WO2023230286A2 - Méthodes et compositions pour le traitement du cancer - Google Patents

Méthodes et compositions pour le traitement du cancer Download PDF

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WO2023230286A2
WO2023230286A2 PCT/US2023/023618 US2023023618W WO2023230286A2 WO 2023230286 A2 WO2023230286 A2 WO 2023230286A2 US 2023023618 W US2023023618 W US 2023023618W WO 2023230286 A2 WO2023230286 A2 WO 2023230286A2
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compound
administering
pharmaceutically
subject
hydrogen
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PCT/US2023/023618
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WO2023230286A3 (fr
WO2023230286A9 (fr
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Steven M. Fruchtman
Matthew PARRIS
Stephen C. Cosenza
Adar Makovski SILVERSTEIN
Gaël ROUÉ
Mark S. GELDER
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Onconova Therapeutics, Inc.
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Publication of WO2023230286A2 publication Critical patent/WO2023230286A2/fr
Publication of WO2023230286A3 publication Critical patent/WO2023230286A3/fr
Publication of WO2023230286A9 publication Critical patent/WO2023230286A9/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings

Definitions

  • Mantle cell lymphoma is an aggressive, rare form of non-Hodgkin lymphoma (NHL).
  • NHL non-Hodgkin lymphoma
  • a method of treating lymphoma in a human subject in need thereof comprising administering to the subject a therapeutically- effective amount of a compound of formula (I) wherein:
  • R 1 is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl, each of which is unsubstituted or substituted, or hydrogen;
  • R 3 is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl or heteroaryl, each of which is unsubstituted or substituted, or hydrogen or halogen;
  • a method of treating lymphoma in a subject in need thereof comprising administering to the subject a therapeutically- effective amount of a compound of formula (I) wherein:
  • R 1 is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl, each of which is unsubstituted or substituted, or hydrogen;
  • R 3 is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl or heteroaryl, each of which is unsubstituted or substituted, or hydrogen or halogen;
  • a method of treating lymphoma in a subject in need thereof comprising administering to the subject a therapeutically- effective amount of a compound of formula (I) wherein:
  • R 1 is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl, each of which is unsubstituted or substituted, or hydrogen;
  • R 3 is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl or heteroaryl, each of which is unsubstituted or substituted, or hydrogen or halogen;
  • a method of treating lymphoma in a subject in need thereof comprising administering to the subject a therapeutically- effective amount of a compound of formula (I) wherein:
  • R 1 is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl, each of which is unsubstituted or substituted, or hydrogen;
  • R 3 is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl or heteroaryl, each of which is unsubstituted or substituted, or hydrogen or halogen;
  • a method of treating lymphoma in a subject in need thereof comprising
  • R 1 is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl, each of which is unsubstituted or substituted, or hydrogen;
  • R 3 is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl or heteroaryl, each of which is unsubstituted or substituted, or hydrogen or halogen;
  • combination comprising:
  • R 1 is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl, each of which is unsubstituted or substituted, or hydrogen;
  • R 3 is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl or heteroaryl, each of which is unsubstituted or substituted, or hydrogen or halogen;
  • the second compound is a BTK inhibitor. In some embodiments, the second compound is ibrutinib or a pharmaceutically-acceptable salt thereof. In some embodiments, the second compound is acalabrutinib or a pharmaceutically- acceptable salt thereof.
  • the compound of formula (1) 8-cyclopentyl-2-((4-(4- methylpiperazin-l-yl)phenyl)amino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6- carbonitrile monolactate or a pharmaceutically-acceptable salt thereof.
  • the compound of formula (I) is 8-cyclopentyl-2-((4-(4-methylpiperazin-l-yl)phenyl)amino)- 7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile achieves synergistic activity in combination with ibrutinib.
  • the synergistic activity is in mantle cell lymphoma cells (MCL).
  • the synergistic activity is in BTK inhibitorresistant MCL cells.
  • the compound of formula (1) 8-cyclopentyl-2-((4-(4- methylpiperazin-l-yl)phenyl)amino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6- carbonitrile monolactate or a pharmaceutically-acceptable salt thereof.
  • the compound of formula (I) is 8-cyclopentyl-2-((4-(4-methylpiperazin-l-yl)phenyl)amino)- 7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile achieves synergistic activity in combination with acalabrutinib.
  • the synergistic activity is in mantle cell lymphoma cells (MCL).
  • MCL mantle cell lymphoma cells
  • the synergistic activity is in BTK inhibitor-resistant MCL cells.
  • the compound of formula (I) is 8-cyclopentyl-2-((4-(4- methylpiperazin-l-yl)phenyl)amino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6- carbonitrile or a pharmaceutically-acceptable salt thereof.
  • the compound of formula (I) is 8-cyclopentyl-2-((4-(4-methylpiperazin-l-yl)phenyl)amino)-7- oxo-7, 8-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile monolactate.
  • a method of treating mantle cell lymphoma in a subject in need thereof comprising orally administering to the subject a solid pharmaceutical composition, the solid pharmaceutical composition comprising 40 mg to 500 mg of a compound that is 8-cyclopentyl-2-((4-(4-methylpiperazin-l-yl)phenyl)amino)-7-oxo- 7,8-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile monolactate, wherein the subject received a therapy other than the compound for the mantle cell lymphoma prior to the administering, wherein the therapy was received after the subject was diagnosed with mantle cell lymphoma, and wherein the subject has not responded to the therapy prior to the administering; and wherein the administering is once daily for at least 3 weeks.
  • a method of treating mantle cell lymphoma in a subject in need thereof comprising, (i) orally administering to the subject a solid pharmaceutical composition, wherein the solid pharmaceutical composition comprises 40 mg to 500 mg of a compound that is 8-cyclopentyl-2-((4-(4-methylpiperazin-l- yl)phenyl)amino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile monolactate, wherein the subject received a therapy other than the compound for the mantle cell lymphoma prior to the administering, wherein the therapy was received after the subject was diagnosed with mantle cell lymphoma, and wherein the subject has not responded to the therapy prior to the administering, and wherein the administering comprises 3 weeks of once- daily administration; and (ii) orally administering to the subject a therapeutically-effective amount of ibrutinib or a pharmaceutical
  • a method of treating mantle cell lymphoma in a subject in need thereof comprising, (i) orally administering to the subject a solid pharmaceutical composition, wherein the solid pharmaceutical composition comprises 40 mg to 500 mg of a compound that is 8-cyclopentyl-2-((4-(4-methylpiperazin-l- yl)phenyl)amino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile monolactate, wherein the subject received a therapy other than the compound for the mantle cell lymphoma prior to the administering, wherein the therapy was received after the subject was diagnosed with mantle cell lymphoma, and wherein the subject has not responded to the therapy prior to the administering, and wherein the administering comprises 3 weeks of once- daily administration; and (ii) orally administering to the subject a therapeutically-effective amount of acalabrutinib or
  • a method of treating Bruton tyrosine kinase inhibitor-resistant mantle cell lymphoma in a subject in need thereof comprising orally administering to the subject a solid pharmaceutical composition, the solid pharmaceutical composition comprising 40 mg to 500 mg of a compound that is 8- cyclopentyl-2-((4-(4-methylpiperazin-l-yl)phenyl)amino)-7-oxo-7,8-dihydropyrido[2,3- d]pyrimidine-6-carbonitrile monolactate, wherein the subject received a therapy other than the compound for the mantle cell lymphoma prior to the administering, wherein the therapy was received after the subject was diagnosed with mantle cell lymphoma, and wherein the subject has not responded to the therapy prior to the administering; and wherein the administering is once daily for at least 3 weeks.
  • a method of treating Bruton tyrosine kinase inhibitor-resistant mantle cell lymphoma in a subject in need thereof comprising, (i) orally administering to the subject a solid pharmaceutical composition, wherein the solid pharmaceutical composition comprises 40 mg to 500 mg of a compound that is 8- cyclopentyl-2-((4-(4-methylpiperazin-l-yl)phenyl)amino)-7-oxo-7,8-dihydropyrido[2,3- d]pyrimidine-6-carbonitrile monolactate, wherein the subject received a therapy other than the compound for the mantle cell lymphoma prior to the administering, wherein the therapy was received after the subject was diagnosed with mantle cell lymphoma, and wherein the subject has not responded to the therapy prior to the administering, and wherein the administering comprises 3 weeks of once-daily administration; and (ii) orally administering to the
  • a method of treating Bruton tyrosine kinase inhibitor-resistant mantle cell lymphoma in a subject in need thereof comprising, (i) orally administering to the subject a solid pharmaceutical composition, wherein the solid pharmaceutical composition comprises 40 mg to 500 mg of a compound that is 8- cyclopentyl-2-((4-(4-methylpiperazin-l-yl)phenyl)amino)-7-oxo-7,8-dihydropyrido[2,3- d]pyrimidine-6-carbonitrile monolactate, wherein the subject received a therapy other than the compound for the mantle cell lymphoma prior to the administering, wherein the therapy was received after the subject was diagnosed with mantle cell lymphoma, and wherein the subject has not responded to the therapy prior to the administering, and wherein the administering comprises 3 weeks of once-daily administration; and (ii) orally administering to the
  • FIG. 1 shows tumors treated with compound- 1 shows a greater reduction in tumor volume compared to the control.
  • FIG. 2 shows mice treated with compound- 1 shows a greater reduction in tumor volume compared to the mice treated with control.
  • FIG. 3 shows Western Blot analysis of MCL cell lines JEKO, UPN-1, REC-1, MINO, GRANTA-519, Z-138, and modified counterpart MCL cell lines UPN-ibrutinib resistant, REC-1 BTK mutant, and REC-1 BTK KO.
  • FIG. 4 shows percentage of cell viability in MCL cell lines JEKO, UPN-1, REC-1, MINO, GRANTA-519, and Z-138, treated with increasing doses of Compound (1) for 72 hours.
  • FIG. 5 shows percentage of cell viability in modified counterpart MCL cell lines UPN-ibrutinib resistant, REC-1 BTK mutant, REC-1 BTK KO, and REC-1 IKAROS KO treated with increasing doses of Compound (1) for 72 hours.
  • FIG. 6 shows Combination Index (CI) from CTG proliferation assays of MCL cell lines JEKO, UPNT-1, REC-1, Z-138, REC-1 IKAROS KO, UPN-ibrutinib resistant, REC-1 BTK mutant, and REC-1 BTK KO for various doses of Compound (1) combined with ibrutinib.
  • CI Combination Index
  • FIG. 7 shows Combination Index (CI) from CTG proliferation assays of MCL cell lines JEKO, UPNT-1, REC-1, Z-138, REC-1 IKAROS KO, UPN-ibrutinib resistant, REC-1 BTK mutant, and REC-1 BTK KO for various doses of Compound (1) combined with acalabrutinib.
  • CI Combination Index
  • FIG. 8 shows a CTG proliferation assay in MCL cell line UPN-1 treated with CDK4/6 inhibitors, BTK inhibitors, and a combination of CDK4/6 inhibitors and BTK inhibitors.
  • FIG. 9 shows a CTG proliferation assay in MCL cell line REC-1 treated with CDK4/6 inhibitors, BTK inhibitors, and a combination of CDK4/6 inhibitors and BTK inhibitors.
  • FIG. 10 shows a CTG proliferation assay in MCL cell line JEKO-1 treated with CDK4/6 inhibitors, BTK inhibitors, and a combination of CDK4/6 inhibitors and BTK inhibitors.
  • FIG. 11 shows a CTG proliferation assay in modified counterpart MCL cell line UPN-ibrutinib resistant (UPN-1 IbruR) treated with CDK4/6 inhibitors, BTK inhibitors, and a combination of CDK4/6 inhibitors and BTK inhibitors.
  • UPN-1 IbruR UPN-ibrutinib resistant
  • FIG. 12 shows a CTG proliferation assay in modified counterpart MCL cell line REC-1 BTK KO treated with CDK4/6 inhibitors, BTK inhibitors, and a combination of CDK4/6 inhibitors and BTK inhibitors.
  • FIG. 13 shows a CTG proliferation assay in modified counterpart MCL cell line REC-1 IKAROS KO treated with CDK4/6 inhibitors, BTK inhibitors, and a combination of CDK4/6 inhibitors and BTK inhibitors.
  • FIG. 14 shows cell cycle analysis in MCL cell line REC-1 treated with Compound (1), BTK inhibitors, and a combination of Compound (1) with BTK inhibitors.
  • FIG. 15 shows cell cycle analysis in MCL cell line Z-138 treated with Compound (1), BTK inhibitors, and a combination of Compound (1) with BTK inhibitors.
  • FIG. 16 shows cell cycle analysis in MCL cell line JEKO-1 treated with Compound (1), BTK inhibitors, and a combination of Compound (1) with BTK inhibitors.
  • FIG. 17 shows cell cycle analysis in MCL cell line UPN-1 treated with Compound (1), BTK inhibitors, and a combination of Compound (1) with BTK inhibitors.
  • FIG. 18 shows cell cycle analysis in modified counterpart MCL cell line UPN- ibrutinib resistant (UPN-1 IbruR) treated with Compound (1), BTK inhibitors, and a combination of Compound (1) with BTK inhibitors.
  • UPN-1 IbruR UPN- ibrutinib resistant
  • FIG. 19 shows cell cycle analysis in MCL cell line JEKO-1 treated with Compound (1), BTK inhibitors, and a combination of Compound (1) with BTK inhibitors.
  • FIG. 20 shows apoptosis analysis of MCL cell line JEKO-1 assessed by AnnexinV+ staining after treatment with Compound (1), BTK inhibitors, and a combination of Compound (1) with BTK inhibitors.
  • FIG. 21 shows apoptosis analysis of MCL cell line JEKO-1 assessed by AnnexinV+ staining after treatment with Compound (1), BTK inhibitors, and a combination of Compound (1) with BTK inhibitors.
  • FIG. 22 shows apoptosis analysis of MCL cell line Z-138 assessed by mitochondrial transmembrane potential (Aym) loss after treatment with Compound (1), BTK inhibitors, and a combination of Compound (1) with BTK inhibitors.
  • FIG. 23 shows apoptosis analysis of MCL cell line JEKO-1 assessed by mitochondrial transmembrane potential (Aym) loss after treatment with Compound (1), BTK inhibitors, and a combination of Compound (1) with BTK inhibitors.
  • FIG. 24 shows Western blot analysis of MCL cell line UPN-1 after treatment with Compound (1), BTK inhibitors, ibrutinib, acalabrutinib, or pirtobrutinib (Loxo-305), and a combination of Compound (1) with BTK inhibitors.
  • FIG. 25 shows Western blot analysis of modified counterpart MCL cell line UPN- ibrutinib resistant (UPN-1 IbruR) after treatment with Compound (1), BTK inhibitors, ibrutinib, acalabrutinib, or pirtobrutinib (Loxo-305), and a combination of Compound (1) with BTK inhibitors.
  • UPN-1 IbruR UPN- ibrutinib resistant
  • BTK inhibitors ibrutinib
  • acalabrutinib acalabrutinib
  • pirtobrutinib Lixo-305
  • FIG. 26 shows qRT-PCR quantification of cell -cycle related transcript AURKB in MCL cell JEKO-1 after treatment with Compound (1), BTK inhibitors, and a combination of Compound (1) with BTK inhibitors.
  • FIG. 27 shows qRT-PCR quantification of cell -cycle related transcript CDK1 in MCL cell JEKO-1 after treatment with Compound (1), BTK inhibitors, and a combination of Compound (1) with BTK inhibitors.
  • FIG. 28 shows qRT-PCR quantification of cell -cycle related transcript Cyclin B2 (CCNB2) in MCL cell JEKO-1 after treatment with Compound (1), BTK inhibitors, and a combination of Compound (1) with BTK inhibitors.
  • CCNB2 cell -cycle related transcript Cyclin B2
  • FIG. 29 shows qRT-PCR quantification of cell -cycle related transcript CDC20 in MCL cell JEKO-1 after treatment with Compound (1), BTK inhibitors, and a combination of Compound (1) with BTK inhibitors.
  • FIG. 30 shows qRT-PCR quantification of cell -cycle related transcript P16 (CDKN2A) in MCL cell JEKO-1 after treatment with Compound (1), BTK inhibitors, and a combination of Compound (1) with BTK inhibitors.
  • FIG. 31 shows qRT-PCR quantification of cell -cycle related transcript P27 (CDKN1B) in MCL cell JEKO-1 after treatment with Compound (1), BTK inhibitors, and a combination of Compound (1) with BTK inhibitors.
  • FIG. 32 shows qRT-PCR quantification of senescence related transcript IL-6 in MCL cell JEKO-1 after treatment with Compound (1), BTK inhibitors, and a combination of Compound (1) with BTK inhibitors.
  • FIG. 33 shows qRT-PCR quantification of senescence related transcript IL-8 in MCL cell JEKO-1 after treatment with Compound (1), BTK inhibitors, and a combination of Compound (1) with BTK inhibitors.
  • FIG. 34 shows qRT-PCR quantification of senescence related transcript CXCL1 in MCL cell JEKO-1 after treatment with Compound (1), BTK inhibitors, and a combination of Compound (1) with BTK inhibitors.
  • FIG. 35 shows qRT-PCR quantification of senescence related transcript MCP1 in MCL cell JEKO-1 after treatment with Compound (1), BTK inhibitors, and a combination of Compound (1) with BTK inhibitors.
  • FIG. 36 shows a heatmap of genes differentially regulated upon treatment with Compound (1) in MCL cell lines (UPN-1, UPN-IbruR, REC-1, JEKO-1 and MINO).
  • FIG. 37 shows a heatmap of genes differentially regulated upon treatment with Compound (1) in MCL cell lines (UPN-1, UPN-IbruR, REC-1, JEKO-1 and MINO).
  • FIG. 38 shows comparison of gene set enrichment analysis (GSEA) and proteomics analysis of MCL cell lines (UPN-1, UPN-1 RES) following exposure to a control compound or to Compound (1).
  • GSEA gene set enrichment analysis
  • FIG. 39 shows GSEA for E2F targets after transcriptomic (RNAseq) characterization of MCL cell lines following exposure to Compound (1).
  • FIG. 40 shows GSEA for MYC targets after transcriptomic (RNAseq) characterization of MCL cell lines following exposure to Compound (1).
