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WO2023230286A2 - Methods and compositions for treating cancer - Google Patents

Methods and compositions for treating cancer Download PDF

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Publication number
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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French (fr)
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WO2023230286A3 (en
WO2023230286A9 (en
Inventor
Steven M. Fruchtman
Matthew PARRIS
Stephen C. Cosenza
Adar Makovski SILVERSTEIN
Gaël ROUÉ
Mark S. GELDER
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Traws Pharma Inc
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Onconova Therapeutics Inc
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Publication of WO2023230286A3 publication Critical patent/WO2023230286A3/en
Publication of WO2023230286A9 publication Critical patent/WO2023230286A9/en
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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.

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Abstract

Disclosed herein is a method of treating lymphoma by administering 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, alone or in combination with a second agent such a BTK inhibitor, for example ibrutinib, acalabrutinib, or a pharmaceutically-acceptable salt thereof. Also disclosed herein are combinations of 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, and second agent such as such a BTK inhibitor, for example ibrutinib or a pharmaceutically-acceptable salt thereof or acalabrutinib or a pharmaceutically-acceptable salt thereof.

Description

METHODS AND COMPOSITIONS FOR TREATING CANCER
CROSS-REFERENCE
[0001] This application claims the benefit of U.S. Provisional Application No. 63/345,630 filed on May 25, 2022; U.S. Provisional Application No. 63/426,235 filed on November 17, 2022; and U.S. Provisional Application No. 63/496,301 filed on April 14, 2023, each of which is incorporated herein by reference in its entirety.
BACKGROUND
[0002] Mantle cell lymphoma (MCL) is an aggressive, rare form of non-Hodgkin lymphoma (NHL). A large subset of lymphomas have alterations in the B cell receptor signaling pathway.
INCORPORATION BY REFERENCE
[0003] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.
SUMMARY
[0004] In some embodiments, disclosed herein is a method of treating lymphoma in a human subject in need thereof, the method comprising administering to the subject a therapeutically- effective amount of a compound of formula (I)
Figure imgf000003_0001
wherein:
R1 is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl, each of which is unsubstituted or substituted, or hydrogen;
R2 is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, -CN, - C(O)R5, -C(O)OR5, -C(O)NR5R6, -C(=N)NR5R6, -OR5, -SR5, -NR5R6, - NR5C(O)R6, -NR5C(O)OR6, -OC(O)R5, -OC(O)NR5R6, -S(O)2R5, - NHS(O)2R5, or -OS(O)2R5, each of which is independently substituted or unsubstituted, or hydrogen or halogen;
R3 is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl or heteroaryl, each of which is unsubstituted or substituted, or hydrogen or halogen;
R4 is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -CN, C(O)R5, -C(O)OR5, -C(O)NR5R6, -C(=N)NR5R6, -OR5, -SR5, -NR5R6, - NR5C(O)R6, -NR5C(O)OR6, -OC(O)R5, -OC(O)NR5R6, -S(O)2R5, - NHS(O)2R5, or -OS(O)2R5, each of which is independently substituted or unsubstituted, or hydrogen or halogen; and each R5 and R6 is independently alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl, each of which is independently substituted or unsubstituted, or hydrogen or halogen; provided that, when R4 is -NR5R6 and one of R5 and R6 is pyridyl, then R2 is not -C(O)CH3, or a pharmaceutically-acceptable salt thereof.
[0005] In some embodiments, disclosed herein is a method of treating lymphoma in a subject in need thereof, the method comprising administering to the subject a therapeutically- effective amount of a compound of formula (I)
Figure imgf000004_0001
wherein:
R1 is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl, each of which is unsubstituted or substituted, or hydrogen;
R2 is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, -CN, - C(O)R5, -C(O)OR5, -C(O)NR5R6, -C(=N)NR5R6, -OR5, -SR5, -NR5R6, - NR5C(O)R6, -NR5C(O)OR6, -OC(O)R5, -OC(O)NR5R6, -S(O)2R5, - NHS(O)2R5, or -OS(O)2R5, each of which is independently substituted or unsubstituted, or hydrogen or halogen;
R3 is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl or heteroaryl, each of which is unsubstituted or substituted, or hydrogen or halogen;
R4 is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -CN, C(O)R5, -C(O)OR5, -C(O)NR5R6, -C(=N)NR5R6, -OR5, -SR5, -NR5R6, - NR5C(O)R6, -NR5C(O)OR6, -OC(O)R5, -OC(O)NR5R6, -S(O)2R5, - NHS(O)2R5, or -OS(O)2R5, each of which is independently substituted or unsubstituted, or hydrogen or halogen; and each R5 and R6 is independently alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl, each of which is independently substituted or unsubstituted, or hydrogen or halogen; provided that, when R4 is -NR5R6 and one of R5 and R6 is pyridyl, then R2 is not -C(O)CH3, or a pharmaceutically-acceptable salt thereof; wherein the administering is once daily for at least 4 weeks.
[0006] In some embodiments, disclosed herein is a method of treating lymphoma in a subject in need thereof, the method comprising administering to the subject a therapeutically- effective amount of a compound of formula (I)
Figure imgf000005_0001
wherein:
R1 is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl, each of which is unsubstituted or substituted, or hydrogen;
R2 is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, -CN, - C(O)R5, -C(O)OR5, -C(O)NR5R6, -C(=N)NR5R6, -OR5, -SR5, -NR5R6, - NR5C(O)R6, -NR5C(O)OR6, -OC(O)R5, -OC(O)NR5R6, -S(O)2R5, - NHS(O)2R5, or -OS(O)2R5, each of which is independently substituted or unsubstituted, or hydrogen or halogen;
R3 is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl or heteroaryl, each of which is unsubstituted or substituted, or hydrogen or halogen;
R4 is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -CN, C(O)R5, -C(O)OR5, -C(O)NR5R6, -C(=N)NR5R6, -OR5, -SR5, -NR5R6, - NR5C(O)R6, -NR5C(O)OR6, -OC(O)R5, -OC(O)NR5R6, -S(O)2R5, - NHS(O)2R5, or -OS(O)2R5, each of which is independently substituted or unsubstituted, or hydrogen or halogen; and each R5 and R6 is independently alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl, each of which is independently substituted or unsubstituted, or hydrogen or halogen; provided that, when R4 is -NR5R6 and one of R5 and R6 is pyridyl, then R2 is not -C(O)CH3, 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. [0007] In some embodiments, disclosed herein is a method of treating lymphoma in a subject in need thereof, the method comprising administering to the subject a therapeutically- effective amount of a compound of formula (I)
Figure imgf000006_0001
wherein:
R1 is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl, each of which is unsubstituted or substituted, or hydrogen;
R2 is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, -CN, - C(O)R5, -C(O)OR5, -C(O)NR5R6, -C(=N)NR5R6, -OR5, -SR5, -NR5R6, - NR5C(O)R6, -NR5C(O)OR6, -OC(O)R5, -OC(O)NR5R6, -S(O)2R5, - NHS(O)2R5, or -OS(O)2R5, each of which is independently substituted or unsubstituted, or hydrogen or halogen;
R3 is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl or heteroaryl, each of which is unsubstituted or substituted, or hydrogen or halogen;
R4 is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -CN, C(O)R5, -C(O)OR5, -C(O)NR5R6, -C(=N)NR5R6, -OR5, -SR5, -NR5R6, - NR5C(O)R6, -NR5C(O)OR6, -OC(O)R5, -OC(O)NR5R6, -S(O)2R5, - NHS(O)2R5, or -OS(O)2R5, each of which is independently substituted or unsubstituted, or hydrogen or halogen; and each R5 and R6 is independently alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl, each of which is independently substituted or unsubstituted, or hydrogen or halogen; provided that, when R4 is -NR5R6 and one of R5 and R6 is pyridyl, then R2 is not -C(O)CH3, or a pharmaceutically-acceptable salt thereof; wherein the subject received a therapy other than the compound for the lymphoma prior to the administering.
[0008] In some embodiments, disclosed herein is a method of treating lymphoma in a subject in need thereof, the method comprising
(i) administering to the subject a therapeutically-effective amount of a first compound, wherein the first compound is a compound of formula (I):
Figure imgf000007_0001
wherein:
R1 is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl, each of which is unsubstituted or substituted, or hydrogen;
R2 is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, -CN, - C(O)R5, -C(O)OR5, -C(O)NR5R6, -C(=N)NR5R6, -OR5, -SR5, -NR5R6, - NR5C(O)R6, -NR5C(O)OR6, -OC(O)R5, -OC(O)NR5R6, -S(O)2R5, - NHS(O)2R5, or -OS(O)2R5, each of which is independently substituted or unsubstituted, or hydrogen or halogen;
R3 is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl or heteroaryl, each of which is unsubstituted or substituted, or hydrogen or halogen;
R4 is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -CN, C(O)R5, -C(O)OR5, -C(O)NR5R6, -C(=N)NR5R6, -OR5, -SR5, -NR5R6, - NR5C(O)R6, -NR5C(O)OR6, -OC(O)R5, -OC(O)NR5R6, -S(O)2R5, - NHS(O)2R5, or -OS(O)2R5, each of which is independently substituted or unsubstituted, or hydrogen or halogen; and each R5 and R6 is independently alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl, each of which is independently substituted or unsubstituted, or hydrogen or halogen; provided that, when R4 is -NR5R6 and one of R5 and R6 is pyridyl, then R2 is not -C(O)CH3, or a pharmaceutically-acceptable salt thereof; and
(ii) administering to the subject a therapeutically-effective amount of a second compound.
[0009] In some embodiments, disclosed herein is combination comprising:
(a) therapeutically-effective amount of a compound of formula (I)
Figure imgf000008_0001
wherein:
R1 is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl, each of which is unsubstituted or substituted, or hydrogen;
R2 is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, -CN, - C(O)R5, -C(O)OR5, -C(O)NR5R6, -C(=N)NR5R6, -OR5, -SR5, -NR5R6, - NR5C(O)R6, -NR5C(O)OR6, -OC(O)R5, -OC(O)NR5R6, -S(O)2R5, - NHS(O)2R5, or -OS(O)2R5, each of which is independently substituted or unsubstituted, or hydrogen or halogen;
R3 is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl or heteroaryl, each of which is unsubstituted or substituted, or hydrogen or halogen;
R4 is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -CN, C(O)R5, -C(O)OR5, -C(O)NR5R6, -C(=N)NR5R6, -OR5, -SR5, -NR5R6, - NR5C(O)R6, -NR5C(O)OR6, -OC(O)R5, -OC(O)NR5R6, -S(O)2R5, - NHS(O)2R5, or -OS(O)2R5, each of which is independently substituted or unsubstituted, or hydrogen or halogen; and each R5 and R6 is independently alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl, each of which is independently substituted or unsubstituted, or hydrogen or halogen; provided that, when R4 is -NR5R6 and one of R5 and R6 is pyridyl, then R2 is not -C(O)CH3, or a pharmaceutically-acceptable salt thereof; and
(ii) a therapeutically-effective amount of a second compound.
[0010] In some embodiments, 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.
[0011] In some embodiments, 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. In some embodiments, 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. In some embodiments, the synergistic activity is in mantle cell lymphoma cells (MCL). In some embodiments, the synergistic activity is in BTK inhibitorresistant MCL cells.
[0012] In some embodiments, 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. In some embodiments, 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. In some embodiments, the synergistic activity is in mantle cell lymphoma cells (MCL). In some embodiments, the synergistic activity is in BTK inhibitor-resistant MCL cells.
[0013] In some embodiments, 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. In some embodiments, 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.
[0014] In some embodiments, disclosed herein is a method of treating mantle cell lymphoma in a subject in need thereof, the method 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.
[0015] In some embodiments, disclosed herein is a method of treating mantle cell lymphoma in a subject in need thereof, the method 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 pharmaceutically-acceptable salt thereof.
[0016] In some embodiments, disclosed herein is a method of treating mantle cell lymphoma in a subject in need thereof, the method 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 pharmaceutically-acceptable salt thereof.
[0017] In some embodiments, disclosed herein is a method of treating Bruton tyrosine kinase inhibitor-resistant mantle cell lymphoma in a subject in need thereof, the method 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.
[0018] In some embodiments, disclosed herein is a method of treating Bruton tyrosine kinase inhibitor-resistant mantle cell lymphoma in a subject in need thereof, the method 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 pharmaceutically-acceptable salt thereof.
[0019] In some embodiments, disclosed herein is a method of treating Bruton tyrosine kinase inhibitor-resistant mantle cell lymphoma in a subject in need thereof, the method 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 pharmaceutically- acceptable salt thereof.
BRIEF DESCRIPTION OF THE DRAWINGS
[0020] FIG. 1 shows tumors treated with compound- 1 shows a greater reduction in tumor volume compared to the control.
[0021] FIG. 2 shows mice treated with compound- 1 shows a greater reduction in tumor volume compared to the mice treated with control.
[0022] 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.
[0023] 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.
[0024] 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.
[0025] 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.
[0026] 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.
[0027] 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. [0028] 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.
[0029] 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.
[0030] 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.
[0031] 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.
[0032] 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.
[0033] 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.
[0034] 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.
[0035] 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.
[0036] 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.
[0037] 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.
[0038] 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.
[0039] 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.
[0040] 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.
[0041] 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.
[0042] 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.
[0043] 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.
[0044] 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.
[0045] 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.
[0046] 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.
[0047] 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.
[0048] 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.
[0049] 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.
[0050] 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.
[0051] 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.
[0052] 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.
[0053] 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.
[0054] 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.
[0055] 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).
[0056] 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).
[0057] 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).
[0058] FIG. 39 shows GSEA for E2F targets after transcriptomic (RNAseq) characterization of MCL cell lines following exposure to Compound (1).
[0059] FIG. 40 shows GSEA for MYC targets after transcriptomic (RNAseq) characterization of MCL cell lines following exposure to Compound (1).
[0060] FIG. 41 shows GSEA for G2/M checkpoints after transcriptomic (RNAseq) characterization of MCL cell lines following exposure to Compound (1).
