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WO2021144302A1 - Biomarqueurs pour déterminer la sensibilité à des dérivés d'oxopipérazine et leurs méthodes d'utilisation - Google Patents

Biomarqueurs pour déterminer la sensibilité à des dérivés d'oxopipérazine et leurs méthodes d'utilisation Download PDF

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Publication number
WO2021144302A1
WO2021144302A1 PCT/EP2021/050574 EP2021050574W WO2021144302A1 WO 2021144302 A1 WO2021144302 A1 WO 2021144302A1 EP 2021050574 W EP2021050574 W EP 2021050574W WO 2021144302 A1 WO2021144302 A1 WO 2021144302A1
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alkyl
cycloalkyl
aryl
heteroaryl
compound
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English (en)
Inventor
Valentino CATTORI
Ulrich Kessler
Beatrice Dolores Pilger KESSLER
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Inthera Bioscience AG
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Inthera Bioscience AG
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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
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • This application relates to the fields of oncology and diagnostics.
  • the disclosure provides methods of treating a subject with a cancer, comprising: (a) determining the activity or expression of at least one gene in a cancer cell of the subject, wherein the at least one gene is selected from the group of genes disclosed in Table 1 and Table 2; and (b) administering a compound of the present disclosure or a pharmaceutically acceptable salt, hydrate, solvate or stereoisomer thereof to the subject when the activity or expression of the at least one gene in the cancer cell is different from the activity or expression of the at least one gene in a non- cancerous control cell.
  • compounds of formula la are functional modulators of CBP/p300 activity.
  • compounds of formula la may inhibit or modulate one or more activities of CBP/p300.
  • the disclosure provides methods of treating a subject with a cancer, comprising: (a) determining the activity or expression of at least one gene in a cancer cell of the subject, wherein the at least one gene is selected from the group of genes disclosed in Table 1 and Table 2; and (b) administering a compound of formula la or a pharmaceutically acceptable salt, hydrate, solvate or stereoisomer thereof to the subject when the activity or expression of the at least one gene in the cancer cell is different from the activity or expression of the at least one gene in a non-cancerous control cell.
  • compounds of formula la are functional modulators of CBP/p300 activity.
  • compounds of formula la may inhibit or modulate one or more activities of CBP/p300.
  • the at least one gene comprises CDKN1 A, CDKN2A, p53, Rb1, or any combination thereof.
  • the difference in the activity or expression of the at least one gene comprises a loss of expression or function of CDKN1 A, CDKN2A, p53, Rb1 or any combination thereof.
  • the at least one gene comprises Rb1, CDKN2B, CDKN2C, BRG1, BRM, Cyclin D1, CDK4, CDK6, E2F1, c-Myc, FOXM1, or HDAC1.
  • the at least one gene further comprises CDKN2A.
  • the difference in the activity or expression of the at least one gene comprises a loss of expression or function of Rb1, CDKN2A, CDKN2B, CDKN2C, BRG1 or BRM, or an increase of expression or function of Cyclin D1, E2F1 or HDAC1.
  • the at least one gene comprises p53, CDKN1A, ATM, ATR, CHK1, CHK2, NBS1, PARPl, c-Abl or MDM2.
  • the at least one gene further comprises CDKN2A.
  • the difference in the activity or expression of the at least one gene comprises a loss of expression or function of p53, CDKN1 A, CDKN2A, ATM, ATR, CHK1, CHK2, NBS1, PARPl, or c-Abl, or an increase in expression or function of MDM2.
  • the at least one gene comprises: (a) Rb1, CDKN2B, CDKN2C, BRG1, BRM, Cyclin D1, CDK4, CDK6, E2F1, c-Myc, FOXM1 or HDAC1; and (b) p53, CDKN1A, ATM, ATR, CHK1, CHK2, NBS1, PARPl, c-Abl or MDM2.
  • the at least one gene comprises (a) Rb1, CDKN2B, CDKN2C, BRG1, BRM, Cyclin D1, CDK4, CDK6, E2F1 or HD AC 1, 53, CDKN1A, ATM, ATR, CHK1, CHK2, c-Abl or MDM2; and (b) CDKN2A.
  • the difference in the activity or expression of the at least one gene comprises: (a) a loss of expression or function of Rb1, CDKN2A, CDKN2B,
  • the at least one gene comprises: (a) a loss of expression or function of Rb1; and (b) a loss of expression or function of p53 or CDKN1A. In some embodiments, the at least one gene further comprises a difference in expression or activity of CDKN2A.
  • the at least one gene comprises Rb1 and p53, and the difference in activity or expression of the at least one gene comprises a loss of expression or function of Rb1 and p53.
  • the difference in the activity or expression of the at least one gene between the cancer cell and the non-cancerous control cell comprises an increase in protein or mRNA level of the at least one gene, a decrease in protein or mRNA level of the at least one gene, a change post-translation protein modification of a protein product of the at least one gene, at least one mutation in the at least one gene, or a change in epigenetic modification of the at least one gene.
  • the change in post- translational protein modification comprises a phosphorylation or acetylation.
  • the epigenetic modification comprises methylation or histone acetylation.
  • the at least one mutation comprises an insertion, a deletion, a point mutation or an inversion.
  • the at least one mutation is in protein coding sequence or regulatory sequence.
  • determining the activity or expression of at least one gene comprises measuring a level of mRNA expression of the at least one gene, measuring protein expression of the at least one gene, determining a genomic or mRNA sequence of the at least one gene, measuring a post-translational modification in the protein product of the at least one gene, or measuring a change in epigenetic modification of the at least one gene.
  • measuring a level of mRNA expression of the at least one gene comprises quantitative RT-PCR, a microarray or high throughput RNA sequencing.
  • measuring protein expression of the at least one gene comprises immunohistochemistry.
  • the immunohistochemistry comprises an antibody stain, an ELISA or a Western blot.
  • measuring the post-translational modification comprises immunohistochemistry with an antibody specific to the post-translational modification, or measuring a change in size of a protein product of the at least one gene.
  • the epigenetic modification of the at least one gene comprises methylation or histone acetylation.
  • measuring the epigenetic modification comprises chromatin immunoprecipitation.
  • the cancer is a DNA repair deficient cancer.
  • the cancer is associated with lineage plasticity.
  • the cancer is pancreatic cancer, osteosarcoma, prostate cancer, breast cancer, small cell lung cancer, gastric cancer, adenocarcinoma, neuroendocrine cancer or melanoma.
  • the prostate cancer is castrate resistant prostate cancer. In some embodiments, the prostate cancer is resistant to androgen receptor (AR) pathway inhibitors. In some embodiments, the AR pathway inhibitors comprise abiraterone acetate, enzalutamide, apalutamide, darolutamide or bicalutamide. In some embodiments, the prostate cancer is neuroendocrine prostate cancer.
  • AR androgen receptor
  • the disclosure provides methods of treating prostate cancer in a subject in need thereof, comprising administering a compound of formula la or a pharmaceutically acceptable salt, hydrate, solvate or stereoisomer thereof to the subject.
  • the prostate cancer is resistant to androgen receptor (AR) pathway inhibitors.
  • the prostate cancer is castrate resistant prostate cancer.
  • the prostate cancer is neuroendocrine prostate cancer (NEPC).
  • the prostate cancer is AR-, androgen independent prostate cancer.
  • the prostate cancer is androgen driven, AR positive adenocarcinoma.
  • the prostate cancer comprises both AR positive and AR negative cells.
  • the methods comprise determining a level of prostate serum antigen (PSA) in the subject.
  • PSA prostate serum antigen
  • the disclosure provides methods of treating a subject with a hematological cancer, comprising: (a) determining the activity or expression of p53, and/or determining the activity or expression of ASXL1 or a paralog thereof and RUNXl or a paralog thereof; and (b) administering a compound of the present disclosure or a pharmaceutically acceptable salt, hydrate, solvate or stereoisomer thereof, to the subject when the activity or expression of p53, and/or the activity or expression of ASXL1 or a paralog thereof and RUNX1 or a paralog thereof is different from the activity or expression of p53, and/or the activity or expression of in a non-cancerous control cell.
  • the method comprises determining the activity or expression of all of p53, ASXL1 or a paralog thereof, and RUNX1 or a paralog thereof.
  • the disclosure provides methods of treating a subject with a hematological cancer, comprising: (a) determining the activity or expression of p53, and/or determining the activity or expression of ASXL1 or a paralog thereof and RUNX1 or a paralog thereof; and (b) administering a compound of formula la or a pharmaceutically acceptable salt, hydrate, solvate or stereoisomer thereof, to the subject when the activity or expression of p53, and/or the activity or expression of ASXL1 or a paralog thereof and RUNX1 or a paralog thereof is different from the activity or expression of p53, and/or the activity or expression of in a non-cancerous control cell.
  • the method comprises determining the activity or expression of all of p53, ASXL1 or a paralog thereof, and RUNX1 or a paralog thereof.
  • the methods comprise determining the activity or expression of p53, ASXL1 or a paralog thereof, and RUNX1 or a paralog thereof. In some embodiments, the methods comprise determining the activity or expression of p53, ASXL1 and RUNX1. In some embodiments, the method comprises determining the activity or expression of p53, and determining the activity or expression of ASXL1 or a paralog thereof, or RUNX1 or a paralog thereof.
  • the hematological cancer is acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), B cell lymphoma (BCL), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), diffuse large B cell lymphoma (DLBCL), Epstein Barr driven hematological cancer, multiple myeloma (MM), T cell lymphoma (TCL), Hodgkin lymphoma or non- Hodgkin lymphoma.
  • ALL acute lymphocytic leukemia
  • AML acute myeloid leukemia
  • BCL B cell lymphoma
  • CLL chronic lymphocytic leukemia
  • CML chronic myeloid leukemia
  • DLBCL diffuse large B cell lymphoma
  • Epstein Barr driven hematological cancer multiple myeloma
  • MM multiple myeloma
  • TCL T cell lymphoma
  • the difference in the activity or expression of p53, and/or the activity or expression of ASXL1 or a paralog thereof and RUNX1 or a paralog thereof between the cancer cell and the non-cancerous control cell comprises an increase in protein or mRNA level, a decrease in protein or mRNA level, a change in post-translation protein modification of a protein product, at least one mutation, or a change in epigenetic modification of p53, and/or ASXL1 or a paralog thereof and RUNX1 or a paralog thereof.
  • the post-translational modification comprises phosphorylation or acetylation.
  • the epigenetic modification comprises methylation or histone acetylation.
  • the at least one mutation comprises an insertion, a deletion, a point mutation, or an inversion.
  • the at least on mutation is in protein coding sequence or regulatory sequence.
  • determining the activity or expression of p53, and/or ASXL1 or a paralog thereof and RUNX1 or a paralog thereof comprises measuring a level of mRNA expression, measuring protein expression, determining a genomic or mRNA sequence, measuring a post-translational modification in the protein product, or measuring a change in epigenetic modification of p53, and/or ASXLl or a paralog thereof and RUNXl or a paralog thereof.
  • measuring the level of mRNA expression comprises quantitative RT-PCR, a microarray or high throughput RNA sequencing.
  • measuring protein expression comprises immunohistochemistry.
  • measuring the post-translational modification comprises immunohistochemistry with an antibody specific to the post-translational modification, or measuring a change in size of a protein product.
  • measuring the epigenetic modification comprises chromatin immunoprecipitation.
  • the cancer is Stage I, Stage II, Stage III or Stage IV.
  • the subject is human.
  • the disclosure provides methods of treating a subject with a cancer, comprising administering a compound of formula la to the subject.
  • the method further comprises an additional cancer therapy.
  • the additional cancer therapy comprises a cyclin dependent kinase inhibitor.
  • the cyclin dependent kinase inhibitor is not a CDK4/6 inhibitor.
  • the cancer comprises a tumor.
  • the tumor is a liquid tumor or a solid tumor.
  • administering the compound of formula la slows or stops tumor progression.
  • slowing or stopping tumor progression comprises inducing senescence of tumor cells.
  • administering the compound of formula la reduces tumor size.
  • reducing tumor size comprises inducing apoptosis of tumor cells.
  • the disclosure provides compounds for use in treating cancer, comprising (a) determining the activity or expression of at least one gene in a cancer cell of the subject, wherein the at least one gene is selected from the group of genes disclosed in Table 1 and Table 2; and (b) administering a compound of the present disclosure or a pharmaceutically acceptable salt, hydrate, solvate or stereoisomer thereof to the subject when the activity or expression of the at least one gene in the cancer cell is different from the activity or expression of the at least one gene in a non-cancerous control cell.
  • the disclosure provides compounds for use in treating prostate cancer, comprising administering a compound of the present disclosure or a pharmaceutically acceptable salt, hydrate, solvate or stereoisomer thereof to the subject.
  • the disclosure provides compounds for use in treating a subject with a hematological cancer, comprising: (a) determining the activity or expression of p53, and/or determining the activity or expression of ASXL1 or a paralog thereof and RUNXl or a paralog thereof; and (b) administering a compound of the present disclosure or a pharmaceutically acceptable salt, hydrate, solvate or stereoisomer thereof, to the subject when the activity or expression of p53, and/or the activity or expression of ASXL1 or a paralog thereof and RUNXl or a paralog thereof, is different from the activity or expression of p53, and/or the activity or expression of ASXLl or a paralog thereof and RUNXl or a paralog thereof in a non-cancerous control cell.
  • the disclosure provides compounds for use in treating cancer, comprising (a) determining the activity or expression of at least one gene in a cancer cell of the subject, wherein the at least one gene is selected from the group of genes disclosed in Table 1 and Table 2; and (b) administering a compound of formula la or a pharmaceutically acceptable salt, hydrate, solvate or stereoisomer thereof to the subject when the activity or expression of the at least one gene in the cancer cell is different from the activity or expression of the at least one gene in a non-cancerous control cell.
  • the disclosure provides compounds for use in treating prostate cancer, comprising administering a compound of formula la or a pharmaceutically acceptable salt, hydrate, solvate or stereoisomer thereof to the subject.
  • the disclosure provides compounds for use in treating a subject with a hematological cancer, comprising: (a) determining the activity or expression of p53, and/or determining the activity or expression of ASXL1 or a paralog thereof and RUNX1 or a paralog thereof; and (b) administering a compound of formula la or a pharmaceutically acceptable salt, hydrate, solvate or stereoisomer thereof, to the subject when the activity or expression of p53, and/or the activity or expression of ASXL1 or a paralog thereof and RUNX1 or a paralog thereof, is different from the activity or expression of p53, and/or the activity or expression of ASXL1 or a paralog thereof and RUNX1 or a paralog thereof in a non-cancerous control cell.
  • the disclosure provides use of a compound of the present disclosure for the manufacture of a medicament for the treatment of cancer, comprising (a) determining the activity or expression of at least one gene in a cancer cell of the subject, wherein the at least one gene is selected from the group of genes disclosed in Table 1 and Table 2; and (b) administering a compound of the present disclosure or a pharmaceutically acceptable salt, hydrate, solvate or stereoisomer thereof to the subject when the activity or expression of the at least one gene in the cancer cell is different from the activity or expression of the at least one gene in a non-cancerous control cell.
  • the disclosure provides use of a compound of the present disclosure for the manufacture of a medicament for the treatment of prostate cancer.
  • the disclosure provides use of a compound of the present disclosure for the manufacture of a medicament for the treatment of a hematological cancer, comprising: (a) determining the activity or expression of p53, and/or determining the activity or expression of ASXL1 or a paralog thereof and RUNX1 or a paralog thereof; and (b) administering a compound of the present disclosure or a pharmaceutically acceptable salt, hydrate, solvate or stereoisomer thereof, to the subject when the activity or expression of p53, and/or the activity or expression of ASXL1 or a paralog thereof and RUNX1 or a paralog thereof, is different from the activity or expression of p53, and/or the activity or expression of ASXL1 or a paralog thereof and RUNX1 or a paralog thereof in a non-cancerous control cell.
  • the disclosure provides use of a compound of formula la for the manufacture of a medicament for the treatment of cancer, comprising (a) determining the activity or expression of at least one gene in a cancer cell of the subject, wherein the at least one gene is selected from the group of genes disclosed in Table 1 and Table 2; and (b) administering a compound of formula la or a pharmaceutically acceptable salt, hydrate, solvate or stereoisomer thereof to the subject when the activity or expression of the at least one gene in the cancer cell is different from the activity or expression of the at least one gene in a non-cancerous control cell.
  • the disclosure provides use of a compound of formula la for the manufacture of a medicament for the treatment of prostate cancer, comprising administering a compound of formula la or a pharmaceutically acceptable salt, hydrate, solvate or stereoisomer thereof to the subject.
  • the disclosure provides use of a compound of formula la for the manufacture of a medicament for the treatment of a hematological cancer, comprising: (a) determining the activity or expression of p53, and/or determining the activity or expression of ASXL1 or a paralog thereof and RUNX1 or a paralog thereof; and (b) administering a compound of formula la or a pharmaceutically acceptable salt, hydrate, solvate or stereoisomer thereof, to the subject when the activity or expression of p53, and/or the activity or expression of ASXL1 or a paralog thereof and RUNX1 or a paralog thereof, is different from the activity or expression of p53, and/or the activity or expression of ASXL1 or a paralog thereof and RUNXl or a paralog thereof in a non-cancerous control cell.
  • the compound of the present disclosure is of formula la: or a pharmaceutically acceptable salt, hydrate, solvate or stereoisomer thereof, wherein: R 1 is selected from H, C 1-7 alkyl, C 2-7 alkenyl, C 2-7 alkynyl, C 3-7 cycloalkyl, C 4-7 cycloalkenyl, and C 1-3 alkyl substituted by cycloalkyl, aryl or heteroaryl, wherein the cycloalkyl, aryl, or the heteroaryl is optionally substituted by halogen, C 1-4 alkyl, or C 3-5 cycloalkyl;
  • R 2 is selected from H, C(O)R 14 , C(O)NR 15 R 15 , C(O)OR 15 , C 1-7 alkyl, C 2-7 alkenyl, C 2-7 alkynyl, C 3-7 cycloalkyl, C 4-7 cycloalkenyl, C 1-5 alkyl-OR 8 , C 1-3 alkanediyl-O- C 1-3 alkanediyl-O-C 1-3 alkanediyl, C 1-5 alkyl-NHCOR 13 , and C 1-3 alkyl substituted by cycloalkyl, aryl or heteroaryl, wherein the cycloalkyl, aryl or the heteroaryl is optionally substituted by halogen, C 1-4 alkyl or C 3-5 cycloalkyl; with the proviso that when R 2 is C(O)NR 15 R 15 , both R 15 can form a ring wherein the ring contains the N of NR 15 R 15 and optional
  • R 3 and R 7 are each independently selected from H, C 1-7 alkyl, C 2-7 alkenyl, C 2-7 alkynyl, C 3-7 cycloalkyl, and C 4-7 cycloalkenyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, or cycloalkenyl are optionally substituted by halogen, OR 8 , or NR 8 R 11 ; or R 3 and R 7 are each independently C 1-3 alkyl substituted by aryl or heteroaryl, wherein the aryl or the heteroaryl is optionally substituted by halogen, C 1-4 alkyl, or C 3-5 cycloalkyl;
  • R 4 is selected from C 1-7 alkyl, C 2-7 alkenyl, C 2-7 alkynyl, C 3-7 cycloalkyl, C 4-7 cycloalkenyl, and C 1-3 alkyl substituted by cycloalkyl, aryl, or heteroaryl, wherein the cycloalkyl, aryl or the heteroaryl is optionally substituted by halogen, C 1-4 alkyl, or C 3-5 cycloalkyl;
  • R 5 is selected from H, C 1-7 alkyl, C 2-7 alkenyl, C 2-7 alkynyl, C 3-7 cycloalkyl, C 4-7 cycloalkenyl, OR 8 , C 1-3 alkyl-OR 8 , and SR 8 ; and wherein R 5 can form a ring with any part of X or Y, wherein the ring optionally contains a carbonyl group;
  • R 6 is selected from H, C 1-7 alkyl, C 2-7 alkenyl, C 2-7 alkynyl, C 3-7 cycloalkyl, and C 4-7 cycloalkenyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, or cycloalkenyl are optionally substituted by halogen, OR 8 , or NR 8 R 11 ; or R 6 is C 1-3 alkyl substituted by C(O)NR 8 R 11 ; or R 6 is C 1-3 alkyl substituted by aryl or heteroaryl, wherein the aryl or the heteroaryl is optionally substituted by halogen, C 1-4 alkyl or C 3-5 cycloalkyl; or R 6 can form a ring with any part of X; or R 6 is imidazolidinone;
  • R 8 and R 11 are each independently selected from H, C 1-7 alkyl, C 2-7 alkenyl, C 2-7 alkynyl, C 3-7 cycloalkyl, and C 4-7 cycloalkenyl;
  • X is selected from a bond, C 1-7 alkanediyl, C 2-7 alkenediyl, C 2-7 alkynediyl, C 3-9 cycloalkanediyl, C 4-6 cycloalkenediyl, -O-, C 1-3 alkanediyl-O-, -O-C 1-7 alkanediyl, -O- C 3-9 cycloalkanediyl, C 1-3 alkanediyl-O-C 1-7 alkanediyl, C 1-7 heteroalkanediyl, and -S-C 1-7 alkanediyl; and wherein X can form a ring or a polycyclic system with any part of R 5 , R 6 , or Y, wherein the ring optionally contains a carbonyl group;
  • Y is selected from H, C(O)NR 10 R 12 , C(O)OR 10 , R 10 NC(O)NR 10 R 12 , OC(O)R 10 , OC(O)NR 10 R 12 , S(O)nR 8 wherein n is 0, 1 or 2, SO 2 NR 10 R 12 , NR 10 SO 2 R 10 , NR 10 R 12 , HNCOR 8 , CN, C 3-7 -cycloalkyl optionally containing a heteroatom in the ring selected from O and N, wherein if the heteroatom is N it is optionally substituted by R 8 , S-aryl, O-aryl, S-heteroaryl, and O-heteroaryl, wherein the S-aryl, O-aryl, S-heteroaryl, or O-heteroaryl are optionally substituted by one or more R 9 or R 14 ; or Y is aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted
  • R 9 is selected from H, halogen, C 1-5 alkyl, C 2 -5 alkenyl, C 2 -5 alkynyl, C 3-5 cycloalkyl, C 1-5 alkyl-OR 8 , C 1-5 alkyl-SR 8 , C 1-5 alkyl-NR 8 R 11 , C 1-5 alkyl- C(O) OR 8 , C 1-5 alkyl-C(O)NR 8 R 11 , C 1-5 alkyl- C(O)R 10 , CN, C(O)R 8 , C(O)NR 8 R 11 , C(O) OR 8 , NR 8 C(O)NR 8 R 11 , OC(O)NR 8 R 11 , SO 2 NR 8 R 11 , NR 8 SO 2 R 8 , OR 8 , NR 8 R 11 , and S(O) n R 8 wherein n is 0, 1 or 2;
  • R 10 and R 12 are each independently selected from H, C 1-7 alkyl, C 2-7 alkenyl, C 2-7 alkynyl, C 3-7 cycloalkyl, C 4-7 cycloalkenyl, C 1-3 alkanediyl-O-C 1-3 alkanediyl-O-C 1-3 alkanediyl, C 1-3 alkyl-aryl, and C 1-3 alkyl-heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, alkanediyl, aryl, or heteroaryl are optionally substituted by halogen, OR 8 , or NR 8 R 11 ;
  • R 13 is C 1-5 alkyl substituted by a bicyclic ring optionally comprising at least one heteroatom and a carbonyl group;
  • R 14 is selected from H, C 1-7 alkyl, C 2-7 alkenyl, C 2-7 alkynyl, C 3-7 cycloalkyl, C 4-7 cycloalkenyl, and C 1-3 alkyl substituted by aryl or heteroaryl, wherein the aryl or the heteroaryl is optionally substituted by halogen, C 1-4 alkyl, or C 3-5 cycloalkyl; and each R 15 is independently selected from H, C 1-7 alkyl, C 2-7 alkenyl, C 2-7 alkynyl, C 3-7 cycloalkyl, C 4-7 cycloalkenyl, OR 8 , and C 1-3 alkyl-OR 8 .
  • the compound of the present disclosure is of formula (I): or a pharmaceutically acceptable salt, hydrate, solvate or stereoisomer thereof, wherein:
  • R 1 is C 1-7 alkyl
  • R 2 is selected from H, C(O)R 14 , C(O)OR 15 , C 1-7 alkyl, C 3-7 cycloalkyl, C 1-5 alkyl-NHCOR 13 , and C 1-3 alkyl substituted by aryl, wherein the aryl is optionally substituted by halogen;
  • R 3 and R 7 are each H
  • R 4 is C 1-7 alkyl
  • R 5 is selected from H, C 1-7 alkyl, OR 8 , and SR 8 ; and wherein R 5 can form a ring with any part of X or Y, wherein the ring optionally contains a carbonyl group;
  • R 6 is selected from H and C 1-7 alkyl
  • R 8 and R 11 are each independently selected from H, C 1-7 alkyl, and C 3-7 cycloalkyl;
  • X is selected from a bond, C 1-7 alkanediyl, -O-C 1-7 alkanediyl, and -S-C 1-7 alkanediyl; and wherein X can form a ring with any part of R 5 or Y;
  • Y is selected from H, NR 10 R 12 , and C 3-7 -cycloalkyl optionally containing a heteroatom in the ring selected from O and N wherein if the heteroatom is N it is optionally substituted by R 8 ; or Y is heteroaryl, wherein the heteroaryl is optionally substituted by one or more of R 8 ; and wherein Y can form a ring with any part of X or R 5 , wherein the ring optionally contains a carbonyl group; with the proviso that when Y is NR 10 R 12 , R 10 and R 12 can form a ring wherein the ring contains the N of NR 10 R 12 and optionally one further heteroatom selected from O and N, wherein if the one further heteroatom is N, it is optionally substituted by R 8 ;
  • R 10 and R 12 are each independently selected from H, C 1-7 alkyl, C 3-7 cycloalkyl, and C 1-3 alkyl- aryl, wherein the alkyl or cycloalkyl, or aryl are optionally substituted by halogen;
  • R 13 is C 1-5 alkyl substituted by a bicyclic ring optionally comprising at least one heteroatom and a carbonyl group;
  • R 14 is selected from H and C 1-7 alkyl; and each R 15 is independently selected from H and C 1-7 alkyl. [0042] In one aspect, the compound is selected from Table A.
  • FIG. 1 A is a plot showing that oxopiperazine derivatives cause cytotoxicity in DU145 cells.
  • Compound #258 has an EC90 of around 10 nM in DU145 cells.
  • FIG. 1B is a plot showing that oxopiperazine derivatives cause cytotoxicity in SNU-5 cells.
  • Compound #258 has an EC90 of around 10 nM in SNU-5 cells.
  • FIG. 1C is a plot showing that oxopiperazine derivatives cause cytotoxicity in H460 cells.
  • Compound #258 has an EC90 of around 10 nM in H460 cells.
  • FIG. ID is a plot showing that oxopiperazine derivatives cause cytotoxicity in Kasumi-1 cells.
  • Compound #258 has an EC90 of around 200 nM in Kasumi-1 cells.
  • FIG. IE is a plot showing that oxopiperazine derivatives cause cytotoxicity in SNU-16 cells.
  • Compound #258 has an EC90 of around 20 nM in SNU-16 cells.
  • FIG. 1F is a plot showing that oxopiperazine derivatives cause cytotoxicity in A375 cells.
  • Compound #258 has an EC90 of around 10 nM in A375 cells.
  • FIG. 1G is a plot showing that oxopiperazine derivatives cause cytotoxicity in Molt-4 cells.
  • Compound #258 has an EC90 of around 20 nM in Molt-4 cells.
  • FIG. 1H is a plot showing that oxopiperazine derivatives cause cytotoxicity in MOLM-13 cells.
  • Compound #258 has an EC90 of around 20 nM in MOLM-13 cells.
  • FIG. 2 is a series of Western Blots profiling molecular markers in 4 prostate cancer cell lines following treatment with varying concentrations of Compound #258.
  • FIG. 3 is a plot showing gene ontology (GO) term analysis of transcripts enriched in 22Rvl and LNCaP prostate cancer cells treated with 200 nM of Compound #258 for 72 hours.
  • GO term enrichment indicates that treatment with Compound #258 disrupts the cell cycle at the G1/S phase transition.
  • FDR False Discovery Rate.
  • FIG. 4A is a plot of cell cycle phase distribution of LNCaP cells stained for DNA and treated with 200 nM of Compound #258. Cells were assayed after 1 hour, 24 hours and 72 hours.
  • FIG. 4B is a plot of cell cycle phase distribution of 22Rvl cells stained for DNA and treated with 200 nM of Compound #258. Cells were assayed after 1 hour, 24 hours and 72 hours.
  • FIG. 4C is a plot of cell cycle phase distribution of DU145 cells which are lacking Rb transcriptional corepressor 1 and have dysfunctional tumor protein p53 (Rb1 /p53 -/- ).
  • Cells were treated with 200 nM of Compound #258 and stained for DNA content after 1 hour, 24 hours and 72 hours. 24 hours treatment with 200 nM of Compound #258 causes S-phase cell cycle arrest.
  • FIG. 5 is a plot showing protein induction following treatment with 200nM Compound #258.
  • 22Rvl, LNCaP and DU145 prostate cancer cells were treated for 72 hours, and then assayed for p53 expression, expression of p53 acetylated at lysine 382 (p53 K832Ac) and p21 (CDKN1A) expression.
  • FIG. 6 is a plot showing caspase 3/7 activity in 22Rvl, LNCaP and DU145 prostate cancer cells following a 72-hour treatment with Compound #258.
  • FIG. 7 is a PVDF membrane total sample protein staining (top) and a Western Blot for Cyclin D1 (bottom) in DU145 cells following no treatment (control, “0”), or treatment with 200 nM Compound #258 for 4, 8, 24, 48 or 72 hours. Arrow indicates the expected size of Cyclin D1, at 36 kilodaltons (KDa).
  • FIG. 8 A is a plot showing Cyclin D1 expression at 4, 8, 24, 48 or 72 hours in control (NK) DU145 cells, or DU145 cells after treatment with 200 nM Compound #258. Cyclin D1 is normalized against 4 hours NK expression.
  • FIG. 8B is a plot showing Cyclin D1 expression at 4, 8, 24, 48 or 72 hours in control (NK) DU145 cells, normalized to NK expression at 4 hours.
  • FIG. 8C is a plot showing Cyclin D1 expression at 4, 8, 24, 48 or 72 hours in DU145 cells treated with 200 nM of Compound #258, normalized against Cyclin D1 expression at 4 hours.
  • FIG. 9 is a table summarizing Cyclin D1 expression at 4, 8, 24, 48 or 72 hours in untreated control (NK) DU145 cells, and DU145 cells treated with 200 nM of Compound #258. Cyclin D1 expression was normalized to 4 hours NK expression (Relative Protein against NK, 4h), or cells treated for 4 hours with Compound #258 (Relative Protein against 4h time points).
  • FIG. 10A is a diagram showing the ECw (in ⁇ M) of Compound #258 in a panel of 52 lines plus three additionally selected cell lines, and the p53 and Rb1 status of those cell lines. Red squares indicate cell lines with mutations or dysregulations in the indicated gene(s).
  • FIG. 10B is a diagram showing the IC 90 (in ⁇ M) of Compound #258 in a panel of 52 lines plus three additionally selected cell lines, and the p53, Rb1 and cyclin dependent kinase inhibitor 2A (CDKN2A) status of those cell lines. Red squares indicate cell lines with mutations or dysregulations in the indicated gene(s).
  • FIG. 11 A is a plot showing tumor volume (in mm 3 ) versus time in immunocompromised mice bearing tumors derived from the 22Rvl prostate cancer cell line. Mice were treated with vehicle alone as a control; with 1 mg/kg of Compound #258 once a day (Q.D.), every day; with 3 mg/kg of Compound #258 once a day, every day; with 3 mg/kg of Compound #258 once a day, on a 7 day on, 7 day off dosing schedule; or with 30 mg/kg of Compound #258 B.I.D. (in two daily doses), on a 1 day on, 6 day off dosing schedule. Error bars indicate standard error of the mean (SEM). Dosing regimens are indicated at the bottom.
  • FIG. 11B is a plot showing tumor volume (in mm 3 ) versus time in immunocompromised mice bearing tumors derived from the SNU-5 gastric cancer cell line. Mice were treated with vehicle alone as a control; with 1 mg/kg of Compound #258 once a day (Q.D.), every day; with 3 mg/kg of Compound #258 once a day, every day; with 3 mg/kg of Compound #258 once a day, on a 7 day on, 7 day off dosing schedule; or with 30 mg/kg of Compound #258 in two daily doses, on a 1 day on, 6 day off dosing schedule. Error bars indicate standard error of the mean (SEM). Dosing regimens are indicated at the bottom.
  • FIG. 11C is a pair of pictures showing cells from animals treated with vehicle and Compound #258 that were stained for Ki67.
  • FIG. 1 ID is a plot showing the effect on body weight of treatment with Compound #258.
  • FIG. 12 is a plot showing tumor volume (in mm 3 ) versus time in immunocompromised mice bearing tumors derived from the SNU-16 cell line.
  • Group 01 vehicle, 0 mg/kg Compound #258, 10 ⁇ L/g.p.o.
  • FIG. 13 is a plot showing the correlation between IC 50 and IC 90 estimates in a 110 cell line panel for Compound #258.
  • Log IC 50 (in nM) is shown on the on the X-axis
  • log IC 90 (in nM) is shown on the Y-axis.
  • R squared 0.64, with the slope significantly non-zero (p ⁇ 0.0001).
  • Dashed lines indicate the 90% prediction bands of the best fit line. Data were analyzed using GraphPad Prism 8.3 using the built-in linear regression fit.
  • FIG. 14 is a plot showing IC 50 values (in nM) in 110 cell lines treated with Compound #258 for 5 days and assayed for proliferation. Red bars indicate those cell lines where greater than 90% inhibition was reached. Cell lines assayed, from top to bottom, are: MM.
  • FIG. 15 is a plot showing IC 50 values (in nM) in 144 cell lines treated with Compound #258 for 5 days and assayed for proliferation.
