WO2020036997A1 - Treatment of relapsed follicular lymphoma - Google Patents

Treatment of relapsed follicular lymphoma Download PDF

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Publication number
WO2020036997A1
WO2020036997A1 PCT/US2019/046408 US2019046408W WO2020036997A1 WO 2020036997 A1 WO2020036997 A1 WO 2020036997A1 US 2019046408 W US2019046408 W US 2019046408W WO 2020036997 A1 WO2020036997 A1 WO 2020036997A1
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WIPO (PCT)
Prior art keywords
compound
mixture
pharmaceutically acceptable
acceptable salt
solvate
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PCT/US2019/046408
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English (en)
French (fr)
Inventor
Daniel P. Gold
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Lite Strategy Inc
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Mei Pharma Inc
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Priority to BR112021002734-3A priority Critical patent/BR112021002734A2/pt
Priority to CA3109377A priority patent/CA3109377A1/en
Priority to EP19849643.2A priority patent/EP3836936A4/en
Priority to AU2019321526A priority patent/AU2019321526A1/en
Priority to US17/268,050 priority patent/US20210196725A1/en
Priority to EA202190361A priority patent/EA202190361A1/ru
Priority to CN201980067638.8A priority patent/CN112839659A/zh
Priority to KR1020217007422A priority patent/KR20210043637A/ko
Application filed by Mei Pharma Inc filed Critical Mei Pharma Inc
Priority to MX2021001765A priority patent/MX2021001765A/es
Priority to SG11202101417XA priority patent/SG11202101417XA/en
Priority to JP2021506718A priority patent/JP2021534116A/ja
Publication of WO2020036997A1 publication Critical patent/WO2020036997A1/en
Priority to IL280721A priority patent/IL280721A/en
Anticipated expiration legal-status Critical
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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
    • A61K31/535—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
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
    • A61K39/3955—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against proteinaceous materials, e.g. enzymes, hormones, lymphokines
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2887—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against CD20
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding

Definitions

  • Follicular lymphoma FL is among the most common malignant lymphomas worldwide and remains incurable for most patients.
  • Some embodiments provided herein describe a method of treating follicular lymphoma (FL), comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I):
  • X, Y, and Z are each independently N or CR X , with the proviso that at least two of X, Y, and Z are
  • R x is hydrogen or Ci_ 6 alkyl
  • R 1 and R 2 are each independently (a) hydrogen, cyano, halo, or nitro;
  • Ci_ 6 alkyl C 2-6 alkenyl, C 2-6 alkynyl, C 3 _i 0 cycloalkyl, C 6 _i 4 aryl, C 7 _i 5 aralkyl, heteroaryl, or
  • each R la , R lb , R lc , and R ld is independently (i) hydrogen;
  • Ci- 6 alkyl C 2-6 alkenyl, C 2-6 alkynyl, C 3 _i 0 cycloalkyl, C 6 _i 4 aryl, C 7 _i 5 aralkyl, heteroaryl, or heterocyclyl; or (iii) R lb and R lc together with the N atom to which they are attached form
  • R 3 and R 4 are each independently hydrogen or Ci_ 6 alkyl; or R 3 and R 4 are linked together to form a bond, Ci_ 6 alkylene, Ci_ 6 heteroalkylene, C 2-6 alkenylene, or
  • R 5a is (a) hydrogen or halo; (b) Ci_ 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3 _i 0 cycloalkyl, C 6 _i 4 aryl, C 7 _i 5
  • R 5b is (a) halo; (b) Ci_ 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3 _i 0 cycloalkyl,
  • R 5C is -(CR 5f R 5g ) ceremoni-(C 6 _i4 aryl) or -(CR 5f R 5g ) ceremoni-heteroaryl;
  • R 5d and R 5e are each independently (a) hydrogen or halo; (b) Ci_ 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3 _i 0 cycloalkyl, C 6 _i 4 aryl, C 7 _i 5 aralkyl, heteroaryl, or heterocyclyl; or (c) -C(0)R la , -C(0)0R la , -
  • R 5f and R 5g are each independently (a) hydrogen or halo; (b) Ci_ 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3 _i 0 cycloalkyl, C 6 _i 4 aryl, C 7 _i 5 aralkyl, heteroaryl, or heterocyclyl; or (c) -C(0)R la , -C(0)0R la , -
  • R 6 is hydrogen, Ci_ 6 alkyl, -S-Ci_ 6 alkyl, -S(0)-Ci_ 6 alkyl, or -S0 2 -Ci_ 6 alkyl;
  • n 0 or 1 ;
  • n 0, 1, 2, 3, or 4;
  • each alkyl, alkylene, heteroalkylene, alkenyl, alkenylene, heteroalkenylene, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl, and heterocyclyl in R 1 , R 2 , R 3 , R 4 , R 6 , R x , R la , R lb , R lc , R ld , R 5a , R 5b , R 5c , R 5d , R 5e , R 5f , and R 5g is optionally substituted with one, two, three, or four substituents Q, wherein each substituent Q is independently selected from (a) oxo, cyano, halo, and nitro; (b) Ci_ 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3 _i 0 cycloalkyl, C 6 _i 4 aryl, C 7 _i 5 aral
  • each R a , R b , R c , and R d is independently (i) hydrogen; (ii) Ci_ 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3 _i 0 cycloalkyl, C 6 _i 4 aryl, C 7 _i 5 aralkyl, heteroaryl, or heterocyclyl, each of which is further optionally substituted with one, two, three, or four substituents Q a ; or (iii) R b and R c together with the N atom to which they are attached form heterocyclyl, which is further optionally substituted with one, two, three, or four substituents Q a ;
  • each Q a is independently selected from the group consisting of (a) oxo, cyano, halo, and nitro; (b) Ci- 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3 _i 0 cycloalkyl, C 6 _i 4 aryl, C 7 _i 5 aralkyl, heteroaryl, and heterocyclyl; and (c) -C(0)R e , -C(0)0R e , -C(0)NR f R g , -C(NR e )NR f R g , -OR e , -0C(0)R e , -
  • each R e , R f , R g , and R h is independently (i) hydrogen; (ii) Ci_ 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3 _i 0 cycloalkyl, C 6 _i 4 aryl, C 7 _i 5 aralkyl, heteroaryl, or heterocyclyl; or (iii) R f and R g together with the N atom to which they are attached form heterocyclyl;
  • R 5b is (a) halo; (b) Ci_ 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3 _i 0 cycloalkyl, C 6 _i 4 aryl, C 7 _i 5 aralkyl, or heteroaryl; or (c) -C(0)R la , -C(0)OR la , -
  • R 5a and R 5b are each independently (a) halo; (b) Ci_ 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3 _i 0 cycloalkyl, C 6 _i 4 aryl, C 7 _i 5 aralkyl, heteroaryl, or
  • R 5a and R 5b are each methyl, optionally substituted with one, two, or three halo(s).
  • n 1
  • R 5f and R 5g are each hydrogen.
  • n 0.
  • m is 0.
  • the compound of Formula (I) is of Formula (XI):
  • R a , R 713 , R 7c , R d , and R ,e are each independently (a) hydrogen, cyano, halo, or nitro; (b) Ci_ 6 alkyl, C 2-6 alkenyl, C 2-f alkynyl, C 3 _i 0 cycloalkyl, C 6 _i 4 aryl, C 7 _i 5 aralkyl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one, two, three, or four substituents Q a ; or (c) -C(0)R a , -
  • R 7a , R 7b , R 7c , R 7d , and R 7e that are adjacent to each other form
  • X, Y, and Z are each N;
  • R 1 and R 2 are each hydrogen
  • R 3 and R 4 are each hydrogen
  • R 5a is C 1-6 alkyl
  • R 5b is Ci_ 6 alkyl
  • R is -(CH 2 )-phenyl, wherein R is optionally substituted with one, two, three, or four substituents
  • R 5d and R 5e are each hydrogen
  • R 6 is CHF 2 ; m is 0; and
  • each alkyl is optionally substituted with one, two, three, or four substituents Q, wherein each substituent Q is independently selected from C 6 _i 4 aryl, heteroaryl, and heterocyclyl, each of which is further optionally substituted with one, two, three, or four substituents Q a , wherein the heteroaryl has from 5 to 10 ring atoms and one or more heteroatoms independently selected from O, S, and N, and the heterocyclyl has from 3 to 15 ring atoms and one or more heteroatoms independently selected from O, S, and N;
  • each Q a is independently selected from the group consisting of halo, Ci_ 6 alkyl, Ci_ 6 alkylsulfonyl and -OR e , wherein R e is hydrogen or Ci_ 6 alkyl.
  • R 5a and R 5b are each methyl, optionally substituted with one or more halos.
  • the compound of Formula (I) is Compound A35:
  • the compound of Formula (I) is Compound A36:
  • the compound of Formula (I) is Compound A68:
  • the compound of Formula (I) is Compound A70:
  • the compound of Formula (I) is Compound A37:
  • the compound of Formula (I) is Compound A38:
  • the compound of Formula (I) is Compound A41:
  • the compound of Formula (I) is Compound A42:
  • the compound of Formula (I) is Compound A43:
  • the compound of Formula (I) is Compound A44:
  • a compound of Formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, is administered to the subject.
  • the compound of Formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, is administered to the subject orally.
  • the compound of Formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, is formulated as a tablet or capsule.
  • the compound of Formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, is administered to the subject daily.
  • the compound of Formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, is administered to the subject once per day, twice per day, or three times per day.
  • the compound of Formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, is administered to the subject once per day.
  • the compound of Formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, is administered to the subject.
  • the subject has progression of disease within 24 months of initiating treatment of FL with first-line immunochemotherapy.
  • the immunochemotherapy comprises administering to the subject a combination of chemotherapy and immunotherapy agents selected from i) bendamustine and rituximab; ii) RCHOP (rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, and prednisone); iii) RCVP (rituximab, cyclophosphamide, vincristine sulfate, prednisone); iv) FCMR (fludarabine, cyclophosphamide, mitoxantrone and rituximab); v) fludarabine + rituximab; and vi) RFND (rituximab, fludarabine, mitoxantrone, dexamethasone).
  • chemotherapy and immunotherapy agents selected from i) bendamustine and rituximab; ii) RCHOP (rituxima
  • the immunochemotherapy comprises administering to the subject R-CHOP (rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, and prednisone).
  • R-CHOP rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, and prednisone.
  • the immunochemotherapy further comprises administering to the subject a BTK inhibitor
  • the method comprises a continuous daily dosing schedule (CS), comprising administering to subject the compound of Formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof once daily for 28 consecutive days in a 28 -day cycle.
  • CS continuous daily dosing schedule
  • the CS is continued until at least one incidence of intolerable toxicity occurs/is observed.
  • the at least one toxicity is enterocolitis, a cutaneous toxicity, liver toxicity, pulmonary toxicity, infection, or any combination thereof.
  • the method comprises at least three 28 -day cycles, wherein: (i) the first two cycles comprise a continuous daily dosing schedule (CS), comprising administering to subject the compound of Formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof once daily for 28 consecutive days in a 28 -day cycle; and
  • CS continuous daily dosing schedule
  • the third and subsequent cycles comprise an intermittent dosing schedule (IS), comprising
  • T-cells are recovered and/or re -populated during the 21 days without treatment.
  • regulatory T-cells and/or effector T-cells are recovered and/or re-populated during the 21 days without treatment.
  • the incidence of at least one toxicity is reduced.
  • the at least one toxicity is enterocolitis, a cutaneous toxicity, liver toxicity, pulmonary toxicity, infection, or any combination thereof.
  • the IS is continued until progression of disease.
  • the subject has progression of disease within 24 months (POD24) of initiating treatment of FL with first-line immunochemotherapy.
  • the first-line immunochemotherapy comprises administering to the subject R-CHOP (rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, and prednisone), G-CHOP (Gazyza, cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, and prednisone), RB (rituximab, bendamustine), R-CVP (rituximab, cyclophosphamide, vincristine sulfate, and prednisone), or similar regimens.
  • R-CHOP rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, and prednisone
  • an additional therapeutic agent is administered in combination with the compound of Formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
  • the additional therapeutic agent is rituximab.
  • rituximab is administered at a dose of about 375 mg/m 2 .
  • 8 doses of rituximab are administered to the subject over a period of about 6 months the subject is treated for a period of about 6 months.
  • composition comprising:
  • X, Y, and Z are each independently N or CR X , with the proviso that at least two of X, Y, and Z are
  • R x is hydrogen or Ci_ 6 alkyl
  • R 1 and R 2 are each independently (a) hydrogen, cyano, halo, or nitro;
  • Ci- 6 alkyl, C 24 alkenyl, C 2-f alkynyl, C 3 _i 0 cycloalkyl, C 6 _i 4 aryl, C 7 _i 5 aralkyl, heteroaryl, or
  • each R la , R lb , R lc , and R ld is independently (i) hydrogen;
  • Ci- 6 alkyl C 2-6 alkenyl, C 2-6 alkynyl, C 3 _i 0 cycloalkyl, C 6 _i 4 aryl, C 7 _i 5 aralkyl, heteroaryl, or heterocyclyl; or (iii) R lb and R lc together with the N atom to which they are attached form
  • R 3 and R 4 are each independently hydrogen or Ci_ 6 alkyl; or R 3 and R 4 are linked together to form a bond, Ci_ 6 alkylene, Ci_ 6 heteroalkylene, C 2-6 alkenylene, or
  • R 5a is (a) hydrogen or halo; (b) Ci_ 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3 _i 0 cycloalkyl, C 6 _i 4 aryl, C 7 _i 5
  • R 5b is (a) halo; (b) Ci_ 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3 _i 0 cycloalkyl,
  • R 5C is -(CR 5f R 5g ) n -(C 6.14 aryl) or -(CR 5f R 5g ) n -heteroaryl;
  • R 5d and R 5e are each independently (a) hydrogen or halo; (b) Ci_ 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3 _i 0 cycloalkyl, C 6 _i 4 aryl, C 7 _i 5 aralkyl, heteroaryl, or heterocyclyl; or (c) -C(0)R la , -C(0)0R la , -
  • R 5f and R 5g are each independently (a) hydrogen or halo; (b) Ci_ 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3 _i 0 cycloalkyl, C 6 _i 4 aryl, C 7 _i 5 aralkyl, heteroaryl, or heterocyclyl; or (c) -C(0)R la , -C(0)0R la , -
  • R 6 is hydrogen, Ci_ 6 alkyl, -S-Ci_ 6 alkyl, -S(0)-Ci_ 6 alkyl, or -S0 2 -Ci_ 6 alkyl;
  • n 0 or 1 ;
  • n 0, 1, 2, 3, or 4;
  • each alkyl, alkylene, heteroalkylene, alkenyl, alkenylene, heteroalkenylene, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl, and heterocyclyl in R 1 , R 2 , R 3 , R 4 , R 6 , R x , R la , R lb , R lc , R ld , R 5a , R 5b , R 5c , R 5d , R 5e , R 5f , and R 5g is optionally substituted with one, two, three, or four substituents Q, wherein each substituent Q is independently selected from (a) oxo, cyano, halo, and nitro; (b) Ci_ 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3 _i 0 cycloalkyl, C 6 _i 4 aryl, C 7 _i 5 aral
  • each R a , R b , R c , and R d is independently (i) hydrogen; (ii) Ci_ 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3 _i 0 cycloalkyl, C 6 _i 4 aryl, C 7 _i 5 aralkyl, heteroaryl, or heterocyclyl, each of which is further optionally substituted with one, two, three, or four substituents Q a ; or (iii) R b and R c together with the N atom to which they are attached form heterocyclyl, which is further optionally substituted with one, two, three, or four substituents Q a ; wherein each Q a is independently selected from the group consisting of (a) oxo, cyano, halo, and nitro; (b) Ci_ 6 alkyl, C 2-6 alkenyl, C 2-6 alkyny
  • each R e , R f , R g , and R h is independently (i) hydrogen; (ii) Ci_ 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3 _i 0 cycloalkyl, C 6 _i 4 aryl, C 7 _i 5 aralkyl, heteroaryl, or heterocyclyl; or (iii) R f and R g together with the N atom to which they are attached form heterocyclyl; and
  • rituximab cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, prednisone, gazyza, fludarabine, mitoxantrone, mitoxantrone, or dexamethasone.
  • composition comprising:
  • X, Y, and Z are each independently N or CR X , with the proviso that at least two of X, Y, and Z are
  • R x is hydrogen or Ci_ 6 alkyl
  • R 1 and R 2 are each independently (a) hydrogen, cyano, halo, or nitro;
  • Ci_ 6 alkyl C 2-6 alkenyl, C 2-6 alkynyl, C 3 _i 0 cycloalkyl, C 6 _i 4 aryl, C 7 _i 5 aralkyl, heteroaryl, or
  • each R la , R lb , R lc , and R ld is independently (i) hydrogen;
  • Ci- 6 alkyl C 2-6 alkenyl, C 2-6 alkynyl, C 3 _i 0 cycloalkyl, C 6 _i 4 aryl, C 7 _i 5 aralkyl, heteroaryl, or heterocyclyl; or (iii) R lb and R lc together with the N atom to which they are attached form
  • R 3 and R 4 are each independently hydrogen or Ci_ 6 alkyl; or R 3 and R 4 are linked together to form a bond, Ci_ 6 alkylene, Ci_ 6 heteroalkylene, C 2-6 alkenylene, or
  • R 5a is (a) hydrogen or halo; (b) Ci_ 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3 _i 0 cycloalkyl, C 6 _i 4 aryl, C 7 _i 5
  • R 5b is (a) halo; (b) Ci_ 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3 _i 0 cycloalkyl,
  • R 5C is -(CR 5f R 5g ) ceremoni-(C 6 _i4 aryl) or -(CR 5f R 5g ) ceremoni-heteroaryl;
  • R 5d and R 5e are each independently (a) hydrogen or halo; (b) Ci_ 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3 _i 0 cycloalkyl, C 6 _i 4 aryl, C 7 _i 5 aralkyl, heteroaryl, or heterocyclyl; or (c) -C(0)R la , -C(0)0R la , -
  • R 5f and R 5g are each independently (a) hydrogen or halo; (b) Ci_ 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3 _i 0 cycloalkyl, C 6 _i 4 aryl, C 7 _i 5 aralkyl, heteroaryl, or heterocyclyl; or (c) -C(0)R la , -C(0)0R la , -
  • R 6 is hydrogen, Ci_ 6 alkyl, -S-Ci_ 6 alkyl, -S(0)-Ci_ 6 alkyl, or -S0 2 -Ci_ 6 alkyl;
  • n 0 or 1 ;
  • n 0, 1, 2, 3, or 4;
  • each alkyl, alkylene, heteroalkylene, alkenyl, alkenylene, heteroalkenylene, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl, and heterocyclyl in R 1 , R 2 , R 3 , R 4 , R 6 , R x , R la , R lb , R lc , R ld , R 5a , R 5b , R 5c , R 5d , R 5e , R 5f , and R 5g is optionally substituted with one, two, three, or four substituents Q, wherein each substituent Q is independently selected from (a) oxo, cyano, halo, and nitro; (b) Ci_ 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3 _i 0 cycloalkyl, C 6 _i 4 aryl, C 7 _i 5 aral
  • each R a , R b , R c , and R d is independently (i) hydrogen; (ii) Ci_ 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3 _i 0 cycloalkyl, C 6 _i 4 aryl, C 7 _i 5 aralkyl, heteroaryl, or heterocyclyl, each of which is further optionally substituted with one, two, three, or four substituents Q a ; or (iii) R b and R c together with the N atom to which they are attached form heterocyclyl, which is further optionally substituted with one, two, three, or four substituents Q a ;
  • each Q a is independently selected from the group consisting of (a) oxo, cyano, halo, and nitro; (b) Ci- 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3 _i 0 cycloalkyl, C 6 _i 4 aryl, C 7 _i 5 aralkyl, heteroaryl, and heterocyclyl;
  • each R e , R f , R g , and R h is independently (i) hydrogen; (ii) Ci_ 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3 _i 0 cycloalkyl, C 6 _i 4 aryl, C 7 _i 5 aralkyl, heteroaryl, or heterocyclyl; or (iii) R f and R g together with the N atom to which they are attached form heterocyclyl;
  • FIGS. 1A-1B Schematic representations of dosing schedules: A depicts the Continuous Schedule (CS); and B depicts the Intermittent Schedule (IS).