  • FIG. 41 shows GSEA for G2/M checkpoints after transcriptomic (RNAseq) characterization of MCL cell lines following exposure to Compound (1).
  • FIG. 42 shows GSEA for DNA repair after transcriptomic (RNAseq) characterization of MCL cell lines following exposure to Compound (1).
  • FIG. 43 shows GSEA for TNFa signaling via NFKB after transcriptomic (RNAseq) characterization of MCL cell lines following exposure to Compound (1).
  • FIG. 44 shows GSEA for inflammatory response after transcriptomic (RNAseq) characterization of MCL cell lines following exposure to Compound (1).
  • FIG. 45 shows a schematic timeline for the chorioallantoic membrane chick embryo (CAM) model.
  • FIG. 46 shows egg weights of eggs inoculated with UPN-1 cells treated twice by CDK4/6 inhibitor or a combination of CDK4/6 inhibitor with ibrutinib.
  • FIG. 47 shows egg weights of eggs inoculated with UPN-IbruR cells treated twice by CDK4/6 inhibitor or a combination of CDK4/6 inhibitor with ibrutinib.
  • FIG. 48 shows embryo weights at day 7 after inoculation after treatment with CDK4/6 inhibitor or a combination of CDK4/6 inhibitor with ibrutinib.
  • FIG. 49 shows tumor weights at day 7 after inoculation with JEKO-1 cells and treatment with CDK4/6 inhibitor, BTK inhibitor ibrutinib, or a combination of CDK4/6 inhibitor with ibrutinib.
  • FIG. 50 shows tumor weights at day 7 after inoculation with UPN-1 cells and treatment with CDK4/6 inhibitor, BTK inhibitor ibrutinib or a combination of CDK4/6 inhibitor with ibrutinib.
  • FIG. 51 shows tumor weights at day 7 after inoculation with UPN-1 cells and treatment with CDK4/6 inhibitor, BTK inhibitor ibrutinib or a combination of CDK4/6 inhibitor with ibrutinib.
  • FIG. 52 shows MCL infiltration properties quantified by qPCR-mediated relative determination of human Alu sequences detected in the spleen of representative CAM-MCL chicken embryos (JEKO-1) after treatment with Compound (1), BTK inhibitor ibrutinib, or combination of Compound (1) with ibrutinib.
  • FIG. 53 shows MCL infiltration properties quantified by qPCR-mediated relative determination of human Alu sequences detected in the spleen of representative CAM-MCL chicken embryos (UPN-1) after treatment with Compound (1), BTK inhibitor ibrutinib, or combination of Compound (1) with ibrutinib.
  • FIG. 54A shows MCL infiltration properties quantified by qPCR-mediated relative determination of human Alu sequences detected in the spleen of representative CAM-MCL chicken embryos (UPN-1 IbruR) after treatment with Compound (1), BTK inhibitor ibrutinib, or combination of Compound (1) with ibrutinib.
  • FIG. 54B shows MCL infiltration properties quantified by qPCR-mediated relative determination of human Alu sequences detected in the spleen of representative CAM-MCL chicken embryos (UPN-1 IbruR) after treatment with Compound (1), BTK inhibitor ibrutinib, or combination of Compound (1) with ibrutinib.
  • FIG. 55 shows MCL infiltration properties quantified by qPCR-mediated relative determination of human Alu sequences detected in bone marrow (BM) of representative CAM-MCL chicken embryos (JEKO-1) after treatment with Compound (1), BTK inhibitor ibrutinib, or combination of Compound (1) with ibrutinib.
  • FIG. 56 shows MCL infiltration properties quantified by qPCR-mediated relative determination of human Alu sequences detected in bone marrow (BM) of representative CAM-MCL chicken embryos (UPN-1) after treatment with Compound (1), BTK inhibitor ibrutinib, or combination of Compound (1) with ibrutinib.
  • FIG. 57 shows MCL infiltration properties quantified by qPCR-mediated relative determination of human Alu sequences detected in bone marrow (BM) of representative CAM-MCL chicken embryos (UPN-1 IbruR) after treatment with Compound (1), BTK inhibitor ibrutinib, or combination of Compound (1) with ibrutinib.
  • compositions and methods for treating mantle cell lymphoma by administering to a subject in need thereof a pharmaceutical composition, the pharmaceutical composition comprising in a unit dosage form a therapeutically-effective amount of a compound described herein (e.g., Compound 1 or compound 1 or compound (1) or Compound (1)) or a pharmaceutically-acceptable salt thereof.
  • a compound described herein e.g., Compound 1 or compound 1 or compound (1) or Compound (1)
  • Compound l is 8-cyclopentyl-2-((4-(4-methylpiperazin-l-yl)phenyl)amino)-7-oxo-7,8- dihydropyrido[2,3-d]pyrimidine-6-carbonitrile.
  • Compound 1 is present in a salt form, e.g., 8-cyclopentyl-2-((4-(4-methylpiperazin-l-yl)phenyl)amino)-7- oxo-7, 8-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile monolactate salt (Compound 1 salt).
  • the methods further comprise administering a second pharmaceutical composition comprising, in a unit dosage form, a therapeutically-effective amount of a second compound, for example an Bruton’s tyrosine kinase (BTK) inhibiting drug.
  • the BTK inhibitor can be selected from but are not limited to Ibrutinib, Acalabrutinib, Zanubrutinib
  • a compound disclosed herein can be of the formula: wherein:
  • R 1 is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl, each of which is unsubstituted or substituted, or hydrogen;
  • R 3 is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl or heteroaryl, each of which is unsubstituted or substituted, or hydrogen or halogen;
  • a compound disclosed herein can be of the formula: wherein:
  • R 1 is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl, each of which is unsubstituted or substituted, or hydrogen;
  • R 3 is C 2 -Ce alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl or heteroaryl, each of which is unsubstituted or substituted, or hydrogen or halogen;
  • a compound disclosed herein can be a pharmaceutically-acceptable salt of the formula: wherein:
  • R 1 is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl, each of which is unsubstituted or substituted, or hydrogen;
  • R 3 is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl or heteroaryl, each of which is unsubstituted or substituted, or hydrogen or halogen;
  • a compound disclosed herein can be a lactate salt of the formula: wherein:
  • R 1 is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl, each of which is unsubstituted or substituted, or hydrogen;
  • R 3 is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl or heteroaryl, each of which is unsubstituted or substituted, or hydrogen or halogen;
  • R 1 is cycloalkyl. In some embodiments, R 1 is C 2 -Cs cycloalkyl. In some embodiments, R 1 is an unsubstituted cyclopentyl. In some embodiments, R 1 is an unsubstituted cyclopentyl. In some embodiments, R 2 is CN. In some embodiments, R 3 is hydrogen.
  • R 4 is -NR 5 R 6 .
  • one of R 5 and R 6 is hydrogen.
  • one of R 5 and R 6 is phenyl.
  • one of R 5 and R 6 is phenyl substituted with heterocyclyl.
  • one of R 5 and R 6 is phenyl substituted with heterocyclyl, wherein the heterocyclyl contains at least one ring nitrogen atom.
  • one of R 5 and R 6 is phenyl substituted with C 2 -Cs heterocyclyl.
  • one of R 5 and R 6 is phenyl substituted with Ce heterocyclyl.
  • one of R 5 and R 6 is phenyl substituted with piperazinyl, wherein the piperazinyl is unsubstituted or substituted. In some embodiments, one of R 5 and R 6 is phenyl substituted with piperazinyl, wherein the piperazinyl is substituted with an alkyl. In some embodiments, one of R 5 and R 6 is phenyl substituted with 4-methyl piperazinyl. [0086] In some embodiments, R 4 is wherein:
  • R 7 is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -OR 5 , - SR 5 , or -NR 5 R 6 , each of which is unsubstituted or substituted, or hydrogen;
  • R 8 is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -OR 5 , - SR 5 , or -NR 5 R 6 , each of which is unsubstituted or substituted, or hydrogen; and R 9 is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -OR 5 , - SR 5 , or -NR 5 R 6 , each of which is unsubstituted or substituted, or hydrogen.
  • R 7 is hydrogen.
  • R 8 is hydrogen.
  • R 9 unsubstituted or substituted heterocyclyl. In some embodiments, R 9 is unsubstituted or substituted piperazinyl. In some embodiments, R 9 is piperazinyl substituted with alkyl. In some embodiments, R 9 is 4-methyl piperazinyl.
  • the compound is a compound of formula (II)
  • the compound is a compound of formula (III)
  • Y is O, S, or NR 11 ; each R 10 is independently alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -OR 5 , -SR 5 , or -NR 5 R 6 , each of which is unsubstituted or substituted;
  • R 11 is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl, each of which is independently substituted or unsubstituted, or hydrogen or halogen; and n is 0, 1, 2, 3, 4, 5, 6, 7, or 8.
  • R 1 is cycloalkyl. In some embodiments, R 1 is Cs-Cs cycloalkyl. In some embodiments, R 1 is an unsubstituted cyclopentyl. In some embodiments, R 1 is an unsubstituted cyclopentyl.
  • Y is NR 11 .
  • R 11 is alkyl.
  • R 11 is methyl.
  • n is 0.
  • Y is NR 11 .
  • R 11 is alkyl.
  • R 11 is methyl.
  • n is 0.
  • the compound is of the formula:
  • the compound is in the form of a salt formed by combining a compound with lactic acid.
  • a compound disclosed herein is 8- cyclopentyl-2-((4-(4-methylpiperazin-l-yl)phenyl)amino)-7-oxo-7,8-dihydropyrido[2,3- d]pyrimidine-6-carbonitrile monolactate.
  • Several moieties described herein can be substituted or unsubstituted.
  • optional substituents include hydroxyl groups, sulfhydryl groups, halogens, amino groups, nitro groups, nitroso groups, cyano groups, azido groups, sulfoxide groups, sulfone groups, sulfonamide groups, carboxyl groups, carboxaldehyde groups, imine groups, alkyl groups, halo-alkyl groups, alkenyl groups, halo-alkenyl groups, alkynyl groups, halo- alkynyl groups, alkoxy groups, aryl groups, aryloxy groups, aralkyl groups, arylalkoxy groups, heterocyclyl groups, acyl groups, acyloxy groups, carbamate groups, amide groups, ureido groups, epoxy groups, and ester groups.
  • Non-limiting examples of alkyl groups include straight, branched, and cyclic alkyl groups.
  • An alkyl group can be, for example, a Ci, C2, C3, C4, C5, Ce, C7, Cs, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, C 24 , C 25 , C 26 , C27, C 28 , C29, C30, C31, C32, C33, C34, C35, C36, C37, C38, C39, C40, C41, C42, C43, C44, C45, C46, C47, C48, C49, or C50 group that is substituted or unsubstituted.
  • Non-limiting examples of straight alkyl groups include methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, and decyl.
  • Branched alkyl groups include any straight alkyl group substituted with any number of alkyl groups.
  • Non-limiting examples of branched alkyl groups include isopropyl, isobutyl, sec-butyl, and t-butyl.
  • Non-limiting examples of substituted alkyl groups includes hydroxymethyl, chloromethyl, trifluoromethyl, aminomethyl, 1 -chloroethyl, 2 -hydroxy ethyl, 1,2- difluoroethyl, and 3-carboxypropyl.
  • Non-limiting examples of cyclic alkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptlyl, and cyclooctyl groups. Cyclic alkyl groups also include fused-, bridged-, and spiro-bicycles and higher fused-, bridged-, and spiro-systems. A cyclic alkyl group can be substituted with any number of straight, branched, or cyclic alkyl groups.
  • Non-limiting examples of cyclic alkyl groups include cyclopropyl, 2-methyl- cycloprop-l-yl, cycloprop-2-en-l-yl, cyclobutyl, 2,3-dihydroxycyclobut-l-yl, cyclobut-2-en- 1-yl, cyclopentyl, cyclopent-2-en-l-yl, cyclopenta-2,4-dien-l-yl, cyclohexyl, cyclohex-2-en- 1-yl, cycloheptyl, cyclooctanyl, 2,5-dimethylcyclopent-l-yl, 3,5-dichlorocyclohex-l-yl, 4- hydroxycyclohex-l-yl, 3,3,5-trimethylcyclohex-l-yl, octahydropentalenyl, octahydro- 1/7- indenyl, 3a,4,5,6,7,7a-
  • Non-limiting examples of alkenyl and alkenylene groups include straight, branched, and cyclic alkenyl groups.
  • the olefin or olefins of an alkenyl group can be, for example, E, Z, cis, trans, terminal, or exo-methylene.
  • An alkenyl or alkenylene group can be, for example, a C 2 , C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , Cio, Cu, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, C24, c 25 , C26, C27, C 28 , C29, C30, C31, C32, C33, C34, c 35 , C36, C37, C 38 , C39, C40, C41, C42, C43, C44, C45, C46, C47, c 48 , C49, or C50 group that is substituted or unsubstituted.
  • Non-limiting examples of alkenyl and alkenylene groups include ethenyl, prop-l-en-l-yl, isopropenyl, but- l-en-4-yl; 2-chloroethenyl, 4-hydroxybuten-l-yl, 7-hydroxy-7-methyloct-4-en-2-yl, and 7- hy droxy-7 -methyloct-3 , 5 -dien-2-yl .
  • Non-limiting examples of alkynyl or alkynylene groups include straight, branched, and cyclic alkynyl groups.
  • the triple bond of an alkylnyl or alkynylene group can be internal or terminal.
  • An alkylnyl or alkynylene group can be, for example, a C 2 , C3, C 4 , C5, Ce, C 7 , C 8 , C 9 , Cio, Cu, C12, C13, C14, C15, C16, C17, Cl 8 , C19, C 2 0, C 2 1, C 2 2, C 2 3, C 2 4, C 25 , C 2 6, C 2 7, C 28 , C29, C 30 , C31, C 32 , C 33 , C 34 , C 35 , C 36 , C 37 , C 38 , C 39 , C40, C41, c 42 , C 43 , C44, c 45 , C 46 , C47, C 48 , C49, or C50 group that
  • Non-limiting examples of alkynyl or alkynylene groups include ethynyl, prop-2-yn-l-yl, prop-l-yn-l-yl, and 2-methyl-hex-4-yn-l- yl; 5-hydroxy-5-methylhex-3-yn-l-yl, 6-hydroxy-6-methylhept-3-yn-2-yl, and 5-hydroxy-5- ethylhept-3 -yn- 1 -yl .
  • a halo-alkyl group can be any alkyl group substituted with any number of halogen atoms, for example, fluorine, chlorine, bromine, and iodine atoms.
  • a halo-alkenyl group can be any alkenyl group substituted with any number of halogen atoms.
  • a halo-alkynyl group can be any alkynyl group substituted with any number of halogen atoms.
  • An alkoxy group can be, for example, an oxygen atom substituted with any alkyl, alkenyl, or alkynyl group.
  • An ether or an ether group comprises an alkoxy group.
  • alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, and isobutoxy.
  • An aryl group can be heterocyclic or non-heterocyclic.
  • An aryl group can be monocyclic or polycyclic.
  • An aryl group can be substituted with any number of substituents described herein, for example, hydrocarbyl groups, alkyl groups, alkoxy groups, and halogen atoms.
  • Non-limiting examples of aryl groups include phenyl, toluyl, naphthyl, pyrrolyl, pyridyl, imidazolyl, thiophenyl, and furyl.
  • Non-limiting examples of substituted aryl groups include 3,4-dimethylphenyl, 4-/c/7-butyl phenyl, 4-cyclopropylphenyl, 4-diethylaminophenyl, 4-(trifluoromethyl)phenyl, 4-(difluoromethoxy)-phenyl, 4-(trifluoromethoxy)phenyl, 3- chlorophenyl, 4-chlorophenyl, 3, 4-di chlorophenyl, 2-fluorophenyl, 2-chlorophenyl, 2- iodophenyl, 3 -iodophenyl, 4-iodophenyl, 2-m ethylphenyl, 3 -fluorophenyl, 3 -methylphenyl, 3 -methoxy phenyl, 4-fluorophenyl, 4-methylphenyl, 4-m ethoxyphenyl, 2,3 -difluorophenyl, 3,4-difluoropheny
  • Non-limiting examples of substituted aryl groups include 2-aminophenyl, 2-(N- methylamino)phenyl, 2-(7V,7V-dimethylamino)phenyl, 2-(7V-ethylamino)phenyl, 2-(N,N- diethylamino)phenyl, 3 -aminophenyl, 3-(7V-methylamino)phenyl, 3-(N,N- dimethylamino)phenyl, 3-(7V-ethylamino)phenyl, 3-(A,A-diethylamino)phenyl, 4- aminophenyl, 4-(A-methylamino)phenyl, 4-(A,A-dimethylamino)phenyl, 4-(N- ethylamino)phenyl, and 4-(7V,7V-diethylamino)phenyl.
  • a heterocycle can be any ring containing a ring atom that is not carbon, for example, N, O, S, P, Si, B, or any other heteroatom.
  • a heterocycle can be substituted with any number of substituents, for example, alkyl groups and halogen atoms.
  • a heterocycle can be aromatic (heteroaryl) or non-aromatic.
  • Non-limiting examples of heterocycles include pyrrole, pyrrolidine, pyridine, piperidine, succinamide, maleimide, morpholine, imidazole, thiophene, furan, tetrahydrofuran, pyran, and tetrahydropyran.