  • Cell lines assayed, from top to bottom, are: NCIH69, SNU398, NCIH82, LN18, RKO, JJN3, DU145, HCC1428, A204, JEG3, A375, HuPT4, 5637, A253, CADOES1, LNCaPcloneFGC, JHH5, A549, SW579, SW1990, SNU5, NUGC4, NCIH2286, Hs852T, FaDu, NCIH1792, Detroit562, 143B, NCIH2122, SW1088, NCIH2009, Calu3, 7860, OVCAR4, BxPC3, A172, NCIH1993, SNU16, NCIH460, 22Rvl, HT1376, KARPAS299, SJCRH30, NCIH1975, A673, HT29, SKES1, MKN1, DU4475, BT20,
  • Cell lines assayed, from top to bottom, are: NCIH69, SNU398, NCIH82, LN18, RKO, JJN3, DU145, HCC1428, A204, JEG3, A375, HuPT4, 5637, A253, CADOES1, LNCaPcloneFGC, JHH5, A549, SW579, SW1990, SNU5, NUGC4, NCIH2286, Hs852T, FaDu, NCIH1792, Detroit562, 143B, NCIH2122, SW1088, NCIH2009, Calu3, 7860, OVCAR4, BxPC3, A172, NCIH1993, SNU16, NCIH460, 22Rvl, HT1376, KARPAS299, SJCRH30, NCIH1975, A673, HT29, SKESl, MKN1, DU4475, BT20, A2058, A2780, LCLC97TM1, KATOIII, HGC27, OVCAR5, Da
  • FIG. 17A is a plot showing mean tumor volume (in mm 3 , Y-axis) post tumor implantation (in days, X-axis) in immunocompromised mice implanted with a tumor derived from the LNCaP cell line. Mice were treated with vehicle alone, with Compound #258 at 1 mg/kg Q.D., and with Compound #258 at 3 mg/kg Q.D., as indicated. AR: Androgen Receptor. The figure also shows the mutation cloud generated by the cell model passport applet site (https://cellmodelpassports.sanger.ac.uk/)
  • FIG. 17B is a plot showing mean tumor volume (in mm 3 , Y-axis) post tumor implantation (in days, X-axis) in immunocompromised mice implanted with a tumor derived from the 22rvl cell line. Mice were treated with vehicle alone, with Compound #258 at 1 mg/kg Q.D., and with Compound #258 at 3 mg/kg Q.D., as indicated. The figure also shows the mutation cloud generated by the cell model passport applet site (cellmodelpassports.sanger.ac.uk/). TP53 and Rb1 mutations are highlighted.
  • FIG. 17C is a plot showing mean tumor volume (in mm 3 , Y-axis) post tumor implantation (in days, X-axis) in immunocompromised mice implanted with a tumor derived from the DU- 145 (also referred to as DU145) cell line. Mice were treated with vehicle alone, with Compound #258 at 1 mg/kg Q.D., with Compound #258 at 3 mg/kg Q.D., and with Compound #258 at 6 mg/kg Q.D.as indicated. The figure also shows the mutation cloud generated by the cell model passport applet site (cellmodelpassports.sanger.ac.uk/). TP53 and Rb1 mutations are highlighted.
  • FIG. 18A is a plot showing that DU145 cells exposed to a short-term high dose of #258 undergo cell cycle arrest. DU145 cells were treated with #258 at 20 nM, 200nM and 2 ⁇ M of #258 for 8 hours, subsequently incubated for an additional 64 hours, and assayed for proliferation.
  • FIG. 18B is a plot showing that the expression of the pro-apoptotic marker Caspase 3/7 is increased upon a short-term high dose of Compound #258.
  • DU145 cells were treated with Compound#258 at 20 nM, 200nM and 2 ⁇ M for 8 hours, subsequently incubated for an additional 64 hours, and assayed for Caspase 3/7 expression.
  • FIG. 18C is a plot showing that the expression of the pro-apoptotic marker Caspase 8 is increased upon a short-term high dose of Compound #258.
  • DU145 cells were treated with Compound #258 at 20 nM, 200nM and 2 ⁇ M for 8 hours, subsequently incubated for an additional 64 hours, and assayed for Caspase 8 expression.
  • FIG. 19 is a series of plots showing that Compound #258 causes cytotoxicity in DU-145, BT- 549, NCI-H69 SCLC and HuT-78 cells.
  • Cells were exposed to Compound #258 at a concentration of 6 ⁇ M, 2 ⁇ M, 0.7 ⁇ M, 0.07 ⁇ M, 0.02 ⁇ M, 0.007 ⁇ M and 0.002 ⁇ M for 72 hours (top row) or 120 hours (bottom row); and assayed for their ability to proliferate relative to an untreated control.
  • FIG. 20A is a plot showing that treatment with Compound #258 for 72 hours can induce Caspase 8 activation in NCI-H69 and HuT-78 cells.
  • FIG. 20B is a plot showing that treatment with Compound #258 for 72 hours can induce Caspase 3/7 activation in NCI-H69 and HuT-78 cells.
  • FIG. 21 A is a plot showing that treatment with Compound #258 for 72 hours can induce Caspase 3/7 activation in the SNU-5 cell line.
  • FIG. 2 IB is a plot showing that treatment with Compound #258 for 72 hours can induce Caspase 8 activation in the SNU-5 cell line.
  • FIG. 21 C is a plot showing that treatment with Compound #258 for 72 hours can induce Caspase 3/7 activation in the SNU-16 cell line.
  • FIG. 21D is a plot showing that treatment with Compound #258 for 72 hours can induce Caspase 8 activation in the SNU-16 cell line.
  • FIG. 22 is a Tukey box plot and a flow chart showing that treatment with Compound #258 reduces proliferation in a panel of 500 cancer cell lines. EC50 (in ⁇ M) values from proliferation assays are shown. Proliferation assays were performed in cells after five days treatment with Compound #258, and cells were quantified at the end of treatment using CellTiter-Glo (Promega).
  • FIG. 23A is a plot and picture of a Western blot showing that A-549 cells with intact Rb and p53 treated with Compound #258 undergo G1 phase arrest and cytostasis.
  • FIG. 23B is a series of plots and pictures of immunoblots showing that NCI H82, NCI H69 and DU-145 cells, which have lost Rb and p53 function, undergo checkpoint failure, S-phase perturbation, apoptosis and regression when treated with Compound #258.
  • FIG. 23C is a pair of plots of control and Compound #258 treated DU-145 cells stained with the apoptosis marker Annexin V and analyzed on a Nucleocounter NC-3000 fluorescence reader.
  • FIG. 23D is a plot, a pair of pictures of a immunoblot, and a bar chart showing that A-549 cells with intact Rb and p53 treated with Compound #258 undergo G1 phase arrest and cytostasis, and do not activate caspase 3/7 upon treatment with Compound #258.
  • FIG. 23E is a series of plots, pictures of immunoblots and bar charts showing that NCI H82, NCI H69 and DU- 145 cells undergo checkpoint failure, S-phase perturbation, and apoptosis when treated with Compound #258.
  • FIG. 24A is a plot showing the identification of apoptotic responders (golden bars) from a solid tumor cell line panel. EC50 values (in nM) in cell lines treated with Compound #258 are shown.
  • FIG. 24B is a table showing that treatment with Compound #258 induces apoptosis in cancer cell lines with both Rb and p53 deletions. Gray boxes indicate negative Rb or p53 status for particular cell lines. S-phase arrest was determined by analysis on a Nucleocounter NC-3000 fluorescence reader, and Caspase 3/7 activation by Promega Caspase Glo assay after 24h hours or 72 hours treatment, respectively, with 2, 20 or 200 nM Compound #258.
  • FIG. 25A is a plot showing that sensitivity to treatment with Compound #258 correlates with sensitivity to treatment with cisplatin in a panel of cancer cell lines.
  • FIG. 25B is a plot showing that sensitivity to treatment with Compound #258 correlates with sensitivity to treatment with cisplatin in a panel of cancer cell lines.
  • FIG. 26A is a series of plots and immunoblots showing treatment with Compound #258 induces S-phase deceleration, DNA damage accumulation, and premature progression into mitosis in Rb/p53 -negative small cell lung carcinoma cells.
  • FIG. 26B is a diagram demonstrating the interaction of Compound #258 with the cell cycle machinery in an Rb/p53-negative cell.
  • ATR binds to the N-terminal region of p300 comprising the CHI domain, as do other proteins involved in the DNA damage (DDR) machinery such as NBSl and PARPl.
  • DDR DNA damage
  • FIG. 27A is a plot showing that treatment with Compound #258 induces Caspase 3/7 in Rb/p53 dysfunctional cancer cell lines.
  • FIG. 27B is a plot showing that treatment with Compound #258 induces Caspase 3/7 in Rb/p53 or CDKN2A dysfunctional cancer cell lines.
  • FIG. 28A is a plot showing that treatment in vivo with Compound #258 induces a reduction of tumor volume in a small cell lung carcinoma cell-line derived xenograft model.
  • FIG. 28B is a plot showing that treatment in vivo with Compound #258 induces a dose- dependent reduction of tumor volume in a prostate cancer cell-line derived xenograft model.
  • FIG. 29A is a plot showing that treatment in vivo with Compound #258 induces a dose- dependent reduction of tumor volume in a patient- derived xenograft model of prostate cancer, compared to treatment with enzalutamide.
  • FIG. 29B is a plot showing that treatment in vivo with Compound #258 induces a dose- dependent reduction of tumor volume in a patient- derived xenograft model of prostate cancer.
  • FIG. 30 is a table and diagram showing the potency of Compound #258 in a panel of cell-line derived xenograft models and patient- derived xenograft (PDX) models, and a proposed mechanism of action.
  • PDX patient- derived xenograft
  • FIG. 31 is a diagram showing the differential response of cells lacking Rb and p53 versus cells with intact p53 to treatment with Compound #258.
  • FIG. 32 is a pair of pictures of an immunoblot showing activation of p53 in a cancer cell line with intact p53 signaling pathway following treatment with 20 nM or 700 nM of Compound #258.
  • FIG. 33 is series of pictures of an immunoblot showing increased cyclins in a cancer cell line without intact p53 and Rb signaling following treatment with 200 nM of Compound #258.
  • FIG. 34 is a series of immunoblots showing the expression of cell cycle and checkpoint markers in control cells and cells treated with 200 nM Compound #258.
  • FIG. 35 is a plot and a series of immunoblots showing that Rb and p53 knockout LNCaP cells phenocopy S-phase deceleration in Rb negative, p53 dysfunctional DU- 145 cells.
  • FIG. 36 is a diagram and a table showing that Compound #258 remains potent beyond AR- loss. Lineage plasticity from AR+ Adeno-PC to AR-/independent state (SC/NEPC) is shown.
  • 1 Faivre, E. et al., Nature 2020 578(7794): 3060310.
  • 2 Pegg, N. et al. Poster #3991 AACR2018.
  • 3 Jin, L. et al. Cancer Res 201777(20): 5564-5575.
  • 4 Lasko, L. et al. ACS Med Chem Lett. 2017 9(1): 28- 33.
  • FIG. 37 is a series of three plots showing that Compound #258 inhibits dihydrotestosterone (DHT) induced expression of AR downstream genes. Dose dependent inhibition of the activation of the AR pathway in testosterone stimulated LNCaP cells (androgen sensitive human prostate adenocarcinoma). P300 acts as an AR coactivator.
  • FIG. 38 is a plot showing serum prostate specific antigen (PSA) in a CRPC patient derived xenograft model (#PR6512, Crown Bioscience UK Ltd Hillcrest, Osgathorpe Leicestershire, UK) treated with vehicle or varying concentrations of Compound #258.
  • PSA serum prostate specific antigen
  • FIG. 39 is a plot showing efficacy of Compound #258 in hematological cancer cell lines. IC50 of cells treated with Compound #258 is shown. Blue bars indicate AML/DLBCL cell lines with ASXL1, Runxl and p53 mutations. Combined blue and red bars indicate cell lines with ASXLx/RLNXx paralog alterations.
  • FIG. 40A is a series of pictures of MOLM13-Luciferase AML orthotopic xenograft model mice treated with vehicle alone, or Compound #258 at 3 mg/kg or 6 mg/kg, p.o. Q.D., as indicated, for 19 days.
  • FIG. 40B is a pair of plots showing photons/seconds (top) or animal weight (bottom) of MOLM13-Luc model mice treated with vehicle, or Compound #258 at 3 mg/kg or 6 mg/kg, p.o. Q.D, as indicated.
  • FIG. 40C is a plot showing tissue tumor invasion in the MOLM-Luc model at day 19, in mice treated with vehicle alone, or Compound #258 at 3 mg/kg or 6 mg/kg, p.o. Q.D.
  • FIG. 41 is a plot showing the effect of repeated once weekly administrations of #258 to in vivo mouse CDX prostate cancer models of NCI-H660 cells. Tumor growth curves are presented. The dosing regimens are indicated as dots below the curves and given in writing in the legend of the different study groups.
  • QW once weekly treatment p.o.: per oral.
  • E1A binding protein (p300) and CBP) are two closely related paralog transcriptional co-activators involved in the expression of oncogenic drivers in cancer cells (Attar and Kurdistani, in Cold Spring Harbor Perspectives in Medicine 7:a026534 (2017)), and are thus therapeutic targets for the treatment of cancer.
  • CBP/p300 interact through their conserved domains with hundreds of proteins. CBP/p300 can act synergistically or antagonistically with other proteins, and modulate downstream biological processes in a highly context-dependent manner to promote either apoptosis or cell proliferation (Bedford and co-workers in Epigenetics 5(1): 9 (2010); Goodman and Smolik in Genes & Development 14(13): 1553 (2000); Dancy and Cole in Chemical Reviews 115(6):2419 (2015)).
  • These domains include the nuclear receptor interaction domain (RID), the cysteine/histidine-rich regions CHI (TAZ1) and CH3 (TAZ2) domains, the CREB and MYB interaction domain (KIX), Bromodomain, the plant homeodomain (PHD), the histone acetyltransferase and/or lysine acetyltransferase domain (KAT/HAT), the ZZ type zinc finger domain (ZZ), and the interferon response binding domain (IBiD (NCBD)).
  • RID nuclear receptor interaction domain
  • CHI cysteine/histidine-rich regions
  • TAZ2 CH3
  • KIX CREB and MYB interaction domain
  • KAT/HAT histone acetyltransferase and/or lysine acetyltransferase domain
  • ZZ ZZ type zinc finger domain
  • NCBD interferon response binding domain
  • E2F-1 a central protein in cell cycle regulation that can act through p53 as well
  • Cyclic- AMP response is both induced and repressed by p300/CBP via CREB binding to the KIX domain, respectively S6 kinase pp90RSK binding to the CH3 domain (Nakajima and co-workers in Cell 86:465 (1996)).
  • Modulation of cancer-relevant pathways by p300/CBP include hormone- dependent androgen receptor signaling in prostate cancer (Culig in Journal of Cell Physiology 231(2):270 (2016)); the HIF-1 alpha/VEGF pathway in hypoxia-dependent tumor growth (Masoud and Li in Acta Pharmacologica Sinica B 5(5):378 (2015)); and the interaction with tumor suppressor p53 and HPV- E6 oncoprotein in HPV-positive carcinomas (Tornesello and co-workers in Cancers (Basel) 10(7)pii:E213 (2016)).
  • p53 tumor protein p53
  • Rb Retinoblastoma
  • Rb1 Retinoblastoma
  • compounds of the present disclosure are able to modulate the activity of specific domains, and specific functions of CBP/p300 in a modular fashion.
  • Compounds of formula la can affect specific domains and activities of CBP/p300 while not affecting, or only minimally affecting, other domains and functions of CBP/p300.
  • the CBP/p300 modulators described herein are able to modulate functions mediated by the N-terminal portion of CBP/p300 (comprising the CHI domain) without affecting, or only minimally affecting, functions mediated by other domains such as the histone acetyltransferase (HAT) domain.
  • Exemplary functions mediated by the N-terminal portion of CBP/p300 that can be modulated by the compounds of formula la described herein include, but are not limited to, interaction with DNA damage repair (DDR) proteins such as ATR, NBS1 and PARPl.
  • DDR DNA damage repair
  • the term “modulation” includes the inhibition of one or more functions of CBP/p300, the increase in one or more functions of CBP/p300, or a qualitative change in one or more functions of CBP/p300.
  • p53 and Rb are tumor suppressors that are central to two regulatory pathways critical for the progression of cancer in cells.
  • the p53 pathway plays a role in the regulation cell cycle progression, apoptosis, and genome stability.
  • upstream signals such as DNA damage or stress
  • P14ARF encoded by the CDKN2A locus, also called ARF and pi 4
  • MDM2 proto-oncogene MDM2 proto-oncogene
  • MDM2 MDM2 proto-oncogene
  • p53-specific E3 ubiquitin ligase MDM2 proto-oncogene
  • MDM2 MDM2 proto-oncogene
  • MDM2 MDM2 proto-oncogene
  • p53 also plays a role in the initiation of apoptosis.
  • p53 target genes include CDKN1 A (also called cyclin dependent kinase inhibitor 1A, or WAF1, or p21), an inhibitor of cyclin dependent kinases (CDKs) that regulates the cell cycle, and BAX (BCL2 associated X, apoptosis regulator), which promotes apoptosis.
  • CDKN1 A also called cyclin dependent kinase inhibitor 1A, or WAF1, or p21
  • CDKs cyclin dependent kinases
  • BAX BCL2 associated X, apoptosis regulator
  • P16INK4A also called PI 6, and INK4
  • P16INK4A inhibits CDKs that phosphorylate, and therefore inactivate, Rb1 during the G1 phase of the cell cycle.
  • Rb1 also controls the expression of numerous genes, for example by recruiting transcription factors and chromatin remodeling proteins.
  • Rb1 interacts with the E2F1 transcription factor to regulate genes involved with cellular processes, such as DNA replication and cell cycle progression, to regulate the G1/S phase cell cycle transition.
  • E2F1 transcription factor to regulate genes involved with cellular processes, such as DNA replication and cell cycle progression, to regulate the G1/S phase cell cycle transition.
  • the anti-proliferative effects of the CBP/p300 functional modulators of the instant disclosure may be influenced by the function of the p53 and Rb pathways in cancer cells.
  • treatment of cancer cells with the CBP/p300 modulators described herein can interfere with regulation of CBP/p300 target genes, resulting in cell cycle checkpoint failure at the G1/S phase transition.
  • treatment with CBP/p300 modulators can cause G1 arrest, and cancer cells become senescent, slowing or halting cancer progression.
  • treatment with CBP/p300 modulators can cause catastrophic failure of cell cycle progression during S phase, apoptosis, and cancer regression.
  • CBP/p300 modulators of the disclosure cause catastrophic failure of cell cycle progression during S phase, apoptosis, and regression in cancers with defective p53 and Rb pathways is through the interaction between CBP/p300 inhibition and replication stress.
  • p300/CBP is an important component of the DNA replication and DNA damage repair (DDR) complexes, and interacts with several proteins involved in the cellular DDR machinery.
  • DDR DNA damage repair
  • the CBP/p300 modulators of the disclosure are able to induce synthetic lethality in the context of p53 and Rb loss.
  • the N terminal region of p300 which includes the CHI domain, interacts with DNA damage repair (DDR) proteins such as ATR (Stauffer and co-workers, in Journal of Biological Chemistry 282(13):9678-9687 (2007)), which controls cell cycle and DNA repair checkpoints.
  • DDR DNA damage repair
  • This N terminal region also interacts with additional DDR proteins, such as NBS1 and PARPl.
  • This region is targeted by the CBP/p300 modulators described herein, allowing the CBP/p300 modulators described herein to specifically affect p300 function in DNA replication.
  • the combined loss of Rb and p53 function promotes unrestricted proliferation, causes loss of G1/S cell cycle checkpoint controls and high levels of replication stress.
  • This S/G2 checkpoint may, potentially be deregulated through the interference with the p300/ATR interaction by compounds of formula la.
  • Cancer cells lacking both Rb and p53 function exhibit compromised G1/S checkpoint control and are particularly vulnerable to replication stress.
  • the CBP/p300 modulators described herein induce deceleration of S-phase, accumulation of DNA damage and premature entry into mitosis followed by mitotic catastrophe. Loss of Rb and p53 function is thus predictive for an apoptotic response to treatment with the CBP/p300 modulators of the instant disclosure, translating into tumor regression in xenograft models of cancers, such as prostate, gastric and small cell lung cancer.
  • the CBP/p300 modulators described herein can modulate the p300/CBP CHI interactome, enabling a tumor-agnostic precision oncology approach for treatment of cancers with high levels of replication stress.
  • Cancers susceptible to the CBP/p300 modulators of the disclosure include cancers that are deficient in DNA repair.
  • CBP/P300 modulators of the disclosure castrate resistant prostate cancer
  • CRPC castrate resistant prostate cancer
  • AR androgen receptor
  • p300 has been associated with tumor progression and poor prognosis in prostate cancer.
  • p300 expression is increased upon ADT and docetaxel treatment.
  • CRPC combined loss of Rb and p53 is a frequent event in resistance development to AR-pathway inhibitors and indicative of lineage plasticity.
  • the CBP/p300 modulators of the disclosure have been found to be efficacious at all levels of lineage plasticity, and to trigger tumor regression in multi-drug resistant patient-derived xenograft models.
  • the disclosure provides methods of treating a cancer in a subject comprising (a) determining the activity or expression of at least one gene in a cancer cell of the subject, wherein the at least one gene is part of the p53 and/or Rb signaling pathways; and (b) administering a CBP/p300 modulator, for example a compound of formula la to the subject when the activity or expression of the at least one gene in the cancer cell is different from the activity or expression of the at least one gene in a non-cancerous control cell.
  • the at least one gene is p53, CDKN1A, Rb1, CDKN2A, or a combination thereof, and the activity, expression or function of the at least one gene is impaired in the cancer cell of the subject.
  • Further types of cancers which can be treated using the compounds of the disclosure include hematological cancers. Changes in p53, RBI, ASXL1, RUNX1, and paralogs of ASXL1 and RUNX1, are correlated with the susceptibility hematological cancers to the compounds of the disclosure. In some embodiments, changes in p52, ASXL1, RUNX1, and paralogs of ASXL1 and RUNX1, are correlated with the susceptibility of hematological cancers to the compounds of the disclosure.
  • the term “gene” has its meaning as understood in the art. However, it will be appreciated by those of ordinary skill in the art that the term “gene” may include gene regulatory sequences (e.g., promoters, enhancers, etc.) and/or intron sequences. It will further be appreciated that definitions of gene include references to nucleic acids that do not encode proteins but rather encode functional RNA molecules such as long non-coding RNAs (IncRNAs). For clarity, the term gene generally refers to a portion of a nucleic acid that encodes a protein; the term may optionally encompass regulatory sequences.
  • Gene has its meaning as understood in the art. However, it will be appreciated by those of ordinary skill in the art that the term “gene” may include gene regulatory sequences (e.g., promoters, enhancers, etc.) and/or intron sequences. It will further be appreciated that definitions of gene include references to nucleic acids that do not encode proteins but rather encode functional RNA molecules such as long non-coding RNAs (IncRNA
  • the term as used in this document refers to a protein coding nucleic acid.
  • the gene includes regulatory sequences involved in transcription, or message production or composition.
  • the gene comprises transcribed sequences that encode for a protein, polypeptide or peptide.
  • the transcribed nucleotide sequence comprises at least one functional protein, polypeptide and/or peptide encoding unit.
  • this functional term “gene” includes both genomic sequences, RNA or cDNA sequences, or smaller engineered nucleic acid segments, including nucleic acid segments of a non-transcribed part of a gene, including but not limited to the non-transcribed promoter or enhancer regions of a gene.
  • the sequences which are located 5' of the coding region and which are present on the mRNA are referred to as 5' untranslated sequences (“5'UTR”).
  • the sequences which are located 3' or downstream of the coding region and which are present on the mRNA are referred to as 3' untranslated sequences, or (“3'UTR”).
  • pathway is intended to mean a set of system components involved in two or more sequential molecular interactions that result in the production of a product or activity.
  • a pathway can produce a variety of products or activities that can include, for example, intermolecular interactions, changes in expression of a nucleic acid or polypeptide, the formation or dissociation of a complex between two or more molecules, accumulation or destruction of a metabolic product, activation or deactivation of an enzyme or binding activity.
  • pathway includes a variety of pathway types, such as, for example, a biochemical pathway, a gene expression pathway, and a regulatory pathway.
  • a pathway can include a combination of these exemplary pathway types.
  • the disclosure provides methods of determining the susceptibility of a cancer to a compound of formula la comprising assaying the activity, expression or function of one or more p53 and/or Rb signaling pathway genes in a cancer cell and a non-cancerous control cell, and comparing the activity, expression or function of one or more p53 and/or Rb signaling pathway genes between the cancer cell and the control cell. Changes in p53 and/or Rb signaling are correlated with the susceptibility cancers to CBP/p300 modulators, such as compounds of formula la. In some embodiments, for example those embodiments where the cancer cell comprises dysfunction p53 and/or Rb pathway genes, a therapeutically effective amount of a CBP/p300 modulator as described herein is administered to the subject.
  • Any genes involved in the p53 and/or Rb signaling pathways whose altered expression, activity or function is correlated with susceptibility of cancer cells to the CBP/p300 modulators described herein is envisaged as within the scope of the instant disclosure.
  • Any genes involved in DNA damage repair (DDR), including genes in the p53 and/or Rb signaling pathways, are envisaged as within the scope of the instant disclosure.
  • Members of the p53 and Rb signaling pathways include, but are not limited to, upstream regulators of p53 and Rb, interaction partners of p53 and Rb, and downstream targets of p53 and Rb.
  • Members of the p53 and Rb pathways, as well as additional DDR genes, are described in Table 1 below. Additional p53 transcriptional target genes are described in Table 2. Any gene described in Table 1 or Table 2 is envisaged as within the scope of the instant disclosure.
  • activatory signals stabilize p53 protein through phosphorylation.
  • p53 is degraded following MDM2-mediated ubiquitination.
  • Signals that activate p53 such as stress, oncogenic activation, or DNA damage, induce stabilization of the p53 protein through phosphorylation by protein kinases including ATM, ATR, Chkl, Chk2 and others. This phosphorylation also promotes binding of p53 to DNA (e.g., at p53 target promoters).
  • the ARF product of the CDKN2A locus also regulates p53 by inhibiting MDM2 regulation of p53, stabilizing p53 as a result. DNA-bound p53 then recruits the transcriptional machinery to activate transcription of p53 target genes.
  • Genes upstream of P53 include, but are not limited to, genes involved in extracellular matrix interactions, hypoxia response, DNA damage response, response to microtubule disruption, regulators of cellular reduction-oxidation states, and regulators of cellular metabolism.
  • Exemplary genes upstream of p53 include, but are not limited to MDM2, and the p14ARF product of the CDKN2A locus.
  • Genes that interact with p53 include, but are not limited to, genes that regulate post- translational modification of p53, genes that inhibit p53 or regulate its interaction with inhibitors, and genes that function as co-factors for p53 or regulate the interaction of p53 with co-factors. Both direct and indirect interactions are within the scope of the instant disclosure.
  • genes involved in the post translational modification of p53 include, but are not limited to, casein kinase 1 alpha 1 (CK1), casein kinase 2 alpha 1 (CK2), kinases such as ATM, ATR, Chkl and Chk2, Pint, DYRK2, HIPK2, MDM2, Copl, ARF, MSL2, TIP60, MOF and CBP/p300.
  • CK1 casein kinase 1 alpha 1
  • CK2 casein kinase 2 alpha 1
  • kinases such as ATM, ATR, Chkl and Chk2, Pint, DYRK2, HIPK2, MDM2, Copl, ARF, MSL2, TIP60, MOF and CBP/p300.
  • CK1 casein kinase 1 alpha 1
  • CK2 alpha 1 kinases
  • kinases such as ATM, ATR, Chkl and Chk2
  • Pint DYRK2
  • p53 generally functions as a transcriptional activator.
  • p53 transcriptional targets include, but are not limited to, genes involved in cell cycle regulation, apoptosis, senescence, genetic stability, cell adhesion, motility, invasion, epithelial to mesenchymal transition (EMT) and angiogenesis.
  • p53 target genes are described in Table 2, below. These include, but are not limited to, target genes involved in cell cycle regulation, such as CDK1, Cyclin A2, E2F7, BTG2, GADD45A, SFN (Stratifin), and CDKN1A; translation control, such as SESN1 and SESN2 (sestrin 2); apoptosis, such as TNFRSF10A-D, TRAF4, PERP, BBC3, PMAIP1, TRIAPl, SUSD6, FAS, BAX, APAFl and AEN; metabolism, such as GLS2, FDXR, FUCA1, PRKAB1, TIGAR and PANK1; autophagy, such as PRKAB1 and DRAM1; and regulation of p53 through feedback mechanisms, such as MDM2, CCNG1 and PPM1D.
  • MMPs matrix metalloproteinases
  • Rb1 signaling genes are provided in Table 1 below.
  • the Rb tumor suppressor gene originally identified in a retinoblastoma, is functionally inactivated cancer cells with high frequency in a majority of human cancers.
  • Mammalian Rb1 is a member of a family of three related proteins, Rb1, pi 07 and pi 30. Phosphorylation plays a key role in regulating Rb family members.
  • Rb1 contains numerous phosphorylation sites that are phosphorylated by cyclin D/CDK4/6, cyclin E/CDK2, and cyclin A/CDK2 complexes during cell cycle progression.
  • hypophosphorylated Rb1 acts to inhibit cell proliferation and tumor suppression, while hyperphosphorylated Rb1 is less active, or inactive.
  • Rb proteins play an important role in regulating the G1 to S phase transition during the cell cycle.
  • Rb family members are hypophosphorylated and associate with E2F transcription factors to prevent the expression of cell cycle expression genes.
  • cyclin D and CDK4/6 promote the hyperphosphorylation of Rb family proteins. This results in dissociation of the Rb protein from E2F transcription factors, and allows progression through G1 and eventually S- phase entry.
  • Rb1 recruits chromatin remodeling factors needed to regulate the expression of genes required for S-phase entry, including histone deacetylases, the SWI/SNF chromatin remodeling complex, and helicases involved in chromatin remodeling such as Brgl and Brm.
  • Rb1 may also regulate transcription via chromatin methylation, which inhibits transcription, and play a role in initiating DNA replication during S-phase.
  • Rb1 also regulates senescence in cells. Under stress conditions, the CDKN2A gene product pl6INK is upregulated, leading to Rb1 upregulation. This leads to chromatin reorganization, repression of E2F target genes, and exit from the cell cycle into senescence. Without wishing to be bound by theory, it is thought that one way that Rb signaling may prevent proliferation of cancer cells is through the promotion of cellular senescence in cancer cells.
  • Rb signaling also likely plays a direct role in regulating cellular differentiation, by interacting not just with E2F family transcription factors, but other developmental transcription factors as well. Without wishing to be bound by theory, it is thought that another way Rb signaling may prevent cancer cell proliferation is by activating cellular differentiation pathways. This causes cancer cells to undergo terminal differentiation and stop proliferating. For example, mutation of Rb in mouse lungs led to more neuroendocrine cell differentiation, which suggested that Rb can regulate differentiation in lung cells by specifically inhibiting neuroendocrine cell fate (Wilkenheiser-Brokamp, K.A., Development, 2004, 131:4299).
  • CBP/p300 modulators described herein can induce apoptosis.
  • Cellcentric’ s bromodomain inhibitor CCS 1477 was able to achieve a weak IC50 of 1.3 ⁇ M in DU145 cells. All of these molecules were tested in cancers where CBP or p300 defects occur frequently (such as bladder or hematological cancers), or in cancers where p300/CBP-mediated acetylation (for example, androgen receptor acetylation in prostate cancer) is crucial.
  • lesions in tumor suppressors such as p53 and Rb1 are commonly considered to contribute to more aggressive and advanced staged cancers, which are less responsive to therapies (see, for example, Beltran (Nat Med. 2016 March ; 22(3): 298-305; for a discussion of the evolution of therapy resistant prostate cancer with loss of RBI and mutation/loss of p53).
  • Beltran Nap300 or CBP (doubleknock outs are not viable), or to tumors driven by androgen receptor (acetylation), such as prostate cancer, to look for genetic markers associated with a positive therapeutic response to CBP/p300 modulation.
  • the disclosure provides methods of determining the susceptibility of a subject with a cancer, or determining the effectiveness of CBP/p300 modulator of formula la in treating a cancer, comprising: (a) determining the activity, function or expression of at least one p53 or Rb pathway gene in a cancer cell of the subject, where dysregulation or loss of function of p53 or Rb pathway signaling indicates that the cancer will respond to treatment with the CBP/p300 modulators of formula la described herein.
  • the disclosure also provides methods of treating a subject with a cancer, comprising: (a) determining the activity or expression of at least one gene in a cancer cell of the subject, wherein the at least one gene is selected from the group of genes disclosed in Table 1 and Table 2; and (b) administering a CBP/p300 modulator of formula la to the subject when the activity or expression of the at least one gene in the cancer is different from the activity or expression of the at least one gene in non-cancerous control cells.
  • the at least one gene comprises Fc-ABL, ASPP1, ASPP2, AKT1, APAFl, ATM, ATR, Bakl, BAX, Bcl2, Bcl2Ll, BID, BRCA1, BP1, DDR1, DYRK2, CDK4, CDK6, CDKN1A, CDKN2A, FOS, CHK1, CHK2, COP1, CSNK1, Cyclin D, Cyclin E, CYCS, E2F1, ERK2, GADD45A, GSK3B, H19, HDAC1, fflFla, HIPK2, INK, JMY, Lmc-ROR, MALAT-1, MDM2, MDMX, MEG3, MOF, MSL2, NBS1, NOXA, p38, p53, PARPl, PCAF, PIAS1, PIGS, PML, PTEN, PUMA, SIRT1, SIRT2, STRAP,
  • the at least one gene comprises at least two genes, and the at least two genes comprise at least one gene selected from the group consisting of c- ABL, ASPP1, ASPP2, AKT1, APAFl, ATM, ATR, Bakl, BAX, Bcl2, Bcl2Ll, BID, BRCA1, BP1, DDR1, DYRK2, CDK4, CDK6, CDKN1A (p21), FOS, CHK1, CHK2, NBS1, PARPl, COP1, CSNK1, Cyclin D, Cyclin E, CYCS, E2F1, ERK2, GADD45A, GSK3B, H19, HDAC1, fflFla, HIPK2, JNK, JMY, Lmc-ROR, MALAT-1, MDM2, MDMX, MEG3, MOF, MSL2, NOXA, p38, p53, PCAF, PIAS1, PIGS, PML, PTEN
  • the at least one gene comprises FOXM1, c-Myc, APAFl, Ampk-alpha2, ASPP2, ATM, Bim, BRG1, Bmi-1, BRM, CASP3, CASP7, CASP8, CASP9, CDC6, CDK1, CDK2, CDK4, CDK6, CDKN1B, CDKN2A, CDKN2B, CDKN2C, CHK1, CHK2, NBSl, PARPl, Cyclin A, Cyclin D, Cyclin E, E2F1, E2F2, E2F3, E2F4, E2F5, E2F6, E2F7, E2F8, Emi-1, HDACl, HELLS, Pol alpha, Pbxl, pl07, pl30, p73, Ras, Rb1, Sival or Tk.
