Combination of a chromene derivative TCR inhibitor and a PDE4 inhibitor

Abstract

Provided herein are methods and compositions involving chromene derivatives acting as TCR or TCR-Nck inhibitors, and PDE4 inhibitors. The provided methods include the use of a chromene derivative in combination with a PDE4 inhibitor for treating a disease or disorder.

Description

COMBINATION OF A CHROMENE DERIVATIVE TCR INHIBITOR AND A PDE4 INHIBITOR CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of and priority to United States Provisional Patent Application serial number 63 / 655,425, 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 use of a chromene derivative in combination with a PDE4 inhibitor 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 and TCRβ 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 tyrosine residues 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)).

[0005] However, the TCR contains motifs additional to the ITAMs and recruit intracellular signaling 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 combination of a chromene derivative as described herein and a PDE4 inhibitor has unexpected advantages compared to each therapeutic agent alone in treating diseases, disorders, or conditions. See, for example, the combination effect as shown in Table 1-1 and FIGs.1-18. Accordingly, provided herein are methods for treating a disease or disorder in a patient, comprising administering to the patient a chromene derivative, in combination with a PDE4 inhibitor.

[0007] In one aspect, the present disclosure provides a method for treating a disease or disorder in a patient, comprising administering a therapeutically effective amount of a chromene derivative, and a therapeutically effective amount of a PDE4 inhibitor to the patient.

[0008] In another aspect, the present disclosure provides a method for increasing or improving a PDE4 inhibitor’s effectiveness in treating a disease or disorder in a patient, comprising administering to the patient a therapeutically effective amount of a chromene derivative, in combination with the PDE4 inhibitor.

[0009] In another aspect, the present disclosure provides a method for increasing or improving a chromene derivative’s effectiveness in treating a disease or disorder in a patient, comprising administering to the patient a therapeutically effective amount of a PDE4 inhibitor, in combination with the chromene derivative.

[0010] In another aspect, the present disclosure provides a composition comprising a therapeutically effective amount of a chromene derivative and a therapeutically effective amount of a PDE4 inhibitor.

[0011] In some embodiments, a chromene derivative is selected from the chromene derivatives as described herein. In some embodiments, a disease or disorder is selected from the diseases and disorders as described herein. In some embodiments, a PDE4 inhibitor is selected from the PDE4 inhibitors as described herein. BRIEF DESCRIPTION OF FIGURES

[0012] FIG. 1 depicts TNFα Cytokine Release after 48 Hours for a comparison of a dose response Otezla® with or without 10 nM A-33.

[0013] FIG. 2 depicts IFNγ Cytokine Release after 48 Hours for a comparison of a dose response Otezla® with or without 10 nM A-33.

[0014] FIG. 3 depicts IL-2 Cytokine Release after 48 Hours for a comparison of a dose response Otezla® with or without 10 nM A-33.

[0015] FIG. 4 depicts IL-17 Cytokine Release after 48 Hours for a comparison of a dose response Otezla® with or without 10 nM A-33.

[0016] FIG. 5 depicts IL-5 Cytokine Release after 48 Hours for a comparison of a dose response Otezla® with or without 10 nM A-33.

[0017] FIG. 6 depicts IL-13 Cytokine Release after 48 Hours for a comparison of a dose response Otezla® with or without 10 nM A-33.

[0018] FIG.7 depicts IL-2 Cytokine Release after 48 Hours for a comparison of multiple doses of Otezla® and multiple doses of A-33.

[0019] FIG.8 depicts IL-2 Cytokine Release after 48 Hours (Axis Reversed) for a comparison of multiple doses of Otezla® and multiple doses of A-33.

[0020] FIG. 9 depicts IL-2 Cytokine Release after 48 Hours for a comparison of a dose response of Otezla® with multiple doses of A-33.

[0021] FIG. 10 depicts TNFα Cytokine Release after 48 Hours for a comparison of multiple doses of Otezla® and multiple doses of A-33.

[0022] FIG. 11 depicts TNFα Cytokine Release after 48 Hours (Axis Reversed) for a comparison of multiple doses of Otezla® and multiple doses of A-33.

[0023] FIG. 12 depicts TNFα Cytokine Release after 48 Hours for a comparison of a dose response of Otezla® with multiple doses of A-33.

[0024] FIG. 13 depicts IFNγ Cytokine Release after 48 Hours for a comparison of multiple doses of Otezla® and multiple doses of A-33.

[0025] FIG. 14 depicts IFNγ Cytokine Release after 48 Hours (Axis Reversed) for a comparison of multiple doses of Otezla® and multiple doses of A-33.

[0026] FIG. 15 depicts IFNγ Cytokine Release after 48 Hours for a comparison of a dose response of Otezla® with multiple doses of A-33.

[0027] FIG.16 depicts IL-17A Cytokine Release after 48 Hours for a comparison of multiple doses of Otezla® and multiple doses of A-33.

[0028] FIG. 17 depicts IL-17A Cytokine Release after 48 Hours (Axis Reversed) for a comparison of multiple doses of Otezla® and multiple doses of A-33.

[0029] FIG. 18 depicts IL-17A Cytokine Release after 48 Hours for a comparison of a dose response of Otezla® with multiple doses of A-33. DETAILED DESCRIPTION OF THE DISCLOSURE 1. General Description of Certain Embodiments of the Disclosure

[0030] In one aspect, the present disclosure provides a method for treating a disease or disorder in a patient, comprising administering a therapeutically effective amount of a chromene derivative as described herein, and a therapeutically effective amount of a PDE4 inhibitor to the patient.

[0031] In another aspect, the present disclosure provides a use of a therapeutically effective amount of a chromene derivative as described herein, and a therapeutically effective amount of a PDE4 inhibitor, for treating a disease or disorder in a patient.

[0032] In another aspect, the present disclosure provides a use of a therapeutically effective amount 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 PDE4 inhibitor.

[0033] In some embodiments, a chromene derivative as described herein inhibits T cell activation mediated by TCR in a patient, wherein the patient receives a PDE4 inhibitor.

[0034] In some embodiments, a chromene derivative as described herein inhibits cytokine (e.g., TNFα, IFNγ, IL-2, ILK-17A, etc.) release mediated by TCR in a patient, wherein the patient receives a PDE4 inhibitor.

[0035] 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 PDE4 inhibitor.

[0036] 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 PDE4 inhibitor.

[0037] In another aspect, the present disclosure provides a composition comprising a therapeutically effective amount of a chromene derivative as described herein and a PDE4 inhibitor. 2. Definitions

[0038] Compounds of the present invention include those described generally herein, and are further illustrated by the classes, subclasses, and species disclosed herein. As used herein, the following definitions shall apply unless otherwise indicated. For purposes of this 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.

[0039] 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 1-4aliphatic 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-C6hydrocarbon 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 alkyl, alkenyl, alkynyl groups and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.

[0040] As used herein, the term “bicyclic ring” or “bicyclic ring system” refers to any bicyclic ring system, i.e. carbocyclic or heterocyclic, saturated or having one or more units of unsaturation, having one or more atoms in common between the two rings of the ring system. Thus, the term includes any permissible ring fusion, such as ortho-fused or spirocyclic. As used herein, the term “heterobicyclic” is a subset of “bicyclic” that requires that one or more heteroatoms are present in one or both rings of the bicycle. Such heteroatoms may be present at ring junctions and are optionally substituted, and may be selected from nitrogen (including N-oxides), oxygen, sulfur (including oxidized forms such as sulfones and sulfonates), phosphorus (including oxidized forms such as phosphates), boron, etc. In some embodiments, a bicyclic group has 7-12 ring members and 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. As used herein, the term “bridged bicyclic” refers to any bicyclic ring system, i.e. carbocyclic or heterocyclic, saturated or partially unsaturated, having at least one bridge. As defined by IUPAC, a “bridge” is an unbranched chain of atoms or an atom or a valence bond connecting two bridgeheads, where a “bridgehead” is any skeletal atom of the ring system which is bonded to three or more skeletal atoms (excluding hydrogen). In some embodiments, a bridged bicyclic group has 7-12 ring members and 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Such bridged bicyclic groups are well-known in the art and include those groups set forth below where each group is attached to the rest of the molecule at any substitutable carbon or nitrogen atom. Unless otherwise specified, a bridged bicyclic group is optionally substituted with one or more substituents as set forth for aliphatic groups. Additionally or alternatively, any substitutable nitrogen of a bridged bicyclic group is optionally substituted. Exemplary bicyclic rings include:Exemplary bridged bicyclics include:

[0041] The term “lower alkyl” refers to a C1–4straight or branched alkyl group. Exemplary lower alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl.

[0042] The term “lower haloalkyl” refers to a C1–4straight or branched alkyl group that is substituted with one or more halogen atoms.

[0043] The term “heteroatom” means one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon (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)).

[0044] The term "unsaturated," as used herein, means that a moiety has one or more units of unsaturation.