  • FIG.3. Graphical representation showing preferential tumor exposure of Compound A35 over a
  • FIG.4 Graphical representation showing preferential retention of Compound A35 compared to idelalisib in murine B-cell tumors.
  • FIG.5 Schematic representation of monotherapy treatment paradigm with Compound A35 in patients with R/R FL.
  • FIGS. 6A-6B Graphical representation of Intermittent Dosing Schedule with Compound A35 (A) compared to parsaclisib (B) to maintain disease control.
  • compositions and methods for treating patients with follicular lymphoma who have early disease progression after immuochemotherapy In some instances, the patients have early disease progression after first-line therapy with
  • compositions comprising a therapeutic agent with a different mechanism of action compared to conventional FL therapy, and methods for treating this group of patients who are uniquely at risk, wherein the treatment provides a high response rate.
  • the therapeutic agent useful for treating this patient group is a PI3K delta inhibitor, alone or in combination with a CD20 inhibitor.
  • the nomenclature used herein and the laboratory procedures in organic chemistry, medicinal chemistry, and pharmacology described herein are those well-known and commonly employed in the art. Unless defined otherwise, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.
  • the term“subject” refers to an animal, including, but not limited to, a primate (e.g., human), cow, pig, sheep, goat, horse, dog, cat, rabbit, rat, or mouse.
  • the terms“subject” and“patient” are used interchangeably herein in reference, for example, to a mammalian subject, such as a human subject, in one embodiment, a human.
  • the terms“treat,”“treating,” and“treatment” are meant to include alleviating or abrogating a disorder, disease, or condition, or one or more of the symptoms associated with the disorder, disease, or condition; or alleviating or eradicating the cause(s) of the disorder, disease, or condition itself.
  • the terms“prevent,”“preventing,” and“prevention” are meant to include a method of delaying and/or precluding the onset of a disorder, disease, or condition, and/or its attendant symptoms; barring a subject from acquiring a disorder, disease, or condition; or reducing a subject’s risk of acquiring a disorder, disease, or condition.
  • therapeutically effective amount or“effective amount” are meant to include the amount of a compound that, when administered, is sufficient to prevent development of, or alleviate to some extent, one or more of the symptoms of the disorder, disease, or condition being treated.
  • therapeutically effective amount or“effective amount” also refer to the amount of a compound that is sufficient to elicit the biological or medical response of a biological molecule (e.g., a protein, enzyme, R A, or DNA), cell, tissue, system, animal, or human, which is being sought by a researcher, veterinarian, medical doctor, or clinician.
  • a biological molecule e.g., a protein, enzyme, R A, or DNA
  • each component is“pharmaceutically acceptable” in the sense of being compatible with other ingredients of a pharmaceutical formulation, and suitable for use in contact with the tissue or organ of humans and animals without excessive toxicity, irritation, allergic response, immunogenicity, or other problems or complications, commensurate with a reasonable benefit/risk ratio. See, Remington: The Science and Practice of Pharmacy, 2lst Edition, Lippincott
  • the term“about” or“approximately” means an acceptable error for a particular value as determined by one of ordinary skill in the art, which depends in part on how the value is measured or determined. In certain embodiments, the term“about” or“approximately” means within 1, 2, 3, or 4 standard deviations. In certain embodiments, the term“about” or“approximately” means within 50%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, or 0.05% of a given value or range.
  • active ingredient and“active substance” refer to a compound, which is administered, alone or in combination with one or more pharmaceutically acceptable excipients, to a subject for treating, preventing, or ameliorating one or more symptoms of a disorder, disease, or condition.
  • active ingredient and“active substance” may be an optically active isomer of a compound described herein.
  • the terms“drug,”“therapeutic agent,” and“chemotherapeutic agent” refer to a compound, or a pharmaceutical composition thereof, which is administered to a subject for treating, preventing, or ameliorating one or more symptoms of a disorder, disease, or condition.
  • the term“PI3K” refers to a phosphoinositide 3-kinase or variant thereof, which is capable of phosphorylating the inositol ring of PI in the D-3 position.
  • the term“PI3K variant” is intended to include proteins substantially homologous to a native PI3K, i.e., proteins having one or more naturally or non- naturally occurring amino acid deletions, insertions, or substitutions (e.g., PI3K derivatives, homologs, and fragments), as compared to the amino acid sequence of a native PI3K.
  • the amino acid sequence of a PI3K variant is at least about 80% identical, at least about 90% identical, or at least about 95% identical to a native PI3K.
  • PI3K examples include, but are not limited to, pl 10a, pl 10b, pl 105, pl 10g, PI3K-C2a, PI3K-C2P, PI3K-C2 . Vps34, mTOR, ATM, ATR, and DNA-PK. See, Fry, Biochem. Biophys. Acta 1994, 1226, 237-268; Vanhaesebroeck and Waterfield, Exp. Cell. Res. 1999, 253, 239-254; and Fry, Breast Cancer Res. 2001, 3, 304-312. PI3Ks are classified into at least four classes. Class I includes pl 10a, pl lOp, pl 105, and pl 10g.
  • Class II includes PI3K-C2a, PI3K-C2P, and PI3K-C2y.
  • Class III includes Vps34.
  • Class IV includes mTOR, ATM, ATR, and DNA-PK.
  • the PI3K is a Class I kinase.
  • the PI3K is pl 10a, pl lOp, pl 105, or pl 10g.
  • the PI3K is PI3K delta.
  • the PI3K is a variant of a Class I kinase.
  • the PI3K is a pl 10a mutant.
  • pl 10a mutants include, but are not limited to, R38H, G106V, K111N, K227E, N345K, C420R, P539R, E542K, E545A, E545G, E545K, Q546K,
  • the PI3K is a Class II kinase.
  • the PI3K is PI3K-C2a, PI3K- C2p, or PI3K-C2y.
  • the PI3K is a Class III kinase.
  • the PI3K is Vps34.
  • the PI3K is a Class IV kinase.
  • the PI3K is mTOR, ATM, ATR, or DNA-PK.
  • CD20 refers to an activated-glycosylated phosphoprotein expressed on the surface of all B-cells beginning at the pro-B phase (CD45R+, CD117+) and progressively increasing in
  • the CD20 protein in humans is encoded by the MS4A1 gene.
  • This gene encodes a member of the membrane -spanning 4A gene family. Members of this nascent protein family are characterized by common structural features and similar intron/exon splice boundaries and display unique expression patterns among hematopoietic cells and nonlymphoid tissues.
  • This gene encodes a B- lymphocyte surface molecule that plays a role in the development and differentiation of B-cells into plasma cells. This family member is localized to 1 lql2, among a cluster of family members. Alternative splicing of this gene results in two transcript variants that encode the same protein.
  • the protein has no known natural ligand and its function is to enable optimal B-cell immune response, specifically against T- independent antigens. It is suspected that it acts as a calcium channel in the cell membrane. It has been shown that CD20 plays a role in the microenvironmental interactions of B cells and are therefore used to treat some types of cancer.
  • antibody refers to (a) immunoglobulin polypeptides and immunologically active portions of immunoglobulin polypeptides, i.e., polypeptides of the immunoglobulin family, or fragments thereof, that contain an antigen binding site that specifically binds to a specific antigen, or (b)
  • antibody fragments include, but are not limited to, a Fab, Fab', F(ab')2, Fd, Fv, scFv and scFv-Fc fragment, diabody, triabody, tetrabody, linear antibody, single-chain antibody, and other multispecific antibodies formed from antibody fragments.
  • the immunoglobulin molecules can be of any type (e.g., IgG, IgE, IgM, IgD, IgA and IgY), class (e.g., IgGl, IgG2, IgG3, IgG4, IgAl and IgA2) or subclass of immunoglobulin molecule. Included in the term immunoglobulin are those immunoglobulin molecules that have modifications in the constant region, including modification (e.g., substitutions, deletions or additions) in amino acid residues that interact with Fey receptors. Antibodies are generally described in, for example, Harlow & Fane, Antibodies: A Faboratory Manual (Cold Spring Harbor Faboratory Press, 1988).
  • the term“monoclonal antibody” refers to an antibody obtained from a population of substantially homogeneous antibodies; that is, the individual antibodies comprising the population are identical except for naturally occurring mutations that may be present in minor amounts. Monoclonal antibodies are highly specific, being directed against a single antigenic determinant, also referred to as an epitope.
  • the modifier“monoclonal” is indicative of a substantially homogeneous population of antibodies directed to the identical epitope and is not to be construed as requiring production of the antibody by any particular method.
  • Monoclonal antibodies can be made by any technique or methodology known in the art; for example, the hybridoma method first described by Kohler et al., 1975, Nature 256:495, or recombinant DNA methods known in the art (see, e.g., U.S. Pat. No. 4,816,567).
  • monoclonal antibodies can also be isolated from phage antibody libraries, using techniques described in Clackson et al., 1991, Nature 352: 624-628, and Marks et al., 1991, J. Mol. Biol. 222:581-597.
  • the antibodies in a preparation of polyclonal antibodies are typically a heterogeneous population of immunoglobulin isotypes and/or classes and also exhibit a variety of epitope specificity.
  • biosimilar or“follow-on biologic” or“subsequent entry biologic” refers to a biologic medical product which is almost an identical copy of an original product that is manufactured by a different company. Biosimilars are officially approved versions of original“innovator” products, and can be manufactured when the original product's patent expires. Reference to the innovator product is an integral component of the approval. A biosimilar biological product is highly similar to the reference product notwithstanding minor differences in clinically inactive components, and there are no clinically meaningful differences between the biological product and the reference product in terms of the safety, purity, and potency of the product.
  • variable when referring to an antibody as disclosed herein can include any antibody that retains at least some of the activity, e.g., antigen- binding activity, of the reference antibody, but which is structurally different.
  • Variants include fragments of antibodies (e.g., Fab, Fab' and F(ab')2, Fd, Fvs, single-chain Fvs (scFv), single-chain antibodies, disulfide-linked Fvs (sdFv) fragments) and also antibodies with altered amino acid sequences, e.g., in the variable domains, due to amino acid
  • Variants can occur spontaneously or be intentionally constructed. Intentionally constructed variants can be produced using art-known mutagenesis techniques. Variant antibodies can comprise conservative or non-conservative amino acid substitutions, deletions or additions. The variations are limited by the constraint that the antibody maintains a function of the reference antibody, e.g., binding to the same epitope as the reference antibody, or competitively inhibiting the reference antibody.
  • the terms“synergy,”“synergism,” or“synergistic” as used herein refer to a combination of therapies (e.g., use of a PI3K inhibitor of Formula (I) and an anti-CD20 antibody) that is more effective than the expected additive effects of any two or more single therapies.
  • a synergistic effect of a combination of therapies permits the use of lower dosages of one or more of the therapies and/or less frequent administration of said therapies to a subject.
  • a synergistic effect can result in improved efficacy of therapies in the prevention, management, treatment, or amelioration of a given disease, such as a B cell malignancy.
  • synergistic effects of a combination of therapies may avoid or reduce adverse or unwanted side effects associated with the use of any single therapy.
  • the “synergy,”“synergism,” or“synergistic” effect of a combination may be determined herein by the methods of Chou et al., and/or Clarke et al. See Ting-Chao Chou, Theoretical Basis, Experimental Design, and Computerized Simulation of Synergism and Antagonism in Drug Combination Studies, Pharmacol Rev 58:621-681 (2006), and Clarke et al., Issues in experimental design and endpoint analysis in the study of experimental cytotoxic agents in vivo in breast cancer and other models, Breast Cancer Research and Treatment 46:255-278 (1997), which are both incorporated by reference for the methods of determining the“synergy,” synergism,” or“synergistic” effect of a combination.
  • an“isotopic variant” refers to a compound that contains an unnatural proportion of an isotope at one or more of the atoms that constitute such a compound.
  • an“isotopic variant” of a compound contains unnatural proportions of one or more isotopes, including, but not limited to, hydrogen ( 1 H)_ deuterium (3 ⁇ 4), tritium (3 ⁇ 4), carbon-l l ( n C), carbon-l2 ( 12 C), carbon-l3 ( 13 C), carbon-
  • an“isotopic variant” of a compound is in a stable form, that is, non radioactive.
  • an“isotopic variant” of a compound contains unnatural proportions of one or more isotopes, including, but not limited to, hydrogen ( 'ft) deuterium (3 ⁇ 4), carbon-l2 ( 12 C), carbon-l3 ( 13 C), nitrogen-l4 ( 14 N), nitrogen-l5 ( 15 N), oxygen-l6 ( 16 0), oxygen-l7 ( 17 0), oxygen-l8 ( 18 0), fluorine-l7 ( 17 F), phosphorus-31 ( 31 P), sulfur-32 ( 32 S), sulfur-33 ( 33 S), sulfur-34 ( 34 S), sulfur-36 ( 36 S), chlorine-35 ( 35 C1), chlorine-37 ( 37 C1), bromine-79 ( 79 Br), bromine-81 ( 81 Br), and iodine-l27 ( 127 I).
  • an“isotopic variant” of a compound is in an unstable form, that is, radioactive.
  • an“isotopic variant” of a compound contains unnatural proportions of one or more isotopes, including, but not limited to, tritium ( H), carbon-l 1 ( C), carbon-l4 ( C), nitrogen-l3 ( N), oxygen-l4 ( 14 0), oxygen-l5 ( 15 0), fluorine-l8 ( 18 F), phosphorus-32 ( 32 P), phosphorus-33 ( 33 P), sulfur-35 ( 35 S), chlorine-36 ( 36 C1), iodine-l23 ( 123 I), iodine-l25 ( 125 I), iodine-l29 ( 129 I), and iodine-l3 l ( 131 I).
  • any hydrogen can be 2 H, for example, or any carbon can be 13 C, for example, or any nitrogen can be 15 N, for example, or any oxygen can be 18 0, for example, where feasible according to the judgment of one of skill.
  • an“isotopic variant” of a compound contains unnatural proportions of deuterium (D).
  • alkyl refers to a linear or branched saturated monovalent hydrocarbon radical, wherein the alkylene may optionally be substituted with one or more substituents Q as described herein.
  • alkyl also encompasses both linear and branched alkyl, unless otherwise specified.
  • the alkyl is a linear saturated monovalent hydrocarbon radical that has 1 to 20 (Ci_ 2 o), 1 to
  • linear Ci_ 6 and branched C 3-6 alkyl groups are also referred as“lower alkyl.”
  • alkyl groups include, but are not limited to, methyl, ethyl, propyl (including all isomeric forms), «-propyl, isopropyl, butyl (including all isomeric forms), «-butyl, isobutyl, vt'c-butyl. /-butyl, pentyl (including all isomeric forms), and hexyl (including all isomeric forms).
  • Ci_ 6 alkyl refers to a linear saturated monovalent hydrocarbon radical of 1 to 6 carbon atoms or a branched saturated monovalent hydrocarbon radical of 3 to 6 carbon atoms.
  • alkylene refers to a linear or branched saturated divalent hydrocarbon radical, wherein the alkylene may optionally be substituted with one or more substituents Q as described herein.
  • alkylene encompasses both linear and branched alkylene, unless otherwise specified.
  • the alkylene is a linear saturated divalent hydrocarbon radical that has 1 to 20 (Ci -2 o), 1 to 15 (C 1-15 ), 1 to 10 (C 1-10 ), or 1 to 6 (C m, ⁇ ,) carbon atoms, or branched saturated divalent hydrocarbon radical of 3 to 20 (C 3-20 ), 3 to 15 (C 3-15 ), 3 to 10 (C 3-i0 ), or 3 to 6 (C 3-6 ) carbon atoms.
  • linear Ci_ 6 and branched C 3-6 alkylene groups are also referred as“lower alkylene.”
  • alkylene groups include, but are not limited to, methylene, ethylene, propylene (including all isomeric forms), «- propylene, isopropylene, butylene (including all isomeric forms), «-butylene, isobutylene, /-butylene, pentylene (including all isomeric forms), and hexylene (including all isomeric forms).
  • Ci_ 6 alkylene refers to a linear saturated divalent hydrocarbon radical of 1 to 6 carbon atoms or a branched saturated divalent hydrocarbon radical of 3 to 6 carbon atoms.
  • heteroalkylene refers to a linear or branched saturated divalent hydrocarbon radical that contains one or more heteroatoms each independently selected from O, S, and N in the hydrocarbon chain.
  • Ci_ 6 heteroalkylene refers to a linear saturated divalent hydrocarbon radical of 1 to 6 carbon atoms or a branched saturated divalent hydrocarbon radical of 3 to 6 carbon atoms.