  • the at least one gene comprises at least two genes, and the at least two genes comprise at least one gene selected from the group consisting of FOXMl, c-Myc, APAFl, Ampk- alpha2, ASPP2, ATM, Bim, BRG1, Bmi-1, BRM, CASP3, CASP7, CASP8, CASP9, CDC6, CDK1, CDK2, CDK4, CDK6, CDKN1B, CDKN2B, CDKN2C, CHK1, CHK2, NBSl, PARPl, Cyclin A, Cyclin D, Cyclin E, E2F1, E2F2, E2F3, E2F4, E2F5, E2F6, E2F7, E2F8, Emi-1, HDACl, HELLS,
  • the at least one gene comprises one gene selected from the group consisting of c-ABL, ASPP1, ASPP2, AKT1, APAFl, ATM, ATR, Bakl, BAX, Bcl2, Bcl2Ll, BID, BRCA1, BP1, DDR1, DYRK2, CDK4, CDK6, CDKN1A (p21), CDKN2A, FOS, CHK1, CHK2, NBSl, PARPl, COP1, CSNK1, Cyclin D, Cyclin E, CYCS, E2F1, ERK2, GADD45A, GSK3B, H19, HDACl, fflFla, HIPK2, JNK, JMY, Lmc-ROR, MALAT-1, MDM2, MDMX, MEG3, MOF, MSL2, NOXA, p38, p53, PCAF, PIAS1, PIGS, PML, PTEN, PUMA, SIRT1, SIRT2, STRAP, T
  • the at least one gene comprises Rb1, CDKN2B, CDKN2C, BRG1, BRM, Cyclin D1, CDK4, CDK6, E2F1, FOXM1, c-Myc, or HD AC 1.
  • the difference in the activity or expression of the at least one gene comprises a loss of expression or function of Rb1, CDKN2A, CDKN2B, CDKN2C, BRG1 or BRM, or an increase of expression or function of Cyclin D1, E2F1, or HDACl.
  • the at least one gene comprises p53, CDKN1A, ATM, ATR, CHK1, CHK2, NBS1, PARPl, c-Abl or MDM2.
  • the difference in the activity or expression of the at least one gene comprises a loss of expression or function of p53, CDKN1A, ATM, ATR, CHK1, CHK2, NBS1, PARPl, or c-Abl, or an increase in expression or function of MDM2.
  • the at least one gene comprises CDKN2A.
  • the CDKN2A gene encodes several proteins, including P16INK4A (also called pi 6, INK4, INK4A and pl6INK4A) and pl4ARF (also called pl4 and ARF).
  • P16INK4A binds to CDK4/6, while pl4ARF prevents p53 degradation.
  • An exemplary human P16INK4A amino acid sequence is provided below:
  • CDKN2A transcripts include, but are not limited to the non-coding RNAs CDKN2B antisense RNA 1 (CKN2B-AS1), and the proteins p14ARF, P16INK4A, isoform p12, isoform p16 and any additional isoforms thereof. All transcript variants and proteins products of CDKN2A are envisaged as within the scope of the disclosure.
  • the change in function, activity or expression of the at least one gene comprises a change in function, activity or expression of CDKN2A.
  • the change in function, activity or expression of CDNKN2A comprises a mutation in the CDKN2A gene. Mutations that alter CDKN2A function can be substitutions, insertions, deletions or inversions.
  • the change in function, activity or expression of CDKN2A comprises a mutation in SEQ ID NO: 4 or SEQ ID NO: 6.
  • Mutations can be in CDKN2A protein coding sequences, e.g., SEQ ID NO: 4 or SEQ ID NO: 6, or in non-coding sequences such as promoters, introns or cis- regulatory elements.
  • the mutation in the CDKN2A protein coding sequence is non-synonymous, i.e. causes a change in the amino acid sequence of SEQ ID NO: 3 or SEQ ID NO: 5, or causes a mis-sense mutation, frameshift mutation or premature stop in SEQ ID NO: 3 or SEQ ID NO: 5.
  • the at least one gene comprises Rb1.
  • the human Rb1 gene is described in part at ncbi.nlm.nih.gov as NCBI Reference Sequence NG 009009.1, the contents of which are incorporated by reference in their entirety herein.
  • An human exemplary Rb1 amino acid sequence is provided below:
  • An exemplary human Rb1 nucleotide sequence comprises SEQ ID NO: 8.
  • the change in function, activity or expression of the at least one gene comprises a change in function, activity or expression of Rb1.
  • the change in function, activity or expression of Rb1 comprises a mutation in the Rb1 gene. Mutations that alter Rb1 function can be substitutions, insertions, deletions or inversions in Rb1 gene sequences.
  • the change in function, activity or expression of Rb1 comprises a mutation in SEQ ID NO: 8. Mutations can be in Rb1 protein coding sequences, e.g., SEQ ID NO: 8, or in non-coding sequences such as promoters, introns or cis-regulatory elements.
  • the mutation in the Rb1 protein coding sequence is non-synonymous, i.e. causes a change in the amino acid sequence of SEQ ID NO: 7, or causes a mis-sense mutation, frameshift mutation or premature stop in SEQ ID NO: 7.
  • the at least one gene comprises p53.
  • the human p53 gene is described in part at ncbi.nlm.nih.gov as NCBI Reference Sequence NG 017013.2, the contents of which are incorporated by reference in their entirety herein.
  • the p53 locus encodes multiple isoforms of p53, all of which are considered as within the scope of the instant disclosure.
  • An human exemplary p53 amino acid sequence is provided below:
  • An exemplary human p53 nucleotide sequence comprises SEQ ID NO: 10.
  • the change in function, activity or expression of the at least one gene comprises a change in function, activity or expression of p53.
  • the change in function, activity or expression of p53 comprises a mutation in the p53 gene. Mutations that alter p53 function can be substitutions, insertions, deletions or inversions in p53 gene sequences.
  • the change in function, activity or expression of p53 comprises a mutation in SEQ ID NO: 10. Mutations can be in p53 protein coding sequences, e.g., SEQ ID NO: 9, or in non-coding sequences such as promoters, introns or cis-regulatory elements.
  • the mutation in the p53 protein coding sequence is non-synonymous, i.e. causes a change in the amino acid sequence of SEQ ID NO: 9, or causes a mis-sense mutation, frameshift mutation or premature stop in SEQ ID NO: 9.
  • the at least one gene comprises CDKN1A (also called p21).
  • CDKN1A also called p21.
  • the human CDKN1A gene is described in part at ncbi.nlm.nih.gov as NCBI Reference Sequence NG_009364.1, the contents of which are incorporated by reference in their entirety herein.
  • the CDKN1A locus encodes multiple isoforms of CDKN1 A, all of which are considered as within the scope of the instant disclosure.
  • An human exemplary CDKN1 A amino acid sequence is provided below:
  • An exemplary human CDKN1A nucleotide sequence comprises SEQ ID NO: 12.
  • the change in function, activity or expression of the at least one gene comprises a change in function, activity or expression of CDKN1A.
  • the change in function, activity or expression of CDKN1A comprises a mutation in the CDKN1 A gene.
  • Mutations that alter CDKN1A function can be substitutions, insertions, deletions or inversions in CDKN1A gene sequences.
  • the change in function, activity or expression of CDKN1 A comprises a mutation in SEQ ID NO: 12.
  • Mutations can be in CDKN1A mRNA or protein coding sequences, e.g., SEQ ID NO: 12, or in non-coding sequences such as promoters, introns or cis- regulatory elements.
  • the mutation in the CDKN1 A protein coding sequence is non-synonymous, i.e. causes a change in the amino acid sequence of SEQ ID NO: 11, or causes a mis- sense mutation, frameshift mutation or premature stop in SEQ ID NO: 11.
  • the at least one gene comprises (a) Rb1, CDKN2B, CDKN2C, BRG1, BRM, Cyclin D1, CDK4, CDK6, E2F1 or HDAC1; and (b) p53, CDKN1A, ATM, ATR, CHK1, CHK2, NBSl, PARPl, c-Abl or MDM2.
  • the at least one gene further comprises CDKN2A.
  • the at least one gene comprises p53, Rb1 and CDKN2A.
  • the at least one gene comprises p53 or CDKN1A, Rb1 and CDKN2A.
  • the at least one gene comprises (a) Rb1, CDKN2B, CDKN2C, BRG1, BRM, Cyclin D1, CDK4, CDK6, E2F1 or HDAC1, 53, CDKN1A, ATM, ATR, CHK1, CHK2,
  • NBSl, PARPl, c-Abl or MDM2; and CDKN2A are examples of CDKN2A.
  • the difference in the activity or expression of the at least one gene comprises: (a) a loss of expression or function of Rb1, CDKN2A, CDKN2B, CDKN2C, BRG1 or BRM, or an increase of expression or function of Cyclin D1, E2F1 or HDAC1; and (b) a loss of expression or function of p53, CDKN1A, ATM, ATR, CHK1, CHK2, NBSl, PARPl, or c-Abl, or an increase in expression or function of MDM2.
  • the at least one gene comprises one of: (a) p53 and CDKN2A; (b) CDKN1A and CDKN2A; (c) Rb1 and CDKN2A; (d) p53 and Rb1; (e) CDKN1A and Rb1; (f) CDKN1A, Rb1 and CDKN2A; or (g) p53, Rb1 and CDKN2A.
  • the difference in the activity or expression of the at least one gene comprises a loss in activity or expression of any one or more of p53, CDKN1A, Rb1 or CDK2NA.
  • At least one gene comprises p53 and Rb1, and the difference in activity or expression of the at least one gene comprises a loss of expression or function of Rb1 and p53.
  • the disclosure provides methods of determining the susceptibility of a hematological cancer to a CBP/p300 modulator of formula la comprising assaying the activity, expression or function of p53 signaling pathway gene in a cancer cell and a non-cancerous control cell, optionally assaying the activity, expression or function of ASXL1 or a paralog thereof, or RUNXl or a paralog thereof, in a cancer cell and a non-cancerous control cell, and comparing the activity, expression or function of a p53 signaling pathway gene and ASXL1 or a paralog thereof, or RUNXl or a paralog thereof, between the cancer cell and the control cell.
  • the methods comprise assaying the activity, expression of function of p53, and both ASXL1 or a paralog thereof, and RUNXl or a paralog thereof. In some embodiments, the methods comprise assaying the activity, expression of function of p53, ASXLl and RUNXl. In other aspects, the methods comprise assaying the activity of p53, and ASXLl or a paralog thereof. In still further aspects, the methods comprise assaying the activity of p53 and RUNXl or a paralog thereof. Changes in p53, ASXLl and RUNXl are correlated with the susceptibility hematological cancers to CBP/p300 modulators.
  • ASXL transcriptional regulator 1 is a chromatin binding protein and member of the Polycomb group of proteins, which are necessary for maintaining stable repression of certain genes.
  • ASXLl paralogs include, but are not limited to, ASXL transcriptional regulator 2 (ASXL2) and ASXL transcriptional regulator 3 (ASXL3).
  • the human ASXLl gene is described in part at ncbi.nlm.nih.gov as NCBI Reference Sequence NP_056153.2, the contents of which are incorporated by reference in their entirety herein.
  • An exemplary human ASXLl isoform 1 sequence comprises a sequence of:
  • VNVTPSSTPE S SPTDCLQNR AFDDELGLGG SCPPMRESDT RQENLKTKAL VSNSSLHWI P
  • An exemplary ASXL1 isoform 1 nucleotide sequence comprises a sequence of SEQ ID NO: 14.
  • the change in function, activity or expression of the at least one gene comprises a change in function, activity or expression of ASXL1 or a paralog thereof.
  • the change in function, activity or expression of ASXL1 or a paralog thereof comprises a mutation in the ASXL1 gene or a paralog thereof. Mutations that alter the function of ASXL1 or a paralog thereof can be substitutions, insertions, deletions or inversions in ASXL1 or a paralog gene sequences.
  • the change in function, activity or expression of ASXL1 or a paralog thereof comprises a mutation in protein coding sequences, or in non-coding sequences such as promoters, introns or cis-regulatory elements.
  • the mutation in the ASXL1 or a paralog thereof protein coding sequence is non-synonymous, i.e. causes a change in the amino acid sequence, or causes a mis-sense mutation, frameshift mutation or premature stop in the amino acid sequence.
  • the change in function, activity or expression of ASXL1 comprises a mutation in SEQ ID NO: 14. Mutations can be in ASXL1 mRNA or protein coding sequences, e.g., SEQ ID NO: 14, or in non-coding sequences such as promoters, introns or cis-regulatory elements.
  • the mutation in the ASXL1 protein coding sequence is non-synonymous, i.e. causes a change in the amino acid sequence of SEQ ID NO: 13, or causes a mis-sense mutation, frameshift mutation, premature stop or truncation in SEQ ID NO: 13.
  • the mutation of ASXL1 is a gain of function mutation of SEQ ID NO: 13.
  • RUNX family transcription factor 1 is a heterodimeric transcription factor that can make up part of the core transcriptional machinery. RUNX1 can be transcribed from two alternative promoters, and also undergo alternative splicing. All RUNX1 isoforms and transcripts are envisaged as within the scope of the instant disclosure.
  • RUNXl paralogs include, but are not limited to, RUNX family transcription factor 2 (RUNX2), and RUNX family transcription factor 3 (RUNX3).
  • the human RUNX1 gene is described in part at ncbi.nlm.nih.gov as NCBI Reference Sequence AAI44054.1, the contents of which are incorporated by reference in their entirety herein.
  • An exemplary human RUNXl isoform 1 sequence comprises a sequence of:
  • ASXL1 isoform 1 nucleotide sequence comprises a sequence of SEQ ID NO: 16.
  • the change in function, activity or expression of the at least one gene comprises a change in function, activity or expression of RUNXl or a paralog thereof.
  • the change in function, activity or expression of RUNX1 or a paralog thereof comprises a mutation in the ASXL1 gene or a paralog thereof. Mutations that alter the function of ASXL1 or a paralog thereof can be substitutions, insertions, deletions or inversions in RUNXl or a paralog gene sequences.
  • the change in function, activity or expression of RUNX1 or a paralog thereof comprises a mutation in protein coding sequences, or in non-coding sequences such as promoters, introns or cis-regulatory elements.
  • the mutation in the RUNXl or a paralog thereof protein coding sequence is non-synonymous, i.e. causes a change in the amino acid sequence, or causes a mis-sense mutation, frameshift mutation or premature stop in the amino acid sequence.
  • the change in function, activity or expression of RUNXl comprises a mutation in SEQ ID NO: 16.
  • Mutations can be in ASXL1 mRNA or protein coding sequences, e.g., SEQ ID NO: 16, or in non-coding sequences such as promoters, introns or cis-regulatory elements.
  • the mutation in the ASXL1 protein coding sequence is non-synonymous, i.e. causes a change in the amino acid sequence of SEQ ID NO: 15, or causes a mis-sense mutation, frameshift mutation or premature stop in SEQ ID NO: 15.
  • the disclosure also provides methods of treating a subject with a cancer with a compound of formula la, or predicting the susceptibility of a cancer to compound of formula la comprising determining the activity or expression of at least on P53 pathway gene as disclosed in Tables 1 and 2; and determining the activity or expression of at least one of an Rb pathway gene as disclosed in Table 1, a DDR gene as disclosed in Table 1, RUNXl or a paralog thereof, or ASXL1 or a paralog thereof.
  • the methods comprise determining the activity or expression of p53, and at least one of the Rb pathway genes as disclosed in Table 1, NBS1, PARPl, RUNXl or a paralog thereof, or ASXL1 or a paralog thereof.
  • the methods comprise determining the activity or expression of p53, and at least one of Rb1, RUNXl or a paralog thereof, or ASXLl or a paralog thereof. In some embodiments, the methods comprise determining the activity or expression of p53, and at least one of Rb1, RUNXl or ASXLl. In some embodiments, the methods comprise determining the activity or expression of p53 and Rb1, or p53, RUNXl and ASXLl. In some embodiments, the methods further comprise administering a compound of formula la to the subject.
  • Differences in activity, expression or function of genes in the Rb and/or p53 pathways, as well as RUNXl, ASXLl or paralogs thereof, between cancer and control cells include, but are not limited to increases and decreases in the levels of protein or RNA products encoded by genes, changes in levels of non-coding RNAs encoded by genes, changes protein modification status, and mutations in the genes in the pathways.
  • protein modification refers to addition of a peptidic or non-peptidic moiety to a protein that cannot be considered as the elongation of the peptidic chain of the protein.
  • the addition of the peptidic or non-peptidic moiety can be in vivo or in vitro.
  • the peptidic or non-peptidic moiety can be added to a pure protein or a protein or peptidic component of a complex containing such protein or peptide. Protein modification frequently occur post-translationally.
  • Exemplary post- translational protein modification include phosphorylation, acetylation, methylation, ADP- ribosylation, SUMOylation, ubiquitination, addition of a polypeptide side chain, addition of a hydrophobic group, and addition of a carbohydrate.
  • Phosphorylation can include phosphorylation of a tyrosine, serine, threonine or histidine.
  • Protein modifications can contribute to the activity of the protein.
  • protein phosphorylation is a common mechanism for switching a protein from its active state to an inactive state.
  • phosphorylation of Rb1 modulates its interaction with E2F family transcription factors.
  • acetylation of p53 is associated with a change of its transcriptional activity after DNA damage.
  • Changes in expression, activity and function of p53 and/or Rb pathway genes, as well as RUNXl, ASXL1 or paralogs thereof, can include changes in the expression of the RNA product encoded by the gene or genes.
  • RNAs include protein coding RNAs (messenger RNAs, or mRNAs) and non-coding RNAs such as long non-coding RNAs (IncRNAs).
  • Changes in expression can be quantitative, i.e., a decrease or increase in the level of the RNA in a cancer cell relative to a control cell, or qualitative, i.e. the expression of an RNA in a cell type that does not normally express the RNA in the control cells, or the loss of expression of an RNA in a cell that normally expresses the RNA (i.e., in the control cells).
  • RNA or protein expression level can be caused by many mechanisms, all of which are envisaged as within the scope of the instant disclosure. For example, increased copy number (expansion) of genes can cause increased expression, while decreases in copy number can cause decreases in expression. Changes in epigenetic modification of DNA, e.g. in histone methylation, ubiquitination, phosphorylation, or acetylation, or mutational changes in non-coding sequences, such as regulatory elements, can also cause changes in gene expression, as can mutations in regulatory regions of genes. Loss of expression can be full, or can be partial.
  • a loss of expression in cancer cells can be a loss of at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% of the expression when compared to expression in non- cancerous control cells.
  • Loss of expression can also be complete loss of expression (100%).
  • Expression, activity and function of p53 and/or Rb pathway genes can be modified by mutation of the genes themselves.
  • the mutation, or mutations can be an insertion, a deletion, a point mutation, an inversion or a combination thereof.
  • Mutations in p53 and/or Rb pathway genes can occur in protein coding sequences (i.e., exons), or in non-coding sequences such as cis-regulatory sequences, introns, promoters, or intergenic regions. Mutations in coding sequences include missense, frameshift mutations, nonsense mutations and mutations that introduce premature stop codons resulting in truncated protein products.
  • mutations can be loss of function, or gain of function, mutations.
  • Loss of function can be partial, i.e. a partial reduction in function, or complete (a null mutation).
  • a loss of function in cancer cells can be a loss of at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% of the function when compared to expression in non-cancerous control cells.
  • Loss of function can also be complete loss of function (100%).
  • Cancer cells can be heterozygous for mutations in p53 and/or Rb pathway genes, as well as RUNX1, ASXL1 or paralogs thereof, homozygous, or hemizygous. Mutations in these genes can be present in some, or all, of the cells of the cancer. For example, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95% or about 99% of the cancer cells may carry a mutation in a p53 or Rb pathway gene as described herein.
  • mutations include missense, nonsense and frameshift mutations in exons 5-8 of p53, which are frequently identified in cancers.
  • determining the activity or expression of at least one gene comprises measuring a level of mRNA expression of the at least one gene, measuring protein expression of the at least one gene, determining a genomic or mRNA sequence of the at least one gene, measuring a post- translational modification in the protein product of the at least one gene, or measuring a change in epigenetic modification of the at least one gene.
  • Levels of p53 and/or Rb pathway proteins, DDR proteins, or ASXL1, RLJNX l or paralogs thereof can be quantified by any method known in the art, including but not limited to, mass spectrometry, Western blot, IBC or ELISA. Means for determining the levels of the proteins of the present disclosure include, but are not limited to, the methods disclosed herein, and their equivalents. [0197] In some embodiments, p53 and/or Rb pathway protein levels, levels of DDR proteins, or levels of ASXL1, RUNXl or paralogs thereof, are determined by Western blot (immunoblot), for example as follows.
  • Samples derived from cancer cells and, optionally, control cells are electrophoresed on 10% sodium dodecyl sulfate polyacrylamide gel (SDS-PAGE) and transferred (e.g. electroblotted) onto nitrocellulose or polyvinylidene fluoride (PVDF) some other suitable membrane.
  • the membrane is then incubated with a primary antibody that binds to the protein being evaluated, washed, optionally incubated with a detectably labeled secondary antibody that binds to the primary antibody, and optionally washed again.
  • the presence of the secondary antibody is then detected (or primary antibody if it is detectably labeled), for example by radioactivity, fluorescence, luminescence, enzymatic activity (e.g.
  • the detectable label is used to produce an autoradiograph, which is scanned and analyzed.
  • the gel is imaged directly without the use of an autoradiograph.
  • Observed protein band intensity may optionally be normalized to a control protein present in the sample, such as a housekeeping gene, for example actin or tubulin.
  • protein levels are determined by enzyme-linked immunosorbent assay (ELISA).
  • ELISA enzyme-linked immunosorbent assay
  • a first antibody specific for the protein of interest (the “capture antibody”) is coated in the well of a plate (e.g. a 96-well microtiter plate), and the plate is then blocked with, e.g., bovine serum albumin (BSA) or casein.
  • BSA bovine serum albumin
  • Standards or samples are pipetted into the wells so that protein present in the samples can bind to the immobilized antibody.
  • the wells are washed and a (second) biotinylated anti-protein antibody is added.
  • This second anti- protein antibody must be able to bind to the protein even while the protein is bound to the first antibody.
  • the second antibody is a distinct, non-cross reacting antibody.
  • the second antibody binds to an entirely separate polypeptide chain, for example when the protein to be detected is present as a heterodimeric complex.
  • the biotinylated antibody can be replaced with an antibody having a directly detectable label, obviating the need for the streptavidin step.
  • the wells are again washed, a TMB substrate solution is added to the wells, and color develops in proportion to the amount of protein bound. Stop solution is added to the reaction, which changes the color from blue to yellow, and the intensity of the color is measured at 450 nm.
  • TMB substrate solution is added to the reaction, which changes the color from blue to yellow, and the intensity of the color is measured at 450 nm.
  • Chem. 266: 18082 A standard curve using known concentrations of protein can be used to determine the concentration of protein in the sample.
  • ELISA formats familiar to those in the art may also be used, such as using direct adsorption to the plate, rather than a capture antibody, to immobilize the protein in the microtiter well.
  • Competitive ELISA may also be used, in which a protein in a sample is detected by its ability to compete with labeled protein molecules present in the assay solution for binding to the plate. The higher the concentration of protein in the sample of interest, the more it will block the binding of labeled proteins, thus lowering the observed signal.
  • Antibodies specific to post-translationally modified forms of proteins for example antibodies specific to K382 acetylated p53, can be used to detect post-translational modifications.
  • methods that determine protein size such as the gel electrophoresis and mass spectrometry methods described herein can be used to characterize protein post-translational modifications.
  • Lateral flow format immunoassays may also be used, in which an aqueous sample is drawn over a surface by capillary action.
  • the surface has a first zone in which is deposited a detection reagent (such as a detectably labeled antibody) and a second zone comprising an immobilized capture reagent (e.g. an antibody).
  • a detection reagent such as a detectably labeled antibody
  • an immobilized capture reagent e.g. an antibody
  • Both the capture reagent and detection reagent specifically bind to the protein of interest, i.e. the protein encoded by a p53 or Rb pathway gene.
  • the detection reagent is solubilized and binds to any analyte (p53 or Rb pathway protein) present in the sample to form a complex.
  • the concentration of particles at the second zone results in a visible color signal.
  • the level of protein may then be assessed qualitatively or quantitatively by the intensity of the signal at the second zone.
  • any other suitable assay format may be used to detect the p53 and/or Rb pathway proteins, DDR proteins, RUNXl, ASXL1 or paralogs thereof, of the instant disclosure, such as radioimmunoassays, nephelometry/turbidimetry, specifically immunoturbidimetry, which involves measurement of light scattering caused by suspended insoluble antigen (p53 or Rb protein)/antibody complexes. See, e.g. U.S. Pat. No. 4,605,305.
  • Other methods include radial immunodiffusion (RID), which is observation of a precipitin ring generated by complex formation between an antigen (p53 or Rb protein) and an antibody, e.g. in an agar/agarose slab. See, e.g. U.S. Pat. No. 3,947,250.
  • the p53 or Rb pathway proteins, DDR proteins, RUNX1, ASXL1 or paralogs thereof, may be detected by mass spectrometric methods.
  • Mass spectrometric methods include time-of-flight, magnetic sector, quadrupole filter, ion trap, ion cyclotron resonance, electrostatic sector analyzer and hybrids of these.
  • the p53 or Rb pathway protein in the sample can be identified and quantified using isotope labeled identical synthetic peptides spiked into the sample.
  • the mass spectrometer is a laser desorption/ionization mass spectrometer.
  • analytes are placed on the surface of a mass spectrometry probe, which presents an analyte for ionization.
  • a laser desorption mass spectrometer employs laser energy, typically from an ultraviolet or infrared laser, to volatilize and ionize analytes for detection by the ion optic assembly.
  • the sample is optionally chromatographically fractionated, and p53 or Rb pathway protein is then captured on a bio-affinity resin, e.g. a resin derivatized with an antibody. The protein is then eluted from the resin and analyzed by MALDI, electrospray, or another ionization method for mass spectrometry.
  • the sample is fractionated on an anion exchange resin and detected directly by MALDI or electrospray mass spectrometry.
  • the level of gene expression of p53 and/or Rb pathway genes, DDR genes, RUNXl, ASXL1 or paralogs thereof may be determined at the RNA level. Gene expression at the nucleic acid level can be quantitated by any method known in the art, including but not limited to, Northern blot analysis, gene chip expression analysis, or RT-PCR (real-time polymerase chain reaction) and high throughput sequencing of either mRNA (RNA-Seq). [0205] In some embodiments, the levels of gene expression of p53 and/or Rb pathway genes, DDR genes, RUNXl, ASXL1 or paralogs thereof, is quantified by Northern blot analysis.
  • Northern blot analysis is a standard method for detection and quantitation of mRNA.
  • RNA is isolated from a sample to be assayed (e.g., a cancer biopsy). RNA is separated by size by electrophoresis in an agarose gel under denaturing conditions, transferred to a membrane, cross-linked, and hybridized with a labeled probe.
  • Northern blot analysis involves radiolabeled or nonisotopically detectably labeled nucleic acids as hybridization probes.
  • the membrane holding the RNA sample is prehybridized, or “blocked,” prior to probe hybridization to reduce non-specific background. Unhybridized probe is removed by washing. The stringency of the wash may be adjusted as is well understood in the art.
  • the blot can be exposed to film for autoradiography e.g., in the presence of a scintillant. If a nonisotopic probe is used, the blot must typically be treated with nonisotopic detection reagents to develop the detectable probe signal prior to film exposure.
  • the relative levels of expression of the genes being assayed can be quantified using, for example, densitometry or visual estimation. The observed expression level may be normalized to the expression level of an abundantly expressed control gene (e.g. ubiquitin).
  • expression of p53 and or Rb pathway genes, DDR genes, RUNXl, ASXL1 or paralogs thereof, is determined using a gene chip (probe array).
  • a biological sample of interest is prepared and hybridized to the chip, which is subsequently washed, stained and scanned.
  • the data are then processed.
  • Target preparation may entail preparing a biotinylated target RNA from the sample to be tested.
  • the target hybridization step may involve preparing a hybridization cocktail, including the fragmented target, probe array controls, BSA, and herring sperm DNA.
  • the target is hybridized to the probe array for 16 hours, which probe is washed, stained and scanned for light emission. The amount of light emitted is proportional to the target bound at each location on the probe array.
  • Computer analysis using commercially available equipment and software is possible (Affymetrix, Santa Clara, Calif., USA).
  • expression of p53 and or Rb pathway genes, DDR genes, RUNXl, ASXL1 or paralogs thereof, is determined using high throughput sequencing.
  • RNA from cancer cells from a subject, and optionally control cells is reverse transcribed to make cDNA, which is used to make high throughput sequencing libraries using methods known in the art, e.g. through amplification and the addition of barcodes, sequencing adapters and the like.
  • the libraries are then sequenced using any suitable sequencing platform, for example via Illumina or IonTorrent.
  • gene expression is determined using real time PCR (RT-PCR).
  • RNA is isolated from cancer cells under RNAse free conditions and converted to DNA using reverse transcriptase, as is well known in the art.
  • RT-PCR probes depend on the 5'-3' nuclease activity of (e.g., Taq) DNA polymerase to hydrolyze an oligonucleotide hybridized to the target amplicon (the p53 or Rb pathway gene).
  • RT-PCR probe oligonucleotides have a fluorescent reporter dye attached to the 5' end and a quencher moiety coupled to the 3' end (or vice versa). These probes are designed to hybridize to an internal region of a PCR product. During amplification, the 5 '-3' nuclease activity of the polymerase cleaves the probe, decoupling the fluorescent dye from the quencher moiety. Fluorescence increases in each cycle as more and more probe is cleaved. The resulting fluorescence signal is monitored in real time during the amplification on standard, commercially available equipment. The quantity of p53 or Rb pathway gene RNA in a sample being evaluated may be determined by comparison with standards containing known quantities of amplifiable RNA.
  • genomic DNA from cancer cells from a subject, and optionally control cells is isolated using methods known in the art and sequenced using high throughput sequencing.
  • High throughput sequencing can be used to determine changes in gene copy number through the quantification of reads, or to identify mutations in genes such as p53 and/or Rb pathway genes, or RUNXl, ASXL1 or paralogs thereof.
  • High throughput sequencing of genomic DNA can be used to identify mutations in genes such as p53 and/or Rb pathway genes and quantify the frequency of such mutations in cancer cells in a subject.
  • P53 or Rb pathway genes, DDR genes, RUNXl, ASXL1 or paralogs thereof, or expression thereof may be detected using commercially available kits and reagents (e.g. as disclosed in the examples), or using custom assays with commercially available antibodies obtained from suppliers well known in the art, or using custom assays and antibodies raised by the investigator.
  • Antibodies to p53 pathway genes will be known to persons of ordinary skill in the art and are commercially available. See, for example www.abcam.com/primary-antibodies/p53 -antibody-marker- panel for a panel of p53 antibodies including antibodies to phosphorylated and acetylated forms of p53.
  • Antibodies to Rb pathway genes will likewise be known to persons of ordinary skill in the art.
  • compounds of the disclosure can inhibit, modulate or modify particular activities of p300 by inhibiting or modifying the activity of any p300 domain.
  • compounds of the disclosure can inhibit, modulate or modify the activity of the CHl/TAZl, CH2/TAZ2, RID, KIX, KAT/HAT, PHD, Bromodomam, ZZ or IBiD domains.
  • the compounds of formula la may inhibit, modulate or modify the activity of any one or more of these domains without affecting all domains of CBP/p300.
  • compounds of the disclosure can modulate activity of the CHI domain.
  • the CHI domain interacts with DNA replication factors such as ATR. Modulation, or inhibition of CHI activity by the instant compounds can occur without affecting other CBP/p300 functions, such as acetyltransf erase activity.
  • Compounds of the disclosure can inhibit or modify the interaction of p300 with any one of its protein interaction partners, or combination of protein interaction partners, through the CHl/TAZl, CH2/TAZ2, RID, KIX, IBiD or any other p300 protein-protein interaction domain.
  • a non-limiting list of p300 interaction partners whose interaction with p300 can be affected by compounds of the disclosure includes transcription coactivator BCL3 (BCL3), beta-catenin, breast cancer 1, early onset (BRCA1), caudal type homeobox 2 (CDX2), CCAAT enhancer binding protein beta (CEBPB) and CCAAT enhancer binding protein epsilon (CEBPE), Cbp/p300 interacting transactivator with Glu/Asp rich carboxy-terminal domain 1 (CITED1), Cbp/p300 interacting transactivator with Glu/Asp rich carboxy-terminal domain 2 (CITED2), DEAD-box helicase 5 (DDX5), deltex E3 ubiquitin ligase 1 (DTX1), EP300 interacting inhibitor of differentiation 1 (EID1), ELK1, ETS transcription factor (ELK1), estrogen receptor 1 (ESR1), flap structure- specific endonuclease 1 (FEN1), G protein pathway suppressor 2 (GP
  • inhibiting or modifying the ability of p300 to interact with protein-protein interaction partners can inhibit or modify the ability of p300 or protein complexes comprising p300 to bind to DNA.
  • a compound of the disclosure can prevent p300 or a protein complex comprising p300 from binding to a target promoter, thereby preventing transcription of a target gene.
  • a compound of the disclosure can prevent p300 or protein complexes comprising p300 from binding to a subset of all p300 target promoters, thereby altering the transcriptional profile of a cell, for example a cancer cell.
  • a compound of the disclosure can inhibit or modify the ability of p300 or a p300 protein complex to recruit one or more additional transcription factors, for example, transcription co-activators, to a promoter.
  • additional transcription factors for example, transcription co-activators
  • a compound of the disclosure can alter the expression of genes involved in cell cycle progression, Wnt, Notch and Hedgehog signaling, DNA damage response, apoptosis, antioxidant response, Cyclic- AMP response, hormone-dependent androgen receptor signaling, hypoxia-dependent tumor growth, hematopoiesis or a combination thereof, thereby reducing the proliferation of or otherwise reducing the viability of cancer cells.
  • compounds of the disclosure can inhibit p300 interaction with CBP-HPVE6-p53, thereby rescuing p53 protein expression and acetylation and restoring the DNA damage response pathway in cervical cancer cells.
  • compounds of the disclosure can inhibit the formation of the p300/CBP-HIFl alpha protein complex and reducing the transcription of growth factors and pro- proliferation genes such as vascular endothelial growth factor A (VEGF) in cancer cells.
  • VEGF vascular endothelial growth factor A
  • compounds of the disclosure can disrupt p300-CHl/TAZl androgen receptor (AR) in castration resistant prostate cancers inhibiting the expression of AR target genes.