[0045] As used herein, the term “bivalent C1–4(or C1–6) saturated or unsaturated, straight or branched, hydrocarbon chain”, refers to bivalent alkylene, alkenylene, and alkynylene chains that are straight or branched as defined herein.

[0046] The term “alkylene” refers to a bivalent alkyl group. An “alkylene chain” is a polymethylene 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.

[0047] The term “alkenylene” refers to a bivalent alkenyl group. A substituted alkenylene chain is a polymethylene group containing at least one double bond in which one or more hydrogenatoms are replaced with a substituent. Suitable substituents include those described below for a substituted aliphatic group.

[0048] As used herein, the term “cyclopropylenyl” refers to a bivalent cyclopropyl group of the following structure:.

[0049] The term “halogen” means F, Cl, Br, or I.

[0050] 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.

[0051] 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 “heteroarylring,” “heteroaryl group,” or “heteroaromatic,” any of which terms include rings that are optionally substituted. The term “heteroaralkyl” refers to an alkyl group substituted by a heteroaryl, wherein the alkyl and heteroaryl portions independently are optionally substituted.

[0052] 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).

[0053] A heterocyclic ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure and any of the ring atoms can be optionally substituted. Examples of such saturated or partially unsaturated heterocyclic radicals include, without limitation, tetrahydrofuranyl, 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.

[0054] As used herein, the term “partially unsaturated” refers to a ring moiety that includes at least 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.

[0055] 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 ateach substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same 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.

[0056] Suitable monovalent substituents on a substitutable carbon atom of an “optionally substituted” group are independently halogen; -(CH2)0–4Rº; -(CH2)0–4ORº; -O(CH2)0-4Rº, -O- (CH2)0–4C(O)OR°; -(CH2)0–4CH(ORº)2; -(CH2)0–4SRº; -(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(Rº)2; -(CH2)0–4N(Rº)C(O)Rº; -N(Rº)C(S)Rº; -(CH2)0–4N(Rº)C(O)NRº2; -N(Rº)C(S)NRº2; -(CH2)0–4N(Rº)C(O)ORº; - N(Rº)N(Rº)C(O)Rº; -N(Rº)N(Rº)C(O)NRº2; -N(Rº)N(Rº)C(O)ORº; -(CH2)0–4C(O)Rº; -C(S)Rº; -(CH2)0–4C(O)ORº; -(CH2)0–4C(O)SRº; -(CH2)0–4C(O)OSiRº3; -(CH2)0–4OC(O)Rº; - OC(O)(CH2)0–4SRº; SC(S)SR°; -(CH2)0–4SC(O)Rº; -(CH2)0–4C(O)NRº2; -C(S)NRº2; –C(S)SR°; - SC(S)SR°; -(CH2)0–4OC(O)NRº2; -C(O)N(ORº)Rº; -C(O)C(O)Rº; -C(O)CH2C(O)Rº; - C(NORº)Rº; -(CH2)0–4SSRº; -(CH2)0–4S(O)2Rº; -(CH2)0–4S(O)2ORº; -(CH2)0–4OS(O)2Rº; - S(O)2NRº2; -S(O)(NRº)Rº; -S(O)2N=C(NRº2)2; -(CH2)0–4S(O)Rº; -N(Rº)S(O)2NRº2; - N(Rº)S(O)2Rº; -N(ORº)Rº; -C(NH)NRº2; -P(O)2Rº; -P(O)Rº2; -OP(O)Rº2; -OP(O)(ORº)2; - SiRº3; -(C1–4straight or branched alkylene)O–N(Rº)2; or -(C1–4straight or branched alkylene)C(O)O–N(Rº)2, wherein each Rº may be substituted as defined below and is independently hydrogen, C1–6aliphatic, -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 Rº, taken together with their intervening atom(s), form a 3–12– membered saturated, partially unsaturated, or aryl mono– or bicyclic ring having 0–4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, which may be substituted as defined below.

[0057] Suitable monovalent substituents on Rº (or the ring formed by taking two independent occurrences of Rº 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●; -(C1–4straight 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 C1–4aliphatic, - 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 Rº include =O and =S.

[0058] 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, C1–6 aliphatic which may be substituted as defined below, or an unsubstituted 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable 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.

[0059] Suitable substituents on the aliphatic group of R* include halogen, -R●; -(haloR●); -OH, -OR●; -O(haloR●); -CN; -C(O)OH; -C(O)OR●; -NH2; -NHR●; -NR●2; or -NO2; wherein each R●is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C1–4aliphatic, -CH2Ph; -O(CH2)0–1Ph; or a 5–6–membered saturated; partially unsaturated; or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0060] Suitable substituents on a substitutable nitrogen of an “optionally substituted” group include -R†; -NR†2; -C(O)R†; -C(O)OR†; -C(O)C(O)R†; -C(O)CH2C(O)R†; -S(O)2R†; -S(O)2NR†2;-C(S)NR†2; -C(NH)NR†2; or -N(R†)S(O)2R†; wherein each R†is independently hydrogen, C1–6aliphatic which may be substituted as defined below, unsubstituted –OPh, or an unsubstituted 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 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.

[0061] Suitable substituents on the aliphatic group of R†are independently halogen, - R●; -(haloR●); -OH; -OR●; -O(haloR●); -CN; -C(O)OH; -C(O)OR●; -NH2; -NHR●; -NR●2; or -NO2; wherein each R●is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C1–4aliphatic, -CH2Ph; -O(CH2)0–1Ph; or a 5–6– membered saturated; partially unsaturated; or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0062] As used herein, the term "pharmaceutically acceptable salt" refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well- known in the art. For example, S. M. Berge et al., 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.

[0063] Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N+(C1–4alkyl)4salts. 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.

[0064] 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.

[0065] As used herein, the term “provided compound” or “compound of the invention” refers to 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.

[0066] As used herein, the term “inhibitor” is defined as a compound that binds to and / or inhibits 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 μM, less than about 50 μM, less than about 1 μM, less than about 500 nM, less than about 100 nM, less than about 10 nM, or less than about 1 nM.

[0067] The terms “measurable affinity” and “measurably inhibit,” as used herein, means a measurable change in a target protein or receptor activity (e.g., TCR activity or TCR-Nck 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.

[0068] The term “modulate” and “modulating,” as used herein, means to influence or alter the activity. Modulation comprises stabilization, destabilization, enhancement, and suppression.

[0069] 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

[0070] In one aspect, the present disclosure provides a method for treating a disease or disorder in a patient, comprising administering a therapeutically effective amount of a chromene derivative as described herein, and a therapeutically effective amount of a PDE4 inhibitor to the patient.

[0071] In another aspect, the present disclosure provides a method for increasing or improving a PDE4 inhibitor’s effectiveness, comprising administering to the patient a therapeutically effective amount of a chromene derivative as described herein, in combination with the PDE4 inhibitor.

[0072] In another aspect, the present disclosure provides a method for inhibiting T cell activation mediated by TCR in a patient, comprising administering a therapeutically effective amount of a chromene derivative to the patient, wherein the patient receives a PDE4 inhibitor. In some embodiments, the present disclosure provides a method for inhibiting cytokine (e.g., TNFα, IFNγ, IL-2, ILK-17A, 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 PDE4 inhibitor. 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 patient, wherein the patient receives a PDE4 inhibitor. In some embodiments, the presentdisclosure 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 PDE4 inhibitor.

[0073] In another aspect, the present disclosure provides a composition comprising a therapeutically effective amount of a chromene derivative as described herein and a PDE4 inhibitor.

[0074] In some embodiments, a chromene derivative is selected from the chromene derivatives as described herein. In some embodiments, a chromene derivative isor a pharmaceutically acceptable salt thereof.

[0075] In some embodiments, a disease or disorder is selected from the diseases or disorders as described herein. In some embodiments, a disease or disorder is Chronic Obstructive Pulmonary Disease (COPD), psoriasis, eczema, or psoriatic arthrititis.

[0076] In some embodiments, a disease or disorder is selected from Krabbe disease, ASL, Glioblastoma, Migraine headache, plaque psoriasis, Atopic dermatitis (AD), Rheumatoid Arthritis, ulcerative colitis, plaque psoriasis, Behçet Disease, ankylosing spondylitis, Seborrheic Dermatitis, Papulopustular Rosacea, Asthma, COPD, Morphea, Brain binding, nervous system disease, PET, major depressive disorder, Alzheimer’s disease, NASH, Allergic Rhinitis, Discoid Lupus Erythematosus, juvenile Batten disease, Huntington’s disease, Psoriasis, Rosacea, psoriasis vulgaris, Fragile X syndrome, Depression, Dementia, Cerebrovascular disorder, and major depressive disorder.

[0077] In some embodiments, a PDE4 inhibitor is Otezla® (Apremilast). In some embodiments, a PDE4 inhibitor is Daliresp® (roflumilast), Zoryve® (roflumilast), or Eucrisa® (Crisaborole).

