^)2; -(CH2)0–4SR^; -(CH2)0–4Ph, which may be substituted with R°; -(CH2)0–4O(CH2)0–1Ph which may be substituted with R°; -CH=CHPh, which may be substituted with R°; -(CH2)0–4O(CH2)0–1-pyridyl which may be substituted with R°; -NO2; -CN; - N3; -(CH2)0–4N(R^)2; -(CH2)0–4N(R^)C(O)R^; -N(R^)C(S)R^; -(CH2)0–4N(R^)C(O)NR^2; -N(R^)C(S)NR^2; -(CH2)0–4N(R^)C(O)OR^; - N(R^)N(R^)C(O)R^; -N(R^)N(R^)C(O)NR^2; -N(R^)N(R^)C(O)OR^; -(CH2)0–4C(O)R^; -C(S)R^; -(CH2)0–4C(O)OR^; -(CH2)0–4C(O)SR^; -(CH2)0–4C(O)OSiR^3; -(CH2)0–4OC(O)R^; - OC(O)(CH2)0–4SRo; SC(S)SR°; -(CH2)0–4SC(O)R^; -(CH2)0–4C(O)NR^2; -C(S)NR^2; –C(S)SR°; - SC(S)SR°; -(CH2)0–4OC(O)NR^2; -C(O)N(OR^)R^; -C(O)C(O)R^; -C(O)CH2C(O)R^; -C(NOR^)R^; -(CH2)0–4SSR^; -(CH2)0–4S(O)2R^; -(CH2)0–4S(O)2OR^; -(CH2)0–4OS(O)2R^; -S(O)2NR^2; -S(O)(NR^)R^; -S(O)2N=C(NR^2)2; -(CH2)0–4S(O)R^; -N(R^)S(O)2NR^2; - N(R^)S(O)2R^; -N(OR^)R^; -C(NH)NR^2; -P(O)2R^; -P(O)R^2; -OP(O)R^2; -OP(O)(OR^)2; - SiR^3; -(C1–4 straight or branched alkylene)O–N(R^)2; or -(C1–4 straight or branched alkylene)C(O)O–N(R^)2, wherein each R^ may be substituted as defined below and is independently hydrogen, C1–6 aliphatic, -CH2Ph, -O(CH2)0–1Ph, -CH2-(5-6 membered heteroaryl ring), or a 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R^, taken together with their intervening atom(s), form a 3–12– membered saturated, partially unsaturated, or aryl mono– or bicyclic ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which may be substituted as defined below. BUSINESS.32999895.1 11397743-013WO (218530)

[0048] Suitable monovalent substituents on R^ (or the ring formed by taking two independentoccurrences of R^ together with their intervening atoms), are independently halogen, -(CH2)0–2R^; -(haloR^); -(CH2)0–2OH; -(CH2)0–2OR^; -(CH2)0–2CH(OR^)2; -O(haloR^); -CN; -N3; -(CH2)0–2C(O)R^; -(CH2)0–2C(O)OH; -(CH2)0–2C(O)OR^; -(CH2)0–2SR^; -(CH2)0–2SH; -(CH2)0–2NH2; - (CH2)0–2NHR^; -(CH2)0–2NR^2; -NO2, -SiR^3; -OSiR^3; -C(O)SR^; -(C1–4 straight or branched alkylene)C(O)OR^; or -SSR^wherein each R^is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently selected from C1–4 aliphatic, - CH2Ph, –O(CH2)0–1Ph, or a 5–6–membered saturated, partially unsaturated, or aryl ring having 0– 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents on a saturated carbon atom of R^ include =O and =S.

[0049] Suitable divalent substituents on a saturated carbon atom of an “optionally substituted”group include the following: =O; =S; =NNR*2; =NNHC(O)R*; =NNHC(O)OR*; =NNHS(O)2R*; =NR*; =NOR*; -O(C(R*2))2–3O-; or -S(C(R*2))2–3S-; wherein each independent occurrence of R*is selected from hydrogen, C1–6aliphatic which may be substituted as defined below, or an unsubstituted 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents that are bound to vicinal substitutable carbons of an “optionally substituted” group include: -O(CR*2)2–3O- , wherein each independent occurrence of R*is selected from hydrogen, C1–6aliphatic which may be substituted as defined below, or an unsubstituted 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0050] Suitable substituents on the aliphatic group of R* include halogen, -R^; -(haloR^); -OH,-OR^; -O(haloR^); -CN; -C(O)OH; -C(O)OR^; -NH2; -NHR^; -NR^2; or -NO2; wherein each R^is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C1–4 aliphatic, -CH2Ph; -O(CH2)0–1Ph; or a 5–6–membered saturated; partially unsaturated; or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0051] Suitable substituents on a substitutable nitrogen of an “optionally substituted” groupinclude -R†; -NR†2; -C(O)R†; -C(O)OR†; -C(O)C(O)R†; -C(O)CH2C(O)R†; -S(O)2R†; -S(O)2NR†2; -C(S)NR†2; -C(NH)NR†2; or -N(R†)S(O)2R†; wherein each R†is independently hydrogen, C1–6aliphatic which may be substituted as defined below, unsubstituted –OPh, or an unsubstituted 5– BUSINESS.32999895.1 12397743-013WO (218530) 6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R†, taken together with their intervening atom(s) form an unsubstituted 3–12–membered saturated, partially unsaturated, or aryl mono– or bicyclic ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0052] Suitable substituents on the aliphatic group of R† are independently halogen, -R^; -(haloR^); -OH; -OR^; -O(haloR^); -CN; -C(O)OH; -C(O)OR^; -NH2; -NHR^; -NR^2; or -NO2; wherein each R^is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C1–4 aliphatic, -CH2Ph; -O(CH2)0–1Ph; or a 5–6– membered saturated; partially unsaturated; or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0053] As used herein, the term "pharmaceutically acceptable salt" refers to those salts whichare, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well- known in the art. For example, S. M. Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1–19, incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2– hydroxy–ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2–naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3–phenylpropionate, phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p–toluenesulfonate, undecanoate, valerate salts, and the like. BUSINESS.32999895.1 13397743-013WO (218530)

[0054] Salts derived from appropriate bases include alkali metal, alkaline earth metal,ammonium and N+(C1–4alkyl)4 salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and aryl sulfonate.

[0055] Unless otherwise stated, structures depicted herein are also meant to include all isomeric(e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations for each asymmetric center, Z and E double bond isomers, and Z and E conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the invention. Unless otherwise stated, all tautomeric forms of the compounds of the invention are within the scope of the invention. Additionally, unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures including the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a13C- or14C-enriched carbon are within the scope of this invention. Such compounds are useful, for example, as analytical tools, as probes in biological assays, or as therapeutic agents in accordance with the present invention.

[0056] As used herein, the term “provided compound” or “compound of the invention” refersto a chromene derivative as described herein, and the term “provided composition” or “composition of the invention” refers to a pharmaceutical composition comprising a chromene derivative as described herein.

[0057] As used herein, the term “inhibitor” is defined as a compound that binds to and / orinhibits a target protein or receptor (e.g., TCR) with measurable affinity. In some embodiments, a chromene derivative as described herein is an inhibitor of TCR-Nck interaction in T-cells. In certain embodiments, an inhibitor has an IC50and / or binding constant of less than about 100 ^M, less than about 50 ^M, less than about 1 ^M, less than about 500 nM, less than about 100 nM, less than about 10 nM, or less than about 1 nM.

[0058] The terms “measurable affinity” and “measurably inhibit,” as used herein, means ameasurable change in a target protein or receptor activity (e.g., TCR activity or TCR-Nck BUSINESS.32999895.1 14397743-013WO (218530) interaction in T-cells) between a sample comprising an inhibitor (e.g., a chromene derivative as described herein), or a composition thereof, and said target protein or receptor, and an equivalent sample comprising said target protein or receptor in the absence of said inhibitor, or a composition thereof.

[0059] The term “modulate” and “modulating,” as used herein, means to influence or alter theactivity. Modulation comprises stabilization, destabilization, enhancement, and suppression.

[0060] As used herein, the terms “about” or “approximately” have the meaning of within 20%of a given value or range. In some embodiments, the term “about” refers to within 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% of a given value. 3. Description of Exemplary Methods and Uses

[0061] In one aspect, the present disclosure provides a method for treating a disease or disorderin a patient, comprising administering a therapeutically effective amount of a chromene derivativeas described herein, and a therapeutically effective amount of a CAR-T therapy to the patient.

[0062] In another aspect, the present disclosure provides a method for preventing or reducingan autoimmune reaction associated with a CAR-T therapy in a patient, comprising administeringto the patient a therapeutically effective amount of a chromene derivative as described herein, incombination with the CAR-T therapy.

[0063] In another aspect, the present disclosure provides a method for increasing or improvinga CAR-T therapy effectiveness, comprising administering to the patient a therapeutically effectiveamount of a chromene derivative as described herein, in combination with the CAR-T therapy.

[0064] In another aspect, the present disclosure provides a method for inhibiting T cellactivation mediated by TCR in a patient, comprising administering a therapeutically effective amount of a chromene derivative to the patient, wherein the patient receives a CAR-T therapy. In some embodiments, the present disclosure provides a method for inhibiting cytokine (e.g., IFNγ, IL-2, etc.) release mediated by TCR in a patient, comprising administering a therapeutically effective amount of a chromene derivative to the patient, wherein the patient receives a CAR-T therapy. In some embodiments, the present disclosure provides a method for inhibiting T cell proliferation and / or T cell efficiency in killing target cells mediated by TCR in a patient, comprising administering a therapeutically effective amount of a chromene derivative to the BUSINESS.32999895.1 15397743-013WO (218530) patient, wherein the patient receives a CAR-T therapy. In some embodiments, the present disclosure provides a method for inhibiting phosphorylation of CD3ζ and / or ERK kinase mediated by TCR in a patient, comprising administering a therapeutically effective amount of a chromene derivative to the patient, wherein the patient receives a CAR-T therapy.

[0065] In some embodiments, a chromene derivative inhibits T cell activation mediated byTCR in a patient, wherein the patient receives a CAR-T therapy, without substantially affecting T cell activation mediated by the CAR of the CAR-T therapy. In some embodiments, a chromene derivative inhibits cytokine (e.g., IFNγ, IL-2, etc.) release mediated by TCR in a patient, wherein the patient receives a CAR-T therapy, without substantially affecting cytokine (e.g., IFNγ, IL-2, etc.) release mediated by the CAR of the CAR-T therapy. In some embodiments, a chromene derivative inhibits T cell proliferation and / or T cell efficiency in killing target cells mediated by TCR in a patient, wherein the patient receives a CAR-T therapy, without substantially affecting T cell proliferation and / or T cell efficiency in killing target cells mediated by the CAR of the CAR- T therapy. In some embodiments, a chromene derivative inhibits phosphorylation of CD3ζ and / or ERK kinase mediated by TCR in a patient, wherein the patient receives a CAR-T therapy, without substantially affecting phosphorylation of CD3ζ and / or ERK kinase mediated by the CAR of the CAR-T therapy.

[0066] In another aspect, the present disclosure provides a method for preparing a CAR-Ttherapy, comprising adding a therapeutically effective amount of a chromene derivative as described herein in the CAR-T therapy.

[0067] In another aspect, the present disclosure provides a composition comprising atherapeutically effective amount of a chromene derivative as described herein and a CAR-T therapy.

[0068] In some embodiments, a chromene derivative is selected from the chromene derivativesas described herein. In some embodiments, a chromene derivative is A-33, or a pharmaceutically acceptable salt thereof.BUSINESS.32999895.1 16397743-013WO (218530)

[0069] In certain embodiments, a disease or disorder is selected from the diseases, disorders, andconditions as described in WO 2019 / 169001, the contents of which are herein incorporated by reference in their entireties.

[0070] In some embodiments, a disease or disorder is selected from the proliferative diseasesand cancers as described herein. In some embodiments, a disease or disorder is selected from the group consisting of Acute lymphoblastic leukemia (ALL), B-cell lymphoma, Follicular lymphoma (FL), Mantle cell lymphoma, and Multiple myeloma.

[0071] In some embodiments, a B-cell lymphoma is Diffuse large B cell lymphoma (DLBCL),including DLBCL arising from indolent lymphoma. In some embodiments, a B-cell lymphoma is High-grade B-cell lymphoma. In some embodiments, a B-cell lymphoma is Primary mediastinal large B-cell lymphoma. In some embodiments, a B-cell lymphoma is Follicular lymphoma. In some embodiments, a B-cell lymphoma is DLBCL that results from follicular lymphoma.

[0072] In some embodiments, a CAR-T therapy is selected from those as described herein. Insome embodiments, a CAR-T therapy is selected from the group consisting of BREYANZI® (lisocabtagene maraleucel), TECARTUS™ (brexucabtagene autoleucel), KYMRIAH™ (tisagenlecleucel), YESCARTA™ (axicabtagene ciloleucel), ABECMA® (idecabtagene vicleucel), or CARVYKTI™ (ciltacabtagene autoleucel).

[0073] In some embodiments, a CAR-T therapy is an allogeneic CAR-T therapy, i.e., T cellsof the CAR-T therapy is allogeneic to the patient. In some embodiments, a CAR-T therapy is an autologous CAR-T therapy, i.e., T cells of the CAR-T therapy is autologous to the patient.

[0074] In one aspect, the present disclosure provides a method for treating Acute lymphoblasticleukemia (ALL) and / or B-cell lymphomain a patient, comprising administering a therapeuticallyeffective amount of a chromene derivative compound A-33, or a pharmaceutically acceptable saltthereof, and a therapeutically effective amount of a CAR-T therapy KYMRIAH™ (tisagenlecleucel) to the patient.