  • heterocycles include: heterocyclic units having a single ring containing one or more heteroatoms, non-limiting examples of which include, diazirinyl, aziridinyl, azetidinyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolinyl, thiazolidinyl, isothiazolinyl, oxathiazolidinonyl, oxazolidinonyl, hydantoinyl, tetrahydrofuranyl, pyrrolidinyl, morpholinyl, piperazinyl, piperidinyl, dihydropyranyl, tetrahydropyranyl, piperidin-2-onyl, 2,3,4,5-tetrahydro-17/-azepinyl, 2,3 -dihydro- 177-indole, and 1,2,3,
  • heteroaryl include: i) heteroaryl rings containing a single ring, non-limiting examples of which include, 1,2,3,4-tetrazolyl, [l,2,3]triazolyl, [l,2,4]triazolyl, triazinyl, thiazolyl, 1/7-imidazolyl, oxazolyl, isoxazolyl, isothiazolyl, furanyl, thiophenyl, pyrimidinyl, 2-phenylpyrimidinyl, pyridinyl, 3-methylpyridinyl, and 4- dimethylaminopyridinyl; and ii) heteroaryl rings containing 2 or more fused rings one of which is a heteroaryl ring, non-limiting examples of which include: 7/7-purinyl, 9/7-purinyl, 6-amino-9Z7-purinyl, 5Z7-pyrrolo[3,2- ]pyrimidinyl, 7Z
  • a compound herein can be least 1% pure, at least 2% pure, at least 3% pure, at least 4% pure, at least 5% pure, at least 6% pure, at least 7% pure, at least 8% pure, at least 9% pure, at least 10% pure, at least 11% pure, at least 12% pure, at least 13% pure, at least 14% pure, at least 15% pure, at least 16% pure, at least 17% pure, at least 18% pure, at least 19% pure, at least 20% pure, at least 21% pure, at least 22% pure, at least 23% pure, at least 24% pure, at least 25% pure, at least 26% pure, at least 27% pure, at least 28% pure, at least 29% pure, at least 30% pure, at least 31% pure, at least 32% pure, at least 33% pure, at least 34% pure, at least 35% pure, at least 36% pure, at least 37% pure, at least 38% pure, at least 39% pure, at least 40% pure, at least 4
  • compositions include, for example, acid-addition salts and base-addition salts.
  • the acid that is added to the compound to form an acid-addition salt can be an organic acid or an inorganic acid.
  • a base that is added to the compound to form a base-addition salt can be an organic base or an inorganic base.
  • Acid addition salts can arise from the addition of an acid to a compound disclosed herein.
  • the acid is organic.
  • the acid is inorganic.
  • the acid is lactic acid, salicylic acid, tartaric acid, ascorbic acid, gentisinic acid, gluconic acid, glucaronic acid, saccaric acid, formic acid, benzoic acid, glutamic acid, pantothenic acid, acetic acid, propionic acid, butyric acid, fumaric acid, succinic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p- toluenesulfonic acid, citric acid, oxalic acid, maleic acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, nitrous acid, sulfuric acid, sulfurous acid, a phosphoric acid, or isonicotinic acid.
  • the salt is an acid addition salt with lactic acid. In some embodiments, the salt is an acid addition salt of 8-cyclopentyl-2-((4-(4- methylpiperazin-l-yl)phenyl)amino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6- carbonitrile with lactic acid.
  • the salt is a lactate salt, a salicylate salt, a tartrate salt, an ascorbate salt, a gentisinate salt, a gluconate salt, a glucaronate salt, a saccarate salt, a formate salt, a benzoate salt, a glutamate salt, a pantothenate salt, an acetate salt, a propionate salt, a butyrate salt, a fumarate salt, a succinate salt, a methanesulfonate salt, an ethanesulfonate salt, a benzenesulfonate salt, a p-toluenesulfonate salt, a citrate salt, an oxalate salt, a maleate salt, hydrochloride salt, a hydrobromide salt, a hydroiodide salt, a nitrate salt, a nitrite salt, a sulfate salt,
  • the salt is a lactate salt. In some embodiments, the salt is a monolactate salt. In some embodiments, the compound is 8-cyclopentyl-2-((4-(4-methylpiperazin-l-yl)phenyl)amino)-7-oxo-7,8- dihydropyrido[2,3-d]pyrimidine-6-carbonitrile monolactate.
  • Metal salts can arise from the addition of an inorganic base to a compound disclosed herein.
  • the inorganic base consists of a metal cation paired with a basic counterion, such as, for example, hydroxide, carbonate, bicarbonate, or phosphate.
  • the metal can be an alkali metal, alkaline earth metal, transition metal, or main group metal.
  • the metal is lithium, sodium, potassium, cesium, cerium, magnesium, manganese, iron, calcium, strontium, cobalt, titanium, aluminum, copper, cadmium, or zinc.
  • a metal salt is a lithium salt, a sodium salt, a potassium salt, a cesium salt, a cerium salt, a magnesium salt, a manganese salt, an iron salt, a calcium salt, a strontium salt, a cobalt salt, a titanium salt, an aluminum salt, a copper salt, a cadmium salt, or a zinc salt.
  • a compound described herein can down-modulate these kinase pathways, or a portion thereof, for example, cyclin-dependent kinases (CDK), e.g., a CDK inhibitor.
  • CDK cyclin-dependent kinases
  • a CDK inhibitor is a compound disclosed herein.
  • Non-limiting examples of CDK inhibitors are listed in Table 1.
  • overexpression of CDK e.g., CDK 4/6 causes cell-cycle deregulation in cancers.
  • modulation of kinase pathways can result in the obstruction of proliferation signal receipt in cells, thus arresting tumor growth.
  • CDK4/6 inhibition can arrest the cell cycle (e.g., through repression of positive regulators of the G2/M cell cycle phase, or increase in G1 cell cycle fraction and G1 blockade).
  • the CDK inhibitor is a compound disclosed herein. In some embodiments, the CDK inhibitor is a CDK4/6 inhibitor. In some embodiments, the CDK4/6 inhibitor is a compound of formula (I), or a pharmaceutically-acceptable salt thereof. In some embodiments, a compound disclosed herein comprises a compound of formula (I), or a pharmaceutically-acceptable salt thereof. In some embodiments, a compound of formula (I) comprises 8-cyclopentyl-2-((4-(4-methylpiperazin-l yl)phenyl)amino)-7-oxo-7,8- dihydropyrido[2,3-d]pyrimidine-6-carbonitrile or a pharmaceutically-acceptable salt thereof.
  • 8-cyclopentyl-2-((4-(4-methylpiperazin-l yl)phenyl)amino)-7-oxo- 7,8-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile or a pharmaceutically-acceptable salt thereof is compound (1).
  • a method disclosed herein comprises administering to the subject a therapeutically-effective amount of a compound disclosed herein or a pharmaceutically-acceptable salt thereof. In some embodiments, a method disclosed herein comprises administering to the subject a therapeutically-effective amount of a compound (1) or a pharmaceutically-acceptable salt thereof.
  • a compound disclosed herein has an enhanced antitumor activity compared to other CDK inhibitors. In some embodiments, a compound disclosed herein has an enhanced antitumor activity compared to palbociclib. In some embodiments, a compound disclosed herein has an enhanced antitumor activity compared to ribociclib. In some embodiments, a compound disclosed herein has an enhanced antitumor activity compared to abemaciclib. In some embodiments, a compound disclosed herein has a greater antitumor activity compared to trilaciclib. In some embodiments, enhanced antitumor activity comprises enhanced tumor growth inhibition. In some embodiments, enhanced antitumor activity comprises increased apoptosis. In some embodiments, enhanced antitumor activity comprises enhanced cell proliferation inhibition.
  • a compound disclosed herein has superior activity compared to other CDK inhibitors. In some embodiments, a compound disclosed herein has superior activity compared to palbociclib. In some embodiments, a compound disclosed herein has superior activity compared to ribociclib. In some embodiments, a compound disclosed herein has superior activity compared to abemaciclib. In some embodiments, a compound disclosed herein has superior activity compared to trilaciclib.
  • a compound disclosed herein represses one or more positive regulators of the G2/M cell cycle phase. In some embodiments, a compound disclosed herein increases loss of phospho-Histone H3. In some embodiments, a compound disclosed herein downregulates phospho-Histone H3/CDK2. In some embodiments, a compound disclosed herein triggers accumulation of CDK inhibitors p21, pl 6, and/or phospho-p27. In some embodiments, a compound disclosed herein upregulates p21, pl 6, and/or phospho-p27. In some embodiments, a compound disclosed herein triggers CDK2 dephosphorylation. In some embodiments, a compound disclosed herein increases a G1 cell cycle blockade. In some embodiments, a compound disclosed herein increases mitochondrial apoptosis.
  • the B cell receptor signaling pathway is essential for B cell development and antibody production and is often affected in hemopoietic cancers, including mantle cell lymphoma.
  • a compound described herein can down-modulate the B cell receptor signaling pathway, or a portion thereof, for example, Bruton tyrosine kinase (BTK).
  • BTK Bruton tyrosine kinase
  • overexpression of BTK causes cell-cycle deregulation in cancers.
  • modulation of kinase pathways can result in the obstruction of proliferation signal receipt in cells, thus arresting tumor growth.
  • a compound described herein can be an inhibitor of tyrosine kinases.
  • a compound described herein can be an inhibitor of Bruton’s tyrosine kinase (BTK).
  • BTK Bruton’s tyrosine kinase
  • the dual inhibitory effect of a compound described herein provides a therapeutic strategy to improve efficacy of BTK inhibition and reduce emergence of resistance.
  • the present disclosure provides a method for the use of a compound disclosed herein, for example, for treating cancer.
  • Cancer is a collection of related diseases characterized by uncontrolled proliferation of cells with the potential to metastasize throughout the body. Cancer can be classified into five broad categories including, for example: carcinomas, which can arise from cells that cover internal and external parts of the body such as the lung, breast, and colon; sarcomas, which can arise from cells that are located in bone, cartilage, fat, connective tissue, muscle, and other supportive tissues; lymphomas, which can arise in the lymph nodes and immune system tissues; leukemia, which can arise in the bone marrow and accumulate in the bloodstream; and adenomas, which can arise in the thyroid, the pituitary gland, the adrenal gland, and other glandular tissues.
  • carcinomas which can arise from cells that cover internal and external parts of the body such as the lung, breast, and colon
  • sarcomas which can arise from cells that are located in bone, cartilage, fat, connective tissue, muscle, and other supportive tissues
  • lymphomas which can arise in the lymph nodes and immune system tissues
  • leukemia which can
  • the cancer is a solid tumor cancer.
  • the cancer is carcinoma.
  • carcinoma include: adenocarcinoma, basal cell carcinoma, squamous cell carcinoma, and transitional cell carcinoma.
  • the cancer is sarcoma.
  • sarcomas include: bone sarcomas and soft tissue sarcomas.
  • the sarcoma is a soft tissue sarcoma.
  • soft-tissue sarcomas include: chondrosarcoma, rhabdomysarcoma, and leiomyosarcoma.
  • the cancer is lymphoma.
  • lymphoma include: subsets of lymphoma, Hodgkin lymphoma, Non-Hodgkin lymphoma, B cell lymphoma, Diffuse large B-cell lymphoma (DLBCL), Mantle cell lymphoma (MCL), Lymphoblastic lymphoma, Burkitt lymphoma (BL), Primary mediastinal (thymic) large B- cell lymphoma (PMBCL), Transformed follicular and transformed mucosa-associated lymphoid tissue (MALT) lymphomas, High-grade B-cell lymphoma with double or triple hits (HBL), Primary cutaneous DLBCL, leg type, Primary DLBCL of the central nervous system, Primary central nervous system (CNS) lymphoma, Acquired immunodeficiency syndrome (AIDS)-associated lymphoma, Follicular lymphoma (FL), Marginal zone lymphoma (MZL),
  • DLBCL Diffuse large B
  • the cancer is breast cancer.
  • the cancer is hormone receptor-positive (HR+), HER2-negative metastatic breast cancer.
  • the cancer is triple negative breast cancer (TNBC).
  • the cancer is lung cancer.
  • the cancer is colon cancer.
  • the cancer is Mantle cell lymphoma (MCL).
  • the cancer is BTKi-resistant MCL.
  • the cancer is B-cell non-Hodgkin lymphoma (B-NHL).
  • the cancer is a carcinoma of the bladder, breast, colon (e.g., colorectal carcinomas such as colon adenocarcinoma and colon adenoma), kidney, epidermis, liver, lung, for example adenocarcinoma, small cell lung cancer and non-small cell lung carcinomas, esophagus, gall bladder, ovary, pancreas e.g., exocrine pancreatic carcinoma, stomach, cervix, thyroid, nose, head and neck, prostate, or skin, for example squamous cell carcinoma; a hematopoietic tumor of lymphoid lineage, for example leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, B-cell lymphoma (such as diffuse large B cell lymphoma), T-cell lymphoma, multiple myeloma, mantle cell lymphoma, Hodgkin’s lymphoma, non-Hodg
  • the cancer is a cancer sensitive to inhibition of one or more cyclin dependent kinases, e.g., CDK4 sensitive cancer, CDK6 sensitive cancer, CDK4/6 sensitive cancer.
  • cyclin dependent kinases e.g., CDK4 sensitive cancer, CDK6 sensitive cancer, CDK4/6 sensitive cancer.
  • the cancer is associated with dysregulation of a gene, e.g., overexpression or underexpression of a gene, e.g., BUB1, BRCA.
  • the cancer is associated with dysregulation of a transcription factor, e.g., overexpression or underexpression of a transcription factor, e.g., MYC, E2F.
  • the cancer is a cancer comprising cancer stem cells (CSCs), e.g., breast cancer.
  • CSCs cancer stem cells
  • the cancer is a refractory cancer.
  • the cancer is a relapsed cancer.
  • the cancer is resistant and/or non-responsive to a first line of therapy.
  • the cancer is associated with poor prognosis and/or low survival probability.
  • the cancer is a cancer of a reproductive organ.
  • the reproductive organ cancer is a breast cancer, ovarian cancer, e.g., serous ovarian cancer, e.g., low grade serous ovarian cancer, endometrial cancer.
  • the breast cancer is a primary breast cancer.
  • the breast cancer is a secondary breast cancer.
  • the breast cancer is a metastatic breast cancer.
  • the breast cancer is hormone receptor positive.
  • the breast cancer is estrogen receptor positive.
  • the breast cancer is estrogen receptor negative.
  • the breast cancer is progesterone receptor positive.
  • the breast cancer is progesterone receptor negative.
  • the breast cancer is HER2 receptor negative. In some embodiments, the breast cancer is estrogen receptor positive and progesterone receptor positive. In some embodiments, the breast cancer is estrogen receptor positive and progesterone receptor negative. In some embodiments, the breast cancer is estrogen receptor negative and progesterone receptor positive. In some embodiments, the breast cancer is estrogen receptor negative and progesterone receptor negative. In some embodiments, the breast cancer is estrogen receptor positive, progesterone receptor positive, and HER2 receptor negative. In some embodiments, the breast cancer is estrogen receptor positive, progesterone receptor negative, and HER2 receptor negative. In some embodiments, the breast cancer is estrogen receptor negative, progesterone receptor positive, and HER2 receptor negative. In some embodiments, the breast cancer is estrogen receptor negative, progesterone receptor positive, and HER2 receptor negative. In some embodiments, the breast cancer is estrogen receptor negative, progesterone receptor positive, and HER2 receptor negative.
  • the breast cancer is estrogen receptor negative, progesterone receptor negative, and HER2 receptor negative. In some embodiments, the breast cancer is TNBC. In some embodiments, the breast cancer is a BRCA positive. In some embodiments, the breast cancer shows BUB1 expression, e.g., very high, high, low, or very low expressions of BUB1. In some embodiments, the breast cancer does not show BUB1 expression, e.g., detectable BUB 1 expression. In some embodiments, the breast cancer showing high expression of BUB1 is associated with low survival probability. In some embodiments, the breast cancer is a refractory and/or relapsed breast cancer.
  • Non-limiting examples of tumors that are treatable by a combination of a compound described herein can include solid tumors, solid tumors that are refractory to prior treatment with conventional chemotherapy, and solid tumors that respond to initial chemotherapy but subsequently relapsed.
  • the tumor is a breast cancer tumor.
  • the tumor is a metastatic breast cancer tumor.
  • the breast cancer tumor is hormone receptor positive.
  • the breast cancer tumor is estrogen receptor positive.
  • the breast cancer tumor is estrogen receptor negative.
  • the breast cancer tumor is progesterone receptor positive.
  • the breast cancer tumor is progesterone receptor negative.
  • the breast cancer tumor is HER2 receptor negative.
  • the breast cancer tumor is estrogen receptor positive and progesterone receptor positive. In some embodiments, the breast cancer tumor is estrogen receptor positive and progesterone receptor negative. In some embodiments, the breast cancer tumor is estrogen receptor negative and progesterone receptor positive. In some embodiments, the breast cancer tumor is estrogen receptor negative and progesterone receptor negative. In some embodiments, the breast cancer tumor is estrogen receptor positive, progesterone receptor positive, and HER2 receptor negative. In some embodiments, the breast cancer tumor is estrogen receptor positive, progesterone receptor negative, and HER2 receptor negative. In some embodiments, the breast cancer tumor is estrogen receptor negative, progesterone receptor positive, and HER2 receptor negative. In some embodiments, the breast cancer tumor is estrogen receptor negative, progesterone receptor positive, and HER2 receptor negative. In some embodiments, the breast cancer tumor is estrogen receptor negative, progesterone receptor positive, and HER2 receptor negative.
  • the breast cancer tumor is estrogen receptor negative, progesterone receptor negative, and HER2 receptor negative. In some embodiments, the breast cancer tumor is TNBC. In some embodiments, the breast cancer tumor is a BRCA positive. In some embodiments, the breast cancer tumor shows BUB1 expression, e.g., very high, high, low, or very low expressions of BUB1. In some embodiments, the breast cancer tumor does not show BUB1 expression, e.g., detectable BUB 1 expression. In some embodiments, the breast cancer tumor showing high expression of BUB1 is associated with low survival probability. In some embodiments, the breast cancer tumor is a refractory and/or relapsed.
  • a method disclosed herein can be used to treat, for example, an infectious disease, a proliferative disease, a cancer, a solid tumor, or a liquid tumor.
  • tumors that are treatable by a combination of a compound described herein can include solid tumors, solid tumors that are refractory to prior treatment with conventional chemotherapy, and solid tumors that respond to initial chemotherapy but subsequently relapsed.
  • the tumor is a solid tumor.
  • solid tumors include: carcinomas, sarcomas, and lymphomas.
  • the solid tumor is a carcinoma.
  • the solid tumor is a sarcoma.
  • the solid tumor is a lymphona.
  • the tumor is a mantle cell lymphoma tumor.
  • a tumor response due to a method herein can be measured based on the Response Evaluation Criteria in Solid Tumors (RECIST) classification of responses.
  • RECIST Response Evaluation Criteria in Solid Tumors
  • To use RECIST requires at least one tumor that can be measured on x-rays, CT scans, or MRI scans.
  • RECIST assigns four categories of response: complete response (CR), a partial response (PR), progressive disease (PD), and stable disease (SD).