[0061] FIG. 42 shows GSEA for DNA repair after transcriptomic (RNAseq) characterization of MCL cell lines following exposure to Compound (1).
[0062] FIG. 43 shows GSEA for TNFa signaling via NFKB after transcriptomic (RNAseq) characterization of MCL cell lines following exposure to Compound (1).
[0063] FIG. 44 shows GSEA for inflammatory response after transcriptomic (RNAseq) characterization of MCL cell lines following exposure to Compound (1).
[0064] FIG. 45 shows a schematic timeline for the chorioallantoic membrane chick embryo (CAM) model.
[0065] 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.
[0066] 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.
[0067] 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.
[0068] 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.
[0069] 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.
[0070] 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.
[0071] 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.
[0072] 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.
[0073] 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.
[0074] 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.
[0075] 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.
[0076] 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.
[0077] 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.
[0078] The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee.
DETAILED DESCRIPTION
[0079] Provided herein are 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. In some embodiments, Compound lis 8-cyclopentyl-2-((4-(4-methylpiperazin-l-yl)phenyl)amino)-7-oxo-7,8- dihydropyrido[2,3-d]pyrimidine-6-carbonitrile. In some embodiments, 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). In some embodiments, 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. In some embodiments, the BTK inhibitor can be selected from but are not limited to Ibrutinib, Acalabrutinib, Zanubrutinib
Compounds of the Disclosure
[0080] A compound disclosed herein can be of the formula:
Figure imgf000018_0001
wherein:
R1 is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl, each of which is unsubstituted or substituted, or hydrogen;
R2 is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, -CN, - C(O)R5, -C(O)OR5, -C(O)NR5R6, -C(=N)NR5R6, -OR5, -SR5, -NR5R6, - NR5C(O)R6, -NR5C(O)OR6, -OC(O)R5, -OC(O)NR5R6, -S(O)2R5, - NHS(O)2R5, or -OS(O)2R5, each of which is independently substituted or unsubstituted, or hydrogen or halogen;
R3 is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl or heteroaryl, each of which is unsubstituted or substituted, or hydrogen or halogen;
R4 is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -CN, C(O)R5, -C(O)OR5, -C(O)NR5R6, -C(=N)NR5R6, -OR5, -SR5, -NR5R6, - NR5C(O)R6, -NR5C(O)OR6, -OC(O)R5, -OC(O)NR5R6, -S(O)2R5, - NHS(O)2R5, or -OS(O)2R5, each of which is independently substituted or unsubstituted, or hydrogen or halogen; and each R5 and R6 is independently alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl, each of which is independently substituted or unsubstituted, or hydrogen or halogen; provided that, when R4 is -NR5R6 and one of R5 and R6 is pyridyl, then R2 is not -C(O)CH3, or a pharmaceutically-acceptable salt thereof.
[0081] A compound disclosed herein can be of the formula:
Figure imgf000019_0001
wherein:
R1 is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl, each of which is unsubstituted or substituted, or hydrogen;
R2 is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, -CN, - C(O)R5, -C(O)OR5, -C(O)NR5R6, -C(=N)NR5R6, -OR5, -SR5, -NR5R6, - NR5C(O)R6, -NR5C(O)OR6, -OC(O)R5, -OC(O)NR5R6, -S(O)2R5, - NHS(O)2R5, or -OS(O)2R5, each of which is independently substituted or unsubstituted, or hydrogen or halogen;
R3 is C2-Ce alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl or heteroaryl, each of which is unsubstituted or substituted, or hydrogen or halogen;
R4 is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -CN, C(O)R5, -C(O)OR5, -C(O)NR5R6, -C(=N)NR5R6, -OR5, -SR5, -NR5R6, - NR5C(O)R6, -NR5C(O)OR6, -OC(O)R5, -OC(O)NR5R6, -S(O)2R5, - NHS(O)2R5, or -OS(O)2R5, each of which is independently substituted or unsubstituted, or hydrogen or halogen; and each R5 and R6 is independently alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl, each of which is independently substituted or unsubstituted, or hydrogen or halogen, or a pharmaceutically-acceptable salt thereof.
[0082] A compound disclosed herein can be a pharmaceutically-acceptable salt of the formula:
Figure imgf000020_0001
wherein:
R1 is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl, each of which is unsubstituted or substituted, or hydrogen;
R2 is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, -CN, - C(O)R5, -C(O)OR5, -C(O)NR5R6, -C(=N)NR5R6, -OR5, -SR5, -NR5R6, - NR5C(O)R6, -NR5C(O)OR6, -OC(O)R5, -OC(O)NR5R6, -S(O)2R5, - NHS(O)2R5, or -OS(O)2R5, each of which is independently substituted or unsubstituted, or hydrogen or halogen;
R3 is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl or heteroaryl, each of which is unsubstituted or substituted, or hydrogen or halogen;
R4 is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -CN, C(O)R5, -C(O)OR5, -C(O)NR5R6, -C(=N)NR5R6, -OR5, -SR5, -NR5R6, - NR5C(O)R6, -NR5C(O)OR6, -OC(O)R5, -OC(O)NR5R6, -S(O)2R5, - NHS(O)2R5, or -OS(O)2R5, each of which is independently substituted or unsubstituted, or hydrogen or halogen; and each R5 and R6 is independently alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl, each of which is independently substituted or unsubstituted, or hydrogen or halogen.
[0083] A compound disclosed herein can be a lactate salt of the formula:
Figure imgf000020_0002
wherein:
R1 is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl, each of which is unsubstituted or substituted, or hydrogen;
R2 is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, -CN, - C(O)R5, -C(O)OR5, -C(O)NR5R6, -C(=N)NR5R6, -OR5, -SR5, -NR5R6, - NR5C(O)R6, -NR5C(O)OR6, -OC(O)R5, -OC(O)NR5R6, -S(O)2R5, - NHS(O)2R5, or -OS(O)2R5, each of which is independently substituted or unsubstituted, or hydrogen or halogen;
R3 is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl or heteroaryl, each of which is unsubstituted or substituted, or hydrogen or halogen;
R4 is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -CN, C(O)R5, -C(O)OR5, -C(O)NR5R6, -C(=N)NR5R6, -OR5, -SR5, -NR5R6, - NR5C(O)R6, -NR5C(O)OR6, -OC(O)R5, -OC(O)NR5R6, -S(O)2R5, - NHS(O)2R5, or -OS(O)2R5, each of which is independently substituted or unsubstituted, or hydrogen or halogen; and each R5 and R6 is independently alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl, each of which is independently substituted or unsubstituted, or hydrogen or halogen.
[0084] In some embodiments, R1 is cycloalkyl. In some embodiments, R1 is C2-Cs cycloalkyl. In some embodiments, R1 is an unsubstituted cyclopentyl. In some embodiments, R1 is an unsubstituted cyclopentyl. In some embodiments, R2 is CN. In some embodiments, R3 is hydrogen.
[0085] In some embodiments, R4 is -NR5R6. In some embodiments, one of R5 and R6 is hydrogen. In some embodiments, one of R5 and R6 is phenyl. In some embodiments, one of R5 and R6 is phenyl substituted with heterocyclyl. In some embodiments, one of R5 and R6 is phenyl substituted with heterocyclyl, wherein the heterocyclyl contains at least one ring nitrogen atom. In some embodiments, one of R5 and R6 is phenyl substituted with C2-Cs heterocyclyl. In some embodiments, one of R5 and R6 is phenyl substituted with Ce heterocyclyl. In some embodiments, one of R5 and R6 is phenyl substituted with piperazinyl, wherein the piperazinyl is unsubstituted or substituted. In some embodiments, one of R5 and R6 is phenyl substituted with piperazinyl, wherein the piperazinyl is substituted with an alkyl. In some embodiments, one of R5 and R6 is phenyl substituted with 4-methyl piperazinyl. [0086] In some embodiments, R4 is
Figure imgf000022_0001
wherein:
R7 is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -OR5, - SR5, or -NR5R6, each of which is unsubstituted or substituted, or hydrogen;
R8 is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -OR5, - SR5, or -NR5R6, each of which is unsubstituted or substituted, or hydrogen; and R9 is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -OR5, - SR5, or -NR5R6, each of which is unsubstituted or substituted, or hydrogen. [0087] In some embodiments, R7 is hydrogen. In some embodiments, R8 is hydrogen. In some embodiments, R9 unsubstituted or substituted heterocyclyl. In some embodiments, R9 is unsubstituted or substituted piperazinyl. In some embodiments, R9 is piperazinyl substituted with alkyl. In some embodiments, R9 is 4-methyl piperazinyl.
[0088] In some embodiments, the compound is a compound of formula (II)
Figure imgf000022_0002
[0089] In some embodiments, the compound is a compound of formula (III)
Figure imgf000023_0001
wherein:
Y is O, S, or NR11; each R10 is independently alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -OR5, -SR5, or -NR5R6, each of which is unsubstituted or substituted;
R11 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.
[0090] In some embodiments, R1 is cycloalkyl. In some embodiments, R1 is Cs-Cs cycloalkyl. In some embodiments, R1 is an unsubstituted cyclopentyl. In some embodiments, R1 is an unsubstituted cyclopentyl.
[0091] In some embodiments, Y is NR11. In some embodiments, R11 is alkyl. In some embodiments, R11 is methyl. In some embodiments, n is 0.
[0092] In some embodiments, Y is NR11. In some embodiments, R11 is alkyl. In some embodiments, R11 is methyl. In some embodiments, n is 0.
[0093] In some embodiments, the compound is of the formula:
Figure imgf000024_0001
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.
[0094] In some embodiments, the compound is in the form of a salt formed by combining a compound with lactic acid. In some embodiments, 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.
[0095] Several moieties described herein can be substituted or unsubstituted. Non-limiting examples of 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.
[0096] 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, C24, C25, C26, C27, C28, 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. [0097] Non-limiting examples of straight alkyl groups include methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, and decyl.
[0098] 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.
[0099] Non-limiting examples of substituted alkyl groups includes hydroxymethyl, chloromethyl, trifluoromethyl, aminomethyl, 1 -chloroethyl, 2 -hydroxy ethyl, 1,2- difluoroethyl, and 3-carboxypropyl.
[0100] 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-hexahydro-3J/-inden-4-yl, decahydroazulenyl, bicyclo-[2.1.1]hexanyl, bicyclo[2.2.1]heptanyl, bicyclo[3.1.1]heptanyl, l,3-dimethyl[2.2.1]heptan-2-yl, bicyclo[2.2.2]octanyl, and bicyclo[3.3.3]undecanyl.
[0101] 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 C2, C3, C4, C5, C6, C7, C8, C9, Cio, Cu, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, C24, c25, C26, C27, C28, 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 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 .
[0102] 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 C2, C3, C4, C5, Ce, C7, C8, C9, Cio, Cu, C12, C13, C14, C15, C16, C17, Cl8, C19, C20, C21, C22, C23, C24, C25, C26, C27, C28, 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 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 .
[0103] 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.
[0104] 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. Nonlimiting examples of alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, and isobutoxy.
[0105] 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-difluorophenyl, 3,5-difluorophenyl, 2,3-dichlorophenyl, 3, 4-di chlorophenyl, 3,5- di chlorophenyl, 2-hydroxyphenyl, 3 -hydroxyphenyl, 4-hydroxyphenyl, 2-methoxyphenyl, 3- methoxyphenyl, 4-methoxyphenyl, 2,3-dimethoxyphenyl, 3,4-dimethoxyphenyl, 3,5- dimethoxyphenyl, 2,4-difluorophenyl, 2,5-difluorophenyl, 2,6-difluorophenyl, 2,3,4- trifluorophenyl, 2,3,5-trifluorophenyl, 2,3,6-trifluorophenyl, 2,4,5-trifluorophenyl, 2,4,6- trifluorophenyl, 2,4-dichlorophenyl, 2,5-dichlorophenyl, 2,6-dichlorophenyl, 3,4- di chlorophenyl, 2,3,4-trichlorophenyl, 2,3,5-trichlorophenyl, 2,3,6-trichlorophenyl, 2,4,5- tri chlorophenyl, 3,4,5-trichlorophenyl, 2,4,6-trichlorophenyl, 2,3 -dimethylphenyl, 2,4- dimethylphenyl, 2,5-dimethylphenyl, 2,6-dimethylphenyl, 2,3,4-trimethylphenyl, 2,3,5- trimethylphenyl, 2,3,6-trimethylphenyl, 2,4,5-trimethylphenyl, 2,4,6-trimethylphenyl, 2- ethylphenyl, 3 -ethylphenyl, 4-ethylphenyl, 2,3-diethylphenyl, 2,4-diethylphenyl, 2,5- diethylphenyl, 2,6-diethylphenyl, 3,4-diethylphenyl, 2,3,4-triethylphenyl, 2,3,5- triethylphenyl, 2,3,6-triethylphenyl, 2,4,5-triethylphenyl, 2,4,6-triethylphenyl, 2- isopropylphenyl, 3-isopropylphenyl, and 4-isopropylphenyl.
[0106] 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.
[0107] 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.
[0108] Non-limiting examples of heterocycles (heterocyclyl) 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 1,2,3,4-tetrahydroquinoline; and ii) heterocyclic units having 2 or more rings one of which is a heterocyclic ring, non-limiting examples of which include hexahydro- 1H- pyrrolizinyl, 3a,4,5,6,7,7a-hexahydro-l//-benzo[d]imidazolyl, 3a,4,5,6,7,7a-hexahydro-l/7- indolyl, 1,2,3,4-tetrahydroquinolinyl, and decahydro- 17/-cycloocta[b]pyrrolyl.
[0109] Non-limiting examples of 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, 7Z7-pyrrolo[2,3- ]pyrimidinyl, pyrido[2,3-d]pyrimidinyl, 4,5,6,7-tetrahydro-l-Z/-indolyl, quinoxalinyl, quinazolinyl, quinolinyl, 8-hydroxy-quinolinyl, and isoquinolinyl.