[0075] In one aspect, the present disclosure provides a method for treating B-cell lymphomaand / or Follicular lymphoma (FL) in a patient, comprising administering a therapeutically effectiveamount of a chromene derivative compound A-33, or a pharmaceutically acceptable salt thereof,and a therapeutically effective amount of a CAR-T therapy YESCARTA™ (axicabtagene ciloleucel) to the patient. BUSINESS.32999895.1 17397743-013WO (218530)

[0076] In one aspect, the present disclosure provides a method for treating B-cell lymphoma ina patient, comprising administering a therapeutically effective amount of a chromene derivativecompound A-33, or a pharmaceutically acceptable salt thereof, and a therapeutically effectiveamount of a CAR-T therapy and BREYANZI® (lisocabtagene maraleucel) to the patient.

[0077] In one aspect, the present disclosure provides a method for treating Mantle celllymphoma in a patient, comprising administering a therapeutically effective amount of a chromenederivative compound A-33, or a pharmaceutically acceptable salt thereof, and a therapeuticallyeffective amount of a CAR-T therapy TECARTUS™ (brexucabtagene autoleucel) to the patient.

[0078] In one aspect, the present disclosure provides a method for treating Multiple myelomain a patient, comprising administering a therapeutically effective amount of a chromene derivativecompound A-33, or a pharmaceutically acceptable salt thereof, and a therapeutically effectiveamount of a CAR-T therapy ABECMA® (idecabtagene vicleucel) to the patient.

[0079] In one aspect, the present disclosure provides a method for treating Multiple myelomain a patient, comprising administering a therapeutically effective amount of a chromene derivativecompound A-33, or a pharmaceutically acceptable salt thereof, and a therapeutically effectiveamount of a CAR-T therapy CARVYKTI™ (ciltacabtagene autoleucel) to the patient. I. Exemplary Chromene Derivatives

[0080] In certain embodiments, a chromene derivative is selected from those as described inWO 2019 / 169001, WO 2015 / 056086, WO 2015 / 056085, WO 2012 / 042078, and WO 2010 / 000900, the contents of each of which are herein incorporated by reference in their entireties. In certain embodiments, a chromene derivative is selected from those described in U.S. Patent 10,696,663, U.S. Patent 11,008,310, and U.S. Patent 11,807,633, U.S. Patent 10,106,518, U.S. Patent 10,131,647, U.S. Patent 9,120,764, and U.S. Patent 8,614,231, the contents of which are herein incorporated by reference in their entirety. Chromene Derivatives of Formula A-I

[0081] In certain embodiments, a chromene derivative is a compound of Formula A-I:BUSINESS.32999895.1 18397743-013WO (218530) or a pharmaceutically acceptable sR1is R, halogen, -CN, -OR, or -N(R)2; R2is R, halogen, -C(O)N(R)2, or -N(R)2; R3is hydrogen or an electron withdrawing group; each R is independently hydrogen or an optionally substituted group selected from C1-6aliphatic, a 3-8 member saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or two R groups on the same nitrogen are taken together with their intervening atoms to form an optionally substituted 5-6 membered heterocyclic ring having 0-1 heteroatoms in addition to the nitrogen attached thereto wherein such heteroatom is oxygen, nitrogen, or sulfur; L1is a covalent bond or a C1-4bivalent straight or branched saturated or unsaturated hydrocarbon chain wherein 1-2 methylene units of the chain are independently and optionally replaced with -O-, -C(O)-, -C(O)O-, -OC(O)-, -C(S)-, -C(R)2-, -C(F)2-, -N(R)-, -C(O)N(R)-, -RNC(O)-, - OC(O)N(R)-, -N(R)C(O)N(R) -, or -Cy-; L2is a covalent bond or a C1-4bivalent straight or branched saturated or unsaturated hydrocarbon chain wherein 1-2 methylene units of the chain are independently and optionally replaced with -O-, -C(O)-, -C(O)O-, -OC(O)-, -C(S)-, -C(R)2-, -CH(R)-, -C(F)2-, -N(R)-, -C(O)N(R)-, - RNC(O)-, -OC(O)N(R)-, or -N(R)C(O)N(R) -; and Cy is a bivalent optionally substituted 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, optionally substituted phenylene, an optionally substituted 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-3 heteroatoms BUSINESS.32999895.1 19397743-013WO (218530) independently selected from nitrogen, oxygen, or sulfur, an optionally substituted 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0082] In some embodiments, a chromene derivative is a compound of Formula A-I whereinsaid compound is other than: ,,BUSINESS.32999895.1 20397743-013WO (218530) ,,BUSINESS.32999895.1 21397743-013WO (218530) 17 18 ,,BUSINESS.32999895.1 22397743-013WO (218530) 27.

[0083] In some embodiments, a chromene derivative is a compound of Formula A-I whereinsaid compound is other than: ,BUSINESS.32999895.1 23397743-013WO (218530) , , ,BUSINESS.32999895.1 24397743-013WO (218530) 43 44 ,

[0084] , , , , , 2.

[0085] In some embodiments, R1 is hydrogen.

[0086] In some embodiments, R1 is halogen or -CN.

[0087] In some embodiments, R1 is R, -OR, or -N(R)2.BUSINESS.32999895.1 25397743-013WO (218530)

[0088] In some embodiments R1 is -CH3 -CD3 -CH(CH3)2 or .

[0089] In some embodiments R1 is or .

[0090] In some embodiments nts, R is optionally substituted C1-6aliphatic. In some embodiments, R is optionally substituted C1-6alkyl. In some embodiments, R is C1-6alkyl optionally substituted by halogen or -COOH. In some embodiments, R is C1-6alkyl substituted 1-6 times by halogen. In some embodiments, R is C1-6 alkyl substituted 1 time by - COOH.

[0091] In some embodiments .

[0092] In some embodiments .

[0093] In some embodiments .

[0094] In some embodimentsor, , .

[0097] As defined above and described herein, R2 is R, halogen, -C(O)N(R)2, or -N(R)2.

[0098] In some embodiments, R2 is hydrogen.

[0099] In some embodiments, R2 is R.

[0100] In some embodiments, R2 is halogen.

[0101] In some embodiments, R2 is -C(O)N(R)2, or -N(R)2.BUSINESS.32999895.1 26397743-013WO (218530)

[0102] In some embodiments, R2 is -C(O)N(R)2, or -N(R)2 wherein each R is independentlyhydrogen or an optionally substituted group selected from C1-6 aliphatic, a 3-8 member saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0103] In some embodiments, R2 is -C(O)N(R)2, or -N(R)2 wherein the two R groups on thenitrogen are taken together with their intervening atoms to form an optionally substituted 5-6 membered heterocyclic ring having 0-1 heteroatoms in addition to the nitrogen attached thereto wherein such heteroatom is oxygen, nitrogen, or sulfur.

[0104] In some embodiments, R2 is -N(R)2 wherein the two R groups on the nitrogen are takentogether with their intervening atoms to form a 5-6 membered heterocyclic ring having no heteroatom in addition to the nitrogen attached thereto, and wherein such 5-6 membered heterocyclic ring is optionally substituted 1-6 times by C1-3aliphatic or halogen.

[0105] In some embodiments, R2 is -NCH2CH3 or -N(CH2)2N(CH3)2.

[0106] In some embodiments .

[0107] In some embodiments R2 i .

[0108] In some embodiments .

[0109] In some embodiments .

[0110] In some embodiments, se depicted in Table 1, below.

[0111] As defined above and described herein, R3 is hydrogen or an electron withdrawinggroup.

[0112] In some embodiments, R3 is hydrogen.

[0113] In other embodiments, R3 is an electron withdrawing group. Electron withdrawinggroups are well-known to one of ordinary skill in the art and include those described in detail in BUSINESS.32999895.1 27397743-013WO (218530) March’s Advanced Organic Chemistry, 5thEd., Ed.: Smith, M.B. and March, J., John Wiley & Sons, New York: 2001.

[0114] In some embodiments, R3 is an electron withdrawing group selected from halogen, -CN, -NO2, or C1-4aliphatic substituted with 1-9 halogens.

[0115] In some embodiments, R3 is halogen.

[0116] In some embodiments, R3 is fluoro, chloro, or bromo.

[0117] In some embodiments, R3 is fluoro.

[0118] In some embodiments, R3 is selected fro .

[0119] In some embodiments .

[0120] In some embodimentsd from those depicted in Table 1, below.

[0121] As defined above and described herein, R is independently hydrogen or an optionallysubstituted group selected from C1-6 aliphatic, a 3-8 member saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or two R groups on the same nitrogen are taken together with their intervening atoms to form an optionally substituted 5-6 membered heterocyclic ring having 0-1 heteroatoms in addition to the nitrogen attached thereto wherein such heteroatom is oxygen, nitrogen, or sulfur.

[0122] In some embodiments R is selected from those depicted in Table 1, below.

[0123] As defined above and described herein, L1 is a covalent bond or a C1-4 bivalent straightor branched saturated or unsaturated hydrocarbon chain wherein 1-2 methylene units of the chain are independently and optionally replaced with -O-, -C(O)-, -C(O)O-, -OC(O)-, -C(S)-, -C(R)2-, - C(F)2-, -N(R)-, -C(O)N(R)-, -RNC(O)-, -OC(O)N(R)-, -N(R)C(O)N(R) -, or -Cy-.

[0124] In some embodiments, L1 is a covenant bond.

[0125] In some embodiments, L1 is a C1-4 bivalent straight or branched saturated or unsaturatedhydrocarbon chain wherein 1-2 methylene units of the chain are independently and optionally BUSINESS.32999895.1 28397743-013WO (218530) replaced with -O-, -C(O)-, -C(O)O-, -OC(O)-, -C(S)-, -C(R)2-, -C(F)2-, -N(R)-, -C(O)N(R)-, - RNC(O)-, -OC(O)N(R)-, or -N(R)C(O)N(R) -.

[0126] In some embodiments, L1 is a C1-4 bivalent straight or branched saturated or unsaturatedhydrocarbon chain wherein 1-2 methylene units of the chain are independently and optionally replaced with -O-, -C(R)2-, -C(O)N(R)-, or -RNC(O)-.

[0127] In some embodiments, L1 is a C1-4 bivalent straight saturated or unsaturated hydrocarbonchain wherein 1-2 methylene units of the chain are independently and optionally replaced with - O-, -C(R)2-, -C(O)N(R)-, or -RNC(O)-.

[0128] In some embodiments, L1 is a C1-4 bivalent branched saturated or unsaturatedhydrocarbon chain wherein 1-2 methylene units of the chain are independently and optionally replaced with -O-, -C(R)2-, -C(O)N(R)-, or -RNC(O)-.

[0129] In some embodiments, L1 is -O-.

[0130] In some embodiments .or

[0133] As defined above and described herein, L2 is a covalent bond or a C1-4 bivalent straightor branched saturated or unsaturated hydrocarbon chain wherein 1-2 methylene units of the chain are independently and optionally replaced with -O-, -C(O)-, -C(O)O-, -OC(O)-, -C(S)-, -C(R)2-, - CH(R)-, -C(F)2-, -N(R)-, -C(O)N(R)-, -RNC(O)-, -OC(O)N(R)-, or -N(R)C(O)N(R) -.

[0134] In some embodiments, L2 is a covalent bond.

[0135] In other embodiments, L2 is a C1-4 bivalent straight or branched saturated or unsaturatedhydrocarbon chain wherein 1-2 methylene units of the chain are independently and optionally replaced with -O-, -C(O)-, -C(O)O-, -OC(O)-, -C(S)-, -C(R)2-, -CH(R)-, -C(F)2-, -N(R)-, - C(O)N(R)-, -RNC(O)-, -OC(O)N(R)-, or -N(R)C(O)N(R) -. BUSINESS.32999895.1 29397743-013WO (218530)

[0136] In some embodiments, L2 is a C1-4 bivalent straight or branched saturated or unsaturatedhydrocarbon chain wherein 1 methylene unit of the chain is replaced with -O-, -C(O)-, -C(O)O-, - OC(O)-, -C(R)2-, -C(F)2-, -N(R)-, -C(O)N(R)-, -RNC(O)-.

[0137] In some embodiments, L2 is a C1-4 bivalent straight or branched saturated or unsaturatedhydrocarbon chain.

[0138] In some embodiments, L2 is -C(O)-.

[0139] In some embodiments, L2 is -CH2- or -(CH2)2-.

[0140] In some embodiments L2 is selected from those depicted in Table 1, below.

[0141] As defined generally above, each -Cy- is independently a bivalent optionally substituted3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, optionally substituted phenylene, an optionally substituted 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, an optionally substituted 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, an optionally substituted 8-10 membered bicyclic or bridged bicyclic saturated or partially unsaturated heterocyclic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an optionally substituted 8-10 membered bicyclic or bridged bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0142] In some embodiments, -Cy- is a bivalent optionally substituted 3-8 membered saturatedor partially unsaturated monocyclic carbocyclic ring. In some embodiments, -Cy- is an optionally substituted phenylene. In some embodiments, -Cy- is an optionally substituted 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, -Cy- is an optionally substituted 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, -Cy- is an optionally substituted 8-10 membered bicyclic or bridged bicyclic saturated or partially unsaturated heterocyclic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, -Cy- is an optionally substituted 8-10 membered bicyclic or bridged bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur. BUSINESS.32999895.1 30397743-013WO (218530)

[0143] In some embodiments, .

[0144] In some embodiments, d in Table 1, below.

[0145] In some embodiments,a chromene derivative is a compound of Formula A-II:or a pharmaceutically acceptable ch R1,2 3 1 2R , R , R, L , L , and -Cy- is defined above and described in the embodiments herein, both singly and in combination.

[0146] In some embodiments, a chromene derivative is a compound of Formula A-III:or a pharmaceutically acceptable salt thereof, wherein each R1, R2, R, L1, L2, and -Cy- is defined above and described in the embodiments herein, both singly and in combination.

[0147] Is some embodiments, a chromene derivative is a compound of Formulae A-IV-a, A-IV-b, A-IV-c, or A-IV-d:BUSINESS.32999895.1 31397743-013WO (218530)or a pharmaceutically acceptable salt thereof, wherein each R1, R, and L2, is defined above and described in the embodiments herein, both singly and in combination.

[0148] In some embodiments, a chromene derivative is a compound of Formulae A-V-a, A-V-b, A-V-c, or A-V-d: or a pharmaceutic, is defined above and described in the embodiments herein, both singly and in combination.