  • the heteroalkylene is a linear saturated divalent hydrocarbon radical that has 1 to 20 (Ci -2 o), 1 to 15 (C 1-15), 1 to 10 (C 1-10 ), or 1 to 6 (C m, ⁇ ,) carbon atoms, or branched saturated divalent hydrocarbon radical of 3 to 20 (C 3-2 o), 3 to 15 (C 3-i5 ), 3 to 10 (C 3-i0 ), or 3 to 6 (C 3-6 ) carbon atoms.
  • linear Ci_ 6 and branched C 3-6 heteroalkylene groups are also referred as“lower heteroalkylene.”
  • heteroalkylene groups include, but are not limited to, -CH 2 0-, -CH 2 OCH 2- , -CH 2 CH 2 0-, -CH 2 NH-, -CH 2 NHCH 2- , -CH 2 CH 2 NH-, -CH 2 S-, -CH 2 SCH 2- , and -CH 2 CH 2 S-.
  • heteroalkylene may also be optionally substituted with one or more substituents Q as described herein.
  • alkenyl refers to a linear or branched monovalent hydrocarbon radical, which contains one or more, in one embodiment, one, two, three, four, or five, in another embodiment, one, carbon- carbon double bond(s).
  • the alkenyl may be optionally substituted with one or more substituents Q as described herein.
  • the term“alkenyl” also embraces radicals having cis and Ira ns configurations, or alternatively,“Z” and“E” configurations, as appreciated by those of ordinary skill in the art.
  • the term“alkenyl” encompasses both linear and branched alkenyl, unless otherwise specified.
  • C 2-6 alkenyl refers to a linear unsaturated monovalent hydrocarbon radical of 2 to 6 carbon atoms or a branched unsaturated monovalent hydrocarbon radical of 3 to 6 carbon atoms.
  • the alkenyl is a linear monovalent hydrocarbon radical of 2 to 20 (C 2-20 ), 2 to 15 (C 2 _i 5 ), 2 to 10 (C 2-i o), or 2 to 6 (C 2-6 ) carbon atoms, or a branched monovalent hydrocarbon radical of 3 to 20 (C 3-2 o), 3 to 15 (C 3-15 ), 3 to 10 (C 3-10 ), or 3 to 6 (C 3-6 ) carbon atoms.
  • alkenyl groups include, but are not limited to, ethenyl, propen-l-yl, propen-2 -yl, allyl, butenyl, and 4-methylbutenyl.
  • alkenylene refers to a linear or branched divalent hydrocarbon radical, which contains one or more, in one embodiment, one, two, three, four, or five, in another embodiment, one, carbon- carbon double bond(s).
  • the alkenylene may be optionally substituted with one or more substituents Q as described herein.
  • the term“alkenylene” also embraces radicals having“cA” and Ira ns configurations, or alternatively,“E” and“Z” configurations.
  • the term“alkenylene” encompasses both linear and branched alkenylene, unless otherwise specified.
  • C 2-6 alkenylene refers to a linear unsaturated divalent hydrocarbon radical of 2 to 6 carbon atoms or a branched unsaturated divalent hydrocarbon radical of 3 to 6 carbon atoms.
  • the alkenylene is a linear divalent hydrocarbon radical of 2 to 20 (C2-20), 2 to 15 (C2-15), 2 to 10 (C 2-i o), or 2 to 6 (C 2 -e) carbon atoms, or a branched divalent hydrocarbon radical of 3 to 20 (C 3-2 o), 3 to 15 (C 3 _i 5 ), 3 to 10 (C 3-i0 ), or 3 to 6 (C 3-6 ) carbon atoms.
  • alkenylene groups include, but are not limited to, ethenylene, allylene, propenylene, butenylene, and 4-methylbutenylene.
  • heteroalkenylene refers to a linear or branched divalent hydrocarbon radical, which contains one or more, in one embodiment, one, two, three, four, or five, in another embodiment, one, carbon-carbon double bond(s), and which contains one or more heteroatoms each independently selected from O, S, and N in the hydrocarbon chain.
  • the heteroalkenylene may be optionally substituted with one or more substituents Q as described herein.
  • the term“heteroalkenylene” embraces radicals having a“cA” or Ira ns configuration or a mixture thereof, or alternatively, a“Z” or“E” configuration or a mixture thereof, as appreciated by those of ordinary skill in the art.
  • C 2-6 heteroalkenylene refers to a linear unsaturated divalent hydrocarbon radical of 2 to 6 carbon atoms or a branched unsaturated divalent hydrocarbon radical of 3 to 6 carbon atoms.
  • the heteroalkenylene is a linear divalent hydrocarbon radical of 2 to 20 (C 2-2 o), 2 to 15 (C 2-15 ), 2 to 10 (C 2-i o), or 2 to 6 (C 2-6 ) carbon atoms, or a branched divalent hydrocarbon radical of 3 to 20 (C 3-2 o), 3 to 15 (C 3-i5 ), 3 to 10 (C 3-i0 ), or 3 to 6 (C 3-6 ) carbon atoms.
  • alkynyl refers to a linear or branched monovalent hydrocarbon radical, which contains one or more, in one embodiment, one, two, three, four, or five, in another embodiment, one, carbon- carbon triple bond(s).
  • the alkynyl may be optionally substituted with one or more substituents Q as described herein.
  • the term“alkynyl” also encompasses both linear and branched alkynyl, unless otherwise specified.
  • the alkynyl is a linear monovalent hydrocarbon radical of 2 to 20 (C2-20), 2 to 15 (C 2-15 ), 2 to 10 (C 2-i o), or 2 to 6 (C 2 -e) carbon atoms, or a branched monovalent hydrocarbon radical of 3 to 20 (C 3-2 o), 3 to 15 (C 3 _i 5 ), 3 to 10 (C 3-i0 ), or 3 to 6 (C 3-6 ) carbon atoms.
  • alkynyl groups include, but are not limited to, ethynyl (-CoCH) and propargyl (- CH 2 CoCH).
  • C 2-( , alkynyl refers to a linear unsaturated monovalent hydrocarbon radical of 2 to 6 carbon atoms or a branched unsaturated monovalent hydrocarbon radical of 3 to 6 carbon atoms.
  • cycloalkyl refers to a cyclic saturated bridged and/or non-bridged monovalent hydrocarbon radical, which may be optionally substituted with one or more substituents Q as described herein.
  • the cycloalkyl has from 3 to 20 (C 3-2 o), from 3 to 15 (C 3-i5 ), from 3 to 10 (C 3 _io), or from 3 to 7 (C 3-7 ) carbon atoms.
  • cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclo[2. l . l]hexyl, bicyclo[2.2. l]heptyl, decalinyl, and adamantyl.
  • cycloalkenyl refers to a cyclic unsaturated, nonaromatic bridged and/or non-bridged monovalent hydrocarbon radical, which may be optionally substituted with one or more substituents Q as described herein.
  • the cycloalkenyl has from 3 to 20 (C 3-2 o), from 3 to 15 (C 3 _i 5 ), from 3 to 10 (C 3 _i 0 ), or from 3 to 7 (C 3-7 ) carbon atoms.
  • Examples of cycloalkyl groups include, but are not limited to, cyclobutenyl, cyclopentenyl, cyclohexenyl, or cycloheptenyl,
  • aryl refers to a monocyclic aromatic group and/or multicyclic monovalent aromatic group that contain at least one aromatic hydrocarbon ring.
  • the aryl has from 6 to 20 (C 6-20 ), from 6 to 15 (C 6 _i 5 ), or from 6 to 10 (C 6 _i 0 ) ring atoms.
  • aryl groups include, but are not limited to, phenyl, naphthyl, fluorenyl, azulenyl, anthryl, phenanthryl, pyrenyl, biphenyl, and terphenyl.
  • Aryl also refers to bicyclic or tricyclic carbon rings, where one of the rings is aromatic and the others of which may be saturated, partially unsaturated, or aromatic, for example, dihydronaphthyl, indenyl, indanyl, or tetrahydronaphthyl (tetralinyl).
  • aryl may be optionally substituted with one or more substituents Q as described herein.
  • aralkyl or“arylalkyl” refers to a monovalent alkyl group substituted with one or more aryl groups.
  • the aralkyl has from 7 to 30 (C 7-30 ), from 7 to 20 (C 7-20 ), or from 7 to 16 (C 7 _i 6 ) carbon atoms.
  • Examples of aralkyl groups include, but are not limited to, benzyl, 2-phenylethyl, and 3-phenylpropyl.
  • the aralkyl are optionally substituted with one or more substituents Q as described herein.
  • heteroaryl refers to a monovalent monocyclic aromatic group or monovalent polycyclic aromatic group that contain at least one aromatic ring, wherein at least one aromatic ring contains one or more heteroatoms independently selected from O, S, N, and P in the ring.
  • a heteroaryl group is bonded to the rest of a molecule through its aromatic ring.
  • Each ring of a heteroaryl group can contain one or two O atoms, one or two S atoms, one to four N atoms, and/or one or two P atoms, provided that the total number of heteroatoms in each ring is four or less and each ring contains at least one carbon atom.
  • the heteroaryl has from 5 to 20, from 5 to 15, or from 5 to 10 ring atoms.
  • monocyclic heteroaryl groups include, but are not limited to, furanyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, thiadiazolyl, thiazolyl, thienyl, tetrazolyl, triazinyl, and triazolyl.
  • bicyclic heteroaryl groups include, but are not limited to, benzofuranyl, benzimidazolyl, benzoisoxazolyl, benzopyranyl, benzothiadiazolyl, benzothiazolyl, benzothienyl, benzotriazolyl, benzoxazolyl, furopyridyl, imidazopyridinyl, imidazothiazolyl, indolizinyl, indolyl, indazolyl, isobenzofuranyl, isobenzothienyl, isoindolyl, isoquinolinyl, isothiazolyl, naphthyridinyl, oxazolopyridinyl, phthalazinyl, pteridinyl, purinyl, pyridopyridyl, pyrrolopyridyl, quinolinyl, quinoxalinyl, quinazolinyl, thiadiazolopyrimi
  • tricyclic heteroaryl groups include, but are not limited to, acridinyl, benzindolyl, carbazolyl, dibenzofuranyl, perimidinyl, phenanthrolinyl, phenanthridinyl, phenarsazinyl, phenazinyl, phenothiazinyl, phenoxazinyl, and xanthenyl.
  • the heteroaryl may also be optionally substituted with one or more substituents Q as described herein as described herein.
  • heterocyclyl refers to a monovalent monocyclic non-aromatic ring system or monovalent polycyclic ring system that contains at least one non-aromatic ring, wherein one or more of the non-aromatic ring atoms are heteroatoms independently selected from O, S, N, and P; and the remaining ring atoms are carbon atoms.
  • the heterocyclyl or heterocyclic group has from 3 to 20, from 3 to 15, from 3 to 10, from 3 to 8, from 4 to 7, or from 5 to 6 ring atoms.
  • a heterocyclyl group is bonded to the rest of a molecule through its non-aromatic ring.
  • the heterocyclyl is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may be spiro, fused, or bridged, and in which nitrogen or sulfur atoms may be optionally oxidized, nitrogen atoms may be optionally quatemized, and some rings may be partially or fully saturated, or aromatic.
  • the heterocyclyl may be attached to the main structure at any heteroatom or carbon atom which results in the creation of a stable compound. Examples of such heterocyclic groups include, but are not limited to, azepinyl, benzodioxanyl, benzodioxolyl, benzofuranonyl, benzopyranonyl, benzopyranyl,
  • dihydropyrazinyl dihydropyridinyl, dihydropyrimidinyl, dihydropyrrolyl, dioxolanyl, l,4-dithianyl, furanonyl, imidazolidinyl, imidazolinyl, indolinyl, isobenzotetrahydrofuranyl, isobenzotetrahydrothienyl, isochromanyl, isocoumarinyl, isoindobnyl, isothiazobdinyl, isoxazolidinyl, morpholinyl,
  • octahydroindolyl octahydroisoindolyl, oxazolidinonyl, oxazobdinyl, oxiranyl, piperazinyl, piperidinyl, 4- piperidonyl, pyrazolidinyl, pyrazolinyl, pyrrolidinyl, pyrrolinyl, quinuclidinyl, tetrahydrofuryl, tetrahydroisoquinolinyl, tetrahydropyranyl, tetrahydrothienyl, thiamorpholinyl, thiazolidinyl,
  • heterocyclyl may also be optionally substituted with one or more substituents Q as described herein.
  • halogen refers to fluorine, chlorine, bromine, and/or iodine.
  • each substituent Q a is independently selected from the group consisting of (a) oxo, cyano, halo, and nitro; and (b) Ci_ 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3 _i 0 cycloalkyl, C 6 _i 4 aryl, C 7 _i 5 aralkyl, heteroaryl, and heterocyclyl; and (c) -C(0)R e , -C(0)0R e , -C(0)NR f R g , -C(NR e )NR f R g , -OR e , - R g , - f , R g , and R h is independently (i) hydrogen, Ci_ 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3 _i 0 cycloalkyl, C 6-i4 aryl, C 7 _
  • “optically active” and’’enantiomerically active” refer to a collection of molecules, which has an enantiomeric excess of no less than about 50%, no less than about 70%, no less than about 80%, no less than about 90%, no less than about 91%, no less than about 92%, no less than about 93%, no less than about 94%, no less than about 95%, no less than about 96%, no less than about 97%, no less than about 98%, no less than about 99%, no less than about 99.5%, or no less than about 99.8%.
  • the compound comprises about 95% or more of the desired enantiomer and about 5% or less of the less preferred enantiomer based on the total weight of the racemate in question.
  • the prefixes R and S are used to denote the absolute configuration of the molecule about its chiral center(s).
  • the (+) and (-) are used to denote the optical rotation of the compound, that is, the direction in which a plane of polarized light is rotated by the optically active compound.
  • the (-) prefix indicates that the compound is levorotatory, that is, the compound rotates the plane of polarized light to the left or counterclockwise.
  • the (+) prefix indicates that the compound is dextrorotatory, that is, the compound rotates the plane of polarized light to the right or clockwise.
  • the sign of optical rotation, (+) and (-) is not related to the absolute configuration of the molecule, R and S.
  • phrase“an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof’ has the same meaning as the phrase“an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant of the compound referenced therein; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug of the compound referenced therein; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug of an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant of the compound referenced therein.”
  • solvate refers to a complex or aggregate formed by one or more molecules of a solute, e.g., a compound provided herein, and one or more molecules of a solvent, which present in a stoichiometric or non-stoichiometric amount.
  • Suitable solvents include, but are not limited to, water, methanol, ethanol, «-propanol, isopropanol, and acetic acid.
  • the solvent is pharmaceutically acceptable.
  • the complex or aggregate is in a crystalline form.
  • the complex or aggregate is in a noncrystalline form.
  • the solvent is water
  • the solvate is a hydrate. Examples of hydrates include, but are not limited to, a hemihydrate, monohydrate, dihydrate, trihydrate, tetrahydrate, and pentahydrate.
  • refractory can refer to a cancer for which treatment (e.g., chemotherapy drugs, biological agents, and/or radiation therapy) has proven to be ineffective.
  • a refractory cancer tumor may shrink, but not to the point where the treatment is determined to be effective. Typically however, the tumor stays the same size as it was before treatment (stable disease), or it grows (progressive disease).
  • the terms“intermittent dosing schedule” or“IS” refer to drugs (e.g., the compound of Formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof) dosed or administered less than once daily.
  • drugs e.g., the compound of Formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof
  • IS refers to dosing or administration of a drug (e.g., the compound of Formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof), to a subject once daily for a period of about 7 days in a 28-day cycle.
  • a drug e.g., the compound of Formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof
  • IS refers to dosing or administration of a drug (e.g., the compound of Formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof) daily for up to three (e.g., two) 28-day cycles and, in the third cycle and subsequent cycles, dosing or administration of the drug to the subject once daily for a period of about 7 days in a 28-day cycle.
  • a drug e.g., the compound of Formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof
  • a drug e.g., the compound of Formula (I), or an enantiomer, a mixture of enantiomers
  • the terms“continuous dosing schedule” or“CS” refer to drugs (e.g., the compound of Formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof) dosed or administered once daily.
  • drugs e.g., the compound of Formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof
  • CS refers to dosing or administration of a drug (e.g., the compound of Formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof), to a subject daily in a 28-day cycle.
  • a drug e.g., the compound of Formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof
  • CS refers to dosing or administration of a drug (e.g., the compound of Formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof) daily for > three 28-day cycles and, in the one or more subsequent cycles, the drug is dosed or administered to the subject once daily for a period of about 7 days in a 28-day cycle (i.e., late switch to IS).
  • the subject on CS is never switched to IS.
  • CS is continued until intolerable toxicity occurs/is observed.
  • Responsiveness or to“respond” to treatment, and other forms of this term, as used herein, refer to the reaction of a subject to treatment with a therapeutic, e.g., a PI3K inhibitor, alone or in combination, e.g., monotherapy or combination therapy. Responsiveness to a therapy, e.g., treatment with a PI3K inhibitor alone or in combination, can be evaluated by comparing a subject's response to the therapy using one or more clinical criteria, such as IWCLL 2008 (for CLL) described in, e.g., Hallek, M. et al.
  • IWCLL 2008 for CLL
  • a subject having CLL can be determined to be in complete remission (CR) or partial remission (PR).
  • CR complete remission
  • PR partial remission
  • a subject is considered to be in CR if at least all of the following criteria as assessed after completion of therapy are met: (i) Peripheral blood lymphocytes (evaluated by blood and different count) below 4 x l0 9 /L (4000 pi); (ii) no hepatomegaly or splenomegaly by physical examination; (iii) absence of constitutional symptoms; and (iv) blood counts (e.g., neutrophils, platelets, hemoglobin) above the values set forth in Hallek, M. et al.
  • blood counts e.g., neutrophils, platelets, hemoglobin
  • Partial remission (PR) for CLL is defined according to IWCLL 2008 as including one of: (i) a decrease in number of blood lymphocytes by 50% or more from the value before therapy; (ii) a reduction in lymphadenopathy, as detected by CT scan or palpation; or (iii) a reduction in pretreatment enlargement of spleen or liver by 50% or more, as detected by CT scan or palpation; and blood counts (e.g., neutrophils, platelets, hemoglobin) according to the values set forth in Hallek, M. et al.
  • a subject having CLL is determined to have progressive disease (PD) or stable disease (SD).
