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WO2024215699A1 - Traitement du lymphome à lymphocytes t - Google Patents

Traitement du lymphome à lymphocytes t Download PDF

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Publication number
WO2024215699A1
WO2024215699A1 PCT/US2024/023786 US2024023786W WO2024215699A1 WO 2024215699 A1 WO2024215699 A1 WO 2024215699A1 US 2024023786 W US2024023786 W US 2024023786W WO 2024215699 A1 WO2024215699 A1 WO 2024215699A1
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Prior art keywords
cell lymphoma
subject
compound
methods
peripheral
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Inventor
Anneleen Daemen
Pratik Sharad MULTANI
Livia ULICNA
Matthew Paul PANUWAT
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Oric Pharmaceuticals Inc
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Oric Pharmaceuticals Inc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/662—Phosphorus acids or esters thereof having P—C bonds, e.g. foscarnet, trichlorfon
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • T-cell lymphomas are a clinically and biologically heterogeneous group of disorders including peripheral T-cell lymphoma (PTCL) and cutaneous T-cell lymphoma (CTCL), characterized by poor outcomes.
  • PTCL peripheral T-cell lymphoma
  • CTCL cutaneous T-cell lymphoma
  • First line therapy for the treatment of some TCL types comprise anthracycline -based chemotherapy, most commonly the CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) regimen, although this regimen became the standard of care based on trials that included mostly patients with diffuse large B cell lymphoma (DLBCL).
  • CHOP cyclophosphamide, doxorubicin, vincristine, and prednisone
  • Subjects that undergo such treatment strategies frequently experience relapse of the disease (also called refractory and/or resistant disease) and have poor outcomes, with 5-year overall survival rates of about 30-40%.
  • the disease in subjects that have experienced relapse often does not respond well to subsequent therapies, such as salvage chemotherapy or single agent strategies, and survival rates in these subjects are poor, particularly for subjects who are not eligible for, and cannot undergo, stem cell transplantation (SCT).
  • SCT stem cell transplantation
  • T-cell lymphoma in a subject, comprising administering to the subject a therapeutically effective amount of an inhibitor of embryonic ectoderm development (EED) protein.
  • EED embryonic ectoderm development
  • Z is O or S;
  • X is O, CR 5 , CR 5 OH, or C(R 5 )2, wherein: when X is 0, - is a single bond; when X is C(R 5 )2, - is a single bond; when X is CR 5 OH, - is a single bond; or when X is CR 5 , - is a double bond;
  • R 1 is aryl, heteroaryl, L-cycloalkyl, -N(R 5 )heterocyclyl, or L-heterocyclyl, wherein the aryl, the heteroaryl or the cyclyl portion of the L-cycloalkyl, -N(R 5 )heterocyclyl, or L-heterocyclyl is optionally substituted with one or more R 4 ;
  • R 2 is cyano, -COOR 5 , -C(O)N(R 5 )2, or -C(O)N(R 5 )2 wherein each R 5 taken together with the nitrogen atom to which they are attached form a 5 - 8 membered heterocyclic ring optionally substituted with one or more R 4 ; each R 3 is independently C1-C3 alkyl or halogen; each R 4 is independently oxo, cyano, halogen, -PCLfC 1 -C3 alkyl)2, hydroxyl, alkoxy, hydroxyalkyl, heteroalkyl, aralkyl, haloalkyl, -COOR 5 , -Y 2 -haloalkyl, -Y’-Ci-Ce alkyl, -Y 2 -Ci-Ce alkyl, -L-cycloalkyl, -L-heteroaryl, -L-heterocyclyl, -Y'-he
  • L is a bond or C1-C4 alkylene
  • Y 1 is a bond, -C(O)-, or -NHC(O)-;
  • Y 2 is a bond, -S-, -SO-, -SO 2 -, or -NR 5 SO 2 -, each R 5 is hydrogen or C1-C3 alkyl;
  • R 6 is hydrogen, C1-C3 alkyl, halogen, haloalkyl, hydroxyalkyl, or heteroalkyl; each R 7 is oxo, cyano, hydroxyl, alkoxy, halogen, haloalkyl, hydroxyalkyl, heteroalkyl, cycloalkyl, -L- N(R 5 ) 2 , Ci-Ce alkyl or -Y’-heterocyclyl; and n is 1 or 2.
  • T-cell lymphoma in a subject comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein T-cell lymphoma in the subject is peripheral T-cell lymphoma.
  • methods treating T-cell lymphoma in a subject comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), wherein T-cell lymphoma in the subject is cutaneous T-cell lymphoma (CTCL).
  • CTCL cutaneous T-cell lymphoma
  • any such methods of treating T-cell lymphoma in a subject comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein the subject is administered a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in combination with one or more additional therapeutic agents.
  • FIG. 1 depicts a 8-point viability curve after 14-day treatment of the HH cell line with Compound 4 from Example 1, showing relative luminescence units (RLU) values relative to DMSO (veh).
  • RLU represents the average of 3 biological replicates ⁇ standard deviation (SD).
  • FIG. 2 depicts a 8-point viability curve after 21-day treatment of the H9 cell line with Compound 4 from Example 1, showing relative luminescence units (RLU) values relative to DMSO (veh).
  • RLU represents the average of 3 biological replicates ⁇ standard deviation (SD).
  • FIG. 3 depicts a 8-point viability curve after 14-day treatment of the SU-DHL-1 cell line with Compound 4 from Example 1, showing relative luminescence units (RLU) values relative to DMSO (veh).
  • RLU represents the average of 3 biological replicates ⁇ standard deviation (SD).
  • administering when used in conjunction with a therapeutic, including the compounds of Formula (I), or a pharmaceutically acceptable salt thereof, and/or the one or more additional therapeutic agents, means to administer a therapeutic systemically or locally, as directly into or onto a target tissue, or to administer a therapeutic to a subject whereby the therapeutic positively impacts the tissue to which it is targeted.
  • administering when used in conjunction with a composition described herein, can include, but is not limited to, providing a composition into or onto the target tissue; providing a composition systemically to a subject by, e.g., oral administration whereby the therapeutic reaches the target tissue or cells.
  • administering a composition may be accomplished by injection, topical administration, and oral administration or by other methods alone or in combination with other known techniques.
  • animal as used herein includes, but is not limited to, humans and non-human vertebrates such as wild, domestic and farm animals.
  • subject refers to include living organisms in which certain conditions as described herein can occur. Examples include humans, monkeys, cows, sheep, goats, dogs, cats, mice, rats, and transgenic species thereof.
  • the subject is a primate.
  • the primate or subject is a human.
  • the human is an adult. In certain instances, the human is child. In further instances, the human is under the age of 12 years. In certain instances, the human is elderly. In other instances, the human is 60 years of age or older.
  • subjects include experimental animals such as mice, rats, dogs, cats, goats, sheep, pigs, and cows.
  • the experimental animal can be an animal model for a disorder, e.g., a transgenic mouse with hypertensive pathology.
  • pharmaceutically acceptable is meant the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
  • composition means a composition comprising at least one active ingredient, whereby the composition is amenable to investigation for a specified, efficacious outcome in a mammal (for example, without limitation, a human).
  • a mammal for example, without limitation, a human.
  • the terms “progressing,” “relapsed,” “refractory, ” “resistant,” and the like as used herein refer to T- cell lymphoma in a subject that appears to grow again after a period or remission, and/or being no longer responsive to the treatment that is currently being administered to the subject or that had been administered to the subject (e.g., prior treatment of a T-cell lymphoma in a subject with chemotherapy).
  • a determination of whether a cancer, or one or more cells comprising a cancer, in a subject is progressing, has relapsed, or has become refractory or resistant to a specific treatment modality, such as chemotherapy, can be made by methods to known to those of ordinary skill in the art.
  • responsiveness, or non-responsiveness, as the case may be, of a cancer in a subject, or one or more cells comprising the cancer in a subject can be assessed by measuring a subject’s clinical symptoms, conducting a biopsy of one or more relevant tissue types (e.g., lymphoid tissue), reduction in the size and/or number of tumor lesions, duration of response, or progression-free survival.
  • relevant tissue types e.g., lymphoid tissue
  • terapéutica means an agent utilized to treat, combat, ameliorate, prevent, or improve an unwanted condition or disease of a subject.
  • a “therapeutically effective amount” or “effective amount” as used herein refers to the amount of active compound or pharmaceutical agent that elicits a biological or medicinal response in a tissue, system, animal, individual or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes one or more of the following: (1) preventing the disease; for example, preventing a disease, condition or disorder in an individual that may be predisposed to the disease, condition or disorder but does not yet experience or display the pathology or symptomatology of the disease, (2) inhibiting the disease; for example, inhibiting a disease, condition or disorder in an individual that is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., arresting further development of the pathology and/or symptomatology), and (3) ameliorating the disease; for example, ameliorating a disease, condition or disorder in an individual that is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., reversing the pathology and/or
  • treat refers to both therapeutic treatment in some embodiments and prophylactic or preventative measures in other embodiments, wherein the object is to prevent or slow (lessen) an undesired physiological condition, disorder, or disease, or to obtain beneficial or desired clinical results.
  • beneficial or desired clinical results include, but are not limited to, alleviation of symptoms; diminishment of the extent of the condition, disorder or disease; stabilization (i.e., not worsening) of the state of the condition, disorder or disease; delay in onset or slowing of the progression of the condition, disorder or disease; amelioration of the condition, disorder or disease state; and remission (whether partial or total), whether detectable or undetectable, or enhancement or improvement of the condition, disorder or disease.
  • Treatment includes eliciting a clinically significant response without excessive levels of side effects. Treatment also includes prolonging survival as compared to expected survival if not receiving treatment.
  • a prophylactic benefit of treatment includes prevention of a condition, retarding the progress of a condition, stabilization of a condition, or decreasing the likelihood of occurrence of a condition.
  • chemical moieties are defined and referred to throughout primarily as univalent chemical moieties (e.g., alkyl, aryl, etc.). Nevertheless, such terms may also be used to convey corresponding multivalent moieties under the appropriate structural circumstances clear to those skilled in the art.
  • an “alkyl” moiety generally refers to a monovalent radical (e.g.
  • a bivalent linking moiety in certain circumstances can be “alkyl,” in which case those skilled in the art will understand the alkyl to be a divalent radical (e.g., -CH2-CH2-), which is equivalent to the term “alkylene.”
  • alkyl a divalent radical
  • aryl a divalent moiety that is required and is stated as being “aryl”
  • All atoms are understood to have their normal number of valences for bond formation (i.e., 4 for carbon, 3 for N, 2 for O, and 2, 4, or 6 for S, depending on the oxidation state of the S).
  • amino refers to -NH2.
  • acetyl refers to “-C(O)CH3.
  • acyl refers to an alkylcarbonyl or arylcarbonyl substituent wherein the alkyl and aryl portions are as defined herein.
  • alkyl refers to straight and branched chain aliphatic groups having from 1 to 12 carbon atoms. As such, “alkyl” encompasses Ci, C2, C3, C4, C5, Ce, C7, Cs, C>, C10, Cn and C12 groups. Examples of alkyl groups include, without limitation, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secbutyl, tert-butyl, pentyl, and hexyl.
  • alkenyl as used herein means an unsaturated straight or branched chain aliphatic group with one or more carbon-carbon double bonds, having from 2 to 12 carbon atoms. As such, “alkenyl” encompasses C2, C3, C4, C5, Ce, C7, Cs, C>, C10, Cn and C12 groups. Examples of alkenyl groups include, without limitation, ethenyl, propenyl, butenyl, pentenyl, and hexenyl.
  • alkynyl as used herein means an unsaturated straight or branched chain aliphatic group with one or more carbon-carbon triple bonds, having from 2 to 12 carbon atoms. As such, “alkynyl” encompasses C2, C3, C4, C5, Ce, C7, Cs, C>, C10, Cn and C12 groups. Examples of alkynyl groups include, without limitation, ethynyl, propynyl, butynyl, pentynyl, and hexynyl.
  • alkylene alkenylene
  • alkynylene alkynylene
  • alkylene groups include, without limitation, methylene, ethylene, propylene, and butylene.
  • alkenylene groups include, without limitation, ethenylene, propenylene, and butenylene.
  • alkynylene groups include, without limitation, ethynylene, propynylene, and butynylene.
  • alkoxy refers to -OCi-Ce alkyl.
  • cycloalkyl as used herein as employed herein is a saturated and partially unsaturated cyclic hydrocarbon group having 3 to 12 carbons.
  • cycloalkyl includes Cs, C4, C5, Ce, C7, Cs, C>, C10, Ci 1 and C12 cyclic hydrocarbon groups.
  • Examples of cycloalkyl groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl.
  • heteroalkyl refers to an alkyl group, as defined hereinabove, wherein one or more carbon atoms in the chain are independently replaced by O, S, or NR X , wherein R x is hydrogen or C1-C3 alkyl.
  • heteroalkyl groups include methoxymethyl, methoxyethyl and methoxypropyl.
  • aryl as used herein means a Ce-Ci4 aromatic moiety comprising one to three aromatic rings. As such, “aryl” includes Ce, C10, C13, and C14 cyclic hydrocarbon groups.
  • An exemplary aryl group is a Ce-Cio aryl group. Particular aryl groups include, without limitation, phenyl, naphthyl, anthracenyl, and fluorenyl.
  • aralkyl and arylalkyl as used herein mean an aryl group covalently linked to an alkylene group wherein the moiety is linked to another group via the alkyl moiety.
  • An exemplary aralkyl group is -(Ci-Ce)alkyl(Ce-Cio)aryl, including, without limitation, benzyl, phenethyl, and naphthylmethyl.
  • heterocyclyl and “heterocyclic” as used herein mean a mono- or bicyclic (fused or spiro) ring structure having from 3 to 12 atoms, (3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 atoms), for example 4 to 8 atoms, wherein one or more ring atoms are independently -C(O)-, N, NR 5 , O, or S, and the remainder of the ring atoms are quaternary or carbonyl carbons.
  • heterocyclic groups include, without limitation, epoxy, oxiranyl, oxetanyl, azetidinyl, aziridinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl, pyrrolidinyl, piperidinyl, piperazinyl, imidazolidinyl, thiazolidinyl, thiatanyl, dithianyl, trithianyl, azathianyl, oxathianyl, dioxolanyl, oxazolidinyl, oxazolidinonyl, decahydroquinolinyl, piperidonyl, 4-piperidonyl, thiomorpholinyl, dimethyl-morpholinyl, and morpholinyl. Specifically excluded from the scope of this term are compounds having adjacent ring O and/or S atoms.
  • L-heterocyclyl as used herein means a heterocyclyl group covalently linked to another group via an alkylene linker L, where L is C1-C4 alkylene.
  • heteroaryl as used herein means a group having 5 to 14 ring atoms, preferably 5, 6, 10, 13 or 14 ring atoms comprising an aromatic heterocyclic ring (e.g., having 6, 10, or 14 71 electrons shared in a cyclic array), and having, in addition to carbon atoms, from one to three heteroatoms that are each independently N, O, or S.
  • Heteroaryl also includes fused multicyclic (e.g., bicyclic) ring systems in which one or more of the fused rings is non-aromatic, provided that at least one ring is aromatic and at least one ring contains an N, O, or S ring atom.
  • heteroaryl groups include acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzo[d]oxazol-2(3H)-one, 2H-benzo[b][l,4]oxazin-3(4H)-one, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, furanyl, furazanyl, imidazolinyl, imidazolyl, IH-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3
  • L-heteroaryl means a group comprising a heteroaryl group covalently linked to another group via an alkylene linker.
  • heteroalkyl groups comprise a Ci-Ce alkyl group and a heteroaryl group having 5, 6, 9, or 10 ring atoms.
  • heteroaralkyl groups include pyridylmethyl, pyridylethyl, pyrrolylmethyl, pyrrolylethyl, imidazolylmethyl, imidazolylethyl, thiazolylmethyl, thiazolylethyl, benzimidazolylmethyl, benzimidazolylethyl quinazolinylmethyl, quinolinylmethyl, quinolinylethyl, benzofuranylmethyl, indolinylethyl isoquinolinylm ethyl, isoinodylmethyl, cinnolinylmethyl, and benzothiophenylethyl.
  • arylene e.g., arylene, teroarylene, and heterocyclylene as used herein mean an bivalent aryl, heteroaryl, or heterocyclyl group, respectively, as defined hereinabove, that is positioned between and serves to connect two other chemical groups.
  • halogen and “halo” as used herein mean chlorine, bromine, fluorine, or iodine.
  • haloalkyl as used herein means an alkyl chain in which one or more hydrogens have been replaced by a halogen. Exemplary haloalkyls are trifluoromethyl, difluoromethyl, fluorochloromethyl, chloromethyl, and fluoromethyl.
  • hydroxy alkyl as used herein means an alkyl chain, as defined herein, wherein at least one hydrogen of the alkyl chain has been replaced by hydroxyl.
  • EED embryonic ectoderm development
  • the EED inhibitor is selected from EED226, A-395, APG-5918, BR-001, BR-002, EEDi-5285, EEDi-1056, FTX-6058, HJM-353, and MAK683.
  • the EED inhibitor is EED226.
  • the EED inhibitor is A-395.
  • the EED inhibitor is APG-5918.
  • the EED inhibitor is BR-001.
  • the EED inhibitor is BR-002. In some embodiments, the EED inhibitor is EEDi-5285. In some embodiments, the EED inhibitor is EEDi-1056. In some embodiments, the EED inhibitor is FTX-6058. In some embodiments, the EED inhibitor is HJM-353. In some embodiments, the EED inhibitor is MAK683.
  • Z is O or S
  • X is O, CR 5 , CR 5 OH, or C(R 5 )2, wherein: when X is O, - is a single bond; when X is C(R 5 )2, - is a single bond; when X is CR 5 OH, - is a single bond; or when X is CR 5 , - is a double bond;
  • R 1 is aryl, heteroaryl, L-cycloalkyl, -N(R 5 )heterocyclyl, or L-heterocyclyl, wherein the aryl, the heteroaryl or the cyclyl portion of the L-cycloalkyl, -N(R 5 )heterocyclyl, or L-heterocyclyl is optionally substituted with one or more R 4 ;
  • R 2 is cyano, -COOR 5 , -C(O)N(R 5 )2, or -C(O)N(R 5 )2 wherein each R 5 taken together with the nitrogen atom to which they are attached form a 5 - 8 membered heterocyclic ring optionally substituted with one or more R 4 ; each R 3 is independently C1-C3 alkyl or halogen; each R 4 is independently oxo, cyano, halogen, -PCFiCi-C alkyl)2, hydroxyl, alkoxy, hydroxyalkyl, heteroalkyl, aralkyl, haloalkyl, -COOR 5 , -Y 2 -haloalkyl, -Y’-Ci-Ce alkyl, -Y 2 -Ci-Ce alkyl, -L-cycloalkyl, -L-heteroaryl, -L-heterocyclyl, -Y'-heterocycl
  • L is a bond or C1-C4 alkylene
  • Y 1 is a bond, -C(O)-, or -NHC(O)-;
  • Y 2 is a bond, -S-, -SO-, -SO 2 -, or -NR 5 SO 2 -, each R 5 is hydrogen or C1-C3 alkyl; R 6 is hydrogen, C1-C3 alkyl, halogen, haloalkyl, hydroxyalkyl, or heteroalkyl; each R 7 is oxo, cyano, hydroxyl, alkoxy, halogen, haloalkyl, hydroxyalkyl, heteroalkyl, cycloalkyl, -L-
  • N(R 5 ) 2 Ci-Ce alkyl or -Y’-heterocyclyl; and n is 1 or 2.
  • n 1
  • R 2 is cyano.
  • R 2 is -COOR 5 or -C(O)N(R 5 )2.
  • R 2 is -COOR 5 .
  • R 2 is -C(O)N(R 5 )2.
  • R 3 is halogen. In some embodiments R 3 is fluorine.
  • X is C(R 5 ) 2 and - is a single bond.
  • X is CR 5 and - is a double bond.
  • X is O and - is a single bond.
  • R 1 is aryl optionally substituted with one or more R 4 .
  • the aryl is phenyl optionally substituted with one or more R 4 .
  • the phenyl is substituted with one, two or three R 4 .
  • the one, two or three R 4 are each independently halogen, -POdCi-C alkyl) 2 , hydroxyl, hydroxyalkyl, aralkyl, haloalkyl, - COOR 5 , -Y’-Ci-Ce alkyl, Y 2 -CI-C 6 alkyl, -L-N(R 5 ) 2 , -O-L-N(R 5 ) 2 , -C(CF 3 )N(R 5 ) 2 , -Y’-N(R 5 ) 2 , -Y 2 -N(R 5 ) 2 , Y 2 -haloalkyl, -L-heteroaryl, -L-heterocyclyl, or -Y 1 -heterocyclyl, wherein the heterocyclyl portion of the -L- heterocyclyl or -Y 1 -heterocyclyl is optionally substituted with one or more R 7 .