[0078] In some embodiments, a PDE4 inhibitor is Ibudilast, Orismilast (LEO-32731), Mufemilast (Hemay-005), PF-07038124 (Pfizer), Tanimilast (CHF6001), Crisaborole, Rolipram (HT-0712), MK0952 (Merck Sharp & Dohme LLC), ASP9831 (Astellas Pharma Inc), GW842470X (GlaxoSmithKline), BLX-028914 (Dart NeuroScience, LLC), Apremilast (CC-10004), GSK256066 (GlaxoSmithKline), PF-06266047 (Pfizer), GSK356278 (GlaxoSmithKline), Oglemilast (GRC3886), Cilomilast, MK-0873 (Merck Sharp & Dohme LLC), Revamilast, Pefcalcitol (M518101), DRM02 (Dermira, Inc.), LEO-29102 (Leo Pharma), OPA-15406 (Otsuka Pharmaceutical Co., Ltd.), E6005 (Dermavant Sciences GmbH), Zatomilast (BPD14770), Roflumilast.

[0079] In one aspect, the present disclosure provides a method for treating psoriasis in a patient, comprising administering a therapeutically effective amount of a chromene derivative compound A-33, or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of Otezla® (Apremilast) to the patient.

[0080] In one aspect, the present disclosure provides a method for treating psoriatic arthritis in a patient, comprising administering a therapeutically effective amount of a chromene derivative compound A-33, or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of Otezla® (Apremilast) to the patient.

[0081] In one aspect, the present disclosure provides a method for treating atopic dermatitis in a patient, comprising administering a therapeutically effective amount of a chromene derivative compound A-33, or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of Otezla® (Apremilast) to the patient. In some embodiments, an atopic dermatitis patient is an adult or a child 12 years of age and older.

[0082] In one aspect, the present disclosure provides a method for treating Discoid Lupus Erythematosus in a patient, comprising administering a therapeutically effective amount of a chromene derivative compound A-33, or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of Otezla® (Apremilast) to the patient.

[0083] In one aspect, the present disclosure provides a method for treating eczema in a patient, comprising administering a therapeutically effective amount of a chromene derivative compound A-33, or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of Otezla® (Apremilast) to the patient. I. Exemplary Chromene Derivatives

[0084] In certain embodiments, a chromene derivative is selected from those as described in WO 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

[0085] In certain embodiments, a 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-;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.

[0086] In some embodiments, a chromene derivative is a compound of Formula A-I wherein said compound is other than:

[0087] In some embodiments, a chromene derivative is a compound of Formula A-I wherein said compound is other than:

[0088] As defined above and described herein, R1is R, halogen, -CN, -OR, or -N(R)2.

[0089] In some embodiments, R1is hydrogen.

[0090] In some embodiments, R1is halogen or -CN.

[0091] In some embodiments, R1is R, -OR, or -N(R)2.

[0092] In some embodiments, R1is -CH3, -CD3, -CH(CH3)2,

[0093] In some embodiments, R1is

[0094] In some embodiments, R1is R. In some embodiments, 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 C1-6alkyl substituted 1 time by - COOH.

[0095] In some embodiments, R1is

[0096] In some embodiments, R1is

[0097] In some embodiments, R1is

[0098] In some embodiments R1is phenyl.

[0099] In some embodiments, R1is

[0100] In some embodiments, R1is selected from those depicted in Table 1, below.

[0101] As defined above and described herein, R2is R, halogen, -C(O)N(R)2, or -N(R)2.

[0102] In some embodiments, R2is hydrogen.

[0103] In some embodiments, R2is R.

[0104] In some embodiments, R2is halogen.

[0105] In some embodiments, R2is -C(O)N(R)2, or -N(R)2.

[0106] In some embodiments, R2is -C(O)N(R)2, or -N(R)2wherein 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.

[0107] In some embodiments, R2is -C(O)N(R)2, or -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.

[0108] In some embodiments, R2is -N(R)2wherein the two R groups on the nitrogen are taken together 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.

[0109] In some embodiments, R2is -NCH2CH3or -N(CH2)2N(CH3)2.

[0110] In some embodiments, R2is

[0111] In some embodiments, R2is

[0112] In some embodiments, R2is

[0113] In some embodiments, R2is

[0114] In some embodiments, R2is selected from those depicted in Table 1, below.

[0115] As defined above and described herein, R3is hydrogen or an electron withdrawing group.

[0116] In some embodiments, R3is hydrogen.

[0117] In other embodiments, R3is an electron withdrawing group. Electron withdrawing groups are well-known to one of ordinary skill in the art and include those described in detail in March’s Advanced Organic Chemistry, 5thEd., Ed.: Smith, M.B. and March, J., John Wiley & Sons, New York: 2001.

[0118] In some embodiments, R3is an electron withdrawing group selected from halogen, - CN, -NO2, or C1–4aliphatic substituted with 1-9 halogens.

[0119] In some embodiments, R3is halogen.

[0120] In some embodiments, R3is fluoro, chloro, or bromo.

[0121] In some embodiments, R3is fluoro.

[0122] In some embodiments, R3is selected from

[0123] In some embodiments, R3is

[0124] In some embodiments R3is selected from those depicted in Table 1, below.

[0125] As defined above and described herein, 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.

[0126] In some embodiments R is selected from those depicted in Table 1, below.

[0127] As defined above and described herein, 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-.

[0128] In some embodiments, L1is a covenant bond.

[0129] In some embodiments, 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-, -C(F)2-, -N(R)-, -C(O)N(R)-, - RNC(O)-, -OC(O)N(R)-, or -N(R)C(O)N(R) -.

[0130] In some embodiments, 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(R)2-, -C(O)N(R)-, or -RNC(O)-.

[0131] In some embodiments, L1is a C1–4bivalent straight 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)-.

[0132] In some embodiments, L1is a C1–4bivalent 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)-.

[0133] In some embodiments, L1is -O-.

[0134] In some embodiments, L1is

[0135] In some embodiments, L1is

[0136] In some embodiments L1is selected from those depicted in Table 1, below.

[0137] As defined above and described herein, 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) -.

[0138] In some embodiments, L2is a covalent bond.

[0139] In other embodiments, L2is 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) -.

[0140] In some embodiments, L2is a C1–4bivalent straight or branched saturated or unsaturated hydrocarbon 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)-.

[0141] In some embodiments, L2is a C1–4bivalent straight or branched saturated or unsaturated hydrocarbon chain.

[0142] In some embodiments, L2is -C(O)-.

[0143] In some embodiments, L2is -CH2- or -(CH2)2-.

[0144] In some embodiments L2is selected from those depicted in Table 1, below.

[0145] As defined generally above, each -Cy- is independently 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, 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.

[0146] In some embodiments, -Cy- is a bivalent optionally substituted 3-8 membered saturated or 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.

[0147] In some embodiments, -Cy- is

[0148] In some embodiments, -Cy- is selected from those depicted in Table 1, below.

[0149] In some embodiments, a chromene derivative is a compound of Formula A-II:or a pharmaceutically acceptable salt thereof, wherein each R1, R2, R3, R, L1, L2, and -Cy- is 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-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.

[0151] Is some embodiments, a chromene derivative is a compound of Formulae A-IV-a, A- IV-b, A-IV-c, or A-IV-d: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.

[0152] Is 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 pharmaceutically acceptable salt thereof, wherein each R1and R is defined above and described in the embodiments herein, both singly and in combination.

[0153] Is 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:or a pharmaceutically acceptable salt thereof, wherein each R1and R, 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 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.

[0155] In some embodiments, a chromene derivative is a compound of Formula A-VIII: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.

[0156] 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.

[0157] In some embodiments, a chromene derivative is a compound of Formula A-X: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.

[0158] In some embodiments, a chromene derivative is a compound of Formulae A-XI-a or XI-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.

[0159] 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.

[0160] In some embodiments, a chromene derivative is a compound of Formula A-XIII:or a pharmaceutically acceptable salt thereof, wherein each R1, R2, R3, and L2, is defined above and described in the embodiments herein, both singly and in combination.

[0161] Exemplary compounds of Formula A-I are set forth in Table 1, below. Table 1. Exemplary Compounds

[0162] In some embodiments, a chromene derivative is a compound set forth in Table 1, above, or a pharmaceutically acceptable salt thereof.

[0163] In certain embodiments, a chromene derivative isA-33, or a pharmaceutically acceptable salt thereof.

[0164] In certain embodiments, a chromene derivative isor a pharmaceutically acceptable salt thereof. Chromene Derivatives of Formula B-I

[0165] In certain embodiments, a chromene derivative is a compound of Formula B-I:or a pharmaceutically acceptable salt, isomer or solvate thereof 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-C6cycloalkyl, 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; R4is halogen; and R5, R6, R7and R8are independently selected from hydrogen, C1-C4alkyl, C3-C6cycloalkyl, aryl, heteroaryl and halogen.