  • AR p300-CHl/TAZl androgen receptor
  • compounds of the disclosure can act by inhibiting or modifying the acetyltransferase activity of the KAT/HAT domain.
  • An exemplary human p300 protein sequence can be found in NCBI NP 001420.2, the contents of which are hereby incorporated by reference in their entirety.
  • An exemplary human p300 protein comprises a sequence of:
  • a p300 protein comprises a protein having at least 85% identity to SEQ ID NO: 1, at least 90% identity to SEQ ID NO: 1, at least 95% identity to SEQ ID NO: 1, at least 96% identity to SEQ ID NO: 1, at least 97% identity to SEQ ID NO: 1, at least 98% identity to SEQ ID NO: 1, at least 99% identity to SEQ ID NO: 1 or at least 99.8% identity to SEQ ID NO: 1.
  • a p300 protein is identical to a protein of SEQ ID NO: 1.
  • the CH1/TAZ domain corresponds approximately to amino acids 347-414 of SEQ ID NO: 1.
  • the KIX domain corresponds approximately to amino acids 566-646 of SEQ ID NO: 1.
  • the bromodomain corresponds approximately to amino acids 1051-1158 of SEQ ID NO: 1.
  • the PHD domain corresponds approximately to amino acids 1243-1277 of SEQ ID NO: 1.
  • the HAT/KAT domain corresponds approximately to amino acids 1306-1612 of SEQ ID NO: 1.
  • the ZZ domain corresponds approximately to amino acids 1668-1708 of SEQ ID NO: 1.
  • the TAZ2 domain corresponds approximately to amino acids 1729-1807 of SEQ ID NO: 1.
  • corresponding to designates the position/identity of a structural element, e.g., of an amino acid residue, a nucleotide residue, or a chemical moiety, in a compound or composition through comparison with an appropriate reference compound or composition.
  • a monomeric residue in a polymer e.g ., an amino acid residue in a polypeptide or a nucleic acid residue in a polynucleotide
  • residues in a polypeptide are often designated using a canonical numbering system based on a reference related polypeptide, so that an amino acid "corresponding to " a residue at position 190, for example, need not actually be the 190th amino acid in a particular amino acid chain but rather corresponds to the residue found at position 190 in the reference polypeptide; those of ordinary skill in the art readily appreciate how to identify "corresponding" amino acids (see. e.g., Benson etal. Nucl. Acids Res. (1 January 2013) 41 (D1): D36-D42; Pearson etal. PNAS Vol.85, pp. 2444-2448, April 1988).
  • sequence alignment strategies including software programs such as, for example, BLAST, CS-BLAST, CUSASW++, DIAMOND, FASTA, GGSEARCH/GLSEARCH, Genoogle, HMMER, HHpred/HHsearch, IDF, Infernal, KLAST, USEARCH, parasail, PSI-BLAST, PSI-Search, ScalaBLAST, Sequilab, SAM,
  • SWAPHI SWAPHI-LS, SWIMM, or SWIPE that can be utilized, for example, to identify "corresponding" residues in polypeptides and/or nucleic acids in accordance with the present disclosure.
  • a domain refers to a section or portion of a polypeptide.
  • a “domain” is associated with a particular structural and/or functional feature of the polypeptide so that, when the domain is physically separated from the rest of its parent polypeptide, it substantially or entirely retains the particular structural and/or functional feature.
  • a domain may include a portion of a polypeptide that, when separated from that (parent) polypeptide and linked with a different (recipient) polypeptide, substantially retains and/or imparts on the recipient polypeptide one or more structural and/or functional features that characterized it in the parent polypeptide.
  • a domain is a section of a polypeptide.
  • a domain is characterized by a particular structural element (e.g., a particular amino acid sequence or sequence motif, alpha-helix character, b-sheet character, coiled-coil character, random coil character), and/or by a particular functional feature (e.g., binding activity, enzymatic activity, folding activity, signaling activity).
  • a particular structural element e.g., a particular amino acid sequence or sequence motif, alpha-helix character, b-sheet character, coiled-coil character, random coil character
  • a particular functional feature e.g., binding activity, enzymatic activity, folding activity, signaling activity.
  • domain boundaries are typically determined experimentally or via sequence alignment, and may be approximate.
  • domain boundaries may vary by at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 10, at least 15 or at least 20 amino acids without affecting the in vivo function of the domain.
  • An exemplary nucleic acid sequence encoding a p300 protein comprises a sequence of:
  • a nucleic acid sequence encoding a p300 protein comprises a nucleic acid sequence encoding a protein having at least 85% identity to SEQ ID NO:l, at least 90% identity to SEQ ID NO: 1, at least 95% identity to SEQ ID NO: 1, at least 96% identity to SEQ ID NO: 1, at least 97% identity to SEQ ID NO: 1, at least 98% identity to SEQ ID NO: 1, at least 99% identity to SEQ ID NO: 1 or at least 99.8% identity to SEQ ID NO: 1.
  • nucleic acid sequence encoding a p300 protein comprises a nucleic acid sequence encoding a protein identical to SEQ ID NO: 1.
  • a nucleic acid sequence encoding a p300 protein comprises a nucleic acid sequence e having at least 85% identity to SEQ ID NO: 2, at least 90% identity to SEQ ID NO: 2, at least 95% identity to SEQ ID NO: 2, at least 96% identity to SEQ ID NO: 2, at least 97% identity to SEQ ID NO: 2, at least 98% identity to SEQ ID NO: 2, at least 99% identity to SEQ ID NO: 2 or at least 99.8% identity to SEQ ID NO: 2.
  • a nucleic acid sequence encoding a p300 protein comprises a nucleic acid sequence identical to SEQ ID NO: 2 or a portion or subsequence thereof.
  • a gene product can be a transcript.
  • a gene product can be a polypeptide.
  • expression of a nucleic acid sequence involves one or more of the following: (1) production of an RNA template from a DNA sequence (e.g., by transcription); (2) processing of an RNA transcript ( e.g by splicing, editing, 5' cap formation, and/or 3' end formation); (3) translation of an RNA into a polypeptide or protein; and/or (4) post-translational modification of a polypeptide or protein.
  • nucleic acid refers to a polymer of at least three nucleotides.
  • a nucleic acid comprises DNA.
  • RNA RNA
  • a nucleic acid is single stranded.
  • a nucleic acid is double- stranded.
  • a nucleic acid comprises both single and double stranded portions.
  • a nucleic acid comprises a backbone that comprises one or more phosphodiester linkages.
  • a nucleic acid comprises a backbone that comprises both phosphodiester and non-phosphodiester linkages.
  • a nucleic acid comprises one or more, or all, natural residues (e.g ., adenine, cytosine, deoxyadenosine, deoxycytidine, deoxyguanosine, deoxythymidine, guanine, thymine, uracil).
  • a nucleic acid comprises on or more, or all, non-natural residues.
  • a non-natural residue comprises a nucleoside analog.
  • a nucleic acid has a nucleotide sequence that encodes a functional gene product such as an RNA or polypeptide.
  • a nucleic acid has a nucleotide sequence that comprises one or more introns.
  • a nucleic acid may be prepared by isolation from a natural source, enzymatic synthesis (e.g., by polymerization based on a complementary template, e.g., in vivo or in vitro, reproduction in a recombinant cell or system, or chemical synthesis).
  • alkyl refers to a saturated straight or branched chain group of carbon atoms derived from an alkane by the removal of one hydrogen atom.
  • C 1-3 alkyl includes, but is not limited to, for example methyl, ethyl, n-propyl, i-propyl.
  • C 1-4 alkyl comprises for example methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, tert-butyl.
  • C 1-5 alkyl comprises for example methyl, ethyl, n- propyl, i-propyl, n-butyl, i-butyl, tert-butyl, n-pentyl
  • C 1-7 alkyl comprises for example methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, tert-butyl, n-pentyl, n-hexyl or n-heptyl.
  • the alkyl groups of this invention can be optionally substituted.
  • C 2-5 alkenyl and “C 2-7 alkenyl” as used herein refers to straight or branched chain hydrocarbon groups having 2 to 5 carbon atoms and 2 to 7 carbon atoms, respectively and at least one double bond.
  • C 2-5 alkynyl and “C 2-7 alkynyl” as used herein refers to straight or branched chain hydrocarbon groups having 2 to 5 carbon atoms and 2 to 7 carbon atoms, respectively and at least one triple bond.
  • C 3-7 cycloalkyl and “C 3-5 cycloalkyl” as used herein refers to a monovalent saturated cyclic or bicyclic hydrocarbon group of 3-7 or 3-5 carbons, respectively derived from a cycloalkane by the removal of a single hydrogen atom.
  • C 3-5 cycloalkyl includes, but is not limited to, cyclopropyl, cyclobutyl, and cyclopentyl.
  • C 3-7 cycloalkyl includes, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.
  • C 3-7 cycloalkyl and “C 3-5 cycloalkyl” as used herein also includes cycloalkyl groups that comprise a C 1-3 -alkyl radical.
  • Examples of such "C 3-7 cycloalky''groups comprise cyclopropylmethyl, 2-cyclopropylethyl, cyclobutylmethyl, 2-cyclobutylethyl, cyclopentylmethyl, 2-cyclopentylethyl.
  • Examples of such “C 3-5 cycloalkyf’groups comprise cyclopropylmethyl, 2-cyclopropylethyl, cyclobutylmethyl.
  • Cycloalkyl groups of this invention can be optionally substituted.
  • Substitutents can be e.g. halogen, C 1-4 alkyl, or C 3-5 cycloalkyl.
  • C 4-7 cycloalkenyl refers to a monovalent cyclic or bicyclic hydrocarbon group of 4-7 carbons having at least one double bond, derived from a cycloalkene by the removal of a single hydrogen atom.
  • C 4-7 cycloalkeny 1 as used herein also includes cycloalkenyl groups that comprise a C 1-3 -alkyl radical.
  • C 1-3 alkanediyl refers to a diradical of a saturated straight or branched chain hydrocarbon group, having 1 to 3, 1 to 6 carbon, and 1 to 7 carbon atoms, respectively.
  • alkanediyl groups include methane-diyl, ethane- 1,2- diyl, and the like.
  • C 2-6 alkenediyl and “C 2-7 alkenediyl” as used herein refers to a diradical of a straight or branched chain hydrocarbon groups having 2 to 6 carbon atoms and 2 to 7 carbon atoms, respectively and at least one double bond.
  • alkenediyl groups include ethene-1,2- diyl and the like.
  • C 2-6 alkynediyl and “C 2-7 alkynediyl” as used herein refers to a diradical of a straight or branched chain hydrocarbon groups having 2 to 6 carbon atoms and 2 to 7 carbon atoms, respectively and at least one triple bond.
  • alkynediyl groups include ethine-1,2-diyl and the like.
  • C 3-6 cycloalkanediyl refers to a diradical saturated cyclic or bicyclic hydrocarbon group of 3-6 carbons.
  • C 3-6 cycloalkenediyl refers to a diradical cyclic or bicyclic hydrocarbon group of 3-6 carbons having at least one double bond.
  • heteroalkyl or “heteroalkanediyl” as used herein refers to an alkyl radical or an alkanediyl radical as defined herein wherein one, two, three or four hydrogen atoms have been replaced with a substituent independently selected from the group consisting of OH, NH 2 and halogen.
  • Representative examples include, but are not limited to, 2-hydroxy ethyl, 2-hydroxypropyl, 3- hydroxypropyl, 2-hydroxy- 1-hy dr oxymethylethyl, 2-hydroxy- 1 -methylethyl, 2,3-dihydroxypropyl, 1- hydroxymethylethyl, 3-hydroxybutyl, 2,3-dihydroxybutyl, 1 -hydroxy-2-methylpropyl, 3 -hydroxy- 1- (2-hydroxyethyl)-propyl, 2-hydroxy- 1 -methylpropyl, 1 , 1 , 1 -trifluoroethyl, and 2, 2,3,3- tetrafluor opropy 1.
  • aryl refers to a mono- or bicyclic carbocyclic ring system having one or two aromatic rings.
  • the aryl group can also be fused to a cyclohexane, cyclohexene, cyclopentane, or cyclopentene ring or to a cyclohexane, cyclohexene, cyclopentane, or cyclopentene ring comprising a carbonyl group.
  • the aryl group includes e.g. indane or mono-oxo substituted indane rings.
  • the aryl groups of this invention can be optionally substituted as further described below. Substitutents can be e.g.
  • the aryl group is a phenyl group.
  • the optionally substituted aryl group is a substituted phenyl group.
  • heteroaryl refers to substituted and unsubstituted aromatic 5-, or 6- membered monocyclic groups and 9- or 10-membered bicyclic groups, which have at least one heteroatom (O, S or N) in at least one of the rings.
  • Each ring of the heteroaryl group containing a heteroatom can contain one or two oxygen or sulfur atoms and/or from one to four nitrogen atoms provided that the total number of heteroatoms in each ring is four or less and each ring has at least one carbon atom.
  • Heteroaryl groups must include at least one fully aromatic ring but the other fused ring or rings may be aromatic or non-aromatic.
  • heteroaryl group may be attached at any available nitrogen or carbon atom of any ring.
  • Heteroaryl groups of this invention can be optionally substituted as further described below.
  • the heteroaryl group is optionally substituted with one heteroatom (O, S or N).
  • the heteroaryl group is optionally substituted with one O or N in the ring.
  • the heteroaryl group is optionally substituted with two N in the ring.
  • the heteroaryl group and optionally substituted heteroaryl group are selected from the group consisting of a pyridinyl group, a substituted pyridinyl group, a imidazole group, a substituted imidazole group, a pyrazole group, a substituted pyrazole group, a triazole group, a substituted triazole group, a benzimidazole group and a substituted benzimidazole group.
  • the heteroaryl group and optionally substituted heteroaryl group are selected from the group consisting of a substituted pyridinyl group, a pyridinyl group, a triazole group, a substituted triazole group, a imidazole group, and/or a substituted imidazole group.
  • the heteroaryl group and optionally substituted heteroaryl group are selected from the group consisting of a substituted pyridinyl group, a pyridinyl group, an imidazole group, and/or a substituted imidazole group, is used as heteroaryl group in the present invention.
  • Substituents can be e.g. halogen, C 1-4 alkyl, or C 3-5 cycloalkyl.
  • S-aryl refers to a radical -SR, where R is an aryl as defined herein.
  • O-aryl refers to a radical -OR, where R is an aryl as defined herein.
  • S-heteroaryl refers to a radical -SR, where R is an heteroaryl as defined herein.
  • O-heteroaryl refers to a radical -OR, where R is an heteroaryl as defined herein.
  • C 1-3 alkyl-aryl refers to a radical of C 1-3 alkyl as defined herein to which an aryl group as defined herein is bonded at any carbon of the alkyl.
  • C 1-3 alkyl-heteroaryl refers to a radical of C 1-3 alkyl as defined herein to which a heteroaryl group as defined herein is bonded at any carbon of the alkyl.
  • halo or halogen as used herein refers to F, Cl, Br, or I.
  • the compound is of Formula (la): or a pharmaceutically acceptable salt, hydrate, solvate or stereoisomer thereof, wherein:
  • R 1 is selected from H, C 1-7 alkyl, C 2-7 alkenyl, C 2-7 alkynyl, C 3-7 cycloalkyl, C 4-7 cycloalkenyl, and C 1-3 alkyl substituted by cycloalkyl, aryl or heteroaryl, wherein the cycloalkyl, aryl, or the heteroaryl is optionally substituted by halogen, C 1-4 alkyl, or C 3-5 cycloalkyl;
  • R 2 is selected from H, C(O)R 14 , C(O)NR 15 R 15 , C(O)OR 15 , C 1-7 alkyl, C 2-7 alkenyl, C 2-7 alkynyl, C 3-7 cycloalkyl, C 4-7 cycloalkenyl, C 1-5 alkyl-OR 8 , C 1-3 alkanediyl-O-C 1-3 alkanediyl-O-C 1-3 alkanediyl, C 1-5 alkyl-NHCOR 13 , and C 1-3 alkyl substituted by cycloalkyl, aryl or heteroaryl, wherein the cycloalkyl, aryl or the heteroaryl is optionally substituted by halogen, C 1-4 alkyl or C 3-5 cycloalkyl; with the proviso that when R 2 is C(O)NR 15 R 15 , both R 15 can form a ring wherein the ring contains the N of NR 15 R 15 and optional
  • R 3 and R 7 are each independently selected from H, C 1-7 alkyl, C 2-7 alkenyl, C 2-7 alkynyl, C 3-7 cycloalkyl, and C 4-7 cycloalkenyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, or cycloalkenyl are optionally substituted by halogen, OR 8 , or NR 8 R 11 ; or R 3 and R 7 are each independently C 1-3 alkyl substituted by aryl or heteroaryl, wherein the aryl or the heteroaryl is optionally substituted by halogen, C 1-4 alkyl, or C 3-5 cycloalkyl;
  • R 4 is selected from C 1-7 alkyl, C 2-7 alkenyl, C 2-7 alkynyl, C 3-7 cycloalkyl, C 4-7 cycloalkenyl, and C 1-3 alkyl substituted by cycloalkyl, aryl, or heteroaryl, wherein the cycloalkyl, aryl or the heteroaryl is optionally substituted by halogen, C 1-4 alkyl, or C 3-5 cycloalkyl;
  • R 5 is selected from H, C 1-7 alkyl, C 2-7 alkenyl, C 2-7 alkynyl, C 3-7 cycloalkyl, C 4-7 cycloalkenyl, OR 8 , C 1-3 alkyl-OR 8 , and SR 8 ; and wherein R 5 can form a ring with any part of X or Y, wherein the ring optionally contains a carbonyl group;
  • R 6 is selected from H, C 1-7 alkyl, C 2-7 alkenyl, C 2-7 alkynyl, C 3-7 cycloalkyl, and C 4-7 cycloalkenyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, or cycloalkenyl are optionally substituted by halogen, OR 8 , or NR 8 R 11 ; or R 6 is C 1-3 alkyl substituted by C(O)NR 8 R 11 ; or R 6 is C 1-3 alkyl substituted by aryl or heteroaryl, wherein the aryl or the heteroaryl is optionally substituted by halogen, C 1-4 alkyl or C 3-5 cycloalkyl; or R 6 can form a ring with any part of X; or R 6 is imidazolidinone;
  • R 8 and R 11 are each independently selected from H, C 1-7 alkyl, C 2-7 alkenyl, C 2-7 alkynyl, C 3-7 cycloalkyl, and C 4-7 cycloalkenyl;
  • X is selected from a bond, C 1-7 alkanediyl, C 2-7 alkenediyl, C 2-7 alkynediyl, C 3-9 cycloalkanediyl, C4-6 cycloalkenediyl, -O-, C 1-3 alkanediyl-O-, -O-C 1-7 alkanediyl, -O-C 3-9 cycloalkanediyl, C 1-3 alkanediyl-O-C 1-7 alkanediyl, C 1-7 heteroalkanediyl, and -S-C 1-7 alkanediyl; and wherein X can form a ring or a polycyclic system with any part of R 5 , R 6 , or Y, wherein the ring optionally contains a carbonyl group;
  • Y is selected from H, C(O)NR 10 R 12 , C(O)OR 10 , R 10 NC(O)NR 10 R 12 , OC(O)R 10 ,
  • R 9 is selected from H, halogen, C 1-5 alkyl, C 2-5 alkenyl, C 2-5 alkynyl, C 3-5 cycloalkyl, C 1-5 alkyl-OR 8 , C 1-5 alkyl-SR 8 , C 1-5 alkyl-NR 8 R 11 , C 1-5 alkyl- C(O) OR 8 , C 1-5 alkyl-C(O)NR 8 R 11 , C 1-5 alkyl- C(O)R 10 , CN, C(O)R 8 , C(O)NR 8 R 11 , C(O)OR 8 , NR 8 C(O)NR 8 R 11 , OC(O)NR 8 R 11 , SO 2 NR 8 R 11 , NR 8 SO 2 R 8 , OR 8 , NR 8 R 11 , and S(O) n R 8 wherein n is 0, 1 or 2;
  • R 10 and R 12 are each independently selected from H, C 1-7 alkyl, C 2-7 alkenyl, C 2-7 alkynyl, C 3-7 cycloalkyl, C 4-7 cycloalkenyl, C 1-3 alkanediyl-O- C 1-3 alkanediyl-O-C 1-3 alkanediyl, C 1-3 alkyl-aryl, and C 1-3 alkyl-heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, alkanediyl, aryl, or heteroaryl are optionally substituted by halogen, OR 8 , or NR 8 R 11 ;
  • R 13 is C 1-5 alkyl substituted by a bicyclic ring optionally comprising at least one heteroatom and a carbonyl group;
  • R 14 is selected from H, C 1-7 alkyl, C 2-7 alkenyl, C 2-7 alkynyl, C 3-7 cycloalkyl, C 4-7 cycloalkenyl, and C 1-3 alkyl substituted by aryl or heteroaryl, wherein the aryl or the heteroaryl is optionally substituted by halogen, C 1-4 alkyl, or C 3-5 cycloalkyl; and each R 15 is independently selected from H, C 1-7 alkyl, C 2-7 alkenyl, C 2-7 alkynyl, C 3-7 cycloalkyl, C 4-7 cycloalkenyl, OR 8 , and C 1-3 alkyl-OR 8 .
  • the compound is of Formula (I): or a pharmaceutically acceptable salt, hydrate, solvate or stereoisomer thereof, wherein: R 1 is C 1-7 alkyl; R 2 is selected from H, C(O)R 14 , C(O)OR 15 , C 1-7 alkyl, C 3-7 cycloalkyl, C 1-5 alkyl-NHCOR 13 , and C 1-3 alkyl substituted by aryl, wherein the aryl is optionally substituted by halogen;
  • R 3 and R 7 are each H
  • R 4 is C 1-7 alkyl
  • R 5 is selected from H, C 1-7 alkyl, OR 8 , and SR 8 ; and wherein R 5 can form a ring with any part of X or Y, wherein the ring optionally contains a carbonyl group;
  • R 6 is selected from H and C 1-7 alkyl
  • R 8 and R 11 are each independently selected from H, C 1-7 alkyl, and C 3-7 cycloalkyl;
  • X is selected from a bond, C 1-7 alkanediyl, -O-C 1-7 alkanediyl, and -S-C 1-7 alkanediyl; and wherein X can form a ring with any part of R 5 or Y;
  • Y is selected from H, NR 10 R 12 , and C 3-7 -cycloalkyl optionally containing a heteroatom in the ring selected from O and N wherein if the heteroatom is N it is optionally substituted by R 8 ; or Y is heteroaryl, wherein the heteroaryl is optionally substituted by one or more of R 8 ; and wherein Y can form a ring with any part of X or R 5 , wherein the ring optionally contains a carbonyl group; with the proviso that when Y is NR 10 R 12 , R 10 and R 12 can form a ring wherein the ring contains the N of NR 10 R 12 and optionally one further heteroatom selected from O and N, wherein if the one further heteroatom is N, it is optionally substituted by R 8 ;
  • R 10 and R 12 are each independently selected from H, C 1-7 alkyl, C 3-7 cycloalkyl, and C 1-3 alkyl- aryl, wherein the alkyl or cycloalkyl, or aryl are optionally substituted by halogen;
  • R 13 is C 1-5 alkyl substituted by a bicyclic ring optionally comprising at least one heteroatom and a carbonyl group;
  • R 14 is selected from H and C 1-7 alkyl; and each R 15 is independently selected from H and C 1-7 alkyl.
  • R 1 is selected from H, C 1-7 alkyl, C 2-7 alkenyl, C 2-7 alkynyl, C 3-7 cycloalkyl, C 4-7 cycloalkenyl, and C 1-3 alkyl substituted by cycloalkyl, aryl or heteroaryl, wherein the cycloalkyl, aryl, or the heteroaryl is optionally substituted by halogen, C 1-4 alkyl, or C 3-5 cycloalkyl.
  • R 1 is selected from H, C 1-7 alkyl, C 2-7 alkenyl, C 2-7 alkynyl, C 3-7 cycloalkyl, C 4-7 cycloalkenyl, and C 1-3 alkyl substituted by aryl or heteroaryl, wherein the aryl or the heteroaryl is optionally substituted by halogen, C 1-4 alkyl, or C 3-5 cycloalkyl.
  • R 1 is selected from C 1-7 alkyl, C 2-7 alkenyl, C 2-7 alkynyl, C 3-7 cycloalkyl, C 4-7 cycloalkenyl, and C 1-3 alkyl substituted by aryl or heteroaryl, wherein the aryl or the heteroaryl is optionally substituted by halogen, C 1-4 alkyl, or C 3-5 cycloalkyl.
  • R 1 is selected from C 2-7 alkyl, C 3-7 cycloalkyl, and C 1-3 alkyl substituted by aryl or heteroaryl, wherein the aryl or the heteroaryl is optionally substituted by halogen, C 1-4 alkyl, or C 3-5 cycloalkyl. In some embodiments, R 1 is selected from C 3-7 alkyl, C 3-7 cycloalkyl, and C 1-3 alkyl substituted by aryl or heteroaryl.
  • R 1 is H. In some embodiments, R 1 is C 3-7 cycloalkyl. In some embodiments, R 1 is C 1-7 alkyl. In some embodiments, R 1 is C 2-7 alkyl.
  • R 1 is C 3-7 alkyl. In some embodiments, R 1 is selected from methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, and tert-butyl. In some embodiments, R 1 is isobutyl.
  • R 2 is selected from H, C(O)R 14 , C(O)NR 15 R 15 , C(O)OR 15 , C 1-7 alkyl, C 2-7 alkenyl, C 2-7 alkynyl, C 3-7 cycloalkyl, C 4-7 cycloalkenyl, C 1-5 alkyl-OR 8 , C 1-3 alkanediyl-O-C 1-3 alkanediyl-O-C 1-3 alkanediyl, C 1-5 alkyl-NHCOR 13 , and C 1-3 alkyl substituted by cycloalkyl, aryl or heteroaryl, wherein the cycloalkyl, aryl, or the heteroaryl is optionally substituted by halogen, C 1-4 alkyl or C 3-5 cycloalkyl; with the proviso that when R 2 is C(O)NR 15 R 15 , both R 15 can form a ring wherein the ring comprises the
  • R 2 is selected from H, C(O)R 14 , C(O)OR 15 , C 1-7 alkyl, C 3-7 cycloalkyl, C 1-3 alkanediyl-O-C 1-3 alkanediyl-O-C 1-3 alkanediyl, C 1-5 alkyl-OR 8 , C 1-5 alkyl-NHCOR 13 , and C 1-3 alkyl substituted by aryl, wherein the aryl is optionally substituted by halogen, C 1-4 alkyl, or C 3-5 cycloalkyl.
  • R 2 is H. In some embodiments, R 2 is C 1-7 alkyl. [0260] In some embodiments, R 2 is selected from C(O)R 14 , C(O)NR 15 R 15 , C(O)OR 15 , C 1-7 alkyl, C 2-7 alkenyl, C 2-7 alkynyl, C 3-7 cycloalkyl, C 4-7 cycloalkenyl, C 1-5 alkyl-OR 8 , C 1-3 alkanediyl-O-C 1-3 alkanediyl-O-C 1-3 alkanediyl, C 1-5 alkyl-NHCOR 13 , and C 1-3 alkyl substituted by cycloalkyl, aryl, or heteroaryl, wherein the cycloalkyl, aryl, or the heteroaryl is optionally substituted by halogen, C 1-4 alkyl, or C 3-5 cycloalkyl; with the proviso that when
  • R 2 is C(O)R 14 , and R 14 is methyl, ethyl, propyl, isopropyl, butyl, sec- butyl, isobutyl, or tert-butyl.
  • R 2 is C(O)NR 15 R 15 , wherein each R 15 is independently selected from H, C 1-7 alkyl, C 2-7 alkenyl, C 2-7 alkynyl, C 3-7 cycloalkyl, C 4-7 cycloalkenyl, OR 8 , and C 1-3 alkyl-OR 8 .
  • R 2 is C 3-7 cycloalkyl. In some embodiments, R 2 is C 1-5 alkyl-OR 8 .
  • R 2 is C 1-3 alkyl substituted by cycloalkyl.
  • R 2 is C 1-3 alkyl substituted by aryl or heteroaryl.
  • R 2 is C 1-3 alkyl substituted by aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted by halogen, C 1-4 alkyl, or C 3-5 cycloalkyl.
  • R 2 is C 1-5 alkyl-NHCOR 13 , wherein R 13 is pentylamino-5-oxopentyl-7- thia-2.4-diazabicyclo[3.3.0] octan-3 -one.
  • R 2 is selected from H; C(O)R 14 , wherein R 14 is C 1-7 alkyl; C 1-7 alkyl; C 3-7 cycloalkyl; C 1-5 alkyl-OR 8 ; C 1-5 alkyl-NHCOR 13 , wherein R 13 is pentylamino-5-oxopentyl-7-thia- 2.4-diazabicyclo[3.3.0]octan-3-one; and C 1-3 alkyl substituted by aryl, wherein the aryl is optionally substituted by halogen, C 1-4 alkyl, or C 3-5 cycloalkyl.
  • R 3 is selected from H, C 1-7 alkyl, C 2-7 alkenyl, C 2-7 alkynyl, C 3-7 cycloalkyl, and C 4-7 cycloalkenyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, or cycloalkenyl is optionally substituted by halogen, OR 8 , or NR 8 R 11 ; or R 3 and R 7 are each independently C 1-3 alkyl substituted by aryl or heteroaryl, wherein the aryl or the heteroaryl is optionally substituted by halogen, C 1-4 alkyl, or C 3-5 cycloalkyl.
  • R 3 is H.
  • R 3 is C 1-7 alkyl, C 2-7 alkenyl, C 2-7 alkynyl, C 3-7 cycloalkyl, or C 4-7 cycloalkenyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, or cycloalkenyl is optionally substituted by halogen, OR 8 , or NR 8 R 11 ; or R 3 and R 7 are each independently C 1-3 alkyl substituted by aryl or heteroaryl, wherein the aryl or the heteroaryl is optionally substituted by halogen, C 1-4 alkyl, or C 3-5 cycloalkyl.
  • R 3 is selected from H, C 1-7 alkyl, C 2-7 alkenyl, C 2-7 alkynyl, C 3-7 cycloalkyl, and C 4-7 cycloalkenyl. In some embodiments, R 3 is C 1-7 alkyl. In some embodiments, R 3 is C 2-7 alkenyl. In some embodiments, R 3 is C 3-7 cycloalkyl.
  • R 3 and R 7 are each independently selected from H, C 1-7 alkyl, C 2-7 alkenyl, C 2-7 alkynyl, C 3-7 cycloalkyl, and C 4-7 cycloalkenyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, or cycloalkenyl is optionally substituted by halogen, OR 8 , or NR 8 R 11 ; or R 3 and R 7 are each independently C 1-3 alkyl substituted by aryl or heteroaryl, wherein the aryl or the heteroaryl is optionally substituted by halogen, C 1-4 alkyl, or C 3-5 cycloalkyl
  • R 3 and R 7 are each independently selected from H, C 1-7 alkyl, C 2-7 alkenyl, C 2-7 alkynyl, C 3-7 cycloalkyl, and C 4-7 cycloalkenyl.
  • R 3 and R 7 are each H. In some embodiments, R 3 and R 7 are each independently C 1-7 alkyl. In some embodiments, R 3 and R 7 are each independently C 2-7 alkenyl. In some embodiments, R 3 and R 7 are each independently C 3-7 cycloalkyl.
  • R 7 is selected from H, C 1-7 alkyl, C 2-7 alkenyl, C 2-7 alkynyl, C 3-7 cycloalkyl, and C 4-7 cycloalkenyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, or cycloalkenyl is optionally substituted by halogen, OR 8 , or NR 8 R 11 ; or R 3 and R 7 are each independently C 1-3 alkyl substituted by aryl or heteroaryl, wherein the aryl or the heteroaryl is optionally substituted by halogen, C 1-4 alkyl, or C 3-5 cycloalkyl.
  • R 7 is H.
  • R 7 is selected from C 1-7 alkyl, C 2-7 alkenyl, C 2-7 alkynyl, C 3-7 cycloalkyl, and C 4-7 cycloalkenyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, or cycloalkenyl is optionally substituted by halogen, OR 8 , or NR 8 R 11 ; or R 3 and R 7 are each independently C 1-3 alkyl substituted by aryl or heteroaryl, wherein the aryl or the heteroaryl is optionally substituted by halogen, C 1-4 alkyl, or C 3-5 cycloalkyl.
  • R 7 is selected from H, C 1-7 alkyl, C 2-7 alkenyl, C 2-7 alkynyl, C 3-7 cycloalkyl, and C 4-7 cycloalkenyl.
  • R 7 is C 1-7 alkyl. In some embodiments, R 7 is methyl.
  • R 7 is C 2-7 alkenyl.
  • R 7 is C 3-7 cycloalkyl.
  • R 4 is selected from H, C 1-7 alkyl, C 2-7 alkenyl, C 2-7 alkynyl, C 3-7 cycloalkyl, C 4-7 cycloalkenyl, and C 1-3 alkyl substituted by cycloalkyl, aryl, or heteroaryl, wherein the cycloalkyl, aryl, or the heteroaryl is optionally substituted by halogen, C 1-4 alkyl, or C 3-5 cycloalkyl.
  • R 4 is H.
  • R 4 is selected from C 1-7 alkyl, C 2-7 alkenyl, C 2-7 alkynyl, C 3-7 cycloalkyl, C 4-7 cycloalkenyl, and C 1-3 alkyl substituted by cycloalkyl, aryl, or heteroaryl, wherein the cycloalkyl, aryl, or the heteroaryl is optionally substituted by halogen, C 1-4 alkyl, or C 3-5 cycloalkyl [0285] In some embodiments, R 4 is selected from C 1-7 alkyl, C 3-7 cycloalkyl, and C 1-3 alkyl substituted by aryl or heteroaryl, wherein the aryl or the heteroaryl is optionally substituted by halogen, C 1-4 alkyl, or C 3-5 cycloalkyl.
  • R 4 is selected from C 2-7 alkyl, C 3-7 cycloalkyl, and C 1-3 alkyl substituted by aryl or heteroaryl, wherein the aryl or the heteroaryl is optionally substituted by halogen, C 1-4 alkyl, or C 3-5 cycloalkyl.
  • R 4 is selected from C 3-7 alkyl, C 3-7 cycloalkyl, and C 1-3 alkyl substituted by aryl or heteroaryl. In some embodiments, R 4 is C 3-7 cycloalkyl.
  • R 4 is C 1-7 alkyl. In some embodiments, R 4 is C 2-7 alkyl. In some embodiments, R 4 is C 3-7 alkyl.