[0110] Any compound herein can be purified. 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 41% pure, at least 42% pure, at least 43% pure, at least 44% pure, at least 45% pure, at least 46% pure, at least 47% pure, at least 48% pure, at least 49% pure, at least 50% pure, at least 51% pure, at least 52% pure, at least 53% pure, at least 54% pure, at least 55% pure, at least 56% pure, at least 57% pure, at least 58% pure, at least 59% pure, at least 60% pure, at least 61% pure, at least 62% pure, at least 63% pure, at least 64% pure, at least 65% pure, at least 66% pure, at least 67% pure, at least 68% pure, at least 69% pure, at least 70% pure, at least 71% pure, at least 72% pure, at least 73% pure, at least 74% pure, at least 75% pure, at least 76% pure, at least 77% pure, at least 78% pure, at least 79% pure, at least 80% pure, at least 81% pure, at least 82% pure, at least 83% pure, at least 84% pure, at least 85% pure, at least 86% pure, at least 87% pure, at least 88% pure, at least 89% pure, at least 90% pure, at least 91% pure, at least 92% pure, at least 93% pure, at least 94% pure, at least 95% pure, at least 96% pure, at least 97% pure, at least 98% pure, at least 99% pure, at least 99.1% pure, at least 99.2% pure, at least 99.3% pure, at least 99.4% pure, at least 99.5% pure, at least 99.6% pure, at least 99.7% pure, at least 99.8% pure, or at least 99.9% pure.
Pharmaceutically Acceptable Salts
[OHl] The method disclosed herein provides the use of pharmaceutically-acceptable salts of any compound described herein. Pharmaceutically-acceptable salts 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.
[0112] Acid addition salts can arise from the addition of an acid to a compound disclosed herein. In some embodiments, the acid is organic. In some embodiments, the acid is inorganic. In some embodiments, 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. In some embodiments, 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.
[0113] In some embodiments, 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, a sulfite salt, a phosphate salt, isonicotinate salt. In some embodiments, 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.
[0114] 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. In some embodiments, the metal is lithium, sodium, potassium, cesium, cerium, magnesium, manganese, iron, calcium, strontium, cobalt, titanium, aluminum, copper, cadmium, or zinc.
[0115] In some embodiments, 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.
Therapeutic Methods
[0116] Kinase activity is central to many signaling pathways and is often de-regulated in cancers. In some embodiments, 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. In some embodiments, a CDK inhibitor is a compound disclosed herein. Non-limiting examples of CDK inhibitors are listed in Table 1. In some embodiments, overexpression of CDK, e.g., CDK 4/6 causes cell-cycle deregulation in cancers. In some embodiments, modulation of kinase pathways can result in the obstruction of proliferation signal receipt in cells, thus arresting tumor growth. In some embodiments, 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).
Table 1: Examples of CDK inhibitors
Figure imgf000030_0001
Figure imgf000031_0001
Figure imgf000032_0001
[0117] In some embodiments, 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. In some embodiments, 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).
[0118] In some embodiments, 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.
[0119] In some embodiments, 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.
[0120] In some embodiments, 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.
[0121] In some embodiments, 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.
[0122] 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. In some embodiments, a compound described herein can down-modulate the B cell receptor signaling pathway, or a portion thereof, for example, Bruton tyrosine kinase (BTK). In some embodiments, overexpression of BTK causes cell-cycle deregulation in cancers. In some embodiments, modulation of kinase pathways can result in the obstruction of proliferation signal receipt in cells, thus arresting tumor growth.
[0123] In some embodiments, a compound described herein can be an inhibitor of tyrosine kinases. In some embodiments, a compound described herein can be an inhibitor of Bruton’s tyrosine kinase (BTK). In some embodiments, 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.
[0124] 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.
[0125] In some embodiments, the cancer is a solid tumor cancer.
[0126] In some embodiments, the cancer is carcinoma. Non-limiting examples of carcinoma include: adenocarcinoma, basal cell carcinoma, squamous cell carcinoma, and transitional cell carcinoma.
[0127] In some embodiments, the cancer is sarcoma. Non-limiting examples of sarcomas include: bone sarcomas and soft tissue sarcomas. In some embodiments, the sarcoma is a soft tissue sarcoma. Non-limiting examples of soft-tissue sarcomas include: chondrosarcoma, rhabdomysarcoma, and leiomyosarcoma.
[0128] In some embodiments, the cancer is lymphoma. Non-limiting examples of 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), Chronic lymphocytic leukemia/small-cell lymphocytic lymphoma (CLL/SLL), Gastric mucosa-associated lymphoid tissue (MALT) lymphoma, Lymphoplasmacytic lymphoma, Waldenstrom macroglobulinemia (WM), Nodal marginal zone lymphoma (NMZL), Splenic marginal zone lymphoma (SMZL), Mature T-cell and natural killer (NK)-cell lymphomas, Peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS), Systemic anaplastic large-cell lymphoma (ALCL), Lymphoblastic lymphoma, Hepatosplenic T-cell lymphoma, Enteropathy-associated intestinal T-cell lymphoma, Monomorphic epitheli otropic intestinal T-cell lymphoma, Angioimmunoblastic T-cell lymphoma (AITL), Adult T-cell leukemia/lymphoma, Extranodal natural killer (NK)/T-cell lymphoma (ENK/TCL), nasal type, Cutaneous T-cell lymphoma (CTCL), Mycosis fungoides (MF), Sezary syndrome (SS), Primary cutaneous anaplastic large-cell lymphoma (pcALCL), Subcutaneous panniculitis-like T-cell lymphoma (SPTCL), and Primary cutaneous gamma delta T-cell lymphoma.
[0129] In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is hormone receptor-positive (HR+), HER2-negative metastatic breast cancer. In some embodiments, the cancer is triple negative breast cancer (TNBC). In some embodiments, the cancer is lung cancer. In some embodiments, the cancer is colon cancer. In some embodiments, the cancer is Mantle cell lymphoma (MCL). In some embodiments, the cancer is BTKi-resistant MCL. In some embodiments, the cancer is B-cell non-Hodgkin lymphoma (B-NHL).
[0130] In some embodiments, 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-Hodgkin’ s lymphoma, hairy cell lymphoma, or Burkett’s lymphoma; a hematopoietic tumor of myeloid lineage, for example acute and chronic myelogenous leukemias, myelodysplastic syndrome, or promyelocytic leukemia; thyroid follicular cancer; a tumor of mesenchymal origin, for example fibrosarcoma or rhabdomyosarcoma; a tumor of the central or peripheral nervous system, for example astrocytoma, neuroblastoma, glioma or schwannoma; melanoma; seminoma; teratocarcinoma; osteosarcoma; xeroderma pigmentosum; keratoacanthoma; thyroid follicular cancer; or Kaposi’s sarcoma.
[0131] In some embodiments, 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.
[0132] In some embodiments, the cancer is associated with dysregulation of a gene, e.g., overexpression or underexpression of a gene, e.g., BUB1, BRCA. In some embodiments, the cancer is associated with dysregulation of a transcription factor, e.g., overexpression or underexpression of a transcription factor, e.g., MYC, E2F.
[0133] In some embodiments, the cancer is a cancer comprising cancer stem cells (CSCs), e.g., breast cancer. In some embodiments, the cancer is a refractory cancer. In some embodiments, the cancer is a relapsed cancer. In some embodiments, the cancer is resistant and/or non-responsive to a first line of therapy. In some embodiments, the cancer is associated with poor prognosis and/or low survival probability.
[0134] In some embodiments, the cancer is a cancer of a reproductive organ. In some embodiments, the reproductive organ cancer is a breast cancer, ovarian cancer, e.g., serous ovarian cancer, e.g., low grade serous ovarian cancer, endometrial cancer. In some embodiments, the breast cancer is a primary breast cancer. In some embodiments, the breast cancer is a secondary breast cancer. In some embodiments, the breast cancer is a metastatic breast cancer. In some embodiments, the breast cancer is hormone receptor positive. In some embodiments, the breast cancer is estrogen receptor positive. In some embodiments, the breast cancer is estrogen receptor negative. In some embodiments, the breast cancer is progesterone receptor positive. In some embodiments, the breast cancer is progesterone receptor negative. In some embodiments, 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 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.
[0135] 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. In some embodiments, the tumor is a breast cancer tumor. In some embodiments, the tumor is a metastatic breast cancer tumor. In some embodiments, the breast cancer tumor is hormone receptor positive. In some embodiments, the breast cancer tumor is estrogen receptor positive. In some embodiments, the breast cancer tumor is estrogen receptor negative. In some embodiments, the breast cancer tumor is progesterone receptor positive. In some embodiments, the breast cancer tumor is progesterone receptor negative. In some embodiments, the breast cancer tumor is HER2 receptor negative. In some embodiments, 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 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.
[0136] 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. 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.
[0137] In some embodiments, the tumor is a solid tumor. Non-limiting examples of solid tumors include: carcinomas, sarcomas, and lymphomas. In some embodiments, the solid tumor is a carcinoma. In some embodiments, the solid tumor is a sarcoma. In some embodiments, the solid tumor is a lymphona.
[0138] In some embodiments, the tumor is a mantle cell lymphoma tumor.
[0139] A tumor response due to a method herein can be measured based on the Response Evaluation Criteria in Solid Tumors (RECIST) classification of responses. 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.
[0140] In some embodiments, 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. In some embodiments, 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. In some embodiments, 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.
[0141] In some embodiments, 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. In some embodiments, 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. In some embodiments, 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.
[0142] In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. [0143] In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, the subject is further treated with a BTK inhibitor, e.g., acalabrutinib. In some embodiments, 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. In some embodiments, the subject is further treated with a BTK inhibitor, e.g., acalabrutinib. In some embodiments, 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. In some embodiments, 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.
[0144] In some embodiments, the administering comprises a second line of therapy. In some embodiments, 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. In some embodiments, the therapy (e.g., BTK inhibitor such as ibrutinib) was received after the subject was diagnosed with the mantle cell lymphoma. In some embodiments, the subject did not respond to the therapy (e.g., BTK inhibitor such as ibrutinib or acalabrutinib). In some embodiments, the subject experienced a relapse of the mantle cell lymphoma after the therapy (e.g., BTK inhibitor such as ibrutinib acalabrutinib). In some embodiments, the subject has primary resistance to one or more BTK inhibitors, e.g., acalabrutinib. In some embodiments, the subject has acquired resistance to one or more BTK inhibitors e.g., acalabrutinib.
[0145] In some embodiments, 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. 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-1 yl)phenyl)amino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6- carbonitrile or a pharmaceutically-acceptable salt thereof. In some embodiments, 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). [0146] Differentially expressed genes
[0147] Cancer development is a multistep process where genetic changes are accumulated, thus progressively transforming cells into a cancerous phenotype. In some embodiments, one or more genes associated with cellular proliferation is upregulated in a cell of a subject having a cancer disclosed herein. In some embodiments, 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.
[0148] In some embodiments, administering a compound disclosed herein alters expression of one or more genes in a cell of a subject having a cancer disclosed herein.
[0149] In some embodiments, 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.
[0150] In some embodiments, 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.
Combination Therapy
[0151] 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. For example, in some embodiments, 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.
[0152] 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. In some embodiments the one or more compounds disclosed herein are co-administered with a second agent. When used in combination therapy, 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. In some embodiments, a compound disclosed herein and a second agent can be simultaneously administered, wherein both the agents are present in separate formulations. In some embodiments, a compound disclosed herein can be administered just followed by a second agent, or vice versa. In some embodiments, 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.
[0153] In some embodiments, the second agent is a biological, pharmaceutical, or chemical compound. Non-limiting examples of 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. Additional non-limiting examples of a second agent include small molecule inhibitors, monoclonal antibodies (mAbs), sdAbs, chimeric antigen receptors (CARs), CAR T-cell therapy, and antibody-drug conjugates (ADCs), and bispecific antibodies. In some embodiments, a second agent is a biologic. Non-limiting examples of biologies include vaccines, blood, and blood components, allergenics, somatic cells, gene therapy, tissues, and recombinant therapeutic proteins. In some embodiments, the method includes administering a procedure. Non-limiting examples of procedures include surgery, radiation treatments (i.e., beam radiation), chemotherapy, immunotherapy, and ablation.
[0154] In some embodiments, 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.
[0155] In some embodiments, 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). In some embodiments, the second therapeutic agent is anAOK5 inhibitor. In some embodiments, the second therapeutic agent is an autophagy inhibitor, e.g., chloroquine, hydroxychloroquine. In some embodiments, the second therapeutic agent is an aromatase inhibitor. In some embodiments, the aromatase inhibitor is letrozole or a pharmaceutically- acceptable salt thereof. In some embodiments, the second therapeutic agent is a selective estrogen receptor degrader. In some embodiments, the second therapeutic agent is a selective estrogen receptor blocker. In some embodiments, the selective estrogen receptor degrader is fulvestrant. In some embodiments, the second therapeutic agent is an autophagy agent, e.g., hydroxychloroquine, chloroquine.
[0156] In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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). In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, a combination therapy includes administration of two, three, four, or five additional agents in combination with a compound disclosed herein. In some embodiments, the third therapeutic agent can be a therapeutic agent disclosed herein. In some embodiments, the fourth therapeutic agent can be a therapeutic agent disclosed herein. In some embodiments, the fifth therapeutic agent can be a therapeutic agent disclosed herein.
[0157] 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.
[0158] 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. In some embodiments, 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. In some embodiments, a compound disclosed herein, for example Compound 1, is administered in combination with a BTK inhibitor.
[0159] In some embodiments, 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.
[0160] In some embodiments, 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. In some embodiments, 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. In some embodiments, 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.
[0161] In some embodiments, 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. In some embodiments, 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.
[0162] In some embodiments, the BTK inhibitor is ibrutinib or a pharmaceutically-acceptable salt thereof. In some embodiments, the BTK inhibitor is acalabrutinib or a pharmaceutically- acceptable salt thereof. In some embodiments, the BTK inhibitor is pirtobrutinib (Loxo-305) or a pharmaceutically-acceptable salt thereof. In some embodiments, the BTK inhibitor is zanubrutinib or a pharmaceutically-acceptable salt thereof. In some embodiments, the BTK inhibitor is tirabrutinib or a pharmaceutically-acceptable salt thereof. In some embodiments, the BTK inhibitor is tolebrutinib or a pharmaceutically-acceptable salt thereof. In some embodiments, 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.