  • R 4 is - Y’-Ci-Ce alkyl and Y 1 is a bond and the Ci-Ce alkyl is methyl, ethyl, isopropyl, butyl or pentyl.
  • R 4 is -Y 2 -Ci-Ce alkyl and Y 2 is a -SO2- and the Ci-Ce alkyl is methyl.
  • R 4 is -Y 2 -haloalkyl and Y 2 is -S- or -SO2- and the haloalkyl is trifluoromethyl.
  • R 4 is -L-N(R 5 )2 and L is a bond and each R 5 is hydrogen, each R 5 is methyl or one R 5 is methyl and one R 5 is hydrogen.
  • R 4 is -L-N(R 5 )2 and L is methylene or ethylene and each R 5 is hydrogen, each R 5 is methyl or one R 5 is methyl and one R 5 is hydrogen.
  • R 4 is -Y'-N(R 5 )2, Y 1 is -C(O)- and each R 5 independently is hydrogen, each R 5 is independently methyl or one R 5 is methyl and one R 5 is hydrogen.
  • R 4 is -Y 2 -N(R 5 ) 2 , Y 2 is -SO2- and each R 5 independently is hydrogen, each R 5 is methyl or one R 5 is methyl and one R 5 is independently hydrogen.
  • R 4 is -Y 1 -heterocyclyl and Y 1 is -C(O)- and the heterocyclyl portion of the L-heterocyclyl is piperazinyl or 4-methyl-piperazinyl.
  • R 4 is -L-heterocyclyl and L is a bond and the heterocyclyl portion of the L-heterocyclyl is azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, or 3/. 2 -azabicyclo
  • R 4 is -L- heterocyclyl, wherein L is a methylene and the heterocyclyl portion of the L-heterocyclyl is azetidinyl, oxetanyl, pyrrolidinyl piperidinyl, each optionally substituted with one or more R 7 selected from C1-C3 alkyl, alkoxy, hydroxyl and halogen.
  • R 4 is -Y 1 -heterocyclyl and Y 1 is -C(O)- and the heterocyclyl portion of the Y 1 -heterocyclyl is morpholinyl optionally substituted with one or more C1-C3 alkyl.
  • R 4 is -L-heteroaryl optionally substituted with one or more R 7 .
  • the -L-heteroaryl is tetrazolyl.
  • R 4 is -POsiCi-Cs alkyl)2.
  • R 4 is -COOR 5 .
  • R 4 is hydroxyalkyl.
  • R 4 is -O-L-N(R 5 )2.
  • R 4 is aralkyl.
  • R 1 is heteroaryl optionally substituted with one or more R 4 .
  • heteroaryl is pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, triazinyl, pyridyl, pyridinyl-2-one, pyrazinyl, pyridazinyl, pyrimidinyl, isoxazolyl, isoindolinyl, naphthyridinyl, 1,2,3,4-tetrahydroisoquinolinyl, or 5,6-dihydro-4H-pyrrolo[l,2-b]pyrazolyl, each optionally substituted with one or more R 4 .
  • the heteroaryl is substituted with one or more R 4 ; wherein each R 4 is independently cyano, halogen, -Y’-Ci-Ce alkyl, -Y 2 -Ci-Ce alkyl, alkoxy, hydroxyalkyl, heteroalkyl, haloalkyl, -L-cycloalkyl, -L-N(R 5 )2, -Y'-N(R 5 )2, -L-heteroaryl, -L-heterocyclyl, or -Y 1 - heterocyclyl, wherein the heteroaryl of the -L-heteroaryl or the heterocyclyl portion of the L-heterocyclyl, or Y 1 -heterocyclyl is optionally substituted with one or more R 7 .
  • the heteroaryl is pyrazolyl optionally substituted with one R 4 independently selected from hydroxyalkyl, heteroalkyl, haloalkyl, -Y’-Ci-Ce alkyl, -L-N(R 5 )2, L-heterocyclyl or L-heteroaryl, wherein the heteroaryl of the L- heteroaryl or the heterocyclyl portion of the L-heterocyclyl is optionally substituted with one or more R 7 .
  • R 4 is -L-heteroaryl and L is methylene wherein the heteroaryl is pyridyl optional substituted with one or more R 7 .
  • R 4 is -L-heterocyclyl optionally substituted with one or more R 7 where L is a bond and the heterocyclyl portion of the L-heterocyclyl is oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, piperazinyl or 4-methylpiperazinyl.
  • R 4 is -L-heterocyclyl optionally substituted with one or more R 7 where L is methylene and the heterocyclyl portion of the L-heterocyclyl is azetidinyl, oxetanyl, pyrrolidinyl, pyrrolidinone, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, piperazinyl or 4-methylpiperazinyl.
  • R 4 is -L-N(R 5 )2 where L is methylene and each R 5 is independently hydrogen, each R 5 is independently C1-C3 alkyl or one R 5 is C1-C3 alkyl and one R 5 is hydrogen.
  • R 4 is - Y’-Ci-Ce alkyl where Y 1 is a bond and the Ci-Ce alkyl is methyl, ethyl or isopropyl.
  • the heteroaryl is pyrazolyl optionally substituted with two R 4 groups each independently selected from hydroxyalkyl, heteroalkyl, haloalkyl, and -Y’-Ci-Ce alkyl.
  • heteroaryl is pyridyl optionally substituted with one R 4 independently selected from cyano, halogen, alkoxy, hydroxyalkyl, heteroalkyl, haloalkyl, -Y’-Ci-Ce alkyl, -L-N(R 5 )2, -Y’-N(R 5 )2, -L-cycloalkyl, or -L- heterocyclyl optionally substituted with one or more R 7 .
  • R 1 is -L-cycloalkyl optionally substituted with one or more R 4 .
  • R 1 is -L-heterocyclyl optionally substituted with one or more R 4 .
  • L is a bond and the heterocyclyl is piperidinyl or tetrahydropyranyl.
  • T-cell lymphoma comprising administering to the subject a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:
  • XRPD x- ray powder diffraction
  • crystalline form of Compound 4 exhibits a further peak in an x-ray powder diffraction (XRPD) pattern at 9.6° ⁇ 0.2° 2-theta. Also provided herein are such methods wherein the crystalline form of Compound 4 exhibits further peaks in an x-ray powder diffraction (XRPD) pattern at 5.7° ⁇ 0.2° 2-theta, 19.7° ⁇ 0.2° 2- theta, and 22.0° ⁇ 0.2° 2-theta. Also provided herein are such methods wherein the crystalline form of Compound 4 exhibits further peaks in an x-ray powder diffraction (XRPD) pattern at 9.8° ⁇ 0.2° 2-theta,
  • crystalline form of Compound 4 exhibits a peak in a differential scanning calorimetry pattern of from about 206 °C to about 210 °C, or from about 207 °C to about 210 °C, or from about 208 °C to about 210 °C, or from about 209 °C to about 210 °C.
  • the crystalline form of Compound 4 exhibits a loss in mass in a thermal gravimetric analysis of less than about 1% upon heating the sample from about 25 °C to a temperature prior to melting.
  • the crystalline form of Compound 4 exhibits a loss in mass in a thermal gravimetric analysis of less than about 1% upon heating the sample from about 25 °C to about 380 °C.
  • crystalline form of Compound 4 exhibits further peaks in an x-ray powder diffraction (XRPD) pattern at 5.5° ⁇ 0.2° 2-theta, 8.6° ⁇ 0.2° 2-theta, 15.9° ⁇ 0.2° 2-theta, 19.9° ⁇ 0.2° 2-theta, and 24.1° ⁇ 0.2° 2-theta.
  • XRPD x-ray powder diffraction
  • crystalline form of Compound 4 exhibits further peaks in an x-ray powder diffraction (XRPD) pattern at 10.6° ⁇ 0.2° 2-theta, 11.0° ⁇ 0.2° 2-theta, 15.4° ⁇ 0.2° 2-theta, 21.0° ⁇ 0.2° 2-theta, and 26.3° ⁇ 0.2° 2-theta.
  • XRPD x-ray powder diffraction
  • crystalline form of Compound 4 exhibits a peak in a differential scanning calorimetry pattern of from about 203 °C to about 208 °C, or from about 203 °C to about 206 °C, or from about 203 °C to about 205 °C. Also provided herein are such methods wherein the crystalline form of Compound 4 exhibits a loss in mass in a thermal gravimetric analysis of less than about 2% upon heating the sample from about 25 °C to about 380 °C. Also provided herein are such methods wherein the crystalline form of Compound 4 exhibits a loss in mass in a thermal gravimetric analysis of less than about 2% upon heating the sample from about 25 °C to about 210 °C.
  • crystalline form of Compound 4 exhibits a peak in an x-ray powder diffraction (XRPD) pattern at 7.7° ⁇ 0.2° 2-theta. Also provided herein are such methods wherein the crystalline form of Compound 4 exhibits further a peak in an x-ray powder diffraction (XRPD) pattern at 15.4° ⁇ 0.2° 2-theta. Also provided herein are such methods wherein the crystalline form of Compound 4 exhibits further a peak in an x-ray powder diffraction (XRPD) pattern at 19.2° ⁇ 0.2° 2-theta.
  • XRPD x-ray powder diffraction
  • crystalline form of Compound 4 exhibits a further peak in an x-ray powder diffraction (XRPD) pattern at 13.7° ⁇ 0.2° 2-theta. Also provided herein are such methods wherein the crystalline form of Compound 4 exhibits further peaks in an x-ray powder diffraction (XRPD) pattern at 5.5° ⁇ 0.2° 2-theta, 8.6° ⁇ 0.2° 2-theta, 15.9° ⁇ 0.2° 2-theta, 19.9° ⁇ 0.2° 2-theta, and 24.1° ⁇ 0.2° 2-theta.
  • crystalline form of Compound 4 exhibits further peaks in an x-ray powder diffraction (XRPD) pattern at 10.6° ⁇ 0.2° 2-theta, 11.0° ⁇ 0.2° 2-theta, 21.0° ⁇ 0.2° 2-theta, and 26.3° ⁇ 0.2° 2-theta.
  • XRPD x-ray powder diffraction
  • the crystalline form of Compound 4 exhibits a peak in a differential scanning calorimetry pattern of from about 203 °C to about 210 °C.
  • the crystalline form of Compound 4 exhibits a peak in a differential scanning calorimetry pattern of from about 206 °C to about 210 °C.
  • crystalline form of Compound 4 exhibits a peak in a differential scanning calorimetry pattern of from about 203 °C to about 208 °C, or from about 203 °C to about 206 °C, or from about 203 °C to about 205 °C. Also provided herein are such methods wherein the crystalline form of Compound 4 exhibits a loss in mass in a thermal gravimetric analysis of less than about 2% upon heating the sample from about 25 °C to about 380 °C. Also provided herein are such methods wherein the crystalline form of Compound 4 exhibits a loss in mass in a thermal gravimetric analysis of less than about 2% upon heating the sample from about 25 °C to about 210 °C.
  • crystalline form of Compound 4 exhibits peaks in an x-ray powder diffraction (XRPD) pattern at 7.7° ⁇ 0.2° 2-theta and 15.4° ⁇ 0.2° 2-theta. Also provided herein are such methods wherein the crystalline form of Compound 4 exhibits a peak in an x-ray powder diffraction (XRPD) pattern at 19.2° ⁇ 0.2° 2-theta. Also provided herein are such methods wherein the crystalline form of Compound 4 exhibits a further peak in an x-ray powder diffraction (XRPD) pattern at 13.7° ⁇ 0.2° 2-theta.
  • XRPD x-ray powder diffraction
  • crystalline form of Compound 4 exhibits further peaks in an x-ray powder diffraction (XRPD) pattern at 5.5° ⁇ 0.2° 2-theta, 8.6° ⁇ 0.2° 2- theta, 15.9° ⁇ 0.2° 2-theta, 19.9° ⁇ 0.2° 2-theta, and 24. 1° ⁇ 0.2° 2-theta.
  • XRPD x-ray powder diffraction
  • crystalline form of Compound 4 exhibits further peaks in an x-ray powder diffraction (XRPD) pattern at 10.6° ⁇ 0.2° 2-theta, 11.0° ⁇ 0.2° 2-theta, 21.0° ⁇ 0.2° 2-theta, and 26.3° ⁇ 0.2° 2-theta.
  • XRPD x-ray powder diffraction
  • the crystalline form of Compound 4 exhibits a peak in a differential scanning calorimetry pattern of from about 203 °C to about 210 °C.
  • the crystalline form of Compound 4 exhibits a peak in a differential scanning calorimetry pattern of from about 206 °C to about 210 °C.
  • crystalline form of Compound 4 exhibits a peak in a differential scanning calorimetry pattern of from about 203 °C to about 208 °C, or from about 203 °C to about 206 °C, or from about 203 °C to about 205 °C. Also provided herein are such methods wherein the crystalline form of Compound 4 exhibits a loss in mass in a thermal gravimetric analysis of less than about 2% upon heating the sample from about 25 °C to about 380 °C. Also provided herein are such methods wherein the crystalline form of Compound 4 exhibits a loss in mass in a thermal gravimetric analysis of less than about 2% upon heating the sample from about 25 °C to about 210 °C.
  • crystalline form of Compound 4 exhibits further peaks in an x-ray powder diffraction (XRPD) pattern at 5.5° ⁇ 0.2° 2-theta, 8.6° ⁇ 0.2° 2- theta, 15.9° ⁇ 0.2° 2-theta, 19.9° ⁇ 0.2° 2-theta, and 24.1° ⁇ 0.2° 2-theta.
  • XRPD x-ray powder diffraction
  • crystalline form of Compound 4 exhibits further peaks in an x-ray powder diffraction (XRPD) pattern at 10.6° ⁇ 0.2° 2-theta, 11.0° ⁇ 0.2° 2-theta, 21.0° ⁇ 0.2° 2-theta, and 26.3° ⁇ 0.2° 2-theta.
  • XRPD x-ray powder diffraction
  • the crystalline form of Compound 4 exhibits a peak in a differential scanning calorimetry pattern of from about 203 °C to about 210 °C.
  • the crystalline form of Compound 4 exhibits a peak in a differential scanning calorimetry pattern of from about 206 °C to about 210 °C.
  • crystalline form of Compound 4 exhibits a peak in a differential scanning calorimetry pattern of from about 203 °C to about 208 °C, or from about 203 °C to about 206 °C, or from about 203 °C to about 205 °C. Also provided herein are such methods wherein the crystalline form of Compound 4 exhibits a loss in mass in a thermal gravimetric analysis of less than about 2% upon heating the sample from about 25 °C to about 380 °C. Also provided herein are such methods wherein the crystalline form of Compound 4 exhibits a loss in mass in a thermal gravimetric analysis of less than about 2% upon heating the sample from about 25 °C to about 210 °C.
  • crystalline form of Compound 4 exhibits less than about 10% degradation when stored at 25 °C and 60% relative humidity for at least 7 days. Also provided herein are such methods wherein the crystalline form of Compound 4 exhibits less than about 1%, or less than about 2%, or less than about 3%, or less than about 4%, or less than about 5%, or less than about 6%, or less than about 7%, or less than about 8%, or less than about 9% degradation when the crystalline form is stored at 25 °C and 60% relative humidity for at least 7 days.
  • crystalline form of Compound 4 exhibits peaks in an x-ray powder diffraction (XRPD) pattern at 9.6° ⁇ 0.2° 2-theta, 5.7° ⁇ 0.2° 2-theta, 19.7° ⁇ 0.2° 2-theta, and 22.0° ⁇ 0.2° 2-theta , and (b) less than about 10% degradation when the crystalline form is stored at 25 °C and 60% relative humidity for at least 7 days.
  • XRPD x-ray powder diffraction
  • crystalline form of Compound 4 exhibits less than about 1%, or less than about 2%, or less than about 3%, or less than about 4%, or less than about 5%, or less than about 6%, or less than about 7%, or less than about 8%, or less than about 9% degradation when the crystalline form is stored at 25 °C and 60% relative humidity for at least 7 days.
  • crystalline form of Compound 4 exhibits (a) peaks in an x-ray powder diffraction (XRPD) pattern at 7.7° ⁇ 0.2° 2-theta, 13.7° ⁇ 0.2° 2-theta, and 19.2° ⁇ 0.2° 2-theta, and (b) less than about 10% degradation when the crystalline form is stored at 25 °C and 60% relative humidity for at least 7 days.
  • XRPD x-ray powder diffraction
  • crystalline form of Compound 4 exhibits less than about 1%, or less than about 2%, or less than about 3%, or less than about 4%, or less than about 5%, or less than about 6%, or less than about 7%, or less than about 8%, or less than about 9% degradation when the crystalline form is stored at 25 °C and 60% relative humidity for at least 7 days.
  • crystalline form of Compound 4 exhibits less than about 10% degradation when the crystalline forms are stored at 40 °C and 75% relative humidity for at least 7 days. Also provided herein are such methods wherein the crystalline form of Compound 4 exhibits less than about 1%, or less than about 2%, or less than about 3%, or less than about 4%, or less than about 5%, or less than about 6%, or less than about 7%, or less than about 8%, or less than about 9% degradation when the crystalline form is stored at 40 °C and 75% relative humidity for at least 7 days.
  • crystalline form of Compound 4 exhibits (a) a peak in an x-ray powder diffraction (XRPD) pattern at 8. 1° ⁇ 0.2° 2-theta, and (b) less than about 10% degradation when the crystalline form is stored at 40 °C and 75% relative humidity for at least 7 days.
  • XRPD x-ray powder diffraction
  • crystalline form of Compound 4 exhibits (a) peaks in an x-ray powder diffraction (XRPD) pattern at 9.6° ⁇ 0.2° 2-theta, 5.7° ⁇ 0.2° 2-theta, 19.7° ⁇ 0.2° 2-theta, and 22.0° ⁇ 0.2° 2-theta , and (b) less than about 10% degradation when the crystalline form is stored at 40 °C and 75% relative humidity for at least 7 days.
  • XRPD x-ray powder diffraction
  • crystalline form of Compound 4 exhibits less than about 1%, or less than about 2%, or less than about 3%, or less than about 4%, or less than about 5%, or less than about 6%, or less than about 7%, or less than about 8%, or less than about 9% degradation when the crystalline form is stored at 40 °C and 75% relative humidity for at least 7 days.
  • crystalline form of Compound 4 exhibits (a) a peak in an x-ray powder diffraction (XRPD) pattern at 7.7° ⁇ 0.2° 2-theta, and (b) less than about 10% degradation when the crystalline form is stored at 40 °C and 75% relative humidity for at least 7 days.
  • XRPD x-ray powder diffraction
  • crystalline form of Compound 4 exhibits (a) peaks in an x-ray powder diffraction (XRPD) pattern at 7.7° ⁇ 0.2° 2-theta, 13.7° ⁇ 0.2° 2-theta, and 19.2° ⁇ 0.2° 2-theta, and (b) less than about 10% degradation when the crystalline form is stored at 40 °C and 75% relative humidity for at least 7 days.
  • XRPD x-ray powder diffraction
  • crystalline form of Compound 4 exhibits less than about 1%, or less than about 2%, or less than about 3%, or less than about 4%, or less than about 5%, or less than about 6%, or less than about 7%, or less than about 8%, or less than about 9% degradation when the crystalline form is stored at 40 °C and 75% relative humidity for at least 7 days.
  • crystalline form of Compound 4 exhibits less than about 10% degradation when the crystalline form is stored at 60 °C for at least one week. Also provided herein are such methods wherein the crystalline form of Compound 4 exhibits less than about 1%, or less than about 2%, or less than about 3%, or less than about 4%, or less than about 5%, or less than about 6%, or less than about 7%, or less than about 8%, or less than about 9% degradation when the crystalline form is stored at 60 °C for at least one week. [0080] In other embodiments are provided the methods disclosed herein, wherein the compound of Formula (Compound 5), or a pharmaceutically acceptable salt thereof.
  • (I) is Compound (Compound 9), or a pharmaceutically acceptable salt thereof.
  • (I) is Compound 12: (Compound 12), or a pharmaceutically acceptable salt thereof.
  • T-cell lymphoma in a subject comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein the T-cell lymphoma in the subject is peripheral T-cell lymphoma.
  • the peripheral T-cell lymphoma in the subject is peripheral T-cell lymphoma, not otherwise specified (PTCL, NOS).