  • R 4 is isobutyl
  • R 4 is C 1-3 alkyl substituted by cycloalkyl.
  • R 4 is C 1-3 alkyl substituted by aryl or heteroaryl.
  • R 5 is selected from H, C 1-7 alkyl, C 2-7 alkenyl, C 2-7 alkynyl, C 3-7 cycloalkyl, C 4-7 cycloalkenyl, OR 8 , C 1-3 alkyl-OR 8 , and SR 8 ; and wherein R 5 can form a ring with any part of X or Y, wherein the ring optionally comprises a carbonyl group.
  • R 5 is selected from H, C 1-7 alkyl, OR 8 , and SR 8 ; and wherein C 1-7 alkyl, OR 8 , or SR 8 of R 5 can form a ring with any part of X or Y, wherein the ring optionally comprises a carbonyl group.
  • R 5 is selected from H, C 1-7 alkyl, OR 8 , and SR 8 ; and wherein C 1-7 alkyl, OR 8 , or SR 8 of R 5 can form a ring with any part of X or, when Y is C(O)NR 10 R 12 or NR 10 R 12 , C 1-7 alkyl of R 5 can form a ring with any part of Y, wherein the ring optionally comprises a carbonyl group.
  • R 5 is selected from H, C 1-7 alkyl, and OR 8 ; and wherein C 1-7 alkyl or OR 8 can form a ring with any part of X or Y, wherein the ring optionally comprises a carbonyl group.
  • R 5 is selected from H, C 1-7 alkyl, and OR 8 ; and wherein C 1-7 alkyl or OR 8 of R 5 can form a ring with any part of X or, when Y is C(O)NR 10 R 12 or NR 10 R 12 , C 1-7 alkyl of R 5 can form a ring with any part of Y, wherein the ring optionally comprises a carbonyl group.
  • R 5 is selected from C 1-7 alkyl, OR 8 , and SR 8 ; wherein C 1-7 alkyl, OR 8 , or SR 8 can form a ring with any part of X.
  • R 5 is OR 8 , wherein R 8 of OR 8 is C 1-7 alkyl, and wherein OR 8 can form a ring with any part of X.
  • R 5 is selected from H and C 1-7 alkyl; and wherein C 1-7 alkyl can form a ring with any part of X or Y, wherein the ring optionally comprises a carbonyl group.
  • R 5 is H.
  • R 6 is selected from H, C 1-7 alkyl, C 2-7 alkenyl, C 2-7 alkynyl, C 3-7 cycloalkyl, and C 4-7 cycloalkenyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, or cycloalkenyl is optionally substituted by halogen, OR 8 , or NR 8 R 11 ; or R 6 is C 1-3 alkyl substituted by C(O)NR 8 R 11 ; or R 6 is C 1-3 alkyl substituted by aryl or heteroaryl, wherein the aryl or the heteroaryl is optionally substituted by halogen, C 1-4 alkyl, or C 3-5 cycloalkyl; and wherein R 6 can form a ring with any part of X; or R 6 is imidazolidinone.
  • R 6 is selected from C 1-7 alkyl, C 2-7 alkenyl, C 2-7 alkynyl, C 3-7 cycloalkyl, and C 4-7 cycloalkenyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, or cycloalkenyl is optionally substituted by halogen, OR 8 , or NR 8 R 11 ; or R 6 is C 1-3 alkyl substituted by C(O)NR 8 R 11 ; or R 6 is C 1-3 alkyl substituted by aryl or heteroaryl, wherein the aryl or the heteroaryl is optionally substituted by halogen, C 1-4 alkyl or C 3-5 cycloalkyl; and wherein R 6 can form a ring with any part of X; or R 6 is imidazolidinone.
  • R 6 is selected from H, C 1-7 alkyl, C 2-7 alkenyl, C 2-7 alkynyl, C 3-7 cycloalkyl, and C 4-7 cycloalkenyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, or cycloalkenyl is optionally substituted by halogen, OR 8 , or NR 8 R 11 ; or R 6 is C 1-3 alkyl substituted by C(O)NR 8 R 11 ; or R 6 is C 1-3 alkyl substituted by aryl or heteroaryl, wherein the aryl or the heteroaryl is optionally substituted by halogen, C 1-4 alkyl, or C 3-5 cycloalkyl; or R 6 is imidazolidinone.
  • R 6 is selected from H, C 1-7 alkyl, C 2-7 alkenyl, C 2-7 alkynyl, C 3-7 cycloalkyl, and C 4-7 cycloalkenyl; or R 6 is imidazolidinone. [0305] In some embodiments, R 6 is selected from H, C 1-7 alkyl, and imidazolidinone. [0306] In some embodiments, R 6 is H or C 1-7 alkyl.
  • R 6 is H.
  • R 6 is C 1-7 alkyl.
  • R 6 is methyl
  • R 6 is in position -2 of the piperidine ring and is methyl.
  • R 6 is selected from the group consisting of H, , and
  • R 6 is in position -2 of the piperidine ring and is selected from the group consisting of H, , and
  • R 6 is
  • R 6 is C 1-3 alkyl substituted by C(O)NR 8 R 11 .
  • R 6 forms a ring with any part of X.
  • R 8 and R 11 are each independently selected from H, C 1-7 alkyl, C 2-7 alkenyl, C 2-7 alkynyl, C 3-7 cycloalkyl, and C 4-7 cycloalkenyl.
  • R 8 and R 11 are each independently H.
  • R 8 and R 11 are each independently selected from C 1-7 alkyl, C 2-7 alkenyl, C 2-7 alkynyl, C 3-7 cycloalkyl, and C 4-7 cycloalkenyl.
  • R 8 and R 11 are each independently selected from H, C 1-7 alkyl, C 2-7 alkenyl, and C 3-7 cycloalkyl.
  • R 8 is selected from H, C 1-7 alkyl, C 2-7 alkenyl, C 2-7 alkynyl, C 3-7 cycloalkyl, and C 4-7 cycloalkenyl.
  • R 8 is H.
  • R 8 is C 1-7 alkyl, C 2-7 alkenyl, C 2-7 alkynyl, C 3-7 cycloalkyl, and C 4-7 cycloalkenyl.
  • R 8 is C 1-7 alkyl.
  • R 11 is selected from H, C 1-7 alkyl, C 2-7 alkenyl, C 2-7 alkynyl, C 3-7 cycloalkyl, and C 4-7 cycloalkenyl.
  • R 11 is H. [0326] In some embodiments, R 11 is C 1-7 alkyl, C 2-7 alkenyl, C 2-7 alkynyl, C 3-7 cycloalkyl, and C 4-7 cycloalkenyl.
  • R 11 is C 1-7 alkyl.
  • R 9 is selected from H, halogen, C 1-5 alkyl, C 2-5 alkenyl, C 2-5 alkynyl, C 3- 5 cycloalkyl, C 1-5 alkyl-OR 8 , C 1-5 alkyl-SR 8 , C 1-5 alkyl-NR 8 R 11 , C 1-5 alkyl-C(O)OR 8 , C 1-5 alkyl- C(O)NR 8 R 11 , C 1-5 alkyl-C(O)R 10 , CN, C(O)R 8 , C(O)NR 8 R 11 , C(O)OR 8 , NR 8 C(O)NR 8 R 11 , OC(O)NR 8 R 11 , SO 2 NR 8 R 11 , NR 8 SO 2 R 8 , OR 8 , NR 8 R 11 , and S(O) n R 8 wherein n is 0, 1 or 2.
  • R 9 is selected from H, C 1-5 alkyl, halogen, C 1-5 alkyl-NR 8 R 11 , C 1-5 alkyl-C(O)OR 8 , C 1-5 alkyl-C(O)NR 8 R 11 , CN, C(O)R 8 , C(O)NR 8 R 11 , C(O)OR 8 , and OR 8 .
  • R 10 and R 12 are each independently selected from H, C 1-7 alkyl, C 2-7 alkenyl, C 2-7 alkynyl, C 3-7 cycloalkyl, C 4-7 cycloalkenyl, C 1-3 alkanediyl-O-C 1-3 alkanediyl-O-C 1-3 alkanediyl, C 1-3 alkyl-aryl, and C 1-3 alkyl-heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, alkanediyl, aryl, or heteroayl is optionally substituted by halogen, OR 8 , or NR 8 R 11 .
  • R 10 and R 12 are each independently selected from H, C 1-7 alkyl, C 2-7 alkenyl, C 3-7 cycloalkyl, C 4-7 cycloalkenyl, C 1-3 alkanediyl-O-C 1-3 alkanediyl-O-C 1-3 alkanediyl, C 1-3 alkyl-aryl, and C 1-3 alkyl-heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, alkanediyl, aryl, or heteroayl is optionally substituted by halogen or OR 8 .
  • R 10 and R 12 are each independently selected from H, C 1-7 alkyl, C 3-7 cycloalkyl, C 1-3 alkanediyl-O-C 1-3 alkanediyl-O-C 1-3 alkanediyl, and C 1-3 alkyl-aryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, alkanediyl, aryl, or heteroayl is optionally substituted by halogen.
  • R 10 is selected from H, C 1-7 alkyl, C 2-7 alkenyl, C 2-7 alkynyl, C 3-7 cycloalkyl, C 4-7 cycloalkenyl, C 1-3 alkanediyl-O-C 1-3 alkanediyl-O-C 1-3 alkanediyl, C 1-3 alkyl-aryl, and C 1-3 alkyl-heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, alkanediyl, aryl, or heteroayl is optionally substituted by halogen, OR 8 , or NR 8 R 11 .
  • R 10 is selected from H, C 1-7 alkyl, C 2-7 alkenyl, C 3-7 cycloalkyl, C 4-7 cycloalkenyl, C 1-3 alkanediyl-O-C 1-3 alkanediyl-O-C 1-3 alkanediyl, C 1-3 alkyl-aryl, and C 1-3 alkyl- heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, alkanediyl, aryl, or heteroayl is optionally substituted by halogen or OR 8 .
  • R 10 is selected from H, C 1-7 alkyl, C 3-7 cycloalkyl, C 1-3 alkanediyl-O-C 1- 3 alkanediyl-O-C 1-3 alkanediyl, and C 1-3 alkyl-aryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, alkanediyl, aryl, or heteroayl is optionally substituted by halogen.
  • R 12 is selected from H, C 1-7 alkyl, C 2-7 alkenyl, C 2-7 alkynyl, C 3-7 cycloalkyl, C 4-7 cycloalkenyl, C 1-3 alkanediyl-O-C 1-3 alkanediyl-O-C 1-3 alkanediyl, C 1-3 alkyl-aryl, and C 1-3 alkyl-heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, alkanediyl, aryl, or heteroayl is optionally substituted by halogen, OR 8 , or NR 8 R 11 .
  • R 12 is selected from H, C 1-7 alkyl, C 2-7 alkenyl, C 3-7 cycloalkyl, C 4-7 cycloalkenyl, C 1-3 alkanediyl-O-C 1-3 alkanediyl-O-C 1-3 alkanediyl, C 1-3 alkyl-aryl, and C 1-3 alkyl- heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, alkanediyl, aryl, or heteroayl is optionally substituted by halogen or OR 8 .
  • R 12 is selected from H, C 1-7 alkyl, C 3-7 cycloalkyl, C 1-3 alkanediyl-O-C 1- 3 alkanediyl-O-C 1-3 alkanediyl, and C 1-3 alkyl-aryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, alkanediyl, aryl, or heteroayl is optionally substituted by halogen.
  • R 13 is C 1-5 alkyl substituted by a bicyclic ring optionally comprising at least one heteroatom and a carbonyl group.
  • R 14 is selected from H, C 1-7 alkyl, C 2-7 alkenyl, C 2-7 alkynyl, C 3-7 cycloalkyl, C 4-7 cycloalkenyl, and C 1-3 alkyl substituted by aryl or heteroaryl, wherein the aryl or the heteroaryl is optionally substituted by halogen, C 1-4 alkyl, or C 3-5 cycloalkyl.
  • R 14 is H.
  • R 14 is selected from C 1-7 alkyl, C 3-7 cycloalkyl, and C 1-3 alkyl substituted by aryl or heteroaryl, wherein the aryl or the heteroaryl is optionally substituted by halogen, C 1-4 alkyl, or C 3-5 cycloalkyl.
  • R 14 is selected from C 1-7 alkyl and C 3-7 cycloalkyl.
  • R 14 is C 1-7 alkyl.
  • each R 15 is independently selected from H, C 1-7 alkyl, C 2-7 alkenyl, C 2-7 alkynyl, C 3-7 cycloalkyl, C 4-7 cycloalkenyl, OR 8 , and C 1-3 alkyl-OR 8 .
  • each R 15 is independently selected from H, C 1-7 alkyl, and C 3-7 cycloalkyl.
  • each R 15 is independently selected from H and C 1-7 alkyl.
  • X is selected from a bond, C 1-7 alkanediyl, C 2-7 alkenediyl, C 2-7 alkynediyl, C 3-9 cycloalkanediyl, C4-6 cycloalkenediyl, -O-, C 1-3 alkanediyl-O-, -O-C 1-7 alkanediyl, -O- C 3-9 cycloalkanediyl, C 1-3 alkanediyl-O-C 1-7 alkanediyl, C 1-7 heteroalkanediyl, and -S-C 1-7 alkanediyl; and wherein X can form a ring or a polycyclic system with any part of R 5 , R 6 , or Y, wherein the ring optionally comprises a carbonyl group.
  • X is selected from a bond, C 1-7 alkanediyl, C 2-7 alkenediyl, C 2-7 alkynediyl, C 3-6 cycloalkanediyl, C4-6 cycloalkenediyl, -O-, C 1-3 alkanediyl-O-, -O-C 1-7 alkanediyl, Ci- 3 alkanediyl-O-C 1-7 alkanediyl, C 1-7 heteroalkanediyl, and -S-C 1-7 alkanediyl; and wherein X can form a ring with any part of R 5 or Y, wherein the ring optionally comprises a carbonyl group.
  • X is selected from a bond, C 1-7 alkanediyl, -O-, C 1-3 alkanediyl-O-, -O- C 1-7 alkanediyl, C 1-3 alkanediyl-O-C 1-7 alkanediyl, C 1-7 heteroalkanediyl, and -S-C 1-7 alkanediyl; and wherein X can form a ring with any part of R 5 and when Y is C(O)NR 10 R 12 or NR 10 R 12 , X can form a ring with any part of Y, wherein the ring optionally comprises a carbonyl group.
  • X is selected from a bond, -O-C 1-7 alkanediyl, -S-C 1-7 alkanediyl, and C 1-7 alkanediyl; and wherein -O-C 1-7 alkanediyl, S-C 1-7 alkanediyl or C 1-7 alkanediyl of X can form a ring with any part of R 5 or Y, wherein the ring optionally comprises a carbonyl group.
  • X is selected from a bond, -O-C 1-7 alkanediyl, and C 1-7 alkanediyl; and wherein -O-C 1-7 alkanediyl or C 1-7 alkanediyl of X can form a ring with any part of R 5 or, when Y is C(O)NR 10 R 12 or NR 10 R 12 , C 1-7 alkanediyl of X can form a ring with any part of Y, wherein the ring optionally comprises a carbonyl group.
  • X is selected from a bond, -O-C 1-7 alkanediyl, S-C 1-7 alkanediyl, and C 1-7 alkanediyl, and wherein -O-C 1-7 alkanediyl, S-C 1-7 alkanediyl or C 1-7 alkanediyl can form a ring with any part of R 5 , wherein the ring optionally comprises a carbonyl group.
  • X is selected from a bond and C 1-7 alkanediyl, and wherein C 1-7 alkanediyl of X can form a ring with any part of Y.
  • X is -O-C 1-7 alkanediyl, wherein -O-C 1-7 alkanediyl can form a ring with any part of R 5 , wherein the ring optionally comprises a carbonyl group.
  • X is -O-C 1-7 alkanediyl, wherein -O-C 1-7 alkanediyl can form a ring with any part of R 5 .
  • X is -O-C 1-7 alkanediyl, wherein -O-C 1-7 alkanediyl can form a ring with any part of R 5
  • Y is C(O)NR 10 R 12 or NR 10 R 12 , wherein R 10 and R 12 can form a ring wherein the ring comprises the N of NR 10 R 12 and optionally one further heteroatom selected from O and N, wherein if the one further heteroatom is N, it is optionally substituted by R 8 .
  • X is -O-C 1-7 alkanediyl, wherein -O-C 1-7 alkanediyl can form a ring with any part of R 5
  • Y is C(O)NR 10 R 12 or NR 10 R 12 , wherein R 10 and R 12 can form a ring wherein the ring comprises the N of NR 10 R 12 .
  • the ring which can be formed by R 5 and any part of X or Y, the ring which can be formed by X and any part of R 5 or Y, and/or the ring which can be formed by Y and any part of X or R 5 is a non-aromatic ring.
  • the non-aromatic ring comprises between four and six atoms (e.g. four and six carbon and heteroatoms).
  • the non-aromatic ring comprises between three and five carbon and one nitrogen atom or a non-aromatic ring comprising between two and four carbon and one or two oxygen or sulfur (e.g., two, oxygen or sulfur).
  • the non-aromatic ring comprises between two and four carbon and one or two oxygen atoms.
  • Y is selected from H, C(O)NR 10 R 12 , C(O)OR 10 , R 10 NC(O)NR 10 R 12 , OC(O)R 10 , OC(O)NR 10 R 12 , S(O) conjunctionR 8 wherein n is 0, 1 or 2, SO 2 NR 10 R 12 , NR 10 SO 2 R 10 , NR 10 R 12 , HNCOR 8 , CN, C 3-7 -cycloalkyl optionally comprising a heteroatom in the ring selected from O and N wherein if the heteroatom is N it is optionally substituted by R 8 , S-aryl, O-aryl, S-heteroaryl, and O- heteroaryl, wherein the S-aryl, O-aryl, S-heteroaryl, or O-heteroaryl is optionally substituted by one or more R 9 or R 14 ; or Y is aryl, heteroaryl wherein the aryl or heteroaryl is
  • Y is selected from NR 10 R 12 and C 3-7 -cycloalkyl optionally comprising a heteroatom in the ring selected from O and N wherein if the heteroatom is N it is optionally substituted by R 8 ; and wherein Y can form a ring with any part of X or R 5 ; with the proviso that when Y is NR 10 R 12 , R 10 and R 12 can form a ring wherein the ring comprises the N of NR 10 R 12 and optionally one further heteroatom selected from O and N, wherein if the one further heteroatom is N, it is optionally substituted by R 8 .
  • Y is NR 10 R 12 , wherein R 10 and R 12 can form a ring wherein the ring comprises the N of NR 10 R 12 and optionally one further heteroatom selected from O and N, wherein if the one further heteroatom is N, it is optionally substituted by R 8 .
  • Y is C(O)NR 10 R 12 or NR 10 R 12
  • R 10 and R 12 can form a ring optionally substituted by R 9 or R 14 ; wherein the ring comprises the N of NR 10 R 12 and optionally one further heteroatom selected from O and N, wherein if the one further heteroatom is N, it is optionally substituted by R 8 .
  • Y is C(O)NR 10 R 12 or NR 10 R 12
  • R 10 and R 12 can form a ring, wherein the ring comprises the N of NR 10 R 12 .
  • Y is C(O)NR 10 R 12 , wherein R 10 and R 12 can form a ring wherein the ring comprises the N of NR 10 R 12 and optionally one further heteroatom selected from O and N, wherein if the one further heteroatom is N, it is optionally substituted by R 8 .
  • Y is selected from O-aryl and O-heteroaryl, wherein the O-aryl and O- heteroaryl are optionally substituted by one or more R 9 or R 14 .
  • Y is selected from H, C(O)NR 10 R 12 , C(O)OR 10 , NR 10 R 12 , CN, C 3-7 - cycloalkyl optionally containing a heteroatom in the ring selected from O and N wherein if the heteroatom is N it is optionally substituted by R 8 , S-aryl, O-aryl, S-heteroaryl, and O-heteroaryl wherein the S-aryl, O-aryl, S-heteroaryl, or O-heteroaryl are optionally substituted by one or more R 9 or R 14 ; or Y is aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted by one or more of R 8 ; and wherein when Y is C(O)NR 10 R 12 or NR 10 R 12 , Y can form a ring with any part of X or R 5 , wherein the ring optionally contains a carbonyl group
  • Y is selected from H, C(O)NR 10 R 12 , C(O)OR 10 , NR 10 R 12 , CN, C 3-7 - cycloalkyl optionally containing a heteroatom in the ring selected from O and N wherein if the heteroatom is N it is optionally substituted by R 8 , S-aryl, O-aryl, S-heteroaryl, and O-heteroaryl wherein the S-aryl, O-aryl, S-heteroaryl, or O-heteroaryl are optionally substituted by one or more R 9 or R 14 ; or Y is aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted by one or more of R 8 ; and wherein Y can form a ring with any part of X or R 5 , wherein the ring optionally contains a carbonyl group; with the proviso that when Y is C(O)NR 10 R 12 or
  • Y is selected from C(O)NR 10 R 12 , NR 10 R 12 , C 3-7 -cycloalkyl optionally containing a heteroatom in the ring selected from O and N wherein if the heteroatom is N it is optionally substituted by R 8 , S-aryl, O-aryl, S-heteroaryl, and O-heteroaryl wherein the S-aryl, O-aryl, S-heteroaryl, or O-heteroaryl are optionally substituted by one or more R 9 or R 14 ; or Y is heteroaryl, wherein the heteroaryl is optionally substituted by one or more of R 8 ; and wherein Y can form a ring with any part of X or R 5 , wherein the ring optionally contains a carbonyl group; with the proviso that when Y is C(O)NR 10 R 12 or NR 10 R 12 , R 10 and R 12 can form a ring wherein the
  • Y is selected from NR 10 R 12 and C 3-7 -cycloalkyl optionally containing a heteroatom in the ring selected from O and N wherein if the heteroatom is N it is optionally substituted by R 8 ; and wherein Y can form a ring with any part of X or R 5 ; with the proviso that when Y is NR 10 R 12 , R 10 and R 12 can form a ring wherein the ring contains the N of NR 10 R 12 and optionally one further heteroatom selected from O and N, wherein if the one further heteroatom is N, the ring is optionally substituted by R 8 .
  • Y is aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted by one or more of R 8 ; or S-heteroaryl, wherein the S-heteroaryl is optionally substituted by one or more R 14 .
  • R 5 is selected from H and C 1-7 alkyl
  • X is selected from a bond and C 1-7 alkanediyl
  • Y is heteroaryl, wherein the heteroaryl is optionally substituted by one or more of R 8 ; or S- heteroaryl, wherein the S-heteroaryl is optionally substituted by one or more R 14 .
  • Y is C(O)NR 10 R 12 ; and R 10 and R 12 can form a ring wherein the ring contains the N of NR 10 R 12 and optionally one further heteroatom selected from O and N, wherein if the one further heteroatom is N, the is optionally substituted by R 8 .
  • Y is C(O)OR 10 .
  • R 5 is selected from H and C 1-7 alkyl; X is selected from a bond and C 1-7 alkanediyl; Y is C(O)OR 10 ; and R 10 is selected from H, C 1-7 alkyl, C 2-7 alkenyl, C 3-7 cycloalkyl, C 4-7 cycloalkenyl, C 1-3 alkanediyl-O-C 1-3 alkanediyl-O-C 1-3 alkanediyl, C 1-3 alkyl-aryl, and C 1-3 alkyl- heteroaryl, wherein alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkanediyl, aryl, or heteroaryl are optionally substituted by OR 8 .
  • Y is H.
  • R 5 is C 1-7 alkyl; X is a bond; and Y is H.
  • Y is CN
  • R 5 is H; X is C 1-7 alkanediyl; and Y is CN.
  • R 5 is selected from H and C 1-7 alkyl
  • X is selected from a bond and C 1-7 alkanediyl
  • Y is C(O)NR 10 R 12 ;
  • R 10 and R 12 can form a ring wherein the ring contains the N of NR 10 R 12 and optionally one further heteroatom selected from O and N, wherein if the one further heteroatom is N, the ring is optionally substituted by R 8 ; and wherein R 10 and R 12 are each independently selected from H, C 1-7 alkyl, C 2-7 alkenyl, C 3-7 cycloalkyl, and C 1-3 alkyl-aryl.
  • Y is selected from S-aryl, O-aryl, S-heteroaryl, and O-heteroaryl, wherein the S-aryl, O-aryl, S-heteroaryl, or O-heteroaryl are optionally substituted by one or more R 9 or R 14 .
  • R 5 is selected from H and C 1-7 alkyl
  • X is selected from a bond and C 1-7 alkanediyl
  • Y is selected from O-aryl and O-heteroaryl, wherein the O-aryl or O-heteroaryl is optionally substituted by one or more R 9 ;
  • R 9 is selected from H, C 1-5 alkyl, halogen, C 1-5 alkyl-NR 8 R 11 , C 1-5 alkyl-C(O)OR 8 , C 1-5 alkyl- C(O)NR 8 R 11 , CN, C(O)R 8 , C(O)NR 8 R 11 , C(O)OR 8 , and OR 8 .
  • R 5 is OR 8 , wherein R 8 is C 1-7 alkyl, wherein OR 8 of R 5 can form a ring with any part of X;
  • X is -O-C 1-7 alkanediyl, wherein -O-C 1-7 alkanediyl of X can form a ring with any part of R 5 ;
  • Y is NR 10 R 12 wherein R 10 and R 12 can form a ring wherein the ring comprises the N of NR 10 R 12 and four or five carbon atoms.
  • the compound is a compound of Formula (I) or Formula (la), wherein: R 1 is selected from C 3-7 alkyl, C 3-7 cycloalkyl, and C 1-3 alkyl substituted by aryl or heteroaryl; R 2 is selected from H, C(O)R 14 , C 1-7 alkyl, C 3-7 cycloalkyl, C 1-5 alkyl-OR 8 , and C 1-5 alkyl- NHCOR 13 , wherein R 13 is pentylamino-5-oxopentyl-7-thia-2.4-diazabicyclo[3.3.0]octan-3-one; or C 1-3 alkyl substituted by aryl, wherein the aryl is optionally substituted by halogen, C 1-4 alkyl or C 3-5 cycloalkyl;
  • R 3 and R 7 are H
  • R 4 is selected from C 3-7 alkyl, C 3-7 cycloalkyl, and C 1-3 alkyl substituted by aryl or heteroaryl;
  • R 5 is selected from H, C 1-7 alkyl, and OR 8 ; and wherein C 1-7 alkyl or OR 8 of R 5 can form a ring with any part of X or, when Y is C(O)NR 10 R 12 or NR 10 R 12 , C 1-7 alkyl of R 5 can form a ring with any part of Y, wherein the ring optionally comprises a carbonyl group;
  • R 6 is H or C 1-7 alkyl
  • R 8 and R 11 are each independently selected from H, C 1-7 alkyl, C 2-7 alkenyl, and C 3-7 cycloalkyl;
  • X is selected from a bond, -O-C 1-7 alkanediyl, and C 1-7 alkanediyl, wherein -O-C 1-7 alkanediyl or C 1-7 alkanediyl of X can form a ring with any part of R 5 or, when Y is C(O)NR 10 R 12 or NR 10 R 12 , C 1-7 alkanediyl of X can form a ring with any part of Y, wherein the ring optionally comprises a carbonyl group;
  • Y is selected from C(O)NR 10 R 12 , C(O)OR 10 , NR 10 R 12 , C 3-7 -cycloalkyl optionally comprises a heteroatom in the ring selected from O and N wherein if the heteroatom is N it is optionally substituted by R 8 , O-aryl, S-heteroaryl, and O-heteroaryl, wherein the O-aryl or the O-heteroaryl is optionally substituted by one or more R 9 and wherein the S-heteroaryl is optionally substituted by one or more R 14 ; or heteroaryl wherein the heteroaryl is optionally substituted by one or more of R 8 ; and wherein, when Y is C(O)NR 10 R 12 or NR 10 R 12 , Y can form a ring with any part of C 1-7 alkanediyl of X or any part of C 1-7 alkyl of R 5 , wherein the ring optionally comprises a carbonyl group; with the
  • R 9 is selected from H, C 1-5 alkyl, halogen, C 1-5 alkyl-NR 8 R 11 , C 1-5 alkyl- C(O)NR 8 R 11 , C 1-5 alkyl-C(O)OR 8 , CN, C(O)R 8 , C(O)NR 8 R 11 , C(O)OR 8 , and OR 8 ;
  • R 10 and R 12 are each independently selected from H, C 1-7 alkyl, C 2-7 alkenyl, C 3-7 cycloalkyl, C 4-7 cycloalkenyl, C 1-3 alkanediyl-O-C 1-3 alkanediyl-O-C 1-3 alkanediyl, C 1-3 alkyl-aryl, or C 1-3 alkyl- heteroaryl, all these groups optionally substituted by halogen or OR 8 ; and R 14 is C 1-7 alkyl.
  • R 5 is selected from H and C 1-7 alkyl; wherein C 1-7 alkyl of R 5 can form a ring with any part of Y;
  • X is selected from a bond and C 1-7 alkanediyl, and wherein C 1-7 alkanediyl of X can form a ring with any part of Y;
  • Y is selected from NR 10 R 12 and C 3-7 -cycloalkyl optionally containing a heteroatom in the ring, wherein the heteroatom is N and is optionally substituted by R 8 , wherein R 8 is C 1-7 alkyl;
  • Y can form a ring with any part of C 1-7 alkanediyl of X or with any part of C 1-7 alkyl of R 5 ; with the proviso that when Y is NR 10 R 12 , R 10 and R 12 can form a ring wherein the ring contains the N of NR 10 R 12 and optionally one further heteroatom selected from O and N, wherein if the one further heteroatom is N, the ring is optionally substituted by R 8 ; and
  • R 10 and R 12 are each independently selected from H, C 1-7 alkyl, C 3-7 cycloalkyl, and C 1-3 alkyl- aryl, wherein alkyl, cycloalkyl, or aryl are optionally substituted by halogen.
  • R 5 is selected from C 1-7 alkyl, OR 8 , and SR 8 ; wherein C 1-7 alkyl, OR 8 , or SR 8 of R 5 can form a ring with any part of X;
  • X is selected from -O-C 1-7 alkanediyl, -S-C 1-7 alkanediyl, and C 1-7 alkanediyl, and wherein -O- C 1-7 alkanediyl, -S-C 1-7 alkanediyl, or C 1-7 alkanediyl of X can form a ring with any part of R 5 ; and
  • Y is NR 10 R 12 wherein R 10 and R 12 can form a ring wherein the ring contains the N of NR 10 R 12 and optionally one further heteroatom selected from O and N, wherein if the one further heteroatom is N, the ring is optionally substituted by R 8 .
  • R 5 is OR 8 , wherein R 8 of OR 8 is C 1-7 alkyl, and wherein OR 8 of R 5 can form a ring with any part of X;
  • X is — O-C 1-7 alkanediyl, and wherein -O-C 1-7 alkanediyl of X can form a ring with any part of
  • Y is NR 10 R 12 , wherein R 10 and R 12 can form a ring wherein the ring contains the N of NR 10 R 12 and four or five carbon atoms.
  • R 5 , X and Y form a spirane or spiro compound at the -4 position of the piperidine ring. [0389] In some embodiments, R 5 , X and Y form a spirane or spiro compound at the -4 position of the common atom of the spirane.
  • R 5 , X and Y form a spirane or spiro compound at the -4 position of the piperidine ring and R 5 , X and Y form
  • R 5 , X and Y form a spirane or spiro compound at the -4 position of the piperidine ring and R 5 , X and Y form , wherein indicates the -4 position of the piperidine ring, the common atom of the spirane.
  • R 5 , X and Y form a spirane or spiro compound at the -4 position of the piperidine ring and R 5 , X and Y form , wherein indicates the -4 position of the piperidine ring, the common atom of the spirane.
  • the compound is of Formula (Ila), (lIb), or (IIc): or a pharmaceutically acceptable salt, hydrate, solvate or stereoisomer thereof, wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , X, and Y are as described herein.
  • the compound is of Formula (Ila) or a pharmaceutically acceptable salt, hydrate, solvate or stereoisomer thereof.
  • the compound is of Formula (lIb) or a pharmaceutically acceptable salt, hydrate, solvate or stereoisomer thereof.
  • the compound is of Formula (IIc) or a pharmaceutically acceptable salt, hydrate, solvate or stereoisomer thereof.
  • the compound is of Formula (Ilia), (Illb), (IIIc), or (IIId): or a pharmaceutically acceptable salt, hydrate, solvate or stereoisomer thereof, wherein R 1 , R 4 , R 5 , R 6 , X, and Y are as described herein.
  • the compound is of Formula (IlIa) or a pharmaceutically acceptable salt, hydrate, solvate or stereoisomer thereof.
  • the compound is of Formula (Illb) or a pharmaceutically acceptable salt, hydrate, solvate or stereoisomer thereof.
  • the compound is of Formula (IIIc) or a pharmaceutically acceptable salt, hydrate, solvate or stereoisomer thereof.
  • the compound is of Formula (IId) or a pharmaceutically acceptable salt, hydrate, solvate or stereoisomer thereof.
  • the compound is of Formula (IVa), (IVb), (IVc) or (IVd):
  • R 1 , R 2 , R 4 , R 5 , R 6 , X, and Y are as described herein.
  • the compound is of Formula (IVa) or a pharmaceutically acceptable salt, hydrate, solvate or stereoisomer thereof.
  • the compound is of Formula (IVb) or a pharmaceutically acceptable salt, hydrate, solvate or stereoisomer thereof.
  • the compound is of Formula (IVc) or a pharmaceutically acceptable salt, hydrate, solvate or stereoisomer thereof.
  • the compound is of Formula (IVd) or a pharmaceutically acceptable salt, hydrate, solvate or stereoisomer thereof.
  • the compound is of Formula (Va), (Vb), (Vc), or (Vd): or a pharmaceutically acceptable salt, hydrate, solvate or stereoisomer thereof, wherein n5 is 0, 1, 2, 3, 4, 5, 6, or 7, preferably 1, 2, or 3, and R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , R 10 and R 12 are as described herein [0408] In some embodiments, the compound is of Formula (Va) or a pharmaceutically acceptable salt, hydrate, solvate or stereoisomer thereof. [0409] In some embodiments, the compound is of Formula (Vb) or a pharmaceutically acceptable salt, hydrate, solvate or stereoisomer thereof.
  • the compound is of Formula (Vc) or a pharmaceutically acceptable salt, hydrate, solvate or stereoisomer thereof.
  • the compound is of Formula (Vd) or a pharmaceutically acceptable salt, hydrate, solvate or stereoisomer thereof.