[0149] In some embodiments, a chromene derivative is a compound of any of Formulae A-VI-a, A-VI-b, A-VI-c, and A-VI-d: BUSINESS.32999895.1 32397743-013WO (218530) or a pharmaceuticis defined above and described in the embodiments herein, both singly and in combination.

[0150] In some embodiments, a chromene derivative is a compound of Formula A-VII:or a pharmaceutically acceptable salt thereof, wherein each R1, R2, R3, R, and L2, is defined above and described in the embodiments herein, both singly and in combination.

[0151] In some embodiments, a chromene derivative is a compound of Formula A-VIII:- BUSINESS.32999895.1 33397743-013WO (218530) or a pharmaceutically acceptable salt thereof, wherein each R2, R3, L1, and L2, is defined above and described in the embodiments herein, both singly and in combination.

[0152] In some embodiments, a chromene derivative is a compound of Formula A-IX:or a pharmaceutically acceptable salt thereof, wherein each R2, R3, and L2, is defined above and described in the embodiments herein, both singly and in combination.

[0153] In some embodiments, a chromene derivative is a compound of Formula A-X:or a pharmaceutically acceptable, R2, R3, and L1, is defined above and described in the embodiments herein, both singly and in combination.

[0154] In some embodiments, a chromene derivative is a compound of Formulae A-XI-a orXI-b:or a pharmaceutically acceptable salt thereof, wherein each R, R2, R3, and L1, is defined above and described in the embodiments herein, both singly and in combination. BUSINESS.32999895.1 34397743-013WO (218530)

[0155] In some embodiments, a chromene derivative is a compound of Formula A-XII:or a pharmaceutically acceptable salt thereof, wherein each R2, R3, L1and L2, is defined above and described in the embodiments herein, both singly and in combination.

[0156] In some embodiments, a chromene derivative is a compound of Formula A-XIII:or a pharmaceutically acceptable1 2 3 2R , R , R , and L , is defined above and described in the embodiments herein, both singly and in combination.

[0157] Exemplary compounds of Formula A-I are set forth in Table 1, below.Table 1. Exemplary Compounds ,BUSINESS.32999895.1 35397743-013WO (218530)BUSINESS.32999895.1 36397743-013WO (218530) A-11 A-12 ,,,,BUSINESS.32999895.1 37397743-013WO (218530) ,,,,BUSINESS.32999895.1 38397743-013WO (218530) A-29 A-30 ,,,BUSINESS.32999895.1 39397743-013WO (218530) ,,BUSINESS.32999895.1 40397743-013WO (218530) A-47 A-48 , , ,BUSINESS.32999895.1 41397743-013WO (218530) ,,BUSINESS.32999895.1 42397743-013WO (218530) ,,,BUSINESS.32999895.1 43397743-013WO (218530) ,,,,BUSINESS.32999895.1 44397743-013WO (218530) or

[0158] In some embodiments, a chromene derivative is a compound set forth in Table 1, above,or a pharmaceutically acceptable salt thereof.

[0159] In certain embodiments, a chromene derivativA-33, or a pharmaceutically acceptable salt thereof.

[0160] In certain embodiments, a chromene derivativ A-68, or a pharmaceutically acceptable salt thereof.Chromene Derivatives of Formula B-I BUSINESS.32999895.1 45397743-013WO (218530)

[0161] In certain embodiments, a chromene derivative is a compound of Formula B-I:or a pharmaceutically acceptable s reof wherein:R1is selected from hydrogen, substituted or not substituted C1-C6alkyl, substituted or not substituted C3-C8cycloalkyl, substituted or not substituted aryl or substituted or not substituted heteroaryl, —COR5, —C(O)OR5, —C(O)NR5R6, —CNR5; X is selected from —OH or —NR2R3; R2and R3are independently selected from hydrogen, substituted or not substituted C1-C6alkyl, substituted or not substituted C3-C6 cycloalkyl, substituted or not substituted aryl, substituted or not substituted heteroaryl, —COR7, —C(O)OR7, —C(O)NR7R8, —CNR7, —OR7, —NR7R8and —NR7C(O)R8; or R2and R3form, together with the nitrogen atom they are bound to, a substituted or not substituted heterocycle; R4 is halogen; and R5, R6, R7and R8are independently selected from hydrogen, C1-C4alkyl, C3-C6cycloalkyl, aryl, heteroaryl and halogen.

[0162] In certain embodiments, a chromene derivative is a compound of Formula B-II:or a pharmaceutically acceptable, eof wherein: R1 is selected from hydrogen, substituted or not substituted C1-C6 alkyl, substituted or not substituted C3-C6 cycloalkyl, substituted or not substituted aryl or substituted or not substituted heteroaryl, —COR5, —C(O)OR5, —C(O)NR5R6, —CNR5; BUSINESS.32999895.1 46397743-013WO (218530) R2and R3are independently selected from hydrogen, substituted or not substituted C1-C6alkyl, substituted or not substituted C3-C6 cycloalkyl, substituted or not substituted aryl, substituted or not substituted heteroaryl, —COR7, —C(O)OR7, —C(O)NR7R8, —CNR7, —OR7, —NR7R8and —NR7C(O)R8; or R2 and R3 form, together with the nitrogen atom they are bound to, a substituted or not substituted heterocycle; R4is halogen; R5, R6, R7 and R8 are independently selected from hydrogen, C1-C4 alkyl, C3-C6 cycloalkyl, aryl, heteroaryl and halogen.

[0163] In some embodiments, a chromene derivative is selected from the group consisting of(4-(4-fluorophenyl)-6-methoxy-2H-chromene-3-yl)(pyrrolidin-1-yl)methanone, B-1; N-ethyl-4- (4-fluorophenyl)-6-methoxy-2H-chromene-3-carboxamide, B-2; (4-(4-fluorophenyl)-6-methox- 2H-chromene-3-yl)(4-methylpiperazin-1-yl)methanone, B-3; N-(2-(dimethylamino)ethyl-4-(4- fluorophenyl)-6-methoxy-2H-chromene-3-carboxamide, B-4; (6-(cyclopropylmethoxy)-4-(4- fluorophenyl)-2H-chromene-3-yl)(pyrrolidin-1-yl)methanone, B-5; 6-(cyclopropylmethoxy)-N- ethyl-4-(4-fluorophenyl)-2H-chromene-3-carboxamide, B-6; (6-(cyclopropylmethoxy)-4-(4- fluorophenyl)-2H-chromene-3-yl)(4-methylpiperazin-1-yl)methanone, B-7; (6- (cyclopropylmethoxy)-4-(4-fluorophenyl)-2H-chromene-3-yl)(pyrrolidin-1-yl)methanone, B-8; 6-(cyclopropylmethoxy)-N-ethyl-4-(4-fluorophenyl)-2H-chromene-3-carboxamide, B-9; (6- (cyclopropylmethoxy)-4-(4-fluorophenyl)-2H-chromene-3-yl)(4-methylpiperazin-1- yl)methanone, B-10; and 6-(cyclopropylmethoxy)-N-(2-(dimethylamino)ethyl)-4-(4- fluorophenyl)-2H-chromene-3-carboxamide, B-11. Chromene Derivatives of Formula C-I

[0164] In certain embodiments, a chromene derivative is a compound of Formula C-I:BUSINESS.32999895.1 47397743-013WO (218530) or a pharmaceutically acceptable salt, isomer or solvate thereof wherein: R1 is selected from hydrogen, substituted or not substituted C1-C6 alkyl, substituted or not substituted C3-C6 cycloalkyl, substituted or not substituted aryl or substituted or not substituted heteroaryl, —COR5, —C(O)OR5, —C(O)NR5R6, —CNR5; R2 and R3 are independently selected from hydrogen, substituted or not substituted C1-C6 alkyl, substituted or not substituted C3-C6 cycloalkyl, substituted or not substituted aryl, substituted or not substituted heteroaryl, —COR7, —O(O)OR7, —C(O)NR7R8, —CNR, —OR7, —NR7R8 and —NR7C(O)R8; or R2 and R3 form, together with the nitrogen atom they are bound to, a substituted or not substituted heterocycle; R4is halogen; R5, R6, R7and R8are independently selected from hydrogen. C1-C4alkyl, C3-C6cycloalkyl, aryl, heteroaryl and halogen; and with the condition that the compound is not 1-((4-(4-fluorophenyl)-6-methoxy-2H-chromene-3- yl)methyl)pyrrolidine.

[0165] In some embodiments, a chromene derivative is selected from the group consisting of4-(4-fluorophenyl)-3-(pyrrolidine-1-ylmethyl)-2H-chromen-6-ol (C-01); 1-((6- (difluoromethoxy)-4-(4-fluorophenyl)-2H-chromen-3-yl)methyl)pyrrolidine (C-02); 1-((4-(4- fluorophenyl)-6-(trifluoromethoxy)-2H-chromen-3-yl)methyl)pyrrolidine (C-03); 1-((6- (cyclopropylmethoxy)-4-(4-fluorophenyl)-2H-chromen-3-yl)methyl)pyrrolidine (C-04); 1-((4-(4- fluorophenyl)-6-methoxy-2H-chromen-3-yl)methyl)-4-methylpiperazine (C-09); N1-((4-(4- fluorophenyl)-6-methoxy-2H-chromen-3-yl)methyl)-N2,N2-dimethylethane-1,2-diamine (C-10); 4-((4-(4-fluorophenyl)-6-methoxy-2H-chromen-3-yl)methyl)morpholine (C-11); N-((4-(4- fluorophenyl)-6-methoxy-2H-chromen-3-yl)methyl)-ethanamine (C-12); 1-((6- (diflueromethoxy)-4-(4-fluorophenyl)-2H-chromen-3-yl)methyl)-4-methylpiperazine (C-17); N1- ((6-(difluoromethoxy)-4-(4-fluorophenyl)-2H-chromen-3-yl)methyl)-N2,N2-dimethylethane-1,2- diamine (C-18); N1-((4-(4-fluorophenyl)-6-(trifluoromethoxy)-2H-chromen-3-yl)methyl)-N2,N2- dimethylethane-1,2-diamine (C-26); 4-((4-(4-fluorophenyl)-6-(trifluoromethoxy)-2H-chromen-3- yl)methyl)morpholine (C-27); N-((4-(4-fluorophenyl)-6-(trifluoromethoxy)-2H-chromen-3- yl)methyl)ethanamine (C-28); 1-((6-(cyclopropylmethoxy)-4-(4-fluorophenyl)-2H-chromen-3- yl)methyl)-4-methylpiperazine (C-33); N1-((6-(cyclopropylmethoxy)-4-(4-fluorophenyl)-2H- chromen-3-yl)methyl)-N2,N2-dimethylethane-1,2-diamine (C-34); 4-((6-(cyclopropylmethoxy)- BUSINESS.32999895.1 48397743-013WO (218530) 4-(4-fluorophenyl)-2H-chromen-3-yl)methyl)morpholine (C-35); and N-((6- (cyclopropylmethoxy)-4-(4-fluorophenyl)-2H-chromen-3-yl)methyl)ethanamine (C-36). Chromene Derivatives of Formula D-I

[0166] In certain embodiments, a chromene derivative is a compound of Formula D-I:or a pharmaceutically acceptable salt, isomer or solvate thereof wherein: each R1 and R3 independently represent hydrogen, C1-4alkyl, C2-4 alkenyl, C2-4alkynyl, hydroxyl, C1-4alkoxyl, C1-4alkoxyC1-4alkyl, haloC1-4alkyl, hydroxyC1-4alkyl, cyanoC1-4alkyl, halogen, —CN, —NO2or Cy2; R2represents hydrogen, C1-4alkyl or Cy2, where C1-4alkyl is optionally substituted by Cy2; Cy1 represents a monocyclic heterocycle of 3 to 7 members or bicyclic from 6 to 11 members, saturated or partially unsaturated which can be joined to the rest of the molecule by any available C or N atom, where Cy1can be optionally merged to a ring of 5 or 6 members carbocyclic or heterocyclic saturated, partly unsaturated or aromatic, where Cy1 can contain from 1 to 4 heteroatoms selected from N, O and S, where one or more atoms of C or S of the ring may be oxidized to form groups CO, SO or SO2, and where Cy1is optionally replaced by one or more R4; each Cy2 independently represents an aromatic ring of 5 to 7 members which can be joined to the rest of the molecule by any C or N available atom, where Cy2can be optionally merged to a ring of 5 or 6 members carbocyclic or heterocyclic saturated, partly unsaturated or aromatic, where Cy2 can contain from 1 to 4 heteroatoms in total selected from N, O and S, where one or more atoms of C or S of the ring can be oxidized to form groups CO, SO or SO2, and where Cy2is optionally replaced by one or more R4; each R4 independently represents, C1-4alkyl, C2-4alkenyl, C2-4alkynyl, hydroxyl, C1-4alkoxyl, C1- 4alkoxyC1-4alkyl, haloC1-4alkyl, hydroxyC1-4alkyl, cyanoC1-4alkyl, halogen, —CN or — NO2; BUSINESS.32999895.1 49397743-013WO (218530) n represents from 0 to 4; and m represents from 0 to 5.

[0167] In some embodiments, a chromene derivative is selected from the group consisting of:BUSINESS.32999895.1 50397743-013WO (218530)Chromene Derivative of Formula E-1

[0168] In some embodiments, a chromene derivative is a compound of formula E-1:or a pharmaceutically acceptable salt thereof. II. Exemplary CAR-T Therapies

[0169] In some embodiments, a CAR-T therapy is BREYANZI® (lisocabtagene maraleucel),TECARTUS™ (brexucabtagene autoleucel), KYMRIAH™ (tisagenlecleucel), YESCARTA™ (axicabtagene ciloleucel), ABECMA® (idecabtagene vicleucel), or CARVYKTI™ (ciltacabtagene autoleucel). In some embodiments, a CAR-T therapy is BREYANZI® (lisocabtagene maraleucel). In some embodiments, a CAR-T therapy is TECARTUS™ (brexucabtagene autoleucel). In some embodiments, a CAR-T therapy is KYMRIAH™ (tisagenlecleucel). In some embodiments, a CAR-T therapy is YESCARTA™ (axicabtagene BUSINESS.32999895.1 51397743-013WO (218530) ciloleucel). In some embodiments, a CAR-T therapy is ABECMA® (idecabtagene vicleucel). In some embodiments, a CAR-T therapy is CARVYKTI™ (ciltacabtagene autoleucel).