  • the peripheral T-cell lymphoma in the subject is angioimmunoblastic T- cell lymphoma (AITL).
  • AITL angioimmunoblastic T- cell lymphoma
  • peripheral T-cell lymphoma in the subject is ALK-1 positive anaplastic large cell lymphoma (ALCL). In further embodiments are provided such methods, wherein the peripheral T-cell lymphoma in the subject is ALK-1 negative anaplastic large cell lymphoma (ALCL). In further embodiments are provided such methods, wherein the peripheral T-cell lymphoma in the subject is enteropathy-associated T-cell lymphoma (EATL). In further embodiments are provided such methods, wherein the peripheral T-cell lymphoma in the subject is monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL).
  • peripheral T-cell lymphoma in the subject is nodal peripheral T-cell lymphoma with T-follicular helper (TFH) phenotype.
  • T-follicular helper T-follicular helper
  • the peripheral T-cell lymphoma in the subject is follicular T-cell lymphoma (FTCL).
  • FTCL follicular T-cell lymphoma
  • the peripheral T-cell lymphoma in the subject is extranodal natural killer (NKj/T-cell lymphoma (ENKTCL).
  • NKj/T-cell lymphoma extranodal natural killer
  • the peripheral T-cell lymphoma in the subject is hepatosplenic T-cell lymphoma (HSTCL).
  • peripheral T-cell lymphoma in the subject is subcutaneous panniculitis-like TCL (SPTCL).
  • SPTCL subcutaneous panniculitis-like TCL
  • ATLL adult T-cell leukemia/lymphoma
  • PCGDTL primary cutaneous gamma-delta T-cell lymphoma
  • PCAECyTCL primary cutaneous aggressive epidermotropic cytotoxic T-cell lymphoma
  • T-cell lymphoma in a subject, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein the T-cell lymphoma in the subject is cutaneous T-cell lymphoma (CTCL).
  • CTCL cutaneous T-cell lymphoma
  • methods of treating T-cell lymphoma in a subject comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein the subject has received at least one therapy prior to the administration to the subject of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
  • the at least one prior therapy is a systemic therapy.
  • T-cell lymphoma in a subject comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein the T-cell lymphoma in the subject is relapsed or refractory T-cell lymphoma.
  • the relapsed or refractory T-cell lymphoma in the subject is peripheral T-cell lymphoma.
  • the peripheral T-cell lymphoma in the subject is peripheral T-cell lymphoma, not otherwise specified (PTCL, NOS).
  • peripheral T-cell lymphoma in the subject is angioimmunoblastic T-cell lymphoma (AITL).
  • AITL angioimmunoblastic T-cell lymphoma
  • the peripheral T-cell lymphoma in the subject is ALK-1 positive anaplastic large cell lymphoma (ALCL).
  • the peripheral T-cell lymphoma in the subject is ALK-1 negative anaplastic large cell lymphoma (ALCL).
  • the peripheral T-cell lymphoma in the subject is enteropathy-associated T-cell lymphoma (EATL).
  • peripheral T-cell lymphoma in the subject is monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL). In further embodiments are provided such methods, wherein the peripheral T-cell lymphoma in the subject is nodal peripheral T-cell lymphoma with T-follicular helper (TFH) phenotype. In further embodiments are provided such methods, wherein the peripheral T-cell lymphoma in the subject is follicular T-cell lymphoma (FTCL). In further embodiments are provided such methods, wherein the peripheral T-cell lymphoma in the subject is extranodal natural killer (NKj/T-cell lymphoma (ENKTCL).
  • NKj/T-cell lymphoma extranodal natural killer
  • peripheral T-cell lymphoma in the subject is hepatosplenic T-cell lymphoma (HSTCL). In further embodiments are provided such methods, wherein the peripheral T-cell lymphoma in the subject is subcutaneous panniculitis-like TCL (SPTCL). In further embodiments are provided such methods, wherein the peripheral T-cell lymphoma in the subject is adult T-cell leukemia/lymphoma (ATLL). In further embodiments are provided such methods, wherein the peripheral T-cell lymphoma in the subject is primary cutaneous gamma-delta T-cell lymphoma (PCGDTL).
  • HTCL hepatosplenic T-cell lymphoma
  • SPTCL subcutaneous panniculitis-like TCL
  • ATLL adult T-cell leukemia/lymphoma
  • PCGDTL primary cutaneous gamma-delta T-cell lymphoma
  • peripheral T-cell lymphoma in the subject is primary cutaneous aggressive epidermotropic cytotoxic T-cell lymphoma (PCAECyTCL).
  • T-cell lymphoma in the subject is cutaneous T-cell lymphoma (CTCL).
  • T-cell lymphoma in a subject comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein the T-cell lymphoma in the subject is relapsed or refractory T-cell lymphoma, and wherein the subject has received at least one prior therapy.
  • the relapsed or refractory T-cell lymphoma in the subject is peripheral T-cell lymphoma.
  • peripheral T-cell lymphoma in the subject is peripheral T-cell lymphoma, not otherwise specified (PTCL, NOS).
  • peripheral T-cell lymphoma in the subject is angioimmunoblastic T-cell lymphoma (AITL).
  • AITL angioimmunoblastic T-cell lymphoma
  • the peripheral T-cell lymphoma in the subject is ALK-1 positive anaplastic large cell lymphoma (ALCL).
  • the peripheral T-cell lymphoma in the subject is ALK-1 negative anaplastic large cell lymphoma (ALCL).
  • the peripheral T-cell lymphoma in the subject is enteropathy-associated T-cell lymphoma (EATL).
  • peripheral T-cell lymphoma in the subject is monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL).
  • peripheral T-cell lymphoma in the subject is nodal peripheral T-cell lymphoma with T-follicular helper (TFH) phenotype.
  • T-follicular helper T-follicular helper
  • FTCL follicular T-cell lymphoma
  • peripheral T-cell lymphoma in the subject is extranodal natural killer (NK)ZT-cell lymphoma (ENKTCL).
  • peripheral T-cell lymphoma in the subject is hepatosplenic T-cell lymphoma (HSTCL). In further embodiments are provided such methods, wherein the peripheral T-cell lymphoma in the subject is subcutaneous panniculitis-like TCL (SPTCL). In further embodiments are provided such methods, wherein the peripheral T-cell lymphoma in the subject is adult T-cell leukemia/lymphoma (ATLL). In further embodiments are provided such methods, wherein the peripheral T-cell lymphoma in the subject is primary cutaneous gamma-delta T-cell lymphoma (PCGDTL).
  • HTCL hepatosplenic T-cell lymphoma
  • SPTCL subcutaneous panniculitis-like TCL
  • ATLL adult T-cell leukemia/lymphoma
  • PCGDTL primary cutaneous gamma-delta T-cell lymphoma
  • peripheral T-cell lymphoma in the subject is primary cutaneous aggressive epidermotropic cytotoxic T-cell lymphoma (PCAECyTCL).
  • T-cell lymphoma in the subject is cutaneous T-cell lymphoma (CTCL).
  • T-cell lymphoma in a subject comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein the T-cell lymphoma in the subject is refractory to at least one prior systemic therapy.
  • the relapsed or refractory T-cell lymphoma in the subject is peripheral T-cell lymphoma.
  • the peripheral T-cell lymphoma in the subject is peripheral T-cell lymphoma, not otherwise specified (PTCL, NOS).
  • peripheral T-cell lymphoma in the subject is angioimmunoblastic T-cell lymphoma (AITL).
  • AITL angioimmunoblastic T-cell lymphoma
  • the peripheral T-cell lymphoma in the subject is ALK-1 positive anaplastic large cell lymphoma (ALCL).
  • the peripheral T-cell lymphoma in the subject is ALK-1 negative anaplastic large cell lymphoma (ALCL).
  • the peripheral T-cell lymphoma in the subject is enteropathy-associated T-cell lymphoma (EATL).
  • peripheral T-cell lymphoma in the subject is monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL).
  • peripheral T-cell lymphoma in the subject is nodal peripheral T-cell lymphoma with T-follicular helper (TFH) phenotype.
  • T-follicular helper T-follicular helper
  • FTCL follicular T-cell lymphoma
  • peripheral T-cell lymphoma in the subject is extranodal natural killer (NK)ZT-cell lymphoma (ENKTCL).
  • peripheral T-cell lymphoma in the subject is hepatosplenic T-cell lymphoma (HSTCL).
  • peripheral T-cell lymphoma in the subject is subcutaneous panniculitis-like TCL (SPTCL).
  • SPTCL subcutaneous panniculitis-like TCL
  • ATLL adult T-cell leukemiaZlymphoma
  • PCGDTL primary cutaneous gamma-delta T-cell lymphoma
  • peripheral T-cell lymphoma in the subject is primary cutaneous aggressive epidermotropic cytotoxic T-cell lymphoma (PCAECyTCL).
  • T-cell lymphoma in the subject is cutaneous T-cell lymphoma (CTCL).
  • T-cell lymphoma in a subject comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein the T-cell lymphoma in the subject has not responded to or has relapsed following treatment with at least one prior chemotherapy agent.
  • the relapsed or refractory T-cell lymphoma in the subject is peripheral T- cell lymphoma.
  • the peripheral T-cell lymphoma in the subject is peripheral T-cell lymphoma, not otherwise specified (PTCL, NOS).
  • peripheral T-cell lymphoma in the subject is angioimmunoblastic T- cell lymphoma (AITL).
  • AITL angioimmunoblastic T- cell lymphoma
  • the peripheral T-cell lymphoma in the subject is ALK-1 positive anaplastic large cell lymphoma (ALCL).
  • the peripheral T-cell lymphoma in the subject is ALK-1 negative anaplastic large cell lymphoma (ALCL).
  • the peripheral T-cell lymphoma in the subject is enteropathy-associated T-cell lymphoma (EATL).
  • peripheral T-cell lymphoma in the subject is monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL).
  • peripheral T-cell lymphoma in the subject is nodal peripheral T-cell lymphoma with T-follicular helper (TFH) phenotype.
  • T-follicular helper T-follicular helper
  • FTCL follicular T-cell lymphoma
  • peripheral T-cell lymphoma in the subject is extranodal natural killer (NK)ZT-cell lymphoma (ENKTCL).
  • peripheral T-cell lymphoma in the subject is hepatosplenic T-cell lymphoma (HSTCL). In further embodiments are provided such methods, wherein the peripheral T-cell lymphoma in the subject is subcutaneous panniculitis-like TCL (SPTCL). In further embodiments are provided such methods, wherein the peripheral T-cell lymphoma in the subject is adult T-cell leukemia/lymphoma (ATLL). In further embodiments are provided such methods, wherein the peripheral T-cell lymphoma in the subject is primary cutaneous gamma-delta T-cell lymphoma (PCGDTL).
  • HTCL hepatosplenic T-cell lymphoma
  • SPTCL subcutaneous panniculitis-like TCL
  • ATLL adult T-cell leukemia/lymphoma
  • PCGDTL primary cutaneous gamma-delta T-cell lymphoma
  • peripheral T-cell lymphoma in the subject is primary cutaneous aggressive epidermotropic cytotoxic T-cell lymphoma (PCAECyTCL).
  • T-cell lymphoma in the subject is cutaneous T-cell lymphoma (CTCL).
  • T-cell lymphoma in a subject comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein the T-cell lymphoma in the subject has progressed following at least one line of primary systemic therapy.
  • the at least one line of prior systemic therapy is at least one prior chemotherapy agent.
  • the relapsed or refractory T-cell lymphoma in the subject is peripheral T-cell lymphoma.
  • peripheral T-cell lymphoma in the subject is peripheral T-cell lymphoma, not otherwise specified (PTCL, NOS).
  • peripheral T-cell lymphoma in the subject is angioimmunoblastic T-cell lymphoma (AITL).
  • AITL angioimmunoblastic T-cell lymphoma
  • the peripheral T-cell lymphoma in the subject is ALK-1 positive anaplastic large cell lymphoma (ALCL).
  • ALK-1 negative anaplastic large cell lymphoma ALK-1 negative anaplastic large cell lymphoma
  • peripheral T-cell lymphoma in the subject is enteropathy-associated T-cell lymphoma (EATL).
  • the peripheral T-cell lymphoma in the subject is monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL).
  • the peripheral T-cell lymphoma in the subject is nodal peripheral T-cell lymphoma with T-follicular helper (TFH) phenotype.
  • T-follicular helper T-follicular helper
  • FTCL follicular T-cell lymphoma
  • peripheral T-cell lymphoma in the subject is extranodal natural killer (NK)ZT-cell lymphoma (ENKTCL).
  • NK extranodal natural killer
  • ENKTCL extranodal natural killer
  • the peripheral T-cell lymphoma in the subject is hepatosplenic T-cell lymphoma (HSTCL).
  • the peripheral T-cell lymphoma in the subject is subcutaneous panniculitis-like TCL (SPTCL).
  • SPTCL subcutaneous panniculitis-like TCL
  • ATLL adult T-cell leukemia/lymphoma
  • peripheral T-cell lymphoma in the subject is primary cutaneous gamma-delta T-cell lymphoma (PCGDTL).
  • peripheral T-cell lymphoma in the subject is primary cutaneous aggressive epidermotropic cytotoxic T-cell lymphoma (PCAECyTCL).
  • T-cell lymphoma in the subject is cutaneous T-cell lymphoma (CTCL).
  • the one or more additional therapeutic agents is selected from a chemotherapeutic agent, a mitotic inhibitors, an antimetabolites, a platinum -based agents, histone deacetylase (HDAC) inhibitors, CD30-directed antibody-drug conjugates, famesyl transferase inhibitors, SYK inhibitors, JAK inhibitors, PI3K inhibitors, immunomodulatory agents, or combinations thereof.
  • the one or more additional therapeutic agents are selected from chemotherapeutic agents.
  • chemotherapeutic agents are selected from actinomycin, azacytidine, azathioprine, bendamustine, bleomycin, bortezomib, chlorambucil, cyclophosphamide, daunorubicin, doxifluridine, doxorubicin, epirubicin, epothilone, etoposide, idarubicin, irinotecan, lurbinectedin, mechlorethamine, mitoxantrone, teniposide, topotecan, valrubicin, vemurafenib, vinblastine, vincristine, and vindesine.
  • the chemotherapeutic agent is actinomycin. In some embodiments, the chemotherapeutic agent is azacytidine. In some embodiments, the chemotherapeutic agent is azathioprine. In some embodiments, the chemotherapeutic agent is bleomycin. In some embodiments, the chemotherapeutic agent is bortezomib. In some embodiments, the chemotherapeutic agent is chlorambucil. In some embodiments, the chemotherapeutic agent is cyclophosphamide. In some embodiments, the chemotherapeutic agent is daunorubicin. In some embodiments, the chemotherapeutic agent is doxifluridine.
  • the chemotherapeutic agent is doxorubicin. In some embodiments, the chemotherapeutic agent is epirubicin. In some embodiments, the chemotherapeutic agent is epothilone. In some embodiments, the chemotherapeutic agent is etoposide. In some embodiments, the chemotherapeutic agent is idarubicin. In some embodiments, the chemotherapeutic agent is irinotecan. In some embodiments, the chemotherapeutic agent is lurbinectedin. In some embodiments, the chemotherapeutic agent is mechlorethamine. In some embodiments, the chemotherapeutic agent is mitoxantrone.
  • the chemotherapeutic agent is teniposide. In some embodiments, the chemotherapeutic agent is topotecan. In some embodiments, the chemotherapeutic agent is valrubicin. In some embodiments, the chemotherapeutic agent is vemurafenib. In some embodiments, the chemotherapeutic agent is vinblastine. In some embodiments, the chemotherapeutic agent is vincristine. In some embodiments, the chemotherapeutic agent is vindesine.
  • the one or more additional therapeutic agents are selected from mitotic inhibitors.
  • the mitotic inhibitors are selected from paclitaxel, docetaxel, cabazitaxel, tesetaxel, and nab -paclitaxel.
  • the mitotic inhibitor is paclitaxel.
  • the mitotic inhibitor is docetaxel.
  • the mitotic inhibitor is cabazitaxel.
  • the mitotic inhibitor is tesetaxel.
  • the mitotic inhibitor is nab -paclitaxel.
  • the one or more additional therapeutic agents are selected from antimetabolites.
  • the one or more antimetabolites are selected from azacytidine, 6- mercaptopurine, capecitabine, hydroxyurea, cladribine, pralatrexate, thioguanine, decitabine, clofarabine, nelarabine, fludarabine, 5 -fluorouracil, gemcitabine, cytarabine, pemetrexed, and methotrexate, cytarabine (Ara-C), floxuridine, fludarabine, pentostatin, and trifluridine/tipiracil combination.
  • the one or more antimetabolites are selected from 6-mercaptopurine, capecitabine, hydroxyurea, cladribine, pralatrexate, thioguanine, decitabine, clofarabine, nelarabine, fludarabine, 5 -fluorouracil, gemcitabine, cytarabine, pemetrexed, and methotrexate.
  • the antimetabolite is azacytidine. In some embodiments, the antimetabolite is 6-mercaptopurine. In some embodiments, the antimetabolite is capecitabine. In some embodiments, the antimetabolite is hydroxyurea. In some embodiments, the antimetabolite is cladribine. In some embodiments, the antimetabolite is pralatrexate. In some embodiments, the antimetabolite is thioguanine. In some embodiments, the antimetabolite is decitabine. In some embodiments, the antimetabolite is clofarabine. In some embodiments, the antimetabolite is nelarabine. In some embodiments, the antimetabolite is fludarabine.
  • the antimetabolite is 5 -fluorouracil. In some embodiments, the antimetabolite is gemcitabine. In some embodiments, the antimetabolite is cytarabine. In some embodiments, the antimetabolite is pemetrexed. In some embodiments, the antimetabolite is and methotrexate. In some embodiments, the antimetabolite is cytarabine (Ara-C). In some embodiments, the antimetabolite is floxuridine. In some embodiments, the antimetabolite is fludarabine. In some embodiments, the antimetabolite is pentostatin. In some embodiments, the antimetabolite is a trifluridine/tipiracil combination.
  • the one or more additional therapeutic agents are selected from platinumbased agents.
  • the platinum -based agents are selected from cisplatin, carboplatin, oxaliplatin, nedaplatin, lobaplatin, triplatin tetranitrate, pheanthriplatin, picoplatin, and satraplatin.
  • the platinum-based agent is cisplatin.
  • the platinum-based agent is carboplatin.
  • the platinum-based agent is oxaliplatin.
  • the platinum -based agent is nedaplatin.
  • the platinum -based agent is lobaplatin.
  • the platinum -based agent is triplatin tetranitrate. In further embodiments, the platinumbased agent is pheanthriplatin. In further embodiments, the platinum-based agent is picoplatin. In further embodiments, the platinum-based agent is satraplatin.
  • the one or more additional therapeutic agents are selected from histone deacetylase (HDAC) inhibitors.
  • HDAC histone deacetylase
  • the histone deacetylase (HDAC) inhibitors are selected from vorinostat, romidepsin, belinostat, tucidinostat, panobinostat, mocetinostat, givinostat, resmiostat, abexinostat, ricolinostat, entinostat, tinostamustin, fimepinostat, CXD-101, quisinostat, and chidamide.
  • the histone deacetylase (HDAC) inhibitor is vorinostat. In further embodiments, the histone deacetylase (HDAC) inhibitor is romidepsin. In further embodiments, the histone deacetylase (HDAC) inhibitor is belinostat. In further embodiments, the histone deacetylase (HDAC) inhibitor is tucidinostat. In further embodiments, the histone deacetylase (HDAC) inhibitor is Panobinostat. In further embodiments, the histone deacetylase (HDAC) inhibitor is mocetinostat. In further embodiments, the histone deacetylase (HDAC) inhibitor is givinostat.
  • the histone deacetylase (HDAC) inhibitor is resmiostat. In further embodiments, the histone deacetylase (HDAC) inhibitor is abexinostat. In further embodiments, the histone deacetylase (HDAC) inhibitor is ricolinostat. In further embodiments, the histone deacetylase (HDAC) inhibitor is entinostat. In further embodiments, the histone deacetylase (HDAC) inhibitor is tinostamustin. In further embodiments, the histone deacetylase (HDAC) inhibitor is fimepinostat. In further embodiments, the histone deacetylase (HDAC) inhibitor is CXD-101. In further embodiments, the histone deacetylase (HDAC) inhibitor is quisinostat. In further embodiments, the histone deacetylase (HDAC) inhibitor is chidamide.
  • the one or more additional therapeutic agents are selected from CD30-directed antibody-drug conjugates.