  • a subject is considered to be in PD during therapy or after therapy if at least one of the following criteria is met: (i) progression on lymphadenopathy; (ii) an increase in pretreatment enlargement of spleen or liver by 50% or more, or de novo appearance of hepatomegaly or splenomegaly; (iii) an increase in the number of blood lymphocytes by 50% or more with at least 5000 B lymphocytes per microliter; (iv) transformation to a more aggressive histology (e.g., Richter syndrome); or (v) occurrence of cytopenia (neutropenia, anemia or thrombocytopenia) attributable to CLL.
  • Stable disease (SD) for CLL is defined according to IWCLL 2008 as a patient who has not achieved CR or a PR, and who has not exhibited progressive disease.
  • a subject with CLL responds to treatment with a PI3K inhibitor, alone or in combination, if at least one of the criteria for disease progression according to IWCLL is retarded or reduced, e.g., by about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or more
  • a subject responds to treatment with a PI3K inhibitor, alone or in combination, if the subject experiences a life expectancy extension, e.g., extended by about 5%, 10%, 20%, 30%, 40%, 50% or more beyond the life expectancy predicted if no treatment is administered.
  • a subject responds to treatment with a PI3K inhibitor, alone or in combination, if the subject has one or more of: an increased progression-free survival, overall survival or increased time to progression (TTP), e.g., as described in Hallek, M. et al.
  • PI3K inhibitors useful for treating relapsed cancer patients identified as early progressors.
  • the PI3K inhibitor is selective for PI3K delta.
  • X, Y, and Z are each independently N or CR X , with the proviso that at least two of X, Y, and Z are
  • R x is hydrogen or Ci_ 6 alkyl
  • R 1 and R 2 are each independently (a) hydrogen, cyano, halo, or nitro; (b) Ci_ 6 alkyl, C 24 , alkenyl, C 24 , alkynyl, C 3 _i 0 cycloalkyl, C 6 _i 4 aryl, C 7 _i 5 aralkyl, heteroaryl, or heterocyclyl; or (c) -C(0)R la , -
  • each R la , R lb , R lc , and R ld is independently (i) hydrogen; (ii) Ci_ 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3 _i 0 cycloalkyl, C 6 _i 4 aryl, C 7 _i 5 aralkyl, heteroaryl, or heterocyclyl; or (iii) R lb and R lc together with the N atom to which they are attached form heterocyclyl;
  • R 3 and R 4 are each independently hydrogen or Ci_ 6 alkyl; or R 3 and R 4 are linked together to form a bond, Ci_ 6 alkylene, Ci_ 6 heteroalkylene, C 2-6 alkenylene, or C 2-6 heteroalkenylene;
  • R 5a is (a) hydrogen or halo; (b) Ci_ 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3 _i 0 cycloalkyl, C 6-i4 aryl, C 7 _i 5 aralkyl, heteroaryl, or heterocyclyl; or (c) -C(0)R la , -C(0)OR la , -C(0)NR lb R lc , -C(NR la )NR lb R lc , -
  • R 5b is (a) halo; (b) Ci_ 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3 _i 0 cycloalkyl, C 6 _i 4 aryl, C 7 _i 5 aralkyl,
  • R 5C is -(CR 5f R 5g ) ceremoni-(C 6 _i4 aryl) or -(CR 5f R 5g ) ceremoni-heteroaryl;
  • R 5d and R 5e are each independently (a) hydrogen or halo; (b) Ci_ 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3 _i 0 cycloalkyl, C 6 _i 4 aryl, C 7 _i 5 aralkyl, heteroaryl, or heterocyclyl; or (c) -C(0)R la , -C(0)0R la , -
  • R 5f and R 5g are each independently (a) hydrogen or halo; (b) Ci_ 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3 _i 0 cycloalkyl, C 6 _i 4 aryl, C 7 _i 5 aralkyl, heteroaryl, or heterocyclyl; or (c) -C(0)R la , -C(0)0R la , -
  • R 6 is hydrogen, Ci_ 6 alkyl, -S-Ci_ 6 alkyl, -S(0)-Ci_ 6 alkyl, or -S0 2 -Ci_ 6 alkyl;
  • n 0 or 1 ;
  • n 0, 1, 2, 3, or 4;
  • each alkyl, alkylene, heteroalkylene, alkenyl, alkenylene, heteroalkenylene, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl, and heterocyclyl in R 1 , R 2 , R 3 , R 4 , R 6 , R x , R la , R lb , R lc , R ld , R 5a , R 5b , R 5c , R 5d , R 5e , R 5f , and R 5g is optionally substituted with one, two, three, four, or five substituents Q, wherein each substituent Q is independently selected from (a) oxo, cyano, halo, and nitro; (b) Ci_ 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3 _i 0 cycloalkyl, C 6 _i 4 aryl, C 7 _i 5
  • R c , and R d is independently (i) hydrogen; (ii) Ci_ 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3 _i 0 cycloalkyl, C 6 _ i4 aryl, C 7 _i 5 aralkyl, heteroaryl, or heterocyclyl, each of which is further optionally substituted with one, two, three, or four substituents Q a ; or (iii) R b and R c together with the N atom to which they are attached form heterocyclyl, which is further optionally substituted with one, two, three, or four substituents Q a ;
  • each Q a is independently selected from the group consisting of (a) oxo, cyano, halo, and nitro; (b) Ci_ 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3 _i 0 cycloalkyl, C 6 _i 4 aryl, C 7 _i 5 aralkyl, heteroaryl, and heterocyclyl; and (c) -C(0)R e , -C(0)0R e , -C(0)NR f R g , -C(NR e )NR f R g , -OR e , -0C(0)R e , -
  • each R e , R f , R g , and R h is independently (i) hydrogen; (ii) Ci_ 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3 _i 0 cycloalkyl, C 6 _i 4 aryl, C 7 _i 5 aralkyl, heteroaryl, or heterocyclyl; or (iii) R f and R g together with the N atom to which they are attached form heterocyclyl;
  • the compound of structural Formula (I) is not 4-(2-(difluoromethyl)- l//- benzo[r/]imidazol-l-yl)-6-morpholino-/V-(2 -phenyl -2-(pyrrolidin-l-yl)ethyl)-l, 3, 5-triazin-2 -amine or 6-(2- (difluoromcthyl)- 1 //-bcnzo
  • X, Y, and Z are each independently N or CR X with the proviso that at least two of X, Y, and Z are nitrogen atoms; where R x is hydrogen or Ci_ 6 alkyl.
  • R x is hydrogen or Ci_ 6 alkyl.
  • X, Y, and Z are N.
  • R 5b is (a) halo; (b) Ci_ 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3 _i 0 cycloalkyl, C 6 _i 4 aryl, C 7 _i 5 aralkyl, or heteroaryl; or (c)
  • R 5a and R 5b are each independently
  • Ci_ 6 alkyl C 2-6 alkenyl, C 2-6 alkynyl, C 3 _i 0 cycloalkyl, C 6 _i 4 aryl, C 7 _i 5 aralkyl, heteroaryl, or
  • R 5a and R 5b are each methyl, optionally substituted with one or more halo.
  • R 5f and R 5g are each hydrogen.
  • X, Y, and Z are each N;
  • R 1 and R 2 are each hydrogen
  • R 3 and R 4 are each hydrogen
  • R 5a is C 1-6 alkyl
  • R 5b is Ci_ 6 alkyl
  • R 5C is -(CH 2 )-phenyl, wherein R 5c is optionally substituted with one, two, three, or four substituents Q;
  • R 5d and R 5e are each hydrogen
  • R 6 is CHF 2 ;
  • n 0;
  • each alkyl is optionally substituted with one, two, three, or four substituents Q, wherein each substituent Q is independently selected from C 6 _i 4 aryl, heteroaryl, and heterocyclyl, each of which is further optionally substituted with one, two, three, or four substituents Q a , wherein the heteroaryl has from 5 to 10 ring atoms and one or more heteroatoms independently selected from O, S, and N, and the heterocyclyl has from 3 to 15 ring atoms and one or more heteroatoms independently selected from O, S, and N;
  • each Q a is independently selected from the group consisting of halo, Ci_ 6 alkyl, Ci_ 6 alkylsulfonyl and -OR e , wherein R e is hydrogen or Ci_ 6 alkyl.
  • X, Y, and Z are each N;
  • R 1 and R 2 are each hydrogen
  • R 3 and R 4 are each hydrogen
  • R 5a and R 5b are each methyl, optionally substituted with one or more halo;
  • R 5C is -(CH 2 )-phenyl, wherein R 5c is optionally substituted with one, two, three, or four substituents Q;
  • R 5d and R 5e are each hydrogen
  • R 6 is CHF 2 ;
  • n 0;
  • each alkyl is optionally substituted with one, two, three, or four substituents Q, wherein each substituent Q is independently selected from C 6 _i 4 aryl, heteroaryl, and heterocyclyl, each of which is further optionally substituted with one, two, three, or four substituents Q a , wherein the heteroaryl has from 5 to 10 ring atoms and one or more heteroatoms independently selected from O, S, and N, and the heterocyclyl has from 3 to 15 ring atoms and one or more heteroatoms independently selected from O, S, and N;
  • each Q a is independently selected from the group consisting of halo, Ci_ 6 alkyl, Ci_ 6 alkylsulfonyl and -OR e , wherein R e is hydrogen or Ci_ 6 alkyl.
  • R 5C is C 6 _i4 aryl, optionally substituted with one or more substituents Q.
  • R 5c is phenyl, optionally substituted with one or more substituents Q.
  • R 5c is naphthyl, optionally substituted with one or more substituents Q.
  • R 5c is -(CR 5f R 5g ) n -(C 6 -i 4 aryl), wherein the aryl is optionally substituted with one or more substituents Q.
  • R 5C is -(CH 2 )-phenyl, wherein the phenyl is optionally substituted with one or more substituents Q.
  • R 5c is -(CH 2 )-naphthyl, wherein the naphthyl is optionally substituted with one or more substituents Q.
  • R 5c is heteroaryl, optionally substituted with one or more substituents Q.
  • R 5c is monocyclic heteroaryl, optionally substituted with one or more substituents Q.
  • R 5c is 5- or 6-membered heteroaryl, optionally substituted with one or more substituents Q.
  • R 5c is bicyclic heteroaryl, optionally substituted with one or more substituents Q.
  • R 5c is -(CR 5f R 5g ) n -heteroaryl, wherein the heteroaryl is optionally substituted with one or more substituents Q.
  • R 5c is - (CR 5f R 5g ) n -(monocyclic heteroaryl), wherein the heteroaryl is optionally substituted with one or more substituents Q.
  • R 5c is -(CR 5f R 5g ) n -(5- or 6-membered heteroaryl), wherein the heteroaryl is optionally substituted with one or more substituents Q.
  • R 5c is -(CR 5f R 5g ) n -(bicyclic heteroaryl), wherein the heteroaryl is optionally substituted with one or more substituents Q.
  • R 7c , R 7d , and R 7e are each independently (a) hydrogen, cyano, halo, or nitro; (b) Ci_ 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3 _i 0 cycloalkyl, C 6 _i 4 aryl, C 7 _i 5 aralkyl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Q; or (c) -C(0)R la , -C(0)0R la , -
  • R 7a , R 7b , R 7c , R 7d , and R 7e that are adjacent to each other form C 3 _i 0 cycloalkenyl, C 6 _i 4 aryl, heteroaryl, or heterocyclyl, each optionally substituted with one or more substituents Q.
  • Formula (IX) or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, wherein:
  • R 7c , R 7d , and R 7e are each independently (a) hydrogen, cyano, halo, or nitro;
  • R 7a is hydrogen, halo, Ci_ 6 alkyl optionally substituted with one or more substituents Q, or -OR la .
  • R 7a is hydrogen. In some embodiments, R 7a is (a) cyano, halo, or nitro; (b) Ci_ 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3 _i 0 cycloalkyl, C 6 _i 4 aryl, C 7 _i 5 aralkyl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Q; or (c) -C(0)R la , -C(0)OR la , -
  • R a is (i) halo; (ii) Ci_ 6 alkyl, C 6-i4 aryl, C 7 _i 5 aralkyl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Q; or (iii) -OR la or -NR lb R lc .
  • R 7b is hydrogen, halo, Ci_ 6 alkyl optionally substituted with one or more substituents Q, or -OR la .
  • R 71 ’ is hydrogen.
  • R 7c is hydrogen, halo, Ci_ 6 alkyl optionally substituted with one or more substituents Q, or -OR la . In some embodiments, R 7c is hydrogen, halo, or -OR la . In some embodiments, R 7C is chloro. In some embodiments, R 7c is -0-Ci_ 6 alkyl, optionally substituted with one or more substituents Q.
  • R 7d is hydrogen, halo, Ci_ 6 alkyl optionally substituted with one or more substituents Q, or -OR la . In some embodiments, R 7d is hydrogen.
  • R 7e is hydrogen, halo, Ci_ 6 alkyl optionally substituted with one or more substituents Q, or -OR la .
  • R 7e is hydrogen.
  • two of R 7a , R 7b , R 7c , R 7d , and R 7e that are adjacent to each other form C 3 _i 0 cycloalkenyl, C 6 _i 4 aryl, heteroaryl, or heterocyclyl, each optionally substituted with one or more substituents Q.
  • R 7a and R 7b together with the carbon atoms to which they are attached form C 6 _i 4 aryl, optionally substituted with one or more substituents Q.
  • R 5a is hydrogen. In some embodiments, R 5a is Ci_ 6 alkyl, optionally substituted with one or more substituents Q. In some embodiments, R 5a is hydrogen, methyl, or ethyl.
  • R 5b is Ci_ 6 alkyl, optionally substituted with one or more substituents Q.
  • R 5b is methyl, ethyl, or propyl.
  • R 5b is -C(0)OR la .
  • R 5b is -C(0)0-Ci_ 6 alkyl.
  • R 5b is -C(0)OCH 3 .
  • R a , R 713 , R 7c , R d , and R 7e are each independently (a) hydrogen, cyano, halo, or nitro; (b) Ci_ 6 alkyl, C 2-f alkenyl, C 2-6 alkynyl, C 3 _i 0 cycloalkyl, C 6 _i 4 aryl, C 7 _i 5 aralkyl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one, two, three, or four substituents Q a ; or (c) -C(0)R a , - R b R c , -C(NR a )NR b R c , -OR a , -0C(0)R a , -0C(0)0R a , -0C(0)NR b R c , - -0S(0)R a , -0S(0) 2 R a , -0S(0)NR b
  • R 5a and R 5b are each independently (a) halo; (b) Ci_ 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3 _i 0 cycloalkyl, C 6 _i 4 aryl, C 7 _i 5 aralkyl, heteroaryl, or heterocyclyl; or (c) -C(0)R la , -
  • one of R 7a , R 7b , R 7c , R 7d , and R 7e is C 6 _i 4 aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one, two, three, or four substituents Q a ; in certain embodiments, one of R 7a , R 7b , R 7c , R 7d , and R 7e is C 6 _i 4 aryl, e.g., phenyl, optionally substituted with one, two, three, or four substituents Q a ; in certain embodiments, one of R 7a , R 7b , R 7c , R 7d , and R 7e is heteroaryl, e.g., 5-membered or 6-membered heteroaryl, optionally substituted with one, two, three, or four substituents Q a ; in certain embodiments, one of R 7a , R 7a , R 7a , R 7a , R 7c ,
  • R 7c , R 7d , and R 7e is heterocyclyl, e.g., 5- membered or 6-membered heterocyclyl, optionally substituted with one, two, three, or four substituents Q a ; in certain embodiments, one of R 7a , R 71 ’.
  • R 7c , R 7d , and R 7e is phenyl, imidazolyl, pyrozolyl, pyridinyl, piperidinyl, or piperazinyl, each optionally substituted with one, two, three, or four substituents Q a ; in certain embodiments, one of R 7a , R 7b , R 7c , R 7d , and R 7e is phenyl, imidazolyl, pyrozolyl, pyridinyl, pyrimidinyl, pyrrolidinyl, piperidinyl, or piperazinyl, each optionally substituted with one or more substituents Q a ; in certain embodiments, one of R 7a , R 71 ’.
  • R 7c , R 7d , and R 7e is phenyl, 2-fluorophenyl, 2- chlorophenyl, 2-bromophenyl, 2-methylphenyl, 2-methoxyphenyl, 3 -fluorophenyl, 3-chlorophenyl, 3- methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-methoxyphenyl, imidazol-l-yl, pyrozol-4-yl, 1 -methyl -pyrozol-4-yl, 2-methylpyrozol-3-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 2- methylpyridin-4-yl, 2-methoxypyridin-4-yl, l-methylpiperidin-4-yl, or 4-methylpiperazin-l-yl; and in certain embodiments, one of R 7a , R 7b , R 7c
  • R 7a is C 6 _i 4 aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one, two, three, or four substituents Q a ; in certain embodiments, R 7a is C 6 _i 4 aryl, e.g., phenyl, optionally substituted with one, two, three, or four substituents Q a ; in certain embodiments, R 7a is heteroaryl, e.g., 5-membered or 6-membered heteroaryl, optionally substituted with one, two, three, or four substituents Q a ; in certain embodiments, R 7a is heterocyclyl, e.g., 5-membered or 6-membered heterocyclyl, optionally substituted with one, two, three, or four substituents Q a ; in certain embodiments, R a is phenyl, imidazolyl, pyrozolyl, pyridinyl, piperidiny
  • R 1 is hydrogen or -OR la , where R la is Ci_ 6 alkyl, optionally substituted with one, two, three, four, or five substituents Q;
  • R 2 is hydrogen
  • R 3 and R 4 are hydrogen
  • R 6 is Ci- 6 alkyl, optionally substituted with one, two, three, four, or five substituents Q;
  • R 5a and R 5b are each independently Ci_ 6 alkyl, optionally substituted with one, two, three, four, or five substituents Q;
  • R 5f and R 5g are each independently hydrogen, halo, Ci_ 6 alkyl, optionally substituted with one, two, three, four, or five substituents Q; or R 5f and R 5g together with the carbon atom to which they are attached form Ci_i 0 cycloalkyl or heterocyclyl, each of which is optionally substituted with one, two, three, four, or five substituents Q;
  • R a is C 6 _i aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one, two, three, or four substituents Q a ;
  • R 715 , R 7c , R 7d , and R 7e are hydrogen
  • X, Y, and Z are each independently N or CR X , with the proviso that at least two of X, Y, and Z are N; where R x is a hydrogen or Ci_ 6 alkyl, optionally substituted with one, two, three, or four substituents
  • R 1 is hydrogen or methoxy
  • R 2 is hydrogen
  • R 3 and R 4 are hydrogen
  • R 6 is Ci- 6 alkyl, optionally substituted with one or more halo
  • R 5a and R 5b are each independently Ci_ 6 alkyl
  • R 5f and R 5g are each independently hydrogen or Ci_ 6 alkyl; or R 5f and R 5g together with the carbon atom to which they are attached form Cn 0 cycloalkyl;
  • R a is C 6 _i aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one, two, three, or four substituents Q a ;
  • R 715 , R 7c , R 7d , and R 7e are hydrogen
  • X, Y, and Z are each independently N or CH.