  • the compound is of Formula (VIa), (VIb), (VIc), or (VId): or a pharmaceutically acceptable salt, hydrate, solvate or stereoisomer thereof, wherein n5 is 0, 1, 2, 3, 4, 5, 6, or 7, preferably 1, 2, or 3, and R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , R 10 and R 12 are as described herein.
  • the compound is of Formula (VIc): or a pharmaceutically acceptable salt, hydrate, solvate or stereoisomer thereof, wherein n5 is 0, 1, 2, 3, 4, 5, 6, or 7.
  • n5 is 0, 1, 2, 3, 4, 5, 6, or 7.
  • n5 is 1, 2, or 3.
  • the compound is of Formula (VIa) or a pharmaceutically acceptable salt, hydrate, solvate or stereoisomer thereof.
  • the compound is of Formula (VIb) or a pharmaceutically acceptable salt, hydrate, solvate or stereoisomer thereof.
  • the compound is of Formula (VIc) or a pharmaceutically acceptable salt, hydrate, solvate or stereoisomer thereof.
  • the compound is of Formula (VId) or a pharmaceutically acceptable salt, hydrate, solvate or stereoisomer thereof.
  • the compound is of Formula (VIla), (Vllb), (VIle), (Vlld), (VIle), or (VIIf): or a pharmaceutically acceptable salt, hydrate, solvate or stereoisomer thereof, wherein n8 is 0, 1, 2, 3, 4, 5, 6, or 7, preferably 1, 2, or 3, and wherein R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , and R 8 are as described herein.
  • the compound is of Formula (VIla) or a pharmaceutically acceptable salt, hydrate, solvate or stereoisomer thereof.
  • the compound is of Formula (VIlb) or a pharmaceutically acceptable salt, hydrate, solvate or stereoisomer thereof.
  • the compound is of Formula (VIle) or a pharmaceutically acceptable salt, hydrate, solvate or stereoisomer thereof.
  • the compound is of Formula (VIld) or a pharmaceutically acceptable salt, hydrate, solvate or stereoisomer thereof.
  • the compound is of Formula (VIle) or a pharmaceutically acceptable salt, hydrate, solvate or stereoisomer thereof.
  • the compound is of Formula (Vllf) or a pharmaceutically acceptable salt, hydrate, solvate or stereoisomer thereof.
  • the compound is of Formula (VIlla), (VIIIb), (VIIIc), (VIIId), (VIIIe), (Vlllf), (Vlllg), (Vlllh), (VIlli), (Vlllj), (Vlllk), or (VIIIl):
  • Q 1 and Q 2 are each independently O, S, NR 8 , or CR 8 , and R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , R 8 , and Y are as described herein.
  • Q 1 and Q 2 are each independently O, S, NR 8 , or CR 8 .
  • Q 1 and Q 2 are each O. In some embodiments, Q 1 is O. In some embodiments, Q 2 is O.
  • the compound is of Formula (VIlla) or a pharmaceutically acceptable salt, hydrate, solvate or stereoisomer thereof.
  • the compound is of Formula (Vlllb) or a pharmaceutically acceptable salt, hydrate, solvate or stereoisomer thereof.
  • the compound is of Formula (VIIIc) or a pharmaceutically acceptable salt, hydrate, solvate or stereoisomer thereof.
  • the compound is of Formula (VIII d) or a pharmaceutically acceptable salt, hydrate, solvate or stereoisomer thereof.
  • the compound is of Formula (VIIIe) or a pharmaceutically acceptable salt, hydrate, solvate or stereoisomer thereof.
  • the compound is of Formula (VIIIf) or a pharmaceutically acceptable salt, hydrate, solvate or stereoisomer thereof.
  • the compound is of Formula (VIIIg) or a pharmaceutically acceptable salt, hydrate, solvate or stereoisomer thereof.
  • the compound is of Formula (VIIIh) or a pharmaceutically acceptable salt, hydrate, solvate or stereoisomer thereof.
  • the compound is of Formula (VIlli) or a pharmaceutically acceptable salt, hydrate, solvate or stereoisomer thereof.
  • the compound is of Formula (VIIIj) or a pharmaceutically acceptable salt, hydrate, solvate or stereoisomer thereof.
  • the compound is of Formula (Vlllk) or a pharmaceutically acceptable salt, hydrate, solvate or stereoisomer thereof.
  • the compound is of Formula (VIIIl) or a pharmaceutically acceptable salt, hydrate, solvate or stereoisomer thereof.
  • the compound is of Formula (VIlli), (Vlllk), or (VIIIl): or a pharmaceutically acceptable salt, hydrate, solvate, or stereoisomer thereof, wherein Q 1 and Q 2 are each independently O, S, NR 8 , or CR 8 , and wherein R 6 , R 8 , and Y are as described herein.
  • the compound is of Formula (Vllla11, (Vlllbl), (VIIIc1), (Vllld1), (Vllle1), (Vlllf1), (Vlllg1), (Vlllh1), (VIIIi1), (Vlllj1), (Vlllk1), or (VIIIl1):
  • n8a is 0, 1, 2, 3, 4, 5, 6, or 7.
  • n8a is 1, 2, or 3.
  • the compound is of Formula (VIIIa1) or a pharmaceutically acceptable salt, hydrate, solvate, or stereoisomer thereof.
  • the compound is of Formula (VIIIb1) or a pharmaceutically acceptable salt, hydrate, solvate, or stereoisomer thereof.
  • the compound is of Formula (VIIIc1) or a pharmaceutically acceptable salt, hydrate, solvate, or stereoisomer thereof.
  • the compound is of Formula (VIIId1) or a pharmaceutically acceptable salt, hydrate, solvate, or stereoisomer thereof.
  • the compound is of Formula (VIIIe1) or a pharmaceutically acceptable salt, hydrate, solvate, or stereoisomer thereof.
  • the compound is of Formula (Vlllf1) or a pharmaceutically acceptable salt, hydrate, solvate, or stereoisomer thereof.
  • the compound is of Formula (Vlllg1) or a pharmaceutically acceptable salt, hydrate, solvate, or stereoisomer thereof.
  • the compound is of Formula (Vlllh1) or a pharmaceutically acceptable salt, hydrate, solvate, or stereoisomer thereof.
  • the compound is of Formula (VIlli1) or a pharmaceutically acceptable salt, hydrate, solvate, or stereoisomer thereof.
  • the compound is of Formula (VIIIj1) or a pharmaceutically acceptable salt, hydrate, solvate, or stereoisomer thereof.
  • the compound is of Formula (VIIIk1) or a pharmaceutically acceptable salt, hydrate, solvate, or stereoisomer thereof.
  • the compound is of Formula (VIIIl1) or a pharmaceutically acceptable salt, hydrate, solvate, or stereoisomer thereof.
  • the compound is of Formula (IXa), (IXb), (IXc), or (IXd): or a pharmaceutically acceptable salt, hydrate, solvate, or stereoisomer thereof, wherein n10 is 0, 1, 2, 3, 4, 5, 6, or 7, preferably 1, 2, or 3, and R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , R 10 , R 12 and Y are as described herein. [0459] In some embodiments, n10 is 0, 1, 2, 3, 4, 5, 6, or 7.
  • n10 is 1, 2, or 3.
  • the compound is of Formula (IXa) or a pharmaceutically acceptable salt, hydrate, solvate, or stereoisomer thereof.
  • the compound is of Formula (IXb) or a pharmaceutically acceptable salt, hydrate, solvate, or stereoisomer thereof.
  • the compound is of Formula (IXc) or a pharmaceutically acceptable salt, hydrate, solvate, or stereoisomer thereof.
  • the compound is of Formula (IXd) or a pharmaceutically acceptable salt, hydrate, solvate, or stereoisomer thereof.
  • the compound is of Formula (IXc) or (IXd): or a pharmaceutically acceptable salt, hydrate, solvate, or stereoisomer thereof, wherein n10 is 0, 1, 2, 3, 4, 5, 6, or 7, and wherein R 6 , R 10 , and R 12 are as described herein.
  • the compound is of Formula (IXd): or a pharmaceutically acceptable salt, hydrate, solvate, or stereoisomer thereof, wherein R 6 , R 10 , and R 12 are as described herein.
  • the compound is of Formula (IXal), (IXbl), (IXcl), or (IXdl):
  • * indicates the Z-isomer of the spiro compound.
  • the compound is of Formula (IXa1) or a pharmaceutically acceptable salt, hydrate, solvate, or stereoisomer thereof.
  • the compound is of Formula (IXb1) or a pharmaceutically acceptable salt, hydrate, solvate, or stereoisomer thereof.
  • the compound is of Formula (IXc1) or a pharmaceutically acceptable salt, hydrate, solvate, or stereoisomer thereof.
  • the compound is of Formula (IXd1) or a pharmaceutically acceptable salt, hydrate, solvate, or stereoisomer thereof.
  • the term "pharmaceutically acceptable salt” refers to those salts of the compounds formed by the process of the present application which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge, et al. describes pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66: 1-19 (1977). The salts can be prepared in situ during the final isolation and purification of the compounds of the application, or separately by reacting the free base or acid function with a suitable acid or base.
  • salts include, but are not limited to, nontoxic acid addition salts: salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid, or with organic acids such as acetic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid
  • organic acids such as acetic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid.
  • salts include, but are not limited to, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamo
  • alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
  • Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, alkyl having from 1 to 6 carbon atoms, sulfonate and aryl sulfonate.
  • prodrugs refers to those prodrugs of the compounds formed by the process of the present application which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals with undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds of the present application.
  • Prodrug means a compound which is convertible in vivo by metabolic means (e.g., by hydrolysis) to afford any compound delineated by the formulae of the instant application.
  • prodrugs are known in the art, for example, as discussed in Bundgaard, (ed.), Design of Prodrugs, Elsevier (1985); Widder, et al. (ed.), Methods in Enzymology, vol. 4, Academic Press (1985); Krogsgaard-Larsen, et al., (ed). "Design and Application of Prodrugs, Textbook of Drug Design and Development, Chapter 5, 113-191 (1991); Bundgaard, et al, Journal of Drug Deliver Reviews, 8:1-38(1992); Bundgaard, J. of Pharmaceutical Sciences,
  • This application also encompasses pharmaceutical compositions comprising, and methods of treating disorders through administering, pharmaceutically acceptable prodrugs of compounds of the application.
  • compounds of the application having free amino, amido, hydroxy or carboxylic groups can be converted into prodrugs.
  • Prodrugs include compounds wherein an amino acid residue, or a polypeptide chain of two or more (e.g ., two, three or four) amino acid residues is covalently joined through an amide or ester bond to a free amino, hydroxy or carboxylic acid group of compounds of the application.
  • the amino acid residues include but are not limited to the 20 naturally occurring amino acids commonly designated by three letter symbols and also includes 4- hydroxyproline, hydroxy lysine, demosine, isodemosine, 3-methylhistidine, norvalin, beta-alanine, gamma-aminobutyric acid, citrulline, homocysteine, homoserine, ornithine and methionine sulfone.
  • prodrugs can be derivatized as amides or alkyl esters.
  • Free hydroxy groups may be derivatized using groups including but not limited to hemisuccinates, phosphate esters, dimethylaminoacetates, and phosphoryloxymethyloxy carbonyls, as outlined in Advanced Drug Delivery Reviews, 1996, 19, 115.
  • Carbamate prodrugs of hydroxy and amino groups are also included, as are carbonate prodrugs, sulfonate esters and sulfate esters of hydroxy groups.
  • acyl group may be an alkyl ester, optionally substituted with groups including but not limited to ether, amine and carboxylic acid functionalities, or where the acyl group is an amino acid ester as described above, are also encompassed.
  • Prodrugs of this type are described in J Med. Chem. 1996, 39, 10. Free amines can also be derivatized as amides, sulfonamides or phosphonamides. All of these prodrug moieties may incorporate groups including but not limited to ether, amine and carboxylic acid functionalities.
  • the application also provides for a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of the application, or an enantiomer, diastereomer, stereoisomer, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • Another aspect is an isotopically labeled compound of any of the formulae delineated herein.
  • Such compounds have one or more isotope atoms which may or may not be radioactive (e.g., 3 H, 2 H, 14 C, 13 C, 18 F, 35 S, 32 P, 125 I, and 131 I) introduced into the compound.
  • isotope atoms which may or may not be radioactive (e.g., 3 H, 2 H, 14 C, 13 C, 18 F, 35 S, 32 P, 125 I, and 131 I) introduced into the compound.
  • radioactive e.g., 3 H, 2 H, 14 C, 13 C, 18 F, 35 S, 32 P, 125 I, and 131 I
  • the salt forms of the compounds of the application can be prepared using salts of the starting materials or intermediates.
  • the free acid or free base forms of the compounds of the application can be prepared from the corresponding base addition salt or acid addition salt from, respectively.
  • a compound of the application in an acid addition salt form can be converted to the corresponding free base by treating with a suitable base (e.g ., ammonium hydroxide solution, sodium hydroxide, and the like).
  • a compound of the application in a base addition salt form can be converted to the corresponding free acid by treating with a suitable acid (e.g., hydrochloric acid, etc.).
  • the compounds of the present invention may be used in the form of pharmaceutically acceptable salts derived from inorganic or organic acids.
  • pharmaceutically-acceptable salt is meant those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable salts are well-known in the art. The salts may be prepared in situ during the final isolation and purification of the compounds of the invention or separately by reacting a free base function with a suitable acid.
  • Representative acid addition salts include, but are not limited to trifluoroacetic acid (TFA), formate, acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate (isethionate), lactate, maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, phosphate, glutamate, bicarbonate,
  • TFA
  • the basic nitrogen-containing groups can be quaternized with such agents as lower alkyl halides such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl and diamyl sulfates; long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides; arylalkyl halides like benzyl and phenethyl bromides and others. Water or oil-soluble or dispersible products are thereby obtained.
  • lower alkyl halides such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides
  • dialkyl sulfates like dimethyl, diethyl, dibutyl and diamyl sulfates
  • long chain halides such as decyl
  • Basic addition salts can be prepared in situ during the final isolation and purification of compounds of this invention by reacting a carboxylic acid-containing moiety with a suitable base such as the hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation or with ammonia or an organic primary, secondary or tertiary amine.
  • a suitable base such as the hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation or with ammonia or an organic primary, secondary or tertiary amine.
  • Pharmaceutically-acceptable basic addition salts include, but are not limited to, cations based on alkali metals or alkaline earth metals such as lithium, sodium, potassium, calcium, magnesium and aluminum salts and the like and nontoxic quaternary ammonia and amine cations including ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine and the like.
  • Other representative organic amines useful for the formation of base addition salts include ethylenediamine, ethanolamine, diethanolamine, piperidine, piperazine and the like.
  • Prodrugs of the compounds of the application can be prepared by methods known to those of ordinary skill in the art (e.g ., for further details see Saulnier et al, (1994), Bioorganic and Medicinal Chemistry Letters, Vol. 4, p. 1985).
  • appropriate prodrugs can be prepared by reacting a non-derivatized compound of the application with a suitable carbamylating agent (e.g., 1,1- acyloxyalkylcarbanochloridate, para-nitrophenyl carbonate, or the like).
  • Protected derivatives of the compounds of the application can be made by means known to those of ordinary skill in the art. A detailed description of techniques applicable to the creation of protecting groups and their removal include, but are not limited to, those illustrated in T. W. Greene, "Protecting Groups in Organic Chemistry", 3rd edition, John Wiley and Sons, Inc., 1999.
  • compounds of the present application are synthesized through the routes disclosed in PCT/US2018/066027, the contents of which is incorporated herein by reference.
  • Compound of the present disclosure can be conveniently prepared or formed during the process of the application, as solvates (e.g., hydrates). Hydrates of compounds of the present application can be conveniently prepared by recrystallization from an aqueous/organic solvent mixture, using organic solvents such as dioxin, tetrahydrofuran or methanol.
  • Acids and bases useful in the methods herein are known in the art.
  • Acid catalysts are any acidic chemical, which can be inorganic (e.g., hydrochloric, sulfuric, nitric acids, aluminum trichloride) or organic (e.g., camphorsulfonic acid, p-toluenesulfonic acid, acetic acid, ytterbium triflate) in nature. Acids are useful in either catalytic or stoichiometric amounts to facilitate chemical reactions.
  • Bases are any basic chemical, which can be inorganic (e.g., sodium bicarbonate, potassium hydroxide) or organic (e.g., triethylamine, pyridine) in nature. Bases are useful in either catalytic or stoichiometric amounts to facilitate chemical reactions.
  • stable refers to compounds which possess stability sufficient to allow manufacture and which maintains the integrity of the compound for a sufficient period of time to be useful for the purposes detailed herein (e.g., therapeutic or prophylactic administration to a subject).
  • any variable e.g., RM
  • its definition at each occurrence is independent of its definition at every other occurrence.
  • RM at each occurrence is selected independently from the definition of RM.
  • substituents and/or variables are permissible, but only if such combinations result in stable compounds within a designated atom’s normal valency.
  • some of the compounds of this application have one or more double bonds, or one or more asymmetric centers.
  • Such compounds can occur as racemates, racemic mixtures, single enantiomers, individual diastereomers, diastereomeric mixtures, and cis- or trans- or E- or Z- double isomeric forms, and other stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as (R)- or (S)-, or as (D)- or (L)- for amino acids.
  • the compounds described herein comprise olefinic double bonds or other centers of geometric asymmetry or even E or Z isomerism across several bonds and/or rings, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers.
  • any carbon-carbon double bond appearing herein is selected for convenience only and is not intended to designate a particular configuration unless the text so states; thus a carbon-carbon double bond depicted arbitrarily herein as trans may be cis, trans, or a mixture of the two in any proportion. All such isomeric forms of such compounds are expressly included in the present application.
  • Optical isomers may be prepared from their respective optically active precursors by the procedures described herein, or by resolving the racemic mixtures.
  • the resolution can be carried out in the presence of a resolving agent, by chromatography or by repeated crystallization or by some combination of these techniques which are known to those skilled in the art. Further details regarding resolutions can be found in Jacques, et al., Enantiomers, Racemates, and Resolutions (John Wiley & Sons, 1981).
  • “Isomerism” means compounds that have identical molecular formulae but differ in the sequence of bonding of their atoms or in the arrangement of their atoms in space. Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers”. Stereoisomers that are not mirror images of one another are termed “diastereoisomers”, and stereoisomers that are non- superimposable mirror images of each other are termed “enantiomers” or sometimes optical isomers.
  • racemic mixture A mixture containing equal amounts of individual enantiomeric forms of opposite chirality is termed a “racemic mixture”.
  • Chiral isomer means a compound with at least one chiral center. Compounds with more than one chiral center may exist either as an individual diastereomer or as a mixture of diastereomers, termed “diastereomeric mixture”. When one chiral center is present, a stereoisomer may be characterized by the absolute configuration (R or S) of that chiral center. Absolute configuration refers to the arrangement in space of the substituents attached to the chiral center. The substituents attached to the chiral center under consideration are ranked in accordance with the Sequence Rule of Cahn, Ingold and Prelog. (Cahn et al.,Angew. Chem. Inter. Edit.
  • “Geometric isomer” means the diastereomers that owe their existence to hindered rotation about double bonds and/or other rigid structures such as a ring or polycyclic system. These configurations are differentiated in their names by the prefixes cis and trans, or Z and E, which indicate that the groups are on the same or opposite side of the double bond and/or other rigid structures such as a ring or a polycyclic system in the molecule according to the Cahn-Ingold-Prelog rules.
  • atropic isomers are a type of stereoisomer in which the atoms of two isomers are arranged differently in space. Atropic isomers owe their existence to a restricted rotation caused by hindrance of rotation of large groups about a central bond. Such atropic isomers typically exist as a mixture, however as a result of recent advances in chromatography techniques; it has been possible to separate mixtures of two atropic isomers in select cases.
  • Tautomer is one of two or more structural isomers that exist in equilibrium and is readily converted from one isomeric form to another. This conversion results in the formal migration of a hydrogen atom accompanied by a switch of adjacent conjugated double bonds. Tautomers exist as a mixture of a tautomeric set in solution. In solid form, usually one tautomer predominates. In solutions where tautomerization is possible, a chemical equilibrium of the tautomers will be reached. The exact ratio of the tautomers depends on several factors, including temperature, solvent and pH. The concept of tautomers that are interconvertable by tautomerizations is called tautomerism.
  • tautomeric pairs are: ketone-enol, amide-nitrile, lactam-lactim, amide- imidic acid tautomerism in heterocyclic rings ( e.g ., in nucleobases such as guanine, thymine and cytosine), amine-enamine and enamine-enamine.
  • the compounds of this application may also be represented in multiple tautomeric forms, in such instances, the application expressly includes all tautomeric forms of the compounds described herein (e.g., alkylation of a ring system may result in alkylation at multiple sites, the application expressly includes all such reaction products).
  • the structural formula of the compound represents a certain isomer for convenience in some cases, but the present application includes all isomers, such as geometrical isomers, optical isomers based on an asymmetrical carbon, stereoisomers, tautomers, and the like.
  • the structural formula of the compound represents a certain isomer for convenience in some cases, but the present application includes all isomers, such as geometrical isomers, optical isomers based on an asymmetrical carbon, stereoisomers, tautomers, and the like.
  • Compounds of the present invention can exist as stereoisomers wherein asymmetric or chiral centers are present.
  • Stereoisomers include enantiomers and diastereomers, and mixtures of enantiomers or diastereomers.
  • Individual stereoisomers of compounds of the present invention can be prepared synthetically from commercially available starting materials which contain asymmetric or chiral centers or by preparation of racemic mixtures followed by resolution well-known to those of ordinary skill in the art.
  • Geometric isomers can also exist in the compounds of the present invention.
  • the present invention contemplates the various geometric isomers and mixtures thereof resulting from the arrangement of substituents around a carbon-carbon double bond or arrangement of substituents around a carbocyclic or heterocyclic ring.
  • racemates which is given the descriptor “ rac ”.
  • racemate means an equimolar mixture of a pair of enantiomers. A racemate is usually formed when synthesis results in the generation of a stereocenter.
  • racemic mixture means racemate.
  • Compounds of the present invention can also exist as diastereomeric meso forms which is given the descriptor “rel.
  • diastereomeric meso form as used herein means achiral forms with a pseudostereogenic C-atom, which is given the descriptor “r”or “s respectively.
  • the compounds of the present application can exist in either hydrated or unhydrated (the anhydrous) form or as solvates with other solvent molecules.
  • Non-limiting examples of hydrates include monohydrates, dihydrates, etc.
  • Non- limiting examples of solvates include ethanol solvates, acetone solvates, etc.
  • Solvate means solvent addition forms that contain either stoichiometric or non stoichiometric amounts of solvent. Some compounds have a tendency to trap a fixed molar ratio of solvent molecules in the crystalline solid state, thus forming a solvate. If the solvent is water the solvate formed is a hydrate; and if the solvent is alcohol, the solvate formed is an alcoholate. Hydrates are formed by the combination of one or more molecules of water with one molecule of the substance in which the water retains its molecular state as H2O.
  • a further embodiment of the present invention may also include compounds which are identical to the compounds of formula (I) or formula (la) except that one or more atoms are replaced by an atom having an atomic mass number or mass different from the atomic mass number or mass usually found in nature, e.g. compounds enriched in 2 H (D), 3 H, 13 C, 127 I, etc.
  • These isotopic analogs and their pharmaceutical salts and formulations are considered useful agents in therapy and/or diagnosis, for example, but not limited to, where a fine-tuning of in vivo half-life time could lead to an optimized dosage regimen.
  • the compounds of this application may be modified by appending various functionalities via any synthetic means delineated herein to enhance selective biological properties. Such modifications are known in the art and include those which increase biological penetration into a given biological system (e.g ., blood, lymphatic system, central nervous system), increase oral availability, increase solubility to allow administration by injection, alter metabolism and alter rate of excretion.
  • the compounds of the application are defined herein by their chemical structures and/or chemical names. Where a compound is referred to by both a chemical structure and a chemical name, and the chemical structure and chemical name conflict, the chemical structure is determinative of the compound's identity.
  • the compound of Formula la is selected from Table A.
  • the compound is selected from Compound Nos. 1, 2, 7, 9, 10, 11, 12,
  • the compound is selected from Compound Nos. 7, 53, 54, 100, 161,
  • the compound is selected from Compound Nos. 230, 231, 245, 246,
  • the compound is selected from Compound Nos. 258, 274, 279, 317, and 318, or a pharmaceutically acceptable salt thereof.
  • the compound is Compound No. 258, or a pharmaceutically acceptable salt thereof.
  • the compound is Compound No. 274, or a pharmaceutically acceptable salt thereof.
  • the compound is Compound No. 279, or a pharmaceutically acceptable salt thereof.
  • the compound is Compound No. 317, or a pharmaceutically acceptable salt thereof.
  • the compound is Compound No. 318, or a pharmaceutically acceptable salt thereof.
  • the compound is selected from the group consisting of:
  • the compound is selected from the group consisting of: or a pharmaceutically acceptable salt thereof.
  • the compound is selected from the group consisting of: or a pharmaceutically acceptable salt thereof.
  • the compound is selected from the group consisting of:
  • compositions [0525]
  • effective amount or “therapeutically effective amount” as used herein refers to an amount capable of invoking one or more of the following effects in a subject receiving the combination of the present invention: (i) inhibition or arrest of tumor growth, including, reducing the rate of tumor growth or causing complete growth arrest; (ii) reduction in the number of tumor cells; (iii) reduction in tumor size; (iv) reduction in tumor number; (v) inhibition of metastasis (i.e., reduction, slowing down or complete stopping) of tumor cell infiltration into peripheral organs; (vi) enhancement of antitumor immune response, which may, but does not have to, result in the regression or elimination of the tumor; (vii) relief, to some extent, of one or more symptoms associated with cancer; (viii) increase in progression-free survival (PFS) and/or; overall survival (OS) of the subject receiving the combination, and (ix) induction of apoptosis or senescence of tumor cells.
  • PFS progression-free survival
  • OS overall
  • the compounds of the present invention may, in accordance with the invention, be administered in single or divided doses by oral, parenteral, inhalatory, rectal or topical administration including cutaneous, ophthalmic, mucosal scalp, sublingual, buccal and intranasal routes of administration; further, the compounds provided by the invention may be formulated to be used for the treatment of leukocyte populations in vivo, ex vivo and in vitro.
  • the compounds of the present invention When the compounds of the present invention are to be administered e.g. by the oral route, they may be administered as medicaments in the form of pharmaceutical compositions which contain them in association with a pharmaceutically acceptable diluent, excipient or carrier material.
  • a pharmaceutical composition comprising the compounds according to the invention as described supra and one or more pharmaceutically acceptable diluent, excipient or carrier.
  • the pharmaceutical compositions can be prepared in a conventional manner and finished dosage forms can be solid dosage forms, for example, tablets, dragees, capsules, and the like, or liquid dosage forms, for example solutions, suspensions, emulsions and the like.
  • Pharmaceutically acceptable diluent, excipient or carrier include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion.
  • sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion.
  • the use of such media and agents for pharmaceutically active substances is known in the art.
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I) or formula (la) according to the invention and at least one pharmaceutically acceptable diluent, excipient or carrier, wherein the composition is a tablet or a capsule.
  • the pharmaceutical composition is a tablet.
  • the amount of the compounds of the invention to be administered will vary depending upon factors such as the particular compound, disease condition and its severity, according to the particular circumstances surrounding the case, including, e.g., the specific compound being administered, the route of administration, the condition being treated, the target area being treated, and the subject or host being treated
  • the application provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of the present application or an enantiomer, diastereomer, or stereoisomer thereof, or pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof, and a pharmaceutically acceptable carrier.
  • Compounds of the application can be administered as pharmaceutical compositions by any conventional route, in particular enterally, e.g., orally, e.g., in the form of tablets or capsules, or parenterally, e.g., in the form of injectable solutions or suspensions, or topically, e.g., in the form of lotions, gels, ointments or creams, or in a nasal or suppository form.
  • Pharmaceutical compositions comprising a compound of the present application in free form or in a pharmaceutically acceptable salt form in association with at least one pharmaceutically acceptable carrier or diluent can be manufactured in a conventional manner by mixing, granulating or coating methods.
  • oral compositions can be tablets or gelatin capsules comprising the active ingredient together with a) diluents, e.g., lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine; b) lubricants, e.g., silica, talcum, stearic acid, its magnesium or calcium salt and/or poly ethyleneglycol; for tablets also c) binders, e.g., magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and or polyvinylpyrrolidone; if desired d) disintegrants, e.g., starches, agar, alginic acid or its sodium salt, or effervescent mixtures; and/or e) absorbents, colorants, flavors and sweeteners.
  • diluents e.g., lactose, dextrose, sucrose
  • compositions can be aqueous isotonic solutions or suspensions, and suppositories can be prepared from fatty emulsions or suspensions.
  • the compositions may be sterilized and/or contain adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure and/or buffers. In addition, they may also contain other therapeutically valuable substances.
  • Suitable formulations for transdermal applications include an effective amount of a compound of the present application with a carrier.
  • a carrier can include absorbable pharmacologically acceptable solvents to assist passage through the skin of the host.
  • transdermal devices are in the form of a bandage comprising a backing member, a reservoir containing the compound optionally with carriers, optionally a rate controlling barrier to deliver the compound to the skin of the host at a controlled and predetermined rate over a prolonged period of time, and means to secure the device to the skin.
  • Matrix transdermal formulations may also be used.
  • Suitable formulations for topical application, e.g., to the skin and eyes, are aqueous solutions, ointments, creams, or gels well-known in the art. Such may contain solubilizers, stabilizers, tonicity enhancing agents, buffers and preservatives.
  • compositions of the present application comprise a therapeutically effective amount of a compound of the present application formulated together with one or more pharmaceutically acceptable carriers.
  • pharmaceutically acceptable carrier means a non-toxic, inert solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type.
  • materials which can serve as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, or potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, polyacrylates, waxes, polyethylenepolyoxy propylene-block polymers, wool fat, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc;
  • compositions of this application can be administered to humans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments, or drops), buccally, or as an oral or nasal spray.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, com, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and
  • the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • injectable preparations for example, sterile injectable aqueous, or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3- butanediol.
  • Suitable vehicles and solvents that may be employed are water, Ringer's solution, U.S.P. and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil can be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid are used in the preparation of injectables.
  • compositions for rectal or vaginal administration are suppositories which can be prepared by mixing the compounds of this application with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
  • suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
  • Solid compositions of a similar type may also be employed as fillers in soft and hard filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
  • the active compounds can also be in micro-encapsulated form with one or more excipients as noted above.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art. In such solid dosage forms the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch.
  • Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose.
  • additional substances other than inert diluents e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose.
  • the dosage forms may also comprise buffering agents.
  • Dosage forms for topical or transdermal administration of a compound of this application include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches.
  • the active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required.
  • Ophthalmic formulation, ear drops, eye ointments, powders and solutions are also contemplated as being within the scope of this application.
  • the ointments, pastes, creams and gels may contain, in addition to an active compound of this application, excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • Powders and sprays can contain, in addition to the compounds of this application, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances.
  • Sprays can additionally contain customary propellants such as chlorofluorohydrocarbons.
  • Transdermal patches have the added advantage of providing controlled delivery of a compound to the body.
  • dosage forms can be made by dissolving or dispensing the compound in the proper medium.
  • Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.
  • Compounds and compositions of the application can be administered in therapeutically effective amounts in a combinational therapy with one or more therapeutic agents (pharmaceutical combinations) or modalities, e.g., an anti-proliferative, anti-cancer, immunomodulatory or anti- inflammatory agent.
  • therapeutic agents pharmaceutical combinations
  • modalities e.g., an anti-proliferative, anti-cancer, immunomodulatory or anti- inflammatory agent.
  • dosages of the co-administered compounds will of course vary depending on the type of co-drug employed, on the specific drug employed, on the condition being treated and so forth.
  • Compounds and compositions of the application can be administered in therapeutically effective amounts in a combinational therapy with one or more therapeutic agents (pharmaceutical combinations) or modalities, e.g., anti-proliferative, anti-cancer, immunomodulatory or anti- inflammatory agent, and/or non-drug therapies, etc.
  • therapeutic agents e.g., anti-proliferative, anti-cancer, immunomodulatory or anti-inflammatory agent, and/or non-drug therapies, etc.
  • therapeutic agents e.g., anti-proliferative, anti-cancer, immunomodulatory or anti-inflammatory agent, and/or non-drug therapies, etc.
  • therapeutic agents e.g., anti-proliferative, anti-cancer, immunomodulatory or anti-inflammatory agent, and/or non-drug therapies, etc.
  • synergistic effects can occur with anti-proliferative, anti-cancer, immunomodulatory or anti-inflammatory substances.
  • dosages of the co- administered compounds will of course vary depending on the
  • Combination therapy includes the administration of the subject compounds in further combination with one or more other biologically active ingredients.
  • the compounds of the application can be used in combination with other pharmaceutically active compounds, (e.g., compounds that are able to enhance the effect of the compounds of the application).
  • the compounds of the application can be administered simultaneously (as a single preparation or separate preparation), in temporal proximity, or sequentially to the other drug therapy or treatment modality.
  • a combination therapy envisions administration of two or more drugs during a single cycle or course of therapy.
  • the compounds may be administered in combination with one or more separate pharmaceutical agents, e.g, a chemotherapeutic agent, an immunotherapeutic agent, or an adjunctive therapeutic agent.
  • Cancer is a disease caused by the uncontrolled division of cells in the body. Abnormally dividing cancer cells can form a primary tumor, which can then invade nearby tissues, and spread throughout the body through the blood and lymphatic systems (metastatic cancers). Cancer can arise from many organs and cell types in the body, including but not limited to, cells of the lymphatic system, bone marrow, blood, brain and nervous system tissue, breast, cervix, ovary, colorectal cells, stomach and gastric cells, head and neck, kidney, liver, lung, oesophagus, pancreas, prostate and skin.
  • tumor refers to an abnormal growth of cells or tissue.
  • a tumor may comprise cells that are precancerous (e.g., benign), malignant, pre- metastatic, metastatic, and/or non-metastatic.
  • a tumor is associated with, or is a manifestation of, a cancer.
  • a tumor may be a disperse tumor or a liquid tumor.
  • Liquid tumors can affect bone marrow, blood cells and the lymphatic system.
  • Exemplary liquid tumors include leukemias and lymphomas.
  • Types of lymphomas include, but are not limited to, Hodgkinlymphomas, non-Hodgkin lymphomas, B cell lymphomas, T-cell lymphomas, Burkitt’s lymphomas, mantle cell lymphomas, small lymphocytic lymphomas, histiocytic lymphomas and primary mediastinal B cell lymphomas.
  • Types of leukemias include, but are not limited to, acute myeloid leukemia, T cell leukemias, acute lymphoblastic leukemias and chronic myelogenous leukemias.