[0170] In one embodiment, the T-cell utilized to generate CAR-T therapy is a naive CD4+ T-cell. In another embodiment, the T-cell utilized to generate CAR-T therapy is a naive CD8+T-cell. In another embodiment, the T-cell utilized to generate CAR-T therapy is an effector T-cell. In another embodiment, the T-cell utilized to generate CAR-T therapy is aregulatory T-cell (Treg). In another embodiment, the T-cell utilized to generate CAR-T therapy is a cytotoxic T-cell. In another embodiment, the CAR-T therapy comprise a high proportion of stem cell memory T cells (TSCM).

[0171] In some embodiments, a CAR-T therapy is selected from the CAR-T therapies describedin Chen et al., Cancers 2023, 15, 663; Marofi et al., Stem Cell Res Ther 12: 81 (2021); Townsend et al., J Exp Clin Cancer Res 37: 163 (2018); Ma et al., Int J Biol Sci 15(12): 2548-2560 (2019); Zhao and Cao, Front Immunol 10: 2250 (2019); and Han et al., J Cancer 12(2): 326-334 (2021), the contents of each of which are incorporated by reference herein in their entirety.

[0172] Exemplary CAR T cell therapies that target EGFR include those investigated or beinginvestigated in clinical trials NCT03179007, NCT01869166, NCT02331693, NCT03182816, NCT03152435, and NCT03525782. Exemplary CAR T cell therapies that target CD70 include those investigated or being investigated in clinical trials NCT03125577 and NCT028307242. Exemplary CAR T cell therapies that target CD138 include those investigated or being investigated in clinical trials NCT01886976 and NCT03672318. Exemplary CAR T cell therapies that target CD38 include those investigated or being investigated in clinical trials NCT03464916, NCT03473496, NCT03473457, NCT03125577, NCT03222674, and NCT032716322. Exemplary CAR T cell therapies that target CD123 include those investigated or being investigated in clinical trials NCT03473457, NCT03125577, NCT02937103, NCT03114670, NCT02159495, NCT03098355, NCT03222674, NCT03203369, and NCT03190278. Exemplary CAR T cell therapies that target CD133 include those investigated or being investigated in clinical trials NCT03473457, NCT03356782, NCT02541370, and NCT03423992. Exemplary CAR T cell therapies that target GPC3 include those investigated or being investigated in clinical trials NCT02905188, NCT02932956, NCT02715362, NCT03130712, NCT02395250, NCT02876978, NCT03198546, NCT02723942, NCT03084380, NCT03302403, NCT03146234, and NCT02959151. Exemplary CAR T cell therapies that target CD5 include those investigated or BUSINESS.32999895.1 52397743-013WO (218530) being investigated in clinical trial NCT03081910. Exemplary CAR T cell therapies that target ROR1 include those investigated or being investigated in clinical trial NCT02706392. Exemplary CAR T cell therapies that target HerinCAR-PD1 include those investigated or being investigated in clinical trials NCT02873390 and NCT02862028. Exemplary CAR T cell therapies that target HER2 include those investigated or being investigated in clinical trials NCT03500991, NCT03423992, NCT02713984, NCT01935843, NCT03267173, NCT02792114, NCT02442297, NCT00889954, NCT03423992, NCT01109095, NCT02706392, NCT00902044, NCT03389230, NCT02713984, NCT02547961, and NCT01818323. Exemplary CAR T cell therapies that target EGFR806 include those investigated or being investigated in clinical trial NCT03179012. Exemplary CAR T cell therapies that target NY-ESO-1 include those investigated or being investigated in clinical trial NCT03029273. Exemplary CAR T cell therapies that target mesothelin include those investigated or being investigated in clinical trials NCT02930993, NCT03182803, NCT03030001, NCT02706782, NCT01583686, NCT03356795, NCT03054298, NCT03267173, NCT02792114, NCT02959151, NCT02580747, NCT02414269, NCT02465983, NCT03182803, and NCT03323944. Exemplary CAR T cell therapies that target PSCA include those investigated or being investigated in clinical trials NCT03198052, NCT02744287, and NCT03267173. Exemplary CAR T cell therapies that target MG7 include those investigated or being investigated in clinical trial NCT02862704. Exemplary CAR T cell therapies that target MUC1 include those investigated or being investigated in clinical trials NCT03179007, NCT02587689, NCT02617134, NCT03198052, NCT03356795, NCT03267173, NCT03222674, and NCT03356782. Exemplary CAR T cell therapies that target Claudin 18.2 include those investigated or being investigated in clinical trials NCT03874897 and NCT03159819. Exemplary CAR T cell therapies that target EpCAM include those investigated or being investigated in clinical trial NCT02915445, NCT03013712, NCT02729493, NCT02725125, NCT02728882, and NCT02735291. Exemplary CAR T cell therapies that target GD2 include those investigated or being investigated in clinical trials NCT04099797, NCT03423992, NCT03356795, NCT02992210, NCT01953900, NCT02761915, NCT03373097, NCT02765243, NCT03423992, NCT03294954, NCT03356782, and NCT02919046. Exemplary CAR T cell therapies that target VEGFR2 include those investigated or being investigated in clinical trial NCT01218867. Exemplary CAR T cell therapies that target AFP include those investigated or being investigated in clinical trial NCT03349255. Exemplary CAR T cell therapies that target Nectin4 / FAP include those investigated or being BUSINESS.32999895.1 53397743-013WO (218530) investigated in clinical trial NCT03932565. Exemplary CAR T cell therapies that target FAP include those investigated or being investigated in clinical trial NCT01722149. Exemplary CAR T cell therapies that target CEA include those investigated or being investigated in clinical trials NCT02850536, NCT02349724, NCT03267173, NCT02959151, and NCT01212887. Exemplary CAR T cell therapies that target Lewis Y include those investigated or being investigated in clinical trial NCT03851146. Exemplary CAR T cell therapies that target Glypican-3 include those investigated or being investigated in clinical trial NCT02932956. Exemplary CAR T cell therapies that target EGFRIII include those investigated or being investigated in clinical trial NCT01454596. Exemplary CAR T cell therapies that target IL-13Rα2 include those investigated or being investigated in clinical trial NCT02208362. Exemplary CAR T cell therapies that target CD171 include those investigated or being investigated in clinical trial NCT02311621. Exemplary CAR T cell therapies that target MUC16 include those investigated or being investigated in clinical trial NCT02311621. Exemplary CAR T cell therapies that target PSMA include those investigated or being investigated in clinical trials NCT03356795, NCT03089203, NCT03185468, and NCT01140373. Exemplary CAR T cell therapies that target AFP include those investigated or being investigated in clinical trial NCT03349255. Exemplary CAR T cell therapies that target AXL include those investigated or being investigated in clinical trial NCT03393936. Exemplary CAR T cell therapies that target CD20 include those investigated or being investigated in clinical trials NCT03893019 and NCT04169932. Exemplary CAR T cell therapies that target CD80 / 86 include those investigated or being investigated in clinical trial NCT03198052. Exemplary CAR T cell therapies that target CD30 include those investigated or being investigated in clinical trials NCT03383965, NCT04134325, and NCT04008394. Exemplary CAR T cell therapies that target c-MET include those investigated or being investigated in clinical trials NCT03060356 and NCT03638206. Exemplary CAR T cell therapies that target DLL-3 include those investigated or being investigated in clinical trial NCT03392064. Exemplary CAR T cell therapies that target DR5 include those investigated or being investigated in clinical trial NCT03638206. Exemplary CAR T cell therapies that target EpHA2 include those investigated or being investigated in clinical trials NCT02575261 and NCT03423992. Exemplary CAR T cell therapies that target FR-α include those investigated or being investigated in clinical trial NCT00019136. Exemplary CAR T cell therapies that target gp100 include those investigated or being investigated in clinical trial NCT03649529. Exemplary CAR T cell therapies that target IL13Ra2 include those investigated or being BUSINESS.32999895.1 54397743-013WO (218530) investigated in clinical trial NCT02208362. Exemplary CAR T cell therapies that target MAGE- A1 / 3 / 4 include those investigated or being investigated in clinical trials NCT03356808 and NCT03535246. Exemplary CAR T cell therapies that target LMP1 include those investigated or being investigated in clinical trial NCT02980315. Exemplary CAR T cell therapies that target EGFRVIII include those investigated or being investigated in clinical trials NCT03283631, NCT02844062, and NCT03170141. Exemplary CAR T cell therapies that target PD-L1 CSR include those investigated or being investigated in clinical trial NCT02937844. Exemplary CAR T cell therapies that target CD19 include those investigated or being investigated in clinical trials NCT02644655, NCT03744676, NCT01087294, NCT03366350, NCT03790891, NCT03497533, NCT04007029, NCT03960840, NCT04049383, NCT04094766, NCT03366324, NCT02546739, NCT03448393, NCT03467256, NCT03488160, NCT04012879, NCT03016377, NCT03468153, NCT03483688, NCT03398967, NCT03229876, NCT03455972, NCT03423706, NCT03497533, and NCT04002401, including FDA-approved products BREYANZI® (lisocabtagene maraleucel), TECARTUS™ (brexucabtagene autoleucel), KYMRIAH™ (tisagenlecleucel), and YESCARTA™ (axicabtagene ciloleucel). Exemplary CAR T cell therapies that target BCMA include those investigated or being investigated in clinical trials NCT03448978, NCT04182581, NCT03271632, NCT03473496, NCT03430011, NCT03455972, NCT02954445, NCT03322735, NCT03338972, NCT03318861, NCT02215967, NCT03093168, NCT03274219, NCT03302403, NCT03492268, NCT03288493, NCT03070327, NCT03196414, NCT03448978, NCT02958410, NCT03287804, NCT03473496, NCT03380039, NCT03430011, NCT03361748, NCT03455972, NCT02546167, NCT03271632, and NCT03548207 (CARVYKTI™ (ciltacabtagene autoleucel)). Exemplary CAR T cell therapies that target BCMA also include FDA-approved products ABECMA® (idecabtagene vicleucel) and CARVYKTI™ (ciltacabtagene autoleucel). Exemplary CAR T cell therapies that target CD33 include those investigated or being investigated in clinical trials NCT03473457, NCT02958397, NCT03126864, and NCT03222674. Exemplary CAR T cell therapies that target GAP include those investigated or being investigated in clinical trial NCT02932956. Exemplary CAR T cell therapies that target Zeushield include those investigated or being investigated in clinical trial NCT03060343. Exemplary CAR T cell therapies that target DLL3 include those investigated or being investigated in clinical trial NCT03392064. 4. Compositions, Formulation and Administration BUSINESS.32999895.1 55397743-013WO (218530) Pharmaceutically acceptable compositions

[0173] According to another embodiment, the disclosure provides a pharmaceuticalcomposition comprising a chromene derivative as described herein, or a pharmaceutically acceptable derivative thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle. In certain embodiments, the amount of a chromene derivative in compositions of this disclosure is such that is effective to measurably inhibit TCR or TCR-Nck interactions in a biological sample or in a patient.

[0174] In some embodiments, the present disclosure provides a composition comprising atherapeutically effective amount of a chromene derivative as described herein and a CAR-T therapy. In certain embodiments, the amount of a chromene derivative in a composition comprising a CAR-T therapy of this disclosure is such that is effective to measurably inhibit TCR in the CAR- T therapy.

[0175] In certain embodiments, a composition of this disclosure is formulated foradministration to a patient in need of such composition. In some embodiments, a composition of this disclosure is formulated for oral administration to a patient. In certain embodiments, a composition comprising a CAR-T therapy of this disclosure is formulated for intravenous infusion administration to a patient in need of such composition.

[0176] As used herein, the terms “subject” and “patient” are used interchangeably and refer toorganisms to be treated by the methods of the present disclosure. Such organisms preferably include, but are not limited to, mammals (e.g., murines, simians, equines, bovines, porcines, canines, felines, and the like), and, most preferably, includes humans.

[0177] The term “pharmaceutically acceptable carrier, adjuvant, or vehicle” refers to a non-toxic carrier, adjuvant, or vehicle that does not destroy the pharmacological activity of the compound with which it is formulated. Pharmaceutically acceptable carriers, adjuvants or vehicles that may be used in the compositions of this invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, 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, BUSINESS.32999895.1 56397743-013WO (218530) polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene- polyoxypropylene-block polymers, polyethylene glycol and wool fat.

[0178] A “pharmaceutically acceptable derivative” means any non-toxic salt, ester, salt of anester or other derivative of a chromene derivative of this disclosure that, upon administration to a recipient, is capable of providing, either directly or indirectly, a chromene derivative of this disclosure or an active metabolite or residue thereof.

[0179] As used herein, the term "active metabolite or residue thereof" means that a metaboliteor residue thereof also inhibits TCR or TCR-Nck interactions in a biological sample or in a patient.

[0180] Compositions of the present disclosure can be administered orally, parenterally, byinhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir. The term "parenteral" as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques. Preferably, the compositions are administered orally, intraperitoneally or intravenously. Sterile injectable forms of the compositions of this disclosure may be aqueous or oleaginous suspension. These suspensions can be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation can also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that can be employed are water, Ringer’s solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium.

[0181] For this purpose, any bland fixed oil can be employed including synthetic mono- or di-glycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions can also contain a long-chain alcohol diluent or dispersant, such as carboxymethyl cellulose or similar dispersing agents that are commonly used in the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions. Other commonly used surfactants, such as Tweens, Spans and other emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for the purposes of formulation. BUSINESS.32999895.1 57397743-013WO (218530)

[0182] Pharmaceutically acceptable compositions of this disclosure can be orally administeredin any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions. In the case of tablets for oral use, carriers commonly used include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried cornstarch. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents can also be added.