[0163] In some embodiments, 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. In some embodiments, 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 In some embodiments, a second compound is a drug. In some embodiments, a second compound is a BTK inhibitor.
[0164] In some embodiments, 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. In some embodiments, 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. In some embodiments, the BTK inhibitor can be ibrutinib or a pharmaceutically-acceptable salt thereof. In some embodiments, the BTK inhibitor can be acalabrutinib or a pharmaceutically- acceptable salt thereof. In some embodiments, 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. [0165] In some embodiments, 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. In some embodiments, 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. In some embodiments, 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). In some embodiments, the combination of compound (1) and ibrutinib a pharmaceutically-acceptable salt thereof achieves synergistic antitumor activity. In some embodiments, the synergistic antitumor activity is shown against a BTK inhibitor-resistant MCL.
[0166] In some embodiments, 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. In some embodiments, 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. In some embodiments, the combination of compound (1) and acalabrutinib or a pharmaceutically acceptable salt thereof achieves synergistic antitumor activity. In some embodiments, the synergistic antitumor activity is shown against a BTK inhibitor-resistant MCL.
[0167] In some embodiments, 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. In some embodiments, 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. In some embodiments, the combination of compound (1) and pirtobrutinib (Loxo-305) or a pharmaceutically acceptable salt thereof achieves synergistic antitumor activity. In some embodiments, the synergistic antitumor activity is shown against a BTK inhibitor-resistant MCL.
[0168] In some embodiments, 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.
[0169] 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. 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.
[0170] In some embodiments, the compound of formula (I) evokes G1 cell cycle blockade. In some embodiments, 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).
[0171] In some embodiments, a compound disclosed herein, e.g., the compound of formula (I), is administered in combination with a second CDK 4/6 inhibitor.
[0172] In some embodiments, 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. In some embodiments, 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. In some embodiments, the combination of compound (1) and acalabrutinib achieves significant synergistic antitumor activity. In some embodiments, the synergistic antitumor activity is shown against a BTK inhibitor-resistant MCL.
BTK Inhibitors
[0173] Bruton’s tyrosine kinase (BTK) 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).
[0174] 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.
[0175] In some embodiments, the BTK inhibitor is ibrutinib or a pharmaceutically-acceptable salt thereof. The structure of ibrutinib is depicted below.
Figure imgf000049_0001
1 -[(3R)-3 -[4- Amino-3 -(4-phenoxyphenyl)- lH-pyrazolo[3 ,4-d]pyrimidin- 1 -yl]piperidin- 1 - yl]prop-2-en-l-one. A pharmaceutically-acceptable salt of l-[(3R)-3-[4-Amino-3-(4- phenoxyphenyl)- lH-pyrazolo[3 ,4-d]pyrimidin- 1 -yl]piperidin- 1 -yl]prop-2-en- 1 -one.
[0176] In some embodiments, the BTK inhibitor is acalabrutinib or a pharmaceutically- acceptable salt thereof. The structure of acalabrutinib is depicted below.
Figure imgf000049_0002
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.
ULK1/2 inhibitors
[0177] 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.
PI3K Inhibitors
[0178] 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.
Autophagy inhibitors
[0179] 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). In some embodiments, 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 inhibitors
[0180] 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. In some embodiments, inhibition of ARK5 induces cell death through PI3K/AKT/mT0R pathway.
Administration of Compounds of the Disclosure
Compound (1)
[0181] 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. In some embodiments, 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. Alternatively, a compound described herein can be formulated as a tablet.
[0182] In some embodiments, the present disclosure provides 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. [0183] In some embodiments, the present disclosure provides 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.
[0184] In some embodiments, the present disclosure provides 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.
[0185] In some embodiments, 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. In some embodiments, 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.
Ibrutinib
[0186] A compound disclosed herein, for example, ibrutinib or a pharmaceutically - acceptable salt thereof, can be formulated as capsule or a tablet. In some embodiments, 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. In some embodiments, 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.
[0187] In some embodiments, 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.
[0188] In some embodiments, 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.
[0189] In some embodiments, 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). In some embodiments, 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.
[0190] In some embodiments, 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). In some embodiments, 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.
[0191] In some embodiments, 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. For example, if a daily dose is about 560 mg, then 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
[0192] A compound disclosed herein, for example, acalabrutinib or a pharmaceutically- acceptable salt thereof, can be formulated as capsule or a tablet. In some embodiments, 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. In some embodiments, 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.
[0193] In some embodiments, 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.
[0194] In some embodiments, 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.
[0195] In some embodiments, 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). In some embodiments, 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.
[0196] In some embodiments, 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). In some embodiments, 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.
[0197] In some embodiments, 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. For example, if a daily dose is about 560 mg, then 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).
Pharmaceutical Compositions
[0198] 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. Pharmaceutical 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. [0199] 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.
[0200] 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.
[0201] Pharmaceutical compositions can be formulated by combining the active compounds with pharmaceutically-acceptable carriers or excipients. Non-limiting examples of 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.
[0202] 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.
[0203] For oral administration, pharmaceutical 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. Non-limiting examples of 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. For this purpose, 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.
[0204] Pharmaceutical preparations 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. In some embodiments, 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. In soft capsules, 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.
[0205] For oral administration of a liquid unit dosage form, pharmaceutical 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.
[0206] 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. Alternatively, the active ingredient can be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.
[0207] 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.
[0208] 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. In suppository forms of the compositions, a low-melting wax such as a mixture of fatty acid glycerides, optionally in combination with cocoa butter, can be used.
[0209] For buccal or sublingual administration, the compositions can be tablets, lozenges, or gels.
[0210] 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. For example, 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.
[0211] For administration by inhalation, 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.
[0212] 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.
[0213] 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.
[0214] In practicing the methods of treatment or use provided herein, therapeutically- effective amounts of the compounds described herein are administered in pharmaceutical compositions to a subject having a disease or condition to be treated. In some embodiments, 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.
[0215] Methods for the preparation of 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. The 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.
[0216] 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.
[0217] 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. [0218] 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. Non-limiting examples of 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.
[0219] In some embodiments, 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. [0220] 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.
[0221] 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.
[0222] Subjects can be, for example, elderly adults, adults, adolescents, pre-adolescents, children, toddlers, infants, neonates, and non-human animals. In some embodiments, a subject is a patient.
[0223] A method disclosed herein relates to administering the compound disclosed herein as part of a pharmaceutical composition. In some embodiments, 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. In some embodiments, the liquid composition is aqueous. Alternatively, the composition can be an ointment. In some embodiments, the composition is an in situ gellable aqueous composition. In some embodiments, the composition is an in situ gellable aqueous solution.
[0224] 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. For example, 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.
[0225] 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 53%, about 54%, about 55%, about 56%, about 57%, about 58%, about 59%, about 60%, about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, about 71%, about 72%, about 73%, about 74%, about 75%, about 76%, about 77%, about 78%, about 79%, about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, about 99.1%, about 99.2%, about 99.3%, about 99.4%, about 99.5%, about 99.6%, about 99.7%, about 99.8%, or about 99.9% by mass of the formulation.
Subjects/patient population
[0226] Subjects can be, humans for example, elderly adults, adults, adolescents, preadolescents, children, toddlers, infants, neonates, and non-human animals, e.g., a mouse. In some embodiments, a subject is a patient. In some embodiments, 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. In some embodiments, the subject has been identified or diagnosed as having a cancer described herein, e.g., breast cancer. In some embodiments, the subject has a cancer and/or tumor that is positive for ibrutinib resistance. In some embodiments, 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. In some embodiments, the subject has received a first line of therapy. In some embodiments, the subject is resistant and/or non-responsive to the first line of therapy.
[0227] In some embodiments, 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.
[0228] A method disclosed herein relates to administering the compound disclosed herein as part of a pharmaceutical composition. In some embodiments, a pharmaceutical composition comprises a compound described herein and a pharmaceutically-acceptable excipient. In some embodiments, 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. In some embodiments, the liquid composition is aqueous. In some embodiments, the composition is an ointment. In some embodiments, the composition is an in situ gellable aqueous composition. In some embodiments, the composition is an in situ gellable aqueous solution.
Dosing
[0229] Pharmaceutical compositions described herein can be in unit dosage forms suitable for single administration of precise dosages. In unit dosage form, 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.
[0230] 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 mg to about 250 mg, or from about 250 mg to about 300 mg.
[0231] 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. [0232] 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. In some embodiments, 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 180 mg/kg, about 200 mg/kg, about 250 mg/kg, about 300 mg/kg, about 350 mg/kg, about 400 mg/kg, about 450 mg/kg, about 500 mg/kg, or about 600 mg/kg of the subject.
Dosing Regimens
[0233] 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. In some embodiments, a compound disclosed herein is administered once daily. In some embodiments, a compound disclosed herein is administered once daily for 28 days (one cycle). In some embodiments, a compound disclosed herein is administered once daily in one or more 28 day cycles. In some embodiments, 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.
[0234] In some embodiments, 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)
Figure imgf000065_0001
wherein:
R1 is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl, each of which is unsubstituted or substituted, or hydrogen;
R2 is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, -CN, - C(O)R5, -C(O)OR5, -C(O)NR5R6, -C(=N)NR5R6, -OR5, -SR5, -NR5R6, - NR5C(O)R6, -NR5C(O)OR6, -OC(O)R5, -OC(O)NR5R6, -S(O)2R5, - NHS(O)2R5, or -OS(O)2R5, each of which is independently substituted or unsubstituted, or hydrogen or halogen;
R3 is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl or heteroaryl, each of which is unsubstituted or substituted, or hydrogen or halogen;
R4 is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -CN, C(O)R5, -C(O)OR5, -C(O)NR5R6, -C(=N)NR5R6, -OR5, -SR5, -NR5R6, - NR5C(O)R6, -NR5C(O)OR6, -OC(O)R5, -OC(O)NR5R6, -S(O)2R5, - NHS(O)2R5, or -OS(O)2R5, each of which is independently substituted or unsubstituted, or hydrogen or halogen; and each R5 and R6 is independently alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl, each of which is independently substituted or unsubstituted, or hydrogen or halogen; provided that, when R4 is -NR5R6 and one of R5 and R6 is pyridyl, then R2 is not -C(O)CH3, or a pharmaceutically-acceptable salt thereof.
[0235] In some embodiments, 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)
Figure imgf000066_0001
wherein:
R1 is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl, each of which is unsubstituted or substituted, or hydrogen;
R2 is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, -CN, - C(O)R5, -C(O)OR5, -C(O)NR5R6, -C(=N)NR5R6, -OR5, -SR5, -NR5R6, - NR5C(O)R6, -NR5C(O)OR6, -OC(O)R5, -OC(O)NR5R6, -S(O)2R5, - NHS(O)2R5, or -OS(O)2R5, each of which is independently substituted or unsubstituted, or hydrogen or halogen;
R3 is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl or heteroaryl, each of which is unsubstituted or substituted, or hydrogen or halogen;
R4 is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -CN, C(O)R5, -C(O)OR5, -C(O)NR5R6, -C(=N)NR5R6, -OR5, -SR5, -NR5R6, - NR5C(O)R6, -NR5C(O)OR6, -OC(O)R5, -OC(O)NR5R6, -S(O)2R5, - NHS(O)2R5, or -OS(O)2R5, each of which is independently substituted or unsubstituted, or hydrogen or halogen; and each R5 and R6 is independently alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl, each of which is independently substituted or unsubstituted, or hydrogen or halogen; provided that, when R4 is -NR5R6 and one of R5 and R6 is pyridyl, then R2 is not -C(O)CH3, or a pharmaceutically-acceptable salt thereof; wherein the administering is once daily for at least 4 weeks.
[0236] In some embodiments, 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)
Figure imgf000067_0001
wherein:
R1 is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl, each of which is unsubstituted or substituted, or hydrogen;
R2 is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, -CN, - C(O)R5, -C(O)OR5, -C(O)NR5R6, -C(=N)NR5R6, -OR5, -SR5, -NR5R6, - NR5C(O)R6, -NR5C(O)OR6, -OC(O)R5, -OC(O)NR5R6, -S(O)2R5, - NHS(O)2R5, or -OS(O)2R5, each of which is independently substituted or unsubstituted, or hydrogen or halogen;
R3 is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl or heteroaryl, each of which is unsubstituted or substituted, or hydrogen or halogen;
R4 is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -CN, C(O)R5, -C(O)OR5, -C(O)NR5R6, -C(=N)NR5R6, -OR5, -SR5, -NR5R6, - NR5C(O)R6, -NR5C(O)OR6, -OC(O)R5, -OC(O)NR5R6, -S(O)2R5, - NHS(O)2R5, or -OS(O)2R5, each of which is independently substituted or unsubstituted, or hydrogen or halogen; and each R5 and R6 is independently alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl, each of which is independently substituted or unsubstituted, or hydrogen or halogen; provided that, when R4 is -NR5R6 and one of R5 and R6 is pyridyl, then R2 is not -C(O)CH3, 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.
[0237] 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. For example, 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.
[0238] 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. In some embodiments, 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 16 months, about 17 months, about 18 months, about 19 months, about 20 months, about 21 months, about 22 months about 23 months, about 2 years, about 2.5 years, about 3 years, about 3.5 years, about 4 years, about 4.5 years, about 5 years, about 6 years, about 7 years, about 8 years, about 9 years, about 10 years, about 11 years, about 12 years, about 13 years, about 14 years, about 15 years, about 16 years, about 17 years, about 18 years, about 19 years, about 20 years, about 21 years, about 22 years, about 23 years, about 24 years, or about 25 years. The length of treatment can vary for each subj ect.
[0239] A dosing schedule for administration of a compound described herein can be consistent for the length of the dosing regimen. For example, a compound can be administered daily. Alternatively, or in addition to, 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.
[0240] 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. For example, 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. For example, a daily dose of 100 mg can be given, for example, once daily (100 mg), twice daily (50 mg per dose).