  • Key features of the RECIST include definitions of minimum size of measurable lesions, instructions on how many lesions to follow, and the use of uni dimensional, rather than bidimensional, measures for overall evaluation of tumor burden.
  • the present disclosure provides a method of treating mantle cell lymphoma in a subject in need thereof, the method comprising administering to the subject a therapeutically-effective amount of a compound of formula (I), or a pharmaceutically-acceptable salt thereof.
  • the present disclosure provides a method of treating mantle cell lymphoma in a subject in need thereof, the method comprising administering to the subject a therapeutically-effective amount of 8-cyclopentyl- 2-((4-(4-methylpiperazin-l yl)phenyl)amino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6- carbonitrile or a pharmaceutically-acceptable salt thereof.
  • the present disclosure provides a method of treating mantle cell lymphoma in a subject in need thereof, the method comprising administering to the subject a therapeutically-effective amount of 8- cyclopentyl-2-((4-(4-methylpiperazin-l yl)phenyl)amino)-7-oxo-7,8-dihydropyrido[2,3- d]pyrimidine-6-carbonitrile monolactate.
  • the present disclosure provides a method of treating mantle cell lymphoma in a subject in need thereof, the method comprising administering to the subject a therapeutically-effective amount of a compound of formula (I), or a pharmaceutically-acceptable salt thereof.
  • the present disclosure provides a method of treating mantle cell lymphoma in a subject in need thereof, the method comprising administering to the subject a therapeutically-effective amount of 8-cyclopentyl- 2-((4-(4-methylpiperazin-l yl)phenyl)amino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6- carbonitrile or a pharmaceutically-acceptable salt thereof.
  • the present disclosure provides a method of treating mantle cell lymphoma in a subject in need thereof, the method comprising administering to the subject a therapeutically-effective amount of 8- cyclopentyl-2-((4-(4-methylpiperazin-l yl)phenyl)amino)-7-oxo-7,8-dihydropyrido[2,3- d]pyrimidine-6-carbonitrile monolactate.
  • the present disclosure provides a method of treating Bruton tyrosine kinase inhibitor-resistant mantle cell lymphoma in a subject in need thereof, the method comprising administering to the subject a therapeutically-effective amount of a compound of formula (I), or a pharmaceutically-acceptable salt thereof.
  • the present disclosure provides a method of treating mantle cell lymphoma in a subject in need thereof, the method comprising administering to the subject a therapeutically- effective amount of 8-cyclopentyl-2-((4-(4-methylpiperazin-l yl)phenyl)amino)-7-oxo-7,8- dihydropyrido[2,3-d]pyrimidine-6-carbonitrile or a pharmaceutically-acceptable salt thereof.
  • the present disclosure provides a method of treating mantle cell lymphoma in a subject in need thereof, the method comprising administering to the subject a therapeutically-effective amount of 8-cyclopentyl-2-((4-(4-methylpiperazin-l yl)phenyl)amino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile monolactate.
  • the present disclosure provides a method of treating Bruton tyrosine kinase inhibitor-resistant mantle cell lymphoma in a subject in need thereof, the method comprising administering to the subject a therapeutically-effective amount of a compound of formula (I), or a pharmaceutically-acceptable salt thereof.
  • the present disclosure provides a method of treating mantle cell lymphoma in a subject in need thereof, the method comprising administering to the subject a therapeutically- effective amount of 8-cyclopentyl-2-((4-(4-methylpiperazin-l yl)phenyl)amino)-7-oxo-7,8- dihydropyrido[2,3-d]pyrimidine-6-carbonitrile or a pharmaceutically-acceptable salt thereof.
  • the present disclosure provides a method of treating mantle cell lymphoma in a subject in need thereof, the method comprising administering to the subject a therapeutically-effective amount of 8-cyclopentyl-2-((4-(4-methylpiperazin-l yl)phenyl)amino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile monolactate.
  • the subject is further treated with a BTK inhibitor, e.g., acalabrutinib.
  • the 8-cyclopentyl-2-((4-(4-methylpiperazin-l yl)phenyl)amino)-7-oxo- 7,8-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile monolactate and the BTK inhibitor, e.g., acalabrutinib are administered concurrently.
  • the subject is further treated with a BTK inhibitor, e.g., acalabrutinib.
  • the 8-cyclopentyl-2- ((4-(4-methylpiperazin-l yl)phenyl)amino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6- carbonitrile monolactate is administered before administering the BTK inhibitor, e.g., acalabrutinib.
  • the 8-cyclopentyl-2-((4-(4-methylpiperazin-l yl)phenyl)amino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile monolactate is administered after administering the BTK inhibitor, e.g., acalabrutinib.
  • the administering comprises a second line of therapy.
  • the subject received a therapy other than the compound for the mantle cell lymphoma (e.g., BTK inhibitor such as ibrutinib or acalabrutinib) prior to the administering.
  • the therapy e.g., BTK inhibitor such as ibrutinib
  • the subject did not respond to the therapy (e.g., BTK inhibitor such as ibrutinib or acalabrutinib).
  • the subject experienced a relapse of the mantle cell lymphoma after the therapy (e.g., BTK inhibitor such as ibrutinib acalabrutinib).
  • BTK inhibitor such as ibrutinib acalabrutinib
  • the subject has primary resistance to one or more BTK inhibitors, e.g., acalabrutinib.
  • the subject has acquired resistance to one or more BTK inhibitors e.g., acalabrutinib.
  • a method disclosed herein comprises administering to the subject a therapeutically-effective amount of a compound of formula (I), or a pharmaceutically-acceptable salt thereof.
  • a compound disclosed herein comprises a compound of formula (I), or a pharmaceutically-acceptable salt thereof.
  • a compound of formula (I) comprises 8-cyclopentyl-2-((4-(4- methylpiperazin-1 yl)phenyl)amino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6- carbonitrile or a pharmaceutically-acceptable salt thereof.
  • 8- cyclopentyl-2-((4-(4-methylpiperazin-l yl)phenyl)amino)-7-oxo-7,8-dihydropyrido[2,3- d]pyrimidine-6-carbonitrile or a pharmaceutically-acceptable salt thereof is compound (1).
  • Cancer development is a multistep process where genetic changes are accumulated, thus progressively transforming cells into a cancerous phenotype.
  • one or more genes associated with cellular proliferation is upregulated in a cell of a subject having a cancer disclosed herein.
  • one or more genes associated with a protein exposed on or secreted from the cell surface is downregulated in a cell of a subject having a cancer disclosed herein.
  • administering a compound disclosed herein alters expression of one or more genes in a cell of a subject having a cancer disclosed herein.
  • a compound disclosed herein downregulates expression of one or more differentially expressed genes in a cell of a subject having a cancer disclosed herein. In some embodiments, a compound disclosed herein downregulates a gene associated with DNA repair. In some embodiments, a compound disclosed herein downregulates a gene associated with G2/M checkpoints. In some embodiments, a compound disclosed herein downregulates a gene associated with E2F targets. In some embodiments, a compound disclosed herein downregulates a gene associated with MYC targets. In some embodiments, a compound disclosed herein downregulates a gene associated with TNFa signaling. In some embodiments, a compound disclosed herein downregulates a gene associated with inflammatory response.
  • a compound disclosed herein upregulates expression of one or more differentially expressed genes in a cell of a subject having a cancer disclosed herein. In some embodiments, a compound disclosed herein upregulates a gene associated with DNA repair. In some embodiments, a compound disclosed herein upregulates a gene associated with G2/M checkpoints. In some embodiments, a compound disclosed herein upregulates a gene associated with E2F targets. In some embodiments, a compound disclosed herein upregulates a gene associated with MYC targets. In some embodiments, a compound disclosed herein upregulates a gene associated with TNFa signaling. In some embodiments, a compound disclosed herein upregulates a gene associated with inflammatory response.
  • the present disclosure also provides method for using such a compound disclosed herein, for example, 8-cyclopentyl-2-((4-(4-methylpiperazin-l yl)phenyl)amino)-7-oxo-7,8- dihydropyrido[2,3-d]pyrimidine-6-carbonitrile or a pharmaceutically-acceptable salt thereof with one or more additional therapeutic agents.
  • Methods disclosed herein further include administering one or more additional agents to treat a disease or disorder in a combination therapy.
  • a combination therapy comprises administering a compound disclosed herein, for example, 8-cyclopentyl-2-((4-(4-methylpiperazin-l yl)phenyl)amino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile or a pharmaceutically-acceptable salt thereof, with (concurrently, simultaneously, or sequentially) a second agent.
  • a compound disclosed herein for example, 8-cyclopentyl-2-((4-(4-methylpiperazin-l yl)phenyl)amino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile or a pharmaceutically-acceptable salt thereof.
  • the compounds described herein for example, 8-cyclopentyl-2-((4-(4- methylpiperazin-1 yl)phenyl)amino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6- carbonitrile or a pharmaceutically-acceptable salt thereof, can be used in combination with agents disclosed herein or other suitable agents, depending on the condition being treated.
  • the one or more compounds disclosed herein are co-administered with a second agent.
  • the compounds described herein are administered with the second agent simultaneously or separately. This administration in combination can include simultaneous administration of the two agents in the same dosage form, simultaneous administration in separate dosage forms, and separate administration.
  • a compound described herein and a second agent can be formulated together in the same dosage form and administered simultaneously.
  • a compound disclosed herein and a second agent can be simultaneously administered, wherein both the agents are present in separate formulations.
  • a compound disclosed herein can be administered just followed by a second agent, or vice versa.
  • a compound disclosed herein and a second agent are administered a one or more minutes apart, one or more hours apart, or one or more days apart.
  • the second agent is a biological, pharmaceutical, or chemical compound.
  • a second agent include a simple or complex organic or inorganic molecule, a peptide, a protein, an oligonucleotide, an epigenetic modulator, hormones (steroidal or peptide), fusion molecules, an antibody, an antibody derivative, antibody fragment, a vitamin derivative, a carbohydrate, a toxin, a vaccine, e.g., cancer vaccine, a chemotherapeutic compound, radiotherapies (y-rays, X-rays, and/or the directed delivery of radioisotopes, microwaves, and UV radiation), gene therapies (e.g., antisense, retroviral therapy) and other immunotherapies.
  • a second agent examples include small molecule inhibitors, monoclonal antibodies (mAbs), sdAbs, chimeric antigen receptors (CARs), CAR T-cell therapy, and antibody-drug conjugates (ADCs), and bispecific antibodies.
  • a second agent is a biologic.
  • Biologicales include vaccines, blood, and blood components, allergenics, somatic cells, gene therapy, tissues, and recombinant therapeutic proteins.
  • the method includes administering a procedure.
  • procedures include surgery, radiation treatments (i.e., beam radiation), chemotherapy, immunotherapy, and ablation.
  • a combination therapy includes the combination of one or more compounds of the disclosure with a second agent to provide a synergistic or additive therapeutic effect.
  • the second therapeutic agent is an autophagy initiating inhibitor, e.g., a small molecule kinase inhibitor, e.g., ULK1/2 inhibitor, e.g., SBI-0206965 (SB I).
  • the second therapeutic agent is anAOK5 inhibitor.
  • the second therapeutic agent is an autophagy inhibitor, e.g., chloroquine, hydroxychloroquine.
  • the second therapeutic agent is an aromatase inhibitor.
  • the aromatase inhibitor is letrozole or a pharmaceutically- acceptable salt thereof.
  • the second therapeutic agent is a selective estrogen receptor degrader.
  • the second therapeutic agent is a selective estrogen receptor blocker.
  • the selective estrogen receptor degrader is fulvestrant.
  • the second therapeutic agent is an autophagy agent, e.g., hydroxychloroquine, chloroquine.
  • a compound of the disclosure e.g., a compound of formula (I), such as 8-cyclopentyl-2-((4-(4-methylpiperazin-l-yl)phenyl)amino)-7-oxo-7,8- dihydropyrido[2,3-d]pyrimidine-6-carbonitrile or a pharmaceutically-acceptable salt thereof, is administered in combination with a second therapeutic agent.
  • a compound of formula (I) such as 8-cyclopentyl-2-((4-(4-methylpiperazin-l-yl)phenyl)amino)-7-oxo-7,8- dihydropyrido[2,3-d]pyrimidine-6-carbonitrile or a pharmaceutically-acceptable salt thereof, is administered in combination with a second therapeutic agent.
  • a compound of the disclosure e.g., a compound of formula (I), such as 8-cyclopentyl-2-((4-(4- methylpiperazin-l-yl)phenyl)amino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6- carbonitrile or a pharmaceutically-acceptable salt thereof, is administered in combination with an estrogen receptor modulator.
  • a compound of the disclosure e.g., a compound of formula (I), such as 8-cyclopentyl-2-((4-(4- methylpiperazin-l-yl)phenyl)amino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6- carbonitrile or a pharmaceutically-acceptable salt thereof, is administered in combination with an estrogen receptor modulator.
  • a compound of the disclosure e.g., a compound of formula (I), such as 8-cyclopentyl-2-((4-(4-methylpiperazin-l- yl)phenyl)amino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile or a pharmaceutically-acceptable salt thereof, is administered in combination with an estrogen receptor blocker, e.g., an aromatase inhibitor such as letrozole or a pharmaceutically- acceptable salt thereof.
  • an estrogen receptor blocker e.g., an aromatase inhibitor such as letrozole or a pharmaceutically- acceptable salt thereof.
  • a compound of the disclosure e.g., a compound of formula (I), such as 8-cyclopentyl-2-((4-(4-methylpiperazin-l- yl)phenyl)amino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile or a pharmaceutically-acceptable salt thereof, is administered in combination with a progestin such as megestrol or esters thereof (e.g., megestrol acetate).
  • a progestin such as megestrol or esters thereof (e.g., megestrol acetate).
  • a compound of the disclosure e.g., a compound of formula (I), such as 8-cyclopentyl-2-((4-(4- methylpiperazin-l-yl)phenyl)amino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6- carbonitrile or a pharmaceutically-acceptable salt thereof, is administered in combination with an estrogen receptor degrader such as fulvestrant.
  • an estrogen receptor degrader such as fulvestrant.
  • a compound of the disclosure e.g., a compound of formula (I), such as 8-cyclopentyl-2-((4-(4- methylpiperazin-l-yl)phenyl)amino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6- carbonitrile or a pharmaceutically-acceptable salt thereof, is administered in combination with an angiogenesis inhibitor.
  • a compound of formula (I) such as 8-cyclopentyl-2-((4-(4- methylpiperazin-l-yl)phenyl)amino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6- carbonitrile or a pharmaceutically-acceptable salt thereof, is administered in combination with an angiogenesis inhibitor.
  • a compound of the disclosure e.g., a compound of formula (I), such as 8-cyclopentyl-2-((4-(4-methylpiperazin-l- yl)phenyl)amino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile or a pharmaceutically-acceptable salt thereof, is administered in combination with a vascular endothelial growth factor (VEGF) inhibitor.
  • VEGF vascular endothelial growth factor
  • a compound of the disclosure e.g., a compound of formula (I), such as 8-cyclopentyl-2-((4-(4-methylpiperazin- l-yl)phenyl)amino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile or a pharmaceutically-acceptable salt thereof, is administered in combination with a phosphoinositide 3 -kinase (PI3K) inhibitor.
  • a combination therapy includes administration of two, three, four, or five additional agents in combination with a compound disclosed herein.
  • the third therapeutic agent can be a therapeutic agent disclosed herein.
  • the fourth therapeutic agent can be a therapeutic agent disclosed herein.
  • the fifth therapeutic agent can be a therapeutic agent disclosed herein.
  • the present disclosure provides a combination and method for using such of a compound disclosed herein, for example, 8-cyclopentyl-2-((4-(4-methylpiperazin-l yl)phenyl)amino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile or a pharmaceutically-acceptable salt thereof, with a BTK inhibitor, for example ibrutinib or a pharmaceutically-acceptable salt thereof, or acalabrutinib or a pharmaceutically-acceptable salt thereof.
  • a BTK inhibitor for example ibrutinib or a pharmaceutically-acceptable salt thereof, or acalabrutinib or a pharmaceutically-acceptable salt thereof.
  • the present disclosure provides a combination and method for using a compound disclosed herein, for example, 8-cyclopentyl-2-((4-(4-methylpiperazin-l yl)phenyl)amino)-7- oxo-7, 8-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile or a pharmaceutically-acceptable salt thereof.
  • a compound disclosed herein comprises 8-cyclopentyl-2-((4- (4-methylpiperazin-l yl)phenyl)amino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6- carbonitrile or a pharmaceutically-acceptable salt thereof, administered in combination with a BTK inhibitor.
  • a compound disclosed herein, for example Compound 1 is administered in combination with a BTK inhibitor.
  • a BTK inhibitor comprises ibrutinib or a pharmaceutically- acceptable salt thereof. In some embodiments, a BTK inhibitor comprises acalabrutinib or a pharmaceutically-acceptable salt thereof. In some embodiments, a BTK inhibitor comprises pirtobrutinib (Loxo-305) or a pharmaceutically acceptable salt thereof.
  • a compound disclosed herein for example 8-cyclopentyl-2- ((4-(4-methylpiperazin-l yl)phenyl)amino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6- carbonitrile or a pharmaceutically-acceptable salt thereof, is administered in combination with ibrutinib or a pharmaceutically-acceptable salt thereof.
  • a compound disclosed herein for example 8-cyclopentyl-2-((4-(4-methylpiperazin-l yl)phenyl)amino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile or a pharmaceutically-acceptable salt thereof, is administered in combination with acalabrutinib or a pharmaceutically-acceptable salt thereof.
  • a compound disclosed herein for example 8-cyclopentyl-2-((4-(4-methylpiperazin-l yl)phenyl)amino)-7-oxo-7,8- dihydropyrido[2,3-d]pyrimidine-6-carbonitrile or a pharmaceutically-acceptable salt thereof, is administered in combination with pirtobrutinib (Loxo-305) or a pharmaceutically acceptable salt thereof.
  • a compound of formula (I), such as 8-cyclopentyl-2-((4-(4- methylpiperazin-l-yl)phenyl)amino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6- carbonitrile or a pharmaceutically-acceptable salt thereof, is administered in combination with a second compound, e.g., a drug.
  • a compound of the disclosure e.g., a compound of formula (I), such as 8-cyclopentyl-2-((4-(4-methylpiperazin-l- yl)phenyl)amino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile or a pharmaceutically-acceptable salt thereof, is administered in combination with a BTK inhibitor.