[0183] Alternatively, pharmaceutically acceptable compositions of this disclosure can beadministered in the form of suppositories for rectal administration. These can be prepared by mixing the agent with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and therefore will melt in the rectum to release the drug. Such materials include cocoa butter, beeswax and polyethylene glycols.

[0184] Pharmaceutically acceptable compositions of this disclosure can also be administeredtopically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.

[0185] Topical application for the lower intestinal tract can be effected in a rectal suppositoryformulation (see above) or in a suitable enema formulation. Topically-transdermal patches can also be used.

[0186] For topical applications, provided pharmaceutically acceptable compositions can beformulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers. Carriers for topical administration of compounds of this disclosure include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water. Alternatively, provided pharmaceutically acceptable compositions can be formulated in a suitable lotion or cream containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2octyldodecanol, benzyl alcohol and water. BUSINESS.32999895.1 58397743-013WO (218530)

[0187] For ophthalmic use, provided pharmaceutically acceptable compositions may beformulated as micronized suspensions in isotonic, pH adjusted sterile saline, or, preferably, as solutions in isotonic, pH adjusted sterile saline, either with or without a preservative such as benzylalkonium chloride. Alternatively, for ophthalmic uses, the pharmaceutically acceptable compositions can be formulated in an ointment such as petrolatum.

[0188] Pharmaceutically acceptable compositions of this disclosure can also be administeredby nasal aerosol or inhalation. Such compositions are prepared according to techniques well- known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and / or other conventional solubilizing or dispersing agents.

[0189] Most preferably, pharmaceutically acceptable compositions of this disclosure areformulated for oral administration. Such formulations may be administered with or without food. In some embodiments, pharmaceutically acceptable compositions of this disclosure are administered without food. In other embodiments, pharmaceutically acceptable compositions of this disclosure are administered with food.

[0190] In some embodiments, the pharmaceutical compositions of this disclosure are brain-penetrant or CNS-penetrant or provide brain exposure. As used herein, the terms “brain-penetrant, “CNS-penetrant, “or “brain exposure” refers that the compounds and pharmaceutical compositions of this disclosure are capable of crossing the blood brain barrier (BBB), and thus are useful for treating a brain or CNS disease, condition, injury or disorder. In some embodiments, a brain or CNS disease, condition, injury or disorder is a neurodegenerative diseases, neuronal injury, stroke, genetic disorders, psychiatric disorders, developmental disorders, inflammation, infection or damage, and brain cancers, spinal cord injury (SCI) and traumatic brain injury (TBI). In certain embodiments, a brain disorder is selected from epilepsy, meningitis, encephalitis including HIV Encephalitis, progressive multifocal leukoencephalopathy, neuromyelitis optica, multiple sclerosis, late-stage neurological trypanosomiasis, amyotrophic lateral sclerosis (ALS), progressive bulbar palsy (PBP), primary lateral sclerosis (PLS), progressive muscular atrophy (PMA), Alzheimer's disease, Parkinson's disease, Huntington's disease, De Vivo disease, and any type of tumor, cancer or hyperproliferative disease in the brain or CNS.

[0191] In some embodiments, a brain or CNS disease, condition, injury or disorder is aneurological disorder which affects the CNS and / or which has an etiology in the CNS, which BUSINESS.32999895.1 59397743-013WO (218530) includes, but is not limited to, neuropathy, amyloidosis, cancer, an ocular disease or disorder, viral or microbial infection, inflammation, ischemia, neurodegenerative disease, seizure, behavioral disorders, and a lysosomal storage disease. For the purposes of this application, the CNS will be understood to include the eye, which is normally sequestered from the rest of the body by the blood-retina barrier.

[0192] The “central nervous system” or “CNS” refers to the complex of nerve tissues thatcontrol bodily function, and includes the brain and spinal cord.

[0193] In those compositions comprising multiple therapeutic agents, the therapeutic agentscan act synergistically. Therefore, the amount of each therapeutic agents in such compositions may be less than that required in a monotherapy utilizing only that therapeutic agent. In some embodiments, the amount of each therapeutic agent in the compositions comprising multiple therapeutic agents ranges from about 50% to 100% of the amount normally present in a composition comprising that agent as the only therapeutically active agent. In some embodiments, a chromene derivative is administered at a dosage of about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, or about 95% of the amount normally administered for that agent. In some embodiments, a CAR-T cell therapy is administered at a dosage of about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, or about 95% of the amount normally administered for that agent. As used herein, the phrase “normally administered” means the amount an FDA approved therapeutic agent is approved for dosing per the FDA label insert.

[0194] It should also be understood that a specific dosage and treatment regimen for anyparticular patient depends upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician and the severity of the particular disease being treated. The amount of a compound of the present disclosure in the composition also depends upon the particular compound in the composition. Uses of Compounds and Pharmaceutically Acceptable Compositions

[0195] In some embodiments, the present disclosure provides a method for treating a diseaseor disorder in a patient, comprising administering a therapeutically effective amount of a chromenederivative as described herein, and a therapeutically effective amount of a CAR-T therapy to theBUSINESS.32999895.1 60397743-013WO (218530) patient. In some embodiments, the present disclosure provides a method for treating a disease or disorder in a patient, comprising administering a composition to the patient, wherein the composition comprises a therapeutically effective amount of a chromene derivative as describedherein, and a therapeutically effective amount of a CAR-T therapy.

[0196] In some embodiments, the present disclosure provides a use of a therapeuticallyeffective amount of a chromene derivative as described herein, and a therapeutically effectiveamount of a CAR-T therapy, for treating a disease or disorder in a patient. In some embodiments, the present disclosure provides a use of a composition for treating a disease or disorder in a patient, wherein the composition comprises a therapeutically effective amount of a chromene derivative asdescribed herein, and a therapeutically effective amount of a CAR-T therapy.

[0197] In some embodiments, the present disclosure provides a use of a therapeuticallyeffective amount of a chromene derivative as described herein for the manufacture of amedicament for treating a disease or disorder in a patient, in combination with a therapeuticallyeffective amount of a CAR-T therapy. In some embodiments, the present disclosure provides a useof a composition for the manufacture of a medicament for treating a disease or disorder in a patient,wherein the composition comprises a therapeutically effective amount of a chromene derivative as described herein and a therapeutically effective amount of a CAR-T therapy.

[0198] In some embodiments, a disease or disorder is a proliferative disorder. In someembodiments, a disease or disorder is a cancer. In some embodiments, a disease or disorder is a proliferative disorder or a cancer as described herein.

[0199] As used herein, “a method for treating a disease or disorder” includes a method oftreating, reducing the severity of, delaying the onset of, or inhibiting the progress of a disease or disorder, or one or more symptoms thereof, of a disease or disorder.

[0200] As used herein, the terms "increase" or "improve" are used interchangeably andencompass any measurable increase in a biological function and / or biological activity. For example, an increase can be by at least about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, about 100%, about 2-fold, about 3-fold, about 4-fold, about 5-fold, about 6-fold, about 7-fold, about 8-fold, about 9-fold, about 10-fold, about 20-fold, about 25-fold, about 50-fold, about BUSINESS.32999895.1 61397743-013WO (218530) 100-fold, or higher, relative to a control or baseline amount of a function, or activity, or concentration.

[0201] As used herein, the term "reduce" encompass any measurable reduction in a biologicalfunction and / or biological activity. For example, a reduction can be by at least about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, about 100%, about 2-fold, about 3-fold, about 4-fold, about 5-fold, about 6-fold, about 7-fold, about 8-fold, about 9-fold, about 10-fold, about 20-fold, about 25-fold, about 50-fold, about 100-fold, or more, relative to a control or baseline amount of a function or activity. Cancer

[0202] In some embodiments, the present disclosure provides a method for treating orpreventing or reducing the risk of a cancer in patient comprising administering to the patient a compound of the disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0203] A "cancer," as used herein, refers a broad group of various diseases characterized by theuncontrolled growth of abnormal cells in the body. Unregulated cell division and growth divide and grow results in the formation of malignant tumors that invade neighboring tissues and can also metastasize to distant parts of the body through the lymphatic system or bloodstream.

[0204] The cancer or proliferative disorder or tumor to be treated using the compounds andmethods and uses described herein include, but are not limited to, a hematological cancer, a lymphoma, a myeloma, a leukemia, a neurological cancer, skin cancer, breast cancer, a prostate cancer, a colorectal cancer, lung cancer, head and neck cancer, a gastrointestinal cancer, a liver cancer, a pancreatic cancer, a genitourinary cancer, a bone cancer, renal cancer, and a vascular cancer.

[0205] In some embodiments of the methods and uses described herein, the cancer is selectedfrom non-small cell lung cancer (NSCLC), pancreatic cancer, colorectal cancer (CRC), uterine carcinoma, endometrial carcinoma, bladder cancer, head and neck cancer, thyroid cancer, melanoma, multiple myeloma, acute myeloid leukemia (AML), low-grade serous ovarian cancer, neurofibroma, and glioma. BUSINESS.32999895.1 62397743-013WO (218530)

[0206] In some embodiments of the methods and uses described herein, the cancer is lungcancer, thyroid cancer, ovarian cancer, colorectal cancer, prostate cancer, cancer of the pancreas, cancer of the esophagus, liver cancer, breast cancer, skin cancer, or mesothelioma. In some embodiments, the cancer is mesothelioma, such as malignant mesothelioma.

[0207] In some embodiments, a cancer includes, without limitation, leukemias (e.g., acuteleukemia, acute lymphocytic leukemia, acute myelocytic leukemia, acute myeloblastic leukemia, acute promyelocytic leukemia, acute myelomonocytic leukemia, acute monocytic leukemia, acute erythroleukemia, chronic leukemia, chronic myelocytic leukemia, chronic lymphocytic leukemia), polycythemia vera, lymphoma (e.g., Hodgkin’s disease or non-Hodgkin’s disease), Waldenstrom's macroglobulinemia, multiple myeloma, heavy chain disease, and solid tumors such as sarcomas and carcinomas (e.g., fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing’s tumor, leiomyosarcoma, rhabdomyosarcoma, colon carcinoma, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinomas, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilm's tumor, cervical cancer, uterine cancer, testicular cancer, lung carcinoma, small cell lung carcinoma, bladder carcinoma, epithelial carcinoma, glioma, astrocytoma, glioblastoma multiforme (GBM, also known as glioblastoma), medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, schwannoma, neurofibrosarcoma, meningioma, melanoma, neuroblastoma, and retinoblastoma).

[0208] In some embodiments, a cancer is glioma, astrocytoma, glioblastoma multiforme(GBM, also known as glioblastoma), medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, schwannoma, neurofibrosarcoma, meningioma, melanoma, neuroblastoma, or retinoblastoma.

[0209] In some embodiments, a cancer is acoustic neuroma, astrocytoma (e.g. Grade I –Pilocytic Astrocytoma, Grade II – Low-grade Astrocytoma, Grade III – Anaplastic Astrocytoma, or Grade IV – Glioblastoma (GBM)), chordoma, CNS lymphoma, craniopharyngioma, brain stem glioma, ependymoma, mixed glioma, optic nerve glioma, subependymoma, medulloblastoma, BUSINESS.32999895.1 63397743-013WO (218530) meningioma, metastatic brain tumor, oligodendroglioma, pituitary tumors, primitive neuroectodermal (PNET) tumor, or schwannoma. In some embodiments, the cancer is a type found more commonly in children than adults, such as brain stem glioma, craniopharyngioma, ependymoma, juvenile pilocytic astrocytoma (JPA), medulloblastoma, optic nerve glioma, pineal tumor, primitive neuroectodermal tumors (PNET), or rhabdoid tumor. In some embodiments, the patient is an adult human. In some embodiments, the patient is a child or pediatric patient.

[0210] Cancer includes, in another embodiment, without limitation, mesothelioma,hepatobilliary (hepatic and billiary duct), bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular melanoma, ovarian cancer, colon cancer, rectal cancer, cancer of the anal region, stomach cancer, gastrointestinal (gastric, colorectal, and duodenal), uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin’s Disease, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, prostate cancer, testicular cancer, chronic or acute leukemia, chronic myeloid leukemia, lymphocytic lymphomas, cancer of the bladder, cancer of the kidney or ureter, renal cell carcinoma, carcinoma of the renal pelvis, non-Hodgkins’s lymphoma, spinal axis tumors, brain stem glioma, pituitary adenoma, adrenocortical cancer, gall bladder cancer, multiple myeloma, cholangiocarcinoma, fibrosarcoma, neuroblastoma, retinoblastoma, or a combination of one or more of the foregoing cancers.

[0211] In some embodiments, a cancer is a solid tumor, such as a sarcoma, carcinoma, orlymphoma. Solid tumors generally comprise an abnormal mass of tissue that typically does not include cysts or liquid areas. In some embodiments, the cancer is selected from renal cell carcinoma, or kidney cancer; hepatocellular carcinoma (HCC) or hepatoblastoma, or liver cancer; melanoma; breast cancer; colorectal carcinoma, or colorectal cancer; colon cancer; rectal cancer; anal cancer; lung cancer, such as non-small cell lung cancer (NSCLC) or small cell lung cancer (SCLC); ovarian cancer, ovarian epithelial cancer, ovarian carcinoma, or fallopian tube cancer; papillary serous cystadenocarcinoma or uterine papillary serous carcinoma (UPSC); prostate cancer; testicular cancer; gallbladder cancer; hepatocholangiocarcinoma; soft tissue and bone synovial sarcoma; rhabdomyosarcoma; osteosarcoma; chondrosarcoma; Ewing sarcoma; anaplastic thyroid cancer; adrenocortical carcinoma; pancreatic cancer; pancreatic ductal BUSINESS.32999895.1 64397743-013WO (218530) carcinoma or pancreatic adenocarcinoma; gastrointestinal / stomach (GIST) cancer; lymphoma; squamous cell carcinoma of the head and neck (SCCHN); salivary gland cancer; glioma, or brain cancer; neurofibromatosis-1 associated malignant peripheral nerve sheath tumors (MPNST); Waldenstrom’s macroglobulinemia; or medulloblastoma.