[0166] In certain embodiments, a chromene derivative is a compound of Formula B-II:or a pharmaceutically acceptable salt, isomer or solvate thereof wherein: R1is selected from hydrogen, substituted or not substituted C1-C6alkyl, substituted or not substituted C3-C6cycloalkyl, substituted or not substituted aryl or substituted or not substituted heteroaryl, —COR5, —C(O)OR5, —C(O)NR5R6, —CNR5; R2and R3are independently selected from hydrogen, substituted or not substituted C1-C6alkyl, substituted or not substituted C3-C6cycloalkyl, 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; R4is halogen; R5, R6, R7and R8are independently selected from hydrogen, C1-C4alkyl, C3-C6cycloalkyl, aryl, heteroaryl and halogen.

[0167] 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

[0168] In certain embodiments, a chromene derivative is a compound of Formula C-I:or a pharmaceutically acceptable salt, isomer or solvate thereof wherein: R1is selected from hydrogen, substituted or not substituted C1-C6alkyl, substituted or not substituted C3-C6cycloalkyl, substituted or not substituted aryl or substituted or not substituted heteroaryl, —COR5, —C(O)OR5, —C(O)NR5R6, —CNR5; R2and R3are independently selected from hydrogen, substituted or not substituted C1-C6alkyl, substituted or not substituted C3-C6cycloalkyl, substituted or not substituted aryl, substituted or not substituted heteroaryl, —COR7, —O(O)OR7, —C(O)NR7R8, —CNR, —OR7, —NR7R8and —NR7C(O)R8; or R2and R3form, 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.

[0169] In some embodiments, a chromene derivative is selected from the group consisting of 4-(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)- 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

[0170] In certain embodiments, a chromene derivative is a compound of Formula D-I:or a pharmaceutically acceptable salt, isomer or solvate thereof wherein: each R1and R3independently represent hydrogen, C1–4alkyl, C2-4alkenyl, 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; Cy1represents 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 Cy1can contain from 1 to 4 heteroatoms selected from N, O and S, where one or more atoms of Cor 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 Cy2independently 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 Cy2can 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 R4independently represents, C1–4alkyl, C2-4alkenyl, C2-4alkynyl, hydroxyl, C1–4alkoxyl, C1-4alkoxyC1-4alkyl, haloC1-4alkyl, hydroxyC1-4alkyl, cyanoC1-4alkyl, halogen, —CN or — NO2; n represents from 0 to 4; and m represents from 0 to 5.

[0171] In some embodiments, a chromene derivative is selected from the group consisting of:Chromene Derivative of Formula E-l

[0172] In some embodiments, a chromene derivative is a compound of formula E-l :or a pharmaceutically acceptable salt thereof. II. Exemplary PDE4 Inhibitors

[0173] In some embodiments, a PDE4 inhibitor is compound that inhibits the enzyme phosphodiesterase-4. In some embodiments, a PDE4 inhibitor suppress the release of cytokines and other inflammatory signals and inhibit the production of reactive oxygen species.

[0174] In some embodiments, a PDE4 inhibitor is Otezla® (Apremilast), Daliresp® (roflumilast), Zoryve® (roflumilast), or Eucrisa® (Crisaborole).

[0175] In some embodiments, a PDE4 inhibitor is Ibudilast, Orismilast (LEO-32731), Mufemilast (Hemay-005), PF-07038124 (Pfizer), Tanimilast (CHF6001), Crisaborole, Rolipram (HT-0712), MK0952 (Merck Sharp & Dohme LLC), ASP9831 (Astellas Pharma Inc), GW842470X (GlaxoSmithKline), BLX-028914 (Dart NeuroScience, LLC), Apremilast (CC- 10004), GSK256066 (GlaxoSmithKline), PF-06266047 (Pfizer), GSK356278 (GlaxoSmithKline), Oglemilast (GRC3886), Cilomilast, MK-0873 (Merck Sharp & Dohme LLC), Revamilast, Pefcalcitol (M518101), DRM02 (Dermira, Inc.), LEO-29102 (Leo Pharma), OPA-15406 (Otsuka Pharmaceutical Co., Ltd.), E6005 (Dermavant Sciences GmbH), Zatomilast (BPD14770), Roflumilast.

[0176] In some embodiments, a PDE4 inhibitor is enprofylline, theophylline, roflumilast, aliflo (silomilast), tofimilast, pumafenthrin, lirimilast, apremilast, allophylline, atizolam, ogremilast, tetomilast; 5-[(N-(2,5-(N-(2,5-Dichloro-3-pyridinyl)-carboxamido]-8-methoxy- quinoline (D-4418), 5-[N-(3,5-dichloro-1-oxide-4-pyridinyl)-carboxamido]-8-methoxy-2N-(3,5- Dichloropyrid-4-yl)-[1-(4-fluorobenzyl)-5-hydroxy-indole-3-(trifluoromethyl)-quinoline(D- 4396(SCH-351591)), glyoxylic acid amide (AWD-12-21(GW-842470)), 9-[(2- fluorophenyl)methyl]-N-methyl-2-(trifluoromethyl)-9H-purine-6-amine(NCS-613), 4-[(2R))-2- [3-(Cyclopentyloxy)-4-methoxyphenyl]-2-phenylethyl]-pyridine(CDP-840), N-[(3R)-3,4,6,7-tetrahydro-9-Methyl-4-oxo-1-phenylpyrrolo[3,2,1-jk][1,4]benzodiazepine-3-yl]-4- pyridinecarboxamide (PD-168787); 4-[6,7-diethoxy-2,3-bis(hydroxymethyl)-1-naphthalenyl]- 1(2-methoxyethyl)-2-(1H)-pyridinone(T-440), 2-[4-[6,7-diethoxy-2,3-bit(Hydroxymethyl)-1- naphthalenyl]-2-pyridinyl]-4-(3-pyridinyl)-1(2H)-phthalazinone(T-2585), (3-(3-cyclopenyloxy- 4-methoxybenzyl))-6-Ethylamino-8-isopropyl-3H-purine (V-11294A), β-[3-(cyclopentyloxy)-4- methoxyphenyl]-1,3-dihydro-1,3-dioxo-2H-Isoindole-2-propanamide (CDC-801), imidazo[1,5- a]pyrido[3,2-e]pyrazin-6(5H)-one, 9-ethyl-2-methoxy-7-methyl-5-propyl-(D-22888), 5-[3- (cyclopentyloxy)-4-methoxyphenyl]-3-[(3-methylphenyl)methyl]-,(3S,5S)-Piperidinone(HT- 0712), 4-[1-[3,4-bis(difluoromethoxy)phenyl]-2-(3-methyl-1-oxide-4-pyridinyl)ethyl]-α,α- bis(Trifluoromethyl)-benzenemethanol(L-826141), N-(3,5-dichloro-1-oxo-pyridin-4-yl)-4- difluoromethoxy-3-cyclopropylmethoxybenzamide, (-)p-[(4aR*,10bS*)-9-ethoxy-1,2,3,4,4a,10b- hexahydro-8-methoxy-2-methylbenzo[s][1,6]naphthyridin-6-yl]-N,N-diisopropylbenzamide; (R)- (+)-1-(4-bromobenzyl)-4-[(3-cyclopentyloxy)-4-methoxyphenyl]-2-pylori3-(Cyclopentyloxy-4- methoxyphenyl)-1-(4-N'-[N-2-cyano-S-methyl-isothioureido]benzyl)-2-pyrrolidone; cis[4-cyano- 4-(3-Cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxylicacid]; 2-carbomethoxy-4- cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-1-one; cis[4-Cyano-4-(3- cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-1-ol]; (R)-(+)-ethyl[4-(3- cyclopentyloxy-4-methoxyphenyl)Pyrrolidin-2-ylidene]acetate; (S)-(-)-ethyl[4-(3- cyclopentyloxy-4-)9-Cyclopentyl-5,6-dihydro-7-ethyl-3-(2-thienyl)-9H-pyrazolo[3,4-c]-1,2,4- Triazolo[4,3-a]pyridine, or 9-cyclopentyl-5,6-dihydro-7-ethyl-3-(tert-butyl)-9H-pyrazolo[3,4-c]- 1,2,4-triazolo[4,3-a]pyridine.