  • the CD30-directed antibody-drug conjugates are selected from brentuximab vedotin and SGN-CD30C.
  • the CD30-directed antibody-drug conjugate is brentuximab vedotin.
  • the CD30-directed antibody-drug conjugate is SGN-CD30C.
  • the one or more additional therapeutic agents are selected from famesyl transferase inhibitors.
  • the famesyl transferase inhibitors are selected from antroquinonol, BMS-214662, L778123, L744832, FTI-276, FTI-277, manumycin A, LB-42708, moverastin, PD169541, ABT-100, FTI-2153, tipifamib and lonafamib.
  • the famesyl transferase inhibitor is antroquinonol.
  • the famesyl transferase inhibitor is BMS-214662.
  • the famesyl transferase inhibitor is L778123. In further embodiments, the famesyl transferase inhibitor is L744832. In further embodiments, the famesyl transferase inhibitor is FTI-276. In further embodiments, the famesyl transferase inhibitor is FTI-277. In further embodiments, the famesyl transferase inhibitor is manumycin A. In further embodiments, the famesyl transferase inhibitor is LB-42708. In further embodiments, the famesyl transferase inhibitor is moverastin. In further embodiments, the famesyl transferase inhibitor is PD 169541. In further embodiments, the famesyl transferase inhibitor is ABT- 100.
  • the famesyl transferase inhibitor is FTI-2153. In further embodiments, the famesyl transferase inhibitor is tipifamib. In further embodiments, the famesyl transferase inhibitor is lonafamib.
  • the one or more additional therapeutic agents are selected from SYK inhibitors.
  • the SYK inhibitors are selected from fostamatinib (R788), entospletinib (GS-9973), cerdulatinib (PRT062070), and TAK-659.
  • the SYK inhibitor is fostamatinib (R788).
  • the SYK inhibitor is entospletinib (GS-9973).
  • the SYK inhibitor is cerdulatinib (PRT062070).
  • the SYK inhibitor is TAK-659.
  • the one or more additional therapeutic agents are selected from JAK inhibitors.
  • the JAK inhibitors are selected from tofacitinib, baricitinib, ruxolitinib, upadacitinib, fedratinib, abrocitinib, and ruxolitinib.
  • the JAK inhibitor is tofacitinib.
  • the JAK inhibitor is baricitinib.
  • the JAK inhibitor is ruxolitinib.
  • the JAK inhibitor is upadacitinib.
  • the JAK inhibitor is fedratinib.
  • the JAK inhibitor is abrocitinib.
  • the JAK inhibitor is ruxolitinib.
  • the one or more additional therapeutic agents are selected from PI3K inhibitors.
  • the PI3K inhibitors are selected from taselisib (GDC-0032), GDC-0077, perifosine, idelalisib, buparlisib (BKM120), duvelisib, (IPI-145), copanlisib (BAY 80-6946), PX-866, dactolisib, CUDC-907, voxtalisib (SAR245409, XL765), ME-401, IPI-549, SF1126, RP6530, INK1117, pictilisib (GDC-0941), XL147 (SAR245408), palomid 529, GSK1059615, ZSTK474, and PWT33597.
  • the PI3K inhibitor is taselisib (GDC-0032). In further embodiments, the PI3K inhibitor is GDC-0077. In further embodiments, the PI3K inhibitor is perifosine. In further embodiments, the PI3K inhibitor is idelalisib. In further embodiments, the PI3K inhibitor is buparlisib (BKM120). In further embodiments, the PI3K inhibitor is duvelisib. In further embodiments, the PI3K inhibitor is (IPI-145). In further embodiments, the PI3K inhibitor is copanlisib (BAY 80-6946). In further embodiments, the PI3K inhibitor is PX-866.
  • the PI3K inhibitor is dactolisib. In further embodiments, the PI3K inhibitor is CUDC- 907. In further embodiments, the PI3K inhibitor is voxtalisib (SAR245409, XL765). In further embodiments, the PI3K inhibitor is ME-401. In further embodiments, the PI3K inhibitor is IPI-549. In further embodiments, the PI3K inhibitor is SF1126. In further embodiments, the PI3K inhibitor is RP6530. In further embodiments, the PI3K inhibitor is INK1117. In further embodiments, the PI3K inhibitor is pictilisib (GDC-0941).
  • the PI3K inhibitor is XL147 (SAR245408). In further embodiments, the PI3K inhibitor is palomid 529. In further embodiments, the PI3K inhibitor is GSK1059615. In further embodiments, the PI3K inhibitor is ZSTK474. In further embodiments, the PI3K inhibitor is PWT33597.
  • the one or more additional therapeutic agents are selected from immunomodulatory agents.
  • the immunomodulatory agents are selected from lenalidomide, PD-1 inhibitors, PD-L1 inhibitors, CTLA-4 agents, T-cell immunoglobulin and ITIM domain (TIGIT) agents, TIM-3 inhibitors, and LAG-3 inhibitors.
  • the methods disclosed herein wherein the one or more additional therapeutic agents are selected from PD-1 inhibitors.
  • the PD-1 inhibitors are selected from pembrolizumab, nivolumab, cemiplimab, JTX-4014, spartalizumab (PDR001), camrelizumab (SHR1210), sintilimab (IBI308), tislelizumab (BGB-A317), toripalimab (JS 001), dostarlimab (TSR-042, WBP-285), INCMGA00012 (MGA012), AMP-224, and AMP-514 (MEDI0680).
  • the PD-1 inhibitor is pembrolizumab. In some embodiments, the PD-1 inhibitor is nivolumab. In some embodiments, the PD-1 inhibitor is cemiplimab. In some embodiments, the PD-1 inhibitor is spartalizumab (PDR001). In some embodiments, the PD-1 inhibitor is camrelizumab (SHR1210). In some embodiments, the PD-1 inhibitor is sintilimab (IBI308). In some embodiments, the PD- 1 inhibitor is tislelizumab (BGB-A317). In some embodiments, the PD-1 inhibitor is toripalimab (JS 001).
  • the PD-1 inhibitor is dostarlimab (TSR-042, WBP-285). In some embodiments, the PD- 1 inhibitor is INCMGA00012 (MGA012). In some embodiments, the PD-1 inhibitor is AMP-224. In some embodiments, the PD-1 inhibitor is AMP-514 (MEDI0680).
  • the methods disclosed herein wherein the one or more additional therapeutic agents are selected from PD-L1 inhibitors.
  • the PD-L1 inhibitors are selected from atezolizumab, avelumab, durvalumab, MPDL3280A (RG7446), MDX-1105 (BMS-936559), BMS-935559, MSB0010718C, and MEDI4736.
  • the PD-L1 inhibitors are selected from atezolizumab, avelumab, durvalumab, KN035, CK-301, AUNP12, CA-170, and BMS-986189.
  • the PD-L1 inhibitor is atezolizumab. In some embodiments, the PD-L1 inhibitor is avelumab. In some embodiments, the PD-L1 inhibitor is durvalumab. In some embodiments, the PD-L1 inhibitor is MPDL3280A (RG7446). In some embodiments, the PD-L1 inhibitor is MDX-1105 (BMS-936559). In some embodiments, the PD-L1 inhibitor is BMS-935559. In some embodiments, the PD- L1 inhibitor is MSB0010718C. In some embodiments, the PD-L1 inhibitor is MEDI4736.
  • CTLA-4 inhibitors are selected from ipilimumab and tremelimumab.
  • the CTLA-4 inhibitor is ipilimumab.
  • the CTLA-4 inhibitor is tremelimumab.
  • the T-cell immunoglobulin and ITIM domain (TIGIT) agents are selected from BMS-986207, BGB-A1217, tiragolumab, AB154, ASP8374, MK- 7684, CD112RCOM701, and LY3435I5L
  • the TIGIT agent is BMS-986207.
  • the TIGIT agent is BGB-A1217.
  • the TIGIT agent is tiragolumab.
  • the TIGIT agent is AB 154.
  • the TIGIT agent is ASP8374.
  • the TIGIT agent is MK-7684.
  • the TIGIT agent is CD112RCOM701.
  • the TIGIT agent is LY3435151.
  • the TIM-3 inhibitors are selected from Sym023, INCAGN02390, LY331367, Sym021, MBG453, BGB-A425, TSR-022, RO7121661, and LU3415244.
  • the TIM-3 inhibitor is Sym023.
  • the TIM-3 inhibitor is INCAGN02390.
  • the TIM-3 inhibitor is LY331367.
  • the TIM-3 inhibitor is Sym021.
  • the TIM-3 inhibitor is MBG453.
  • the TIM-3 inhibitor is BGB-A425.
  • the TIM-3 inhibitor is TSR-022.
  • the TIM-3 inhibitor is RO7121661.
  • the TIM-3 inhibitor is LU3415244.
  • the LAG-3 inhibitors are selected from relatlimab, tebotelimab, chlorogenic acid, RO-7247669, favezelimab, INCAGN-2385, IBI-110, eftilagimod alpha, Sym-022, LBL-007, ABL-501, HLX 26, IBI-323, ieramilimab, FS 118, EMB-02, and fmalimab.
  • the LAG-3 inhibitor is relatlimab.
  • the LAG-3 inhibitor is tebotelimab.
  • the LAG-3 inhibitor is chlorogenic acid.
  • the compounds of Formula (I), or pharmaceutically acceptable salts thereof may be prepared using commercially available reagents and intermediates in the synthetic methods and reaction schemes described herein, those described in United States Patent No. 11,091,495, or may be prepared using other reagents and conventional methods well known to those skilled in the art.
  • United States Patent No. 11091,495 the contents of United States Patent No. 11091,495.
  • R2 -ester substituted imidazo[l,2-c]pyrimidine A is coupled to R3 optionally substituted intermediate amine B by nucleophilic substitution to yield Intermediate C.
  • a boronic acid derivative (Y)-Rl D is coupled via a Suzuki reaction with halogen substituted Intermediate C in the presence of a suitable base, e.g., sodium carbonate, and the R2 ester is converted to the acid by saponification with NaOH to generate intermediate acid E.
  • the acid is converted to the corresponding amide, which is dehydrated to form title compound nitrile G.
  • halogenated Intermediate C containing a suitable R2 reactant e.g., an ester
  • a suitable base is converted to acid intermediate by saponification, then treated with NH4C1 in the presence of HATU to form the amide which is subsequently dehydrated to form nitrile Intermediate H.
  • R1 is coupled to Intermediate H via a Suzuki reaction using boronic acid derivative (Y) in the presence of base.
  • Y boronic acid derivative
  • the nitrile group of R1 -containing Intermediate G is hydrolyzed in the presence of acid and water to afford title compound amide F.
  • a pharmaceutically acceptable salts of the compounds of Formula (I) comprising administering to the subject a pharmaceutically acceptable salts of the compounds of Formula (I).
  • the desired salt may be prepared by any suitable method available in the art, for example, treatment of the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, or with an organic acid, such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, a pyranosidyl acid, such as glucuronic acid or galacturonic acid, an alpha-hydroxy acid, such as citric acid or tartaric acid, an amino acid, such as aspartic acid or glutamic acid, an aromatic acid, such as benzoic acid or cinnamic acid, a sulfonic acid,
  • an inorganic acid such
  • isotopes suitable for inclusion in the compounds of the invention include isotopes of hydrogen, such as 2 H and 3 H, carbon, such as n C, 13 C and 14 C, chlorine, such as 36 C1, fluorine, such as 18 F, iodine, such as 123 I and 125 I, nitrogen, such as 13 N and 15 N, oxygen, such as 15 0, 17 O and 18 O, phosphorus, such as 32 P, and sulfur, such as 35 S.
  • isotopically-labeled compounds of the invention for example, those incorporating a radioactive isotope, are useful in drug and/or substrate tissue distribution studies.
  • radioactive isotopes tritium ( 3 H) and carbon-14 ( 14 C) are particularly useful for this purpose in view of their ease of incorporation and ready means of detection.
  • Substitution with heavier isotopes such as deuterium, 2 H may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances.
  • Substitution with positron emitting isotopes, such as n C, 18 F, 15 O and 13 N can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy.
  • PET Positron Emission Topography
  • Isotopically- labeled compounds of Formula (I), or a pharmaceutically acceptable salt thereof can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described herein, using an appropriate isotopically-labeled reagent in place of the non-labeled reagent otherwise employed.
  • compositions described herein comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, are used for the treatment of T-cell lymphoma in subjects.
  • Such compositions may be prepared in pharmaceutically acceptable dosage forms for administration to subjects.
  • Pharmaceutically acceptable dosage forms include, for example, liquids, suspensions, powders for reconstitution, tablets, pills, sachets, or capsules of hard or soft gelatin (See, e.g., Remington: The Science and Practice of Pharmacy (Gennaro, 21 st Ed. Mack Pub. Co., Easton, PA (2005)).
  • the compounds of Formula (I), or a pharmaceutically acceptable salt thereof may be formulated into pharmaceutical compositions as described below in any pharmaceutical form recognizable to the skilled artisan as being suitable.
  • Pharmaceutical compositions of the invention comprise a therapeutically effective amount of at least one compound of Formula (I), or a pharmaceutically acceptable salt thereof, and an inert, pharmaceutically acceptable carrier or diluent.
  • the pharmaceutical carriers employed may be either solid or liquid.
  • Exemplary solid carriers are lactose, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid, and the like.
  • Exemplary liquid carriers are syrup, peanut oil, olive oil, water, and the like.
  • the compositions may include time-delay or time-release material known in the art, such as glyceryl monostearate or glyceryl distearate alone or with a wax, ethylcellulose, hydroxypropylmethylcellulose, methylmethacrylate or the like. Further additives or excipients may be added to achieve the desired formulation properties.
  • a bioavailability enhancer such as Labrasol, Gelucire or the like, or formulator, such as CMC (carboxymethylcellulose), PG (propyleneglycol), or PEG (polyethyleneglycol), may be added.
  • CMC carboxymethylcellulose
  • PG propyleneglycol
  • PEG polyethyleneglycol
  • a semi-solid vehicle that protects active ingredients from light, moisture, and oxidation may be added, e.g., when preparing a capsule formulation.
  • the preparation can be tableted, placed in a hard gelatin capsule in powder or pellet form, or formed into a troche or lozenge.
  • the amount of solid carrier may vary, but generally will be from about 25 mg to about 1 g.
  • the preparation may be in the form of syrup, emulsion, soft gelatin capsule, sterile injectable solution or suspension in an ampoule or vial or non-aqueous liquid suspension.
  • a semi-solid carrier is used, the preparation may be in the form of hard and soft gelatin capsule formulations.
  • the inventive compositions are prepared in unit-dosage form appropriate for the mode of administration, e.g. parenteral or oral administration.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof may be dissolved in an aqueous solution of an organic or inorganic acid, such as a 0.3 M solution of succinic acid or citric acid. If a soluble salt form is not available, the compound, or a pharmaceutically acceptable salt thereof, may be dissolved in a suitable co-solvent or combinations of cosolvents.
  • suitable co-solvents include alcohol, propylene glycol, polyethylene glycol 300, polysorbate 80, glycerin and the like in concentrations ranging from 0 to 60% of the total volume.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof is dissolved in DMSO and diluted with water.
  • the composition may also be in the form of a solution of a salt form of the active ingredient in an appropriate aqueous vehicle such as water or isotonic saline or dextrose solution.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof may be formulated into aqueous solutions, preferably in physiologically compatible buffers such as Hanks solution, Ringer's solution, or physiological saline buffer.
  • physiologically compatible buffers such as Hanks solution, Ringer's solution, or physiological saline buffer.
  • penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art.
  • the compounds can be formulated by combining the active compounds with pharmaceutically acceptable carriers known in the art.
  • Such carriers enable the compounds of the invention to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions, and the like, for oral ingestion by a subject to be treated.
  • Pharmaceutical preparations for oral use can be obtained using a solid excipient in admixture with the active ingredient (agent), optionally grinding the resulting mixture, and processing the mixture of granules after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores.
  • Suitable excipients include: fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; and cellulose preparations, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, or polyvinylpyrrolidone (PVP).
  • PVP polyvinylpyrrolidone
  • disintegrating agents may be added, such as crosslinked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.
  • Dragee cores are provided with suitable coatings.
  • suitable coatings may be used, which may optionally contain gum arabic, polyvinyl pyrrolidone, Carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures.
  • Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active agents.
  • compositions that can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol.
  • the push-fit capsules can contain the active ingredients in admixture with fillers such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate, and, optionally, stabilizers.
  • the active agents may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols.
  • stabilizers may be added. All formulations for oral administration should be in dosages suitable for such administration.
  • the compositions may take the form of tablets or lozenges formulated in conventional manner.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof may be conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebulizer, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • a suitable propellant e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • the dosage unit may be determined by providing a valve to deliver a metered amount.
  • Capsules and cartridges of gelatin for use in an inhaler or insufflator and the like may be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.
  • the compounds may be formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion.
  • Formulations for injection may be presented in unit-dosage form, e.g., in ampoules or in multi -dose containers, with an added preservative.
  • the compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
  • Pharmaceutical formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form. Additionally, suspensions of the active agents may be prepared as appropriate oily injection suspensions.
  • Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes.
  • Aqueous injection suspensions may contain substances that increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran.
  • the suspension may also contain suitable stabilizers or agents that increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.
  • the active ingredient may be in powder form for constitution with a suitable vehicle, e.g. sterile pyrogen-free water, before use.
  • a suitable vehicle e.g. sterile pyrogen-free water
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof may also be formulated as a depot preparation.
  • Such long -acting formulations may be administered by implantation (for example, subcutaneously or intramuscularly) or by intramuscular injection.
  • the compounds may be formulated with suitable polymeric or hydrophobic materials (for example, as an emulsion in an acceptable oil) or ion-exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
  • a pharmaceutical carrier for hydrophobic compounds is a co-solvent system comprising benzyl alcohol, a non-polar surfactant, a water-miscible organic polymer, and an aqueous phase.
  • the co-solvent system may be a VPD co-solvent system.
  • VPD is a solution of 3% w/v benzyl alcohol, 8% w/v of the non-polar surfactant polysorbate 80, and 65% w/v polyethylene glycol 300, made up to volume in absolute ethanol.
  • the VPD co-solvent system (VPD: 5W) contains VPD diluted 1: 1 with a 5% dextrose in water solution. This co-solvent system dissolves hydrophobic compounds well, and itself produces low toxicity upon systemic administration.
  • the proportions of a co-solvent system may be suitably varied without destroying its solubility and toxicity characteristics.
  • identity of the co-solvent components may be varied: for example, other low-toxicity non-polar surfactants may be used instead of polysorbate 80; the fraction size of polyethylene glycol may be varied; other biocompatible polymers may replace polyethylene glycol, e.g. polyvinyl pyrrolidone; and other sugars or polysaccharides may be substituted for dextrose.
  • hydrophobic pharmaceutical compounds may be employed.
  • Liposomes and emulsions are known examples of delivery vehicles or carriers for hydrophobic drugs.
  • Certain organic solvents such as dimethylsulfoxide (DMSO) also may be employed, although usually at the cost of greater toxicity due to the toxic nature of DMSO.
  • the compounds may be delivered using a sustained-release system, such as semipermeable matrices of solid hydrophobic polymers containing the therapeutic agent.
  • sustained-release materials have been established and are known by those skilled in the art. Sustained-release capsules may, depending on their chemical nature, release the compounds for a few weeks up to over 100 days.
  • additional strategies for protein stabilization may be employed.
  • the pharmaceutical compositions also may comprise suitable solid- or gel-phase carriers or excipients. These carriers and excipients may provide marked improvement in the bioavailability of poorly soluble drugs. Examples of such carriers or excipients include calcium carbonate, calcium phosphate, sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycols.
  • the pharmaceutical composition may be incorporated into a skin patch for delivery of the drug directly onto the skin.
  • the pharmaceutically acceptable formulations of the compounds of Formula (I), or a pharmaceutically acceptable salt thereof, that may be used to practice the methods disclosed herein may contain a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in an amount of from about 0.5 w/w % to about 95 w/w %, or from about 1 w/w % to about 95 w/w %, or from about 1 w/w % to about 75 w/w %, or from about 5 w/w % to about 75 w/w %, or from about 10 w/w % to about 75 w/w %, or from about 10 w/w % to about 50 w/w %.
  • the actual dosages of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, to be administered to a subject in need thereof will vary according to the particular agent being used, the particular composition formulated, the mode of administration, and the particular site, host, and disease being treated. Those skilled in the art using conventional dosage -determination tests in view of the experimental data for a given compound may ascertain optimal dosages for a given set of conditions.
  • an exemplary daily dose generally employed will be from about 0.001 to about 1000 mg/kg of body weight, with courses of treatment repeated at appropriate intervals.