  • a compound of formula (I) such as 8-cyclopentyl-2-((4-(4-methylpiperazin-l- yl)phenyl)amino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile or a pharmaceutically-acceptable salt thereof, is administered in combination with a BTK inhibitor.
  • the BTK inhibitor is ibrutinib or a pharmaceutically-acceptable salt thereof.
  • the BTK inhibitor is acalabrutinib or a pharmaceutically- acceptable salt thereof.
  • the BTK inhibitor is pirtobrutinib (Loxo-305) or a pharmaceutically-acceptable salt thereof.
  • the BTK inhibitor is zanubrutinib or a pharmaceutically-acceptable salt thereof.
  • the BTK inhibitor is tirabrutinib or a pharmaceutically-acceptable salt thereof.
  • the BTK inhibitor is tolebrutinib or a pharmaceutically-acceptable salt thereof.
  • the BTK inhibitor is evobrutinib or a pharmaceutically-acceptable salt thereof. In some embodiments, the BTK inhibitor is fenebrutinib or a pharmaceutically-acceptable salt thereof. In some embodiments, the BTK inhibitor is spebrutinib or a pharmaceutically- acceptable salt thereof.
  • a compound of the disclosure for example, a compound of formula (I) or a pharmaceutically-acceptable salt thereof, is administered in combination with a second compound.
  • a compound of the disclosure for example 8- cyclopentyl-2-((4-(4-methylpiperazin-l-yl)phenyl)amino)-7-oxo-7,8-dihydropyrido[2,3- d]pyrimidine-6-carbonitrile or a pharmaceutically-acceptable salt thereof, is administered in combination with a second compound
  • a second compound is a drug.
  • a second compound is a BTK inhibitor.
  • the present disclosure provides a pharmaceutical combination comprising a compound of the disclosure, e.g., a compound of formula (I), such as 8- cyclopentyl-2-((4-(4-methylpiperazin-l-yl)phenyl)amino)-7-oxo-7,8-dihydropyrido[2,3- d]pyrimidine-6-carbonitrile or a pharmaceutically-acceptable salt thereof, and a second compound, e.g., a drug.
  • a compound of the disclosure e.g., a compound of formula (I), such as 8- cyclopentyl-2-((4-(4-methylpiperazin-l-yl)phenyl)amino)-7-oxo-7,8-dihydropyrido[2,3- d]pyrimidine-6-carbonitrile or a pharmaceutically-acceptable salt thereof, and a second compound, e.g., a drug.
  • a compound of the disclosure e.g., a compound of formula (I), such as 8-cyclopentyl-2-((4-(4-methylpiperazin-l- yl)phenyl)amino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile or a pharmaceutically-acceptable salt thereof, is in combination with a BTK inhibitor.
  • the BTK inhibitor can be ibrutinib or a pharmaceutically-acceptable salt thereof.
  • the BTK inhibitor can be acalabrutinib or a pharmaceutically- acceptable salt thereof.
  • the compound of formula (I) and the second compound can be in a one pharmaceutical composition. In some embodiments, the compound of formula (I) and the second compound can be in separate pharmaceutical compositions.
  • the present disclosure provides a pharmaceutical combination comprising a compound of the disclosure, e.g., a compound of formula (I), such as 8- cyclopentyl-2-((4-(4-methylpiperazin-l-yl)phenyl)amino)-7-oxo-7,8-dihydropyrido[2,3- d]pyrimidine-6-carbonitrile or a pharmaceutically-acceptable salt thereof, and a second compound, e.g., a drug.
  • a compound of formula (I) such as 8- cyclopentyl-2-((4-(4-methylpiperazin-l-yl)phenyl)amino)-7-oxo-7,8-dihydropyrido[2,3- d]pyrimidine-6-carbonitrile or
  • a compound of the disclosure e.g., a compound of formula (I), such as 8-cyclopentyl-2-((4-(4-methylpiperazin-l- yl)phenyl)amino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile or a pharmaceutically-acceptable salt thereof, is in combination with ibrutinib or a pharmaceutically acceptable salt thereof.
  • a compound of formula (I) such as 8-cyclopentyl-2-((4-(4-methylpiperazin-l- yl)phenyl)amino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile or a pharmaceutically-acceptable salt thereof, is in combination with ibrutinib or a pharmaceutically acceptable salt thereof.
  • 8-cyclopentyl-2-((4-(4- methylpiperazin-l-yl)phenyl)amino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6- carbonitrile or a pharmaceutically-acceptable salt thereof is compound (1).
  • the combination of compound (1) and ibrutinib a pharmaceutically-acceptable salt thereof achieves synergistic antitumor activity.
  • the synergistic antitumor activity is shown against a BTK inhibitor-resistant MCL.
  • the present disclosure provides a pharmaceutical combination comprising a compound of the disclosure, e.g., a compound of formula (I), such as 8- cyclopentyl-2-((4-(4-methylpiperazin-l-yl)phenyl)amino)-7-oxo-7,8-dihydropyrido[2,3- d]pyrimidine-6-carbonitrile or a pharmaceutically-acceptable salt thereof, and a second compound, e.g., a drug.
  • a compound of the disclosure e.g., a compound of formula (I), such as 8- cyclopentyl-2-((4-(4-methylpiperazin-l-yl)phenyl)amino)-7-oxo-7,8-dihydropyrido[2,3- d]pyrimidine-6-carbonitrile or a pharmaceutically-acceptable salt thereof, and a second compound, e.g., a drug.
  • a compound of the disclosure e.g., a compound of formula (I), such as 8-cyclopentyl-2-((4-(4-methylpiperazin-l- yl)phenyl)amino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile or a pharmaceutically-acceptable salt thereof, is in combination with acalabrutinib or a pharmaceutically acceptable salt thereof.
  • the combination of compound (1) and acalabrutinib or a pharmaceutically acceptable salt thereof achieves synergistic antitumor activity.
  • the synergistic antitumor activity is shown against a BTK inhibitor-resistant MCL.
  • the present disclosure provides a pharmaceutical combination comprising a compound of the disclosure, e.g., a compound of formula (I), such as 8- cyclopentyl-2-((4-(4-methylpiperazin-l-yl)phenyl)amino)-7-oxo-7,8-dihydropyrido[2,3- d]pyrimidine-6-carbonitrile or a pharmaceutically-acceptable salt thereof, and a second compound, e.g., a drug.
  • a compound of the disclosure e.g., a compound of formula (I), such as 8- cyclopentyl-2-((4-(4-methylpiperazin-l-yl)phenyl)amino)-7-oxo-7,8-dihydropyrido[2,3- d]pyrimidine-6-carbonitrile or a pharmaceutically-acceptable salt thereof, and a second compound, e.g., a drug.
  • a compound of the disclosure e.g., a compound of formula (I), such as 8-cyclopentyl-2-((4-(4-methylpiperazin-l- yl)phenyl)amino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile or a pharmaceutically-acceptable salt thereof, is in combination with pirtobrutinib (Loxo-305) or a pharmaceutically acceptable salt thereof.
  • the combination of compound (1) and pirtobrutinib (Loxo-305) or a pharmaceutically acceptable salt thereof achieves synergistic antitumor activity.
  • the synergistic antitumor activity is shown against a BTK inhibitor-resistant MCL.
  • the synergistic antitumor activity is cytotoxic synergy. In some embodiments, the synergy comprises increased antitumor activity compared to monotherapy. In some embodiments, the synergy comprises increased antitumor activity compared to monotherapy comprising a compound disclosed herein. In some embodiments, the synergy comprises increased antitumor activity compared to monotherapy comprising a compound disclosed herein. In some embodiments, the synergy comprises increased antitumor activity compared to monotherapy comprising the second compound. In some embodiments the synergy comprises increased cytotoxic activity compared to monotherapy. In some embodiments the synergy comprises increased cytotoxic activity compared to monotherapy comprising a compound disclosed herein. In some embodiments the synergy comprises increased cytotoxic activity compared to monotherapy comprising the second compound.
  • the second compound exhibits an additive therapeutic effect to the compound of formula (I). In some embodiments, the compound of formula (I), exhibits an additive therapeutic effect to the second compound. In some embodiments, the second compound exhibits an additive therapeutic effect to the compound of formula (I). In some embodiments, the compound of formula (I), exhibits an additive therapeutic effect to the second compound.
  • the compound of formula (I) evokes G1 cell cycle blockade.
  • a second compound administered in combination with the compound of formula (I) increases G1 cell cycle blockade compared to monotherapy comprising compound of formula (I).
  • a compound disclosed herein e.g., the compound of formula (I) is administered in combination with a second CDK 4/6 inhibitor.
  • the present disclosure provides a pharmaceutical combination comprising a compound of the disclosure, e.g., a compound of formula (I), such as 8- cyclopentyl-2-((4-(4-methylpiperazin-l-yl)phenyl)amino)-7-oxo-7,8-dihydropyrido[2,3- d]pyrimidine-6-carbonitrile or a pharmaceutically-acceptable salt thereof, and a second compound, e.g., a drug.
  • a compound of the disclosure e.g., a compound of formula (I), such as 8- cyclopentyl-2-((4-(4-methylpiperazin-l-yl)phenyl)amino)-7-oxo-7,8-dihydropyrido[2,3- d]pyrimidine-6-carbonitrile or a pharmaceutically-acceptable salt thereof, and a second compound, e.g., a drug.
  • a compound of the disclosure e.g., a compound of formula (I), such as 8-cyclopentyl-2-((4-(4-methylpiperazin-l- yl)phenyl)amino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile or a pharmaceutically-acceptable salt thereof, is in combination with acalabrutinib.
  • the combination of compound (1) and acalabrutinib achieves significant synergistic antitumor activity.
  • the synergistic antitumor activity is shown against a BTK inhibitor-resistant MCL.
  • Bruton’s tyrosine kinase is a kinase which plays a key role in B cell development.
  • BTK contains five protein interaction domains and functions to transmit signals from the pre-B cell receptor during B cell development. Activation of BTKs encourages B- cell proliferation. The suppression of BTK in mantle cell lymphoma can be achieved by inhibiting BTK.
  • Non-limiting examples of BTK inhibitors include: ibrutinib, acalabrutinib, zanubrutinib, tirabrutinib, tolebrutinib, evobrutinib, fenebrutinib, spebrutinib, and pirtobrutinib (Loxo-305).
  • Ibrutinib is a small molecule drug that irreversibly binds to the BTK protein. Blocking BTK inhibits the B cell receptor pathway, which is often aberrantly active in B cell cancers. Treatment of B cell cancers with ibrutinib significantly lowers B cell proliferation.
  • the BTK inhibitor is ibrutinib or a pharmaceutically-acceptable salt thereof.
  • the structure of ibrutinib is depicted below.
  • the BTK inhibitor is acalabrutinib or a pharmaceutically- acceptable salt thereof.
  • the structure of acalabrutinib is depicted below. 4- ⁇ 8-amino-3 - [(2 S)- 1 -(but-2-ynoyl)pyrrolidin-2-yl]imidazo[ 1 ,5-a]pyrazin- 1 -yl ⁇ -N-(pyridin- 2-yl)benzamide.
  • a pharmaceutically-acceptable salt of 4- ⁇ 8-amino-3-[(2S)-l-(but-2- ynoyl)pyrrolidin-2-yl]imidazo[l,5-a]pyrazin-l-yl ⁇ -N-(pyridin-2-yl)benzamide can also be used.
  • Unc-51-like kinase 1/2 (ULK 1/2) inhibitors inhibit the phosphorylation of ULK1 or ULK2, which regulates autophagy and lysosomal fusion, thereby blocking autophagy flux.
  • ULK plays critical role during initial stages of autophagy which is a vital response to nutrient starvation.
  • ULK1/2 is an essential and early autophagy regulator that are frequently activated in many cancers, e.g., KRAS mutant cancers.
  • Non-limiting examples of ULK 1/ 2 include SBI-0206965 (SBI), MRT68921, DCC-3116, MRT67307, or pharmaceutical salts thereof.
  • Phosphoinositide 3-kinase (PI3K) inhibitors inhibit one or more of the phosphoinositide 3-kinase enzymes. These enzymes form part of the PI3K/AKT/mT0R pathway, which is a pathway involved in cell growth and survival, and other processes that are frequently activated in many cancers. By inhibiting these enzymes, PI3K inhibitors cause cell death, inhibit the proliferation of malignant cells, and interfere with several signaling pathways. PI3K inhibitors are usually given to treat certain cancers that have relapsed or are unresponsive to other cancer treatments. Non-limiting examples of PI3K inhibitors include alpelisib, copanlisib, duvelisib, and idelalisib.
  • Small molecule inhibitors of autophagy can suppress tumor growth both in vitro and in vivo. Inhibition of autophagy sensitizes cancer cells to therapy, enhancing the cytotoxic effects induced by chemotherapeutic agents.
  • Autophagy is a key pathway in the development of endocrine resistance in breast cancer. In some embodiments, targeting autophagy can reverse antiestrogen resistance.
  • Autophagy inhibitors can be weak bases. Non-limiting examples of autophagy inhibitors include hydroxychloroquine (HCQ), chloroquine (CQ).
  • HCQ hydroxychloroquine
  • CQ chloroquine
  • the unprotonated form of CQ/HCQ can diffuse through cell membranes and enter into organelles such as lysosomes, where the high concentration of H+ induces their protonation and consequently increases lysosomal pH.
  • AMPK-related protein kinase 5 regulates Atk-dependent cell survival and migration (e.g., formation of metastases) through inhibition of cellular metabolism.
  • ARK5 overexpression is found in multiple tumors and is associated with poor prognosis in metastatic breast cancer, multiple myeloma, and hepatocellular carcinoma.
  • inhibition of ARK5 induces cell death through PI3K/AKT/mT0R pathway.
  • a compound disclosed herein for example, 8-cyclopentyl-2-((4-(4-methylpiperazin- l-yl)phenyl)amino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile (formula 1) or a pharmaceutically-acceptable salt thereof, can be formulated as a capsule.
  • a capsule can be a hard capsule.
  • a capsule can be a soft capsule.
  • a capsule can be a soft gelatin capsule.
  • a compound disclosed herein can be formulated as a hard capsule, the hard capsule comprising an amount of 8-cyclopentyl-2-((4-(4-methylpiperazin-l- yl)phenyl)amino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile monolactate equivalent to 40 mg of 8-cyclopentyl-2-((4-(4-methylpiperazin-l-yl)phenyl)amino)-7-oxo-7,8- dihydropyrido[2,3-d]pyrimidine-6-carbonitrile.
  • a compound described herein can be formulated as a tablet.
  • the present disclosure provides a pharmaceutical composition
  • a pharmaceutical composition comprising, in a unit dosage form, an amount of 8-cyclopentyl-2-((4-(4-methylpiperazin-l- yl)phenyl)amino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile or a pharmaceutically-acceptable salt thereof, equivalent to 40 mg of a compound described herein.
  • the present disclosure provides a pharmaceutical composition
  • a pharmaceutical composition comprising, in a unit dosage form, an amount of 8-cyclopentyl-2-((4-(4-methylpiperazin-l- yl)phenyl)amino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile monolactate, equivalent to 40 mg of 8-cyclopentyl-2-((4-(4-methylpiperazin-l-yl)phenyl)amino)-7-oxo-7,8- dihydropyrido[2,3-d]pyrimidine-6-carbonitrile.
  • the present disclosure provides a pharmaceutical composition
  • a pharmaceutical composition comprising, in a unit dosage form, 48.4 mg of 8-cyclopentyl-2-((4-(4-methylpiperazin-l- yl)phenyl)amino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile monolactate.
  • 8-cyclopentyl-2-((4-(4-methylpiperazin-l-yl)phenyl)amino)-7- oxo-7, 8-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile or a pharmaceutically-acceptable salt is administered in oral capsules, swallowed with water in the morning in a fasted state, at least 1 hour before ingesting food. In some embodiments, a morning dose is taken after an overnight fast an hour before ingesting food. In some embodiments, a compound described herein is administered every day. In some embodiments, a compound described herein is administered every day for 4 weeks.
  • a compound described herein is administered on a 4-week cycle of: (i) a continuous, three-week period of once-daily administration; and (ii) immediately following the three-week period, one week of no administration. In some embodiments, a compound described herein is administered every 2 days.
  • a compound disclosed herein for example, ibrutinib or a pharmaceutically - acceptable salt thereof, can be formulated as capsule or a tablet.
  • ibrutinib or a pharmaceutically-acceptable salt thereof can be formulated as a capsule, the capsule comprising, in a unit dosage form, a therapeutically-effective amount of ibrutinib or a pharmaceutically-acceptable salt thereof, and a pharmaceutically-acceptable excipient.
  • ibrutinib or a pharmaceutically-acceptable salt thereof can be formulated as a tablet, the tablet comprising, in a unit dosage form, a therapeutically-effective amount of ibrutinib, and a pharmaceutically-acceptable excipient.
  • ibrutinib or a pharmaceutically-acceptable salt thereof is provided as an about 70 mg or about 140 mg capsule for oral administration.
  • the capsule can be colored (e.g., yellow) or not colored (e.g., white).
  • the capsule shell can contain gelatin, titanium dioxide, yellow iron oxide and/or black ink.
  • Inactive ingredients can include croscarmellose sodium, magnesium stearate, microcrystalline cellulose, and/or sodium lauryl sulfate.
  • ibrutinib or a pharmaceutically-acceptable salt thereof is provided as an about 140 mg, about 280 mg, about 420 mg, or about 560 mg tablet for oral administration.
  • the tablets can be colored (e.g., yellow, purple, green, or orange), and can be uncoated or film-coated.
  • a film coating can contain ferrosoferric oxide, polyvinyl alcohol, polyethylene glycol, red iron oxide, talc, titanium dioxide, and/or yellow iron oxide.
  • Inactive ingredients can include colloidal silicon dioxide, croscarmellose sodium, lactose monohydrate, magnesium stearate, microcrystalline cellulose, povidone, and/or sodium lauryl sulfate.
  • ibrutinib or a pharmaceutically-acceptable salt thereof is given at a dose of one about 560 mg tablet administered once a day with water. In some embodiments, ibrutinib or a pharmaceutically-acceptable salt thereof is given at a dose of two about 280 mg tablets, which can be taken in one dose or in two doses daily (e.g., once per day or twice per day). In some embodiments, ibrutinib or a pharmaceutically-acceptable salt thereof is given at a dose of four about 140 mg tablets, which can be taken in one dose or multiple doses (e.g., two, three or four doses per day).