[0212] In some embodiments, a cancer is hepatocellular carcinoma (HCC). In someembodiments, the cancer is hepatoblastoma. In some embodiments, the cancer is colon cancer. In some embodiments, the cancer is rectal cancer. In some embodiments, the cancer is ovarian cancer, or ovarian carcinoma. In some embodiments, the cancer is ovarian epithelial cancer. In some embodiments, the cancer is fallopian tube cancer. In some embodiments, the cancer is papillary serous cystadenocarcinoma. In some embodiments, the cancer is uterine papillary serous carcinoma (UPSC). In some embodiments, the cancer is hepatocholangiocarcinoma. In some embodiments, the cancer is soft tissue and bone synovial sarcoma. In some embodiments, the cancer is rhabdomyosarcoma. In some embodiments, the cancer is osteosarcoma. In some embodiments, the cancer is anaplastic thyroid cancer. In some embodiments, the cancer is adrenocortical carcinoma. In some embodiments, the cancer is pancreatic cancer, or pancreatic ductal carcinoma. In some embodiments, the cancer is pancreatic adenocarcinoma. In some embodiments, the cancer is glioma. In some embodiments, the cancer is malignant peripheral nerve sheath tumors (MPNST). In some embodiments, the cancer is neurofibromatosis-1 associated MPNST. In some embodiments, the cancer is Waldenstrom’s macroglobulinemia. In some embodiments, the cancer is medulloblastoma.

[0213] In some embodiments, a cancer is a viral-associated cancer, including humanimmunodeficiency virus (HIV) associated solid tumors, human papilloma virus (HPV)-16 positive incurable solid tumors, and adult T-cell leukemia, which is caused by human T-cell leukemia virus type I (HTLV-I) and is a highly aggressive form of CD4+ T-cell leukemia characterized by clonal integration of HTLV-I in leukemic cells (See https: / / clinicaltrials.gov / ct2 / show / study / NCT02631746); as well as virus-associated tumors in gastric cancer, nasopharyngeal carcinoma, cervical cancer, vaginal cancer, vulvar cancer, squamous cell carcinoma of the head and neck, and Merkel cell carcinoma. (See https: / / clinicaltrials.gov / ct2 / show / study / NCT02488759; see also https: / / clinicaltrials.gov / ct2 / show / study / NCT0240886; https: / / clinicaltrials.gov / ct2 / show / NCT02426892) BUSINESS.32999895.1 65397743-013WO (218530)

[0214] In some embodiments, the methods or uses described herein inhibit or reduce or arrestor ameliorate the growth or spread of a cancer or tumor. In some embodiments, the tumor is treated by arresting, reducing, or inhibiting further growth of the cancer or tumor. In some embodiments, the methods or uses described herein increase or potentiate or activate one or more immune responses to inhibit or reduce or arrest or ameliorate the growth or spread of a cancer or tumor. In some embodiments, the cancer or tumor is treated by reducing the size (e.g., volume or mass) of the cancer or tumor by at least 5%, at least 10%, at least 25%, at least 50%, at least 75%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% relative to the size of the cancer or tumor prior to treatment. In some embodiments, cancers or tumors are treated by reducing the quantity of the cancers or tumors in the patient by at least 5%, at least 10%, at least 25%, at least 50%, at least 75%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% relative to the quantity of cancers or tumors prior to treatment.

[0215] In some embodiments, a patient treated using the methods or uses described hereinexhibits progression-free survival of at least about one month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about one year, at least about eighteen months, at least about two years, at least about three years, at least about four years, or at least about five years after the treatment is initiated. In some embodiments, a patient treated using the methods or uses described herein exhibits an overall survival of at least about one month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about one year, at least about 14 months, at least about 16 months, at least about 18 months, at least about 20 months, at least about 22 months, at least about two years, at least about three years, at least about four years, or at least about five years after the treatment is initiated.

[0216] In some embodiments, a patient treated using the methods or uses described hereinexhibits an objective response rate (ORR) of at least about 15%, at least about 20%, at least about 25%, at least about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100%. BUSINESS.32999895.1 66397743-013WO (218530) Administration

[0217] The compounds and compositions, according to the method of the present disclosure,may be administered using any amount and any route of administration effective for inhibiting TCR and treating or lessening the severity of a disease, for example, as those described herein. The exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the disease or condition, the particular agent, its mode of administration, and the like. Compounds of the disclosure are preferably formulated in dosage unit form for ease of administration and uniformity of dosage. The expression “dosage unit form” as used herein refers to a physically discrete unit of agent appropriate for the patient to be treated. It will be understood, however, that the total daily usage of the compounds and compositions of the present disclosure will be decided by the attending physician within the scope of sound medical judgment. The specific effective dose level for any particular patient or organism will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed, and like factors well known in the medical arts. The term “patient”, as used herein, means an animal, preferably a mammal, and most preferably a human.

[0218] A chromene derivative as described herein can be administered separately from a CAR-T therapy, as part of a multiple dosage regimen. Alternatively, a chromene derivative as described herein may be part of a single dosage form, mixed together with a CAR-T therapy in a single composition. If administered as a multiple dosage regime, a chromene derivative as described herein and a CAR-T therapy can be administered simultaneously, sequentially or within a period of time from one another, for example within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 hours from one another. In some embodiments, a chromene derivative as described herein and a CAR-T therapy are administered as a multiple dosage regimen with greater than 24 hours apart.

[0219] In some embodiments, the initiation of administration of a chromene derivative asdescribed herein is carried out 7 to 14 days after the initiation of administration of a CAR-T therapy. In some of any of the provided embodiments, the initiation of the administration of a BUSINESS.32999895.1 67397743-013WO (218530) chromene derivative as described herein is carried out at or about 7 days, at or about 8 days, at or about 9 days, at or about 10 days, at or about 11 days, at or about 12 days, at or about 13 days, at or about 14 days, at or about 15 days, at or about 16 days, at or about 17 days, at or about 18 days, at or about 19 days, or at or about 20 days after the initiation of administration of a CAR-T therapy.

[0220] In some embodiments, at the time of initiation of administration of a chromenederivative as described herein, a patient has been previously administered a CAR-T therapy. In some embodiments, a chromene derivative as described herein is administered to a patient before a CAR-T therapy is administered.

[0221] In some embodiments, a CAR-T therapy comprises a dose of cells from about 1×105 to1×109total recombinant receptor-expressing T cells, inclusive. In some embodiments, a CAR-T therapy comprises a dose of cells from about 1×105to 5×108total recombinant receptor-expressing T cells, 1×106to 2.5×108total recombinant receptor-expressing T cells, 5×106to 1×108total recombinant receptor-expressing T cells, 1×107to 2.5×108total recombinant receptor-expressing T cells, or 5×107to 1×108total recombinant receptor-expressing T cells, each inclusive. In some embodiments, a CAR-T therapy comprises a dose of cells from about 1.5×107to 6×108total recombinant receptor-expressing T cells, 1.5×108to 6×108total recombinant receptor-expressing T cells, or 1.5×108to 4.5×108total recombinant receptor-expressing T cells, each inclusive.

[0222] In some embodiments, a CAR-T therapy comprises administration of a dose comprisinga number of cells that is at least about or is about 0.1×106cells / kg body weight of the subject, 0.2×106cells / kg, 0.3×106cells / kg, 0.4×106cells / kg, 0.5×106cells / kg, 1×106cell / kg, 2.0×106cells / kg, 3×106cells / kg or 5×106cells / kg.

[0223] In some embodiments, a CAR-T therapy comprises administration of a dose comprisinga number of cells between about 0.1×106cells / kg body weight of the subject and 1.0×107cells / kg, between about 0.5×106cells / kg and 5×106cells / kg, between about 0.5×106cells / kg and 3×106cells / kg, between about 0.5×106cells / kg and 2×106cells / kg, between about 0.5×106cells / kg and 1×106cell / kg, between about 1.0×106cells / kg body weight of the subject and 5×106cells / kg, between about 1.0×106cells / kg and 3×106cells / kg, between about 1.0×106cells / kg and 2×106cells / kg, between about 2.0×106cells / kg body weight of the subject and 5×106cells / kg, between about 2.0×106cells / kg and 3×106cells / kg, or between about 3.0×106cells / kg body weight of the subject and 5×106cells / kg, each inclusive. BUSINESS.32999895.1 68397743-013WO (218530)

[0224] In some embodiments, a CAR-T therapy is administered parenterally, optionallyintravenously. In some embodiments, a CAR-T therapy is administered intravenously.

[0225] As used herein, the term “combination,” “combined,” and related terms refers to thesimultaneous or sequential administration of therapeutic agents in accordance with this disclosure. For example, a chromene derivative as described herein can be administered with a CAR-T therapy simultaneously or sequentially in separate unit dosage forms or together in a single unit dosage form. Accordingly, the present disclosure provides a single unit dosage form comprising a chromene derivative as described herein and a CAR-T therapy, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

[0226] Pharmaceutically acceptable compositions of this disclosure can be administered tohumans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments, or drops), bucally, as an oral or nasal spray, or the like, depending on the severity of the disease or disorder being treated. In certain embodiments, the compounds or composition of the disclosure may be administered orally or parenterally at dosage levels of about 0.01 mg / kg to about 50 mg / kg and preferably from about 1 mg / kg to about 25 mg / kg, of subject body weight per day, one or more times a day, to obtain the desired therapeutic effect.

[0227] Liquid dosage forms for oral administration include, but are not limited to,pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0228] Injectable preparations, for example, sterile injectable aqueous or oleaginoussuspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for BUSINESS.32999895.1 69397743-013WO (218530) example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S.P. and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables, as are natural pharmaceutically acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions can also contain a long-chain alcohol diluent or dispersant, such as carboxymethyl cellulose or similar dispersing agents that are commonly used in the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions. Other commonly used surfactants, such as Tweens, Spans and other emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms can also be used for the purposes of formulation.

[0229] Injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

[0230] In order to prolong the effect of a compound of the present invention, it is often desirableto slow the absorption of the compound from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the compound then depends upon its rate of dissolution that, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered compound form is accomplished by dissolving or suspending the compound in an oil vehicle. Injectable depot forms are made by forming microencapsule matrices of the compound in biodegradable polymers such as polylactide-polyglycolide. Depending upon the ratio of compound to polymer and the nature of the particular polymer employed, the rate of compound release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.

[0231] Compositions for rectal or vaginal administration are preferably suppositories whichcan be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at BUSINESS.32999895.1 70397743-013WO (218530) ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.

[0232] Solid dosage forms for oral administration include capsules, tablets, pills, powders, andgranules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier 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 may also comprise buffering agents.

[0233] Solid compositions of a similar type may 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. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well-known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. Solid compositions of a similar type may 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.

[0234] The active compounds can also be in micro-encapsulated form with one or moreexcipients as noted above. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well-known in the pharmaceutical formulating art. In such solid dosage forms the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch. BUSINESS.32999895.1 71397743-013WO (218530) Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.

[0235] Dosage forms for topical or transdermal administration of a compound of this inventioninclude ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required. Ophthalmic formulation, ear drops, and eye drops are also contemplated as being within the scope of this invention. Additionally, the present invention contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of a compound to the body. Such dosage forms can be made by dissolving or dispensing the compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel. EXEMPLIFICATION

[0236] The following examples are included to demonstrate various aspects of the presentdisclosure. It should be appreciated by those of skill in the art that the techniques disclosed in the examples that follow represent techniques discovered by the inventors to function well in the practice of the disclosure, and thus can be considered to constitute preferred modes for its practice. However, those of skill in the art should, in light of the present disclosure, appreciate that many changes can be made in the specific examples which are disclosed and still obtain a like or similar result without departing from the spirit and scope of the disclosure. 1. MATERIALS AND METHODS 1.1 Human blood samples and cell lines

[0237] Leukopak-derived blood was diluted 3x with phosphate-buffered saline (PBS) andcarefully layered onto 15 mL Lymphoprep™ (STEMCELL technologies, Vancouver, Canada) in BUSINESS.32999895.1 72397743-013WO (218530) 50 mL Falcon tubes (Corning, NY, USA), then centrifuged at 2100rpm for 30min and at 22 °C without brake in a Heraeus Megafuge 40R (ThermoFisher Scientific, Waltham, MA, USA). The floating mononuclear cells were collected in a single tube, filled with PBS and centrifuged at 1500rpm for 10min and at 16 °C. The cells were washed three times with PBS. Afterwards, cells were cultured in a culture flask of an appropriate volume (ThermoFisher Scientific, Waltham, MA, USA) in full RPMI culture mediuam at a density of 106cells / mL, supplemented with 500 U / ml recombinant human interleukin-2 (hIL-2) (PeproTech, Cranbury, NJ, USA) for 24-48 h at 37 °C and 5% CO2. The cells were activated with Dynabeads™ Human T-Activator CD3 / CD28 for T Cell Expansion and Activation (ThermoFisher Scientific, Waltham, MA, USA). Lentiviral transduction was performed typically 24h and 48h post-activation, after evaluation of activation according to CD69 expression by flow cytometry. 1.2 Generation of viral transducing supernatants