[0241] Multiple therapeutic agents can be administered in any order or simultaneously. In some embodiments, 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. In some embodiments, 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. If simultaneously, 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.
Compound (1) dosing regimens
[0242] 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. Alternatively, 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. In some embodiments, the dosing is oral.
[0243] In some embodiments, 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 some embodiments, 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). In some embodiments, 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. In some embodiments, 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.
[0244] In some embodiments, 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.
[0245] In some embodiments, 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.
BTK inhibitor dosing regimens
[0246] 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. In some embodiment, the dosing is oral. In some embodiments, a BTK inhibitor disclosed herein is ibrutinib or a pharmaceutically-acceptable salt thereof or acalabrutinib or a pharmaceutically-acceptable salt thereof. In some embodiments, 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.
[0247] In some embodiments, 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, DECR1, EIF4G1, FOS, FOSB, FOXK1, LYN, LYPLA2, MAP2K5, MAP3K20, MARK2, MICALL2, NPM1, PUS7L, RPS6KA3, SART3, SCP2, SHCBP1, SMAD1, SNX30, SNX6, STK3, TLE5, YES1, ZNF608, AAK1, ADAR, AGRN, AHCTF1, APLP2, APP, ARRB2, AXL, BMP2K, CAVIN1, CAVIN3, CBX5, CCN1, CDC5L, CDK17, CELF1, CERS2, CLPP, CLUH, COL2A1, CPD, CRAT, CSNK2A2, CST3, DBNDD2, DDX21, DHX9, DNAJC13, ECE1, ELAVL1, ELL, ESYT1, FASTKD5, FBRS, FGFRL1, FUBP3, GAK, GALNT7, GCAT, GSK3A, GSK3B, GSKIP, HNRNPA0, HNRNPA1, HNRNPA2B1, HNRNPA3, HNRNPC, HNRNPL,HNRNPR, HNRNPU, HNRNPU, HNRNPUL2, HSPA13, HSPG2, IFT52, IGFBP4, IGFBP7, ILF3 , INCENP, JMY, LAMA5, LAMC1, LAMTOR2, LEO1, LMAN2, LOXL2, LRCH4, LRPPRC , LRRC59, LTBP2, MAMDC2, MAN2A1, MATR3, METTL18, MLEC, MPHOSPH8, MRC2, MRPL55, MTG1, NAP1L1, NAPG, NRP1, PHF8, PIK3C3, PIK3R4, PIP4K2A, PIP4K2B, PIP4P2, PRPF4B, PTX3, RAE1, RBM34, RIPK1, RNF5, RRAS2, RSF1, SCAF1, SGPP1, SIK2, SMU1, SND1, STK10, STX5, SYNCRIP, SYNE2, TAF15, TIMP2, TTK, UFL1, WTAP, and ZFR.
[0248] Non-limiting examples of a comparator include palbociclib, abemaciclib, and riboci clib.
[0249] In some embodiments, 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.
[0250] In some embodiments, 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. In some embodiments, 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. In some embodiments, 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.
EXAMPLES
EXAMPLE 1: Study to Evaluate an Oral Pharmaceutical Composition Disclosed Herein for Treating a Disease in a Subject.
[0251] Summary: 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). In addition, the study explores efficacy of compound (1) in cancer patients.
[0252] 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. [0253] 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). The dose 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 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. If only one of the six patients in the cohort experiences a DLT in the first 28 days, then enrollment to the next cohort begins at the next dose level. If at any time two or more patients in a cohort experience a DLT in the first 28 days, the cohort is closed. The dose of that cohort is considered non-tolerable, and the prior dose level is defined as the MTD. Patients continue in the study until disease progression or intolerance or a decision to discontinue is reached.
[0254] Study Objectives and Endpoints
[0255] 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. [0256] 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).
[0257] 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).
[0258] Pharmacokinetics
[0259] Blood samples are collected pre-and post-dose on days 1 and 8 of the first cycle and pre-dose on day 1 of cycles 2 and 3 for pharmacokinetic (PK) analysis. 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.
[0260] The following 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.
[0261] 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.
[0262] 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.
[0263] 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. [0264] 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). In addition, the study explores efficacy of compound (1) in cancer patients.
[0265] 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.
[0266] 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.
[0267] Patients receive study drug orally under fasted conditions before breakfast. Compound (1) is administered once daily continuously for 3 weeks with one week break. Safety, tolerability, and dose-limiting toxicity are evaluated after 4 weeks (28 days) of dosing.
[0268] 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.
[0269] 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.
[0270] Study Objectives and Endpoints
[0271] The primary objective of this study is to evaluate the tolerance, safety, and the antitumor efficacy of compound (1) in patients having advanced tumors.
[0272] 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). 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.
[0273] Pharmacokinetics
[0274] Blood samples are collected pre-and post-dose on days 1 and 8 of the first cycle and pre-dose on day 4 of the first cycle for pharmacokinetic (PK) analysis. Compound (1) PK is determined as described in Example 1.
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. (2) Disease Control Rate (DCR), defined as the proportion of subjects with complete remission (CR), partial remission (PR), and disease stabilization (SD) after treatment. (3) Time to remission (DOR), defined as the time from the initial recording of objective remission to the first occurrence of tumor progression, or death from any cause. And (4) Progression free survival (PFS), defined as treatment from initiation to tumor progression or death from any cause.
EXAMPLE 3: Dosing Regimen to Evaluate an Oral Pharmaceutical Composition Disclosed Herein with a BTK Inhibitor in a Subject
[0275] 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.
[0276] 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.
[0277] 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.
[0278] 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.
[0279] Alternatively, 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.
[0280] 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.
[0281] Primary outcome measures Primary outcome measures are increase in Progression- Free Survival (PFS) in experimental arm versus comparator arm.
[0282] Secondary Outcome Measures are:
1. Overall survival (OS): time from registration to death due to any cause.
2. Duration of response (DOR): time from documentation of tumor response to disease progression. 3. Overall Response Rate (ORR): proportion of patients with reduction in tumor burden of a predefined amount.
4. Complete Response (CR): disappearance of all non-target lesions and normalization of tumor marker level.
5. Toxicity: Incidence and severity of adverse events by summaries of toxicity data/contingency tables.
[0283] Toxicity/efficacy of the various compounds of the disclosure are analyzed and compared.
EXAMPLE 4 Evaluation of the efficacy and safety of Compound (1) vs CDK inhibitors palbociclib, abemaciclib, or ribociclib in association with BTK inhibitors [0284] In vitro
[0285] A panel of mantle cell lymphoma (MCL) cell lines (n=10) with distinct sensitivity to ibrutinib or acalabrutinib were treated with compound (1), Palbociclib, abemaciclib, ribociclib, alone or in combination (e.g. compound (1), compound (1) + ibrutinib, compound (1) + acalabrutinib). Treatment effect was measured by CellTiter-Glo proliferation assay, FACS-mediated quantification of cell cycle and apoptosis, RT-PCR, and western blot validations.
[0286] 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).
[0287] Table 2. IC50 in MCL cell lines JEKO, UPN-1, REC-1, MINO, GRANTA-519, and Z-138, and in modified MCL cell lines UPN-ibrutinib resistant, REC-1 BTK mutant, and REC-1 BTK KO, and REC-1 IKAROS KO.
Figure imgf000078_0001
Figure imgf000079_0001
[0288] 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).
[0289] 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. In BTK inhibitor-sensitive cells, 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.
[0290] In vivo
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.
EXAMPLE 5 Evaluation of the anti-tumor activity of Compound (1) vs CDK inhibitors palbociclib, abemaciclib, or ribociclib independent of sensitivity to BTK inhibitors
[0291] Various assays to detect anti-tumor activity were designed and tested as shown and described for FIGs. 3-5.
[0292] A panel of mantle cell lymphoma (MCL) cell lines (n=10) with distinct sensitivity to ibrutinib or acalabrutinib were treated with compound (1). Treatment effect was measured by western blot validations and CellTiter-Glo (CTG) proliferation assay.
[0293] In vitro - Western Blot
[0294] 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).
[0295] In vitro - CTG assay
[0296] 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).
[0297] Cell viability was quantified by CTG assay, in modified MCL cell lines UPN- ibrutinib resistant, REC-1 BTK mutant, and REC-1 BTK KO, and REC-1 IKAROS KO, treated with increasing doses of Compound (1) for 72 hours (FIG. 5). Cell viability decreased with increasing concentrations of Compound (1).
[0298] EXAMPLE 6 Evaluation of the synergy of Compound (1) in combination with CDK inhibitors palbociclib, abemaciclib, ribociclib in association with BTK inhibitors ibrutinib or acalabrutinib
[0299] Various assays to detect synergy were designed and tested as shown and described for
FIGs. 6-13
[0300] A panel of mantle cell lymphoma (MCL) cell lines (n=10) with distinct sensitivity to ibrutinib or acalabrutinib were treated with compound (1), palbociclib, abemaciclib, ribociclib, alone or in combination with BTK inhibitors (e.g. compound (1), compound (1) + ibrutinib, compound (1) + acalabrutinib).
[0301] 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).
[0302] CTG proliferation assays in MCL cell lines UPN-1 (FIG. 8), REC-1 (FIG. 9), JEKO- 1 (FIG. 10), and Z-138 (FIG. 13) treated with 0.5pM CDK4/6 inhibitor (e.g., Compound (1), abemaciclib, and palbociclib), alone and in combination with IpM BTK inhibitor (e.g., ibrutinib, acalabrutinib, and Loxo-305) for 72 hours. CI values were indicated when a synergistic activity was found.
[0303] CTG proliferation assays in modified MCL cell lines UPN-ibrutinib resistant (FIG.
11) and REC-1 BTK mutant (FIG. 12), with 0.5pM CDK4/6 inhibitor (e.g., Compound (1), abemaciclib, and palbociclib), alone and in combination with IpM BTK inhibitor (e.g., ibrutinib, acalabrutinib, and Loxo-305) for 72 hours. CI values were indicated when a synergistic activity was found.
[0304] 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.
[0305] 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
[0306] Various assays to detect cell cycle activity were designed and tested as shown and described for FIGs. 14-35.
[0307] Cell cycle analysis from MCL cells treated with Compound (1) (0.5pM) alone and in combination with BTK inhibitor ibrutinib (IpM) or acalabrutinib (IpM) for 24 hours (FIGs.
14-19)
[0308] 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.
[0309] Western blot analysis of MCL cells after treatment with Compound (1) (0.5pM alone and in combination with BTK inhibitors ibrutinib (IB) (IpM), acalabrutinib (AC) (IpM), or Loxo-305 (LX) (IpM) for 24 hours (FIGs. 24-25).
[0310] qRT-PCR quantification of cell-cycle related and senescence-related transcripts in JEKO-1 cells after treatment with Compound (1) alone and in combination with BTK inhibitors ibrutinib or acalabrutinib for 24 hours (FIGs. 26-35).
[0311] Compound (1) evokes a G1 cell cycle blockade. The blockade by was improved when Compound (1) was combined with BTK inhibitors.
[0312] EXAMPLE 8 Evaluation of gene regulation of Compound (1)
[0313] Various assays to detect cell cycle activity were designed and tested as shown and described for Table 3 and FIGs. 36-44.
[0314] Table 3. Gene Set Enrichment Analysis
Figure imgf000081_0001
Figure imgf000082_0001
[0315] Heatmaps of genes differentially regulated upon treatment with Compound (1) in MCL cell lines (FIG. 36-37).
[0316] Gene set enrichment analysis (GSEA) after transcriptomic (RNAsea) characterization following treatment with Compound (1) for 24 hours in MCL cell lines (n=5) (FIGs. 38-44). 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. To distinguish between differences among up- and down-regulated proteins, groups were analyzed in terms of characterization, including by gene ontology (GO) biological process.
[0317] 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.
[0318] EXAMPLE 9 Evaluation of anti-tumor activity of Compound (1) in a CAM xenograft model
[0319] Various assays to detect anti-tumor activity were designed and tested in an immune- competent, chicken embryo chorioallantonic membrane (CAM) xenograft model of MCL as shown and described for FIGs. 45-57.
[0320] 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.
[0321] Significant reduction in tumor weights was observed at day 7 after inoculation (n=10 eggs per group) following treatment with CDK4/6 inhibitor and/or ibrutinib (FIGs. 49-51). [0322] MCL infiltration properties by qPCR-mediated relative determination of human Alu sequences were detected in the chicken embryo to characterize the invasion of MCL into the spleen and bone marrow (BM) following treatment with compound 1 and/or ibrutinib (FIGs.
52-57).
[0323] Compound (1) exhibited significant anti-tumor activity that was improved when combined with ibrutinib in a in vivo CAM xenograft model of MCL.

Claims

WHAT IS CLAIMED IS:
1. A method of treating lymphoma in a human subject in need thereof, the method comprising administering to the subject a therapeutically-effective amount of a compound of formula (I)
Figure imgf000084_0001
wherein:
R1 is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl, each of which is unsubstituted or substituted, or hydrogen;
R2 is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, -CN, - C(O)R5, -C(O)OR5, -C(O)NR5R6, -C(=N)NR5R6, -OR5, -SR5, -NR5R6, - NR5C(O)R6, -NR5C(O)OR6, -OC(O)R5, -OC(O)NR5R6, -S(O)2R5, - NHS(O)2R5, or -OS(O)2R5, each of which is independently substituted or unsubstituted, or hydrogen or halogen;
R3 is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl, each of which is unsubstituted or substituted, or hydrogen or halogen;
R4 is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -CN, C(O)R5, -C(O)OR5, -C(O)NR5R6, -C(=N)NR5R6, -OR5, -SR5, -NR5R6, - NR5C(O)R6, -NR5C(O)OR6, -OC(O)R5, -OC(O)NR5R6, -S(O)2R5, - NHS(O)2R5, or -OS(O)2R5, each of which is independently substituted or unsubstituted, or hydrogen or halogen; and each R5 and R6 is independently alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl, each of which is independently substituted or unsubstituted, or hydrogen or halogen; provided that, when R4 is -NR5R6 and one of R5 and R6 is pyridyl, then R2 is not -C(O)CH3, or a pharmaceutically-acceptable salt thereof.