  • the methods disclosed herein wherein the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered to the subject in an amount between about 0.01 mg/kg per day to about 300 mg/kg per day. In other embodiments are provided the methods disclosed herein, wherein the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered to the subject in an amount between about 0.1 mg/kg per day to about 100 mg/kg per day. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered in an amount between about 10 mg to 500 mg per day. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered in an amount between about 100 mg to about 400 mg per day.
  • the compound of Formula (I), or a pharmaceutically acceptable salt thereof is administered in an amount between about 150 mg to about 350 mg per day. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered in an amount between about 150 mg to about 300 mg per day. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered in an amount between about 160 mg to about 300 mg per day. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered in an amount of about 160 mg per day. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered in an amount of about 200 mg per day.
  • the compound of Formula (I), or a pharmaceutically acceptable salt thereof is administered in an amount of about 240 mg per day. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered in an amount of about 280 mg per day. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered in an amount of about 320 mg per day.
  • the pharmaceutically acceptable formulations of the compounds of Formula (I), or a pharmaceutically acceptable salt thereof, that may be used to practice the methods disclosed herein may contain a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in an amount of about 10 mg to about 2000 mg, or from about 10 mg to about 1500 mg, or from about 10 mg to about 1000 mg, or from about 10 mg to about 750 mg, or from about 10 mg to about 500 mg, or from about 25 mg to about 500 mg, or from about 50 mg to about 500 mg, or from about 100 mg to about 500 mg.
  • the compound of Formula (I), or a pharmaceutically acceptable salt thereof is administered to a subject in need thereof once a day. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered to a subject in need thereof twice a day. the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered to a subject in need thereof three times a day.
  • the compound of Formula (I), or a pharmaceutically acceptable salt thereof is administered to a subject in need thereof in 28-day cycles. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered to a subject in need thereof in multiple 28-day cycles. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered to a subject in need thereof for at least one 28-day cycle. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered to a subject in need thereof on each day of each 28-day cycle.
  • the methods described herein comprise administering the compositions and formulations comprising the compounds of Formula (I), or a pharmaceutically acceptable salt thereof, in combination with one or more additional therapeutic agents, to the subject or subject in need thereof in multiple cycles repeated on a regular schedule with periods of rest in between each cycle.
  • treatment given for one week followed by three weeks of rest is one treatment cycle.
  • the length of a treatment cycle depends on the treatment being given. In some embodiments, the length of a treatment cycle ranges from two to six weeks. In some embodiments, the length of a treatment cycle ranges from three to six weeks. In some embodiments, the length of a treatment cycle ranges from three to four weeks.
  • the length of a treatment cycle is three weeks (or 21 days). In some embodiments, the length of a treatment cycle is four weeks (28 days). In some embodiments, the length of a treatment cycle is 56 days. In some embodiments, a treatment cycle lasts one, two, three, or four weeks. In some embodiments, a treatment cycle lasts three weeks. In some embodiments, a treatment cycle lasts four weeks. The number of treatment doses scheduled within each cycle also varies depending on the drugs being given.
  • Dosages of compositions described herein can be determined by any suitable method.
  • Maximum tolerated doses (MTD) and maximum response doses (MRD) for the compounds of Formula (I), or a pharmaceutically acceptable salt thereof, and the additional therapeutic agents when administered to the subject can be determined via established animal and human experimental protocols as well as in the examples described herein.
  • toxicity and therapeutic efficacy of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, and the additional therapeutic agent can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, including, but not limited to, for determining the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population).
  • the dose ratio between the toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio between LD50 and ED50.
  • the data obtained from cell culture assays and animal studies can be used in formulating a range of dosage for use in a human.
  • the dosage of such compounds lies preferably within a range of circulating concentrations that include the ED50 with minimal toxicity.
  • the dosage may vary within this range depending upon the dosage form employed and the route of administration utilized. Additional relative dosages, represented as a percent of maximal response or of maximum tolerated dose, are readily obtained via the protocols.
  • the amount of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, and/or pharmaceutical formulations comprising them that corresponds to such an amount varies depending upon factors such as the particular salt or form, disease condition and its severity, the identity (e.g., age, weight, sex) of the subject or host in need of treatment, but can nevertheless be determined according to the particular circumstances surrounding the case, including, e.g., the specific agent being administered, the liquid formulation type, the condition being treated, and the subject or host being treated.
  • Biomarkers that may be used according to the methods disclosed herein are those known to those having ordinary skill in the art, including, but not limited to, those disclosed in The Fifth edition of the World Health Organization Classification of Haematolymphoid Tumours: Lymphoid Neoplasms, Leukemia, July 2022, vol. 36, no. 7, pagesl720-1748.
  • the presence of one or more biomarkers described herein indicate the T-cell lymphoma in the subject is peripheral T-cell lymphoma or cutaneous T-cell lymphoma.
  • the presence, absence, or level, of such biomarkers may be measured, collectively or individually, in a biological sample obtained from a subject, such as a sample of a solid tumor, such as a T-cell lymphoma, or from a sample of a relevant biological fluid, such as a blood sample.
  • a biological sample obtained from a subject such as a sample of a solid tumor, such as a T-cell lymphoma, or from a sample of a relevant biological fluid, such as a blood sample.
  • the one or more biomarkers are detected in plasma or serum that is derived from a blood sample obtained from the subject.
  • the methods of detection disclosed herein are useful for predicting a therapeutic response to a therapy described herein (e.g., the administration to a subject of a compound of Formula (I), or a pharmaceutically acceptable salt thereof), monitor the treatment using the therapy of, and treating with the therapy, a proliferative disease or condition described herein in a subject.
  • a therapy described herein e.g., the administration to a subject of a compound of Formula (I), or a pharmaceutically acceptable salt thereof
  • the expression of a biomarker in a biological sample from a subject is measured by use of immunohistochemistry (IHC) assays.
  • immunohistochemistry (IHC) assays are commercially available, or may be developed and utilized according to methods known to those having ordinary skill in the art.
  • Immunohistochemistry techniques utilize an antibody to probe and visualize cellular antigens in situ, generally by chromogenic or fluorescent methods.
  • antibodies or antisera, polyclonal antisera, or monoclonal antibodies specific for each marker are used to detect expression.
  • the antibodies can be detected by direct labeling of the antibodies themselves, for example, with radioactive labels, fluorescent labels, hapten labels such as, biotin, or an enzyme such as horse radish peroxidase or alkaline phosphatase.
  • unlabeled primary antibody is used in conjunction with a labeled secondary antibody, comprising antisera, polyclonal antisera, or a monoclonal antibody specific for the primary antibody.
  • Immunohistochemistry protocols and kits are well known in the art and are commercially available.
  • Two general methods of IHC are generally available; direct and indirect assays.
  • binding of antibody to the target antigen is determined directly.
  • This direct assay uses a labeled reagent, such as a fluorescent tag or an enzyme -labeled primary antibody, which can be visualized without further antibody interaction.
  • a labeled reagent such as a fluorescent tag or an enzyme -labeled primary antibody, which can be visualized without further antibody interaction.
  • unconjugated primary antibody binds to the antigen and then a labeled secondary antibody binds to the primary antibody.
  • a chromagenic or fluorogenic substrate is added to provide visualization of the antigen. Signal amplification occurs because several secondary antibodies may react with different epitopes on the primary antibody.
  • the primary and/or secondary antibody used for immunohistochemistry typically will be labeled with a detectable moiety.
  • Numerous labels are available which can be generally grouped into the following categories.
  • the antibody can be labeled with the radioisotope using the techniques described in Current Protocols in Immunology, Volumes 1 and 2, Coligen et al., Ed. Wiley-Interscience, New York, N.Y., Pubs. (1991) for example and radioactivity can be measured using scintillation counting.
  • colloidal gold particles are colloidal gold particles.
  • fluorescent labels including, but are not limited to, rare earth chelates (europium chelates), Texas Red, rhodamine, fluorescein, dansyl, Lissamine, umbelliferone, phycocrytherin, phycocyanin, or commercially available fluorophores such SPECTRUM ORANGE® and SPECTRUM GREEN® and/or derivatives of any one or more of the above.
  • the fluorescent labels can be conjugated to the antibody using the techniques disclosed in Current Protocols in Immunology, supra, for example. Fluorescence can be quantified using a fluorimeter.
  • Fourth are various enzyme-substrate labels are available and U.S. Pat. No. 4,275,149 provides a review of some of these.
  • the enzyme generally catalyzes a chemical alteration of the chromogenic substrate that can be measured using various techniques.
  • the enzyme may catalyze a color change in a substrate, which can be measured spectrophotometrically.
  • the enzyme may alter the fluorescence or chemiluminescence of the substrate. Techniques for quantifying a change in fluorescence are described above.
  • the chemiluminescent substrate becomes electronically excited by a chemical reaction and may then emit light which can be measured (using a chemiluminometer, for example) or donates energy to a fluorescent acceptor.
  • Examples of enzymatic labels include luciferases (e.g., firefly luciferase and bacterial luciferase; U.S. Pat.
  • luciferin 2,3 -dihydrophthalazinediones, malate dehydrogenase, urease, peroxidase such as horseradish peroxidase (HRPO), alkaline phosphatase, [3- galactosidase, glucoamylase, lysozyme, saccharide oxidases (e.g., glucose oxidase, galactose oxidase, and glucose-6-phosphate dehydrogenase), heterocyclic oxidases (such as uricase and xanthine oxidase), lactoperoxidase, microperoxidase, and the like.
  • HRPO horseradish peroxidase
  • alkaline phosphatase [3- galactosidase, glucoamylase, lysozyme
  • saccharide oxidases e.g., glucose oxidase, galactose oxidase,
  • 3 -Diaminobenzidine may also be used to visualize the HRP -labeled antibody; (ii) alkaline phosphatase (AP) with para-Nitrophenyl phosphate as chromogenic substrate; and (iii) -D-galactosidase ([3- D-Gal) with a chromogenic substrate (e.g., p-nitrophenyl-p-D-galactosidase) or Anorogenic substrate (e.g., 4-methylumbelliferyl-P-D-galactosidase).
  • a chromogenic substrate e.g., p-nitrophenyl-p-D-galactosidase
  • Anorogenic substrate e.g., 4-methylumbelliferyl-P-D-galactosidase
  • the label is indirectly conjugated with the antibody.
  • the antibody can be conjugated with biotin and any of the four broad categories of labels mentioned above can be conjugated with avidin, or vice versa. Biotin binds selectively to avidin and thus, the label can be conjugated with the antibody in this indirect manner.
  • the antibody is conjugated with a small hapten and one of the different types of labels mentioned above is conjugated with an anti -hapten antibody.
  • indirect conjugation of the label with the antibody can be achieved.
  • a pathologist or the like would review the slides and identify normal cells and abnormal cells (such as abnormal or tumor cells).
  • Any means of defining the loci of the cells of interest may be used (e.g., coordinates on an X-Y axis.
  • tissue section prior to, during or following IHC may be desired.
  • epitope retrieval methods such as heating the tissue sample in citrate buffer may be carried out [see, e.g., Leong et al. Appl.
  • tissue section is exposed to primary antibody for a sufficient period of time and under suitable conditions such that the primary antibody binds to the target protein antigen in the tissue sample. Appropriate conditions for achieving this can be determined by routine experimentation.
  • the label is an enzymatic label (e.g. HRPO) which catalyzes a chemical alteration of the chromogenic substrate such as 3,3 ’-diaminobenzidine chromogen.
  • the enzymatic label is conjugated to antibody which binds specifically to the primary antibody (e.g. the primary antibody is rabbit polyclonal antibody and secondary antibody is goat anti -rabbit antibody). Specimens thus prepared may be mounted and coverslipped. Slide evaluation is then determined, e.g. using a microscope.
  • IHC may be combined with morphological staining, either prior to or thereafter.
  • the sections mounted on slides may be stained with a morphological stain for evaluation.
  • the morphological stain to be used provides for accurate morphological evaluation of a tissue section.
  • the section may be stained with one or more dyes each of which distinctly stains different cellular components.
  • hematoxylin is use for staining cellular nucleic of the slides. Hematoxylin is widely available.
  • An example of a suitable hematoxylin is Hematoxylin II (Ventana).
  • a bluing reagent may be used following hematoxylin staining.
  • staining may be optimized for a given tissue by increasing or decreasing the length of time the slides remain in the dye.
  • the tissue section may be analyzed by standard techniques of microscopy.
  • a pathologist or the like assesses the tissue for the presence of abnormal or normal cells or a specific cell type and provides the loci of the cell types of interest.
  • a pathologist or the like would review the slides and identify normal cells and abnormal cells (such as abnormal or tumor cells).
  • Any means of defining the loci of the cells of interest may be used (e.g., coordinates on an X-Y axis).
  • the presence or an absence, and/or a level of expression of the biomarker is detected in the sample obtained from a subject by analyzing the genetic material in the sample.
  • the genetic material is obtained from blood, serum, plasma, sweat, hair, tears, urine, and other techniques known by one of skill in the art.
  • the sample comprises circulating tumor RNA (ctRNA).
  • the sample comprises peripheral blood mononuclear cells (PBMCs).
  • the sample comprises circulating tumor cells (CTCs).
  • the genetic material is obtained from a tumor biopsy or liquid biopsy.
  • a tumor biopsy comprises a formalin-fixed paraffin embedded biopsy, a fresh frozen biopsy, a fresh biopsy, or a frozen biopsy.
  • a liquid biopsy comprises PBMCs, circulating tumor RNA, plasma cell-free RNA, or circulating tumor cells (CTCs). Tumor and liquid biopsies can undergo additional analytic processing for sample dissociation, cell sorting, and enrichment of cell populations of interest.
  • methods of detecting a presence, absence, or level of a biomarker in a biologic sample obtained from the subject involve detecting a nucleic acid sequence.
  • the nucleic acid sequence comprises deoxyribonucleic acid (DNA), such as in the case of detecting complementary DNA (cDNA) of an mRNA transcript.
  • the nucleic acid sequence comprises a denatured DNA molecule or fragment thereof.
  • the nucleic acid sequence comprises DNA selected from: genomic DNA, viral DNA, mitochondrial DNA, plasmid DNA, amplified DNA, circular DNA, circulating DNA, cell-free DNA, or exosomal DNA.
  • the DNA is single -stranded DNA (ssDNA), double -stranded DNA, denaturing double -stranded DNA, synthetic DNA, and combinations thereof.
  • the circular DNA may be cleaved or fragmented.
  • the nucleic acid sequence comprises ribonucleic acid (RNA).
  • the nucleic acid sequence comprises fragmented RNA.
  • the nucleic acid sequence comprises partially degraded RNA.
  • the nucleic acid sequence comprises a microRNA or portion thereof.
  • the nucleic acid sequence comprises an RNA molecule or a fragmented RNA molecule (RNA fragments) selected from: a microRNA (miRNA), a pre-miRNA, a pri-miRNA, a mRNA, a pre-mRNA, a viral RNA, a viroid RNA, a virusoid RNA, circular RNA (circRNA), a ribosomal RNA (rRNA), a transfer RNA (tRNA), a pre-tRNA, a long non-coding RNA (IncRNA), a small nuclear RNA (snRNA), a circulating RNA, a cell- free RNA, an exosomal RNA, a vector-expressed RNA, an RNA transcript, a synthetic RNA, and combinations thereof.
  • miRNA microRNA
  • pre-miRNA pre-miRNA
  • a pri-miRNA a RNA
  • mRNA a pre-mRNA
  • a pri-miRNA a
  • a biomarker is detected by subjecting a sample obtained from the subject to a nucleic acid-based detection assay.
  • the nucleic acid-based detection assay comprises quantitative polymerase chain reaction (qPCR), reverse transcription PCT (RT-qPCR), gel electrophoresis (including for e.g., Northern or Southern blot), immunohistochemistry (IHC), immunofluorescence (IF), in situ hybridization (ISH) such as fluorescent in situ hybridization (FISH), cytochemistry, microarray, or sequencing.
  • the sequencing technique comprises next generation sequencing.
  • the methods involve a hybridization assay such as Anorogenic qPCR (e.g., TaqManTM, SYBR green, SYBR green I, SYBR green II, SYBR gold, ethidium bromide, methylene blue, Pyronin Y, DAPI, acridine orange, Blue View or phycoerythrin), which involves a nucleic acid amplification reaction with a specific primer pair, and hybridization of the amplified nucleic acid probes comprising a detectable moiety or molecule that is specific to a target nucleic acid sequence.
  • a number of amplification cycles for detecting a target nucleic acid in a qPCR assay is about 5 to about 30 cycles.
  • the number of amplification cycles for detecting a target nucleic acid is at least about 5 cycles. In some instances, the number of amplification cycles for detecting a target nucleic acid is at most about 30 cycles. In some instances, the number of amplification cycles for detecting a target nucleic acid is about 5 to about 10, about 5 to about 15, about 5 to about 20, about 5 to about 25, about 5 to about 30, about 10 to about 15, about 10 to about 20, about 10 to about 25, about 10 to about 30, about 15 to about 20, about 15 to about 25, about 15 to about 30, about 20 to about 25, about 20 to about 30, or about 25 to about 30 cycles.
  • the probe may be a hydrolysable probe comprising a Auorophore and quencher that is hydrolyzed by DNA polymerase when hybridized to a target nucleic acid.
  • the presence of a target nucleic acid is determined when the number of amplification cycles to reach a threshold value is less than 30, 29, 28, 27, 26, 25, 24, 23, 22, 21, or 20 cycles.
  • hybridization may occur at standard hybridization temperatures, e.g., between about 35 °C and about 65 °C in a standard PCR buffer.
  • An additional exemplary nucleic acid-based detection assay comprises the use of nucleic acid probes conjugated or otherwise immobilized on a bead, multi-well plate, or other substrate, wherein the nucleic acid probes are configured to hybridize with a target nucleic acid sequence.
  • the nucleic acid probe is specific to one or more of a polynucleotide sequence that encodes a relevant biomarker as disclosed herein.
  • the nucleic acid probe specific to a biomarker comprises a nucleic acid probe sequence sufficiently complementary to the polynucleotide sequence that encodes the relevant biomarker protein.
  • the probe comprises a transcribed polynucleotide sequence (e.g., RNA, cDNA).
  • the nucleic acid probe can be, for example, a full-length cDNA, or a portion thereof, such as an oligonucleotide of at least about 7, 8, 9, 10, 11, 12, 13, 14, 15, 20, 25, 30, 35, 40, 45, or 50 nucleotides in length and sufficient to specifically hybridize under standard hybridization conditions to the target nucleic acid sequence.
  • the target nucleic acid sequence is immobilized on a solid surface and contacted with a probe, for example by running the isolated target nucleic acid sequence on an agarose gel and transferring the target nucleic acid sequence from the gel to a membrane, such as nitrocellulose.
  • the probe(s) are immobilized on a solid surface, for example, in an Affymetrix gene chip array, and the probe(s) are contacted with the target nucleic acid sequence.
  • the term “probe” with regards to nucleic acids refers to any nucleic acid molecule that is capable of selectively binding to a specifically intended target nucleic acid sequence.
  • probes are specifically designed to be labeled, for example, with a radioactive label, a fluorescent label, an enzyme, a chemiluminescent tag, a colorimetric tag, or other labels or tags that are known in the art.
  • the fluorescent label comprises a fluorophore.
  • the fluorophore is an aromatic or heteroaromatic compound.
  • the fluorophore is a pyrene, anthracene, naphthalene, acridine, stilbene, benzoxazole, indole, benzindole, oxazole, thiazole, benzothiazole, canine, carbocyanine, salicylate, anthranilate, xanthenes dye, coumarin.
  • xanthene dyes include, e.g., fluorescein and rhodamine dyes.
  • Fluorescein and rhodamine dyes include, but are not limited to 6-carboxyfluorescein (FAM), 2'7'-dimethoxy-4'5'-dichloro-6-carboxyfluorescein (JOE), tetrachlorofluorescein (TET), 6-carboxyrhodamine (R6G), N,N,N; N'-tetramethyl-6-carboxyrhodamine (TAMRA), 6-carboxy-X-rhodamine (ROX).
  • Suitable fluorescent probes also include the naphthylamine dyes that have an amino group in the alpha or beta position.
  • naphthylamino compounds include l-dimethylaminonaphthyl-5 -sulfonate, l-anilino-8-naphthalene sulfonate, and 2-p-toluidinyl-6- naphthalene sulfonate, 5 -(2 '-aminoethyl)aminonaphthalene-l -sulfonic acid (EDANS).