[0238] Human HEK-293T cells were plated on 100 mm-diameter Petri culture dishes (Corning,NY, USA) at a density of 3x106cells / dish in complete DMEM medium (ThermoFisher Scientific, Waltham, MA, USA), supplemented with 10% FBS (Sigma-Aldrich, St. Louis, MO, USA), 10 mM HEPES pH= 7.4, 2 mM L-Gln, 100 U / ml penicillin and streptomycin the day prior to transfection. Transfection was performed using jetPEI® transfection reagent (Polyplus, Illkirch- Graffenstaden, France). A total of 10µg of the CD19-CAR vector (Clinical Cancer Research.19, 3153–3164 (2013)) plus 6.6 µg of the gag-pol vector (pCMV-DR) and 3 µg of the VSV Env vetor (pMD2.G) were mixed in a 1.5 mL Eppendorf tube with 150 mM NaCl solution up to a total volume of 250 µL. In a separate tube, 40µL jetPEI® was mixed with 220 µl of 150 mM NaCl per sample. Subsequently, both solutions were mixed vigorously and incubated for 15-20min at room temperature. The culture medium for the HEK-293T cells was exchanged for complete RPMI- 1640, supplemented with 10% FBS, 10 mM HEPES, 2 mM L-Gln, 100 U / mL penicillin and streptomycin. The transfection mixture was added dropwise added to the HEK-293T culture plate and incubated at 37 °C in a 5% CO2 incubator. After 24h, the culture supernatant was collected as a first lentiviral supernatant and fresh RPMI medium was added to the HEK-293T cells. At 48h after transfection, the culture supernatant was again collected and mixed with the 24h one; the mixture was filtered through 0.45 µm polyethersulfone filters (Sartorius, Göttingen, Germany) and then either used fresh for T cell transduction or stored at -80°C until use. 1.3 Lentiviral transduction of human blood T cells BUSINESS.32999895.1 73397743-013WO (218530)

[0239] For transduction of primary human T cells, PBMC were seeded on 24-well culture plates(Corning, Corning, NY, USA) at a concentration of 106cells / well in RPMI-1640 supplemented with 5 U / mL recombinant hIL-7 and hIL15. The lentiviral particle-containing HEK-293T cell supernatant was added dropwise and the plates were centrifuged for 1h at 2100rpm at 32 °C and subsequently incubated overnight at 37 °C in a 5% CO2 incubator. The same protocol was repeated the following day, carefully removing the old viral supernatant and adding fresh one. Transduced PBLs were typically expanded up to a week in appropriate culture plates in full RPMI medium at densities of 1-2x106cells / mL in the presence of hIL-7 and hIL-15 at 5 ng / mL. Transduction efficiency was evaluated by flow cytometry after staining with anti egfr BV421 (Ref.: 352911, BioLegend). 1.4 Cytokine release assays

[0240] Detection of human IL-2 and human IFN-γ was performed using DuoSet® ELISAdevelopment system kits (R&D Systems, Minneapolis, MN, USA) according to the manufacturer’s protocol. In short: 96-well ELISA plates were coated with capture antibodies anti-hIL-2 (4µg / ml) or anti-hIFN-γ (2 µg / ml) respectively (100 µl / well), sealed and incubated overnight at room temperature. The coated antibodies were discarded, and the plates were washed with Wash buffer (PBS with 0.05% Tween®-20), then incubated with Block buffer (PBS with 1% bovine serum albumin (BSA), 0.22µm filtered) for 1h at room temperature. The plates were washed three times with Wash buffer and the samples (cell culture supernatants) were plated at 100 µl / well undiluted or diluted with Reagent diluent (Tris-buffered saline (TBS) with 0.1% BSA, 0.05% Tween®-20, pH 7.2-7.4; 0.22µm filtered). Dilutions of recombinant human IL-2 or IFN-γ standards (as recommended by the manufacturer) were prepared in Reagent diluent and made in duplicates for generation of the standard curve. The plates were sealed and incubated for 2h at room temperature. The plates were washed three times with Wash buffer and then detection antibodies goat-anti-hIL- 2-BIO (100ng / mL) or mouse-anti-hIFN-γ-BIO (125 ng / mL) diluted in Reagent diluent were added to the plates at 100 µL / well and sealed and incubated for 2h at room temperature. The plates were washed three times with Wash buffer, then incubated with streptavidin-horseradish peroxidase (STV-HRP) (40x dilution in Reagent diluent) 100 µl / well for 20min at room temperature in the dark. The plates were washed three times with Wash buffer and then 100 µL / well Substrate solution (1:1 mix of 3,3',5,5'-tetramethylbenzidine (TMB) and H2O2) were added to the wells and incubated up to 20min at room temperature in the dark. The reaction was halted with the addition BUSINESS.32999895.1 74397743-013WO (218530) of 50 µL / well Stop solution (2N H2SO4) and optical density was measured immediately using iMark™ microplate absorbance reader (Bio-Rad Laboratories, Hercules, CA, USA) at 450nm with subtractive correction at 595nm. Calculations of cytokine concentrations were carried out using four parameter logistic (4-PL) curve-fit. 1.5 Proliferation assays

[0241] In order to determine T-cell proliferative capacity, tritiated thymidine incorporation intothe DNA of proliferating cells was measured. For each condition (2:1 or 4:1), a total of 2 × 105 or4 × 105effector cells were stimulated with 2 × 105irradiated target cells (Raji cells).72 h later, 1 μCi / well [3H]thymidine (Perkin Elmer) was added in each well, and counted after 24h in a 1450 microbeta Wallac Trilux liquid scintillation counter. 1.6 Target cell killing assay

[0242] Raji tumor cells were labeled with Cell trace Far red (ref:C34572, Thermofisher) beforestarting the experiment. Different effector / target cell ratios were tested, 1x10⁵ target cells were incubated with different number of effector cells. The samples were incubated for 24 hours, and cells were collected and labeled with DAPI as viability marker and in order to calculate the number of live cells. To this end, CountigBright beads (Ref: C36950, Thermofisher) were added. Finally the samples were analyzed by FACs (CantoII, Beckman Coulter). 1.7 SDS-PAGE and Western blotting

[0243] For determination of phosphorylation status of proteins, 1x106 CAR-Tcells were usedper point. The phosphorylation levels were determined in both basal and after stimulation conditions. In the case of the basal phosphorylation levels, cells were lysed in 0.3% Brij96 lysis buffer for 15 minutes on ice. The nuclear fraction was removed by centrifugation (15 min; Vmax at 4ºC). For the determination of protein phosphorylation levels after stimulation, cells were stimulated in 50μL pre-warmed RMPI medium with 5μg / mL anti-CD3ε (OKT3) or with 1x106target cells (Raji cell line) for different time intervals. To stop the reaction, 100μl lysis buffer was added, containing 0.3% Brij 96 and phosphatase inhibitors during 30min on ice. Nuclei were removed by centrifugation and the postnuclear supernatant was combined with a half volume of 3x non-reducing loading buffer and stored at -20ºC until SDS-PAGE was run. Boiled samples were separated on 10% or 12% acrylamide gels under both reducing or non-reducing conditions. Proteins were transferred to nitrocellulose membranes using a semidry transfer procedure. Membranes were blocked in TBS plus 5%BSA for at least 1h at RT and then incubated with BUSINESS.32999895.1 75397743-013WO (218530) phospho-specific pζ (Y142) and pERK (T202Y204) antibodies. As loading control, anti-total CD3ζ (448 rabbit antiserum) antibodies were used. Membranes were developed using either chemoluminescent system (ImageQuant LAS 4000) or X-Ray blue system (Kodak X-OMAT 2000 Processor). Analysis and quantification were done using the ImageJ program. 1.8 Statistical analysis

[0244] All statistical analyses were performed using GraphPad PRISM 7.0. One-way and two-way ANOVA analyses were performed to analyze the significance of the results. Results were considered statistically significant if p<0.05. 2. RESULTS 2.1 Cytokine release by TCR-dependent and CAR-dependent stimuli

[0245] In order to determine if compound A-68 had a differential effect on the activation of Tcells via the TCR and the CAR construct, human blood T cells transduced with an anti-CD19 CAR were stimulated with either beads coated with anti-CD3 plus anti-CD28 antibodies or with the CD19+ human B cell line Raji. The effect of the drug on stimulation was assessed according to the secretion of cytokines IL-2 and IFNγ to the culture supernatant after 24 h of stimulation.

[0246] FIG. 1 depicts effect of compound A-68 on cytokine release by CAR-bearing T cells inresponse to CAR and TCR triggering. Human blood T cells transduced with the anti-CD19 CAR construct were stimulated with either anti-CD3 / CD28-coated beads (3 beads per T cell, Left panel), or with Raji cells at the indicated T cell:Raji cell ratios (Right panel) in the presence of the indicated concentrations of compound A-68. In parallel T-cell:Raji cell co-cultures were incubated with 5 µM of the Lck inhibitor A770041. As a negative control of CAR-dependent cytokine release, CAR-bearing T cells were incubated at a 1:3 effector / target ratio with the CD19-negative human monocytic cell line U937. Data are presented as the mean±SD of triplicate datasets. **, p<0.01; ***, p< 0.001 (Two-way ANOVA test).

[0247] As shown in FIG. 1, compound A-68 inhibited the release of IFNγ in a dose-responsemanner when cells were triggered through the TCR. The release of IL-2 was also significantly inhibited at the concentration of 1 µM (FIG.1, left panel). By contrast, IL-2 and IFNγ release was not affected by addition of CD19+ Raji cells by any of the concentrations of compound A-68 tested. The Lck inhibitor A740041 (FIG. 1, right panel) suggesting that the activation of T cells through the CAR is insensitive to compound A-68 but sensitive to the Lck inhibitor. In conclusion, BUSINESS.32999895.1 76397743-013WO (218530) data in FIG.1 suggest that compound A-68 inhibits T cell activation through the TCR is inhibited by compound A-68 but not T cell activation mediated by the CAR construct. 2.2 CAR-induced T cell proliferation and target cell killing

[0248] In order to determine if compound A-68 affected T cell activation mediated by the CARin assays other than cytokine release, different doses of compound A-68 was first tested in terms of their capacity to inhibit the killing of CD19+ Raji target by the CAR anti-CD19 construct at two different effector-to-target cell ratios.

[0249] FIG.2 depicts effect of compound A-68 on CAR-triggered T cell proliferation and targetcell killing. (a) Human blood T cells transduced with the anti-CD19 CAR construct were incubated for 24 h with CD19+ Raji cells at the indicated effector / target ratios and the concentrations of compound A-68 indicated. The percentage of dead Raji target cells was calculated by flow cytometry using the GhostDye540 as a dead cell marker. A control of Raji cell viability in the absence of effector T cells was carried out in parallel. Data are presented as the mean±sem oftriplicate datasets. (b) Human blood T cells transduced with the anti-CD19 CAR construct wereincubated for 4 days with CD19+ irradiated Raji cells at the effector / target ratio and concentrations of compound A-68 indicated. A negative control with mock-transduced human blood T cells (CAR-negative) was carried out in parallel. The Src kinase inhibitor PP2 was used at a concentration of 20 µM as positive control of CAR signaling blockade. Data are presented as the mean±sem of triplicate datasets.

[0250] At a 1:1 and a 2:1 effector / target ratios, a 35% and 50% of the target cells were killedby the CAR-T cells, respectively (FIG. 2a). Killing efficiency was not inhibited by any of the concentrations of compound A-68 (up to 1 µM), suggesting again that compound A-68 did not affect target cell killing triggered by the CAR.

[0251] It was then interrogated if compound A-68 affected the capacity of CAR-T cells toproliferate in response to stimulation mediated by the CAR construct. To answer this question, CAR19-transduced human T cells and mock-transduced control cells from the same donor were incubated with irradiated Raji cells at two different ratios, and the T cell proliferation was assessed 5 days later according to the capacity of the cells to incorporate tritiated thymidine. As shown in FIG.2b, compound A-68 did not impair T cell proliferation mediated by the CAR, unlike the Src kinase inhibitor PP2 which completely abrogated the CAR-dependent response. The results of BUSINESS.32999895.1 77397743-013WO (218530) FIG.1 and 2 indicate that compound A-68 does not affect T cell activation mediated by the CAR anti-CD19 measured by the release of cytokines, T cell proliferation and target cell killing. 2.3 Effect of Compound A-68 on TCR-triggered allogeneic responses

[0252] In order to determine if compound A-68 inhibited TCR responses to allo-HLA antigens,a mixed lymphocyte reaction (MLR) experiment in one-way was first carried out. In this type of experiment, the proliferation of reacting T cells in response to lethally-irradiated PBMC from an unrelated human blood donor is measured.

[0253] FIG. 3 depicts effect of compound A-68 on TCR-mediated allogeneic responses. (a)Mixed lymphocyte reaction (MLR) of T cells from PBMC of human blood donor 1 mixed at 1:0.5 effector / target ratio with irradiated PBMC from human blood donor 2 for 5 days in the presence of the indicated concentrations of compound A-68. Proliferation of responding cells was assessed by incorporation of tritiated thymidine. As a negative control, PBMC from donor 1 were mixed with irradiated PBMC from the same donor (syngeneic setting) at a 1:0.5 effector / target cell ratio. Data are presented as the mean±SD of septuplicate datasets. ****, p=0.0001; ***, p< 0.001 (One- way ANOVA test). (b) MLR of human T cells from blood donor 1 transduced with the anti-CD19 CAR construct and incubated for 5 days with irradiated PBMC from blood donor 2 at the indicated effector / target cell ratios and the presence of the indicated concentrations of compound A-68. As a negative control, CAR-transduced T cells from donor 1 were mixed with irradiated PBMC from the same donor (syngeneic setting) at the same effector / target cell ratios. The Src kinase inhibitor PP2 was used at a concentration of 20 µM as positive control of TCR signaling inhibition. Data are presented as the mean±SD of triplicate datasets. ****, p=0.0001; ***, p< 0.001; **, p< 0.01; *, p< 0.05 (One-way ANOVA test). (c) IL-2 cytokine release by human T cells from blood donor 1 transduced with the anti-CD19 CAR construct and incubated for 24 h with irradiated PBMC from blood donor 2 at the indicated effector / target cell ratios and the presence of the indicated concentrations of compound A-68. As a negative control, CAR-transduced T cells from donor 1 were mixed with irradiated PBMC from the same donor (syngeneic setting) at the same effector / target cell ratios. The Src kinase inhibitor PP2 was used at a concentration of 20 µM as positive control of TCR signaling inhibition. Data are presented as the mean±SD of triplicate datasets. ***, p< 0.001; **, p< 0.01; *, p< 0.05 (One-way ANOVA test).