  • a tumor may be a solid tumor.
  • solid tumors include, but are not limited to Carcinomas, Sarcomas, Myelomas, germ cell tumors, carcinoid tumors, neuroendocrine tumors and tumors of mixed type (a tumor which comprises multiple types of cancer cells).
  • Carcinomas arise from epithelial tissues, either internal or external, such as cells of the gastrointestinal tract.
  • Exemplary carcinomas include adenocarcinoma, which develops in an organ or gland, and squamous cell carcinoma, which originates in the squamous epithelium.
  • Sarcomas are cancers that originate in supportive or connective tissues such as bones, tendons, cartilage, muscle and fat.
  • Exemplary sarcomas include osteosarcoma, chondrosarcoma, leiomyosarcoma, rhabdomyosarcoma, mesothelial sarcoma, fibrosarcoma, angiosarcoma, liposarcoma, glioma or astrocytoma, myxosarcoma and mesenchymous or mixed mesodermal tumors.
  • Tumors can arise from most organs and tissue in the body, including, but not limited to, brain and nervous tissue, breast, cervix, ovary, uterus, colorectal, stomach and gastric tissue, kidney, liver, lung oesophagus, pancreas, prostate, skin, bone, head and neck, and lung.
  • exemplary brain and nervous system cancers include neurogliomas and glioblastomas.
  • Exemplary breast cancers include human breast carcinomas, breast adenocarcinomas and invasive ductal carcinomas.
  • Exemplary cervical cancers include epidermoid carcinomas, cervical carcinomas and HPV positive cervical cancers.
  • Exemplary ovarian cancers include ovarian carcinomas.
  • Exemplary colorectal cancers include colorectal carcinomas and colon colorectal adenocarcinomas.
  • Exemplary stomach and gastric cancers include gastric adenocarcinomas, stomach adenocarcinomas and gastric carcinomas.
  • Exemplary kidney cancers include renal cell adenocarcinomas and kidney clear cell carcinomas.
  • Exemplary liver cancers include hepatocellular carcinomas and hepatomas.
  • Exemplary lung cancers include small cell lung cancers, non-small cell lung cancers, lung carcinomas, lung adenocarcinomas, squamous cell carcinomas and large cell carcinomas.
  • Exemplary esophageal cancers include esophageal squamous cell carcinoma.
  • Exemplary pancreatic cancers include pancreatic carcinoma and pancreatic ductal adenocarcinoma.
  • Exemplary prostate cancers include prostate carcinomas, prostate adenocarcinomas and castrate resistant prostate cancers.
  • Exemplary skin cancers include melanomas, squamous cell carcinomas and basal cell carcinomas.
  • Exemplary head and neck cancers include squamous cell carcinomas.
  • the cancer is associated with lineage plasticity.
  • lineage plasticity refers to a process by which differentiated cells can display plasticity by changing their identity, either by dedifferentiation to a progenitor-like state or by transdifferentiation to an alternative differentiated cell type.
  • Exemplary cancers that exhibit lineage plasticity include castrate resistant prostate cancer (CRPC), in which CRPC tumors with neuroendocrine features evolve from CRPC tumors with adenocarcinoma-like features.
  • Lineage plasticity of CRPC tumors is associated with the development of resistance to androgen receptor based cancer therapies. Additional cancers thought to exhibit lineage plasticity include, but are not limited to breast cancer, small cell lung cancer and melanoma.
  • Lineage plasticity may also be associated with Rb dysfunction in cancer cells.
  • loss of Rb1 even late in cancer progression, lead to both an increase in androgen receptor (AR) levels, which was mediated by E2F1, and an increase in AR target gene expression.
  • AR androgen receptor
  • the cancer is pancreatic cancer, osteosarcoma, gastric cancer, prostate cancer, breast cancer, small cell lung cancer, adenocarcinoma, melanoma or neuroendocrine cancer.
  • the cancer is pancreatic cancer, osteosarcoma, gastric cancer, prostate cancer, breast cancer, small cell lung cancer, adenocarcinoma, neuroendocrine cancer, or melanoma or lymphoma.
  • the prostate cancer is castrate resistant prostate cancer.
  • the prostate cancer is resistant to androgen receptor (AR) pathway inhibitors.
  • AR pathway inhibitors include, but are not limited to, abiraterone acetate, enzalutamide, apalutamide, darolutamide or bicalutamide.
  • the prostate cancer is neuroendocrine prostate cancer.
  • the prostate cancer is adenocarcinoma prostate cancer.
  • the prostate cancer is the prostate cancer is neuroendocrine prostate cancer (NEPC).
  • NEPC neuroendocrine prostate cancer
  • AR- AR negative
  • the prostate cancer is androgen driven, AR positive adenocarcinoma.
  • the prostate cancer comprises both AR positive and AR negative cells.
  • the cancer is a hematological cancer.
  • the hematological cancer is acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), B cell lymphoma (BCL), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), diffuse large B cell lymphoma (DLBCL), Epstein Barr driven hematological cancer, multiple myeloma (MM), T cell lymphoma (TCL), Hodgkin lymphoma or non-Hodgkin lymphoma.
  • ALL acute lymphocytic leukemia
  • AML acute myeloid leukemia
  • BCL B cell lymphoma
  • CLL chronic lymphocytic leukemia
  • CML chronic myeloid leukemia
  • DLBCL diffuse large B cell lymphoma
  • Epstein Barr driven hematological cancer multiple myeloma
  • MM multiple myeloma
  • TCL T cell lymphoma
  • the term "subject" refers to an organism, for example, a mammal (e.g ., a human, a non-human mammal, a non-human primate, a primate, a laboratory animal, a mouse, a rat, a hamster, a gerbil, a cat, a dog).
  • a human subject is an adult, adolescent, or pediatric subject (a child).
  • a subject is suffering from a disease, disorder or condition, e.g., a disease, disorder or condition that can be treated as provided herein, e.g., a cancer or a tumor listed herein.
  • a subject displays one or more symptoms of a disease, disorder or condition. In some embodiments, a subject does not display a particular symptom (e.g., clinical manifestation of disease) or characteristic of a disease, disorder, or condition. In some embodiments, a subject does not display any symptom or characteristic of a disease, disorder, or condition. In some embodiments, a subject is a patient. In some embodiments, a subject is an individual to whom diagnosis and/or therapy is and/or has been administered.
  • a cancer that is to be treated can be staged according to the American Joint Committee on Cancer (AJCC) TNM classification system, where the tumor (T) has been assigned a stage of TX, Tl, Tlmic, Tla, Tib, Tic, T2, T3, T4, T4a, T4b, T4c, or T4d; and where the regional lymph nodes (N) have been assigned a stage of NX, NO, Nl, N2, N2a, N2b, N3, N3a, N3b, or N3c; and where distant metastasis (M) can be assigned a stage of MX, M0, or Ml.
  • AJCC American Joint Committee on Cancer
  • a cancer that is to be treated can be staged according to an American Joint Committee on Cancer (AJCC) classification as Stage I, Stage IIA, Stage IIB, Stage IIIA, Stage IIIB, Stage IIIC, or Stage IV.
  • AJCC American Joint Committee on Cancer
  • a cancer that is to be treated can be assigned a grade according to an AJCC classification as Grade GX (e.g., grade cannot be assessed), Grade 1, Grade 2, Grade 3 or Grade 4.
  • a cancer that is to be treated can be staged according to an AJCC pathologic classification (pN) of pNX, pNO, PNO (I-), PNO (I+), PNO (mol-), PNO (mol+), PN1, PN 1 (mi), PNla, PNlb, PNlc, pN2, pN2a, pN2b, pN3, pN3a, pN3b, or pN3c.
  • pN AJCC pathologic classification
  • a cancer that is to be treated can be evaluated by DNA cytometry, flow cytometry, or image cytometry.
  • a cancer that is to be treated can be typed as having 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% of cells in the synthesis stage of cell division (e.g., in S phase of cell division).
  • a cancer that is to be treated can be typed as having a low S-phase fraction or a high S-phase fraction.
  • a "normal cell” is a cell that cannot be classified as part of a "cell proliferative disorder".
  • a normal cell lacks unregulated or abnormal growth, or both, that can lead to the development of an unwanted condition or disease.
  • a normal cell possesses normally functioning cell cycle checkpoint control mechanisms.
  • contacting a cell refers to a condition in which a compound or other composition of matter is in direct contact with a cell, or is close enough to induce a desired biological effect in a cell.
  • monotherapy refers to the administration of a single active or therapeutic compound to a subject in need thereof.
  • monotherapy will involve administration of a therapeutically effective amount of an active compound.
  • cancer monotherapy with one of the compound of the present invention, or a pharmaceutically acceptable salt, polymorph, solvate, analog or derivative thereof to a subject in need of treatment of cancer.
  • Monotherapy may be contrasted with combination therapy, in which a combination of multiple active compounds is administered, with each component of the combination present in a therapeutically effective amount.
  • monotherapy with a compound of the present invention, or a pharmaceutically acceptable salt, polymorph or solvate thereof is more effective than combination therapy in inducing a desired biological effect.
  • treating describes the management and care of a patient for the purpose of combating a disease, condition, or disorder and includes the administration of a compound of the present invention, or a pharmaceutically acceptable salt, polymorph or solvate thereof, to alleviate one or more symptoms or complications of a disease, condition or disorder, or to eliminate the disease, condition or disorder.
  • the term “treat” can also include treatment of a cell in vitro or an animal model.
  • a compound of the present invention can also be used to prevent a disease, condition or disorder, or used to identify suitable candidates for such purposes.
  • preventing or “prevent” describes reducing or eliminating the onset of the symptoms or complications of the disease, condition or disorder.
  • the term "alleviate” is meant to describe a process by which the severity of a sign or symptom of a disorder is decreased. Importantly, a sign or symptom can be alleviated without being eliminated. In some embodiments, the administration of pharmaceutical compositions of the invention leads to the elimination of a sign or symptom, however, elimination is not required.
  • Effective dosages are expected to decrease the severity of a sign or symptom.
  • a sign or symptom of a disorder such as cancer which can occur in multiple locations, is alleviated if the severity of the cancer is decreased within at least one of multiple locations.
  • severity is meant to describe the potential of cancer to transform from a precancerous, or benign, state into a malignant state.
  • severity is meant to describe a cancer stage, for example, according to the TNM system (accepted by the International Union against Cancer (UICC) and the American Joint Committee on Cancer (AJCC)) or by other art-recognized methods.
  • TNM system accepted by the International Union against Cancer (UICC) and the American Joint Committee on Cancer (AJCC)
  • UNM system International Union against Cancer
  • AJCC American Joint Committee on Cancer
  • Cancer stage refers to the extent or severity of the cancer, based on factors such as the location of the primary tumor, tumor size, number of tumors, and lymph node involvement (spread of cancer into lymph nodes).
  • Tumor grade is a system used to classify cancer cells in terms of how abnormal they look under a microscope and how quickly the tumor is likely to grow and spread. Many factors are considered when determining tumor grade, including the structure and growth pattern of the cells. The specific factors used to determine tumor grade vary with each type of cancer. Severity also describes a histologic grade, also called differentiation, which refers to how much the tumor cells resemble normal cells of the same tissue type (see, National Cancer Institute, www.cancer.gov).
  • severity describes a nuclear grade, which refers to the size and shape of the nucleus in tumor cells and the percentage of tumor cells that are dividing (see, National Cancer Institute, www.cancer.gov).
  • severity describes the degree to which a tumor has secreted growth factors, degraded the extracellular matrix, become vascularized, lost adhesion to juxtaposed tissues, or metastasized.
  • severity describes the number of locations to which a primary tumor has metastasized.
  • severity includes the difficulty of treating tumors of varying types and locations. For example, inoperable tumors, those cancers which have greater access to multiple body systems (hematological and immunological tumors), and those which are the most resistant to traditional treatments are considered most severe.
  • symptom is defined as an indication of disease, illness, injury, or that something is not right in the body. Symptoms are felt or noticed by the individual experiencing the symptom, but may not easily be noticed by others. Others are defined as non- health-care professionals.
  • the term "sign” is also defined as an indication that something is not right in the body. Signs are defined as things that can be seen by a doctor, nurse, or other health care professional. [0575] Cancer is a group of diseases that may cause almost any sign or symptom. The signs and symptoms will depend on where the cancer is, the size of the cancer, and how much it affects the nearby organs or structures. If a cancer spreads (metastasizes), then symptoms may appear in different parts of the body.
  • Treating cancer can result in a reduction in size of a tumor.
  • a reduction in size of a tumor may also be referred to as "tumor regression".
  • tumor size is reduced by 5% or greater relative to its size prior to treatment; tumor size is reduced by 10% or greater; reduced by 20% or greater; reduced by 30% or greater; reduced by 40% or greater; reduced by 50% or greater; or reduced by greater than 75% or greater.
  • Size of a tumor may be measured by any reproducible means of measurement. The size of a tumor may be measured as a diameter of the tumor.
  • Treating cancer can result in a reduction in tumor volume.
  • tumor volume is reduced by 5% or greater relative to its size prior to treatment; tumor volume is reduced by 10% or greater; reduced by 20% or greater; reduced by 30% or greater; reduced by 40% or greater; reduced by 50% or greater; or reduced by greater than 75% or greater.
  • Tumor volume may be measured by any reproducible means of measurement.
  • Treating cancer results in a decrease in number of tumors.
  • tumor number is reduced by 5% or greater relative to number prior to treatment; tumor number is reduced by 10% or greater; reduced by 20% or greater; reduced by 30% or greater; reduced by 40% or greater; reduced by 50% or greater; or reduced by greater than 75%.
  • Number of tumors may be measured by any reproducible means of measurement.
  • the number of tumors may be measured by counting tumors visible to the naked eye or at a specified magnification. In some embodiments, the specified magnification is 2x, 3x, 4x, 5x, lOx, or 50x.
  • Treating cancer can result in a decrease in number of metastatic lesions in other tissues or organs distant from the primary tumor site.
  • the number of metastatic lesions is reduced by 5% or greater relative to number prior to treatment; the number of metastatic lesions is reduced by 10% or greater; reduced by 20% or greater; reduced by 30% or greater; reduced by 40% or greater; reduced by 50% or greater; or reduced by greater than 75%.
  • the number of metastatic lesions may be measured by any reproducible means of measurement.
  • the number of metastatic lesions may be measured by counting metastatic lesions visible to the naked eye or at a specified magnification. In some embodiments, the specified magnification is 2x, 3x, 4x, 5x, lOx, or 5 Ox.
  • Treating cancer can result in an increase in average survival time of a population of treated subjects in comparison to a population receiving carrier alone.
  • the average survival time is increased by more than 30 days; by more than 60 days; by more than 90 days; or by more than 120 days.
  • An increase in average survival time of a population may be measured by any reproducible means.
  • An increase in average survival time of a population may be measured, for example, by calculating for a population the average length of survival following initiation of treatment with an active compound.
  • An increase in average survival time of a population may also be measured, for example, by calculating for a population the average length of survival following completion of a first round of treatment with an active compound.
  • Treating cancer can result in an increase in average survival time of a population of treated subjects in comparison to a population of untreated subjects.
  • the average survival time is increased by more than 30 days; by more than 60 days; by more than 90 days; or by more than 120 days.
  • An increase in average survival time of a population may be measured by any reproducible means.
  • An increase in average survival time of a population may be measured, for example, by calculating for a population the average length of survival following initiation of treatment with an active compound.
  • An increase in average survival time of a population may also be measured, for example, by calculating for a population the average length of survival following completion of a first round of treatment with an active compound.
  • Treating cancer can result in increase in average survival time of a population of treated subjects in comparison to a population receiving monotherapy with a drug that is not a compound of the present invention, or a pharmaceutically acceptable salt, polymorph, solvate, analog or derivative thereof.
  • the average survival time is increased by more than 30 days; by more than 60 days; by more than 90 days; or by more than 120 days.
  • An increase in average survival time of a population may be measured by any reproducible means.
  • An increase in average survival time of a population may be measured, for example, by calculating for a population the average length of survival following initiation of treatment with an active compound.
  • An increase in average survival time of a population may also be measured, for example, by calculating for a population the average length of survival following completion of a first round of treatment with an active compound.
  • Treating cancer can result in a decrease in the mortality rate of a population of treated subjects in comparison to a population receiving carrier alone. Treating cancer can result in a decrease in the mortality rate of a population of treated subjects in comparison to an untreated population. Treating cancer can result in a decrease in the mortality rate of a population of treated subjects in comparison to a population receiving monotherapy with a drug that is not a compound of the present invention, or a pharmaceutically acceptable salt, polymorph, solvate, analog or derivative thereof. In some embodiments, the mortality rate is decreased by more than 2%; by more than 5%; by more than 10%; or by more than 25%. A decrease in the mortality rate of a population of treated subjects may be measured by any reproducible means.
  • a decrease in the mortality rate of a population may be measured, for example, by calculating for a population the average number of disease-related deaths per unit time following initiation of treatment with an active compound.
  • a decrease in the mortality rate of a population may also be measured, for example, by calculating for a population the average number of disease-related deaths per unit time following completion of a first round of treatment with an active compound.
  • Treating cancer can result in a decrease in tumor growth rate.
  • tumor growth rate is reduced by at least 5% relative to number prior to treatment; tumor growth rate is reduced by at least 10%; reduced by at least 20%; reduced by at least 30%; reduced by at least 40%; reduced by at least 50%; reduced by at least 50%; or reduced by at least 75%.
  • Tumor growth rate may be measured by any reproducible means of measurement. Tumor growth rate can be measured according to a change in tumor diameter per unit time.
  • Treating cancer can result in a decrease in tumor regrowth.
  • tumor regrowth is less than 5%; tumor regrowth is less than 10%; less than 20%; less than 30%; less than 40%; less than 50%; less than 50%; or less than 75%.
  • Tumor regrowth may be measured by any reproducible means of measurement. Tumor regrowth is measured, for example, by measuring an increase in the diameter of a tumor after a prior tumor shrinkage that followed treatment. A decrease in tumor regrowth is indicated by failure of tumors to reoccur after treatment has stopped.
  • Treating cancer can result in a reduction in the rate of cellular proliferation.
  • the rate of cellular proliferation is reduced by at least 5%; by at least 10%; by at least 20%; by at least 30%; by at least 40%; by at least 50%; by at least 50%; or by at least 75%.
  • the rate of cellular proliferation may be measured by any reproducible means of measurement.
  • the rate of cellular proliferation is measured, for example, by measuring the number of dividing cells in a tissue sample per unit time.
  • Treating cancer can result in a reduction in the proportion of proliferating cells.
  • the proportion of proliferating cells is reduced by at least 5%; by at least 10%; by at least 20%; by at least 30%; by at least 40%; by at least 50%; by at least 50%; or by at least 75%.
  • the proportion of proliferating cells may be measured by any reproducible means of measurement.
  • the proportion of proliferating cells is measured, for example, by quantifying the number of dividing cells relative to the number of non-dividing cells in a tissue sample.
  • the proportion of proliferating cells can be equivalent to the mitotic index.
  • Treating cancer can result in a decrease in size of an area or zone of cellular proliferation.
  • size of an area or zone of cellular proliferation is reduced by at least 5% relative to its size prior to treatment; reduced by at least 10%; reduced by at least 20%; reduced by at least 30%; reduced by at least 40%; reduced by at least 50%; reduced by at least 50%; or reduced by at least 75%.
  • Size of an area or zone of cellular proliferation may be measured by any reproducible means of measurement.
  • the size of an area or zone of cellular proliferation may be measured as a diameter or width of an area or zone of cellular proliferation.
  • Treating cancer can result in a decrease in the number or proportion of cells having an abnormal appearance or morphology.
  • the number of cells having an abnormal morphology is reduced by at least 5% relative to its size prior to treatment; reduced by at least 10%; reduced by at least 20%; reduced by at least 30%; reduced by at least 40%; reduced by at least 50%; reduced by at least 50%; or reduced by at least 75%.
  • An abnormal cellular appearance or morphology may be measured by any reproducible means of measurement.
  • An abnormal cellular morphology can be measured by microscopy, e.g., using an inverted tissue culture microscope.
  • An abnormal cellular morphology can take the form of nuclear pleiomorphism.
  • Treating cancer can result in cell death.
  • cell death results in a decrease of at least 10% in number of cells in a population.
  • cell death means a decrease of at least 20%; a decrease of at least 30%; a decrease of at least 40%; a decrease of at least 50%; or a decrease of at least 75%.
  • Number of cells in a population may be measured by any reproducible means.
  • a number of cells in a population can be measured by fluorescence-activated cell sorting (FACS), immunofluorescence microscopy and light microscopy. Methods of measuring cell death are as shown in Li et al, Proc Natl Acad Sci U S A. 100(5): 2674-8, 2003. In an aspect, cell death occurs by apoptosis.
  • a compound of the present invention, or a pharmaceutically acceptable salt, polymorph or solvate thereof acts selectively on a cancer or precancerous cell but not on a normal cell.
  • a compound of the present invention, or a pharmaceutically acceptable salt, polymorph or solvate thereof acts selectively to modulate one molecular target (e.g., p300) but does not significantly modulate another molecular target (e.g., a non-target protein).
  • the invention also provides a method for selectively inhibiting the activity of a protein such as p300.
  • an event occurs selectively in population A relative to population B if it occurs greater than two times more frequently in population A as compared to population B.
  • An event occurs selectively if it occurs greater than five times more frequently in population A.
  • An event occurs selectively if it occurs greater than ten times more frequently in population A; greater than fifty times; greater than 100 times; or greater than 1000 times more frequently in population A as compared to population B.
  • cell death would be said to occur selectively in cancer cells if it occurred greater than twice as frequently in cancer cells as compared to normal cells.
  • a compound of the present invention, or a pharmaceutically acceptable salt, polymorph or solvate thereof can modulate the activity of a molecular target (e.g., p300). Modulating refers to stimulating or inhibiting an activity of a molecular target.
  • a compound of the present invention, or a pharmaceutically acceptable salt, polymorph or solvate thereof modulates the activity of a molecular target if it stimulates or inhibits the activity of the molecular target by at least 2-fold relative to the activity of the molecular target under the same conditions but lacking only the presence of said compound.
  • a compound of the present invention modulates the activity of a molecular target if it stimulates or inhibits the activity of the molecular target by at least 5 -fold, at least 10-fold, at least 20-fold, at least 50-fold, or at least 100-fold relative to the activity of the molecular target under the same conditions but lacking only the presence of said compound.
  • the activity of a molecular target may be measured by any reproducible means.
  • the activity of a molecular target may be measured in vitro or in vivo.
  • the activity of a molecular target may be measured in vitro by an enzymatic activity assay or a DNA binding assay, or the activity of a molecular target may be measured in vivo by assaying for expression of a reporter gene.
  • a compound of the present invention does not significantly modulate the activity of a molecular target if the addition of the compound does not stimulate or inhibit the activity of the molecular target by greater than 10% relative to the activity of the molecular target under the same conditions but lacking only the presence of said compound.
  • a compound of the present invention demonstrates this differential across the range of inhibition, and the differential is exemplified at the IC50, i.e., a 50% inhibition, for a molecular target of interest.
  • Administering a compound of the present invention, or a pharmaceutically acceptable salt, polymorph or solvate thereof, to a cell or a subject in need thereof can result in modulation (i.e., stimulation or inhibition) of an activity of CBP/p300.
  • Administering a compound of the present invention, or a pharmaceutically acceptable salt, polymorph or solvate thereof, to a cell or a subject in need thereof results in modulation (i.e., stimulation or inhibition) of an activity of an intracellular target (e.g., substrate).
  • an intracellular target e.g., substrate
  • an effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, polymorph or solvate thereof is not significantly cytotoxic to normal cells.
  • a therapeutically effective amount of a compound is not significantly cytotoxic to normal cells if administration of the compound in a therapeutically effective amount does not induce cell death in greater than 10% of normal cells.
  • a therapeutically effective amount of a compound does not significantly affect the viability of normal cells if administration of the compound in a therapeutically effective amount does not induce cell death in greater than 10% of normal cells. In an aspect, cell death occurs by apoptosis.
  • administering to a subject in need thereof a compound of the present invention, or a pharmaceutically acceptable salt, polymorph or solvate thereof induces cell death selectively in one or more cells affected by a cell proliferative disorder.
  • the present disclosure provides methods of treating a subject with a cancer which can be ameliorated by modulation of CBP/p300, by administering to the subject an effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, or a corresponding pharmaceutical composition.
  • the present disclosure provides methods of predicting the efficacy or therapeutic effect, of a compound of formula la of the disclosure for the treatment of cancer, comprising determining the expression, activity or function of one or more of the p53 or Rb1 pathway genes disclosed in tables 1 and 2, or RUNXl or ASXL1 or a paralog thereof, in cancer cells and comparing the activity of function of the one or more genes in cancer cells and non-cancerous control cells.
  • the present disclosure provides a method of treating a subject with prostate, breast or small cell lung cancer, the method comprising administering a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, or a corresponding pharmaceutical composition.
  • the present disclosure provides a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in treating cancer in a subject in need thereof, wherein the cancer can be ameliorated by modulation of CBP/p300.
  • the present disclosure provides a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in treating prostate cancer in a subject in need thereof.
  • the present disclosure provides use of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of cancer in a subject in need thereof, wherein the cancer can be ameliorated by inhibition of CBP/p300.
  • the present disclosure provides use of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of prostate cancer in a subject in need thereof.
  • the CBP/p300 modulator is of formula la: or a pharmaceutically acceptable salt, hydrate, solvate or stereoisomer thereof, wherein the variables are described as above.
  • the CBP/p300 modulator is of formula I: or a pharmaceutically acceptable salt, hydrate, solvate or stereoisomer thereof, wherein the variables are described as above.
  • the CBP/p300 modulator is a compound of Formula la selected from Table A.
  • the CBP/p300 modulator is selected from Compound Nos. 1, 2, 7, 9, 10, 11, 12, 14, 15, 20, 21, 26, 27, 29, 30, 31, 37, 38, 43, 46, 47, 53, 54, 55, 56, 57, 58, 60, 63, 64, 65, 66, 69, 75, 76, 77, 79, 80, 81, 83, 86, 87, 100, 133, 138, 141, 152, 155, 156, 157, 158, 159, 160, 161, 162, 164, 166, 167, 168, 169, 170, 171, 172, 174, 175, 176, 178, 188, 189, 191, 192, 199, 200, 201,
  • the CBP/p300 modulator is selected from Compound Nos. 7, 53, 54, 100, 161, 162, 230, 231, 232, 235, 238, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, 250, 251,
  • the CBP/p300 modulator is selected from Compound Nos. 230, 231,
  • the CBP/p300 modulator is selected from Compound Nos. 258, 274, 279, 317, and 318, or a pharmaceutically acceptable salt thereof.
  • the present disclosure provides a method of treating a subject with cancer which can be ameliorated by modulation of CBP/p300, by administering to the subject an effective amount of Compound 258, or a pharmaceutically acceptable salt thereof, or a corresponding pharmaceutical composition.
  • the present disclosure provides a method of treating a subject with prostate cancer, the method comprising administering a therapeutically effective amount of Compound 258, or a pharmaceutically acceptable salt thereof, or a corresponding pharmaceutical composition.
  • the present disclosure provides Compound 258, or a pharmaceutically acceptable salt thereof, for use in treating cancer in a subject in need thereof, wherein the cancer can be ameliorated by modulation of p300.
  • the present disclosure provides Compound 258, or a pharmaceutically acceptable salt thereof, for use in treating prostate cancer in a subject in need thereof.
  • the present disclosure provides a use of a Compound 258, in the manufacture of a medicament for the treatment of cancer in a subject in need thereof, wherein the cancer can be ameliorated by modulation of p300.
  • the present disclosure provides use of Compound 258, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of prostate cancer in a subject in need thereof.
  • An exemplary treatment regime entails administration once daily, twice daily, three times daily, every second day, twice per week, once per week.
  • the composition of the invention is usually administered on multiple occasions. Intervals between single dosages can be, for example, less than a day, daily, every second day, twice per week, or weekly.
  • the composition of the invention may be given as a continuous uninterrupted treatment.
  • the compound of formula (I) or formula (la) according to the invention can be administered from 0.1 - 1500 mg per day.
  • the term "therapeutically effective amount” refers to an amount that produces a desired effect (e.g., a desired biological, clinical, or pharmacological effect) in a subject or population to which it is administered. In some embodiments, the term refers to an amount statistically likely to achieve the desired effect when administered to a subject in accordance with a particular dosing regimen (e.g., a therapeutic dosing regimen).
  • the term refers to an amount sufficient to produce the effect in at least a significant percentage (e.g., at least about 25%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 95%, or more) of a population that is suffering from and/or susceptible to a disease, disorder, and/or condition.
  • a therapeutically effective amount is one that reduces the incidence and/or severity of, and/or delays onset of, one or more symptoms of the disease, disorder, and/or condition.
  • a therapeutically effective amount does not in fact require successful treatment be achieved in a particular individual.
  • a therapeutically effective amount may be an amount that provides a particular desired response in a significant number of subjects when administered to patients in need of such treatment, e.g., in at least about 25%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 95%, or more patients within a treated patient population.
  • reference to a therapeutically effective amount may be a reference to an amount sufficient to induce a desired effect as measured in one or more specific tissues (e.g a tissue affected by the disease, disorder or condition) or fluids (e.g., blood, saliva, serum, sweat, tears, urine).
  • a therapeutically effective amount of a particular agent or therapy may be formulated and/or administered in a single dose.
  • a therapeutically effective agent may be formulated and/or administered in a plurality of doses, for example, as part of a dosing regimen.
  • a compound or pharmaceutical composition for use in accordance with the present disclosure is formulated, dosed, and/or administered in a therapeutically effective amount using pharmaceutical compositions and dosing regimens that are consistent with good medical practice and appropriate for the relevant agent(s) and subject(s).
  • compounds and pharmaceutical compositions can be administered by any appropriate method known in the art, including, without limitation, oral, mucosal, by-inhalation, topical, buccal, nasal, rectal, or parenteral (e.g.
  • the compound or pharmaceutical composition is administered directly to the tumor (e.g., by intratumoral injection).
  • a dosing regimen for a particular active agent may involve intermittent or continuous (e.g., by perfusion or other slow release system) administration, for example to achieve a particular desired pharmacokinetic profile or other pattern of exposure in one or more tissues or fluids of interest in the subject receiving therapy.
  • different agents administered in combination may be administered via different routes of delivery and/or according to different schedules.
  • one or more doses of a first active agent is administered substantially simultaneously with, and in some embodiments via a common route and/or as part of a single composition with, one or more other active agents.
  • Factors to be considered when optimizing routes and/or dosing schedule for a given therapeutic regimen may include, for example, the particular indication being treated, the clinical condition of a subject (e.g., age, overall health, prior therapy received and/or response thereto) the site of delivery of the agent, the nature of the agent (e.g. an antibody or other polypeptide-based compound), the mode and/or route of administration of the agent, the presence or absence of combination therapy, and other factors known to medical practitioners.
  • relevant features of the indication being treated may include, for example, one or more of cancer type, stage, location.
  • one or more features of a particular pharmaceutical composition and/or of a utilized dosing regimen may be modified over time (e.g., increasing or decreasing the amount of active agent in any individual dose, increasing or decreasing time intervals between doses), for example in order to optimize a desired therapeutic effect or response (e.g., inhibition or modulation of a p300 gene or gene product).
  • type, amount, and frequency of dosing of compounds or pharmaceutical compositions in accordance with the present invention are governed by safety and efficacy requirements that apply when one or more relevant agent(s) is/are administered to a mammal (e.g., a human).
  • a mammal e.g., a human
  • such features of dosing are selected to provide a particular, and typically detectable, therapeutic response as compared to what is observed absent therapy.
  • a "therapeutically effective amount” or “therapeutically effective dose” is an amount of a compound or pharmaceutical composition of the disclosure, or a combination of two or more compounds or pharmaceutical compositions of the disclosure, or a combination of a compound or pharmaceutical composition of the disclosure with one or more additional therapeutic agent(s), which inhibits, totally or partially, the progression of the condition or alleviates, at least partially, one or more symptoms of the condition.
  • a therapeutically effective amount can be an amount which is prophylactically effective.
  • an amount which is therapeutically effective may depend upon a patient's size and/or gender, the condition to be treated, severity of the condition and/or the result sought.
  • a therapeutically effective amount refers to that amount that results in amelioration of at least one symptom in a patient.
  • a therapeutically effective amount may be determined by methods known to those of skill in the art.
  • toxicity and/or therapeutic efficacy of a compound or pharmaceutical composition of the disclosure can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the maximum tolerated dose (MTD) and the ED50 (effective dose for 50% maximal response).
  • MTD maximum tolerated dose
  • ED50 effective dose for 50% maximal response
  • the dose ratio between toxic and therapeutic effects is the therapeutic index; in some embodiments, this ratio can be expressed as the ratio between MTD and ED50.
  • dosage may be guided by monitoring the effect of a compound or pharmaceutical composition of the disclosure on one or more pharmacodynamic markers of p300 function in diseased or surrogate tissue.
  • dosage of a compound or pharmaceutical composition of the disclosure lies within a range of circulating concentrations that include the ED50 with little or no toxicity.
  • dosage may vary within such a range, for example depending upon the dosage form employed and/or the route of administration utilized. The exact formulation, route of administration and dosage can be chosen by the individual physician in view of the patient's condition. In the treatment of crises or severe conditions, administration of a dosage approaching the MTD may be required to obtain a rapid response.
  • dosage amount and/or interval may be adjusted individually, for example to provide plasma levels of an active moiety which are sufficient to maintain, for example a desired effect, or a minimal effective concentration (MEC) for a period of time required to achieve therapeutic efficacy.
  • MEC for a particular compound or pharmaceutical composition of the disclosure can be estimated, for example, from in vitro data and/or animal experiments. Dosages necessary to achieve the MEC will depend on individual characteristics and route of administration. In some embodiments, high pressure liquid chromatography (HPLC) assays or bioassays can be used to determine plasma concentrations.
  • HPLC high pressure liquid chromatography
  • dosage intervals can be determined using the MEC value.
  • a compound or pharmaceutical composition of the disclosure should be administered using a regimen which maintains plasma levels above the MEC for 10-90% of the time, between 30-90%, or between 50-90% until the desired amelioration of a symptom is achieved.
  • different MEC plasma levels will be maintained for differing amounts of time.
  • the effective local concentration of the drug may not be related to plasma concentration.
  • compounds or pharmaceutical compositions of the disclosure can be administered to a subject in need thereof as a cancer monotherapy.
  • compounds or pharmaceutical compositions of the disclosure can be administered to a subject in need thereof in combination with at least one additional cancer therapy.