  • Exemplary coumarins include, e.g., 3-phenyl-7-isocyanatocoumarin; acridines, such as 9-isothiocyanatoacridine and acridine orange; N-(p-(2-benzoxazolyl)phenyl) maleimide; cyanines, such as, e.g., indodicarbocyanine 3 (Cy3), indodicarbocyanine 5 (Cy5), indodicarbocyanine 5.5 (Cy5.5), 3-(-carboxy-pentyl)-3'-ethyl-5,5'- dimethyloxacarbocyanine (CyA); 1H, 5H, 11H, 15H-Xantheno[2,3, 4-ij: 5,6, 7-i'j']diquinolizin-18-ium, 9-[2 (or 4)-[[[6-[2,5-dioxo-l-pyrrolidinyl)oxy]-6
  • detecting the one or more biomarkers comprises sequencing genetic material obtained from a sample from the subject.
  • Sequencing can be performed with any appropriate sequencing technology, including but not limited to single-molecule real-time (SMRT) sequencing, Polony sequencing, sequencing by ligation, reversible terminator sequencing, proton detection sequencing, ion semiconductor sequencing, nanopore sequencing, electronic sequencing, pyrosequencing, Maxam -Gilbert sequencing, chain termination (e.g., Sanger) sequencing, +S sequencing, or sequencing by synthesis.
  • Sequencing methods also include next-generation sequencing, e.g., modem sequencing technologies such as Illumina sequencing (e.g., Solexa), Roche 454 sequencing, Ion torrent sequencing, and SOLiD sequencing. In some cases, nextgeneration sequencing involves high-throughput sequencing methods. Additional sequencing methods available to one of skill in the art may also be employed.
  • a number of nucleotides that are sequenced are at least 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 100, 150, 200, 300, 400, 500, 2000, 4000, 6000, 8000, 10000, 20000, 50000, 100000, or more than 100000 nucleotides.
  • the number of nucleotides sequenced is in a range of about 1 to about 100000 nucleotides, about 1 to about 10000 nucleotides, about 1 to about 1000 nucleotides, about 1 to about 500 nucleotides, about 1 to about 300 nucleotides, about 1 to about 200 nucleotides, about 1 to about 100 nucleotides, about 5 to about 100000 nucleotides, about 5 to about 10000 nucleotides, about 5 to about 1000 nucleotides, about 5 to about 500 nucleotides, about 5 to about 300 nucleotides, about 5 to about 200 nucleotides, about 5 to about 100 nucleotides, about 10 to about 100000 nucleotides, about 10 to about 10000 nucleotides, about 10 to about 1000 nucleotides, about 10 to about 500 nucleotides, about 10 to about 300 nucleotides, about 10 to about 200 nucleotides, about 10 to about 100 nucleotides, about
  • a hybridization assay such as those described herein, is used to detect the mRNA encoding the biomarker in the sample.
  • Exemplary probe sequences that are hybridizable to a target nucleic acid sequence comprise at least 10, but no more than 100 contiguous nucleotides comprising the relevant sequence.
  • RNA sequencing RNAseq is used to detect the mRNA encoding the relevant biomarker protein.
  • Detection of the mRNA involves amplification of the subject’s nucleic acid by the polymerase chain reaction (PCR).
  • the PCR assay involves use of a pair of primers capable of amplifying at least about 10 contiguous nucleobases within a nucleic acid sequence, thereby amplifying the one or more gene products in the biomarker.
  • Anorogenic quantitative PCR quantitation is based on amount of fluorescence signals (TaqMan and SYBR green).
  • the nucleic acid probe is conjugated to a detectable molecule.
  • the detectable molecule may be a fluorophore.
  • the nucleic acid probe may also be conjugated to a quencher.
  • the primers comprises a first primer with a nucleic acid sequence comprising at least 10 but not more than 50 contiguous nucleic acids within a relevant nucleic acid sequence that binds to atop strand of the doublestranded hybridization product; and a second primer with a nucleic acid sequence comprising at least 10 but not more than 50 contiguous nucleic acids within a nucleic acid sequence that is reverse complement to the relevant nucleic acid sequence that binds to a bottom strand of the double -stranded hybridization product.
  • methods comprising preparing a complementary DNA (cDNA) library.
  • the cDNA library is sequenced using suitable sequence methodologies disclosed herein.
  • the cDNA library is labeled, a plurality of nucleic acid probes is generated, and fixed to an immobile surface (such as a microarray).
  • the plurality of nucleic acid probes is capable of hybridizing to at least about 10 contiguous nucleotides of the two or more genes in a sample obtained from the subject.
  • detecting the presence of or absence of a biomarker includes detecting a high or a low level of expression of one or more genes as compared to a reference level.
  • genetic material is extracted from a biologic sample obtained from a subject, e.g., a sample of blood, serum, or tissue.
  • the nucleic acids are extracted using any technique that does not interfere with subsequent analysis.
  • this technique uses alcohol precipitation using ethanol, methanol, or isopropyl alcohol.
  • this technique uses phenol, chloroform, or any combination thereof.
  • this technique uses cesium chloride.
  • this technique uses sodium, potassium or ammonium acetate or any other salt commonly used to precipitate DNA.
  • this technique utilizes a column or resin based nucleic acid purification scheme such as those commonly sold commercially, one non-limiting example would be the GenElute Bacterial Genomic DNA Kit available from Sigma Aldrich.
  • the nucleic acid is stored in water, Tris buffer, or Tris-EDTA buffer before subsequent analysis.
  • the nucleic acid material is extracted in water. In some cases, extraction does not comprise nucleic acid purification.
  • RNA may be extracted from cells using RNA extraction techniques including, for example, using acid phenol/guanidine isothiocyanate extraction (RNAzol B; Biogenesis), RNeasy RNA preparation kits (Qiagen) or PAXgene (PreAnalytix, Switzerland).
  • RNAzol B acid phenol/guanidine isothiocyanate extraction
  • Qiagen RNeasy RNA preparation kits
  • PAXgene PreAnalytix, Switzerland.
  • circulating tumor RNA circulating tumor RNA (ctRNA) is used to assess the expression levels of RNA molecules, shed by the tumor into the blood stream.
  • detection of ctRNA is useful, for example, for detecting and diagnosing a tumor. Because tumor DNA and RNA has acquired multiple genetic mutations, leading to tumor development, ctRNA are not an exact match to the individual’s DNA and RNA, respectively.
  • Finding DNA and RNA with genetic differences aids in tumor detection. Diagnosing the type of tumor using ctRNA can reduce the need for getting a sample of the tumor tissue (tumor biopsy), which can be challenging when a tumor is difficult to access, such as a tumor in the brain or lung.
  • a decrease in the quantity of ctRNA suggests the solid tumor is shrinking and treatment with a compound of Formula (I), or a pharmaceutically acceptable salt thereof, is effective.
  • a lack of ctRNA in the bloodstream indicates that the cancer has not returned after treatment with a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
  • the genomic profiling is performed after each treatment cycle with a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
  • the gene alterations indicate that the cancer is becoming resistant to the treatment with a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
  • the lack of gene alterations indicate that the cancer is not becoming resistant to the treatment with a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
  • the genomic profiling is performed after each treatment cycle with a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
  • the gene alterations indicate that the cancer is becoming resistant to the treatment with a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
  • the lack of gene alterations indicate that the cancer is not becoming resistant to the treatment with a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
  • the expression of a biomarker is measured by immunofluorescence (IF) assays. In some embodiments, the expression of a biomarker is measured by in situ hybridization (ISH) assays. In some embodiments, the expression of a biomarker transcript levels are measured using assays such as quantitative polymerase chain reaction (qPCR), microarray, and RNA sequencing, or assays commercially available from companies such as Fluidigm and Nanostring.
  • IF immunofluorescence
  • ISH in situ hybridization
  • the expression of a biomarker transcript levels are measured using assays such as quantitative polymerase chain reaction (qPCR), microarray, and RNA sequencing, or assays commercially available from companies such as Fluidigm and Nanostring.
  • a subject having T-cell lymphoma comprising: (a) providing a biologic sample obtained from a subject having T-cell lymphoma; (b) assaying to detect in the biologic sample obtained from the subject a presence or absence of a biomarker; (c) detecting the presence or absence of the biomarker in the biologic sample using the methods described herein; and (d) administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, if the biomarker is present in the biological sample.
  • expression of a biomarker is based on the expression level of the biomarker deviating from a reference expression level.
  • the expression level is high, relative to the reference expression level. In some embodiments, the expression level is low, relative to the reference expression level. In some embodiments, the reference expression level is derived from an individual, or a group of individuals, that do not have cancer. In some embodiments, the reference expression level is derived from an individual, or a group of individuals, that have cancer that does not therapeutically respond to the compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the expression level deviates from the reference expression level by at least 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 100%.
  • the determination of expression or the presence of a biomarker is defined based on the percentage of cells that stain weakly, moderately, or strongly for the relevant biomarker, with the threshold defining the minimal percentage of cells that are required to stain positive at the various intensity levels (>a% of tumor cells stain weakly, >b% of tumor cells stain moderately, >c% of tumor cells stain strongly, or a combination thereof).
  • the one or more of the cells comprising the cancer has been determined to express a biomarker when > 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%, or > about 95% of the tumor cells stain weakly for the biomarker; when > 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%, or > about 95% of the tumor cells stain moderately for the biomarker; when > about 10%, > about 15%, > about 20%, > about 25%, > about 30%, > about 35%, > about 40%, > about 45%, > about 50%, > about 55%
  • kits and articles of manufacture for use with one or more methods and compositions described herein.
  • Such kits include a carrier, package, or container that is compartmentalized to receive one or more containers such as vials, tubes, and the like, each of the container(s) comprising one of the separate elements to be used in a method described herein.
  • Suitable containers include, for example, bottles, vials, syringes, and test tubes.
  • the containers are formed from a variety of materials such as glass or plastic.
  • a kit typically includes labels listing contents and/or instructions for use, and package inserts with instructions for use. A set of instructions will also typically be included.
  • a label is on or associated with the container.
  • a label is on a container when letters, numbers or other characters forming the label are attached, molded, or etched into the container itself, a label is associated with a container when it is present within a receptacle or carrier that also holds the container, e.g., as a package insert.
  • a label is used to indicate that the contents are to be used for a specific therapeutic application. The label also indicates directions for use of the contents, such as in the methods described herein.
  • the pharmaceutical compositions are presented in a pack or dispenser device which contains one or more unit dosage forms containing a compound provided herein.
  • the pack for example, contains metal or plastic foil, such as a blister pack.
  • the pack or dispenser device is accompanied by instructions for administration.
  • the pack or dispenser is also accompanied with a notice associated with the container in form prescribed by a governmental agency regulating the manufacture, use, or sale of pharmaceuticals, which notice is reflective of approval by the agency of the form of the drug for human or veterinary administration.
  • a notice associated with the container in form prescribed by a governmental agency regulating the manufacture, use, or sale of pharmaceuticals which notice is reflective of approval by the agency of the form of the drug for human or veterinary administration.
  • Such notice for example, is the labeling approved by the U.S. Food and Drug Administration for drugs, or the approved product insert.
  • compositions containing a compound provided herein formulated in a compatible pharmaceutical carrier are also prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.
  • kits comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in treating T-cell lymphoma in a subject in need thereof and a package insert comprising instructions for measuring the expression of a biomarker described herein in one or more of the cells comprising the T-cell lymphoma and using the compound of Formula (I), or a pharmaceutically acceptable salt thereof, if one or more of the cells comprising the T-cell lymphoma has been determined to express the biomarker.
  • Embodiment 1 A method of treating T-cell lymphoma in a subject, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I)
  • Z is O or S
  • X is O, CR 5 , CR 5 OH, or C(R 5 )2, wherein: when X is O, - is a single bond; when X is C(R 5 )2, - is a single bond; when X is CR 5 OH, - is a single bond; or when X is CR 5 , - is a double bond;
  • R 1 is aryl, heteroaryl, L-cycloalkyl, -N(R 5 )heterocyclyl, or L-heterocyclyl, wherein the aryl, the heteroaryl or the cyclyl portion of the L-cycloalkyl, -N(R 5 )heterocyclyl, or L-heterocyclyl is optionally substituted with one or more R 4 ;
  • R 2 is cyano, -COOR 5 , -C(O)N(R 5 )2, or -C(O)N(R 5 )2 wherein each R 5 taken together with the nitrogen atom to which they are attached form a 5 - 8 membered heterocyclic ring optionally substituted with one or more R 4 ; each R 3 is independently C1-C3 alkyl or halogen; each R 4 is independently oxo, cyano, halogen, -POdC i-C alkyl)2, hydroxyl, alkoxy, hydroxyalkyl, heteroalkyl, aralkyl, haloalkyl, -COOR 5 , -Y 2 -haloalkyl, -Y’-Ci-Ce alkyl, -Y 2 -Ci-Ce alkyl, -L-cycloalkyl, -L-heteroaryl, -L-heterocyclyl, -Y'-hetero
  • L is a bond or C1-C4 alkylene
  • Y 1 is a bond, -C(O)-, or -NHC(O)-;
  • Y 2 is a bond, -S-, -SO-, -SO 2 -, or -NR 5 SO 2 -, each R 5 is hydrogen or C1-C3 alkyl;
  • R 6 is hydrogen, C1-C3 alkyl, halogen, haloalkyl, hydroxyalkyl, or heteroalkyl; each R 7 is oxo, cyano, hydroxyl, alkoxy, halogen, haloalkyl, hydroxyalkyl, heteroalkyl, cycloalkyl, -L- N(R 5 ) 2 , Ci-Ce alkyl, or -Y’-heterocyclyl; and n is 1 or 2.
  • Embodiment 2 The method of embodiment 1, wherein in the compound of Formula (I), or a pharmaceutically acceptable salt thereof, Z is O.
  • Embodiment 3 The method of embodiment 1, wherein in the compound of Formula (I), or a pharmaceutically acceptable salt thereof, Z is S.
  • Embodiment 4 The method of any of embodiments 2 or 3, wherein in the compound of Formula (I), or a pharmaceutically acceptable salt thereof, n is 1.
  • Embodiment 5 The method of any of embodiments 1-4, wherein in the compound of Formula (I), or a pharmaceutically acceptable salt thereof, R 2 is cyano.
  • Embodiment 6 The method of any of embodiments 1-4, wherein in the compound of Formula (I), or a pharmaceutically acceptable salt thereof, R 2 is -COOR 5 .
  • Embodiment 7 The method of any of embodiments 1-4, wherein in the compound of Formula (I), or a pharmaceutically acceptable salt thereof, R 2 is -C(O)N(R 5 )2.
  • Embodiment 8 The method of any of embodiments 1-7, wherein in the compound of Formula (I), or a pharmaceutically acceptable salt thereof, R 3 is halogen.
  • Embodiment 9 The method of embodiment 8, wherein in the compound of Formula (I), or a pharmaceutically acceptable salt thereof, the halogen is fluorine.
  • Embodiment 10 The method of any of embodiments 1-9, wherein in the compound of Formula (I), or a pharmaceutically acceptable salt thereof, X is C(R 5 )2 and - is a single bond.
  • Embodiment 11 The method of any of embodiments 1-9, wherein in the compound of Formula (I), or a pharmaceutically acceptable salt thereof, X is CR 5 and - is a double bond.
  • Embodiment 12 The method of any of embodiments 1-9, wherein in the compound of Formula (I), or a pharmaceutically acceptable salt thereof, X is O and - is a single bond.
  • Embodiment 13 The method of any of embodiments 1-12, wherein in the compound of Formula (I), or a pharmaceutically acceptable salt thereof, R 1 is aryl optionally substituted with one or more R 4 .
  • Embodiment 14 The method of embodiment 13, wherein in the compound of Formula (I), or a pharmaceutically acceptable salt thereof, the aryl is phenyl optionally substituted with one or more R 4 .
  • Embodiment 15 The method of embodiment 14, wherein in the compound of Formula (I), or a pharmaceutically acceptable salt thereof, the phenyl is substituted with one, two or three R 4 .
  • Embodiment 16 The method of embodiment 15, wherein in the compound of Formula (I), or a pharmaceutically acceptable salt thereof, the one, two or three R 4 are each independently halogen, -POsCCi- C 3 alkyl)2, hydroxyl, hydroxyalkyl, aralkyl, haloalkyl, -COOR 5 , -Y’-Ci-Ce alkyl, Y 2 -Ci-Ce alkyl, -L-N(R 5 )2, -O-L-N(R 5 )2, -C(CF3)N(R 5 )2, -Y’-N(R 5 )2, -Y 2 -N(R 5 )2, Y 2 -haloalkyl, -L-heteroaryl, -L-heterocyclyl, or -Y 1 - heterocyclyl, wherein the heterocyclyl portion of the -L-heterocyclyl or -Y'-heter
  • Embodiment 17 The method of embodiment 16, wherein in the compound of Formula (I), or a pharmaceutically acceptable salt thereof, R 4 is -Y’-Ci-Ce alkyl and Y 1 is a bond and the Ci-Ce alkyl is methyl, ethyl, isopropyl, butyl, or pentyl.
  • Embodiment 18 The method of embodiment 16, wherein in the compound of Formula (I), or a pharmaceutically acceptable salt thereof, R 4 is -Y 2 -Ci-Ce alkyl and Y 2 is a -SO2- and the Ci-Ce alkyl is methyl.
  • Embodiment 19 The method of embodiment 16, wherein in the compound of Formula (I), or a pharmaceutically acceptable salt thereof, R 4 is -Y 2 -haloalkyl and Y 2 is -S- or -SO2- and the haloalkyl is trifluoromethyl.
  • Embodiment 21 The method of embodiment 16, wherein in the compound of Formula (I), or a pharmaceutically acceptable salt thereof, R 4 is -L-N(R 5 )2 and L is methylene or ethylene and each R 5 is hydrogen, each R 5 is methyl or one R 5 is methyl and one R 5 is hydrogen.
  • Embodiment 26 The method of embodiment 16, wherein in the compound of Formula (I), or a pharmaceutically acceptable salt thereof, R 4 is -L-heterocyclyl, wherein L is a methylene and the heterocyclyl portion of the L-heterocyclyl is azetidinyl, oxetanyl, pyrrolidinyl piperidinyl, each optionally substituted with one or more R 7 selected from C1-C3 alkyl, alkoxy, hydroxyl and halogen.
  • Embodiment 28 The method of embodiment 16, wherein in the compound of Formula (I), or a pharmaceutically acceptable salt thereof, R 4 is -L-heteroaryl optionally substituted with one or more R 7 .
  • Embodiment 29 The method of embodiment 28, wherein in the compound of Formula (I), or a pharmaceutically acceptable salt thereof, the -L-heteroaryl is tetrazolyl.
  • Embodiment 30 The method of embodiment 16, wherein in the compound of Formula (I), or a pharmaceutically acceptable salt thereof, R 4 is -POTCi-C alkyl)2.
  • Embodiment 32 The method of embodiment 16, wherein in the compound of Formula (I), or a pharmaceutically acceptable salt thereof, R 4 is hydroxyalkyl.
  • Embodiment 33 The method of embodiment 16, wherein in the compound of Formula (I), or a pharmaceutically acceptable salt thereof, R 4 is -O-L-N(R 5 )2.
  • Embodiment 35 The method of any of embodiments 1-12, wherein in the compound of Formula (I), or a pharmaceutically acceptable salt thereof, R 1 is heteroaryl optionally substituted with one or more R 4 .
  • Embodiment 36 The method of embodiment 35, wherein in the compound of Formula (I), or a pharmaceutically acceptable salt thereof, R 1 is pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, triazinyl, pyridyl, pyridinyl-2-one, pyrazinyl, pyridazinyl, pyrimidinyl, isoxazolyl, isoindolinyl, naphthyridinyl, 1,2,3,4-tetrahydroisoquinolinyl, or 5,6-dihydro-4H-pyrrolo[l,2-b]pyrazolyl, each optionally substituted with one or more R 4 .
  • Embodiment 38 The method of embodiment 37, wherein in the compound of Formula (I), or a pharmaceutically acceptable salt thereof, R 1 is pyrazolyl optionally substituted with one R 4 independently selected from hydroxyalkyl, heteroalkyl, haloalkyl, -Y’-Ci-Ce alkyl, -L-N(R 5 )2, L-heterocyclyl or L- heteroaryl, wherein the heteroaryl of the L-heteroaryl or the heterocyclyl portion of the L-heterocyclyl is optionally substituted with one or more R 7 .