2. The method of claim 1, wherein R1 is cycloalkyl.
3. The method of claim 1, wherein R1 is cyclopentyl.
4. The method of claim 1, wherein R2 is CN.
5. The method of claim 1, wherein R3 is hydrogen.
6. The method of claim 1, wherein R4 is -NR5R6.
7. The method of claim 6, wherein one of R5 and R6 is hydrogen.
8. The method of claim 6, wherein one of R5 and R6 is phenyl.
9. The method of claim 6, wherein one of R5 and R6 is phenyl substituted with heterocyclyl.
10. The method of claim 6, wherein one of R5 and R6 is phenyl substituted with piperazinyl.
11. The method of claim 6, wherein one of R5 and R6 is phenyl substituted with 4-methyl piperazinyl.
12. The method of claim 1, wherein R4 is
Figure imgf000085_0001
wherein:
R7 is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -OR5, - SR5, or -NR5R6, each of which is unsubstituted or substituted, or hydrogen;
R8 is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -OR5, - SR5, or -NR5R6, each of which is unsubstituted or substituted, or hydrogen; and R9 is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -OR5, - SR5, or -NR5R6, each of which is unsubstituted or substituted, or hydrogen.
13. The method of claim 12, wherein R7 is hydrogen.
14. The method of claim 12, wherein R8 is hydrogen.
15. The method of claim 12, wherein R9 unsubstituted or substituted heterocyclyl.
16. The method of claim 12, wherein R9 is unsubstituted or substituted piperazinyl.
17. The method of claim 12, wherein R9 is 4-methyl piperazinyl.
18. The method of claim 12, wherein the compound is a compound of formula (II)
Figure imgf000086_0001
19. The method of claim 12, wherein the compound is a compound of formula (III)
Figure imgf000086_0002
wherein:
Y is O, S, or NR11; each R10 is independently alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -OR5, -SR5, or -NR5R6, each of which is unsubstituted or substituted;
R11 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. . The method of claim 19, wherein R1 is cycloalkyl. . The method of claim 19, wherein R1 is cyclopentyl. . The method of claim 19, wherein Y is NR11. . The method of claim 22, wherein R11 is alkyl. . The method of claim 22, wherein R11 is methyl. . The method of claim 19, wherein n is 0. . The method of claim 1, wherein the compound 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 method of claim 26, wherein the compound is the pharmaceutically-acceptable salt and the pharmaceutically-acceptable salt is monolactate. . The method of claim 1, wherein the lymphoma is a non-Hodgkin’s lymphoma.. The method of claim 28, wherein the non-Hodgkin’s lymphoma is a mantle cell lymphoma. . The method of claim 1, wherein the therapeutically-effective amount is about 40 mg to about 500 mg per day. . The method of claim 1, wherein the subject received a therapy other than the compound for the lymphoma prior to the administering. . The method of claim 31, wherein the therapy is a BTK inhibitor therapy. . The method of claim 32, wherein the BTK inhibitor therapy is ibrutinib or a pharmaceutically-acceptable salt thereof. . The method of claim 32, wherein the BTK inhibitor therapy is acalabrutinib or a pharmaceutically-acceptable salt thereof. . The method of claim 31, wherein the therapy was received after the subject was diagnosed with lymphoma. . The method of claim 31, wherein the subject has not responded to the therapy. . The method of claim 31, wherein the subject experienced a relapse of the lymphoma after the therapy. The method of claim 31, wherein the subject has primary resistance to BTK inhibitor therapy.
39. The method of claim 31, wherein the subject has acquired resistance to BTK inhibitor therapy.
40. The method of claim 1, wherein the administering is oral.
41. The method of claim 1, wherein the administering is intravenous.
42. The method of claim 1, wherein the compound is administered in a pharmaceutical composition, wherein the pharmaceutical composition is in a unit dosage form, the unit dosage form further comprising a pharmaceutically-acceptable excipient.
43. The method of claim 42, wherein the unit dosage form comprises about 40 mg of 8- cyclopentyl-2-((4-(4-methylpiperazin-l-yl)phenyl)amino)-7-oxo-7,8- dihydropyrido[2,3-d]pyrimidine-6-carbonitrile.
44. The method of claim 42, wherein unit dosage form comprises about 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.
45. The method of claim 42, wherein the unit dosage form is a capsule.
46. The method of claim 42, wherein the unit dosage form is a tablet.
47. The method of claim 1, wherein the administering occurs in a morning of a day.
48. The method of claim 1, wherein the subject is in a fasted state.
49. The method of claim 1, wherein the administering is once daily for at least 4 weeks.
50. The method of claim 1, 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.
51. The method of claim 1, wherein the administering is a 4-week cycle of:
(i) a continuous, three-week period of once-daily, morning administration, wherein the therapeutically-effective amount of the first compound is from about 40 mg to about 500 mg; and ii) immediately following the three-week period, one week of no administration.
52. The method of claim 1, further comprising administering to the subject a therapeutically-effective amount of a second compound.
53. The method of claim 52, wherein the second compound is a BTK inhibitor.
54. The method of claim 53, wherein the BTK inhibitor is ibrutinib or a pharmaceutically- acceptable salt thereof.
55. The method of claim 53, wherein the BTK inhibitor is acalabrutinib or a pharmaceutically-acceptable salt thereof.
56. The method of claim 54, wherein the therapeutically-effective amount of ibrutinib or pharmaceutically-acceptable salt thereof is about 560 mg per day.
57. The method of claim 52, wherein the second compound is administered in a pharmaceutical composition, wherein the pharmaceutical composition is in a unit dosage form, the unit dosage form further comprising a pharmaceutically-acceptable excipient.
58. The method of claim 56, wherein the unit dosage form is a tablet.
59. The method of claim 56, wherein the unit dosage form is a capsule.
60. The method of claim 52, wherein the administering of the second compound is once daily.
61. The method of claim 52, wherein the administering of the second compound is oral.
62. The method of claim 52, wherein the administering of the compound of formula (I) is oral, and the administering of the second compound is oral.
63. The method of claim 52, wherein the administering of the compound of formula (I) is prior to the administering of the second compound.
64. The method of claim 52, wherein the administering of the second compound is prior to the administering of the compound of formula (I).
65. The method of claim 52, wherein the administering of the compound of formula (I) is concurrently with the administering of the second compound.
66. The method of claim 53, wherein the administering of the second compound results in synergistic activity with the first.
67. A method of treating lymphoma in a subject in need thereof, the method comprising administering to the subject a therapeutically-effective amount of a compound of formula (I)
Figure imgf000089_0001
wherein: R1 is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl, each of which is unsubstituted or substituted, or hydrogen;
R2 is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, -CN, - C(O)R5, -C(O)OR5, -C(O)NR5R6, -C(=N)NR5R6, -OR5, -SR5, -NR5R6, - NR5C(O)R6, -NR5C(O)OR6, -OC(O)R5, -OC(O)NR5R6, -S(O)2R5, - NHS(O)2R5, or -OS(O)2R5, each of which is independently substituted or unsubstituted, or hydrogen or halogen;
R3 is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl or heteroaryl, each of which is unsubstituted or substituted, or hydrogen or halogen;
R4 is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -CN, C(O)R5, -C(O)OR5, -C(O)NR5R6, -C(=N)NR5R6, -OR5, -SR5, -NR5R6, - NR5C(O)R6, -NR5C(O)OR6, -OC(O)R5, -OC(O)NR5R6, -S(O)2R5, - NHS(O)2R5, or -OS(O)2R5, each of which is independently substituted or unsubstituted, or hydrogen or halogen; and each R5 and R6 is independently alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl, each of which is independently substituted or unsubstituted, or hydrogen or halogen; provided that, when R4 is -NR5R6 and one of R5 and R6 is pyridyl, then R2 is not -C(O)CH3, or a pharmaceutically-acceptable salt thereof; wherein the administering is once daily for at least 4 weeks. The method of claim 67, wherein R1 is cycloalkyl. The method of claim 67, wherein R1 is cyclopentyl. The method of claim 67, wherein R2 is CN. The method of claim 67, wherein R3 is hydrogen. The method of claim 67, wherein R4 is -NR5R6. The method of claim 72, wherein one of R5 and R6 is hydrogen. The method of claim 72, wherein one of R5 and R6 is phenyl. The method of claim 72, wherein one of R5 and R6 is phenyl substituted with heterocyclyl. The method of claim 72, wherein one of R5 and R6 is phenyl substituted with piperazinyl. The method of claim 72, wherein one of R5 and R6 is phenyl substituted with 4-methyl piperazinyl. 8. The method of claim 67, wherein R4 is
Figure imgf000091_0001
wherein:
R7 is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -OR5, - SR5, or -NR5R6, each of which is unsubstituted or substituted, or hydrogen;
R8 is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -OR5, - SR5, or -NR5R6, each of which is unsubstituted or substituted, or hydrogen; and R9 is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -OR5, - SR5, or -NR5R6, each of which is unsubstituted or substituted, or hydrogen.9. The method of claim 78, wherein R7 is hydrogen. 0. The method of claim 78, wherein R8 is hydrogen. 1. The method of claim 78, wherein R9 unsubstituted or substituted heterocyclyl. 2. The method of claim 78, wherein R9 is unsubstituted or substituted piperazinyl. 3. The method of claim 78, wherein R9 is 4-methyl piperazinyl. 4. The method of claim 78, wherein the compound is a compound of formula (II)
Figure imgf000091_0002
5. The method of claim 78, wherein the compound is a compound of formula (III)
Figure imgf000092_0001
wherein:
Y is O, S, or NR11; each R10 is independently alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -OR5, -SR5, or -NR5R6, each of which is unsubstituted or substituted;
R11 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. 6. The method of claim 85, wherein R1 is cycloalkyl. 7. The method of claim 85, wherein R1 is cyclopentyl. 8. The method of claim 85, wherein Y is NR11. 9. The method of claim 85, wherein R11 is alkyl. 0. The method of claim 88, wherein R11 is methyl. 1. The method of claim 85, wherein n is 0. 2. The method of claim 67, wherein the compound 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 method of claim 92, wherein the compound is the pharmaceutically-acceptable salt and the pharmaceutically-acceptable salt is monolactate. The method of claim 92, wherein the lymphoma is a non-Hodgkin’s lymphoma. The method of claim 94, wherein the non-Hodgkin’s lymphoma is a mantle cell lymphoma. The method of claim 67, wherein the therapeutically-effective amount is about 40 mg to about 500 mg per day. The method of claim 67, wherein the subject received a therapy other than the compound for the lymphoma prior to the administering. The method of claim 97, wherein the therapy is a BTK inhibitor therapy. The method of claim 98, wherein the BTK inhibitor therapy is ibrutinib or a pharmaceutically-acceptable salt thereof. . The method of claim 98, wherein the BTK inhibitor therapy is acalabrutinib or a pharmaceutically-acceptable salt thereof. . The method of claim 97, wherein the therapy was received after the subject was diagnosed with lymphoma. . The method of claim 97, wherein the subject has not responded to the therapy. . The method of claim 97, wherein the subject experienced a relapse of the lymphoma after the therapy. . The method of claim 98, wherein the subject has primary resistance to BTK inhibitor therapy. . The method of claim 98, wherein the subject has acquired resistance to BTK inhibitor therapy. . The method of claim 67, wherein the administering is oral. . The method of claim 67, wherein the administering is intravenous. . The method of claim 67, wherein the compound is administered in a pharmaceutical composition, wherein the pharmaceutical composition is in a unit dosage form, the unit dosage form further comprising a pharmaceutically-acceptable excipient. . The method of claim 108, wherein the unit dosage form comprises about 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 method of claim 108, wherein unit dosage form comprises about 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. . The method of claim 108, wherein the unit dosage form is a capsule. . The method of claim 108, wherein the unit dosage form is a tablet. . The method of claim 67, wherein the administering occurs in a morning of a day.. The method of claim 67, wherein the subject is in a fasted state. . The method of claim 67, further comprising administering to the subject a therapeutically-effective amount of a second compound. . The method of claim 115, wherein the second compound is a BTK inhibitor. . The method of claim 116, wherein the BTK inhibitor is ibrutinib or a pharmaceutically-acceptable salt thereof. . The method of claim 116, wherein the BTK inhibitor is acalabrutinib or a pharmaceutically-acceptable salt thereof. . The method of claim 117, wherein the therapeutically-effective amount of ibrutinib or pharmaceutically-acceptable salt thereof is about 560 mg per day. . The method of claim 117, wherein the therapeutically-effective amount of ibrutinib or pharmaceutically-acceptable salt thereof is about 560 mg per day. . The method of claim 115, wherein the second compound is administered in a pharmaceutical composition, wherein the pharmaceutical composition is in a unit dosage form, the unit dosage form further comprising a pharmaceutically-acceptable excipient. . The method of claim 121, wherein the unit dosage form is a tablet. . The method of claim 121, wherein the unit dosage form is a capsule. . The method of claim 115, wherein the administering of the second compound is once daily. . The method of claim 115, wherein the administering of the second compound is oral.. The method of claim 115, wherein the administering of the compound of formula (I) is oral, and the administering of the second compound is oral. . The method of claim 115, wherein the administering of the compound of formula (I) is prior to the administering of the second compound. . The method of claim 115, wherein the administering of the second compound is prior to the administering of the compound of formula (I). . The method of claim 115, wherein the administering of the compound of formula (I) is concurrently with the administering of the second compound.