  • R 1 is hydrogen or methoxy
  • R 2 is hydrogen
  • R 3 and R 4 are hydrogen
  • R 6 is difluoromethyl
  • R 5a and R 5b are methyl
  • R 5f and R 5g are hydrogen; or R 5f and R 5g together with the carbon atom to which they are attached form cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl;
  • R a is C 6 _i4 aryl, monocyclic heteroaryl, or monocyclic heterocyclyl, each of which is optionally substituted with one, two, three, or four substituents Q a ;
  • R 715 , R 7c , R 7d , and R 7e are hydrogen
  • X, Y, and Z are each independently N or CH.
  • R 1 is hydrogen or methoxy
  • R 2 is hydrogen
  • R 3 and R 4 are hydrogen
  • R 6 is difluoromethyl
  • R 5a and R 5b are methyl
  • R 5f and R 5g are hydrogen; or R 5f and R 5g together with the carbon atom to which they are attached form cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl;
  • R a is phenyl, 5- or 6-membered heteroaryl, or 5- or 6-membered heterocyclyl, each of which is optionally substituted with one, two, three, or four substituents Q a ;
  • R 715 , R 7c , R 7d , and R 7e are hydrogen
  • X, Y, and Z are each independently N or CH.
  • R 1 is hydrogen or methoxy
  • R 2 is hydrogen
  • R 3 and R 4 are hydrogen
  • R 6 is difluoromethyl
  • R 5a and R 5b are methyl
  • R 5f and R 5g are hydrogen; or R 5f and R 5g together with the carbon atom to which they are attached form cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl;
  • R a is phenyl, imidazolyl, pyrozolyl, pyridinyl, pyrimidinyl, pyrrolidinyl, piperidinyl, or piperazinyl, each of which is optionally substituted with one, two, three, or four substituents Q a ;
  • R 715 , R 7c , R 7d , and R 7e are hydrogen
  • X, Y, and Z are each independently N or CH.
  • R 7a is phenyl, imidazolyl, pyrozolyl, pyridinyl, piperidinyl, or piperazinyl, each of which is optionally substituted with one, two, three, or four substituents Q a .
  • R 7a is phenyl, imidazolyl, pyrozolyl, pyridinyl, piperidinyl, or piperazinyl, each of which is optionally substituted with one, two, three, or four substituents Q a .
  • R 5a is Ci_ 6 alkyl, optionally substituted with one or more substituents Q. In some embodiments, R 5a is methyl.
  • R 5b is Ci_ 6 alkyl, optionally substituted with one or more substituents Q. In some embodiments, R 5b is methyl.
  • R 5a and R 5b are methyl.
  • R 7a is hydrogen, halo, Ci_ 6 alkyl, C 6 _i 4 aryl, heteroaryl, or heterocyclyl, where the alkyl, aryl, heteroaryl, and heterocyclyl are each optionally substituted with one or more substituents Q.
  • R 7a is C 6 _i 4 aryl, optionally substituted with one or more substituents Q.
  • R 7a is phenyl, optionally substituted with one or more substituents Q
  • R 7a is phenyl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 2-methylphenyl, 2-(3-dimethylaminopropyl)phenyl, 2-methoxyphenyl, 3 -fluorophenyl, 3-chlorophenyl, 3-methylphenyl, 3- methoxyphenyl, 4-f orophenyl, 4-chlorophenyl, 4-bromophenyl, 4-methoxyphenyl, 2,4-difluorophenyl, 2,6-dif uorophenyl, 4-fluoro-3-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, or 3-morpholin-4- ylmethylphenyl.
  • R 7a is heteroaryl, optionally substituted with one or more substituents Q. In some embodiments, R 7a is monocyclic heteroaryl, optionally substituted with one or more substituents Q. In some embodiments, R 7a is 5- or 6-membered heteroaryl, each optionally substituted with one or more substituents Q. In some embodiments, R 7a is imidazolyl, pyrozolyl, pyridinyl, or pyrimidinyl, each optionally substituted with one or more substituents Q.
  • R 7a is imidazol-l-yl, pyrozol-4-yl, 1 -methyl -pyrozol-4-yl, 2-methylpyrozol-3-yl, pyridin-2- yl, pyridin-3-yl, pyridin-4-yl, 2-fluoropyridin-3-yl, 2-methylpyridin-4-yl, 2-(4-methylpiperazin-l- yl)pyridin-4-yl, 2-methoxypyridin-4-yl, pyrimidin-5-yl.
  • R 7a is heterocyclyl, optionally substituted with one or more substituents Q.
  • R 7a is monocyclic heterocyclyl, optionally substituted with one or more substituents Q. In some embodiments, R 7a is 5- or 6- membered heterocyclyl, each optionally substituted with one or more substituents Q. In some
  • R 7a is pyrrolidinyl, piperidinyl, or piperazinyl, each optionally substituted with one or more substituents Q.
  • R 7a is pyrrolidin-3-yl, l-methylpyrrolidin-3-yl, piperidin-4-yl, 1- methylpiperidin-4-yl, l-ethylpiperidin-4-yl, l-isopropylpiperidin-4-yl, 1 -acetylpiperidin-4-yl, 1- methylsulfonylpiperidin-4-yl, or
  • R 7b is hydrogen, halo, or Ci_ 6 alkyl optionally substituted with one or more substituents Q. In some embodiments, R 7b is hydrogen.
  • R 7c is hydrogen, halo, or Ci_ 6 alkyl optionally substituted with one or more substituents Q. In some embodiments, R 7c is hydrogen.
  • R 7d is hydrogen, halo, or Ci_ 6 alkyl optionally substituted with one or more substituents Q. In some embodiments, R 7d is hydrogen.
  • R 7e is hydrogen, halo, or Ci_ 6 alkyl optionally substituted with one or more substituents Q. In some embodiments, R 7e is hydrogen.
  • R 7a is C 6 _i 4 aryl, heteroaryl, or heterocyclyl, each optionally substituted with one or more substituents Q; and R 7b , R 7c , R 7d , and R 7e are hydrogen.
  • one of R 7a , R b . R 7c , R 7d , and R 7e is C 6 _i 4 aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one, two, three, or four substituents Q a ; and R 1 , R 2 , R 3 , R 4 , R 6 , R 5a , R 5b , the remaining of R 7a , R 7b , R 7c , R 7d , and R 7e , X, Y, and Z are each as defined herein.
  • one of R 7a , R 7b , R 7c , R 7d , and R 7e is C 6 _i 4 aryl, which is optionally substituted with one, two, three, or four substituents Q a ; and R 1 , R 2 , R 3 , R 4 , R 6 ,
  • R 5b the remaining of R 7a , R 7b , R 7c , R 7d , and R 7e , X, Y, and Z are each as defined herein.
  • one of R 7a , R 715 , R 7c , R 7d , and R 7e is heteroaryl, which is optionally substituted with one, two, three, or four substituents Q a ; and R 1 , R 2 , R 3 , R 4 , R 6 , R 5a , R 5b , the remaining of R 7a , R 7b , R 7c , R 7d , and R 7e , X, Y, and Z are each as defined herein.
  • one of R 7a , R 715 , R 7c , R 7d , and R 7e is heterocyclyl, which is optionally substituted with one, two, three, or four substituents Q a ; and R 1 , R 2 , R 3 , R 4 , R 6 , R 5a , R 5b , the remaining of R 7a , R 7b , R 7c , R 7d , and R 7e , X, Y, and Z are each as defined herein.
  • one of R 7a , R 715 , R 7c , R 7d , and R 7e is
  • one of R 7a , R 715 , R 7c , R 7d , and R 7e is phenyl, imidazolyl, pyrozolyl, pyridinyl, pyrimidinyl, pyrrolidinyl, piperidinyl, or piperazinyl, each optionally substituted with one, two, three, or four substituents Q a ; and R 1 , R 2 , R 3 , R 4 , R 6 , R 5a , R 5b , the remaining of R 7a , R 7b , R 7c , R 7d , and R 7e , X, Y, and Z are each as defined herein.
  • one of R 7a , R 715 , R 7c , R 7d , and R 7e is phenyl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 2-methylphenyl, 2-(3- dimethylaminopropyl)phenyl, 2-methoxyphenyl, 3 -fluorophenyl, 3-chlorophenyl, 3-methylphenyl, 3- methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-methoxyphenyl, 2,4-difluorophenyl, 2,6-difluorophenyl, 4-fluoro-3-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3-morpholin-4- ylmethylphenyl, imidazol-l-yl, pyrozol-4-yl, 1
  • R 7c , R 7d , and R 7e is phenyl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 2-methylphenyl, 2-methoxyphenyl, 3- fluorophenyl, 3-chlorophenyl, 3-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4- methoxyphenyl, imidazol-l-yl, pyrozol-4-yl, 1 -methyl -pyrozol-4-yl, 2-methylpyrozol-3-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 2-methylpyridin-4-yl, 2-methoxypyridin-4-yl, l-methylpiperidin-4-yl, or 4- methylpipe
  • R 7a is C 6 _i 4 aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one, two, three, or four substituents Q a ; and R 1 , R 2 , R 3 , R 4 , R 6 , R a .
  • R 5b , R 7b , R 7c , R 7d , R 7e , X, Y, and Z are each as defined herein.
  • R 7a is heterocyclyl, which is optionally substituted with one, two, three, or four substituents Q a ; and R 1 , R 2 , R 3 , R 4 , R 6 , R 5a , R 5b , R 7b ,
  • R 7c , R 7d , R 7e , X, Y, and Z are each as defined herein.
  • R 7a is 5-membered or 6-membered heterocyclyl, which is optionally substituted with one, two, three, or four substituents Q a ; and R 1 , R 2 , R 3 , R 4 , R 6 , R 5a , R 5b , R b , R 7c , R d , R 7e , X, Y, and Z are each as defined herein.
  • R 7a is phenyl, imidazolyl, pyrozolyl, pyridinyl, pyrimidinyl, pyrrolidinyl, piperidinyl, or piperazinyl, each optionally substituted with one, two, three, or four substituents Q a ; and R 1 , R 2 , R 3 , R 4 , R 6 , R 5a , R 5b , R 7b , R 7c , R 7d , R 7e , X, Y, and Z are each as defined herein.
  • R 7a is phenyl, 2-fluorophenyl, 2- chlorophenyl, 2-bromophenyl, 2-methylphenyl, 2-(3-dimethylaminopropyl)phenyl, 2-methoxyphenyl, 3- fluorophenyl, 3-chlorophenyl, 3-methylphenyl, 3-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 4- bromophenyl, 4-methoxyphenyl, 2,4-difluorophenyl, 2,6-difluorophenyl, 4-fluoro-3-methoxyphenyl, 3- methoxyphenyl, 4-methoxyphenyl, 3-morpholin-4-ylmethylphenyl, imidazol-l-yl, pyrozol-4-yl, 1 -methyl - pyrozol-4-yl, 2-methylpyrozol-3-yl, pyr
  • R 7a is phenyl, 2-fluorophenyl, 2- chlorophenyl, 2-bromophenyl, 2-methylphenyl, 2-methoxyphenyl, 3 -fluorophenyl, 3-chlorophenyl, 3- methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-methoxyphenyl, imidazol-l-yl, pyrozol-4-yl, 1 -methyl -pyrozol-4-yl, 2-methylpyrozol-3-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 2- methylpyridin-4-yl, 2-methoxypyridin-4-yl, l-methylpiperidin-4-yl, or 4-methylpiperazin-l-yl; and R 1 ,
  • R 2 , R 3 , R 4 , R 6 , R 5a , R 5b , R b , R 7c , R 7d , R 7e , X, Y, and Z are each as defined herein.
  • R 1 is hydrogen or -OR la , where R la is Ci_ 6 alkyl, optionally substituted with one, two, three, four, or five substituents Q;
  • R 2 is hydrogen
  • R 3 and R 4 are hydrogen
  • R 6 is Ci_ 6 alkyl, optionally substituted with one, two, three, four, or five substituents Q;
  • R 5a and R 5b are each independently Ci_ 6 alkyl, optionally substituted with one, two, three, four, or five substituents Q;
  • R a is C 6 _i aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Q a ;
  • R 715 , R 7c , R 7d , and R 7e are hydrogen.
  • R 1 is hydrogen or methoxy
  • R 2 is hydrogen
  • R 3 and R 4 are hydrogen
  • R 6 is Ci- 6 alkyl, optionally substituted with one or more halo
  • R 5a and R 5b are each independently Ci_ 6 alkyl
  • R a is C 6 _i aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one, two, three, or four substituents Q a ;
  • R 715 , R 7c , R 7d , and R 7e are hydrogen.
  • R 1 is hydrogen or methoxy
  • R 2 is hydrogen
  • R 3 and R 4 are hydrogen
  • R 6 is difluoromethyl
  • R 5a and R 5b are methyl
  • R a is phenyl, imidazolyl, pyrozolyl, pyridinyl, pyrimidinyl, pyrrolidinyl, piperidinyl, or piperazinyl, each of which is optionally substituted with one, two, three, four, or five substituents Q; and R 715 , R 7c , R 7d , and R 7e are hydrogen.
  • R 5a and R 5b are each independently (a) halo; (b) Ci_ 6 alkyl, C 2-6 alkenyl, C 2-f alkynyl, C 3 _i 0 cycloalkyl, C 6 _i 4 aryl, C 7 _i 5 aralkyl, heteroaryl, or
  • R 1 is hydrogen or -OR la , where R la is Ci_ 6 alkyl, optionally substituted with one, two, three, four, or five substituents Q;
  • R 2 is hydrogen
  • R 3 and R 4 are hydrogen
  • R 6 is Ci_ 6 alkyl, optionally substituted with one, two, three, four, or five substituents Q;
  • R 5a and R 5b are each independently hydrogen or Ci_ 6 alkyl optionally substituted with one, two, three, four, or five substituents Q;
  • R a is C 6 _i aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one, two, three, or four substituents Q a ;
  • R 715 , R 7c , R 7d , and R 7e are hydrogen
  • X, Y, and Z are each independently N or CR X , with the proviso that at least two of X, Y, and Z are N; where R x is a hydrogen or Ci_ 6 alkyl, optionally substituted with one, two, three, or four substituents
  • R 1 is hydrogen or methoxy
  • R 2 is hydrogen
  • R 3 and R 4 are hydrogen
  • R 6 is Ci_ 6 alkyl, optionally substituted with one or more halo
  • R 5a and R 5b are each independently hydrogen or Ci_ 6 alkyl
  • R a is C 6 _i aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one, two, three, or four substituents Q a ;
  • R 715 , R 7c , R 7d , and R 7e are hydrogen
  • X, Y, and Z are each independently N or CH.
  • R 1 is hydrogen or methoxy
  • R 2 is hydrogen
  • R 3 and R 4 are hydrogen
  • R 6 is difluoromethyl
  • R 5a and R 5b are each independently hydrogen or Ci_ 6 alkyl
  • R a is C 6 _i aryl, monocyclic heteroaryl, or monocyclic heterocyclyl, each of which is optionally substituted with one, two, three, or four substituents Q a ;
  • R 715 , R 7c , R 7d , and R 7e are hydrogen
  • X, Y, and Z are each independently N or CH.
  • R 1 is hydrogen or methoxy
  • R 2 is hydrogen
  • R 3 and R 4 are hydrogen
  • R 6 is difluoromethyl
  • R 5a and R 5b are each independently hydrogen or Ci_ 6 alkyl
  • R a is phenyl, 5- or 6-membered heteroaryl, or 5- or 6-membered heterocyclyl, each of which is optionally substituted with one, two, three, or four substituents Q a ;
  • R 715 , R 7c , R 7d , and R 7e are hydrogen
  • X, Y, and Z are each independently N or CH.
  • R 1 is hydrogen or methoxy
  • R 2 is hydrogen
  • R 3 and R 4 are hydrogen
  • R 6 is difluoromethyl
  • R 5a and R 5b are each independently hydrogen or Ci_ 6 alkyl
  • R a is phenyl, imidazolyl, pyrozolyl, pyridinyl, pyrimidinyl, pyrrolidinyl, piperidinyl, or piperazinyl, each of which is optionally substituted with one, two, three, or four substituents Q a ;
  • R 715 , R 7c , R 7d , and R 7e are hydrogen
  • X, Y, and Z are each independently N or CH.
  • R 1 is hydrogen or methoxy
  • R 2 is hydrogen
  • R 3 and R 4 are hydrogen
  • R 6 is difluoromethyl
  • R 5a and R 5b are each independently hydrogen or Ci_ 6 alkyl
  • R a is phenyl, imidazolyl, pyrozolyl, pyridinyl, piperidinyl, or piperazinyl, each of which is optionally substituted with one, two, three, or four substituents Q a ;
  • R 715 , R 7c , R 7d , and R 7e are hydrogen
  • X, Y, and Z are each independently N or CH.
  • R 1 is hydrogen. In one embodiment of any of the formulae provided herein, R 1 is -OR la . In one embodiment of any of the formulae provided herein, R 1 is -0-Ci_ 6 alkyl. In one embodiment of any of the formulae provided herein, R 1 is methoxy.
  • R 2 is hydrogen. In one embodiment of any of the formulae provided herein, R 2 is -NR lb R lc . In one embodiment of any of the formulae provided herein, R 2 is amino.
  • R 3 is hydrogen
  • R 4 is hydrogen
  • R 6 is Ci_ 6 alkyl, optionally substituted with one or more substituents Q. [0172] In one embodiment of any of the formulae provided herein, R 6 is methyl, fluoromethyl, difluoromethyl, or trifluoromethyl. In one embodiment of any of the formulae provided herein, R 6 is difluoromethyl.
  • n is 0. In certain embodiments, m is 1.