[0177] In some embodiments, a PDE4 inhibitors is selected from the group consisting of Drotaverine hydrochloride, Cilomilast, Denbufylline, Rolipram, Tetomilast, Arofylline, Cipamfylline, Tofimilast, Filaminast, Piclamilast, (R)-(+)-4-[2-(3-Cyclopentyloxy-4- methoxyphenyl)-2-phenylethyl]pyridine, Mesopram, N-(3,5-Dichloro-4-pyridinyl)-2-[1-(4- fluorobenzyl)-5-hydroxy-1 H-indol-3-yl]-2-oxoacetamide, CDC-801 (ex. Celgene), CC-1088 (ex. Celgene), Lirimilast, ONO-6126 (ex. Ono), CC-10004 (ex. Celgene), MN-001 (ex. Kyorin), KW- 4490 (ex. Kyowa Hakko), Benafentrine dimaleate, Zardaverine, Tolafentrine, 3-[3- (Cyclopentyloxy)-4-methoxybenzyl]-6-(ethylamino)-8-isopropyl-3H-purine hydrochloride, N- (3,5-Dichloro-4-pyridinyl)-8-methoxyquinoline-5-carboxamide, 4-(3-Chlorophenyl)-1,7- diethylpyrido[2,3-d]pyrimidin-2(1 H)-one, N-[9-Methyl-4-oxo-1 -phenyl-3,4,6,7-tetrahydropyrrolo[3,2,1-jk][1,4]benzodiazepin-3(R)-13-yl]pyridine-4-carboxamide, 3,5- Dichloro-4-[8-methoxy-2-(trifluoromethyl)quinolin-5-ylcarboxamido]pyridine-1-oxide, NIK-616 (ex.Nikken Chemicals), CDC-998 (ex. Celgene), Project PDE 4 (ex. Celltech), EHT-0202 (ex. ExonHit Therapeutics), 5(S)-[3-(Cyclopentyloxy)-4-methoxyphenyl]-3(S)-(3-methyl benzyl)piperidin-2-one, ND-1251 (ex. Neuro3d), GRC-3886 (ex. Glenmark Pharmaceuticals), Atizoram, Pumafentrine, 4-[6,7-Diethoxy-2,3-bis(hydroxymethyl)naphthalen-1-yl]-1-(2- methoxyethyl)pyridin-2(1H)-one, 2-[4-[6,7-Diethoxy-2,3-bis(hydroxymethyl)naphthalen-1- yl]pyridin-2-yl]-4-(3-pyridyl)phthalazin-1(2H)-one hydrochloride, 1-Ethyl-8-methoxy-3-methyl- 5-propylimidazo[1,5-a]pyrid o[3,2-e] pyrazin-4(5H)-one, 4-(3-Bromophenyl)-1-ethyl-7-methyl- 1,8-naphthyridin-2(1H)-one, and N-[9-Amino-4-oxo-1-phenyl-3,4,6,7- tetrahydropyrrolo[3,2,1jk][1,4]benzodiazepin-3(R)-yl]pyridine-3-carboxamide, hydroxypumafentrine.

[0178] In some embodiments, a PDE4 inhibitor is Cilomilast (SB-207499); Filaminast; Tibenelast (LY-186655); Ibudilast; Piclamilast (RP 73401); Doxofylline; Cipamfylline (HEP- 688); atizoram (CP-80633); theophylline; isobutylmethylxanthine; Mesopram (ZK-117137); Zardaverine; vinpocetine; Rolipram (ZK-62711); Arofylline (LAS-31025); roflumilast (BY-217); Pumafentrin (BY-343); Denbufylline; EHNA; milrinone; Siguazodan; Zaprinast; Tolafentrine; Isbufylline; IBMX; 1C-485; dyphylline; verolylline; bamifylline; pentoxyfilline; enprofilline; lirimilast (BAY 19-8004); filaminast (WAY-PDA-641); benafentrine; trequinsin; nitroquazone; Tetomilast (OPC-6535); AH-21-132; AWD-12-343; AWD-12-281; AWD-12-232; CC-7085; CDC-801; CDC-998; CDP-840; CH-422; CH-673; CH-928; CH-3697; CH-3442; CH-2874; CH- 4139; Chiroscience 245412; CI-1018; CI-1044; CI-1118; CP-353164; CP-77059; CP-146523; CP- 293321; CP-220629; CT-2450; CT-2820; CT-3883; CT-5210; D-4418; D-22888; E-4021; EMD 54622; GF-248; GW-3600; IC-485; ICI 63197; IPL-4088; KF-19514; KW-4490; L-787258; L- 826141; L-791943; NCS-613; Org-30029; Org-20241; Org-9731; PD-168787; PD-190749; PD- 190036; PDB-093; PLX650; PLX369; PLX371; PLX788; PLX939; Ro-20-1724; RPR-132294; RPR-117658A; RPR-114597; RPR-122818; RPR-132703; RS-17597; RS-25344; RS-14203; SCA 40; Sch-351591; SDZ-ISQ-844; SKF-107806; SKF 96231; T-440; T-2585; WAY-126120; WAY- 122331; WAY-127093B; V-11294A; VMX 554; VMX 565; XT-044; XT-611; YM-58897; YM- 976; methyl 3-[6-(2H-3,4,5,6-tetrahydropyran-2-yloxy)-2-(3-thienylcarbonyl)benzo[b]furan-3- yl]propanoate; 4-[4-methoxy-3-(5-phenylpentyloxy)phenyl]-2-methylbenzoic acid; methyl 3-{2-[(4-chlorophenyl)carbonyl]-6-hydroxybenzo[b]furan-3-yl }propanoate; (R*,R*)-(±)-methyl 3- acetyl-4-[3-(cyclopentyloxy)-4-methoxyphenyl]-3-methyl-3-pyrrolidinecarboxylate; or 4-(3- bromophenyl)-1-ethyl-7-methylhydropyridino[2,3-b]pyridin-2-one.

[0179] In some embodiments, a PDE4 inhibitor is Roflumilast, Apremilast (CC-10004), Ibudilast, Orismilast (LEO-32731), Mufemilast (Hemay-005), Tanimilast (CHF6001), PF- 07038124, Crisaborole (AN2728), Rolipram (HT-0712), MK-0952, ASP9831, GW842470X, BLX-028914, GSK256066, PF-06266047, GSK356278, Oglemilast (GRC3886), Cilomilast, MK- 0873, Revamilast (GRC 4039), E6005, OPA-15406, LEO-29102, DRM02, Pefcalcitol (M518101), and Zatomilast (BPD14770). In some embodiments, a PDE4 inhibitor is a mixed PDE4 / PDE3 inhibitor selected from RPL554 or Ensifentrina. 4. Compositions, Formulation and Administration Pharmaceutically acceptable compositions

[0180] According to another embodiment, the disclosure provides a pharmaceutical composition 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.

[0181] In some embodiments, the present disclosure provides a composition comprising a therapeutically effective amount of a chromene derivative as described herein and a PDE4 inhibitor. In certain embodiments, the amount of a chromene derivative in a composition comprising a PDE4 inhibitor of this disclosure is such that is effective to measurably inhibit TCR in the PDE4 inhibitor treatment.

[0182] In certain embodiments, a composition of this disclosure is formulated for administration 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 PDE4 inhibitor of this disclosure is formulated for intravenous infusion administration to a patient in need of such composition.

[0183] As used herein, the terms “subject” and “patient” are used interchangeably and refer to organisms to be treated by the methods of the present disclosure. Such organisms preferablyinclude, but are not limited to, mammals (e.g., murines, simians, equines, bovines, porcines, canines, felines, and the like), and, most preferably, includes humans.

[0184] The term “pharmaceutically acceptable carrier, adjuvant, or vehicle” refers to a nontoxic 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, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene- polyoxypropylene-block polymers, polyethylene glycol and wool fat.

[0185] A “pharmaceutically acceptable derivative” means any non-toxic salt, ester, salt of an ester 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.

[0186] As used herein, the term "active metabolite or residue thereof means that a metabolite or residue thereof also inhibits TCR or TCR-Nck interactions in a biological sample or in a patient.

[0187] Compositions of the present disclosure can be administered orally, parenterally, by inhalation 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, intrastemal, 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 sodiumchloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium.

[0188] For this purpose, any bland fixed oil can be employed including synthetic mono- or diglycerides. 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.

[0189] Pharmaceutically acceptable compositions of this disclosure can be orally administered in 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 com 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.

[0190] Alternatively, pharmaceutically acceptable compositions of this disclosure can be administered 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.

[0191] Pharmaceutically acceptable compositions of this disclosure can also be administered topically, 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.

[0192] Topical application for the lower intestinal tract can be effected in a rectal suppository formulation (see above) or in a suitable enema formulation. Topically-transdermal patches can also be used.

[0193] For topical applications, provided pharmaceutically acceptable compositions can be formulated 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.

[0194] For ophthalmic use, provided pharmaceutically acceptable compositions may be formulated 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.

[0195] Pharmaceutically acceptable compositions of this disclosure can also be administered by 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.

[0196] Most preferably, pharmaceutically acceptable compositions of this disclosure are formulated 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.

[0197] In some embodiments, the pharmaceutical compositions of this disclosure are brainpenetrant 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 compositionsof 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.

[0198] In some embodiments, a brain or CNS disease, condition, injury or disorder is a neurological disorder which affects the CNS and / or which has an etiology in the CNS, which 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.