  • ibrutinib or a pharmaceutically-acceptable salt thereof is given at a dose of an about 420 mg tablet administered once a day with water. In some embodiments, ibrutinib or a pharmaceutically- acceptable salt thereof is given at a dose of an about 280 mg tablet administered once a day with water. In some embodiments, ibrutinib or a pharmaceutically-acceptable salt thereof is given at a dose of an about 140 mg tablet administered once a day with water. In some embodiments, ibrutinib or a pharmaceutically-acceptable salt thereof is given at a dose of an about 70 mg tablet administered once a day with water.
  • ibrutinib or a pharmaceutically-acceptable salt thereof is given at a dose of one about 560 mg capsule administered once a day with water. In some embodiments, ibrutinib or a pharmaceutically-acceptable salt thereof is given at a dose of two about 280 mg capsules, which can be taken in one dose or in two doses daily (e.g., once per day or twice per day). In some embodiments, ibrutinib or a pharmaceutically-acceptable salt thereof is given at a dose of four about 140 mg capsules, which can be taken in one dose or multiple doses (e.g., two, three or four doses per day).
  • ibrutinib or a pharmaceutically-acceptable salt thereof is given at a dose of an about 420 mg capsule administered once a day with water. In some embodiments, ibrutinib or a pharmaceutically- acceptable salt thereof is given at a dose of an about 280 mg capsule administered once a day with water. In some embodiments, ibrutinib or a pharmaceutically-acceptable salt thereof is given at a dose of an about 140 mg capsule administered once a day with water. In some embodiments, ibrutinib or a pharmaceutically-acceptable salt thereof is given at a dose of an about 70 mg capsule administered once a day with water.
  • a daily dose of ibrutinib or a pharmaceutically-acceptable salt thereof can be taken in a single tablet. In some embodiments, a daily dose of ibrutinib or a pharmaceutically-acceptable salt thereof can be taken in a single capsule. In some embodiments, a daily dose of ibrutinib or a pharmaceutically-acceptable salt thereof can be taken in multiple tablets. In some embodiments, a daily dose of ibrutinib or a pharmaceutically-acceptable salt thereof can be taken in multiple capsules.
  • a daily dose is about 560 mg
  • the daily dose can be administered in an about 560 mg tablet taken once a day, two about 280 mg tablets taken together in one dose, two about 280 mg tablets taken apart (e.g., twice daily), four about 140 mg tablets taken together in one dose, or four about 140 mg tablets taken apart (e.g., twice, thrice, or four times daily).
  • Acalabrutinib is administered in an about 560 mg tablet taken once a day, two about 280 mg tablets taken together in one dose, two about 280 mg tablets taken apart (e.g., twice daily), four about 140 mg tablets taken together in one dose, or four about 140 mg tablets taken apart (e.g., twice, thrice, or four times daily).
  • a compound disclosed herein for example, acalabrutinib or a pharmaceutically- acceptable salt thereof, can be formulated as capsule or a tablet.
  • acalabrutinib or a pharmaceutically-acceptable salt thereof can be formulated as a capsule, the capsule comprising, in a unit dosage form, a therapeutically-effective amount of acalabrutinib or a pharmaceutically-acceptable salt thereof, and a pharmaceutically- acceptable excipient.
  • acalabrutinib or a pharmaceutically-acceptable salt thereof can be formulated as a tablet, the tablet comprising, in a unit dosage form, a therapeutically-effective amount of acalabrutinib, and a pharmaceutically-acceptable excipient.
  • acalabrutinib or a pharmaceutically-acceptable salt thereof is provided as an about 70 mg or about 140 mg capsule for oral administration.
  • the capsule can be colored (e.g., yellow) or not colored (e.g., white).
  • the capsule shell can contain gelatin, titanium dioxide, yellow iron oxide and/or black ink.
  • Inactive ingredients can include croscarmellose sodium, magnesium stearate, microcrystalline cellulose, and/or sodium lauryl sulfate.
  • acalabrutinib or a pharmaceutically-acceptable salt thereof is provided as an about 140 mg, about 280 mg, about 420 mg, or about 560 mg tablet for oral administration.
  • the tablets can be colored (e.g., yellow, purple, green, or orange), and can be uncoated or film-coated.
  • a film coating can contain ferrosoferric oxide, polyvinyl alcohol, polyethylene glycol, red iron oxide, talc, titanium dioxide, and/or yellow iron oxide.
  • Inactive ingredients can include colloidal silicon dioxide, croscarmellose sodium, lactose monohydrate, magnesium stearate, microcrystalline cellulose, povidone, and/or sodium lauryl sulfate.
  • acalabrutinib or a pharmaceutically-acceptable salt thereof is given at a dose of one about 560 mg tablet administered once a day with water. In some embodiments, acalabrutinib or a pharmaceutically-acceptable salt thereof is given at a dose of two about 280 mg tablets, which can be taken in one dose or in two doses daily (e.g., once per day or twice per day). In some embodiments, acalabrutinib or a pharmaceutically- acceptable salt thereof is given at a dose of four about 140 mg tablets, which can be taken in one dose or multiple doses (e.g., two, three or four doses per day).
  • acalabrutinib or a pharmaceutically-acceptable salt thereof is given at a dose of an about 420 mg tablet administered once a day with water. In some embodiments, acalabrutinib or a pharmaceutically-acceptable salt thereof is given at a dose of an about 280 mg tablet administered once a day with water. In some embodiments, acalabrutinib or a pharmaceutically-acceptable salt thereof is given at a dose of an about 140 mg tablet administered once a day with water. In some embodiments, acalabrutinib or a pharmaceutically-acceptable salt thereof is given at a dose of an about 70 mg tablet administered once a day with water.
  • acalabrutinib or a pharmaceutically-acceptable salt thereof is given at a dose of one about 560 mg capsule administered once a day with water. In some embodiments, acalabrutinib or a pharmaceutically-acceptable salt thereof is given at a dose of two about 280 mg capsules, which can be taken in one dose or in two doses daily (e.g., once per day or twice per day). In some embodiments, acalabrutinib or a pharmaceutically- acceptable salt thereof is given at a dose of four about 140 mg capsules, which can be taken in one dose or multiple doses (e.g., two, three or four doses per day).
  • acalabrutinib or a pharmaceutically-acceptable salt thereof is given at a dose of an about 420 mg capsule administered once a day with water. In some embodiments, acalabrutinib or a pharmaceutically-acceptable salt thereof is given at a dose of an about 280 mg capsule administered once a day with water. In some embodiments, acalabrutinib or a pharmaceutically-acceptable salt thereof is given at a dose of an about 140 mg capsule administered once a day with water. In some embodiments, acalabrutinib or a pharmaceutically-acceptable salt thereof is given at a dose of a 70 mg capsule administered once a day with water.
  • a daily dose of acalabrutinib or a pharmaceutically-acceptable salt thereof can be taken in a single tablet. In some embodiments, a daily dose of acalabrutinib or a pharmaceutically-acceptable salt thereof can be taken in a single capsule. In some embodiments, a daily dose of acalabrutinib or a pharmaceutically-acceptable salt thereof can be taken in multiple tablets. In some embodiments, a daily dose of acalabrutinib or a pharmaceutically-acceptable salt thereof can be taken in multiple capsules.
  • a daily dose is about 560 mg
  • the daily dose can be administered in an about 560 mg tablet taken once a day, two about 280 mg tablets taken together in one dose, two about 280 mg tablets taken apart (e.g., twice daily), four about 140 mg tablets taken together in one dose, or four about 140 mg tablets taken apart (e.g., twice, thrice, or four times daily).
  • a pharmaceutical composition of the disclosure can be a combination of any pharmaceutical compounds described herein with other chemical components, such as carriers, stabilizers, diluents, dispersing agents, suspending agents, thickening agents, and/or excipients.
  • a pharmaceutical composition of the disclosure can comprise Compound 1 or Compound 1 salt and a pharmaceutically acceptable excipient. The pharmaceutical composition facilitates administration of the compound to an organism.
  • compositions can be administered in therapeutically-effective amounts as pharmaceutical compositions by various forms and routes including, for example, intravenous, subcutaneous, intramuscular, inhalation, oral, parenteral, ophthalmic, otic, subcutaneous, transdermal, nasal, intravitreal, intratracheal, intrapulmonary, transmucosal, vaginal, and topical administration.
  • routes including, for example, intravenous, subcutaneous, intramuscular, inhalation, oral, parenteral, ophthalmic, otic, subcutaneous, transdermal, nasal, intravitreal, intratracheal, intrapulmonary, transmucosal, vaginal, and topical administration.
  • Formulations can be modified depending upon the route of administration chosen.
  • Pharmaceutical compositions comprising a compound described herein can be manufactured, for example, by mixing, dissolving, emulsifying, encapsulating, entrapping, or compression processes.
  • Non-limiting examples of dosage forms suitable for use in a method disclosed herein include feed, food, pellet, lozenge, liquid, elixir, aerosol, inhalant, spray, powder, tablet, pill, capsule, gel, geltab, nanosuspension, nanoparticle, microgel, suppository troches, aqueous or oily suspensions, ointment, patch, lotion, dentifrice, emulsion, creams, drops, dispersible powders or granules, emulsion in hard or soft gel capsules, syrups, phytoceuticals, nutraceuticals, and any combination thereof.
  • compositions can be formulated by combining the active compounds with pharmaceutically-acceptable carriers or excipients.
  • pharmaceutically-acceptable excipients suitable for use in the method disclosed herein include granulating agents, binding agents, lubricating agents, disintegrating agents, sweetening agents, glidants, anti -adherents, anti-static agents, surfactants, anti-oxidants, gums, coating agents, coloring agents, flavoring agents, coating agents, plasticizers, preservatives, suspending agents, emulsifying agents, anti-microbial agents, plant cellulosic material and spheronization agents, and any combination thereof.
  • Non-limiting examples of pharmaceutically-acceptable carriers include saline solution, Ringer’s solution and dextrose solution. Further carriers include sustained release preparations such as semipermeable matrices of solid hydrophobic polymers containing the compound disclosed herein, where the matrices are in the form of shaped articles, such as films, liposomes, microparticles, and microcapsules.
  • compositions can be formulated by combining the active compounds with pharmaceutically-acceptable carriers or excipients into a unit dosage form which can be solid or liquid.
  • oral solid forms include tablets, powders, pills, dragees, capsules, liquids, gels, syrups, elixirs, slurries, or suspensions for oral ingestion by a subject.
  • Pharmaceutical preparations for oral use can be obtained by mixing one or more solid excipients with one or more compounds described herein, optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores. Cores can be provided with suitable coatings.
  • concentrated sugar solutions can be used.
  • the solutions can contain an excipient such as gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures.
  • Dyestuffs or pigments can be added to the tablets or dragee coatings, for example, for identification or to characterize different combinations of active compound doses.
  • compositions that can be used orally include push-fit capsules made of gelatin and soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol.
  • Pharmaceutical preparations that can be used orally include coated and uncoated tablets.
  • the capsule comprises a hard gelatin capsule, the capsule comprising one or more of pharmaceutical, bovine, and plant gelatins.
  • a gelatin can be alkaline-processed.
  • the capsule or tablet can contain the active ingredients in admixture with filler such as lactose, binders such as starches, or lubricants such as talc or magnesium stearate, and stabilizers.
  • the active compounds can be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. Stabilizers can be added. All formulations for oral administration are provided in dosages suitable for such administration.
  • compositions can be formulated by combining the active compounds with pharmaceutically-acceptable carriers or excipients.
  • Such carriers can be used to formulate liquids, gels, syrups, elixirs, slurries, or suspensions, for oral ingestion by a subject.
  • Non-limiting examples of solvents used in an oral dissolvable formulation can include water, ethanol, isopropanol, saline, physiological saline, DMSO, dimethylformamide, potassium phosphate buffer, phosphate buffer saline (PBS), sodium phosphate buffer, 4-2-hy droxy ethyl- 1 -piperazineethanesulfonic acid buffer (HEPES), 3-(N-morpholino)propanesulfonic acid buffer (MOPS), piperazine-N,N'-bis(2- ethanesulfonic acid) buffer (PIPES), and saline sodium citrate buffer (SSC).
  • Non-limiting examples of co-solvents used in an oral dissolvable formulation can include sucrose, urea, cremaphor, DMSO, and potassium phosphate buffer.
  • Parenteral injections can be formulated for bolus injection or continuous infusion.
  • the pharmaceutical compositions can be in a form suitable for parenteral injection as a sterile suspension, solution, or emulsion in oily or aqueous vehicles such as saline or water for injection, and can contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
  • Pharmaceutical formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form. Suspensions of the active compounds can be prepared as oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes.
  • the suspension can also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.
  • the active ingredient can be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.
  • the active compounds can be administered topically and can be formulated into a variety of topically administrable compositions, such as solutions, suspensions, lotions, gels, pastes, medicated sticks, balms, creams, and ointments.
  • Such pharmaceutical compositions can contain solubilizers, stabilizers, tonicity enhancing agents, buffers and preservatives.
  • the compounds of the disclosure can be applied topically to the skin, or a body cavity, for example, oral, vaginal, bladder, cranial, spinal, thoracic, or pelvic cavity of a subject.
  • the compounds of the disclosure can be applied to an accessible body cavity.
  • the compounds can also be formulated in rectal compositions such as enemas, rectal gels, rectal foams, rectal aerosols, suppositories, jelly suppositories, or retention enemas, containing conventional suppository bases such as cocoa butter or other glycerides, and synthetic polymers such as polyvinylpyrrolidone and PEG.
  • rectal compositions such as enemas, rectal gels, rectal foams, rectal aerosols, suppositories, jelly suppositories, or retention enemas
  • conventional suppository bases such as cocoa butter or other glycerides
  • synthetic polymers such as polyvinylpyrrolidone and PEG.
  • a low-melting wax such as a mixture of fatty acid glycerides, optionally in combination with cocoa butter, can be used.
  • compositions can be tablets, lozenges, or gels.
  • Formulations suitable for transdermal administration of the active compounds can employ transdermal delivery devices and transdermal delivery patches, and can be lipophilic emulsions or buffered aqueous solutions, dissolved, or dispersed in a polymer or an adhesive. Such patches can be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical compounds. Transdermal delivery can be accomplished by iontophoretic patches. Transdermal patches can provide controlled delivery. The rate of absorption can be slowed by using rate-controlling membranes or by trapping the compound within a polymer matrix or gel.
  • Absorption enhancers can be used to increase absorption.
  • An absorption enhancer or carrier can include absorbable pharmaceutically-acceptable solvents to assist passage through the skin.
  • transdermal devices can be in the form of a bandage comprising a backing member, a reservoir containing compounds and carriers, a rate controlling barrier to deliver the compounds to the skin of the subject at a controlled and predetermined rate over a prolonged period of time, and adhesives to secure the device to the skin or the eye.
  • the active compounds can be in a form as an aerosol, a vapor, a mist, or a powder. Inhalation can occur through by nasal delivery, oral delivery, or both.
  • Nasal or intranasal administration involves insufflation of compounds through the nose, for example, nasal drops and nasal sprays. This route of administration can result in local and/or systemic effects.
  • Inhaler or insufflator devices can be used for nose-to-lung delivery of compounds described herein.
  • a pharmaceutical composition can be administered in a local or systemic manner, for example, via injection of the compound directly into an organ, optionally in a depot or sustained release formulation or implant.
  • Pharmaceutical compositions can be provided in the form of a rapid release formulation, in the form of an extended release formulation, or in the form of an intermediate release formulation.
  • a rapid release form can provide an immediate release.
  • An extended release formulation can provide a controlled release or a sustained delayed release.
  • therapeutically- effective amounts of the compounds described herein are administered in pharmaceutical compositions to a subject having a disease or condition to be treated.
  • the subject is a mammal such as a human.
  • a therapeutically-effective amount can vary widely depending on the severity of the disease, the age and relative health of the subject, the potency of the compounds used, and other factors.
  • the compounds can be used singly or in combination with one or more therapeutic agents as components of mixtures.
  • compositions comprising the compounds described herein include formulating the compounds with one or more inert, pharmaceutically- acceptable excipients or carriers to form a solid, semi-solid, or liquid composition.
  • Solid compositions include, for example, powders, tablets, dispersible granules, capsules, and cachets.
  • Liquid compositions include, for example, solutions in which a compound is dissolved, emulsions comprising a compound, or a solution containing liposomes, micelles, or nanoparticles comprising a compound as disclosed herein.
  • Semi-solid compositions include, for example, gels, suspensions, and creams.
  • compositions can be in liquid solutions or suspensions, solid forms suitable for solution or suspension in a liquid prior to use, or as emulsions. These compositions can also contain minor amounts of nontoxic, auxiliary substances, such as wetting or emulsifying agents, pH buffering agents, and other pharmaceutically-acceptable additives.
  • Non-limiting examples of dosage forms suitable for use in the disclosure include liquid, powder, gel, nanosuspension, nanoparticle, microgel, aqueous or oily suspensions, emulsion, and any combination thereof.
  • Non-limiting examples of pharmaceutically-acceptable excipients suitable for use in the disclosure include binding agents, disintegrating agents, anti-adherents, anti-static agents, surfactants, anti-oxidants, coating agents, coloring agents, plasticizers, preservatives, suspending agents, emulsifying agents, anti-microbial agents, spheronization agents, solubilizers, stabilizers, tonicity enhancing agents, buffers and any combination thereof.
  • a composition of the disclosure can be, for example, an immediate release form or a controlled release formulation.
  • An immediate release formulation can be formulated to allow the compounds to act rapidly.
  • Non-limiting examples of immediate release formulations include readily dissolvable formulations.
  • a controlled release formulation can be a pharmaceutical formulation that has been adapted such that release rates and release profiles of the active agent can be matched to physiological and chronotherapeutic requirements or, alternatively, has been formulated to effect release of an active agent at a programmed rate.
  • controlled release formulations include granules, delayed release granules, hydrogels (e.g., of synthetic or natural origin), other gelling agents (e.g., gelforming dietary fibers), matrix-based formulations (e.g., formulations comprising a polymeric material having at least one active ingredient dispersed through), granules within a matrix, polymeric mixtures, and granular masses.