  • n is 0. In certain embodiments, n is 1. In certain embodiments, n is 2. In certain embodiments, n is 3. In certain embodiments, n is 4. In certain embodiments, n is 0, 1, or 2. In certain embodiments, n is 0, 1, 2, or 3. In certain embodiments, n is 1, 2, or 3. In certain embodiments, n is 1 or 2.
  • m is 0, and n is 0, 1, 2, or 3. In certain embodiments, m is 0, n is 0, 1, or 2. In certain embodiments, m is 0, n is 0 or 1. In certain embodiments, m is 0, n is 0. In certain embodiments, m is 0 and n is 1. In certain embodiments, m is 1, n is 0, 1, 2, or 3. In certain embodiments, m is 1, n is 0, 1, or 2. In certain embodiments, m is 1, n is 0 or 1. In certain embodiments, m is 1, n is 0. In certain embodiments, m is 1, n is 1.
  • n is 1
  • R 5a and R 5b are each methyl.
  • X is N. In certain embodiments, X is CR X , wherein R x is as defined herein. In certain embodiments, X is CH.
  • Y is N. In certain embodiments, Y is CR X , wherein R x is as defined herein. In certain embodiments, Y is CH.
  • Z is N. In certain embodiments, Z is CR X , wherein R x is as defined herein. In certain embodiments, Z is CH.
  • X, Y, and Z are N. In certain embodiments, X and Y are N, and Z is CH. In certain embodiments, X and Z are N, and Y is CH. In certain embodiments, Y and Z are N, and X is CH.
  • the compound provided herein is not 4-(2-(difluoromethyl)- l//- benzo[ ⁇ 2]imidazol-l-yl)-6-morpholino-/V-(2 -phenyl -2-(pyrrolidin-l-yl)ethyl)-l, 3, 5-triazin-2 -amine.
  • the compound provided herein is not 6-(2-(difluoromethyl)- l//-benzo
  • R 5b when X, Y, and Z are N, and R 5a is hydrogen, R 5b is not heterocyclyl. In certain embodiments, when X, Y, and Z are N, and R 5a is hydrogen, R 5b is not 5-membered heterocyclyl. In certain embodiments, when X, Y, and Z are N, and R 5a is hydrogen, R 5b is not pyrrolidinyl. In certain embodiments, when X, Y, and Z are N, and R 5a is hydrogen, R 5b is not pyrrolidin-l-yl.
  • R 5a is hydrogen
  • R 5b is morpholino- substituted phenyl.
  • R 5a is hydrogen
  • R 5b is not 4-((R)-3 -(methoxymethyl)morpholino)phenyl .
  • the PI3K inhibitor is Compound A35, or an isotopic variant
  • the PI3K inhibitor is Compound A36, or an isotopic variant, pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
  • the PI3K inhibitor is Compound A68, or an isotopic variant, pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
  • the PI3K inhibitor is Compound A70, or an isotopic variant, pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
  • the PI3K inhibitor is Compound A37, or an isotopic variant, pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
  • the PI3K inhibitor is Compound A38, or an isotopic variant, pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
  • the PI3K inhibitor is Compound A41, or an isotopic variant, pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
  • the PI3K inhibitor is Compound A42, or an isotopic variant, pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
  • the PI3K inhibitor is Compound A43, or an isotopic variant, pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
  • the PI3K inhibitor is Compound A44, or an isotopic variant, pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. In one embodiment, the PI3K inhibitor is Compound A62, or an isotopic variant, pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. In one embodiment, the PI3K inhibitor is Compound A63, or an isotopic variant, pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. In one embodiment, the PI3K inhibitor is Compound A64, or an isotopic variant, pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
  • the PI3K inhibitor is Compound A65, or an isotopic variant, pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. In one embodiment, the PI3K inhibitor is Compound A66, or an isotopic variant, pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. In one embodiment, the PI3K inhibitor is Compound A67, or an isotopic variant, pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
  • PI3K inhibitors in combination with CD20 inhibitors useful for treating relapsed cancer patients identified as early progressors.
  • B lymphocytes are the origin of humoral immunity, represent a substantial portion of
  • CD20 a B cell-specific member of the MS4A gene family, is expressed on the surface of immature and mature B cells and their malignant counterparts.
  • mouse CD20 is also B cell-specific. Both human and mouse CD20 cDNAs encode a membrane-embedded protein with hydrophobic regions of sufficient length to pass through the membrane four times.
  • Mouse and human CD20 are well conserved (73%) in amino acid sequence, particularly the transmembrane and long amino- and carboxyl -terminal cytoplasmic domains. The cytoplasmic domains are serine- and threonine -rich with multiple consensus sequences for phosphorylation.
  • Human CD20 is not glycosylated, but three isoforms (33-, 35- and 37,000 Mr) result from the differential phosphorylation of a single protein on different serine and threonine residues.
  • CD20 plays a role in the regulation of human B cell activation, proliferation, and Ca 2+ transport.
  • Antibody ligation of CD20 can generate transmembrane signals that result in enhanced CD20 phosphorylation, induction of c-myc and B-myb oncogene expression, induced serine/threonine and tyrosine phosphorylation of cellular proteins, increased CD 18, CD58 and MHC class II molecule expression, and protein tyrosine kinase activation that induces B cell adhesion.
  • CD20 ligation promotes transmembrane Ca 2+ transport, but does not usually lead to increased intracellular calcium ([Ca 2+ ]i) 3 levels, except after extensive crosslinking.
  • CD20 Antibody binding to CD20 inhibits B cell progression from the Gl phase into the S/G2+M stages of cell cycle following mitogen stimulation, and inhibits mitogen- induced B cell differentiation and antibody secretion. Extensive CD20 cross-linking can also influence apoptosis. These divergent observations may be explained in part by the finding that CD20 is a component of an oligomeric complex that forms a membrane transporter or Ca 2+ ion channel that is activated during cell cycle progression. Despite this, B cell development and function in a line of CD20- deficient (CD20-/-) mice is reported to be normal.
  • any suitable CD20 inhibitor may be used in combination with a PI3K inhibitor described herein.
  • the CD20 inhibitor is an antagonist of CD20.
  • the CD20 inhibitor is an antibody, variant, or biosimilar thereof.
  • the CD20 inhibitor is a monoclonal antibody.
  • CD20 inhibitors for use in pharmaceutical compositions and methods provided herein include but are not limited to ofatumumab, obinutuzumab, rituximab, ocaratuzumab, ocrelizumab, tositumomab, ibritumomab tiuxetan, tisotumab vedotin, ublituximab, TRU-015, veltuzumab, BTCT4465A (RG7828), EDC9, MT-3724, BLX-301, 1 F5, ATCC deposit HB-96450, BM-ca, C2H7, PR0131921, BVX-20, MEDI-522, or a variant or biosimilar thereof, or combinations thereof.
  • the CD20 inhibitor for use in pharmaceutical compositions and methods provided herein is ofatumumab, obinutuzumab, rituximab, ocaratuzumab, ocrelizumab, tositumomab, ibritumomab tiuxetan, tisotumab vedotin, ublituximab, TRU-015, veltuzumab, BTCT4465A (RG7828), EDC9, MT-3724, or a variant or biosimilar thereof, or combinations thereof.
  • the CD20 inhibitor for use in pharmaceutical compositions and methods provided herein is ofatumumab, obinutuzumab, rituximab, ocaratuzumab, ocrelizumab, tositumomab, ibritumomab tiuxetan, tisotumab vedotin, ublituximab, veltuzumab, or a variant or biosimilar thereof, or combinations thereof.
  • the CD20 inhibitor for use in pharmaceutical compositions and methods provided herein is obinutuzumab or rituximab, or a variant or biosimilar thereof, or combinations thereof.
  • the CD20 inhibitor is ofatumumab, an ofatumumab variant, or an ofatumumab biosimilar. In some embodiments, the CD20 inhibitor is obinutuzumab, an obinutuzumab variant, or an obinutuzumab biosimilar. In some embodiments, the CD20 inhibitor is rituximab, a rituximab variant, or a rituximab biosimilar.
  • the rituximab biosimilar is CT-P10, Reditux ® , ABP 798, AcellBia, BI 695500, Maball, JHL1101, Novex, MabionCD20, PF-05280586, Kikuzubam, SAIT101, GP 2013, HLX01, CMAB304, BT-D004, AP-052 or TL-011.
  • the CD20 inhibitor is ocaratuzumab, an ocaratuzumab variant, or an ocaratuzumab biosimilar.
  • the CD20 inhibitor is ocrelizumab, an ocrelizumab variant, or an ocrelizumab biosimilar.
  • the CD20 inhibitor is tositumomab, a tositumomab variant, or a tositumomab biosimilar. In some embodiments, the CD20 inhibitor is ibritumomab tiuxetan, an ibritumomab tiuxetan variant, or an ibritumomab tiuxetan biosimilar. In some embodiments, the CD20 inhibitor is tisotumab vedotin, a tisotumab vedotin variant, or a tisotumab vedotin biosimilar.
  • the CD20 inhibitor is ublituximab, an ublituximab variant, or an ublituximab biosimilar. In some embodiments, the CD20 inhibitor is TRU-015, a TRU-015 variant, or a TRU-015 biosimilar. In some embodiments, the CD20 inhibitor is veltuzumab, a veltuzumab variant, or a veltuzumab biosimilar. In some embodiments, the CD20 inhibitor is BTCT4465A (RG7828), a BTCT4465A (RG7828) variant, or a BTCT4465A (RG7828) biosimilar.
  • the CD20 inhibitor is EDC9, an EDC9 variant, or an EDC9 biosimilar. In some embodiments, the CD20 inhibitor is MT-3724, a MT-3724 variant, or a MT-3724 biosimilar.
  • a method for treating a patient with follicular lymphoma (FL) having early disease progression after immuochemotherapy treatment comprising administering to the patient an effective amount of a PI3K inhibitor of Formula (I).
  • a method of preventing relapse in a patient with follicular lymphoma having early disease progression after immunochemotherapy treatment comprising administering to the patient an effective amount of a PI3K inhibitor of Formula (I).
  • a method for achieving and retaining partial cancer remission a patient with follicular lymphoma having early disease progression after immuochemotherapy treatment comprising administering to the patient an effective amount of a PI3K inhibitor of Formula (I).
  • a method for achieving and retaining complete cancer remission in a patient with follicular lymphoma having early disease progression after immuochemotherapy treatment comprising administering to the patient an effective amount of a PI3K inhibitor of Formula (I).
  • the methods described above further comprise administering to the patient an effective amount of a CD20 inhibitor.
  • the patient has progression of disease within 24 months of treatment of FL. In some embodiments of the methods described above, the patient has progression of disease after initiation of treatment of FL with immunochemotherapy. In some embodiments of the methods described above, the patient has progression of disease within 24 months after initiation of treatment of FL with
  • the immunochemotherapy treatment is first-line. In some embodiments of the methods described above, the immunochemotherapy treatment is subsequent to first-line treatment.
  • the methods described herein avoid and/or reduce adverse or unwanted side effects associated with the use of the PI3K inhibitor or immunochemotherapy. In some embodiments, the methods described herein avoid, reduce, or minimize the risk of death due to infections associated with PI3K inhibitor treatment or immunochemotherapy. In some embodiments, the methods described herein avoid, reduce, or minimize infections, neutropenia, diarrhea/colitis, elevated liver transaminases (alanine aminotransferase/aspartate aminotransferase > 5x upper limit of normal), pneumonitis, rash, hepatic impairment, renal impairment, pyrexia, or increased triglycerides, or a combination thereof in patients receiving the treatment described herein.
  • the methods described herein avoid, reduce, or minimize the incidence of infection. In certain embodiments, the methods described herein avoid, reduce, or minimize the incidence of neutropenia. In certain embodiments, the methods described herein avoid, reduce, or minimize the incidence of diarrhea/colitis.
  • the methods described herein avoid, reduce, or minimize the incidence of elevated liver transaminases. In certain embodiments, the methods described herein avoid, reduce, or minimize the incidence of pneumonitis. In certain embodiments, the methods described herein avoid, reduce, or minimize the incidence of a rash. In certain embodiments, the methods described herein avoid, reduce, or minimize the incidence of hepatic impairment or renal impairment. In certain embodiments, the methods described herein avoid, reduce, or minimize the incidence of pyrexia. In certain
  • the methods described herein avoid, reduce, or minimize the incidence of increased triglycerides. In certain embodiments, the methods described herein avoid, reduce, or minimize enterocolitis (manifested as diarrhea), cutaneous toxicities, liver toxicity (manifested as elevation of transaminases), pulmonary toxicity (manifested as non-infectious pneumonitis), infections, or combinations thereof.
  • enterocolitis manifested as diarrhea
  • liver toxicity manifested as elevation of transaminases
  • pulmonary toxicity manifested as non-infectious pneumonitis
  • the methods described herein provides a high objective response rate (ORR) as determined by tumor assessment from radiological tests and/or physical examination.
  • the methods described herein provide a durable response (DR) and/or increased durable response rate (DRR; a continuous response [complete or partial objective response] beginning within 12 months of treatment and lasting >6 months) in the subject or patient.
  • the methods described herein provide complete remission.
  • the methods described herein provide a better response compared to the monotherapy treatment of a compound of Formula (I) and/or a CD20 inhibitor.
  • the methods described herein provide complete remission beginning within 12 months of treatment and lasting >6 months.
  • the methods described herein provide a complete response (CR) and/or no evidence of disease (NED) beginning within 12 months of treatment and lasting >6 months.
  • the discontinuation rate due to adverse events is less than 25%, less than 20%, less than 15%, less than 10%, less than 8%, less than 5%.
  • The“discontinuation rate” is defined as the number of subjects who discontinue the study drugs prior to the study completion divided by the number of subjects treated.
  • the discontinuation rate due to adverse events is less than 25%, less than 20%, less than 15%, less than 10%, less than 8%, less than 5%. In some embodiments, the discontinuation rate due to adverse events is less than 25%. In some embodiments, the discontinuation rate due to adverse events is less than 20%. In some embodiments, the discontinuation rate due to adverse events is less than 15%. In some embodiments, the discontinuation rate due to adverse events is less than 10%. In some embodiments, the discontinuation rate due to adverse events is less than 8%. In some embodiments, the discontinuation rate due to adverse events is about 4%.
  • the discontinuation rate due to adverse events when the subjects are administered a compound of Formula (I), or an isotopic variant thereof or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug is less for subjects on an intermittent dosing schedule (IS) than the discontinuation rate observed for subjects on a continuous dosing schedule (CS).
  • IS intermittent dosing schedule
  • CS continuous dosing schedule
  • provided herein are methods for treating or preventing a disease comprising administering an effective amount of a compound of Formula (I), or an isotopic variant thereof or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug.
  • the compound of Formula (I) is Compound A35 or an isotopic variant, pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
  • the compound of Formula (I) is Compound A36 or an isotopic variant, pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
  • the compound of Formula (I) is Compound A68 or an isotopic variant, pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
  • the compound of Formula (I) is Compound A70 or an isotopic variant, pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. In some embodiments, the compound of Formula (I) is Compound A37 or an isotopic variant, pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. In some embodiments, the compound of Formula (I) is Compound A38 or an isotopic variant, pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. In some embodiments, the compound of Formula (I) is Compound A41 or an isotopic variant, pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
  • the compound of Formula (I) is Compound A42 or an isotopic variant, pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. In some embodiments, the compound of Formula (I) is Compound A43 or an isotopic variant, pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. In some embodiments, the compound of Formula (I) is Compound A44 or an isotopic variant, pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. In some embodiments, the compound of Formula (I) is Compound A62 or an isotopic variant, pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
  • the compound of Formula (I) is Compound A63 or an isotopic variant, pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. In some embodiments, the compound of Formula (I) is Compound A64 or an isotopic variant, pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. In some embodiments, the compound of Formula (I) is Compound A65 or an isotopic variant, pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. In some embodiments, the compound of Formula (I) is Compound A66 or an isotopic variant, pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
  • the compound of Formula (I) is Compound A67 or an isotopic variant, pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
  • the methods further comprise administering the patient or subject with a CD20 inhibitor, wherein the CD20 inhibitor is ofatumumab, obinutuzumab, rituximab, ocaratuzumab, ocrelizumab, tositumomab, ibritumomab tiuxetan, tisotumab vedotin, ublituximab, TRU-015, veltuzumab, BTCT4465A (RG7828), EDC9, MT-3724, or a variant or biosimilar thereof.
  • the CD20 inhibitor is rituximab, obinutuzumab, ofatumumab, ocaratuzumab, tositumomab, ibritumomab tiuxetan, ublituximab, EDC9, MT-3724, or a variant, or biosimilar thereof.
  • the CD20 inhibitor is rituximab, or a variant or biosimilar thereof.
  • Resistent, relapsed or refratory refers to when a cancer that has a reduced responsiveness to a treatment, e.g., up to the point where the cancer does not respond to treatment.
  • the cancer can be resistant at the beginning of treatment, or it may become resistant during treatment.
  • the term“refractory” can refer to a cancer for which treatment (e.g. chemotherapy drugs, biological agents, and/or radiation therapy) has proven to be ineffective.
  • a refractory cancer tumor may shrink, but not to the point where the treatment is determined to be effective. Typically however, the tumor stays the same size as it was before treatment (stable disease), or it grows (progressive disease).
  • the methods provided herein comprise administering a compound of Formula (I), or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
  • the method further comprises administering a CD20 inhibitor to the patient simultaneously or sequentially by the same or different routes of administration.
  • the compound of Formula (I), or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof and a CD20 inhibitor is administered simultaneously, at essentially the same time, or sequentially. If administration takes place sequentially, the CD20 inhibitor may be administered before or after administration of a compound of Formula (I), or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
  • the CD20 inhibitor is administered before administration of a compound of Formula (I), or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. In some embodiments, the CD20 inhibitor is administered simultaneously with administration of a compound of Formula (I), an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. In some embodiments, the CD20 inhibitor is administered after the administration of a compound of Formula (I), an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
  • the methods described herein further comprise administering the PI3K inhibitor in combination with CD20 inhibitor to the subject or patient in need thereof in multiple cycles repeated on a regular schedule with periods of rest in between each cycle. For example, in some instances, treatment is given for one week followed by three weeks of rest is one treatment cycle.
  • a cycle comprises administration of the PI3K inhibitor at the same time as administration of the CD20 inhibitor.