[0199] The “central nervous system” or “CNS” refers to the complex of nerve tissues that control bodily function, and includes the brain and spinal cord.

[0200] In those compositions comprising multiple therapeutic agents, the therapeutic agents can 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 PDE4 inhibitor 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 usedherein, the phrase “normally administered” means the amount an FDA approved therapeutic agent is approved for dosing per the FDA label insert. For example, the dosage of Otezla® (apremilast) normally administered can be found on the Rinvoq® label, which is incorporated herein by reference in its entirety.

[0201] It should also be understood that a specific dosage and treatment regimen for any particular 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

[0202] In some embodiments, the present disclosure provides a method for treating a disease or disorder in a patient, comprising administering a therapeutically effective amount of a chromene derivative as described herein, and a therapeutically effective amount of a PDE4 inhibitor to the 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 described herein, and a therapeutically effective amount of a PDE4 inhibitor.

[0203] In some embodiments, the present disclosure provides a use of a therapeutically effective amount of a chromene derivative as described herein, and a therapeutically effective amount of a PDE4 inhibitor, 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 as described herein, and a therapeutically effective amount of a PDE4 inhibitor.

[0204] In some embodiments, the present disclosure provides a use of a therapeutically effective amount 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 PDE4 inhibitor. In some embodiments, the present disclosure provides a use of 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 PDE4 inhibitor.

[0205] As used herein, “a method for treating a disease or disorder” includes a method of treating, 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.

[0206] As used herein, the terms "increase" or "improve" are used interchangeably and encompass 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 100-fold, or higher, relative to a control or baseline amount of a function, or activity, or concentration.

[0207] As used herein, the term "reduce" encompass any measurable reduction in a biological function 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. Diseases and Disorders

[0208] In some embodiments, the present disclosure provides a method for treating or preventing or reducing the risk of a disease or disorder in a patient comprising administering to the patient a compound of the disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0209] In certain embodiments, a disease or disorder is selected from the diseases, disorders, and conditions as described in WO 2019 / 169001, the contents of which are herein incorporated by reference in their entireties.

[0210] In some embodiments, a disease or disorder is a “PDE4-mediated” disorder, disease, and / or condition in which PDE4 or a mutant thereof is known to play a role. Accordingly, another embodiment of the present invention relates to treating or lessening the severity of one or more diseases in which PDE4, or a mutant thereof, is known to play a role.

[0211] In some embodiments, a disease or disorder is selected from the diseases or disorders as described herein. In some embodiments, a disease or disorder is Chronic Obstructive Pulmonary Disease (COPD), psoriasis, eczema, or psoriatic arthrititis.

[0212] In some embodiments, a disease or disorder is selected from Krabbe disease, ASL, Glioblastoma, Migraine headache, plaque psoriasis, Atopic dermatitis (AD), Rheumatoid Arthritis, ulcerative colitis, plaque psoriasis, Behçet Disease, ankylosing spondylitis, Seborrheic Dermatitis, Papulopustular Rosacea, Asthma, COPD, Morphea, Brain binding, nervous system disease, PET, major depressive disorder, Alzheimer’s disease, NASH, Allergic Rhinitis, Discoid Lupus Erythematosus, juvenile Batten disease, Huntington’s disease, Psoriasis, Rosacea, psoriasis vulgaris, Fragile X syndrome, Depression, Dementia, Cerebrovascular disorder, and major depressive disorder.

[0213] In some embodiments, a disease or disorder is a diseases and disorders of the nervous system, including but not limited to: cortical dementias including Alzheimer's disease, AIDS- related dementia (HIV dementia), and mild cognitive impairment (MCI). In some embodiments, a disease or disorder is a neurodegenerative disorders, including but not limited to: nerve degeneration or nerve necrosis in disorders such as hypoxia, hypoglycemia, epilepsy, and in cases of central nervous system (CNS) trauma (such as spinal cord and head injury), hyperbaric oxygen convulsions and toxicity, dementia e.g. pre-senile dementia, and HIV-associated neurodegenerative disorder (HAND), cachexia, Sydenham's chorea, Huntington's disease, Parkinson's Disease, amyotrophic lateral sclerosis (ALS), Korsakoff's syndrome, and impairment relating to a cerebral vessel disorder. In some embodiments, a disease or disorder is a neuropathy of the central and peripheral nervous system, including but not limited to: IgA neuropathy, membranous neuropathy, idiopathic neuropathy, drug-induced peripheral neuropathy, diabetic neuropathy, HIV-associated neuropathy, and chronic inflammatory demyelinating polyneuropathy; as well as transverse myelitis, Guillain-Barre disease, encephalitis, and cancers of the nervous system. In some embodiments, a disease or disorder is a psychological disorders including but not limited to anxiety, depression, major depressive disorder (MDD), bipolardisorder, and post-traumatic stress disorder. In some embodiments, a disease or disorder is a nervous system damage, for example that resulting from stroke, ischemias including cerebral ischemia (both focal ischemia, thrombotic stroke and global ischemia, for example, secondary to cardiac arrest and ischemic heart disease) and ischemia / reperfusion, ototoxicity and hearing loss, acute insults to the inner ear, including acoustic trauma, blast noise (for example, as experienced by military personnel), exposure to ototoxic chemotherapeutic agents for cancer therapy (such as cisplatin) and treatment with aminoglycoside antibiotics and other nervous system trauma.

[0214] In some embodiments, a disease or disorder is a traumatic brain injury (TBI), spinal cord injury (SCI), or a symptom thereof.

[0215] In some embodiments, a disease or disorder is a opiate tolerance in patients needing protracted opiate analgesics, and benzodiazepine tolerance in patients taking benzodiazepines, and other addictive behavior, for example, nicotine addiction, alcoholism, and eating disorders. In some embodiments, a disease or disorder is a drug withdrawal symptom, for example treatment or prevention of symptoms of withdrawal from opiate, alcohol, or tobacco addiction.

[0216] In some embodiments, a disease or disorder is an acute and chronic pain and inflammation. In some embodiments, a disease or disorder is a neuropathy, neuropathic pain, or inflammatory pain such as reflex sympathetic dystrophy / causalgia (nerve injury), peripheral neuropathy (including diabetic neuropathy), intractable cancer pain, complex regional pain syndrome, and entrapment neuropathy (carpel tunnel syndrome). In some embodiments, a disease or disorder is a pain associated with acute herpes zoster (shingles), postherpetic neuralgia (PHN), and associated pain syndromes such as ocular pain. In some embodiments, a disease or disorder is a pain indication, including but not limited to: post-surgical pain for various surgical procedures including post-cardiac surgery, dental pain / dental extraction, pain resulting from cancer, muscular pain, mastalgia, pain resulting from dermal injuries, lower back pain, headaches of various etiologies, including migraine, and the like. In some embodiments, a disease or disorder is a pain- related disorders such as tactile allodynia and hyperalgesia. In some embodiments, a pain is somatogenic (either nociceptive or neuropathic), acute and / or chronic.

[0217] In some embodiments, a disease or disorder is insulin resistance and other metabolic disorders such as atherosclerosis that are typically associated with an exaggerated inflammatory signaling.

[0218] In some embodiments, a disease or disorder is respiratory disease or conditions, including therapeutic methods of use in medicine for preventing and treating a respiratory disease or condition including: asthmatic conditions including allergen-induced asthma, exercise-induced asthma, pollution-induced asthma, cold-induced asthma, and viral-induced-asthma; asthma-related diseases such as airway hyperreactivity and small airway disease; chronic obstructive pulmonary diseases including chronic bronchitis with normal airflow, chronic bronchitis with airway obstruction (chronic obstructive bronchitis), emphysema, asthmatic bronchitis, and bullous disease; and other pulmonary diseases involving inflammation including bronchiolitis, bronchi oectasis, cystic fibrosis, pigeon fancier's disease, farmer's lung, acute respiratory distress syndrome, pneumonia, pneumonitis, aspiration or inhalation injury, fat embolism in the lung, acidosis inflammation of the lung, acute pulmonary edema, acute mountain sickness, acute pulmonary hypertension, persistent pulmonary hypertension of the newborn, perinatal aspiration syndrome, hyaline membrane disease, acute pulmonary thromboembolism, heparin-protamine reactions, sepsis, status asthamticus, hypoxia, dyspnea, hypercapnia, hyperinflation, hypoxemia, and cough. In some embodiments, a disease or disorder is an allergic disorder such as delayed type hypersensitivity reaction, allergic contact dermatitis, allergic rhinitis, and chronic sinusitis.