30. The method of claim 115, where in the administering of the second compound results in synergistic activity with the compound of formula (1). 31. The method of claim 67, wherein the subject is a human. 32. A method of treating lymphoma in a subject in need thereof, the method comprising administering to the subject a therapeutically-effective amount of a compound of formula (I)
Figure imgf000095_0001
wherein:
R1 is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl, each of which is unsubstituted or substituted, or hydrogen;
R2 is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, -CN, - C(O)R5, -C(O)OR5, -C(O)NR5R6, -C(=N)NR5R6, -OR5, -SR5, -NR5R6, - NR5C(O)R6, -NR5C(O)OR6, -OC(O)R5, -OC(O)NR5R6, -S(O)2R5, - NHS(O)2R5, or -OS(O)2R5, each of which is independently substituted or unsubstituted, or hydrogen or halogen;
R3 is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl or heteroaryl, each of which is unsubstituted or substituted, or hydrogen or halogen;
R4 is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -CN, C(O)R5, -C(O)OR5, -C(O)NR5R6, -C(=N)NR5R6, -OR5, -SR5, -NR5R6, - NR5C(O)R6, -NR5C(O)OR6, -OC(O)R5, -OC(O)NR5R6, -S(O)2R5, - NHS(O)2R5, or -OS(O)2R5, each of which is independently substituted or unsubstituted, or hydrogen or halogen; and each R5 and R6 is independently alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl, each of which is independently substituted or unsubstituted, or hydrogen or halogen; provided that, when R4 is -NR5R6 and one of R5 and R6 is pyridyl, then R2 is not -C(O)CH3, 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.33. The method of claim 132, wherein R1 is cycloalkyl. 34. The method of claim 132, wherein R1 is cyclopentyl. 35. The method of claim 132, wherein R2 is CN. 36. The method of claim 132, wherein R3 is hydrogen. 37. The method of claim 132, wherein R4 is -NR5R6. 38. The method of claim 137, wherein one of R5 and R6 is hydrogen. 39. The method of claim 137, wherein one of R5 and R6 is phenyl. 40. The method of claim 137, wherein one of R5 and R6 is phenyl substituted with heterocyclyl. 41. The method of claim 137, wherein one of R5 and R6 is phenyl substituted with piperazinyl. 42. The method of claim 137, wherein one of R5 and R6 is phenyl substituted with 4- methyl piperazinyl. 43. The method of claim 132, wherein R4 is
Figure imgf000096_0001
wherein:
R7 is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -OR5, - SR5, or -NR5R6, each of which is unsubstituted or substituted, or hydrogen;
R8 is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -OR5, - SR5, or -NR5R6, each of which is unsubstituted or substituted, or hydrogen; and R9 is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -OR5, - SR5, or -NR5R6, each of which is unsubstituted or substituted, or hydrogen.44. The method of claim 143, wherein R7 is hydrogen.
45. The method of claim 143, wherein R8 is hydrogen. 46. The method of claim 143, wherein R9 unsubstituted or substituted heterocyclyl. 47. The method of claim 143, wherein R9 is unsubstituted or substituted piperazinyl. 48. The method of claim 143, wherein R9 is 4-methyl piperazinyl. 49. The method of claim 143, wherein the compound is a compound of formula (II)
Figure imgf000097_0001
50. The method of claim 143, wherein the compound is a compound of formula (III)
Figure imgf000097_0002
wherein:
Y is O, S, or NR11; each R10 is independently alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -OR5, -SR5, or -NR5R6, each of which is unsubstituted or substituted;
R11 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. . The method of claim 150, wherein R1 is cycloalkyl. . The method of claim 150, wherein R1 is cyclopentyl. . The method of claim 150, wherein Y is NR11. . The method of claim 153, wherein R11 is alkyl. . The method of claim 153, wherein R11 is methyl. . The method of claim 150, wherein n is 0. . The method of claim 132, wherein the compound 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 method of claim 157, wherein the compound is the pharmaceutically-acceptable salt and the pharmaceutically-acceptable salt is monolactate. . The method of claim 132, wherein the therapeutically-effective amount is about 40 mg to about 500 mg per day. . The method of claim 132, wherein the lymphoma is a non-Hodgkin’s lymphoma.. The method of claim 160, wherein the non-Hodgkin’s lymphoma is a mantle cell lymphoma. . The method of claim 132, wherein the subject received a therapy other than the compound for the lymphoma prior to the administering. . The method of claim 162, wherein the therapy is a BTK inhibitor therapy. . The method of claim 163, wherein the BTK inhibitor therapy is ibrutinib or a pharmaceutically-acceptable salt thereof. . The method of claim 163, wherein the BTK inhibitor therapy is acalabrutinib or a pharmaceutically-acceptable salt thereof. . The method of claim 162, wherein the therapy was received after the subject was diagnosed with lymphoma. . The method of claim 162, wherein the subject has not responded to the therapy.
68. The method of claim 162, wherein the subject experienced a relapse of the lymphoma after the therapy. 69. The method of claim 162, wherein the subject has primary resistance to BTK inhibitor therapy. 70. The method of claim 162, wherein the subject acquired resistance to BTK inhibitor therapy. 71. The method of claim 132, wherein the administering is oral. 72. The method of claim 132, wherein the administering is intravenous. 73. The method of claim 132, wherein the compound is administered in a pharmaceutical composition, wherein the pharmaceutical composition is in a unit dosage form, the unit dosage form further comprising a pharmaceutically-acceptable excipient. 74. The method of claim 173, wherein the unit dosage form comprises about 40 mg of 8- cyclopentyl-2-((4-(4-methylpiperazin-l-yl)phenyl)amino)-7-oxo-7,8- dihydropyrido[2,3-d]pyrimidine-6-carbonitrile. 75. The method of claim 173, wherein unit dosage form comprises about 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. 76. The method of claim 173, wherein the unit dosage form is a capsule. 77. The method of claim 173, wherein the unit dosage form is a tablet. 78. The method of claim 132, wherein the administering occurs in a morning of a day.79. The method of claim 132, wherein the subject is in a fasted state. 80. The method of claim 132, wherein the administering is once daily for at least 4 weeks. 81. The method of claim 132, 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. 82. The method of claim 132, wherein the administering is a 4-week cycle of:
(i) a continuous, three-week period of once-daily, morning administration, wherein the therapeutically-effective amount of the first compound is from about 40 mg to about 500 mg; and ii) immediately following the three-week period, one week of no administration. 83. The method of claim 132, further comprising administering to the subject a therapeutically-effective amount of a second compound. 84. The method of claim 183, wherein the second compound is a BTK inhibitor.
. The method of claim 184, wherein the BTK inhibitor is ibrutinib or a pharmaceutically-acceptable salt thereof. . The method of claim 184, wherein the BTK inhibitor is acalabrutinib or a pharmaceutically-acceptable salt thereof. . The method of claim 185, wherein the therapeutically-effective amount of ibrutinib or pharmaceutically-acceptable salt thereof is about 560 mg per day. . The method of claim 183, wherein the second compound is administered in a pharmaceutical composition, wherein the pharmaceutical composition is in a unit dosage form, the unit dosage form further comprising a pharmaceutically-acceptable excipient. . The method of claim 188, wherein the unit dosage form is a tablet. . The method of claim 188, wherein the unit dosage form is a capsule. . The method of claim 183, wherein the administering of the second compound is once daily. . The method of claim 183, wherein the administering of the second compound is oral.. The method of claim 183, wherein the administering of the compound of formula (I) is oral, and the administering of the second compound is oral. . The method of claim 183, wherein the administering of the compound of formula (I) is prior to the administering of the second compound. . The method of claim 183, wherein the administering of the second compound is prior to the administering of the compound of formula (I). . The method of claim 183, wherein the administering of the compound of formula (I) is concurrently with the administering of the second compound. . The method of claim 183, wherein the administering of the second compound results in synergistic activity with the compound of formula (I). . The method of claim 132, wherein the subject is a human. . A method of treating lymphoma in a subject in need thereof, the method comprising administering to the subject a therapeutically-effective amount of a compound of formula (I)
Figure imgf000101_0001
wherein:
R1 is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl, each of which is unsubstituted or substituted, or hydrogen;
R2 is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, -CN, - C(O)R5, -C(O)OR5, -C(O)NR5R6, -C(=N)NR5R6, -OR5, -SR5, -NR5R6, - NR5C(O)R6, -NR5C(O)OR6, -OC(O)R5, -OC(O)NR5R6, -S(O)2R5, - NHS(O)2R5, or -OS(O)2R5, each of which is independently substituted or unsubstituted, or hydrogen or halogen;
R3 is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl or heteroaryl, each of which is unsubstituted or substituted, or hydrogen or halogen;
R4 is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -CN, C(O)R5, -C(O)OR5, -C(O)NR5R6, -C(=N)NR5R6, -OR5, -SR5, -NR5R6, - NR5C(O)R6, -NR5C(O)OR6, -OC(O)R5, -OC(O)NR5R6, -S(O)2R5, - NHS(O)2R5, or -OS(O)2R5, each of which is independently substituted or unsubstituted, or hydrogen or halogen; and each R5 and R6 is independently alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl, each of which is independently substituted or unsubstituted, or hydrogen or halogen; provided that, when R4 is -NR5R6 and one of R5 and R6 is pyridyl, then R2 is not -C(O)CH3, or a pharmaceutically-acceptable salt thereof; wherein the subject received a therapy other than the compound for the lymphoma prior to the administering.
200. The method of claim 199, wherein R1 is cycloalkyl.
201. The method of claim 199, wherein R1 is cyclopentyl.
202. The method of claim 199, wherein R2 is CN.
03. The method of claim 199, wherein R3 is hydrogen. 04. The method of claim 199, wherein R4 is -NR5R6. 05. The method of claim 204, wherein one of R5 and R6 is hydrogen. 06. The method of claim 204, wherein one of R5 and R6 is phenyl. 07. The method of claim 204, wherein one of R5 and R6 is phenyl substituted with heterocyclyl. 08. The method of claim 204, wherein one of R5 and R6 is phenyl substituted with piperazinyl. 09. The method of claim 204, wherein one of R5 and R6 is phenyl substituted with 4- methyl piperazinyl. 10. The method of claim 199, wherein R4 is
Figure imgf000102_0001
wherein:
R7 is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -OR5, - SR5, or -NR5R6, each of which is unsubstituted or substituted, or hydrogen;
R8 is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -OR5, - SR5, or -NR5R6, each of which is unsubstituted or substituted, or hydrogen; and R9 is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -OR5, - SR5, or -NR5R6, each of which is unsubstituted or substituted, or hydrogen.11. The method of claim 210, wherein R7 is hydrogen. 12. The method of claim 210, wherein R8 is hydrogen. 13. The method of claim 210, wherein R9 unsubstituted or substituted heterocyclyl. 14. The method of claim 210, wherein R9 is unsubstituted or substituted piperazinyl.15. The method of claim 210, wherein R9 is 4-methyl piperazinyl. 16. The method of claim 210, wherein the compound is a compound of formula (II)
Figure imgf000103_0001
wherein:
Y is O, S, or NR11; each R10 is independently alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -OR5, -SR5, or -NR5R6, each of which is unsubstituted or substituted;
R11 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. 18. The method of claim 217, wherein R1 is cycloalkyl.
. The method of claim 217, wherein R1 is cyclopentyl. . The method of claim 217, wherein Y is NR11. . The method of claim 220, wherein R11 is alkyl. . The method of claim 220, wherein R11 is methyl. . The method of claim 217, wherein n is 0. . The method of claim 197, wherein the compound 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 method of claim 224, wherein the compound is the pharmaceutically-acceptable salt and the pharmaceutically-acceptable salt is monolactate. . The method of claim 199, wherein the lymphoma is a non-Hodgkin’s lymphoma.. The method of claim 226, wherein the non-Hodgkin’s lymphoma is a mantle cell lymphoma. . The method of claim 199, wherein the therapeutically-effective amount is about 40 mg to about 500 mg per day. . The method of claim 199, wherein the therapy is a BTK inhibitor therapy. . The method of claim 229, wherein the BTK inhibitor therapy is ibrutinib or a pharmaceutically-acceptable salt thereof. . The method of claim 229, wherein the BTK inhibitor therapy is acalabrutinib or a pharmaceutically-acceptable salt thereof. . The method of claim 199, wherein the therapy was received after the subject was diagnosed with lymphoma. . The method of claim 199, wherein the subject has not responded to the therapy. . The method of claim 199, wherein the subject experienced a relapse of the lymphoma after the therapy. . The method of claim 199, wherein the subject has primary resistance to BTK inhibitor therapy. . The method of claim 199, wherein the subject has acquired resistance to BTK inhibitor therapy. . The method of claim 199, wherein the administering is oral. . The method of claim 199, wherein the administering is intravenous. . The method of claim 199, wherein the compound is administered in a pharmaceutical composition, wherein the pharmaceutical composition is in a unit dosage form, the unit dosage form further comprising a pharmaceutically-acceptable excipient. . The method of claim 239, wherein the unit dosage form comprises about 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 method of claim 239, wherein the unit dosage form comprises about 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. . The method of claim 239, wherein the unit dosage form is a capsule. . The method of claim 239, wherein the unit dosage form is a tablet. . The method of claim 199, wherein the administering occurs in a morning of a day.. The method of claim 199, wherein the subject is in a fasted state. . The method of claim 199, further comprising administering to the subject a therapeutically-effective amount of a second compound. . The method of claim 246, wherein the second compound is a BTK inhibitor. . The method of claim 247, wherein the BTK inhibitor is ibrutinib or a pharmaceutically-acceptable salt thereof. . The method of claim 247, wherein the BTK inhibitor is acalabrutinib or a pharmaceutically-acceptable salt thereof. . The method of claim 248, wherein the therapeutically-effective amount of ibrutinib or the pharmaceutically-acceptable salt thereof is about 560 mg per day. . The method of claim 248, wherein the therapeutically-effective amount of acalabrutinib or the pharmaceutically-acceptable salt thereof is about 560 mg per day.. The method of claim 246, wherein the second compound is administered in a pharmaceutical composition, wherein the pharmaceutical composition is in a unit dosage form, the unit dosage form further comprising a pharmaceutically-acceptable excipient. . The method of claim 252, wherein the unit dosage form is a tablet. . The method of claim 252, wherein the unit dosage form is a capsule. . The method of claim 246, wherein the administering of the second compound is once daily. . The method of claim 246, wherein the administering of the second compound is oral.. The method of claim 246, wherein the administering of the compound of formula (I) is oral, and the administering of the second compound is oral.