  • the PI3K inhibitor and the CD20 inhibitor are administered for about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 7 days, about 8 days, about 9 days, about 10 days, about 11 days, about 12 days, about 13 days, about 14 days, about 15 days, about 16 days, about 17 days, about 18 days, about 19 days, about 20 days, about 21 days, about 22 days, about 23 days, about 24 days, about 25 days, about 26 days, about 27 days, or about 28 days.
  • a cycle comprises administration of the PI3K inhibitor first followed by administration of the CD20 inhibitor second.
  • the PI3K inhibitor is administered for about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 7 days, about 8 days, about 9 days, about 10 days, about 11 days, about 12 days, about 13 days, or about 14 days followed by administration of the CD20 inhibitor for about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 7 days, about 8 days, about 9 days, about 10 days, about 11 days, about 12 days, about 13 days, or about 14 days.
  • a cycle comprises administration of the PI3K inhibitor first followed by concurrent administration of the CD20 inhibitor.
  • the PI3K inhibitor is first
  • the PI3K inhibitor is first administered for about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, or about 7 days followed by the concurrent administration of the CD20 inhibitor for about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 7 days, about 8 days, about 9 days, about 10 days, about 11 days, about 12 days, about 13 days, or about 14 days.
  • the PI3K inhibitor is first administered for about 7 days followed by the concurrent administration of the CD20 inhibitor for about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 7 days, about 8 days, about 9 days, about 10 days, about 11 days, about 12 days, about 13 days, or about 14 days. In some instances, the PI3K inhibitor is first administered for about 7 days followed by the concurrent administration of the CD20 inhibitor for about 10 days, about 11 days, about 12 days, about 13 days, or about 14 days.
  • a cycle comprises administration of the PI3K inhibitor only.
  • the PI3K inhibitor is administered for about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 7 days, about 8 days, about 9 days, about 10 days, about 11 days, about 12 days, about 13 days, about 14 days, about 15 days, about 16 days, about 17 days, about 18 days, about 19 days, about 20 days, about 21 days, about 22 days, about 23 days, about 24 days, about 25 days, about 26 days, about 27 days, or about 28 days.
  • the method for multiple cycle chemotherapy comprises the administration of a second cycle within about 60 days or about 3 months. In some instances, the method for multiple cycle chemotherapy comprises the administration of a second cycle within 50 days. In another instance, the second cycle is administered within 45, 40, 35, 30, 25, 21, 20, 15, 14, 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1 day(s) of the first cycle. In some embodiments, the administration of any additional cycles is within 50 days of the previous cycle. In some embodiments, the administration of any additional cycles is within 10 days of the previous cycle. In some embodiments, the administration of any additional cycles is within 9 days of the previous cycle. In some embodiments, the administration of any additional cycles is within 8 days of the previous cycle.
  • the administration of any additional cycles is within 7 days of the previous cycle. In some embodiments, the administration of any additional cycles is within 6 days of the previous cycle. In some embodiments, the administration of any additional cycles is within 5 days of the previous cycle. In some embodiments, the administration of any additional cycles is within 4 days of the previous cycle. In some embodiments, the administration of any additional cycles is within 3 days of the previous cycle. In some embodiments, the administration of any additional cycles is within 2 days of the previous cycle. In some embodiments, the administration of any additional cycles is within 1 day of the previous cycle. In another embodiment, the additional cycle is administered within 45, 40, 35, 30, 25, 21, 20, 15, 14, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 days of the previous 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 four to six weeks. In some embodiments, the length of a treatment cycle is 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 four weeks. The number of treatment doses scheduled within each cycle also varies depending on the drugs being given.
  • the compound of Formula (I), or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof is administered to the subject for at least one 28-day cycle.
  • pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof is administered to the subject for at least two 28-day cycles.
  • the compound of Formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof is administered to the subject for a period of up to about 7 days.
  • the days over which the compound of Formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof are intermittent.
  • administering to subject the compound of Formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof for about 7 consecutive days in a 28-day cycle.
  • the method comprises an intermittent dosing schedule (IS), comprising administering to subject the compound of Formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof once daily for 7 consecutive days followed by 21 days without treatment in a 28-day cycle.
  • IS intermittent dosing schedule
  • the compound of Formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, is administered to the subject for at least one 28-day cycle.
  • the IS avoids or reduces adverse or unwanted side effects associated with the use of the PI3K inhibitor, such as enterocolitis (manifested as diarrhea), cutaneous toxicities, liver toxicity (manifested as elevation of transaminases), pulmonary toxicity (manifested as non-infectious pneumonitis), and infections.
  • the IS avoids or reduces enterocolitis, rash, transaminitis, or combinations thereof.
  • the method comprises administering to subject the compound of Formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof on a 28-day cycle.
  • the compound of Formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof is administered to the subject for at least one 28-day cycle.
  • the compound of Formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof is administered to the subject once daily for 28 consecutive days in a 28-day cycle.
  • the compound of Formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof is administered to the subject on continuous dosing schedule (CS).
  • CS continuous dosing schedule
  • the continuous dosing schedule comprises once daily administration of compound of Formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof to the subject for 28 consecutive days in a 28-day cycle.
  • the compound of Formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof is administered to the subject for at least two 28-day cycles.
  • the compound of Formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof is administered to the subject for at least three 28-day cycles.
  • the compound of Formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, is administered daily to the subject on a 28-day continuous schedule until progression of disease or intolerable toxicity.
  • the compound of Formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, is administered to the subject once daily for a period of up to about 7 days in a 28-day cycle.
  • the compound of Formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, is administered to the subject once daily for a period of up to about 7 intermittent days in a 28-day cycle.
  • the compound of Formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, is administered to the subject once daily for a period of up to about 7 consecutive days in a 28-day cycle.
  • the compound of Formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof is administered to the subject once daily for a period of up to about 7 consecutive days in a 28-day cycle.
  • the compound of Formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof is administered to the subject on an intermittent dosing schedule (IS).
  • IS intermittent dosing schedule
  • the intermittent dosing schedule comprises once daily administration of compound of Formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof to the subject for 7 consecutive days followed by 21 days without treatment in a 28 -day cycle.
  • the compound of Formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof is administered to the subject for at least three 28-day cycles, wherein: the first two 28-day cycles comprise a continuous daily dosing schedule (CS), comprising administering to the subject the compound of Formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, once daily for two 28- day cycles; and the third 28-day cycle comprises an intermittent dosing schedule (IS), comprising administering to the subject the compound of Formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two
  • the compound of Formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof is administered to the subject for at least three cycles, wherein: the first two cycles comprise a continuous daily dosing schedule (CS), comprising administering to the subject the compound of Formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof once daily for two cycles; and the subsequent cycle(s) comprises an intermittent dosing schedule (IS), comprising administering to subject the compound of Formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof
  • the compound of Formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof is administered to the subject for four or more 28-day cycles, wherein: the first two or three 28-day cycles comprise a continuous daily dosing schedule (CS), comprising administering to the subject the compound of Formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, once daily for three or more 28-day cycles; and the subsequent 28-day cycle(s) comprise(s) an intermittent dosing schedule (IS), comprising administering to the subject the compound of Formula (I), or an enantiomer, a mixture of enantiomers
  • CS refers to continuous daily dosing to a subject the compound of Formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof once daily on a 28-day schedule with no switch to IS.
  • CS refers to continuous daily dosing to a subject the compound of Formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof once daily on a 28-day schedule for four or more cycles followed by a switch to IS (i.e., late switch to IS).
  • pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof is administered to a subject on an intermittent dosing schedule (IS) until progression of disease.
  • IS intermittent dosing schedule
  • the subject upon progression of disease, resumes continuous daily dosing (CS) of the compound of Formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
  • the method comprises a continuous daily dosing schedule (CS) for at least two CS 28-day cycles, followed by an intermittant dosing schedule (IS), comprising administering to subject the compound of Formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof once daily for 7 consecutive days followed by 21 days without treatment in a 28 -day cycle after the at least two CS 28-day cycles.
  • CS continuous daily dosing schedule
  • IS intermittant dosing schedule
  • the dosing schedule avoids or reduces adverse or unwanted side effects associated with the use of the PI3K inhibitor, such as enterocolitis (manifested as diarrhea), cutaneous toxicities, liver toxicity (manifested as elevation of transaminases), pulmonary toxicity (manifested as non-infectious pneumonitis), and infections.
  • the dosing schedule avoids or reduces enterocolitis, rash, transaminitis, or combinations thereof.
  • the compound of Formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, is administered to the subject on an intermittent dosing schedule (IS) until disease progression occurs.
  • IS intermittent dosing schedule
  • the compound of Formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, is administered daily to the subject on a continuous dosing schedule (CS) after disease progression occurs on an intermittent dosing schedule (IS).
  • CS continuous dosing schedule
  • IS intermittent dosing schedule
  • the methods of treatment and dosing regimens and schedules described herein improve the frequency, severity and time to onset of the adverse events (AEs) associated with PI3K delta inhibitors. In some embodiments, the methods of treatment and dosing regimens and schedules described herein, including IS dosing regimens, result in partial or complete remission.
  • AEs adverse events
  • the methods of treatment and dosing regimens and schedules described herein, including IS dosing regimens result in partial or complete remission.
  • the compound of Formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof is administered to the subject on an intermittent dosing schedule (IS) resulting in disease stabilization.
  • the compound of Formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof is administered to the subject on an intermittent dosing schedule (IS) resulting in disease regression.
  • the compound of Formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, is administered to the subject on an intermittent dosing schedule (IS) resulting in an objective rseponse.
  • IS intermittent dosing schedule
  • the compound of Formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof is administered to the subject on an intermittent dosing schedule (IS) until disease stabilization is no longer observed.
  • the compound of Formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof is administered to the subject on an intermittent dosing schedule (IS) until disease progression is observed.
  • the treatment regimen comprising administration of the compound of Formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof for two cycles of continuous daily administration (CS) followed by daily administration for only the first seven days of each subsequent (IS) cycle, the CS and IS cycles are 28-day cycles, wherein the IS cycle is repeated until disease regression is no longer observed.
  • the subject resumes the 28-day cycles of continuous daily administration (CS) until disease regression or stabilization are observed.
  • the treatment regimen comprising administration of the compound of Formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof for two 28-day cycles of continuous daily administration (CS) followed by daily administration for only the first seven days of each subsequent (IS) 28-day cycle; wherein disease regression or stabilization is no longer observed in the subject on the intermittent dosing schedule (IS) cycle, the subject resumes 28-day cycles of continuous daily administration (CS) until disease regression or stabilization are observed.
  • CS continuous daily administration
  • the methods of treatment and dosing regimens and schedules described herein provide an efficaious and tolerable treatment of cancer. In some embodiments, the methods of treatment and dosing regimens and schedules described herein improve the frequency, severity and time to onset of the adverse events (AEs) associated with PI3K delta inhibitors. In some embodiments, the methods of treatment and dosing regimens and schedules described herein, including IS dosing regimens, result in partial or complete remission.
  • AEs adverse events
  • the method for the administration of multiple compounds comprises administering compounds within 48 hours or less of each other. In some embodiments administration occurs within 24 hours, 12 hours, 6 hours, 3 hours, 1 hour, or 15 minutes. In some instances, the compounds are administered simultaneously.
  • simultaneous administration is the injection of one compound immediately before, after, or during the oral administration of the second compound, immediately referring to a time less than about 5 minutes.
  • the method for the administration of multiple compounds occurs in a sequential order, wherein the PI3K inhibitor is administered before the CD20 inhibitor. In another instance, the CD20 inhibitor is administered before the PI3K inhibitor.
  • the method for administering the PI3K inhibitor is oral and the method for administering the CD20 inhibitor is by injection. In some instances, the method for administering the PI3K inhibitor is by inhalation and the method for administering the CD20 inhibitor is by injection. In some instances, the method for administering the PI3K inhibitor is by injection and the method for administering the CD20 inhibitor is by injection.
  • a compound of Formula (I), or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof and a CD20 inhibitor is cyclically administered to a patient.
  • cycling therapy involves the administration of an active agent or a combination of active agents for a period of time, followed by a rest for a period of time, and repeating this sequential administration.
  • cycling therapy reduces the development of resistance to one or more of the therapies, avoid or reduce the side effects of one of the therapies, and/or improves the efficacy of the treatment.
  • the compound of Formula (I) is administered daily, every other day, every other day 3 times a week, every 2 weeks, every 3 weeks, every
  • the compound of Formula (I) is administered daily.
  • the CD20 inhibitor is administered daily, every other day, every other day 3 times a week, every 3 days, every 4 days, every 5 days, every 6 days, weekly, every 2 weeks, every 3 weeks, every 4 weeks, every 5 weeks, bi-weekly, 3 times a week, 4 times a week, 5 times a week, 6 times a week, once a month, twice a month, 3 times a month, once every 2 months, once every 3 months, once every 4 months, once every 5 months, or once every 6 months.
  • the CD20 inhibitor is administered 8 times in 6 months.
  • the compound of Formula (I) or the CD20 inhibitor is optionally given continuously; alternatively, the dose of drug being administered is temporarily reduced or temporarily suspended for a certain length of time (i.e., a“drug holiday”).
  • a“drug holiday” a“drug holiday”.
  • the length of the drug holiday varies between 2 days and 1 year, including by way of example only, 2 days, 3 days, 4 days,
  • the dose reduction during a drug holiday includes from 10%-100%, including, by way of example only, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%.
  • an appropriate dosage level of a compound of Formula (I), or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof generally is ranging from about 1 to 1000 mg, from about 1 to about 500 mg, from about 5 to about 500 mg, from about 5 to about 200 mg, from about 5 to about 250 mg or from about 10 to about 150 mg which can be administered in single or multiple doses.
  • the compound of Formula (I), or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof is administered in an amount of about 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175,
  • the compound of Formula (I), or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof is administered in an amount of about 60 mg, about 120 mg, about 150 mg, or about 180 mg. In certain embodiments, the compound of Formula (I), or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof is administered in an amount of about 60 mg.
  • the compound of Formula (I), or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof is administered in an amount of about 1, about 5, about 10, about 15, about 20, about 25, about 30, about 35, about 40, about 45, about 50, about 55, about 60, about 65, about 70, about 75, about 80, about 85, about 90, about 95, about 100, about 105, about 110, about 115, about 120, about 125, about 130, about 135, about 140, about 145, about 150, about 155, about 160, about 165, about 170, about 175, about 180, about 185, about 190, about 195, about 200, about 225, about 250, about 275, about 300, about 325, about 350, about 375, about 400, about 450, or about 500 mg/day.
  • the compound of Formula (I), or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof is administered in an amount of about 45 mg/day. In certain embodiments, the compound of Formula (I), or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof is administered in an amount of about 60 mg/day. In certain embodiments, the compound of Formula (I), or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof is administered in an amount of about 90 mg/day.
  • the compound of Formula (I), or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof is administered in an amount of about 120 mg/day. In certain embodiments, the compound of Formula (I), or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof is administered in an amount of about 150 mg/day. In certain embodiments, the compound of Formula (I), or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof is administered in an amount of about 180 mg/day.
  • the pharmaceutical compositions provided herein can be formulated in the form of tablets containing from about 1.0 to about 1,000 mg of a compound of Formula (I), or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, in one embodiment, about 1, about 5, about 10, about 15, about 20, about 25, about 50, about 75, about 100, about 150, about 200, about 250, about 300, about 400, about 500, about 600, about 750, about 800, about 900, and about 1,000 mg of the a compound of Formula (I), or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof for the symptomatic adjustment of the dosage to the patient to be treated.
  • the pharmaceutical compositions provided herein can be formulated in the form of tablets containing about 45 mg of a compound of Formula (I), or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
  • the pharmaceutical compositions can be administered on a regimen of 1 to 4 times per day, including once, twice, three times, and four times per day.
  • a compound of Formula (I), or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof is administered to a patient in need thereof in an amount of about 45 mg daily for 28 days or 56 days.
  • a compound of Formula (I), or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof is administered to a patient in need thereof in an amount of about 45 mg daily for 28 days.
  • a compound of Formula (I), or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof is administered to a patient in need thereof in an amount of about 45 mg daily for 56 days.
  • a compound of Formula (I), or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof is administered to a patient in need thereof in an amount of about 45 mg daily until disease progression or intolerable toxicity.
  • the pharmaceutical compositions provided herein can be formulated in the form of tablets containing about 60 mg of a compound of Formula (I), or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
  • the pharmaceutical compositions can be administered on a regimen of 1 to 4 times per day, including once, twice, three times, and four times per day.
  • a compound of Formula (I), or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof is administered to a patient in need thereof in an amount of about 60 mg daily for 28 days or 56 days.
  • a compound of Formula (I), or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof is administered to a patient in need thereof in an amount of about 60 mg daily for 28 days. In other specific embodiments, a compound of Formula (I), or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof is administered to a patient in need thereof in an amount of about 60 mg daily for 56 days.
  • a compound of Formula (I), or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof is administered to a patient in need thereof in an amount of about 60 mg daily until disease progression or intolerable toxicity.
  • the pharmaceutical compositions provided herein can be formulated in the form of tablets containing about 90 mg of a compound of Formula (I), or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
  • the pharmaceutical compositions can be administered on a regimen of 1 to 4 times per day, including once, twice, three times, and four times per day.
  • a compound of Formula (I), or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof is administered to a patient in need thereof in an amount of about 90 mg daily for 28 days or 56 days.
  • a compound of Formula (I), or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof is administered to a patient in need thereof in an amount of about 90 mg daily for 28 days.
  • a compound of Formula (I), or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof is administered to a patient in need thereof in an amount of about 90 mg daily for 56 days.
  • a compound of Formula (I), or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof is administered to a patient in need thereof in an amount of about 90 mg daily until disease progression or intolerable toxicity.
  • the pharmaceutical compositions provided herein can be formulated in the form of tablets containing about 120 mg of a compound of Formula (I), or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
  • the pharmaceutical compositions can be administered on a regimen of 1 to 4 times per day, including once, twice, three times, and four times per day.
  • a compound of Formula (I), or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof is administered to a patient in need thereof in an amount of about 120 mg daily for 28 days or 56 days.
  • a compound of Formula (I), or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof is administered to a patient in need thereof in an amount of about 120 mg daily for 28 days.
  • a compound of Formula (I), or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof is administered to a patient in need thereof in an amount of about 120 mg daily for 56 days.
  • a compound of Formula (I), or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof is administered to a patient in need thereof in an amount of about 120 mg daily until disease progression or intolerable toxicity.