[0219] In some embodiments, a disease or disorder is an inflammation and related disorder. In some embodiments, a disease or disorder is arthritis, including but not limited to rheumatoid arthritis, spondyloarthropathies, gouty arthritis, osteoarthritis, juvenile arthritis, acute rheumatic arthritis, enteropathic arthritis, neuropathic arthritis, psoriatic arthritis, reactive arthritis (Reiter's syndrome), and pyogenic arthritis, and autoimmune diseases, including systemic lupus erythematosus, hemolytic syndromes, autoimmune hepatitis, autoimmune neuropathy, vitiligo (autoimmune thyroiditis), Hashimoto's thyroiditis, anemias, myositis including polymyositis, alopecia greata, Goodpasture's syndrome, hypophysitis, and pulmonary fibrosis.

[0220] In some embodiments, a disease or disorder is osteoporosis and other related bone disorders.

[0221] In some embodiments, a disease or disorder is gastrointestinal conditions including but not limited to reflux esophagitis, diarrhea, inflammatory bowel disease, Crohn's disease, gastritis, irritable bowel syndrome, Graves' disease (hyperthyroidism), necrotizing enterocolitis, and ulcerative colitis. In some embodiments, a disease or disorder is pulmonary inflammation, such as that associated with viral infections and cystic fibrosis.

[0222] In some embodiments, a disease or disorder is graft vs. host reaction (i.e., graft vs. host disease), allograft rejections (e.g., acute allograft rejection, and chronic allograft rejection), transplant reperfusion injury, and early transplantation rejection (e.g., acute allograft rejection).

[0223] In some embodiments, a disease or disorder is pruritus and vitiligo.

[0224] In some embodiments, a disease or disorder is a tissue damage in such diseases as vascular diseases, migraine headaches, periarteritis nodosa, thyroiditis, aplastic anemia, Hodgkin's disease, scleroderma, rheumatic fever, type I diabetes, neuromuscular junction disease including myasthenia gravis, white matter disease including multiple sclerosis, sarcoidosis, nephritis, nephrotic syndrome, Langerhans' cell histiocytosis, glomerulonephritis, reperfusion injury, pancreatitis, interstitial cystitis, Behcet's syndrome, polymyositis, gingivitis, periodontitis, hypersensitivity, swelling occurring after injury, ischemias including myocardial ischemia, cardiovascular ischemia, and ischemia secondary to cardiac arrest, cirrhosis, septic shock, endotoxic shock, gram negative sepsis, toxic shock syndrome, stroke, ischemia reperfusion injury, multi-organ dysfunction, restenosis including restenosis following coronary bypass surgery, and the like.

[0225] In some embodiments, a disease or disorder is systemic hypotension associated with septic and / or toxic hemorrhagic shock induced by a wide variety of agents.

[0226] In some embodiments, a disease or disorder is cancer, such as colorectal cancer, and cancer of the breast, lung, prostate, bladder, cervix and skin. Compounds of the invention may be used in the treatment and prevention of neoplasias including but not limited to brain cancer, bone cancer, leukemia, lymphoma, epithelial cell-derived neoplasia (epithelial carcinoma) such as basal cell carcinoma, adenocarcinoma, gastrointestinal cancer such as lip cancer, mouth cancer, esophageal cancer, small bowel cancer and stomach cancer, colon cancer, liver cancer, bladder cancer, pancreas cancer, ovary cancer, cervical cancer, lung cancer, breast cancer and skin cancer, such as squamous cell and basal cell cancers, prostate cancer, renal cell carcinoma, and other known cancers that effect epithelial cells throughout the body. The neoplasia can be selected from gastrointestinal cancer, liver cancer, bladder cancer, pancreas cancer, ovary cancer, prostate cancer, cervical cancer, lung cancer, breast cancer and skin cancer, such as squamous cell and basal cell cancers. The present compounds and methods may also be used to treat the fibrosis which occurs with radiation therapy. In some embodiments, a disease or disorder is adenomatous polyps, including those with familial adenomatous polyposis (FAP).

[0227] In some embodiments, a disease or disorder is otic disease and otic allergic disorder, including eustachian tube itching.

[0228] In some embodiments, a disease or disorder is ophthalmic diseases. In some embodiments, a disease or disorder is menstrual cramps, dysmenorrhea, premature labor, endometriosis, tendonitis, bursitis, skin-related conditions such as psoriasis, eczema, bums, sunburn, dermatitis, pancreatitis, hepatitis, lichen planus, scleritis, scleroderma, dermatomyositis, and the like. In some embodiments, a disease or disorder is diabetes (type I or type II), atherosclerosis, congestive heart failure, myocarditis, atherosclerosis, cerebral ischemia, angiogenesis, pulmonary hypertension, and aortic aneurysm.

[0229] In some embodiments, a disease or disorder is an acute or chronic pulmonary disease such as obstructive diseases (e.g. asthma, chronic obstructive pulmonary disease (COPD), cystic fibrosis), interstitial lung diseases (e.g. idiopathic pulmonary fibrosis, sarcoidosis), vascular lung diseases (e.g. pulmonary hypertension), bronchitis, allergic bronchitis, or emphysema. In some embodiments, a disease or disorder is CNS diseases such as Alzheimer's disease, Parkinson's disease and Huntington's chorea; inflammatory autoimmune diseases such as multiple sclerosis, rheumatoid arthritis and Crohn's disease as well as other inflammatory disorders, such as cerebral ischemia, inflammatory bowel disease, ulcerative colitis, and atopic dermatitis; bone disease, such as osteoporosis, osteopetrosis, and Paget's disease; cancers, such as diffuse large-cell B cell lymphoma, chronic lymphocytic leukemia, acute lymphoblastic leukemia; Severe Acute Respiratory Syndrome; and pre-term labor.

[0230] In some embodiments, a disease or disorder is an ophthalmic disease, such as dry eye, glaucoma, corneal neovascularization, optic neuritis, Sjogren's syndrome, retinal ganglion degeneration, ocular ischemia, retinitis, retinopathies, uveitis, ocular photophobia, and of inflammation and pain associated with acute injury to the eye tissue. In some embodiments, a disease or disorder is glaucomatous retinopathy and / or diabetic retinopathy. In some embodiments, a disease or disorder is post-operative inflammation or pain as from ophthalmic surgery such as cataract surgery and refractive surgery.

[0231] In one embodiment, a disease or disorder is an inflammatory disease or disorder, selected from the group consisting of asthma, chronic obstructive pulmonary disease (COPD), asthma and COPD overlap syndrome (ACOS), atopic dermatitis, nasal polyps, an allergic response, chronic bronchitis, emphysema, chronic rhinosinusitis with or without nasal polyps,inflammatory bowel disease, Crohn's disease, ulcerative colitis, hypersensitivity pneumonitis, multiple sclerosis, arthritis (including osteoarthritis, rheumatoid arthritis, or psoriatic arthritis), allergic rhinitis, fibrosis, eosinophilic esophagitis, vasculitis, urticaria, Churg Strauss syndrome, inflammatory pain and psoriasis.

[0232] In some embodiments, a disease or disorder is a respiratory disease such as COPD (chronic bronchitis and emphysema), asthma, allergic rhinitis and atopic dermatitis; allergic disease states, inflammatory arthritis; Crohn's disease; reperfusion injury of the myocardium and brain; cystic fibrosis, arterial restenosis, atherosclerosis, keratosis, rheumatoid spondylitis, osteoarthritis, pyresis, diabetes mellitus, pneumoconiosis, toxic and allergic contact eczema; systemic lupus erythematosus, follicular and wide-area pyodermias, endogenous and exogenous acne, acne rosacea, Beghet's disease, anaphylactoid purpura nephritis, inflammatory bowel disease, leukemia, multiple sclerosis, gastrointestinal diseases, autoimmune disease; neurological and psychiatric disorders; stroke and spinal cord injury.

[0233] In some embodiments, a disease or disorder is allergic disease states such as atopic dermatitis, urticaria, allergic rhinitis, allergic conjunctivitis, vernal conjunctivitis, eosinophilic granuloma, psoriasis, inflammatory arthritis, rheumatoid arthritis, septic shock, ulcerative colitis, Crohn's disease, reperfusion injury of the myocardium and brain, chronic glomerulonephritis, endotoxic shock, cystic fibrosis, arterial restenosis, atherosclerosis, keratosis, rheumatoid spondylitis, osteoarthritis, pyresis, diabetes mellitus, pneumoconiosis, toxic and allergic contact eczema, atopic eczema, seborrheic eczema, lichen simplex, sunburn, itching in the anogenital area, alopecia areata, hypertrophic scars, discoid lupus erythematosus, systemic lupus erythematosus, follicular and wide-area pyodermias, endogenous and exogenous acne, acne rosacea, Behcet's disease, anaphylactoid purpura nephritis, inflammatory bowel disease, leukemia, multiple sclerosis, gastrointestinal diseases, autoimmune diseases and the like. They also include neurological and psychiatric disorders such as Alzheimer's disease, multiple sclerosis, amylolaterosclerosis (ALS), multiple systems atrophy (MSA), schizophrenia, Parkinson's disease, Huntington's disease, Pick's disease, depression, stroke, or spinal cord injury.