  • R 4 independently selected from hydroxyalkyl, heteroalkyl, haloalkyl, -Y’-Ci-Ce alkyl, -L-N(R 5 )2, L-heterocyclyl or L- heteroaryl, wherein the heteroaryl of the L-heteroaryl or the heterocyclyl portion of the L-heterocyclyl is optionally substituted
  • Embodiment 39 The method of embodiment 38, wherein in the compound of Formula (I), or a pharmaceutically acceptable salt thereof, R 4 is -L-heteroaryl and L is methylene wherein the heteroaryl is pyridyl optional substituted with one or more R 7 .
  • Embodiment 40 The method of embodiment 38, wherein in the compound of Formula (I), or a pharmaceutically acceptable salt thereof, R 4 is -L-heterocyclyl optionally substituted with one or more R 7 where L is a bond and the heterocyclyl portion of the L-heterocyclyl is oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, piperazinyl, or 4-methylpiperazinyl.
  • Embodiment 41 The method of embodiment 38, wherein in the compound of Formula (I), or a pharmaceutically acceptable salt thereof, R 4 is -L-heterocyclyl optionally substituted with one or more R 7 where L is methylene and the heterocyclyl portion of the L-heterocyclyl is azetidinyl, oxetanyl, pyrrolidinyl, pyrrolidinone, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, piperazinyl, or 4-methylpiperazinyl.
  • Embodiment 42 The method of embodiment 38, wherein in the compound of Formula (I), or a pharmaceutically acceptable salt thereof, R 4 is -L-N(R 5 )2 where L is methylene and each R 5 is independently hydrogen, each R 5 is independently C1-C3 alkyl or one R 5 is C1-C3 alkyl and one R 5 is hydrogen.
  • Embodiment 43 The method of embodiment 38, wherein in the compound of Formula (I), or a pharmaceutically acceptable salt thereof, R 4 is -Y’-Ci-Ce alkyl where Y 1 is a bond and the Ci-Ce alkyl is methyl, ethyl, or isopropyl.
  • Embodiment 44 The method of embodiment 38, wherein in the compound of Formula (I), or a pharmaceutically acceptable salt thereof, the heteroaryl is pyrazolyl optionally substituted with two R 4 groups each independently selected from hydroxyalkyl, heteroalkyl, haloalkyl, and -Y’-Ci-Ce alkyl.
  • Embodiment 45 The method of embodiment 36, wherein in the compound of Formula (I), or a pharmaceutically acceptable salt thereof, the heteroaryl is pyridyl optionally substituted with one R 4 independently selected from cyano, halogen, alkoxy, hydroxyalkyl, heteroalkyl, haloalkyl, -Y’-Ci-Ce alkyl, - L-N(R 5 )2, -Y’-N(R 5 )2, -L-cycloalkyl, or -L-heterocyclyl optionally substituted with one or more R 7 .
  • R 4 independently selected from cyano, halogen, alkoxy, hydroxyalkyl, heteroalkyl, haloalkyl, -Y’-Ci-Ce alkyl, - L-N(R 5 )2, -Y’-N(R 5 )2, -L-cycloalkyl, or -L-heterocyclyl optionally substituted with one or
  • Embodiment 46 The method of any of embodiments 1-12 wherein in the compound of Formula (I), or a pharmaceutically acceptable salt thereof, R 1 is -L-cycloalkyl optionally substituted with one or more R 4 .
  • Embodiment 47 The method of any of embodiments 1-12 wherein in the compound of Formula (I), or a pharmaceutically acceptable salt thereof, R 1 is -L-heterocyclyl optionally substituted with one or more R 4 .
  • Embodiment 48 The method of embodiment 47, wherein in the compound of Formula (I), or a pharmaceutically acceptable salt thereof, L is a bond and the heterocyclyl is piperidinyl or tetrahydropyranyl .
  • Embodiment 49 The method of any of embodiments 1-3, wherein in the compound of Formula (I), or a pharmaceutically acceptable salt thereof, n is 2.
  • Embodiment 50 A method of treating T-cell lymphoma in a subject, comprising administering to the subject a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:
  • Embodiment 51 A method of treating T-cell lymphoma in a subject, comprising administering to the subject a therapeutically effective amount of a compound selected from the group consisting of:
  • Embodiment 53 The method of embodiment 51, wherein the compound is: pharmaceutically acceptable salt thereof.
  • Embodiment 54 The method of embodiment 51, wherein the compound is: a pharmaceutically acceptable salt thereof.
  • Embodiment 55 The method of embodiment 51, wherein the compound is: a pharmaceutically acceptable salt thereof.
  • Embodiment 56 The method of embodiment 51, wherein the compound is: a pharmaceutically acceptable salt thereof.
  • Embodiment 57 The method of embodiment 51, wherein the compound is: a pharmaceutically acceptable salt thereof.
  • Embodiment 58 The method of embodiment 51, wherein the compound is: a pharmaceutically acceptable salt thereof.
  • Embodiment 59 The method of embodiment 51, wherein the compound is: a pharmaceutically acceptable salt thereof.
  • Embodiment 60 The method of embodiment 51, wherein the compound is: a pharmaceutically acceptable salt thereof.
  • Embodiment 61 The method of embodiment 51 , wherein the compound is: a pharmaceutically acceptable salt thereof.
  • Embodiment 62 The method of embodiment 51, wherein the compound is: a pharmaceutically acceptable salt thereof.
  • Embodiment 63 The method of embodiment 51, wherein the compound is: or a pharmaceutically acceptable salt thereof.
  • Embodiment 64 A method of any one of embodiments 1 to 63, wherein the T-cell lymphoma in the subject is peripheral T-cell lymphoma.
  • Embodiment 65 The method of embodiment 64, wherein the peripheral T-cell lymphoma in the subject is peripheral T-cell lymphoma, not otherwise specified (PTCL, NOS).
  • Embodiment 66 The method of embodiment 64, wherein the peripheral T-cell lymphoma in the subject is angioimmunoblastic T-cell lymphoma (AITL).
  • AITL angioimmunoblastic T-cell lymphoma
  • Embodiment 67 The method of embodiment 64, wherein the peripheral T-cell lymphoma in the subject is ALK-1 positive anaplastic large cell lymphoma (ALCL).
  • ACL ALK-1 positive anaplastic large cell lymphoma
  • Embodiment 68 The method of embodiment 64, wherein the peripheral T-cell lymphoma in the subject is ALK-1 negative anaplastic large cell lymphoma (ALCL).
  • ACL ALK-1 negative anaplastic large cell lymphoma
  • Embodiment 69 The method of embodiment 64, wherein the peripheral T-cell lymphoma in the subject is enteropathy-associated T-cell lymphoma (EATL).
  • EATL enteropathy-associated T-cell lymphoma
  • Embodiment 70 The method of embodiment 64, wherein the peripheral T-cell lymphoma in the subject is monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL).
  • MEITL monomorphic epitheliotropic intestinal T-cell lymphoma
  • Embodiment 71 The method of embodiment 64, wherein the peripheral T-cell lymphoma in the subject is nodal peripheral T-cell lymphoma with T-follicular helper (TFH) phenotype.
  • T-follicular helper T-follicular helper
  • Embodiment 72 The method of embodiment 64, wherein the peripheral T-cell lymphoma in the subject is follicular T-cell lymphoma (FTCL).
  • FTCL follicular T-cell lymphoma
  • Embodiment 73 The method of embodiment 64, wherein the peripheral T-cell lymphoma in the subject is extranodal natural killer (NKj/T-cell lymphoma (ENKTCL).
  • NKj/T-cell lymphoma ENKTCL
  • Embodiment 76 The method of embodiment 64, wherein the peripheral T-cell lymphoma in the subject is adult T-cell leukemia/lymphoma (ATLL).
  • ATLL adult T-cell leukemia/lymphoma
  • Embodiment 77 The method of embodiment 64, wherein the peripheral T-cell lymphoma in the subject is primary cutaneous gamma-delta T-cell lymphoma (PCGDTL).
  • PCGDTL primary cutaneous gamma-delta T-cell lymphoma
  • Embodiment 79 A method of any one of embodiments 1 to 63, wherein the T-cell lymphoma in the subject is cutaneous T-cell lymphoma (CTCL).
  • CTCL cutaneous T-cell lymphoma
  • Embodiment 80 A method of any one of embodiments 1 to 63, wherein the subject has received at least one therapy prior to the administration to the subject of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
  • Embodiment 82 A method of any one of embodiments 1 to 63, wherein the T-cell lymphoma in the subject is relapsed or refractory T-cell lymphoma.
  • Embodiment 84 The method of embodiment 83, wherein the peripheral T-cell lymphoma in the subject is peripheral T-cell lymphoma, not otherwise specified (PTCL, NOS).
  • Embodiment 86 The method of embodiment 83, wherein the peripheral T-cell lymphoma in the subject is ALK-1 positive anaplastic large cell lymphoma (ALCL).
  • ACL ALK-1 positive anaplastic large cell lymphoma
  • Embodiment 88 The method of embodiment 83, wherein the peripheral T-cell lymphoma in the subject is enteropathy-associated T-cell lymphoma (EATL).
  • EATL enteropathy-associated T-cell lymphoma
  • Embodiment 89 The method of embodiment 83, wherein the peripheral T-cell lymphoma in the subject is monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL).
  • MEITL monomorphic epitheliotropic intestinal T-cell lymphoma
  • Embodiment 91 The method of embodiment 83, wherein the peripheral T-cell lymphoma in the subject is follicular T-cell lymphoma (FTCL).
  • FTCL follicular T-cell lymphoma
  • Embodiment 92 The method of embodiment 83, wherein the peripheral T-cell lymphoma in the subject is extranodal natural killer (NK)ZT-cell lymphoma (ENKTCL).
  • Embodiment 93 The method of embodiment 83, wherein the peripheral T-cell lymphoma in the subject is hepatosplenic T-cell lymphoma (HSTCL).
  • HSCL hepatosplenic T-cell lymphoma
  • Embodiment 94 The method of embodiment 83, wherein the peripheral T-cell lymphoma in the subject is subcutaneous panniculitis-like TCL (SPTCL).
  • SPTCL subcutaneous panniculitis-like TCL
  • Embodiment 95 The method of embodiment 83, wherein the peripheral T-cell lymphoma in the subject is adult T-cell leukemia/lymphoma (ATLL).
  • ATLL adult T-cell leukemia/lymphoma
  • Embodiment 96 The method of embodiment 83, wherein the peripheral T-cell lymphoma in the subject is primary cutaneous gamma-delta T-cell lymphoma (PCGDTL).
  • PCGDTL primary cutaneous gamma-delta T-cell lymphoma
  • Embodiment 97 The method of embodiment 83, wherein the peripheral T-cell lymphoma in the subject is primary cutaneous aggressive epidermotropic cytotoxic T-cell lymphoma (PCAECyTCL).
  • PCAECyTCL primary cutaneous aggressive epidermotropic cytotoxic T-cell lymphoma
  • Embodiment 98 The method of embodiment 82, wherein the T-cell lymphoma in the subject is cutaneous T-cell lymphoma (CTCL).
  • CTCL cutaneous T-cell lymphoma
  • Embodiment 99 A method of any one of embodiments 1 to 63, wherein the T-cell lymphoma in the subject is relapsed or refractory T-cell lymphoma, and wherein the subject has received at least one prior therapy.
  • Embodiment 100 The method of embodiment 99, wherein the relapsed or refractory T-cell lymphoma in the subject is peripheral T-cell lymphoma.
  • Embodiment 101 The method of embodiment 100, wherein the peripheral T-cell lymphoma in the subject is peripheral T-cell lymphoma, not otherwise specified (PTCL, NOS).
  • Embodiment 102 The method of embodiment 100, wherein the peripheral T-cell lymphoma in the subject is angioimmunoblastic T-cell lymphoma (AITL).
  • AITL angioimmunoblastic T-cell lymphoma
  • Embodiment 103 The method of embodiment 100, wherein the peripheral T-cell lymphoma in the subject is ALK-1 positive anaplastic large cell lymphoma (ALCL).
  • ALK-1 positive anaplastic large cell lymphoma ACL
  • Embodiment 104 The method of embodiment 100, wherein the peripheral T-cell lymphoma in the subject is ALK-1 negative anaplastic large cell lymphoma (ALCL).
  • ACL ALK-1 negative anaplastic large cell lymphoma
  • Embodiment 105 The method of embodiment 100, wherein the peripheral T-cell lymphoma in the subject is enteropathy-associated T-cell lymphoma (EATL).
  • EATL enteropathy-associated T-cell lymphoma
  • Embodiment 106 The method of embodiment 100, wherein the peripheral T-cell lymphoma in the subject is monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL).
  • MEITL monomorphic epitheliotropic intestinal T-cell lymphoma
  • Embodiment 107 The method of embodiment 100, wherein the peripheral T-cell lymphoma in the subject is nodal peripheral T-cell lymphoma with T-follicular helper (TFH) phenotype.
  • T-follicular helper T-follicular helper
  • Embodiment 108 The method of embodiment 100, wherein the peripheral T-cell lymphoma in the subject is follicular T-cell lymphoma (FTCL).
  • FTCL follicular T-cell lymphoma
  • Embodiment 109 The method of embodiment 100, wherein the peripheral T-cell lymphoma in the subject is extranodal natural killer (NK)ZT-cell lymphoma (ENKTCL).
  • NK extranodal natural killer
  • ENKTCL extranodal natural killer
  • Embodiment 110 The method of embodiment 100, wherein the peripheral T-cell lymphoma in the subject is hepatosplenic T-cell lymphoma (HSTCL).
  • Embodiment 111 The method of embodiment 100, wherein the peripheral T-cell lymphoma in the subject is subcutaneous panniculitis-like TCL (SPTCL).
  • SPTCL subcutaneous panniculitis-like TCL
  • Embodiment 112 The method of embodiment 100, wherein the peripheral T-cell lymphoma in the subject is adult T-cell leukemia/lymphoma (ATLL).
  • ATLL adult T-cell leukemia/lymphoma
  • Embodiment 113 The method of embodiment 100, wherein the peripheral T-cell lymphoma in the subject is primary cutaneous gamma-delta T-cell lymphoma (PCGDTL).
  • PCGDTL primary cutaneous gamma-delta T-cell lymphoma
  • Embodiment 114 The method of embodiment 100, wherein the peripheral T-cell lymphoma in the subject is primary cutaneous aggressive epidermotropic cytotoxic T-cell lymphoma (PCAECyTCL).
  • PCAECyTCL primary cutaneous aggressive epidermotropic cytotoxic T-cell lymphoma
  • Embodiment 115 The method of embodiment 99, wherein the T-cell lymphoma in the subject is cutaneous T-cell lymphoma (CTCL).
  • CTCL cutaneous T-cell lymphoma
  • Embodiment 116 A method of any one of embodiments 1 to 63, wherein the T-cell lymphoma in the subject is refractory to at least one prior systemic therapy.
  • Embodiment 117 The method of embodiment 116, wherein the relapsed or refractory T-cell lymphoma in the subject is peripheral T-cell lymphoma.
  • Embodiment 118 The method of embodiment 117, wherein the peripheral T-cell lymphoma in the subject is peripheral T-cell lymphoma, not otherwise specified (PTCL, NOS).
  • Embodiment 119 The method of embodiment 117, wherein the peripheral T-cell lymphoma in the subject is angioimmunoblastic T-cell lymphoma (AITL).
  • AITL angioimmunoblastic T-cell lymphoma
  • Embodiment 120 The method of embodiment 117, wherein the peripheral T-cell lymphoma in the subject is ALK-1 positive anaplastic large cell lymphoma (ALCL).
  • ACL ALK-1 positive anaplastic large cell lymphoma
  • Embodiment 121 The method of embodiment 117, wherein the peripheral T-cell lymphoma in the subject is ALK-1 negative anaplastic large cell lymphoma (ALCL).
  • ACL ALK-1 negative anaplastic large cell lymphoma
  • Embodiment 122 The method of embodiment 117, wherein the peripheral T-cell lymphoma in the subject is enteropathy-associated T-cell lymphoma (EATL).
  • EATL enteropathy-associated T-cell lymphoma
  • Embodiment 123 The method of embodiment 117, wherein the peripheral T-cell lymphoma in the subject is monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL).
  • MEITL monomorphic epitheliotropic intestinal T-cell lymphoma
  • Embodiment 124 The method of embodiment 117, wherein the peripheral T-cell lymphoma in the subject is nodal peripheral T-cell lymphoma with T-follicular helper (TFH) phenotype.
  • T-follicular helper T-follicular helper
  • Embodiment 125 The method of embodiment 117, wherein the peripheral T-cell lymphoma in the subject is follicular T-cell lymphoma (FTCL).
  • FTCL follicular T-cell lymphoma
  • Embodiment 126 The method of embodiment 117, wherein the peripheral T-cell lymphoma in the subject is extranodal natural killer (NK)ZT-cell lymphoma (ENKTCL).
  • NK extranodal natural killer
  • ENKTCL extranodal natural killer
  • Embodiment 127 The method of embodiment 117, wherein the peripheral T-cell lymphoma in the subject is hepatosplenic T-cell lymphoma (HSTCL).
  • HSCL hepatosplenic T-cell lymphoma
  • Embodiment 129 The method of embodiment 117, wherein the peripheral T-cell lymphoma in the subject is adult T-cell leukemia/lymphoma (ATLL).
  • Embodiment 130 The method of embodiment 117, wherein the peripheral T-cell lymphoma in the subject is primary cutaneous gamma-delta T-cell lymphoma (PCGDTL).
  • PCGDTL primary cutaneous gamma-delta T-cell lymphoma
  • Embodiment 131 The method of embodiment 117, wherein the peripheral T-cell lymphoma in the subject is primary cutaneous aggressive epidermotropic cytotoxic T-cell lymphoma (PCAECyTCL).
  • PCAECyTCL primary cutaneous aggressive epidermotropic cytotoxic T-cell lymphoma
  • Embodiment 132 The method of embodiment 116, wherein the T-cell lymphoma in the subject is cutaneous T-cell lymphoma (CTCL).
  • CTCL cutaneous T-cell lymphoma
  • Embodiment 134 The method of embodiment 133, wherein the relapsed or refractory T-cell lymphoma in the subject is peripheral T-cell lymphoma.
  • Embodiment 136 The method of embodiment 134, wherein the peripheral T-cell lymphoma in the subject is angioimmunoblastic T-cell lymphoma (AITL).
  • AITL angioimmunoblastic T-cell lymphoma
  • Embodiment 137 The method of embodiment 134, wherein the peripheral T-cell lymphoma in the subject is ALK-1 positive anaplastic large cell lymphoma (ALCL).
  • ACL ALK-1 positive anaplastic large cell lymphoma
  • Embodiment 138 The method of embodiment 134, wherein the peripheral T-cell lymphoma in the subject is ALK-1 negative anaplastic large cell lymphoma (ALCL).
  • ALK-1 negative anaplastic large cell lymphoma ACL
  • Embodiment 139 The method of embodiment 134, wherein the peripheral T-cell lymphoma in the subject is enteropathy-associated T-cell lymphoma (EATL).
  • EATL enteropathy-associated T-cell lymphoma
  • Embodiment 140 The method of embodiment 134, wherein the peripheral T-cell lymphoma in the subject is monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL).
  • MEITL monomorphic epitheliotropic intestinal T-cell lymphoma
  • Embodiment 141 The method of embodiment 134, wherein the peripheral T-cell lymphoma in the subject is nodal peripheral T-cell lymphoma with T-follicular helper (TFH) phenotype.
  • T-follicular helper T-follicular helper
  • Embodiment 142 The method of embodiment 134, wherein the peripheral T-cell lymphoma in the subject is follicular T-cell lymphoma (FTCL).
  • FTCL follicular T-cell lymphoma
  • Embodiment 143 The method of embodiment 134, wherein the peripheral T-cell lymphoma in the subject is extranodal natural killer (NK)ZT-cell lymphoma (ENKTCL).
  • NK extranodal natural killer
  • ENKTCL extranodal natural killer
  • Embodiment 144 The method of embodiment 134, wherein the peripheral T-cell lymphoma in the subject is hepatosplenic T-cell lymphoma (HSTCL).
  • HSCL hepatosplenic T-cell lymphoma
  • Embodiment 145 The method of embodiment 134, wherein the peripheral T-cell lymphoma in the subject is subcutaneous panniculitis-like TCL (SPTCL).
  • SPTCL subcutaneous panniculitis-like TCL
  • Embodiment 146 The method of embodiment 134, wherein the peripheral T-cell lymphoma in the subject is adult T-cell leukemia/lymphoma (ATLL).
  • ATLL adult T-cell leukemia/lymphoma
  • Embodiment 147 The method of embodiment 134, wherein the peripheral T-cell lymphoma in the subject is primary cutaneous gamma-delta T-cell lymphoma (PCGDTL).