58. The method of claim 246, wherein the administering of the compound of formula (I) is prior to the administering of the second compound. 59. The method of claim 246, wherein the administering of the second compound is prior to the administering of the compound of formula (I). 60. The method of claim 246, wherein the administering of the compound of formula (I) is concurrently with the administering of the second compound. 61. The method of claim 246, wherein the administering of the second compound results in synergistic activity with the compound of formula (I). 62. The method of claim 199, wherein the subject is a human. 63. A method of treating lymphoma in a subject in need thereof, the method comprising:
(i) administering to the subject a therapeutically-effective amount of a first compound, wherein the first compound is a compound of formula (I):
Figure imgf000106_0001
wherein:
R1 is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl, each of which is unsubstituted or substituted, or hydrogen;
R2 is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, -CN, - C(O)R5, -C(O)OR5, -C(O)NR5R6, -C(=N)NR5R6, -OR5, -SR5, -NR5R6, - NR5C(O)R6, -NR5C(O)OR6, -OC(O)R5, -OC(O)NR5R6, -S(O)2R5, - NHS(O)2R5, or -OS(O)2R5, each of which is independently substituted or unsubstituted, or hydrogen or halogen;
R3 is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl or heteroaryl, each of which is unsubstituted or substituted, or hydrogen or halogen;
R4 is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -CN, C(O)R5, -C(O)OR5, -C(O)NR5R6, -C(=N)NR5R6, -OR5, -SR5, -NR5R6, - NR5C(O)R6, -NR5C(O)OR6, -OC(O)R5, -OC(O)NR5R6, -S(O)2R5, - NHS(O)2R5, or -OS(O)2R5, each of which is independently substituted or unsubstituted, or hydrogen or halogen; and each R5 and R6 is independently alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl, each of which is independently substituted or unsubstituted, or hydrogen or halogen; provided that, when R4 is -NR5R6 and one of R5 and R6 is pyridyl, then R2 is not -C(O)CH3, or a pharmaceutically-acceptable salt thereof; and
(ii) administering to the subject a therapeutically-effective amount of a second compound. 64. The method of claim 263, wherein R1 is cycloalkyl. 65. The method of claim 263, wherein R1 is cyclopentyl. 66. The method of claim 263, wherein R2 is CN. 67. The method of claim 263, wherein R3 is hydrogen. 68. The method of claim 263, wherein R4 is -NR5R6. 69. The method of claim 268, wherein one of R5 and R6 is hydrogen. 70. The method of claim 268, wherein one of R5 and R6 is phenyl. 71. The method of claim 268, wherein one of R5 and R6 is phenyl substituted with heterocyclyl. 72. The method of claim 268, wherein one of R5 and R6 is phenyl substituted with piperazinyl. 73. The method of claim 268, wherein one of R5 and R6 is phenyl substituted with 4- methyl piperazinyl. 74. The method of claim 263, wherein R4 is
Figure imgf000107_0001
wherein:
R7 is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -OR5, - SR5, or -NR5R6, each of which is unsubstituted or substituted, or hydrogen;
R8 is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -OR5, - SR5, or -NR5R6, each of which is unsubstituted or substituted, or hydrogen; and R9 is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -OR5, - SR5, or -NR5R6, each of which is unsubstituted or substituted, or hydrogen.thod of claim 274, wherein R7 is hydrogen. thod of claim 274, wherein R8 is hydrogen. thod of claim 274, wherein R9 unsubstituted or substituted heterocyclyl.thod of claim 274, wherein R9 is unsubstituted or substituted piperazinyl.thod of claim 274, wherein R9 is 4-methyl piperazinyl. thod of claim 274, wherein the first compound is a compound of formula (II)
Figure imgf000108_0001
thod of claim 274, wherein the first compound is a compound of formula (III)
Figure imgf000109_0001
wherein:
Y is O, S, or NR11; each R10 is independently alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -OR5, -SR5, or -NR5R6, each of which is unsubstituted or substituted;
R11 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. 82. The method of claim 281, wherein R1 is cycloalkyl. 83. The method of claim 281, wherein R1 is cyclopentyl. 84. The method of claim 281, wherein Y is NR11. 85. The method of claim 284, wherein R11 is alkyl. 86. The method of claim 284, wherein R11 is methyl. 87. The method of claim 281, wherein n is 0. 88. The method of claim 263, wherein the lymphoma is a non-Hodgkin’s lymphoma.89. The method of claim 288, wherein the non-Hodgkin’s lymphoma is a mantle cell lymphoma. 90. The method of claim 263, wherein the first compound 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 method of claim 290, wherein the compound is the pharmaceutically-acceptable salt and the pharmaceutically-acceptable salt is monolactate. . The method of claim 263, wherein the therapeutically-effective amount of the first compound is about 40 mg to about 500 mg per day. . The method of claim 263, wherein the subject received a BTK inhibitor therapy for the lymphoma prior to the administering. . The method of claim 293, wherein the BTK inhibitor therapy is ibrutinib or a pharmaceutically-acceptable salt thereof. . The method of claim 293, wherein the subject has not responded to the therapy. . The method of claim 293, wherein the subject experienced a relapse of the lymphoma after the therapy. . The method of claim 293, wherein the subject has primary resistance to BTK inhibitor therapy. . The method of claim 293, wherein the subject has acquired resistance to BTK inhibitor therapy. . The method of claim 263, wherein the administering of the first compound is oral.. The method of claim 263, wherein the administering of the first compound is intravenous. . The method of claim 263, wherein the first compound and the second compound are each administered in a pharmaceutical composition, wherein the pharmaceutical composition is in a unit dosage form, the unit dosage form further comprising a pharmaceutically-acceptable excipient. . The method of claim 263, wherein the administering is once daily for at least 4 weeks.. The method of claim 263, 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.. The method of claim 263, wherein the administering is a 4-week cycle of:
(i) a continuous, three-week period of once-daily, morning administration, wherein the therapeutically-effective amount of the first compound is from about 40 mg to about 500 mg; and ii) immediately following the three-week period, one week of no administration.. The method of claim 263, wherein the first compound is administered in a pharmaceutical composition, wherein the pharmaceutical composition is in a unit dosage form, the unit dosage form further comprising a pharmaceutically-acceptable excipient. . The method of claim 305, wherein the unit dosage form comprises about 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 method of claim 305, wherein the unit dosage form comprises about 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. . The method of claim 305, wherein the unit dosage form is a capsule. . The method of claim 305, wherein the unit dosage form is a tablet. . The method of claim 263, wherein the administering of the second compound is once daily. . The method of claim 263 , wherein the subj ect is in a fasted state. . The method of claim 263, wherein the second compound is a BTK inhibitor. . The method of claim 312, wherein the BTK inhibitor is ibrutinib or a pharmaceutically-acceptable salt thereof. . The method of claim 312, wherein the BTK inhibitor is acalabrutinib or a pharmaceutically-acceptable salt thereof. . The method of claim 313, wherein the therapeutically-effective amount of ibrutinib or pharmaceutically-acceptable salt thereof is about 560 mg per day. . The method of claim 263, wherein the second compound is administered in a pharmaceutical composition, wherein the pharmaceutical composition is in a unit dosage form, the unit dosage form further comprising a pharmaceutically-acceptable excipient. . The method of claim 316, wherein the unit dosage form comprises about 560 mg of ibrutinib or a pharmaceutically-acceptable salt thereof. . The method of claim 263, wherein the administering of the second compound is once daily. . The method of claim 263, wherein the administering of the second compound is oral.. The method of claim 263, wherein the administering of the second compound is intravenous. . The method of claim 263, wherein the administering of the compound of formula (I) is oral, and the administering of the second compound is oral. 22. The method of claim 263, wherein the administering of the compound of formula (I) is prior to the administering of the second compound. 23. The method of claim 263, wherein the administering of the second compound is prior to the administering of the compound of formula (I). 24. The method of claim 263, wherein the administering of the compound of formula (I) is concurrently with the administering of the second compound. 25. The method of claim 263, wherein the administering of the second compound results in synergistic activity with the compound of formula (I). 26. The method of claim 263, wherein the subject is a human. 27. A combination comprising:
(a) therapeutically-effective amount of a compound of formula (I)
Figure imgf000112_0001
wherein:
R1 is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl, each of which is unsubstituted or substituted, or hydrogen;
R2 is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, -CN, - C(O)R5, -C(O)OR5, -C(O)NR5R6, -C(=N)NR5R6, -OR5, -SR5, -NR5R6, - NR5C(O)R6, -NR5C(O)OR6, -OC(O)R5, -OC(O)NR5R6, -S(O)2R5, - NHS(O)2R5, or -OS(O)2R5, each of which is independently substituted or unsubstituted, or hydrogen or halogen;
R3 is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl or heteroaryl, each of which is unsubstituted or substituted, or hydrogen or halogen;
R4 is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -CN, C(O)R5, -C(O)OR5, -C(O)NR5R6, -C(=N)NR5R6, -OR5, -SR5, -NR5R6, - NR5C(O)R6, -NR5C(O)OR6, -OC(O)R5, -OC(O)NR5R6, -S(O)2R5, - NHS(O)2R5, or -OS(O)2R5, each of which is independently substituted or unsubstituted, or hydrogen or halogen; and each R5 and R6 is independently alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl, each of which is independently substituted or unsubstituted, or hydrogen or halogen; provided that, when R4 is -NR5R6 and one of R5 and R6 is pyridyl, then R2 is not -C(O)CH3, or a pharmaceutically-acceptable salt thereof; and
(ii) a therapeutically-effective amount of a second compound.
328. The combination of claim 327, wherein R1 is cycloalkyl.
329. The combination of claim 327, wherein R1 is cyclopentyl.
330. The combination of claim 327, wherein R2 is CN.
331. The combination of claim 327, wherein R3 is hydrogen.
332. The combination of claim 327, wherein R4 is -NR5R6.
333. The combination of claim 332, wherein one of R5 and R6 is hydrogen.
334. The combination of claim 332, wherein one of R5 and R6 is phenyl.
335. The combination of claim 332, wherein one of R5 and R6 is phenyl substituted with heterocyclyl.
336. The combination of claim 332, wherein one of R5 and R6 is phenyl substituted with piperazinyl.
337. The combination of claim 332, wherein one of R5 and R6 is phenyl substituted with 4- methyl piperazinyl.
338. The combination of claim 327, wherein R4 is
Figure imgf000113_0001
wherein:
R7 is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -OR5, - SR5, or -NR5R6, each of which is unsubstituted or substituted, or hydrogen; R8 is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -OR5, - SR5, or -NR5R6, each of which is unsubstituted or substituted, or hydrogen; and R9 is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -OR5, - SR5, or -NR5R6, each of which is unsubstituted or substituted, or hydrogen.. The combination of claim 338, wherein R7 is hydrogen. . The combination of claim 338, wherein R8 is hydrogen. . The combination of claim 338, wherein R9 unsubstituted or substituted heterocyclyl.. The combination of claim 338, wherein R9 is unsubstituted or substituted piperazinyl.. The combination of claim 338, wherein R9 is 4-methyl piperazinyl. . The combination of claim 338, wherein the first compound is a compound of formula
(II)
Figure imgf000114_0001
. The combination of claim 338, wherein the first compound is a compound of formula
(Ill)
Figure imgf000115_0001
wherein:
Y is O, S, or NR11; each R10 is independently alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -OR5, -SR5, or -NR5R6, each of which is unsubstituted or substituted;
R11 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. 46. The combination of claim 345, wherein R1 is cycloalkyl. 47. The combination of claim 345, wherein R1 is cyclopentyl. 48. The combination of claim 345, wherein Y is NR11. 49. The combination of claim 345, wherein R11 is alkyl. 50. The combination of claim 345, wherein R11 is methyl. 51. The combination of claim 345, wherein n is 0. 52. The combination of claim 327, wherein the first compound 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. 53. The combination of claim 352, wherein the first compound is the pharmaceutically- acceptable salt and the pharmaceutically-acceptable salt is monolactate.
. The combination of claim 327, wherein the therapeutically-effective amount of the first compound is about 40 mg to about 500 mg per day. . The combination of claim 327, wherein the first compound is present in a pharmaceutical composition, wherein the pharmaceutical composition is in a unit dosage form, the unit dosage form further comprising a pharmaceutically-acceptable excipient. . The combination of claim 355, wherein the unit dosage form comprises about 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 combination of claim 355, wherein unit dosage form comprises about 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. . The combination of claim 355, wherein the unit dosage form is a capsule. . The combination of claim 355, wherein the unit dosage form is a tablet. . The combination of claim 327, wherein the second compound is a BTK inhibitor.. The combination of claim 360, wherein the BTK inhibitor is ibrutinib or a pharmaceutically-acceptable salt thereof. . The combination of claim 360, wherein the BTK inhibitor is acalabrutinib or a pharmaceutically-acceptable salt thereof. . The combination of claim 361, wherein a therapeutically-effective amount of ibrutinib or pharmaceutically-acceptable salt thereof is about 560 mg per day. . The combination of claim 327, wherein the second compound is present in a pharmaceutical composition, wherein the pharmaceutical composition is in a unit dosage form, the unit dosage form further comprising a pharmaceutically-acceptable excipient. . The combination of claim 364, wherein the unit dosage form is a tablet. . The combination of claim 364, wherein the unit dosage form is a capsule. . The combination of claim 327, wherein the compound or the pharmaceutically acceptable salt thereof and the second compound are in one unit dosage form. . The combination of claim 327, wherein the compound or the pharmaceutically acceptable salt thereof and the second compound are in separate dosage forms. . A method of treating mantle cell lymphoma in a subject in need thereof, the method 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. 70. A method of treating mantle cell lymphoma in a subject in need thereof, the method 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 pharmaceutically-acceptable salt thereof. 71. A method of treating Bruton tyrosine kinase inhibitor-resistant mantle cell lymphoma in a subject in need thereof, the method 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. 72. A method of treating Bruton tyrosine kinase inhibitor-resistant mantle cell lymphoma in a subject in need thereof, the method 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 pharmaceutically-acceptable salt thereof. 73. A method of treating Bruton tyrosine kinase inhibitor-resistant mantle cell lymphoma in a subject in need thereof, the method 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 pharmaceutically-acceptable salt thereof.
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