[0254] As shown in FIG. 3, mixing PBMC from donor 1 with irradiated cells from donor 2produced an substantial increase in T cell proliferation above the levels registered when donor 1’s BUSINESS.32999895.1 78397743-013WO (218530) PBMC were mixed with irradiated cells of the same donor in an autologous fashion. Such T cell proliferation in response to allo-HLA was already significantly inhibited at concentration of 10 nM compound A-68 and was totally abrogated at a concentration of 1 µM (FIG.3a).

[0255] The experiment in FIG. 3a was carried out by mixing non-transduced PBMC from twoblood donors. To determine if CAR-bearing human T cells could also generate TCR-mediated responses to allo-HLA and if such response is affected by compound A-68, a proliferation experiment in a one-way MLR setting was carried out, but this time using as responding cells human T cells transduced with the CD19-specific CAR. CAR-expressing T cells elicited a dose- dependent proliferative response to allo-HLA that was significantly inhibited by compound A-68 at the lowest concentration tested (10 nM) at produced a dose-response effect depending on the effector-to-target cell ratio (FIG.3b). Interestingly, the Src kinase inhibitor had a non-significant effect in this assay.

[0256] The alloresponse of CAR-bearing T cells was also measured according to the release ofIL-2 produced when CAR-bearing T cells were mixed with irradiated T cells from an unrelated blood donor. Compared to the control in syngeneic conditions, mixing T cells (one bearing the CAR construct) from two different blood donors resulted in an increased release of IL-2 that was totally blocked by compound A-68 at the lowest concentration tested (10 nM, FIG. 3c). Interestingly, unlike in the proliferation experiments of FIG.3b, PP2 inhibited the TCR-triggered release of IL-2 in response to allo-HLA (FIG.3c). 2.4 Effect of Compound A-68 on early TCR and CAR signaling

[0257] Since both the TCR and the anti-CD19 CAR construct contain the cytoplasmic tail ofCD3ζ, a phosphospecific antibody to tyrosine residue 142 was used to determine if compound A- 68 differentially affected that early activation event common to the TCR and the CAR.

[0258] FIG.4 depicts effect of compound A-68 on early CAR and TCR signaling. Human bloodT cells transduced with the anti-CD19 CAR construct were stimulated with either soluble anti- CD3 (10 µg / mL, Left panel), or with Raji cells at a 1:2 effector / target cell ratio (Right panel) for the indicated time points in the presence or not of 10 nM compound A-68. Postnuclear whole cell lysates were subjected to SDS-PAGE under non-reducing conditions and western blotting was sequentially carried out with an anti-phosphoTyr142 of CD3ζ and anti-phosphoERK antibody. The positions of the tyrosine phosphorylated CD3 and CAR construct, and of phosphoERK, are indicated. BUSINESS.32999895.1 79397743-013WO (218530)

[0259] It was found that 10 nM compound A-68 inhibited the time-dependent phosphorylationof CD3ζ when CAR-bearing T cells were stimulated with anti-CD3 antibody but did not affect the phosphorylation of the CAR construct when stimulated with CD19+ Raji B cells (FIG. 4). Likewise, phosphorylation of downstream ERK kinase was inhibited in the presence of 10 nM compound A-68 when T cells were stimulated through the TCR with a soluble antibody but not when stimulated through the CAR (FIG.4). 3. CONCLUSIONS

[0260] Compound A-68 inhibits TCR-mediated T cell activation, both in response to anti-CD3antibodies and in response to human cells with unmatched HLA. Thus, compound A-68 inhibits human T cell alloresponses at concentrations of 10 nM.

[0261] Compound A-68 did not affect the activity of a CD19-specific CAR construct expressedin primary human T cells in terms of inducing cytokine production, T cell proliferation and target cell killing at concentrations up to 1 µM. INCORPORATION BY REFERENCE

[0262] The entire disclosure of each of the patent documents and scientific articles referred toherein is incorporated by reference for all purposes. EQUIVALENTS

[0263] The disclosure may be embodied in other specific forms without departing from thespirit or essential characteristics thereof. The foregoing embodiments are therefore to be considered in all respects illustrative rather than limiting the disclosure described herein. Scope of the disclosure is thus indicated by the appended claims rather than by the foregoing description, and all changes that come within the meaning and range of equivalency of the claims are intended to be embraced therein. BUSINESS.32999895.1 80

Claims

397743-013WO (218530) CLAIMS 1. A method for treating a disease or disorder in a patient, comprising administering atherapeutically effective amount of a chromene derivative, and a therapeutically effective amountof a CAR-T therapy to the patient, wherein the chromene derivative is a compound of Formula A- I:or a pharmaceutically acceptable salt thereof, wherein: R1is R, halogen, -CN, -OR, or -N(R)2; R2is R, halogen, -C(O)N(R)2, or -N(R)2; R3is hydrogen or an electron withdrawing group; each R is independently hydrogen or an optionally substituted group selected from C1-6aliphatic, a 3-8 member saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or two R groups on the same nitrogen are taken together with their intervening atoms to form an optionally substituted 5-6 membered heterocyclic ring having 0-1 heteroatoms in addition to the nitrogen attached thereto wherein such heteroatom is oxygen, nitrogen, or sulfur; L1is a covalent bond or a C1-4bivalent straight or branched saturated or unsaturated hydrocarbon chain wherein 1-2 methylene units of the chain are independently and optionally replaced with -O-, -C(O)-, -C(O)O-, -OC(O)-, -C(S)-, -C(R)2-, -C(F)2-, -N(R)-, -C(O)N(R)-, -RNC(O)-, - OC(O)N(R)-, -N(R)C(O)N(R) -, or -Cy-; BUSINESS.32999895.1 81397743-013WO (218530) L2is a covalent bond or a C1-4bivalent straight or branched saturated or unsaturated hydrocarbon chain wherein 1-2 methylene units of the chain are independently and optionally replaced with -O-, -C(O)-, -C(O)O-, -OC(O)-, -C(S)-, -C(R)2-, -CH(R)-, -C(F)2-, -N(R)-, -C(O)N(R)-, - RNC(O)-, -OC(O)N(R)-, or -N(R)C(O)N(R) -; and Cy is a bivalent optionally substituted 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, optionally substituted phenylene, an optionally substituted 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, an optionally substituted 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

2. A method for preventing or reducing an autoimmune reaction associated with a CAR-T therapy in a patient having a disease or disorder, comprising administering a therapeuticallyeffective amount of a chromene derivative, and a therapeutically effective amount of a CAR-Ttherapy to the patient, wherein the chromene derivative is a compound of Formula A-I:or a pharmaceutically acceptable salt thereof, wherein: R1is R, halogen, -CN, -OR, or -N(R)2; R2is R, halogen, -C(O)N(R)2, or -N(R)2; R3is hydrogen or an electron withdrawing group; each R is independently hydrogen or an optionally substituted group selected from C1-6 aliphatic, a 3-8 member saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or BUSINESS.32999895.1 82397743-013WO (218530) two R groups on the same nitrogen are taken together with their intervening atoms to form an optionally substituted 5-6 membered heterocyclic ring having 0-1 heteroatoms in addition to the nitrogen attached thereto wherein such heteroatom is oxygen, nitrogen, or sulfur; L1is a covalent bond or a C1-4 bivalent straight or branched saturated or unsaturated hydrocarbon chain wherein 1-2 methylene units of the chain are independently and optionally replaced with -O-, -C(O)-, -C(O)O-, -OC(O)-, -C(S)-, -C(R)2-, -C(F)2-, -N(R)-, -C(O)N(R)-, -RNC(O)-, - OC(O)N(R)-, -N(R)C(O)N(R) -, or -Cy-; L2is a covalent bond or a C1-4 bivalent straight or branched saturated or unsaturated hydrocarbon chain wherein 1-2 methylene units of the chain are independently and optionally replaced with -O-, -C(O)-, -C(O)O-, -OC(O)-, -C(S)-, -C(R)2-, -CH(R)-, -C(F)2-, -N(R)-, -C(O)N(R)-, - RNC(O)-, -OC(O)N(R)-, or -N(R)C(O)N(R) -; and Cy is a bivalent optionally substituted 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, optionally substituted phenylene, an optionally substituted 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, an optionally substituted 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

3. A method for increasing or improving a CAR-T therapy effectiveness in a patient having a disease or disorder, comprising administering a therapeutically effective amount of a chromenederivative, and a therapeutically effective amount of a CAR-T therapy to the patient, wherein thechromene derivative is a compound of Formula A-I:or a pharmaceutically acceptable salt thereof, wherein: R1is R, halogen, -CN, -OR, or -N(R)2; BUSINESS.32999895.1 83397743-013WO (218530) R2is R, halogen, -C(O)N(R)2, or -N(R)2; R3is hydrogen or an electron withdrawing group; each R is independently hydrogen or an optionally substituted group selected from C1-6 aliphatic, a 3-8 member saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or two R groups on the same nitrogen are taken together with their intervening atoms to form an optionally substituted 5-6 membered heterocyclic ring having 0-1 heteroatoms in addition to the nitrogen attached thereto wherein such heteroatom is oxygen, nitrogen, or sulfur; L1is a covalent bond or a C1-4 bivalent straight or branched saturated or unsaturated hydrocarbon chain wherein 1-2 methylene units of the chain are independently and optionally replaced with -O-, -C(O)-, -C(O)O-, -OC(O)-, -C(S)-, -C(R)2-, -C(F)2-, -N(R)-, -C(O)N(R)-, -RNC(O)-, - OC(O)N(R)-, -N(R)C(O)N(R) -, or -Cy-; L2is a covalent bond or a C1-4bivalent straight or branched saturated or unsaturated hydrocarbon chain wherein 1-2 methylene units of the chain are independently and optionally replaced with -O-, -C(O)-, -C(O)O-, -OC(O)-, -C(S)-, -C(R)2-, -CH(R)-, -C(F)2-, -N(R)-, -C(O)N(R)-, - RNC(O)-, -OC(O)N(R)-, or -N(R)C(O)N(R) -; and Cy is a bivalent optionally substituted 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, optionally substituted phenylene, an optionally substituted 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, an optionally substituted 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. BUSINESS.32999895.1 84397743-013WO (218530) 4. The method of any one of claims 1-3, wherein the disease or disorder is the group consisting of Acute lymphoblastic leukemia (ALL), B-cell lymphoma, Follicular lymphoma (FL), Mantle cell lymphoma, and Multiple myeloma.

5. The method of any one of claims 1-4, wherein the CAR-T therapy is selected from the group consisting of BREYANZI® (lisocabtagene maraleucel), TECARTUS™ (brexucabtagene autoleucel), KYMRIAH™ (tisagenlecleucel), YESCARTA™ (axicabtagene ciloleucel), ABECMA® (idecabtagene vicleucel), or CARVYKTI™ (ciltacabtagene autoleucel).

6. The method of any one of claims 1-5, wherein the CAR-T therapy is an allogeneic CAR- T therapy, i.e., T cells of the CAR-T therapy is allogeneic to the patient.

7. The method of any one of claims 1-6, wherein the chromene derivative inhibits T cell activation mediated by TCR.

8. The method of any one of claims 1-7, wherein the chromene derivative inhibits cytokine (e.g., IFNγ, IL-2, etc.) release mediated by TCR.

9. The method of any one of claims 1-8, wherein the chromene derivative inhibits T cell proliferation and / or T cell efficiency in killing target cells mediated by TCR.

10. The method of any one of claims 1-9, wherein the chromene derivative inhibits phosphorylation of CD3ζ and / or ERK kinase mediated by TCR.

11. The method of any one of claims 1-10, wherein the chromene derivative is administered with the CAR-T therapy simultaneously, or sequentially in separate unit dosage forms or together in a single unit dosage form.

12. The method of any one of claims 1-11, wherein the chromene derivative is a compound of Formulae: BUSINESS.32999895.1 85397743-013WO (218530)BUSINESS.32999895.1 86397743-013WO (218530)13. The method of any one of claims 1-12, wherein R2is -N(R)2wherein the two R groups on the nitrogen are taken together with their intervening atoms to form an optionally substituted 5-6 membered heterocyclic ring having 0-1 heteroatoms in addition to the nitrogen attached thereto wherein such heteroatom is oxygen, nitrogen, or sulfur.

14. The method of claim 13, wherein R2i ,.BUSINESS.32999895.1 87397743-013WO (218530) 15. The method of any one of claims 1-14, wherein R3is halogen, -CN, -NO2, or C1-4aliphatic substituted with 1-9 halogens.

16. The method of claim 15, wherein R3is C1-4aliphatic substituted with 1-9 halogens, optionally wherein R3is selected fro .

17. The method of claim 15, wherein R3is halogen, optionally wherein R3is F.

18. The method of any one of claims 1-17, wherein L1is a C1-4bivalent straight or branched saturated or unsaturated hydrocarbon chain wherein 1-2 methylene units of the chain are independently and optionally replaced with -O-, -C(O)-, -C(O)O-, -OC(O)-, -C(S)-, -C(R)2-, - CH(R)-, -C(F)2-, -N(R)-, -C(O)N(R)-, -RNC(O)-, -OC(O)N(R)-, -N(R)C(O)N(R) -, or -Cy-.

19. The method of claim 18, wherein L1is a C1-4 bivalent straight or branched saturated or unsaturated hydrocarbon chain wherein 1-2 methylene units of the chain are independently and optionally replaced with -O-, -C(R)2-, -C(O)N(R)-, or -RNC(O)-.

20. The method of claim 18, wherein L1is a C1-4 bivalent straight or branched saturated or unsaturated hydrocarbon chain wherein 1-2 methylene unit of the chain is replaced with -O- or - C(O)-. or22. The method of any one of claims 1-21, wherein L2is C1-4bivalent straight or branched saturated or unsaturated hydrocarbon chain wherein 1 methylene unit of the chain is optionally replaced with -C(O)-. BUSINESS.32999895.1 88397743-013WO (218530) 23. The method of any one of claims 1-22, wherein the compound is selected from those as set forth in Table 1, or a pharmaceutically acceptable salt thereof. BUSINESS.32999895.1 89

Images