  • Embodiment 148 The method of embodiment 134, wherein the peripheral T-cell lymphoma in the subject is primary cutaneous aggressive epidermotropic cytotoxic T-cell lymphoma (PCAECyTCL).
  • PCAECyTCL primary cutaneous aggressive epidermotropic cytotoxic T-cell lymphoma
  • Embodiment 149 The method of embodiment 133, wherein the T-cell lymphoma in the subject is cutaneous T-cell lymphoma (CTCL).
  • CTCL cutaneous T-cell lymphoma
  • Embodiment 150 A method of any one of embodiments 1 to 63, wherein the T-cell lymphoma in the subject has progressed following at least one line of primary systemic therapy.
  • Embodiment 151 The method of embodiment 150, wherein the at least one line of prior systemic therapy is at least one prior chemotherapy agent.
  • Embodiment 152 The method of embodiment 150 or 151, wherein the relapsed or refractory T-cell lymphoma in the subject is peripheral T-cell lymphoma.
  • Embodiment 153 The method of embodiment 152, wherein the peripheral T-cell lymphoma in the subject is peripheral T-cell lymphoma, not otherwise specified (PTCL, NOS).
  • Embodiment 154 The method of embodiment 152, wherein the peripheral T-cell lymphoma in the subject is angioimmunoblastic T-cell lymphoma (AITL).
  • AITL angioimmunoblastic T-cell lymphoma
  • Embodiment 155 The method of embodiment 152, wherein the peripheral T-cell lymphoma in the subject is ALK-1 positive anaplastic large cell lymphoma (ALCL).
  • ALK-1 positive anaplastic large cell lymphoma ACL
  • Embodiment 156 The method of embodiment 152, wherein the peripheral T-cell lymphoma in the subject is ALK-1 negative anaplastic large cell lymphoma (ALCL).
  • ALK-1 negative anaplastic large cell lymphoma ACL
  • Embodiment 157 The method of embodiment 152, wherein the peripheral T-cell lymphoma in the subject is enteropathy-associated T-cell lymphoma (EATL).
  • EATL enteropathy-associated T-cell lymphoma
  • Embodiment 158 The method of embodiment 152, wherein the peripheral T-cell lymphoma in the subject is monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL).
  • MEITL monomorphic epitheliotropic intestinal T-cell lymphoma
  • Embodiment 159 The method of embodiment 152, wherein the peripheral T-cell lymphoma in the subject is nodal peripheral T-cell lymphoma with T-follicular helper (TFH) phenotype.
  • T-follicular helper T-follicular helper
  • Embodiment 160 The method of embodiment 152, wherein the peripheral T-cell lymphoma in the subject is follicular T-cell lymphoma (FTCL).
  • FTCL follicular T-cell lymphoma
  • Embodiment 161 The method of embodiment 152, wherein the peripheral T-cell lymphoma in the subject is extranodal natural killer (NK)ZT-cell lymphoma (ENKTCL).
  • NK extranodal natural killer
  • ENKTCL extranodal natural killer
  • Embodiment 162 The method of embodiment 152, wherein the peripheral T-cell lymphoma in the subject is hepatosplenic T-cell lymphoma (HSTCL).
  • HSCL hepatosplenic T-cell lymphoma
  • Embodiment 163 The method of embodiment 152, wherein the peripheral T-cell lymphoma in the subject is subcutaneous panniculitis-like TCL (SPTCL).
  • SPTCL subcutaneous panniculitis-like TCL
  • Embodiment 164 The method of embodiment 152, wherein the peripheral T-cell lymphoma in the subject is adult T-cell leukemia/lymphoma (ATLL).
  • ATLL adult T-cell leukemia/lymphoma
  • Embodiment 165 The method of embodiment 152, wherein the peripheral T-cell lymphoma in the subject is primary cutaneous gamma-delta T-cell lymphoma (PCGDTL).
  • PCGDTL primary cutaneous gamma-delta T-cell lymphoma
  • Embodiment 166 The method of embodiment 152, wherein the peripheral T-cell lymphoma in the subject is primary cutaneous aggressive epidermotropic cytotoxic T-cell lymphoma (PCAECyTCL).
  • Embodiment 167 The method of embodiment 150 or 151, wherein the T-cell lymphoma in the subject is cutaneous T-cell lymphoma (CTCL).
  • CCL cutaneous T-cell lymphoma
  • Embodiment 168 A method of any one of embodiments 1 to 167, wherein the subject is administered a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in combination with one or more additional therapeutic agents.
  • Embodiment 169 The method of embodiment 168, wherein the one or more additional therapeutic agents is selected from a chemotherapeutic agent, a mitotic inhibitors, an antimetabolites, a platinum -based agents, histone deacetylase (HDAC) inhibitors, CD30-directed antibody-drug conjugates, famesyl transferase inhibitors, SYK inhibitors, JAK inhibitors, PI3K inhibitors, immunomodulatory agents, or combinations thereof.
  • HDAC histone deacetylase
  • Embodiment 170 The method of embodiment 169 wherein the one or more additional therapeutic agents are selected from chemotherapeutic agents.
  • Embodiment 171 The method of embodiment 170, wherein the chemotherapeutic agents are selected from actinomycin, azacytidine, azathioprine, bendamustine, bleomycin, bortezomib, chlorambucil, cyclophosphamide, daunorubicin, doxifluridine, doxorubicin, epirubicin, epothilone, etoposide, idarubicin, irinotecan, lurbinectedin, mechlorethamine, mitoxantrone, teniposide, topotecan, valrubicin, vemurafenib, vinblastine, vincristine, and vindesine.
  • the chemotherapeutic agents are selected from actinomycin, azacytidine, azathioprine, bendamustine, bleomycin, bortezomib, chlorambucil, cyclophosp
  • Embodiment 172 The method of embodiment 169, wherein the one or more additional therapeutic agents are selected from mitotic inhibitors.
  • Embodiment 173 The method of embodiment 172, wherein the mitotic inhibitors are selected from paclitaxel, docetaxel, cabazitaxel, tesetaxel, and nab -paclitaxel.
  • Embodiment 174 The method of embodiment 169, wherein the one or more additional therapeutic agents are selected from antimetabolites.
  • Embodiment 175 The method of embodiment 174, wherein the antimetabolites are selected from 6- mercaptopurine, capecitabine, hydroxyurea, cladribine, pralatrexate, thioguanine, decitabine, clofarabine, nelarabine, fludarabine, 5 -fluorouracil, gemcitabine, cytarabine, pemetrexed, and methotrexate.
  • the antimetabolites are selected from 6- mercaptopurine, capecitabine, hydroxyurea, cladribine, pralatrexate, thioguanine, decitabine, clofarabine, nelarabine, fludarabine, 5 -fluorouracil, gemcitabine, cytarabine, pemetrexed, and methotrexate.
  • Embodiment 176 The method of embodiment 169, wherein the one or more additional therapeutic agents are selected from platinum -based agents.
  • Embodiment 177 The method of embodiment 176, wherein the platinum -based agents are selected from cisplatin, carboplatin, oxaliplatin, nedaplatin, lobaplatin, triplatin tetranitrate, pheanthriplatin, picoplatin, and satraplatin.
  • Embodiment 178 The method of embodiment 169, wherein the one or more additional therapeutic agents are selected from histone deacetylase (HDAC) inhibitors.
  • HDAC histone deacetylase
  • Embodiment 179 The method of embodiment 178, wherein the histone deacetylase (HDAC) inhibitors are selected from vorinostat, romidepsin, belinostat, tucidinostat, panobinostat, mocetinostat, givinostat, resmiostat, abexinostat, ricolinostat, entinostat, tinostamustin, fimepinostat, CXD-101, quisinostat, and chidamide.
  • HDAC histone deacetylase
  • Embodiment 181 The method of embodiment 180, wherein the CD30-directed antibody-drug conjugates are selected from brentuximab vedotin and SGN-CD30C.
  • Embodiment 182 The method of embodiment 169, wherein the one or more additional therapeutic agents are selected from famesyl transferase inhibitors.
  • Embodiment 183 The method of embodiment 182, wherein the famesyl transferase inhibitors are selected from antroquinonol, BMS-214662, L778123, L744832, FTI-276, FTI-277, manumycin A, LB- 42708, moverastin, PD169541, ABT-100, FTI-2153, tipifamib and lonafamib.
  • the famesyl transferase inhibitors are selected from antroquinonol, BMS-214662, L778123, L744832, FTI-276, FTI-277, manumycin A, LB- 42708, moverastin, PD169541, ABT-100, FTI-2153, tipifamib and lonafamib.
  • Embodiment 184 The method of embodiment 169, wherein the one or more additional therapeutic agents are selected from SYK inhibitors.
  • Embodiment 185 The method of embodiment 184, wherein the SYK inhibitors are selected from fostamatinib (R788), entospletinib (GS-9973), cerdulatinib (PRT062070), and TAK-659.
  • SYK inhibitors are selected from fostamatinib (R788), entospletinib (GS-9973), cerdulatinib (PRT062070), and TAK-659.
  • Embodiment 186 The method of embodiment 169, wherein the one or more additional therapeutic agents are selected from JAK inhibitors.
  • Embodiment 187 The method of embodiment 186, wherein the JAK inhibitors are selected from tofacitinib, baricitinib, ruxolitinib, upadacitinib, fedratinib, abrocitinib, and ruxolitinib.
  • Embodiment 188 The method of embodiment 169, wherein the one or more additional therapeutic agents are selected from PI3K inhibitors.
  • Embodiment 189 The method of embodiment 188, wherein the PI3K inhibitors are selected from taselisib (GDC-0032), GDC-0077, perifosine, idelalisib, buparlisib (BKM120), duvelisib, (EPI- 145), copanlisib (BAY 80-6946), PX-866, dactolisib, CUDC-907, voxtalisib (SAR245409, XL765), ME-401, IPI- 549, SF1126, RP6530, INK1117, pictilisib (GDC-0941), XL147 (SAR245408), palomid 529, GSK1059615, ZSTK474, and PWT33597.
  • the PI3K inhibitors are selected from taselisib (GDC-0032), GDC-0077, perifosine, ide
  • Embodiment 190 The method of embodiment 169, wherein the one or more additional therapeutic agents are selected from immunomodulatory agents.
  • Embodiment 191 The method of embodiment 190, wherein the immunomodulatory agents are selected from lenalidomide, PD-1 inhibitors, PD-L1 inhibitors, CTLA-4 agents, T-cell immunoglobulin and ITIM domain (TIGIT) agents, TIM-3 inhibitors, and LAG-3 inhibitors.
  • the immunomodulatory agents are selected from lenalidomide, PD-1 inhibitors, PD-L1 inhibitors, CTLA-4 agents, T-cell immunoglobulin and ITIM domain (TIGIT) agents, TIM-3 inhibitors, and LAG-3 inhibitors.
  • Embodiment 192 The method of embodiment 191, wherein the PD-1 inhibitors are selected from pembrolizumab, nivolumab, cemiplimab, JTX-4014, spartalizumab (PDR001), camrelizumab (SHR1210), sintilimab (IBI308), tislelizumab (BGB-A317), toripalimab (JS 001), dostarlimab (TSR-042, WBP-285), INCMGA00012 (MGA012), AMP-224, and AMP-514 (MEDI0680).
  • PDR001 spartalizumab
  • SHR1210 camrelizumab
  • IBI308 sintilimab
  • BGB-A317 tislelizumab
  • JSR-042, WBP-285 toripalimab
  • INCMGA00012 MAA012
  • AMP-224 AMP-224
  • AMP-514 AMP-514
  • Embodiment 193 The method of embodiment 191, wherein the PD-L1 inhibitors are selected from atezolizumab, avelumab, durvalumab, KN035, CK-301, AUNP12, CA-170, and BMS-986189.
  • Embodiment 194 The method of embodiment 191, wherein the CTLA-4 inhibitors are selected from ipilimumab and tremelimumab.
  • Embodiment 195 The method of embodiment 191, wherein the T-cell immunoglobulin and ITIM domain (TIGIT) agents are selected from BMS-986207, BGB-A1217, tiragolumab, AB154, ASP8374, MK- 7684, CDI I2RCOM70I, and LY3435I5I.
  • TAGIT T-cell immunoglobulin and ITIM domain
  • Embodiment 196 The method of embodiment 191, wherein the TIM-3 inhibitors are selected from Sym023, INCAGN02390, LY331367, Sym021, MBG453, BGB-A425, TSR-022, RO7121661, and LU3415244.
  • Embodiment 197 The method of embodiment 191, wherein the LAG-3 inhibitors are selected from relatlimab, tebotelimab, chlorogenic acid, RO-7247669, favezelimab, INCAGN-2385, IBI-110, eftilagimod alpha, Sym-022, LBL-007, ABL-501, HLX 26, IBI-323, ieramilimab, FS 118, EMB-02, and finalimab.
  • the LAG-3 inhibitors are selected from relatlimab, tebotelimab, chlorogenic acid, RO-7247669, favezelimab, INCAGN-2385, IBI-110, eftilagimod alpha, Sym-022, LBL-007, ABL-501, HLX 26, IBI-323, ieramilimab, FS 118, EMB-02, and finalimab.
  • Example 1 Effect of Compound 4 on T-cell lymphoma cell lines
  • non-Hodgkin lymphoma cell lines were purchased from ATCC (American Type Culture Collection): HH (CRL-2105), H9 (HTB-176), and SU-DHL-1 (CRL-2955).
  • Cell lines were cultured according to ATCC recommendations in RPMI-1640 medium supplemented with 10% fetal bovine serum.
  • Cell viability experiments were performed using a CellTiter-Glo 2.0 Cell viability assay (Promega) following manufacturer protocol. In short, cells were seeded in 96 well plates and treated with Compound 4 at 24 hours post seeding in triplicates. Compound concentrations started from 10 pM in 1:3 serial dilutions. During the duration of treatment cell culture media was refreshed every 3 days.
  • DMSO Dimethyl sulfoxide
  • DMSO Dimethyl sulfoxide
  • Luminescence was measured 14 or 21 -days after starting the treatment.
  • CTCL cutaneous T-cell lymphoma
  • PTCL peripheral T-cell lymphoma
  • HH cells were derived from a patient with Mycosis Fungoides (MF) type of CTCL, the most common lymphoma of the skin.
  • H9 cells were derived from a patient with Sezary Syndrome (SS, rare and aggressive) type of CTCL.
  • SU-DHL-1 cells represent ALK-positive anaplastic large cell lymphoma (ALCL), a type of PTCL.
  • Example 3B Preparation of crystalline Form 2 of Compound 4 [00385] A quantity of the free base of Compound 4 was dissolved in 2 -methyltetrahydrofuran (10 volumes) and then distilled to 3 volumes. The temperature of the solution was adjusted to about 25 °C and the resulting slurry was stirred for greater than 30 minutes. To the slurry was added n-heptane (7 volumes) over 2 hours and the resulting mixture was stirred for greater than 4 hours. The resulting solid was fdtered, the fdter cake was washed with 30% 2 -methyltetrahydrofuran /heptane (2 volumes) and dried in a vacuum oven to provide Form 2 of Compound 4.
  • Example 4 X-ray powder diffraction (XRPD) analysis of Form 1 and Form 2 of Compound 4
  • Polymorphic Form 1 of Compound 4 was analyzed by XRPD as set forth above and exhibited the peaks set forth in Table 2. The error associated with each °2 -theta position was determined to be ⁇ 0.2° theta.
  • Polymorphic Form 2 of Compound 4 was analyzed by XRPD as set forth above and exhibited the peaks set forth in Table 3. The error associated with each °2 -theta position was determined to be ⁇ 0.2 °- theta.
  • Example 5 Thermal gravimetric analyses and differential scanning calorimetry analyses of Form 1 and Form 2 of Compound 4
  • TGA Thermal gravimetric analysis
  • DSC differential scanning calorimetry
  • Table 4 [00390] A thermal gravimetric analysis (TGA) of a sample of Form 1 of Compound 4, when conducted under the conditions set forth in Table 4, exhibited a weight loss of about 1% upon heating the sample from room temperature to about the onset of melting (about 207 °C). A differential scanning calorimetry (DSC) analysis of Form 1 of Compound 4, when conducted under the conditions set forth in Table 4, exhibited peaks at between about 170 °C and 172 °C, and between about 207 °C and 208 °C.
  • TGA thermal gravimetric analysis
  • DSC differential scanning calorimetry
  • a reactor was evacuated and charged with nitrogen to atmospheric pressure. The reactor was then charged with a solution of Compound 4 (approximately 2.41 kg as determined by solution assay using HPLC) in 2 -methyltetrahydrofuran (2-MeTHF, 36 kg, 15 volumes) and the batch was concentrated to a batch volume of about 5 L (about 2 volumes) via distillation under reduced pressure. The resulting solution was adjusted to about 25 °C and then n-heptane (0.4 kg, 0.2 volumes) was added in portions over a period of about 3 hours.
  • Compound 4 approximately 2.41 kg as determined by solution assay using HPLC
  • 2-MeTHF 2 -methyltetrahydrofuran

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Abstract

Sont divulguées des méthodes de traitement du lymphome T chez un patient par administration au patient d'un composé de formule (I) ou d'un sel pharmaceutiquement acceptable de celui-ci.
PCT/US2024/023786 2023-04-11 2024-04-10 Traitement du lymphome à lymphocytes t Pending WO2024215699A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2025082481A1 (fr) * 2023-10-20 2025-04-24 Ascentage Pharma (Suzhou) Co., Ltd. Combinaison pharmaceutique et son utilisation

Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20160176882A1 (en) * 2014-12-23 2016-06-23 Novartis Ag Triazolopyrimidine compounds and uses thereof
WO2017221100A1 (fr) * 2016-06-20 2017-12-28 Novartis Ag Composés d'imidazopyrimidine utiles pour le traitement du cancer
WO2019152419A1 (fr) * 2018-01-31 2019-08-08 Mirati Therapeutics, Inc Inhibiteurs de prc2
US20200261459A1 (en) * 2017-09-28 2020-08-20 Shanghai Institute Of Materia Medica, Chinese Academy Of Sciences Triazolopyrimidine, triazolopyridine compounds, and the composition thereof for treating prc2-mediated diseases
WO2020247475A1 (fr) * 2019-06-05 2020-12-10 Mirati Therapeutics, Inc. Dérivés d'imidazo [1,2-c]pyrimidine utilisés comme inhibiteurs de prc2 pour le traitement du cancer
WO2023049724A1 (fr) * 2021-09-24 2023-03-30 Oric Pharmaceuticals, Inc. Inhibiteurs de prc2 destinés à être utilisés dans le traitement de troubles sanguins
WO2023049723A1 (fr) * 2021-09-24 2023-03-30 Oric Pharmaceuticals, Inc. Inhibiteurs de prc2 destinés à être utilisés dans le traitement de troubles sanguins
WO2024059607A1 (fr) * 2022-09-14 2024-03-21 Oric Pharmaceuticals, Inc. Formes physiques d'un inhibiteur de prc2

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20160176882A1 (en) * 2014-12-23 2016-06-23 Novartis Ag Triazolopyrimidine compounds and uses thereof
WO2017221100A1 (fr) * 2016-06-20 2017-12-28 Novartis Ag Composés d'imidazopyrimidine utiles pour le traitement du cancer
US20200261459A1 (en) * 2017-09-28 2020-08-20 Shanghai Institute Of Materia Medica, Chinese Academy Of Sciences Triazolopyrimidine, triazolopyridine compounds, and the composition thereof for treating prc2-mediated diseases
WO2019152419A1 (fr) * 2018-01-31 2019-08-08 Mirati Therapeutics, Inc Inhibiteurs de prc2
WO2020247475A1 (fr) * 2019-06-05 2020-12-10 Mirati Therapeutics, Inc. Dérivés d'imidazo [1,2-c]pyrimidine utilisés comme inhibiteurs de prc2 pour le traitement du cancer
WO2023049724A1 (fr) * 2021-09-24 2023-03-30 Oric Pharmaceuticals, Inc. Inhibiteurs de prc2 destinés à être utilisés dans le traitement de troubles sanguins
WO2023049723A1 (fr) * 2021-09-24 2023-03-30 Oric Pharmaceuticals, Inc. Inhibiteurs de prc2 destinés à être utilisés dans le traitement de troubles sanguins
WO2024059607A1 (fr) * 2022-09-14 2024-03-21 Oric Pharmaceuticals, Inc. Formes physiques d'un inhibiteur de prc2

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2025082481A1 (fr) * 2023-10-20 2025-04-24 Ascentage Pharma (Suzhou) Co., Ltd. Combinaison pharmaceutique et son utilisation

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