  • the pharmaceutical compositions provided herein can be formulated in the form of tablets containing about 150 mg of a compound of Formula (I), or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
  • the pharmaceutical compositions can be administered on a regimen of 1 to 4 times per day, including once, twice, three times, and four times per day.
  • a compound of Formula (I), or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof is administered to a patient in need thereof in an amount of about 150 mg daily for 28 days or 56 days.
  • a compound of Formula (I), or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof is administered to a patient in need thereof in an amount of about 150 mg daily for 28 days.
  • a compound of Formula (I), or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof is administered to a patient in need thereof in an amount of about 150 mg daily for 56 days.
  • a compound of Formula (I), or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof is administered to a patient in need thereof in an amount of about 150 mg daily until disease progression or intolerable toxicity.
  • the pharmaceutical compositions provided herein can be formulated in the form of tablets containing about 180 mg of a compound of Formula (I), or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
  • the pharmaceutical compositions can be administered on a regimen of 1 to 4 times per day, including once, twice, three times, and four times per day.
  • a compound of Formula (I), or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof is administered to a patient in need thereof in an amount of about 180 mg daily for 28 days or 56 days.
  • a compound of Formula (I), or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof is administered to a patient in need thereof in an amount of about 180 mg daily for 28 days.
  • a compound of Formula (I), or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof is administered to a patient in need thereof in an amount of about 180 mg daily for 56 days.
  • a compound of Formula (I), or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof is administered to a patient in need thereof in an amount of about 180 mg daily until disease progression or intolerable toxicity.
  • the CD20 inhibitor used in combination with a compound of Formula (I), or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug is rituximab.
  • the methods described herein further comprise administering rituximab as an intravenous infusion in 28 days cycles.
  • rituximab is administered as an intravenous infusion for multiple 28 days cycles.
  • rituximab is administered as an intravenous infusion at a dose of 375 mg/m 2 in the first cycle and 500 mg/m 2 in cycles 2-6.
  • rituximab is administered intravenously as an infusion at a dose of 375 mg/m 2 per cycle. In certain embodiments, rituximab is administered as an intravenous infusion at a dose of 375 mg/m 2 for a total of 8 doses in 6 months. In certain embodiments, rituximab, or a variant or biosimilar thereof, is administered as an intravenous infusion at a dose of 375 mg/m 2 until disease progression or intolerable toxicity.
  • the CD20 inhibitor used in combination with a compound of Formula (I), or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug, is ofatumumab.
  • the methods described herein further comprise administering ofatumumab as an intravenous infusion every week.
  • ofatumumab is administered as an intravenous infusion for multiple cycles.
  • ofatumumab is administered as an intravenous infusion at a dose of 300 mg initial dose, followed 1 week later by 2,000 mg weekly for 7 doses, followed 4 weeks later by 2,000 mg every 4 weeks for 4 doses.
  • the CD20 inhibitor used in combination with a compound of Formula (I), or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug is obinutuzumab.
  • the methods described herein further comprise administering obinutuzumab as an intravenous infusion in 28 days cycles.
  • obinutuzumab is administered as an intravenous infusion for multiple cycles 28 days cycles.
  • obinutuzumab is administered as an intravenous infusion at a dose of 100 mg on day 1 and 900 mg on day 2 Cycle 1, 1000 mg on day 8 and 15 of Cycle 1, and 1000 mg on day 1 of Cycles 2-6.
  • obinutuzumab is administered as an intravenous infusion at a dose of 1000 mg on day 1, 8 and 15 of Cycle 1, and 1000 mg on day 1 of Cycles 2-6, and then every 2 months for 2 years.
  • the CD20 inhibitor used in combination with a compound of Formula (I), or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug is ocaratuzumab.
  • the methods described herein further comprise administering ocaratuzumab as a subcutaneous injection every week.
  • ocaratuzumab is administered as a subcutaneous injection for multiple cycles.
  • ocaratuzumab is administered at a dose between about 20 mg to about 100 mg per week.
  • ocaratuzumab is administered at a dose of about 40 mg per week.
  • ocaratuzumab is administered at a dose of about 80 mg per week.
  • the CD20 inhibitor used in combination with a compound of Formula (I), or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug is ocrelizumab.
  • the methods described herein further comprise administering ocrelizumab as an intravenous infusion in 24 weeks cycles.
  • ocrelizumab is administered as an intravenous infusion for multiple cycles.
  • ocrelizumab is administered as an intravenous infusion at a dose of 600 mg as a 300 mg infusion on days 1 and 15 for the first dose and as a single infusion of 600 mg for all subsequent infusions every 24 weeks.
  • the CD20 inhibitor used in combination with a compound of Formula (I), or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug is ublituximab.
  • the methods described herein further comprise administering ublituximab as an intravenous infusion in cycles.
  • ublituximab is administered as an intravenous infusion for multiple cycles.
  • ublituximab is administered as an intravenous infusion at day 1, day 8 and day 15 of every cycle.
  • the CD20 inhibitor used in combination with a compound of Formula (I), or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug is BTCT4465A.
  • the methods described herein further comprise administering BTCT4465A as an intravenous infusion in 21 days cycles.
  • BTCT4465A is administered as an intravenous infusion for multiple cycles.
  • BTCT4465A is administered as an intravenous infusion on Day 1 of each 21 -day cycle.
  • BTCT4465A is administered as an intravenous infusion on Days 1, 8, and 15 of Cycle 1 and thereafter on Day 1 of each 21 -day cycle.
  • the CD20 inhibitor used in combination with a compound of Formula (I), or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug is veltuzumab.
  • the methods described herein further comprise administering veltuzumab as an intravenous infusion or a subcutaneous injection in weekly cycles.
  • veltuzumab is administered as an intravenous infusion or a subcutaneous injection for multiple weekly cycles.
  • veltuzumab is administered as an intravenous infusion or a subcutaneous injection at a dose of 80 mg/m 2 once weekly for 4 weeks.
  • veltuzumab is administered as an intravenous infusion or a subcutaneous injection at a dose of 120 mg/m 2 once weekly for 4 weeks. In certain embodiments, veltuzumab is administered as an intravenous infusion or a subcutaneous injection at a dose of 200 mg/m 2 once weekly for 4 weeks. In certain embodiments, veltuzumab is administered as an intravenous infusion or a subcutaneous injection at a dose of 375 mg/m 2 once weekly for 4 weeks.
  • the CD20 inhibitor used in combination with a compound of Formula (I), or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug is TRU- 015.
  • the methods described herein further comprise administering TRU-015 as an intravenous infusion in weekly cycles.
  • TRU-015 is administered as an intravenous infusion for multiple weekly cycles.
  • TRU-015 is administered at a dose between about 100 mg to about 1200 mg per week.
  • TRU-015 is administered at a dose of about 400 mg per week.
  • TRU-015 is administered at a dose of about 700 mg per week.
  • TRU-015 is administered at a dose of about 1000 mg per week.
  • the CD20 inhibitor is administered weekly. In certain embodiments, the CD20 inhibitor is administered once every two, three, four, or five weeks. In certain embodiments, the CD20 inhibitor is administered once every four weeks. In certain embodiments, the CD20 inhibitor is administered is 21 days cycles. In certain embodiments, the CD20 inhibitor is administered is 28 days cycles. In certain embodiments, the CD20 inhibitor is administered intravenously. In certain embodiments,
  • the CD20 inhibitor is administered as an intravenous infusion. In certain embodiments, the CD20 inhibitor is administered subcutaneously.
  • Some embodiments provided herein describe treating patients with follicular lymphoma who have early disease progression after immuochemotherapy treatment.
  • the follicular lymphoma who have early disease progression after immuochemotherapy treatment.
  • the immunochemotherapy treatment is first-line treatment or first-line therapy. In some embodiments, the immunochemotherapy treatment is an additional (or subsequent) line of treatment or an additional (or subsequent) line of therapy. In some embodiments, the immunochemotherapy treatment is second-line treatment or second-line therapy. In some embodiments, the immunochemotherapy treatment is third-line treatment or third-line therapy. In some embodiments, the immunochemotherapy treatment is fourth-line treatment or fourth-line therapy. In some embodiments of the methods provided herein, the FL is relapsed/refractory FL. In some embodiments of the methods provided herein, the FL is
  • the FL is relapsed/refractory FL after failure of at least two prior lines of systemic therapy in the subject, wherein the systemic therapy comprises an antiCD20 antibody and/or chemotherapy with an alkylating agent or a purine analogue.
  • the two prior lines of systemic therapy comprise an antiCD20 antibody and/or chemotherapy with an alkylating agent or a purine analogue.
  • the immunochemotherapy treatment the patient previously received is i) BR (bendamustine and rituximab); ii) RCHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone); iii) RCVP (rituximab, cyclophosphamide, vincristine sulfate, prednisone); iv) FCMR (fludarabine, cyclophosphamide, mitoxantrone and rituximab); v) fludarabine and rituximab; vi) RFND (rituximab, fludarabine, mitoxantrone, dexamethasone); vii) R-MCP (rituximab with mitoxantrone, chlorambucil, and prednisolone); viii) R-FM (rituximab with mitoxan
  • the immunochemotherapy treatment the patient previously received is i) BR (bendamustine and rituximab); ii) RCHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone); iii) RCVP (rituximab, cyclophosphamide, vincristine sulfate, prednisone); iv) FCMR (fludarabine, cyclophosphamide, mitoxantrone and rituximab); v) fludarabine and rituximab; vi) RFND (rituximab, fludarabine, mitoxantrone, dexamethasone); or a combination thereof.
  • BR biendamustine and rituximab
  • RCHOP rituximab, cyclophosphamide, doxorubicin, vincris
  • the immunochemotherapy treatment the patient previously received is i) RB (rituximab and bendamustine) ; ii) RCHOP (rituximab, cyclophosphamide, doxorubicin
  • RCVP rituximab, cyclophosphamide, vincristine sulfate, prednisone
  • FCMR fludarabine, cyclophosphamide, mitoxantrone and rituximab
  • fludarabine and rituximab fludarabine and rituximab
  • RFND rituximab, fludarabine, mitoxantrone, dexamethasone
  • the immunochemotherapy treatment the patient previously received is RB (rituximab and bendamustine).
  • the immunochemotherapy the patient previously received is R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone).
  • the immunochemotherapy treatment the patient previously received is RCVP (rituximab, cyclophosphamide, vincristine sulfate, prednisone).
  • the immunochemotherapy treatment the patient previously received is FCMR (fludarabine, cyclophosphamide, mitoxantrone and rituximab).
  • the immunochemotherapy treatment the patient previously received is fludarabine and rituximab. In some embodiments, the immunochemotherapy treatment the patient previously received is RFND (rituximab, fludarabine, mitoxantrone, dexamethasone). In some embodiments, the immunochemotherapy treatment the patient previously received is R-MCP (rituximab with mitoxantrone, chlorambucil, and prednisolone). In some embodiments, the immunochemotherapy treatment the patient previously received is R-FM (rituximab with fludarabine and mitoxantrone). In some embodiments, the immunochemotherapy treatment the patient previously received is G-CHOP (Gazyza, cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, and prednisone)
  • the first-line immunochemotherapy treatment the patient previously received is RB (rituximab and bendamustine).
  • the first-line immunochemotherapy treatment the patient previously received is RCHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone).
  • the first-line immunochemotherapy treatment the patient previously received is RCVP (rituximab, cyclophosphamide, vincristine sulfate, prednisone).
  • the first-line immunochemotherapy treatment the patient previously received is FCMR (fludarabine, cyclophosphamide, mitoxantrone and rituximab). In some embodiments, the first- line immunochemotherapy treatment the patient previously received is fludarabine and rituximab. In some embodiments, the first-line immunochemotherapy treatment the patient previously received is RFND (rituximab, fludarabine, mitoxantrone, dexamethasone). In some embodiments, the first -line immunochemotherapy treatment the patient previously received is R-MCP (rituximab with mitoxantrone, chlorambucil, and prednisolone). In some embodiments, the first-line immunochemotherapy treatment the patient previously received is R-FM (rituximab with fludarabine and mitoxantrone).
  • FCMR fludarabine, cyclophosphamide, mitoxantrone and rituximab
  • the additional (or subsequent) line of treatment the patient previously received is BR (bendamustine and rituximab).
  • the additional (or subsequent) line of treatment the patient previously received is RCHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone).
  • the additional (or subsequent) line of treatment the patient previously received is RCVP (rituximab, cyclophosphamide, vincristine sulfate, prednisone).
  • the additional (or subsequent) line of treatment the patient previously received is FCMR (fludarabine, cyclophosphamide, mitoxantrone and rituximab). In some embodiments, the additional (or subsequent) line of treatment the patient previously received is fludarabine and rituximab.
  • the additional (or subsequent) line of treatment the patient previously received is RFND (rituximab, fludarabine, mitoxantrone, dexamethasone).
  • the additional (or subsequent) line of treatment the patient previously received is R-MCP (rituximab with mitoxantrone, chlorambucil, and prednisolone).
  • the additional (or subsequent) line of treatment the patient previously received is R-FM (rituximab with fludarabine and mitoxantrone).
  • the immunochemotherapy treatment described above further comprises a BTK inhibitor.
  • the BTK inhibitor is ibrutinib, BGB-3111, CC-292 (AVL-292), ACP 196 (Acalabrutinib), CNX-774, CGI1746, LFM-A13, CNX-774, ONO-4059, RN486 CPI-0610, DUAL946, GSK525762, 1-BET151, JQ1, OTX015, PFI-l, RVX-208, RVX2135, or TEN-010, or a combination thereof.
  • the BTK inhibitor is ibrutinib.
  • the compounds provided herein can also be provided as an article of manufacture using packaging materials well known to those of skill in the art. See, e.g., U.S. Pat. Nos. 5,323,907; 5,052,558; and 5,033,252.
  • packaging materials include, but are not limited to, blister packs, bottles, tubes, inhalers, pumps, bags, vials, containers, syringes, and any packaging material suitable for a selected formulation and intended mode of administration and treatment.
  • kits which, when used by the medical practitioner, can simplify the administration of appropriate amounts of active ingredients to a subject.
  • the kit provided herein includes one or more containers and a dosage form of a compound of Formula (I), or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof and a CD20 inhibitor.
  • the kit provided herein includes one or more containers and a dosage form of a compound of Formula (I), or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof and CD20 inhibitor.
  • Kits provided herein can further include devices that are used to administer the active ingredients. Examples of such devices include, but are not limited to, syringes, needle-less injectors drip bags, patches, and inhalers.
  • Kits provided herein can further include pharmaceutically acceptable vehicles that can be used to administer one or more active ingredients.
  • the kit can comprise a sealed container of a suitable vehicle in which the active ingredient can be dissolved to form a particulate -free sterile solution that is suitable for parenteral administration.
  • Examples of pharmaceutically acceptable vehicles include, but are not limited to: aqueous vehicles, including, but not limited to, Water for Injection USP, Sodium Chloride Injection, Ringer’s Injection, Dextrose Injection, Dextrose and Sodium Chloride Injection, and Lactated Ringer’s Injection; water-miscible vehicles, including, but not limited to, ethyl alcohol, polyethylene glycol, and polypropylene glycol; and non-aqueous vehicles, including, but not limited to, com oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.
  • aqueous vehicles including, but not limited to, Water for Injection USP, Sodium Chloride Injection, Ringer’s Injection, Dextrose Injection, Dextrose and Sodium Chloride Injection, and Lactated Ringer’s Injection
  • water-miscible vehicles including, but not limited to,
  • Example 1 Study of Treatment of Patients with Early Disease Progression
  • infusional rituximab at a dose of 375 mg/m 2 administered for a total of 8 doses in 6 months
  • CHOP rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone
  • comparable regimens CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) or comparable regimens.
  • Example 2 Effect of Compound A35 and Rituximab on Treatment Efficacy in FL
  • Example 3 Effect of Dosing Schedule of Compound A35 Alone or with Rituximab in Relapsed/Refractory (R/R) Follicular Lymphoma (FL)
  • Compound A35 a potent and selective oral PI3k5 inhibitor, is being evaluated in a Phase lb study in patients (pts) with R/R B-cell malignancies.
  • the intermittent schedule (IS) group is defined as patients who received Compound A35 alone or with rituximab daily for 2 cycles then switched to an intermittent schedule of 1 week per cycle
  • the continous schedule (CS) group is defined as patients who never switched to intermittent dosing or switched to intermittent dosing in cycle 4 or later cycles.
  • Toxicity on CS is managed by a switch to IS.
  • Progression of disease (POD) on IS is managed by a switch to CS.
  • Table 5 Patients with Adverse Events of Special Interest with Compound A35 Single Agent Therapy

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CN201980067638.8A CN112839659A (zh) 2018-08-14 2019-08-13 复发性滤泡性淋巴瘤的治疗
EP19849643.2A EP3836936A4 (en) 2018-08-14 2019-08-13 TREATMENT OF RECURRENT FOLLICULAR LYMPHOMA
AU2019321526A AU2019321526A1 (en) 2018-08-14 2019-08-13 Treatment of relapsed follicular lymphoma
US17/268,050 US20210196725A1 (en) 2018-08-14 2019-08-13 Treatment of relapsed follicular lymphoma
EA202190361A EA202190361A1 (ru) 2019-04-19 2019-08-13 Лечение рецидивирующей фолликулярной лимфомы
KR1020217007422A KR20210043637A (ko) 2018-08-14 2019-08-13 재발성 여포성 림프종의 치료
MX2021001765A MX2021001765A (es) 2018-08-14 2019-08-13 Tratamiento del linfoma follicular reicindido.
BR112021002734-3A BR112021002734A2 (pt) 2018-08-14 2019-08-13 tratamento de linfoma folicular reincidente
CA3109377A CA3109377A1 (en) 2018-08-14 2019-08-13 Treatment of relapsed follicular lymphoma
SG11202101417XA SG11202101417XA (en) 2018-08-14 2019-08-13 Treatment of relapsed follicular lymphoma
JP2021506718A JP2021534116A (ja) 2018-08-14 2019-08-13 再発性の濾胞性リンパ腫の処置
IL280721A IL280721A (en) 2018-08-14 2021-02-08 A method for treating relapse of follicular lymphoma

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MA53237A (fr) 2021-06-23
CA3109377A1 (en) 2020-02-20
IL280721A (en) 2021-03-25
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TW202021593A (zh) 2020-06-16
MX2021001765A (es) 2021-04-19
AU2019321526A1 (en) 2021-03-25
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KR20210043637A (ko) 2021-04-21
CN112839659A (zh) 2021-05-25

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