  • a controlled release formulation is a delayed release form.
  • a delayed release form can be formulated to delay a compound’s action for an extended period of time.
  • a delayed release form can be formulated to delay the release of an effective dose of one or more compounds, for example, for about 4, about 8, about 12, about 16, or about 24 h.
  • a controlled release formulation can be a sustained release form.
  • a sustained release form can be formulated to sustain, for example, the compound’s action over an extended period of time.
  • a sustained release form can be formulated to provide an effective dose of any compound described herein (e.g., provide a physiologically-effective blood profile) over about 4, about 8, about 12, about 16, or about 24 h.
  • Non-limiting examples of pharmaceutically-acceptable excipients can be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington’s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999), each of which is incorporated by reference in its entirety.
  • Subjects can be, for example, elderly adults, adults, adolescents, pre-adolescents, children, toddlers, infants, neonates, and non-human animals.
  • a subject is a patient.
  • compositions of a compound disclosed herein can comprise a liquid comprising an active agent in solution, in suspension, or both.
  • Liquid compositions can include gels.
  • the liquid composition is aqueous.
  • the composition can be an ointment.
  • the composition is an in situ gellable aqueous composition.
  • the composition is an in situ gellable aqueous solution.
  • a pharmaceutically-acceptable excipient can be present in a pharmaceutical composition at a mass of between about 0.1% and about 99% by mass of the composition.
  • a pharmaceutically-acceptable excipient can be present in a pharmaceutical composition at a mass of between about 0.1% and about 95%, between about 0.1% and about 90%, between about 0.1% and about 85%, between about 0.1% and about 80%, between about 0.1% and about 75%, between about 0.1% and about 70%, between about 0.1% and about 65%, between about 0.1% and about 60%, between about 0.1% and about 55%, between about 0.1% and about 50%, between about 0.1% and about 45%, between about 0.1% and about 40%, between about 0.1% and about 35%, between about 0.1% and about 30%, between about 0.1% and about 25%, between about 0.1% and about 20%, between about 0.1% and about 15%, between about 0.1% and about 10%, between about 0.1% and about 5%, or between about 0.1% and about 1%, by mass of the formulation.
  • a pharmaceutically-acceptable excipient can be present at about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 51%, about 52%, about
  • Subjects can be, humans for example, elderly adults, adults, adolescents, preadolescents, children, toddlers, infants, neonates, and non-human animals, e.g., a mouse.
  • a subject is a patient.
  • a subject has experienced and/or exhibited at least one symptom of the disease or disorder to be treated and/or reduced in likelihood to occur.
  • the subject has been identified or diagnosed as having a cancer described herein, e.g., breast cancer.
  • the subject has a cancer and/or tumor that is positive for ibrutinib resistance.
  • the subject is predisposed and/or at risk to having a cancer, e.g., breast cancer, based on presence of a mutation in a gene, e.g., BRCA1 mutation.
  • the subject has received a first line of therapy.
  • the subject is resistant and/or non-responsive to the first line of therapy.
  • a method of treatment disclosed herein comprises, identification of a patient population based on one or more selection criteria, e.g., biomarkers, failure to respond to a primary therapy and administering a compound disclosed herein, e.g., Compound 1 to treat the patient.
  • the patient population selection criteria can include but are not limited to, presence of a biomarker, e.g., marker associate with a particular disease, a marker associated with poor prognosis of a disease, failure to respond to an initial therapy, age, gender, health of the patient.
  • the screening procedure may include but are not limited to blood and/or tissue sample analysis, genetic tests, genetic screening, biopsy, drug sensitivity/resistance test.
  • compositions of a compound disclosed herein can comprise a liquid comprising an active agent in solution, in suspension, or both.
  • Liquid compositions can include gels.
  • the liquid composition is aqueous.
  • the composition is an ointment.
  • the composition is an in situ gellable aqueous composition.
  • the composition is an in situ gellable aqueous solution.
  • compositions described herein can be in unit dosage forms suitable for single administration of precise dosages.
  • the formulation is divided into unit doses containing appropriate quantities of one or more compounds.
  • the unit dosage can be in the form of a package containing discrete quantities of the formulation.
  • Nonlimiting examples are packaged injectables, vials, or ampoules.
  • Aqueous suspension compositions can be packaged in single-dose non-reclosable containers. Multiple-dose reclosable containers can be used, for example, in combination with or without a preservative.
  • Formulations for parenteral injection can be presented in unit dosage form, for example, in ampoules, or in multi-dose containers with a preservative.
  • a compound described herein can be present in a composition in a range of from about 1 mg to about 5 mg, from about 5 mg to about 10 mg, from about 10 mg to about 15 mg, from about 15 mg to about 20 mg, from about 20 mg to about 25 mg, from about 25 mg to about 30 mg, from about 30 mg to about 35 mg, from about 35 mg to about 40 mg, from about 40 mg to about 45 mg, from about 45 mg to about 50 mg, from about 50 mg to about 55 mg, from about 55 mg to about 60 mg, from about 60 mg to about 65 mg, from about 65 mg to about 70 mg, from about 70 mg to about 75 mg, from about 75 mg to about 80 mg, from about 80 mg to about 85 mg, from about 85 mg to about 90 mg, from about 90 mg to about 95 mg, from about 95 mg to about 100 mg, from about 100 mg to about 125 mg, from about 125 mg to about 150 mg, from about 150 mg to about 175 mg, from about 175 mg to about 200 mg, from about 200 mg to about 225 mg, from about 225
  • a compound described herein can be present in a composition in an amount of about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 120 mg, about 140 mg, about 160 mg, about 180 mg, about 200 mg, about 220 mg, about 240 mg, about 260 mg, about 280 mg, about 300 mg, about 320 mg, about 340 mg, about 360 mg, about 380 mg, about 400 mg, about 420 mg, about 440 mg, about 460 mg, about 480 mg, about 500 mg, about 520 mg, about 540 mg, about 560 mg, about 580 mg, or about 600 mg.
  • a compound described herein can be administered to a subject in an amount of about 0.1 mg/kg to about 500 mg/kg, about 1 mg/kg to about 500 mg/kg, about 0.1 mg/kg to about 300 mg/kg, about 1 mg/kg to about 300 mg/kg, or about 0.1 mg/kg to about 30 mg/kg.
  • the compound disclosed herein is administered to a subject in an amount of about 1 mg/kg, about 2 mg/kg, about 3 mg/kg, about 4 mg/kg, about 5 mg/kg, about 6 mg/kg, about 7 mg/kg, about 8 mg/kg, about 9 mg/kg, about 10 mg/kg, about 11 mg/kg, about 12 mg/kg, about 13 mg/kg, about 14 mg/kg, about 15 mg/kg, about 16 mg/kg, about 17 mg/kg, about 18 mg/kg, about 19 mg/kg, about 20 mg/kg, about 25 mg/kg, about 30 mg/kg, about 35 mg/kg, about 40 mg/kg, about 45 mg/kg, about 50 mg/kg, about 55 mg/kg, about 60 mg/kg, about 65 mg/kg, about 70 mg/kg, about 75 mg/kg, about 80 mg/kg, about 85 mg/kg, about 90 mg/kg, about 95 mg/kg, about 100 mg/kg, about 120 mg/kg, about 150 mg/kg, about 160 mg/kg, about
  • a dosing regimen disclosed herein can be, for example, once a day, twice a day, thrice a day, once a week, twice a week, or thrice a week.
  • a compound disclosed herein is administered once daily.
  • a compound disclosed herein is administered once daily for 28 days (one cycle).
  • a compound disclosed herein is administered once daily in one or more 28 day cycles.
  • a compound disclosed herein is administered in a four-week cycle of consecutive once daily administration for three weeks, followed by one week with no administrations.
  • the present disclosure provides a method of treating mantle cell lymphoma in a subject in need thereof, the method comprising administering to the subject a therapeutically-effective amount of a compound of formula (I) wherein:
  • R 1 is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl, each of which is unsubstituted or substituted, or hydrogen;
  • R 3 is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl or heteroaryl, each of which is unsubstituted or substituted, or hydrogen or halogen;
  • the present disclosure provides a method of treating mantle cell lymphoma in a subject in need thereof, the method comprising administering to the subject a therapeutically-effective amount of a compound of formula (I) wherein:
  • R 1 is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl, each of which is unsubstituted or substituted, or hydrogen;
  • R 3 is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl or heteroaryl, each of which is unsubstituted or substituted, or hydrogen or halogen;
  • the present disclosure provides a method of treating mantle cell lymphoma in a subject in need thereof, the method comprising administering to the subject a therapeutically-effective amount of a compound of formula (I) wherein:
  • R 1 is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl, each of which is unsubstituted or substituted, or hydrogen;
  • R 3 is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl or heteroaryl, each of which is unsubstituted or substituted, or hydrogen or halogen;
  • a compound described herein can be administered before, during, or after the occurrence of a disease or condition, and the timing of administering the composition containing a compound can vary.
  • a compound can be used as a prophylactic and can be administered continuously to subjects with a propensity to conditions or diseases to lessen or reduce a likelihood of the occurrence of the disease or condition.
  • a compound and composition can be administered to a subject during or as soon as possible after the onset of the symptoms.
  • the administration of a compound can be initiated within the first 48 hours of the onset of the symptoms, within the first 24 hours of the onset of the symptoms, within the first 6 hours of the onset of the symptoms, or within 3 hours of the onset of the symptoms.
  • the initial administration can be via any route practical, such as by any route described herein using any formulation described herein.
  • a compound can be administered as soon as is practical after the onset of a disease or condition is detected or suspected, and for a length of time necessary for the treatment of the disease, such as, for example, from about 1 month to about 3 months.
  • the length of time a compound can be administered can be about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 1 month, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 2 months, about 9 weeks, about 10 weeks, about 11 weeks, about 12 weeks, about 3 months, about 13 weeks, about 14 weeks, about 15 weeks, about 16 weeks, about 4 months, about 17 weeks, about 18 weeks, about 19 weeks, about 20 weeks, about 5 months, about 21 weeks, about 22 weeks, about 23 weeks, about 24 weeks, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 1 year, about 13 months, about 14 months, about 15 months, about 20 weeks, about
  • a dosing schedule for administration of a compound described herein can be consistent for the length of the dosing regimen.
  • a compound can be administered daily.
  • a dosing schedule for administration of a compound described herein can include portions of time where dosing is paused. For example, a compound can be administered every day for 3 weeks and then not be administered for one week.
  • a dosing schedule for administration of a compound described herein can include once daily (QD), twice daily (BID), three times daily (TID), four times daily (QID), once weekly, twice weekly, three times weekly, once monthly, twice monthly, and once every other month.
  • a daily dose can be given in a single dose or divided into multiple doses to be administered in intervals, e.g., twice daily or three times daily.
  • a daily dose of 100 mg can be given, for example, once daily (100 mg), twice daily (50 mg per dose).
  • a compound of the disclosure is administered in combination with, before, or after treatment with another therapeutic agent, e.g., a drug, such as an aromatase inhibitor.
  • a compound of the disclosure is administered at regular intervals, such as, for example, once daily, twice daily, thrice daily, etc. and the second therapeutic agent is administered daily or intermittently or on an as-needed basis.
  • the multiple therapeutic agents can be provided in a single, unified form, or in multiple forms, for example, as multiple separate unit dosage forms.
  • the agents can be packed together or separately, in a single package or in a plurality of packages.
  • One or all the therapeutic agents can be given in multiple doses. If not simultaneous, the timing between the multiple doses can vary to as much as about a month.
  • a dosing regimen disclosed herein can be, for example, one dose of 40 mg, one dose of 80 mg, one dose of 120 mg, one dose of 160 mg, or one dose of 200 mg of oral 8- cyclopentyl-2-((4-(4-methylpiperazin-l-yl)phenyl)amino)-7-oxo-7,8-dihydropyrido[2,3- d]pyrimidine-6-carbonitrile or a pharmaceutically-acceptable salt per day.
  • the dosing regimen disclosed herein can be, for example, 40 mg twice daily, 60 mg twice daily, 80 mg twice daily, or 100 mg twice daily.
  • the dosing is oral.
  • 8-cyclopentyl-2-((4-(4-methylpiperazin-l-yl)phenyl)amino)-7- oxo-7, 8-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile or a pharmaceutically-acceptable salt is administered once daily.
  • 8-cyclopentyl-2-((4-(4-methylpiperazin-l- yl)phenyl)amino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile or a pharmaceutically-acceptable salt is administered once daily for 28 days (one cycle).
  • 8-cyclopentyl-2-((4-(4-methylpiperazin-l-yl)phenyl)amino)-7-oxo-7,8- dihydropyrido[2,3-d]pyrimidine-6-carbonitrile or a pharmaceutically-acceptable salt is administered once daily in one or more 28 day cycles.
  • 8-cyclopentyl- 2-((4-(4-methylpiperazin-l-yl)phenyl)amino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6- carbonitrile is administered in a four-week cycle of consecutive once daily administration for three weeks, followed by one week with no administrations.
  • the present disclosure provides a method of treating mantle cell lymphoma in a subject in need thereof, the method comprising administering to the subject a therapeutically-effective amount of 8-cyclopentyl-2-((4-(4-methylpiperazin-l yl)phenyl)amino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile or a pharmaceutically-acceptable salt thereof, wherein the administering is once daily for at least 4 weeks.
  • the present disclosure provides a method of treating mantle cell lymphoma in a subject in need thereof, the method comprising administering to the subject a therapeutically-effective amount of 8-cyclopentyl-2-((4-(4-methylpiperazin-l yl)phenyl)amino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile or a pharmaceutically-acceptable salt thereof, wherein the administering is a 4-week cycle of: (i) a continuous, three-week period of once-daily administration; and ii) immediately following the three-week period, one week of no administration.
  • a dosing regimen disclosed herein can be, for example, once a day, twice a day, thrice a day, once a week, twice a week, or thrice a week.
  • the dosing is oral.
  • a BTK inhibitor disclosed herein is ibrutinib or a pharmaceutically-acceptable salt thereof or acalabrutinib or a pharmaceutically-acceptable salt thereof.
  • a suitable amount ibrutinib or a pharmaceutically- acceptable salt thereof or acalabrutinib or a pharmaceutically-acceptable salt thereof can range from about 50 mg to about 600 mg per day, for example about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 120 mg, about 140 mg, about 160 mg, about 180 mg, about 200 mg, about 220 mg, about 240 mg, about 260 mg, about 280 mg, about 300 mg, about 320 mg, about 340 mg, about 360 mg, about 380 mg, about 400 mg, about 420 mg, about 440 mg, about 460 mg, about 480 mg, about 500 mg, about 520 mg, about 540 mg, about 560 mg, about 580 mg, or about 600 mg per day, based on the mass of ibrutinib or acalabrutinib.
  • a composition of the disclosure binds to different cellular proteins than a comparator molecule. In some embodiments, a composition of the disclosure binds to different cellular proteins than palbociclib. In some embodiments, a composition of the disclosure binds to one or more of the following cellular proteins : CDC42BPB, CHEK1, DGCR6, MAP-KAPK5, TBK1, UVSSA, ZNF260, AAK1, ATAT1, AURKA, BMP2K, BUB1, CDK2, CDK5, CPQ, EPHA2, FKBP8, GSK3A, GSK3B, LIMK1, MAP11, PER3, SLK, STK17A, STK17B, TFEB, TGFBR2, USF2, ZCRB1, ACAA1, AIFM2, ANP32B, AP2A1, AP2M1, AP2S1, AVEN, BOD1L1, CDK12, CDK7, CDKN1A, CHEK1, COG8, DECR
  • Non-limiting examples of a comparator include palbociclib, abemaciclib, and riboci clib.
  • a composition of the disclosure deregulates cellular phosphopeptide levels. In some embodiments, a composition of the disclosure deregulates a unique cellular phosphopeptide profile compared to a comparator molecule. In some embodiments, a composition of the disclosure deregulates one or more peptides selected from the list consisting of: PRKD1, ULK1, RAFI, MAP2K2, CAMK2D, LYN, PRKD2, AKT2, TLK1, GTF2F1, STK3, CAMK1, LATS1, BRAF, NUAK1, HCK, BUB1, ARAF, MAP2K5, CDK16, and MAPK7.
  • a composition disclosed herein modulate expression of one or more genes selected from one or more of RCAP3, CD86, SNX20, TAGAP, ZNF782, TAPRPL, ACOX1, NCOA1, FCRL1, NCF2, DALRD3, CLRA1, PFKFR2, MFSD3, NCKAPIL, C2orf81, PTTG1, FAM22C, HMGN2, CFNPF, PPL1RAP7, CDC20, CENPW, AUPKR, CCNR2, HMMP, DLGAP5, SPC25, PIF1, RPA3, PRC1, RIPC5, NDCRO, CDK1, HMGR2, ITGR1RP2, FLK1, KIFAR, TD3, TURAIR, CEP55, LIGI, PHF19, CFNPH, H2AZ2, NIF2, LTB, CCL22, MARCKSL1, EEF1A1, BLTP2, CUX1, CD83, and HNRNPA2B1.
  • a composition disclosed herein overexpresses the expression of one or more genes selected from RCAP3, CD86, SNX20, TAGAP, ZNF782, TAPRPL, ACOX1, NCOA1, FCRL1, NCF2, DALRD3, CLRA1, PFKFR2, MFSD3, NCKAPIL, C2orf81, LTB, CCL22, MARCKSL1, EEF1A1, BLTP2, CUX1, and CD83.
  • a composition disclosed herein suppresses the expression of one or more genes selected from PTTG1, FAM22C, HMGN2, CFNPF, PPL1RAP7, CDC20, CENPW, AUPKR, CCNR2, HMMP, DLGAP5, SPC25, PIF1, RPA3, PRC1, RIPC5, NDCRO, CDK1, HMGR2, ITGR1RP2, FLK1, KIFAR, TD3, TURAIR, CEP55, LIGI, PHF19, CFNPH, H2AZ2, NIF2, and HNRNPA2B1.
  • EXAMPLE 1 Study to Evaluate an Oral Pharmaceutical Composition Disclosed Herein for Treating a Disease in a Subject.