[0234] In some embodiments, a disease or disorder is selected from various origin-generated acute and chronic (in particular, inflammatory and allergen induced) respiratory tract diseases (e.g. bronchial asthma, chronic obstructive pulmonary disease, etc.); dermatoses (in particular, hyperplastic, inflammatory, and allergic diseases) (e.g. psoriasis (vulgaris) , toxic and allergiccontact eczema, atopic dermatitis, alopecia areata, and other hyperplastic, inflammatory and allergic dermatoses) ; nervous function abnormality diseases such as learning, memory, and / or cognition disorders associated with Alzheimer's and Parkinson's diseases; diseases associated with mental function abnormality (e.g. manic-depressive psychosis, schizophrenia, anxiety disorder, etc.); systemic and local arthritic disorders (e.g. knee osteoarthritis, articular rheumatism, etc.); gastrointestinal diffuse inflammation (e.g. Crohn's disease and ulcerative colitis); allergic and / or chronic immune-mediated inflammatory diseases in the upper respiratory tract (cavum pharynges, nose) and its vicinity (sinuses, eyes) (e.g. allergic rhinitis / sinusitis, chronic rhinitis / sinusitis, allergic conjunctivitis), and the like.

[0235] In some embodiments, the methods or uses described herein inhibit or reduce or arrest or ameliorate the growth or spread of a disease or disorder. In some embodiments, a disease or disorder is treated by arresting, reducing, or inhibiting further growth of the a disease or disorder. 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 disease or disorder. In some embodiments, a disease or disorder is treated by reducing the size (e.g., volume or mass) of the disease or disorder 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 disease or disorder prior to treatment. In some embodiments, a disease or disorder is 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 the disease or disorder prior to treatment.

[0236] In some embodiments, a patient treated using the methods or uses described herein exhibits 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 7months, 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.

[0237] In some embodiments, a patient treated using the methods or uses described herein exhibits 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%.Administration

[0238] 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.

[0239] A chromene derivative as described herein can be administered separately from a PDE4 inhibitor, as part of a multiple dosage regimen. Alternatively, a chromene derivative as describedherein may be part of a single dosage form, mixed together with a PDE4 inhibitor in a single composition. If administered as a multiple dosage regime, a chromene derivative as described herein and a PDE4 inhibitor 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 PDE4 inhibitor are administered as a multiple dosage regimen with greater than 24 hours apart.

[0240] In some embodiments, the initiation of administration of a chromene derivative as described herein is carried out 7 to 14 days after the initiation of administration of a PDE4 inhibitor. In some of any of the provided embodiments, the initiation of the administration of a 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 PDE4 inhibitor.

[0241] In some embodiments, at the time of initiation of administration of a chromene derivative as described herein, a patient has been previously administered a PDE4 inhibitor. In some embodiments, a chromene derivative as described herein is administered to a patient before a PDE4 inhibitor is administered.

[0242] In some embodiments, a PDE4 inhibitor is administered parenterally, optionally intravenously. In some embodiments, a PDE4 inhibitor is administered intravenously.

[0243] As used herein, the term “combination,” “combined,” and related terms refers to the simultaneous or sequential administration of therapeutic agents in accordance with this disclosure. For example, a chromene derivative as described herein can be administered with a PDE4 inhibitor 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 PDE4 inhibitor, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

[0244] Pharmaceutically acceptable compositions of this disclosure can be administered to humans 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 certainembodiments, 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.

[0245] 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.

[0246] Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions 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 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.

[0247] 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.

[0248] In order to prolong the effect of a compound of the present invention, it is often desirable to 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.

[0249] Compositions for rectal or vaginal administration are preferably suppositories which can 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 ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.

[0250] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. 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, sodiumlauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.

[0251] Solid compositions of a similar type may also be employed as fdlers 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.

[0252] The active compounds can also be in micro-encapsulated form with one or more excipients 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. 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.

[0253] Dosage forms for topical or transdermal administration of a compound of this invention include 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 theadded 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

[0254] The following examples are included to demonstrate various aspects of the present disclosure. 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. Cytokine Release Assay, Combination Studies 1.1 Human blood samples and cell lines

[0255] Frozen PBMCs (Stem Cell Technologies) were plated at 2X106 cells / mL and pre- incubated with each compound alone or in combination at various concentrations of each for 30 minutes. Then they were stimulated with 0.3 mg / mL anti-CD3 antibody (OKT-3 clone, Invitrogen) and 0.3 mg / mL anti-CD28 stock (Millipore). Cells were incubated at 37 ˚C for two or three days. Cells were then spun down and supernatants collected. Cytokines in supernatants were analyzed using Procarta Plex (ThermoFisher) according to kit instructions and measured on a Luminex 200.

[0256] The data are shown in FIGs.1-18, and in Table 1-1 below. Table 1-1: PBMC Cytokine Release Assay Combination Effects.0: no effect; +: modest effect (~40-60%); ++: strong effect (>60%); +++: Additive effect (>A-33 Alone)

[0257] Conclusions ● The data confirms the initial Otezla® data for each Cytokine. ● In this context, A-33 is more potent than Otezla® for each Cytokine and has greater efficacy for each Cytokine. ● IL-2 is the Cytokine that Otezla® is most efficacious on. ● There is an additive effect of the two compounds. ● This suggests that they have independent mechanisms. ● The data supports the notion that they could be used in combination. INCORPORATION BY REFERENCE

[0258] The entire disclosure of each of the patent documents and scientific articles referred to herein is incorporated by reference for all purposes. EQUIVALENTS

[0259] The disclosure may be embodied in other specific forms without departing from the spirit 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.

Claims

CLAIMS 1. A method for treating a disease or disorder in a patient, comprising administering a therapeutically effective amount of a chromene derivative, and a therapeutically effective amount of a PDE4 inhibitor 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-;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. The method of claim 1, wherein the disease or disorder is selected from the group consisting of Krabbe disease, ASL, Glioblastoma, Migraine headache, plaque psoriasis, Atopic dermatitis (AD), Rheumatoid Arthritis, ulcerative colitis, plaque psoriasis, Behçet Disease, ankylosing spondylitis, Seborrheic Dermatitis, Papulopustular Rosacea, Asthma, COPD, Morphea, Brain binding, nervous system disease, PET, major depressive disorder, Alzheimer’s disease, NASH, Allergic Rhinitis, Discoid Lupus Erythematosus, juvenile Batten disease, Huntington’s disease, Psoriasis, Rosacea, psoriasis vulgaris, Fragile X syndrome, Depression, Dementia, Cerebrovascular disorder, and major depressive disorder.

3. The method of claim 1 or 2, wherein a PDE4 inhibitor is Otezla® (Apremilast), Daliresp® (roflumilast), Zoryve® (roflumilast), or Eucrisa® (Crisaborole).

4. The method of any one of claims 1-3, wherein the chromene derivative inhibits T cell activation mediated by TCR.

5. The method of any one of claims 1-4, wherein the chromene derivative inhibits cytokine (e.g., TNFα, IFNγ, IL-2, ILK-17A, etc.) release mediated by TCR.

6. The method of any one of claims 1-5, wherein the chromene derivative inhibits T cell proliferation and / or T cell efficiency in killing target cells mediated by TCR.

7. The method of any one of claims 1-6, wherein the chromene derivative inhibits phosphorylation of CD3ζ and / or ERK kinase mediated by TCR.

8. The method of any one of claims 1-7, wherein the chromene derivative is administered with the PDE4 inhibitor simultaneously, or sequentially in separate unit dosage forms or together in a single unit dosage form.

9. The method of any one of claims 1-8, wherein the chromene derivative is a compound of Formulae:

10. The method of any one of claims 1-9, 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.

11. The method of claim 10, wherein R2is, , , ,12. The method of any one of claims 1-11, wherein R3is halogen, -CN, -NO2, or C1–4aliphatic substituted with 1-9 halogens.

13. The method of claim 12, wherein R3is C1–4aliphatic substituted with 1-9 halogens, optionally wherein R3is selected from.

14. The method of claim 13, wherein R3is halogen, optionally wherein R3is F.

15. The method of any one of claims 1-14, wherein L1is a C1-4bivalent straight or branched saturated or unsaturated hydrocarbon chain wherein 1-2 methylene units of the chain areindependently 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-.

16. The method of claim 15, 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(R)2-, -C(O)N(R)-, or -RNC(O)-.

17. The method of claim 15, wherein L1is a C1–4bivalent straight or branched saturated or unsaturated hydrocarbon chain wherein 1-2 methylene unit of the chain is replaced with -O- or - C(O)-.

18. The method of claim 15, wherein L1is.

19. The method of any one of claims 1-18, 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)-.

20. The method of any one of claims 1-19, wherein the compound is selected from those as set forth in Table 1, or a pharmaceutically acceptable salt thereof.

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