  • This study is a dose escalation study to investigate the safety, tolerability, and PK characteristics of 8-cyclopentyl-2-((4-(4-methylpiperazin-l-yl)phenyl)amino)-7-oxo- 7,8-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile [compound (1)] in patients with advanced cancers who have received and failed at least one prior treatment.
  • the primary objective of this study is to assess the safety and tolerability of repeated daily dosing of compound 1 in patients with relapsed and/or refractory advanced cancers.
  • the secondary objective of this study is to establish a maximum tolerated dose (MTD) and a recommend phase 2 dose (RP2D) of orally administered compound (1).
  • MTD maximum tolerated dose
  • R2D recommend phase 2 dose
  • the study explores efficacy of compound (1) in cancer patients.
  • Study Design This study is a dose finding study using 3+3 design for dose escalation. Three to six patients are enrolled per dose cohort, followed by up to 12 additional patients at the RP2D. Approximately 36 patients with advanced cancers are enrolled in the study, based on 4 dose levels and an expansion cohort. If additional dose escalations are required to establish the MTD/RP2D, then 3-6 additional patients are added per dose level.
  • Compound (1) is given in the form of a hard capsule comprising 48.4 mg 8- cyclopentyl-2-((4-(4-methylpiperazin-l-yl)phenyl)amino)-7-oxo-7,8-dihydropyrido[2,3- d]pyrimidine-6-carbonitrile monolactate, equivalent to 40 mg of 8-cyclopentyl-2-((4-(4- methylpiperazin-l-yl)phenyl)amino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6- carbonitrile.
  • the initial dose is 40 mg (one capsule) taken once daily for 28 days (one cycle).
  • Dose increments in the dose escalation 3+3 study are 40 mg of compound (1) per cycle. Dose levels are 40mg, 80mg, 120 mg, 160mg, etc., until a RP2D/MTD is reached.
  • Each of the first three patients in the first and subsequent cohorts is assessed for dose limiting toxicities (DLT) during the first 28 days of treatment. If no patients experience a DLT, then enrollment to the next cohort begins at the next dose level. If one patient of the first three patients in a cohort experiences a DLT in the first 28 days, then an additional three patients are enrolled to that cohort for a total of six patients.
  • DLT dose limiting toxicities
  • the primary objective of this study is to assess the safety and tolerability of repeated daily dosing of compound (1) in patients with relapsed and/or refractory advanced cancers.
  • the primary endpoints include (DLTs, adverse events (AEs), deaths and other serious AEs.
  • the secondary objectives of this study are to establish a MTD of compound (1) and a RP2D of orally administered compound (1) and to characterize pharmacokinetics of compound (1) following oral administration in patients with relapsed and/or refractory advanced cancers. Secondary endpoints include maximum plasma concentration (Cmax), area under the plasma concentration time curve (AUC), and half-life (t 1/2).
  • Exploratory objectives of this study are to assess the efficacy of compound (1), by objective responses per RECIST, wherever appropriate for applicable tumors.
  • Assessment of non- Hodgkin's Lymphoma and CNS tumors is by imaging techniques (CT, PET, MRI).
  • PK pharmacokinetic
  • Compound (1) concentrations are determined in plasma samples by a validated liquid chromatographytandem mass spectrometry (LC-MS/MS) assay. Levels of compound (1) are determined at specified time points in the PK profile.
  • LC-MS/MS liquid chromatographytandem mass spectrometry
  • PK parameters are derived using model-independent analysis: time to reach Cmax (Tmax), Cmax, PA, AUCO-t, AUCO-a, CL, and Vss. Descriptive statistics (mean, median, range, standard deviation) for these parameters are provided and summarized by each dose group.
  • Cmax and Tmax are determined from the plasma concentration-time profile, and tl/2[3 is calculated as 0.693/k (where k is the terminal elimination rate constant, calculated by log- linear regression of the terminal portion of the concentration-time profile).
  • AUCO-t is calculated by the linear trapezoidal rule and extrapolated to infinity using k to obtain AUCO-oo.
  • Pharmacokinetic parameters are calculated from compound (1) concentration-time data using standard non-compartmental methods as implemented in WinNonlin.
  • the maximum plasma concentration (Cmax) and time to reach Cmax (Tmax) are the observed values.
  • the area under the plasma concentration-time curve (AUC) value is calculated to the last quantifiable sample (AUClast) by use of the linear trapezoidal rule.
  • the AUC values are extrapolated to infinity (AUCinf) by dividing the last quantifiable concentration by the terminal disposition rate constant (Xz), which is determined from the slope of the terminal phase of the concentration-time profile.
  • the terminal half-life (Tl/2) is calculated as 0.693 divided by Xz.
  • the apparent oral clearance (Cl/F) is calculated by dividing the dose administered by AUCinf.4.
  • Pharmacokinetic data are analyzed by cohort.
  • efficacy analysis The efficacy variable is best overall response (ORR), using RECIST criteria, version 1.1. Objective tumor response is tabulated and summarized by the primary tumor type. If warranted, additional efficacy endpoints, such as duration of response or time to progression, are analyzed.
  • EXAMPLE 2 Study to Evaluate PK/PD results for a Pharmaceutical Composition Disclosed Herein for Treating a Disease in a Subject.
  • Summary This study is a dose escalation study to investigate the safety, tolerability, and PK characteristics of in-patients with advanced solid tumors who have received and failed at least one prior treatment.
  • the primary objective of this study is to assess the safety and tolerability of repeated daily dosing of 8-cyclopentyl-2-((4-(4-methylpiperazin-l- yl)phenyl)amino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile (compound (1)) in patients with relapsed and/or refractory advanced cancers.
  • the secondary objective of this study is to establish a MT of compound (1) and RP2D of orally administered compound (1).
  • the study explores efficacy of compound (1) in cancer patients.
  • Study design The study includes a treatment period (1 year) and a follow-up period (90 days after the last dose). Subjects are pathologically confirmed to have malignant solid tumors, or advanced (metastatic or unresectable) malignant solid tumors and have previously failed standard treatment (e.g., targeted therapy, chemotherapy, biotherapy, immunotherapy, etc.), as evidenced by disease progression or intolerance toxicity.
  • standard treatment e.g., targeted therapy, chemotherapy, biotherapy, immunotherapy, etc.
  • the study is divided into two stages, including a dosage escalation and a dose expansion cohort.
  • the first phase is a dose escalation, using 3+3 design to determine MTD and/or RP2D.
  • Three to six patients are enrolled per dose cohort, followed by up to 12 additional patients at the RP2D.
  • Approximately 9-30 patients are enrolled in the first phase. If additional dose escalations are required to establish the MTD/RP2D, then 3-6 additional patients are added per dose level.
  • Compound (1) is given in the form of a hard capsule comprising 48.4 mg 8- cyclopentyl-2-((4-(4-methylpiperazin-l-yl)phenyl)amino)-7-oxo-7,8-dihydropyrido[2,3- d]pyrimidine-6-carbonitrile monolactate salt, equivalent to 40 mg of 8-cyclopentyl-2-((4-(4- methylpiperazin-l-yl)phenyl)amino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6- carbonitrile.
  • the dose (one capsule) is taken in the morning, on an empty stomach.
  • Dose increments in the dose escalation 3+3 study are 40 mg of compound (1) per cycle. Dose levels are 40 mg, 80 mg, 120 mg, 160 mg, and 200 mg, or until a RP2D/MTD is reached. The highest escalation dose in the study is set at 200 mg. Dose escalation is performed as described in Example 1.
  • the second stage of the study is a dose expansion stage.
  • the dose expansion stage enrolls 9-12 cancer patients (primarily mantle cell lymphoma patients). Test procedures are the same as in the dose expansion phase.
  • the primary objective of this study is to evaluate the tolerance, safety, and the antitumor efficacy of compound (1) in patients having advanced tumors.
  • the secondary objective of this study is to characterize pharmacokinetics of compound (1) following oral administration of single and multiple doses of compound (1) in patients with relapsed and/or refractory advanced cancer. Secondary endpoints include maximum plasma concentration (Cmax), area under the plasma concentration time curve (AUC), and half-life (tl/2).
  • Cmax maximum plasma concentration
  • AUC area under the plasma concentration time curve
  • tl/2 half-life
  • the study evaluates the efficacy of compound (1) in patients with tumors, including objective response rate ORR, progression-free survival PFS, duration of remission DOR, disease control rate DCR, etc.
  • PK pharmacokinetic
  • Efficacy analysis The efficacy variable of this study is best overall response (ORR), using RECIST criteria, version 1.1.
  • Efficacy analysis includes: (1) Objective Remission Rate (ORR), defined as the proportion of subjects with complete remission (CR) and partial remission (PR) after treatment.
  • ORR Objective Remission Rate
  • DCR Disease Control Rate
  • SD disease stabilization
  • DOR Time to remission
  • PFS Progression free survival
  • EXAMPLE 3 Dosing Regimen to Evaluate an Oral Pharmaceutical Composition Disclosed Herein with a BTK Inhibitor in a Subject
  • the study is a randomized, double-blind, placebo-controlled, study of 8-cyclopentyl- 2-((4-(4-methylpiperazin-l-yl)phenyl)amino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6- carbonitrile (compound (1) in combination with a BTK inhibitor (e.g., ibrutinib or a pharmaceutically-acceptable salt thereof) versus placebo in combination with a BTK inhibitor (e.g., ibrutinib or a pharmaceutically-acceptable salt thereof) for patients with mantle cell lymphoma.
  • a BTK inhibitor e.g., ibrutinib or a pharmaceutically-acceptable salt thereof
  • Study Design This study is a treatment response study using 1 : 1 randomized doubleblind study. Patients are randomized into one of two treatment arms: Arm A: (placebo): ibrutinib-placebo combination therapy; and Arm B (experimental): ibrutinib-compound (1) combination therapy. Each cycle in the study is 28 days of treatment with tumors assessed every 12 weeks.
  • Compound (1) is given in the form of a hard capsule comprising 48.4 mg 8- cyclopentyl-2-((4-(4-methylpiperazin-l-yl)phenyl)amino)-7-oxo-7,8-dihydropyrido[2,3- d]pyrimidine-6-carbonitrile monolactate salt, equivalent to 40 mg of 8-cyclopentyl-2-((4-(4- methylpiperazin-l-yl)phenyl)amino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6- carbonitrile.
  • Compound (1) is taken once daily for 28 days (one cycle). Alternatively, compound (1) is taken once daily continuously for 3 weeks with one week of no administration for a total of 28 days. Treatment continues until progression of disease or unacceptable toxicity. Compound (1) is taken in the morning, on an empty stomach.
  • Ibrutinib or a pharmaceutically-acceptable salt thereof is given in the form of a 560 mg tablet.
  • One 560 mg ibrutinib tablet is taken once on days 1-28 (one cycle). Treatment continues until progression of disease or unacceptable toxicity. Ibrutinib is taken in the morning with water, at the same time as either compound (1) or the placebo.
  • Doses can be split into multiple dosage forms. For example, a 560 mg dose can be taken as two 280 mg tablets, four 140 mg tablets, or eight 70 mg tablets.
  • ibrutinib is given in the form of a 420 mg tablet, a 280 mg tablet, a 140 mg tablet, a 140 mg capsule, or a 70 mg capsule. Doses can be split into multiple dosage forms. For example, a 280 mg dose can be taken as two 140 mg tablets or four 70 mg tablets. A 140 mg dose can be taken as two 70 mg tablets.
  • a dose of One ibrutinib tablet or one ibrutinib capsule is taken once on days 1-28 (one cycle). Treatment continues until progression of disease or unacceptable toxicity. Ibrutinib is taken in the morning with water, at the same time as either compound (1) or the placebo.
  • Primary outcome measures Primary outcome measures are increase in Progression- Free Survival (PFS) in experimental arm versus comparator arm.
  • OS Overall survival
  • Toxicity Incidence and severity of adverse events by summaries of toxicity data/contingency tables.
  • Toxicity/efficacy of the various compounds of the disclosure are analyzed and compared.
  • Treatment effect was measured by CellTiter-Glo proliferation assay, FACS-mediated quantification of cell cycle and apoptosis, RT-PCR, and western blot validations.
  • Compound (1) exhibited significant antitumor activity in MCL cell lines independent of their sensitivity to ibrutinib with calculated half maximal inhibitory concentration (IC50) at 72 hours ranging for 0.7 to 7.1 pM (mean 3.61 ⁇ 2.1 pM) (Table 2).
  • Compound (1) was more potent in MCL cell lines than the CDK inhibitors Palbociclib and riboci clib (mean IC50 26.92 pM and 20.91 pM, respectively) and was similarly potent as abemaciclib (6.56 pM) (Table 2).
  • Compound (1) treatment repressed the activity of positive regulators of the G2/M cell cycle (Aurora kinase B, CDC20, CDK1, and cyclin B); decreased phosphor-Histone H3 levels, increased levels of the CDK inhibitors p21, pl6, and CDK2 phosphorylation resulting in a 20-35% increase in the G1 cell cycle fraction at 24 hours that preceded the onset of mitochondrial apoptosis.
  • the antitumor activity of compound (1) was similar to that of ibrutinib but more potent than acalabrutinib.
  • Combination treatment with compound (1) and ibrutinib resulted in antitumor activity at 72 hours with synergistic combination indexes in BTK-sensitive and BTK-resistant MCL cell lines, resulting from a 10-15% augmentation of G1 blockade at 24 hours, downregulation of phospho-histone H2 and phospho-CDK2, and upregulation of phospho-p27/p27 and pl 6.
  • Efficacy and safety of compound (1) was assessed in an immune-competent, chicken embryo chorioallantonic membrane (CAM) xenograft model of MCL.
  • Compound (1) treatment resulted in 32% tumor growth inhibition in the CAM-MCL model with no detectable toxicity observed.
  • MCL mantle cell lymphoma
  • the target protein expression for phosphorylated retinoblastoma protein (pRb), Rb, CDK4, and CDK6 proteins were determined by western blot analysis in MCL cell lines JEKO, UPN-1, REC-1, MINO, GRANTA-519, Z-138, and the modified counterpart MCL cell lines UPN-ibrutinib resistant, REC-1 BTK mutant, and REC-1 BTK KO (FIG. 3).
  • Cell viability was quantified by CellTiter-Glo ⁇ (CTG) proliferation assay in MCL cell lines JEKO, UPN-1, REC-1, MINO, GRANTA-519, and Z-138, treated with increasing doses of Compound (1) for 72 hours (FIG. 4). Cell viability decreased with increasing concentrations of Compound (1).
  • CCG CellTiter-Glo ⁇
  • MCL mantle cell lymphoma
  • CI values were calculated using the Compusyn Software (Chou-Talalay method) from CTG proliferation assays of MCL cell lines treated with different doses of Compound (1) combined with BTK inhibitors ibrutinib (FIG. 6) or acalabrutinib (FIG. 7).
  • 0.5pM CDK4/6 inhibitor e.g., Compound (1), abemaciclib, and palbociclib
  • IpM BTK inhibitor e.g., ibrutinib, acalabrutinib, and Loxo-305
  • REC-1 BTK mutant FIG. 12
  • 0.5pM CDK4/6 inhibitor e.g., Compound (1), abemaciclib, and palbociclib
  • IpM BTK inhibitor e.g., ibrutinib, acalabrutinib, and Loxo-305
  • Compound 1 exhibited superior activity to comparator CDK inhibitors. Compound 1 exhibited significant antitumor activity in MCL cell lines, independently of sensitivity to BTK inhibitors. Combination of CDK4/6 inhibitor Compound (1) with BTK inhibitors ibrutinib or acalabrutinib were found to be synergistic in MCL cell lines.
  • EXAMPLE 7 Evaluation of cell cycle activity of Compound (1) in combination with CDK inhibitors palbociclib, abemaciclib, or ribociclib in association with BTK inhibitors ibrutinib, acalabrutinib, or Loxo-305
  • Apoptosis analysis was assessed by AnnexinV+ staining (FIGs. 20-21) and mitochondrial transmembrane potential loss (FIGS. 22-23) after treatment with Compound (1) (0.5pM) alone and in combination with combined with BTK inhibitors ibrutinib (IpM) or acalabrutinib (IpM) for 72 hours.
  • Compound (1) evokes a G1 cell cycle blockade.
  • the blockade by was improved when Compound (1) was combined with BTK inhibitors.
  • Gene-set enrichment analysis was performed to identify the types of proteins with an altered pattern of gene expression.
  • An enrichment analysis of the differentially expressed genes was performed.
  • Enrichment analysis was performed in relation to detected genes.
  • groups were analyzed in terms of characterization, including by gene ontology (GO) biological process.
  • Treatment with Compound 1 was found to modulate various genes in MCL, including G2/M checkpoints, E2F target genes, MYC target genes, DNA repair, TNFa signaling via NFKB, and inflammatory response.
  • Compound (1) treatment resulted in 32% tumor growth inhibition in the CAM-MCL model (FIG. 45) with no detectable toxicity observed according to egg weights of eggs inoculated with CDK4/6 inhibitor and/or ibrutinib (FIGs. 46-47) or embryo weight at day 7 following treatment with CDK4/6 inhibitor and/or ibrutinib (FIG. 48).
  • Toxicity assays including determinations of egg weights and embryo weights, were conducted.
  • Compound (1) exhibited significant anti-tumor activity that was improved when combined with ibrutinib in a in vivo CAM xenograft model of MCL.

Abstract

Est présentement divulguée une méthode de traitement d'un lymphome par l'administration de 8-cyclopentyl-2-((4-(4-méthylpipérazin-1-yl)phényl)amino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile ou d'un sel pharmaceutiquement acceptable de celui-ci, seul ou en combinaison avec un deuxième agent tel qu'un inhibiteur de BTK, par exemple l'ibrutinib, l'acalabrutinib, ou un sel pharmaceutiquement acceptable de celui-ci. Sont également divulgués des combinaisons de 8-cyclopentyl-2-((4-(4-méthylpiperazin-1-yl)phényl)amino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile ou d'un sel pharmaceutiquement acceptable de celui-ci, et d'un deuxième agent tel qu'un tel inhibiteur de BTK, par exemple l'ibrutinib ou un sel pharmaceutiquement acceptable de celui-ci ou de l'acalabrutinib ou un sel pharmaceutiquement acceptable de celui-ci.
PCT/US2023/023618 2022-05-25 2023-05-25 Méthodes et compositions pour le traitement du cancer WO2023230286A2 (fr)

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