  • the at least one additional cancer therapy comprises a standard of care for the cancer of the subject.
  • standard of care refers to a treatment of a particular cancer that is accepted by persons of skill in the art as the generally accepted treatment for that indication, and whose practice is common amongst medical professionals.
  • standard of care for primary tumors that can be surgically resected without undue risk to the subject comprises surgical removal of the tumor.
  • the person of ordinary skill in the art will readily understand what is a “standard of care” for a particular cancer indication.
  • the at least one additional cancer therapy comprises surgical resection of the cancer, radiation therapy, or a combination thereof.
  • compounds or pharmaceutical compositions of the disclosure can be used in combination with another therapeutic agent to treat cancer in the subject in a combinational therapy.
  • the combinational therapy is in addition to a standard of care therapies, surgical resection and/or radiation therapy.
  • compounds or pharmaceutical compositions of the disclosure can optionally contain, and/or be administered in combination with, one or more additional therapeutic agents, such as a cancer therapeutic agent, e.g., a chemotherapeutic agent or a biological agent.
  • a cancer therapeutic agent e.g., a chemotherapeutic agent or a biological agent.
  • An additional agent can be, for example, a therapeutic agent that is e.g., an anti-cancer agent, or an agent that ameliorates a symptom associated with the disease or condition being treated.
  • the additional agent also can be an agent that imparts a beneficial attribute to the therapeutic composition (e.g., an agent that affects the viscosity of the composition).
  • compounds or pharmaceutical compositions of the disclosure are administered to a subject who has received, is receiving, and/or will receive therapy with another therapeutic agent or modality (e.g., with a chemotherapeutic agent, surgery, radiation, or a combination thereof).
  • Some embodiments of combination therapy modalities provided by the present disclosure provide, for example, administration of compounds or pharmaceutical compositions of the disclosure and additional cancer therapeutic agent(s) in a single pharmaceutical formulation.
  • Some embodiments provide administration of compounds or pharmaceutical compositions of the disclosure and administration of additional cancer therapeutic agent(s) in separate pharmaceutical formulations.
  • the compounds or pharmaceutical compositions of the disclosure and the additional cancer therapeutic agent are administered simultaneously. Simultaneous administration can be by the same modality (e.g., both by oral administration), or by different modalities (e.g., one oral, one injected).
  • the compounds or pharmaceutical compositions of the disclosure and the additional cancer therapeutic agent are administered in temporal proximity.
  • the compounds or pharmaceutical compositions of the disclosure and the additional cancer therapeutic agent are administered within 1 minute, 2 minutes, 5 minutes, 10 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 12 hours or 24 hours of each other.
  • the compounds or pharmaceutical compositions of the disclosure and the additional cancer therapeutic agent are administered in sequence.
  • the compounds or pharmaceutical compositions of the disclosure and the additional cancer therapeutic agent can be administered in an alternating sequence.
  • the at least one additional cancer therapeutic agent comprises a chemotherapeutic agent.
  • chemotherapeutic agents examples include platinum compounds (e.g., cisplatin, carboplatin, and oxaliplatin), alkylating agents (e.g., cyclophosphamide, ifosfamide, chlorambucil, nitrogen mustard, thiotepa, melphalan, busulfan, procarbazine, streptozocin, temozolomide, dacarbazine, and bendamustine), antitumor antibiotics (e.g., daunorubicin, doxorubicin, idarubicin, epirubicin, mitoxantrone, bleomycin, mytomycin C, plicamycin, and dactinomycin), taxanes (e.g., paclitaxel and docetaxel), antimetabolites (e.g., 5-fluorouracil, cytarabine, premetrexed
  • alkylating agents e.g., cyclophosp
  • an additional anticancer agent affects (e.g., inhibits) histone modifications, such as histone acetylation or histone methylation.
  • an additional anticancer agent is selected from the group consisting of chemotherapeutics (such as 2CdA, 5-FU, 6-Mercaptopurine, 6-TG, AbraxaneTM, Accutane®, Actinomycin-D, Adriamycin®, Alimta®, all-trans retinoic acid, amethopterin, Ara-C, Azacitadine, BCNU, Blenoxane®, Camptosar®, CeeNU®, Clofarabine, ClolarTM, Cytoxan®, daunorubicin hydrochloride, DaunoXome®, Dacogen®, DIC, Doxil®, Ellence®, Eloxatin®, Emcyt®, etoposide phosphate, Fludara®, FUDR®, Gemzar®, Gleevec
  • chemotherapeutics
  • Examples of biological agents that can be used in combination with the compositions and methods described herein include monoclonal antibodies (e.g., rituximab, cetuximab, obinutuzumab, ofatumumab, ibritumomab, brentuximab, bevacizumab, panitumumab, pembrolizumab, tositumomab, trastuzumab, alemtuzumab, gemtuzumab ozogamicin, bevacizumab, catumaxomab, denosumab, obinutuzumab, ofatumumab, ramucirumab, pertuzumab, ipilimumab, nivolumab, nimotuzumab, lambrolizumab, pidilizumab, siltuximab, tremelimumab, or others known in the art), enzymes (e.g
  • biological agents comprise adoptive cell therapies.
  • adoptive cell therapies For example, chimeric antigen receptor T cell (CAR-T) therapies.
  • the adoptive cell therapy is autologous.
  • the adoptive cell therapy is allogeneic.
  • the at least one additional cancer therapeutic agent comprises a cyclin dependent kinase (CDK) inhibitor.
  • the CDK inhibitor comprises a CDK2/9 inhibitor.
  • Exemplary CDK2/9 inhibitors include CCT68127, CYC065, SNS-032, and Dinaciclib.
  • the CDK inhibitor is not a CDK4/6 inhibitor.
  • the CDK inhibitor is a broad spectrum CDK inhibitor, for example flavopiridol.
  • the CDK inhibitor is a CDKl/2 inhibitor, for example AT7519.
  • the CDK inhibitor is a CDK1 inhibitor, for example P276-00.
  • the CDK inhibitor is a CDK2/5 inhibitor, for example roscovitine.
  • the at least one additional cancer therapeutic agent comprises an immune checkpoint inhibitor.
  • Immune checkpoint inhibitors target immune checkpoints, which regulate the immune system, and under certain circumstances, can prevent the immune system from targeting tumors.
  • the immune checkpoint comprises a PD-1/PD-L1 immune checkpoint.
  • the immune checkpoint comprises a CLTA-4 immune checkpoint.
  • the immune checkpoint inhibitor is an antibody or a small molecule.
  • Exemplary PD-1 inhibitors include, but are not limited, nivolumab and pembrolizumab.
  • Exemplary PD-L1 inhibitors include, but are not limited to, atezolizumab, avelumab and durvalumab.
  • Exemplary CLTA-4 inhibitors include, but are not limited to, ipilimumab.
  • treatment methods described herein are performed on subjects for which other treatments of the medical condition have failed or have had less success in treatment through other means, e.g., in subjects having a cancer refractory to standard-of-care treatment. Additionally, the treatment methods described herein can be performed in conjunction with one or more additional treatments of the medical condition, e.g., in addition to or in combination with standard-of-care treatment. For instance, the method can comprise administering a cancer regimen, e.g., nonmyeloablative chemotherapy, surgery, hormone therapy, and/or radiation, prior to, substantially simultaneously with, in temporal proximity to, in sequence with or after the administration of a compound or pharmaceutical composition described herein.
  • a cancer regimen e.g., nonmyeloablative chemotherapy, surgery, hormone therapy, and/or radiation
  • the invention encompasses methods comprising providing at least one compound, measuring the activity of the compound and determining if the activity of the compound is above or below a predetermined level.
  • Methods of measuring the activity of a compound will be readily apparent to one of ordinary skill in the art.
  • Exemplary methods include measuring growth-inhibitory concentration (GI50) in vitro in a cell proliferation assay or a colony survival assay.
  • Cell proliferation can be measured using any technique known in the art. For example, cell proliferation can be measured by measuring colony formation using stains such as Crystal Violet/DBPS and measuring 600 nm absorbance.
  • cells can be treated with a dye that permeabilizes the cells and reacts with certain enzymes to provide a measure of metabolic activity (for example, MTT or WST-1).
  • Proliferation can be measured using fluorescence dyes such as CyQUANT (ThermoFisher Scientific).
  • cell proliferation can be measured by examining one or more proliferation markers, such as BrdU incorporation or proliferating cell nuclear antigen (PCNA) expression.
  • PCNA cell nuclear antigen
  • the method of measuring activity of a compound of the disclosure comprises measuring an effect of the compound on tumor growth in an animal.
  • animal cancer models include, but are not limited to, patient derived xenograft (PDX) cancer models, transgenic models and gene knock out or gene knock in models that modify one or more tumor suppressor or oncogenes and syngeneic models.
  • PDX patient derived xenograft
  • transgenic models and gene knock out or gene knock in models that modify one or more tumor suppressor or oncogenes and syngeneic models.
  • a PDX model cancer cells derived from a patient or cell line isolated or derived from a cancer of interest are transplanted into an immune deficient animal.
  • the immune deficient animal is a severely compromised immune deficient (SCID) mouse, a NOD-SCID mouse, or a recombination-activity gene 2 (Rag2) knockout mouse, which prevents transplant rejection.
  • SCID severely compromised immune deficient
  • NOD-SCID mouse NOD-SCID mouse
  • Rag2 recombination-activity gene 2
  • a syngeneic model e.g. a syngeneic mouse model, tumor tissues from the same genetic background as the given immuno-competent mouse strain are transplanted into the mouse to induce tumor formation.
  • the method of measuring activity comprises measuring a change in RNA expression of certain genes in tumor-derived cell cultures, blood, diseased tissues or diseased organs of treated individuals.
  • the gene or genes can be, for example, genes that are regulated by p300.
  • p300 regulation of target genes can be either direct (e.g. transcriptional regulation, through p300 activity at the cognate gene promoter), or indirect (e.g., through p300 regulation of upstream transcription factors involved in regulation of a target gene).
  • Exemplary p300 target genes include, but are not limited to, androgen response genes such as kallikrein related peptidase 3/prostate-specific antigen (KLK3/PSA), transmembrane serine protease 2 (TMPRSS2) and solute carrier family 45 member 3 (SLC45A3), VEGF and P53.
  • KLK3/PSA kallikrein related peptidase 3/prostate-specific antigen
  • TMPRSS2 transmembrane serine protease 2
  • SLC45A3 solute carrier family 45 member 3
  • the method of measuring activity comprises measuring the change in RNA expression of p300 target genes in vitro in cell culture assays.
  • Methods of measuring RNA expression of p300 target genes will be readily apparent to one of ordinary skill in the art.
  • levels of RNA expression can be measured using high throughput sequencing methods, microarrays, reverse transcription polymerase chain reaction (RT-PCR), quantitative RT-PCR (RT- qPCR) and droplet digital PCR (ddPCR) as well as any other method known in the art.
  • the method of measuring activity comprises measuring the change in RNA expression of Androgen Receptor - responsive genes in vitro in cell culture assays (for example, KLK3, TMPRSS2 and/or SLC45A3). In some embodiments, the method of measuring activity comprises measuring the amount of Tumor-specific Protein 53 (p53) in vitro in cell culture assays. [0658] In some embodiments, the method of measuring activity comprises measuring the amount of acetylated p53 lysine 382 (p53K382Ac) in vitro in cell culture assays. The amount of acetylated p53 lysine 382 can be measured, for example, by using a p53K382Ac specific antibody and Western Blot. [0659] In some embodiments, the method of measuring activity comprises measuring the amount of Prostate- Specific Antigen protein in serum of treated individuals. The amount of PSA can be measured, for example, with a PSA specific antibody and by Western Blot or ELISA.
  • kits comprising reagents for assaying the expression of one or more p53 or Rb pathway genes, or ASXL1, RUNXl or a paralog thereof, and instructions for use in diagnosing a cancer in a subject as susceptible to compounds of formula la as described herein.
  • exemplary reagents include, but are not limited to antibodies, PCR primers for RT-PCR and generating high throughput sequencing libraries, microarrays, RT-PCR probes, and enzymes.
  • kits further comprise the compounds of formula la of the instant disclosure and pharmaceutical compositions comprising same.
  • kits further comprise at least one additional cancer therapeutic agent. Any additional cancer therapeutic described herein is envisaged as being within the scope of a kit of the disclosure.
  • the compounds or pharmaceutical compositions of the disclosure and the at least one additional cancer therapeutic are different compositions.
  • the compounds or pharmaceutical compositions of the disclosure and the at least one additional cancer therapeutic formulated in the same composition.
  • Kits comprising reagents for assaying p53 and/or Rb gene expression, or RUNXl or ASXL1 gene expression or a paralog thereof, and the compounds and pharmaceutical compositions of the disclosure are for the use in treating a cancer in a subject.
  • Exemplary cancers include prostate cancer, breast cancer and small cell lung cancer.
  • Articles of manufacture include, but are not limited to labels, instructional pamphlets, vials and syringes.
  • Cells were expanded and aliquots kept frozen in liquid nitrogen according to manufacturer’s instructions. Once thawed, aliquots were passaged every second or third day at a seed density of 10,000-20,000 cells/cm 2 (corresponding to 25,000-50,000 cells/ml culture medium for suspension cells) and used for a maximum of twenty passages.
  • Cell density was determined with a Via-1 Cassette (Chemometec, Allerod, Denmark) on a Nucleocounter NC 3000 (Chemometec). The required amount of cells was first diluted 1:10 in ready -to-use RPMI; cells pipetted five times up-down with a serological pipette; and the 1:10 solution added to the final volume needed for the whole assay setup. Cells were mixed again by pipetting up and down twenty times with a serological pipette. The final cell density was 70 cells/ml.
  • Treatment Compound stock solutions were prepared at a concentration of 30mM in 50% DMSO/50% water; and diluted in the same solution so that the volume added to the wells was of 5 ⁇ l and the final DMSO well concentration 0.08%. Untreated cells (negative controls) were incubated in a) medium only; and b) 0.08% DMSO. Test performance was monitored by a standard treatment with a fixed concentration of a reference compound (10 ⁇ M Compound 57) that resulted in -80-90% inhibition of colony formation. Tests showing less than 75% or more than 95% inhibition were repeated. The plates were swirled gently after addition of the compounds and the cells incubated for 14 days at 37°C. Culture incubation solutions were replaced after one week.
  • Cell seeding (day -1). When necessary, cells were trypsinized using standard methods. Cells were collected and resuspended in 15 mL of appropriate culture medium, counted and diluted to the needed density. Ninety ⁇ l (microliter) cells were seeded per well in a 96-well plate. Extra four wells per cell line were seeded on an additional plate for Day 0 reading (baseline cell density). Cells were incubated at 37°C overnight.
  • Endpoint CTG reading (day 3 or day 5). The amounts of cells in the plates was determined by endpoint CTG-test. Fifty ⁇ l of CTG were added to the 100 ⁇ l of cell culture per well, contents mixed for 2 min on a plate shaker, and the plates incubated for 10 min at room temperature in the dark. Luminescence was recorded on an EnVision Multi Label Reader.
  • mice Male BALB/c nude mice (7-9 weeks of age) were injected with human cancer cells. The cells were inoculated subcutaneously into the left flank of the mice. Mice were inoculated with 22Rvl, LNCaP, DU145, SNU-16 or SNU-5 cancer cells. When tumors reached a mean volume of approximately 100mm 3 , mice were randomly assigned to treatment groups.
  • mice were randomly assigned to 5 treatment groups.
  • Group 01 was treated with vehicle alone, 10 ⁇ L/g.p.o., daily (Q.D.), for 6 weeks.
  • Group 02 was treated with 1 mg/kg Compound #258, 10 ⁇ L/g.p.o., Q.D., for 6 weeks.
  • Group 03 was treated with 3 mg/kg Compound #258, 10 ⁇ L/g.p.o., Q.D., for 6 weeks.
  • Group 04 was treated with 3 mg/kg Compound #258, 10 ⁇ L/g.p.o., Q.D., repeated cycles of 7 day on P day off, up to 6 weeks.
  • Group 05 was treated with 30 mg/kg Compound #258, 10 ⁇ L/g.p.o., B.I.D. (2 daily doses), repeated cycles of 1 day on/ 6 days off, for 6 weeks. Tumor burden was assessed by caliper measurement two to three times weekly.
  • mice were randomly assigned to 3 or 4 treatment groups. Mice were treated with vehicle alone, 1 mg/kg Compound #258 Q.D., or 3 mg/kg Compound #258 Q.D, for at least 30 days. DU145 xenograft mice were also treated with 6 mg/kg Compound #258 Q.D. Tumor burden was assessed by caliper measurement two to three times weekly.
  • test compounds Tenfold final concentrations of test compounds were prepared in cell culture media (work dilutions). Ten ⁇ l of work dilution solutions were dispensed into the corresponding wells in 96- well plates to bring the total volume up to IOOmI. Conditions were tested in quadruplicate. The plates were then incubated at 37°C for three to five days.
  • Detection of Caspase 3/7 activity was performed using the Promega Caspase-Glo® 3/7 Assay System (Promega Corporation, Madison, WI, USA; Cat#G8091) according to manufacturer’s instructions. Luminescence was recorded on a Tecan Spark Microplate Reader (Tecan Trading AG, Maennedorf, Switzerland).
  • Detection of Caspase 8 activity was performed using the Promega Caspase-Glo® 8 Assay System (Promega Corporation, Madison, WI, USA; Cat#G8201) according to manufacturer’s instructions. Luminescence was recorded on a Tecan Spark Microplate Reader (Tecan trading AG, Maennedorf, Switzerland). Fluorescence-Based Detection of Cell Cycle Arrest
  • Cell culture For cell cycle assays, cells used were cultured at 37°C with 5% C02. Compound stock solutions (1.5 mM) were made in sterile water, aliquoted and stored at room temperature. Plastic consumables, culture media and supplements were purchased from well-known suppliers (Table 3) [0686] Cell seeding. When necessary, cells were trypsinized using standard methods. Cells were collected and resuspended in 10 mL of appropriate culture medium, counted and diluted to the needed density. Three ml of cells (for a total of 100,000-250,000 cells) were seeded per well in a 6-well tissue culture treated plate. Cells were incubated at 37°C overnight with 5% C02.
  • test compounds were prepared in cell culture media (work dilutions). Five ⁇ l of work dilution solutions were dispensed into the corresponding wells of the 6-well plates. The plates were then incubated at 37°C for the required time.
  • test compounds were prepared in cell culture media (work dilutions). Five ⁇ l of work dilution solutions were dispensed into the corresponding wells of the 6-well plates. The plates were then incubated at 37°C for the required time.
  • test compounds were prepared in cell culture media (work dilutions). Fifty ⁇ l of work dilution solutions were dispensed into the corresponding flasks. The plates were then incubated at 37°C with 5% C02 for the required time.
  • RNA isolation and quality control After the incubation, cells were trypsinized/collected following standard procedures in 1.5ml Eppendorf tubes, centrifuged at l,500g for 5 minutes, the supernatant removed and the cells resuspended in 600 ⁇ l RNAProtect Cell Reagent (Cat#76526, QIAGEN, Germantown, MD USA). Total RNA was isolated using the RNeasy Mini Kit (QIAGEN). An on-column DNase digestion step was included in the RNA isolation protocol. The final volume of the eluate was 40 ⁇ l. RNA concentration and purity were assessed on a NanoDrop ND-1000 spectral photometer (Thermo Fisher Scientific, Waltham, MA, USA). RNA integrity was determined on the 2100 Bioanalyzer (Agilent Technologies, Santa Clara, CA, USA) using RNA Nano LabChip Kits (Agilent Technologies).
  • LNCaP, 22Rvl, PC3 and DU145 cell lines were treated with 2 nM, 20 nM or 200 nM of Compound #258 for 1, 2, 4, 8, 24, 48 or 72 hours and the protein expression of p53, p53 acetylated at lysine 382 (K382Ac), p21, MDM2 and E2F1 were assayed at each time point and concentration via Western blot (FIG. 2).
  • the p53, Rb1 and CDK2NA status of FNCaP, 22Rvl and DU145 is shown in Table 5, below.
  • PC3 cells do not express p53 protein, but are wild type for Rb1 and CDK2NA.
  • FIG. 2 shows that changes in E2F1 and p21 are correlated with the strong effect of Compound #258 in DU145 cells.
  • PCa prostate cancer
  • WT wild type
  • Mut mutation
  • IHC immunohistochemistry
  • Example 4 Treatment of prostate cancer cell lines with Compound #258 disrupts the cell cycle at the G1/S transition
  • FIG. 3 shows a gene ontology analysis of transcripts that are significantly enriched for biological processes relative to untreated controls (FDR-adjusted q value ⁇ 0.05) for both 22Rvl and FNCaP after treatment with 200 nM of Compound #258 for 72 hours.
  • genes associated with cell cycle progression, cell cycle checkpoints, chromosome organization, DNA replication and the G1/S phase transition are significantly enriched in 22Rvl and LNCaP cells treated with Compound #258.
  • Data was analyzed with GOrilla (Gene Ontology enRIchment anaLysis and visuaLizAtion tool. Eden and co-workers, in BMC Bioinformatics 10:48 (2009)).
  • LNCaP, 22Rvl and DU145 prostate cancer cells were assayed for their ability to proceed through the cell cycle when treated with 200 nM of Compound #258.
  • LNCaP, 22Rvl and DU145 were treated with Compound #258; and the amount of DNA in the cells was assayed by intracellular fluorescence staining.
  • 22Rvl and DU145 cell lines both show in increase in the proportion of cells in S phase following 24 hours exposure to Compound #258. The effect is extremely pronounced in DU145 cells (PIG. 4C).
  • LNCaP cells show an increase in the proportion of cells in the G1 phase, and a decrease and in the proportion of cells in G2/M phase, when compared to untreated controls following 24 hours exposure to compound #258.
  • LNCaP, 22Rvl and DU145 prostate cancer cells were assayed for the expression of p53, p53 K382Ac and p21 protein expression following 72 hours treatment with 200 nM of Compound #258.
  • DU145 cells showed no regulation of p53 and lysine 382 acetylated p53 (PIG. 5).
  • K382 acetylation of p53 is thought to play a role in binding of p53 to DNA and its interaction with co-factors. Thus, p53 is not activated in DU145 cells when treated with 200 nM Compound #258.
  • LNCaP, 22Rvl and DU145 prostate cancer cells were assayed for Caspase 3/7 activity following 72 hours treatment with 2 nM, 20 nM or 200 nM of Compound #258.
  • Caspases 3 and 7 are effector caspases that are activated early in apoptosis and are thus robust markers for cellular entry into the pro-apoptotic pathway.
  • DU145 cells show high levels of active Caspase 3/7 (PIG. 6), indicating that DU145 cells, but not LNCaP and 22Rvl cells, are undergoing apoptosis in response to Compound #258.
  • Example 5 Cyclin expression in DU145 cells following treatment with Compound #258
  • DU145 cells were assayed for the expression of Cyclin D1 when treated with 200 nM of Compound #258 (FIGS. 7, 8 A, 8B, 8C and 9). Cyclin D1 accumulates during G1, and then is degraded as the cell enters S phase. Cyclin D1 forms a complex with cyclin dependent kinases (CDK) CDK4 and CDK6, and acts with CDK4/6 to regulate the G1/S cell cycle transition.
  • CDK cyclin dependent kinases
  • FIGS. 7, 8A, 8B, 8C and 9 DU145 cells treated with Compound #258 accumulate Cyclin D1 following 24, 48 and 72 hours of treatment with 200 nM Compound #258, unlike untreated control cells, which exhibit the opposite behavior.
  • Example 6 Correlation of sensitivity to Compound #258 with p53, Rbl and CDK2NA in cell lines
  • FIG. 14 Panels of 110 cell lines (FIG. 14) and 144 cell lines (FIGS. 15-16) were screened for their response to Compound #258 in a cell proliferation assay, and the half maximal inhibitory concentration (IC 50 ) and the concentration that gives 90% of maximum inhibition (IC 90 ) of Compound #258 were calculated for each cell line.
  • FIG. 13 shows that the IC 50 and IC 90 estimates for Compound #258 in the 110 cell line panel are correlated.
  • FIG. 14 shows the IC 50 values for the 110 cell line panel treated with Compound #258. Red bars indicate cell lines where greater than 90% inhibition was reached. As can be seen from FIG.
  • FIG. 10A The p53 and Rb1 status of a panel of 52 cell lines is shown in FIG. 10A.
  • the two cell lines of the panel with dysfunctional p53 and Rb1 have EC90 values for Compound #258 of less than 10 ⁇ M, and the three cell lines selected based on presence of p53/Rb1 dysfunctions (right-hand side of the panel) all exhibited an IC 90 of less than 20nM.
  • IC 90 less than 20nM.
  • FIG. 10B The p53, Rb1 and CDKN2A status of a panel of 52 cell lines is shown in FIG. 10B. Of the five p53 and Rb1 negative lines with an EC 90 of less than 10 ⁇ M, 4 were also CDKN2A negative. Furthermore, of the 17 lines with an IC 90 of less than 10 ⁇ M, 12 were CDKN2A negative.
  • Example 7 Intermittent dosing of Compound #258 in a mouse tumor model [0717] The ability of Compound #258 to treat tumors in immunocompromised mice bearing tumors from cancer cell lines with the “apoptotic genotype” such as SNU-5 and SNU-16, or the “senescent genotype” such as 22Rvl was assayed.
  • apoptotic genotype such as SNU-5 and SNU-16
  • the “senescent genotype” such as 22Rvl
  • Example 8 Efficacy of Compound #258 in late stage castration resistant prostate cancer (CRPC)
  • Castration resistant prostate cancer (CRPC) cell lines LNCaP, 22Rvl and DU145 were tested in a mouse xenograft model. Mice implanted with LNCaP, 22Rvl or DU145 cancer cells were treated with vehicle alone, 1 mg/kg Compound #258 Q.D. or 3 mg/kg Compound #258 Q.D. DU145 implanted mice were also treated with 6 mg/kg Compound #258 Q.D. In LNCaP and 22Rvl implanted mice, treatment with Compound #258 was able to slow or arrest tumor progression (FIGS. 17A-17B). In contrast, in DU145 implanted mice, treatment with 6 mg/kg of Compound #258 was able to reverse tumor progression.
  • CRPC Castration resistant prostate cancer
  • Compound #258 increases with disease progression and hormone independence of the prostate cancer (FIGS. 17A-17C). This indicates that Compound #258 can be used to treat late stage CRPC in patients that are failing on Androgen Receptor (AR) antagonist therapies. These preclinical models indicate the potential for a change of the current treatment paradigm enabling partial or complete responses in currently untreatable patients.
  • AR Androgen Receptor
  • Example 10 Compound #258 can reduce proliferation in BT-549, NCI-H69 and HuT-78 cells [0721] The effect of Compound #258 was tested on BT-549, NCI-H69, and HuT-78 cells in a proliferation assay.
  • BT-549 cells are p53 -/-
  • Rb 1 -/- NCI-H69 cells are p53 -/-
  • HuT-78 cells are p53 -/- , Rb1 -/- , CDKN2A -/- .
  • Compound #258 was able to decrease cell proliferation at 72 and 120 hours in a concentration dependent manner (FIG. 19).
  • Example 11 Compound #258 can induce apoptosis in CDK2NA negative Stomach cancer cell lines
  • Compound #258 was also able to induce apoptosis in the SNU-5 and SNU-16 gastric cancer cell lines.
  • SNU-5 and SNU-16 are p53-/- and CDKN2A-/-.
  • 0.2 ⁇ M of Compound #258 was able to induce activation of Caspase 3/7 and Caspase 8 in SNU-5 and SNU-16 cells at 72 hours (FIGS. 21 A- 21D).
  • Example 12 Compound #258 exhibits broad anti-proliferative efficacy in a large cell line panel [0724]
  • a panel of 500 cancer cell lines representing 23 different tumor types were assayed for their response to Compound #258 (FIG. 22).
  • Proliferation assays were performed with CellTiter-Glo (Promega) in cells after five days treatment with compound #258 in a dose-dependent manner and EC50 values were calculated.
  • the EC50 value for 381 of the 500 cell lines tested was below 100 nM. Over 90% inhibition was observed in 25% of the cell lines tested.
  • prostate cancer cell lines were one of the most sensitive types of cell lines.
  • Example 13 Compound #258 induces apoptosis in cancer cell lines with loss of Rb and p53 function

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Abstract

L'invention concerne des méthodes de traitement d'un sujet atteint d'un cancer comprenant la détermination de l'expression ou de l'activité d'un ou de plusieurs gènes dans les voies p53 et/ou Rb, et l'administration d'un composé modulateur CBP/p300.
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Cited By (3)

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Publication number Priority date Publication date Assignee Title
WO2021255239A1 (fr) * 2020-06-19 2021-12-23 Inthera Bioscience AG Dérivés d'oxopipérazine pour le traitement du cancer
US12012393B2 (en) 2017-12-15 2024-06-18 Inthera Bioscience AG Oxopiperazine derivatives
WO2024245974A1 (fr) * 2023-05-26 2024-12-05 Inthera Bioscience AG Dérivés d'oxopipérazine pour le traitement du cancer

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3947250A (en) 1974-06-21 1976-03-30 Baxter Laboratories, Inc. Method of immunodiffusion
US4605305A (en) 1982-07-06 1986-08-12 Centre National De La Recherche Scientifique Laser nephelometer for sensing antigens and antibodies characterized in having measuring cell comprised of capiliary tube with the diameter of laser beam
US20030153014A1 (en) 1999-10-08 2003-08-14 Li Shen Compositions and methods for detecting protein modification and enzymatic activity
US20110212104A1 (en) 2008-11-03 2011-09-01 Schering Corporation Inflammatory bowel disease biomarkers and related methods of treatment
WO2015179547A2 (fr) * 2014-05-21 2015-11-26 New York University Mimétiques d'hélice d'oxopipérazine pour le contrôle de l'expression génétique inductible par hypoxie
WO2019118973A1 (fr) * 2017-12-15 2019-06-20 Inthera Bioscience AG Dérivés de 1-(pipéridinocarbonylméthyl)-2-oxopipérazine pour le traitement du cancer

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3947250A (en) 1974-06-21 1976-03-30 Baxter Laboratories, Inc. Method of immunodiffusion
US4605305A (en) 1982-07-06 1986-08-12 Centre National De La Recherche Scientifique Laser nephelometer for sensing antigens and antibodies characterized in having measuring cell comprised of capiliary tube with the diameter of laser beam
US20030153014A1 (en) 1999-10-08 2003-08-14 Li Shen Compositions and methods for detecting protein modification and enzymatic activity
US20110212104A1 (en) 2008-11-03 2011-09-01 Schering Corporation Inflammatory bowel disease biomarkers and related methods of treatment
WO2015179547A2 (fr) * 2014-05-21 2015-11-26 New York University Mimétiques d'hélice d'oxopipérazine pour le contrôle de l'expression génétique inductible par hypoxie
WO2019118973A1 (fr) * 2017-12-15 2019-06-20 Inthera Bioscience AG Dérivés de 1-(pipéridinocarbonylméthyl)-2-oxopipérazine pour le traitement du cancer

Non-Patent Citations (69)

* Cited by examiner, † Cited by third party
Title
"Design and Application of Prodrugs, Textbook of Drug Design and Development", 1991, pages: 113 - 191
"Immunology Methods Manual", 1997, ACADEMIC PRESS
"Methods in Enzymology", vol. 4, 1985, ACADEMIC PRESS
"Viral Vectors", 1995, ACADEMIC PRESS
ADVANCED DRUG DELIVERY REVIEWS, vol. 19, 1996, pages 115
AKAMATSU ET AL.: "Clinical and molecular features of treatment-related neuroendocrine prostate cancer", INTERNATIONAL JOURNAL OF UROLOGY, vol. 25, 2018, pages 345 - 35
ALICO-WORKERS, CHEMICAL REVIEWS, vol. 118, no. 3, 2018, pages 1216
ANGERVO ET AL., BIOCHEM. BIOPHYS. RES. COMM., vol. 189, 1992, pages 1177
ASADA SHUHEI ET AL: "The role of ASXL1 in hematopoiesis and myeloid malignancies", CMLS CELLULAR AND MOLECULAR LIFE SCIENCES, BIRKHAUSER VERLAG, HEIDELBERG, DE, vol. 76, no. 13, 30 March 2019 (2019-03-30), pages 2511 - 2523, XP036815981, ISSN: 1420-682X, [retrieved on 20190330], DOI: 10.1007/S00018-019-03084-7 *
ATTARKURDISTANI, COLD SPRING HARBOR PERSPECTIVES IN MEDICINE, vol. 7, 2017, pages a026534
AUSUBEL ET AL.: "Current Protocols in Molecular Biology", 2005, JOHN WILEY AND SONS, INC.
AVANTAGGIATI MARIA LAURA ET AL: "Recruitment of p300/CBP in p53-Dependent Signal Pathways", CELL, vol. 89, no. 7, 1997, pages 1175 - 1184, XP085009453, ISSN: 0092-8674, DOI: 10.1016/S0092-8674(00)80304-9 *
AVANTAGGIATICO-WORKERS, CELL, vol. 89, 1997, pages 1175
BEDFORDCO-WORKERS, EPIGENETICS, vol. 5, no. 1, 2010, pages 9
BELTRAN, NAT MED, vol. 22, no. 3, March 2016 (2016-03-01), pages 298 - 305
BENSON ET AL., NUCL. ACIDS RES., vol. 41, no. D1, 1 January 2013 (2013-01-01), pages D36 - D42
BERNARD TESTAJOACHIM MAYER: "Hydrolysis In Drug And Prodrug Metabolism: Chemistry, Biochemistry And Enzymology", 2002, JOHN WILEY AND SONS, LTD.
BERNATCO-WORKERS, ONCOGENE, vol. 22, no. 39, 2003, pages 7871
BLOBEL, BLOOD, vol. 95, no. 3, 2000, pages 745
BREENMAPP, CURRENT OPINION IN CHEMICAL BIOLOGY, vol. 45, 2018, pages 195 - 203
BUNDGAARD ET AL., JOURNAL OF DRUG DELIVER REVIEWS, vol. 8, 1992, pages 1 - 38
BUNDGAARD, J., PHARMACEUTICAL SCIENCES, vol. 77, 1988, pages 285
BURSLEMCO-WORKERS, CHEMICAL SCIENCE, vol. 8, no. 6, 2017, pages 4188
CAHN ET AL., ANGEW. CHEM. INTER. EDIT., vol. 5, 1966, pages 385
CAHN ET AL., ANGEW. CHEM., vol. 78, 1966, pages 413
CAHN, EXPERIENTIA, vol. 12, 1956, pages 81
CAHN, J. CHEM. EDUC., vol. 41, 1964, pages 116
CAHNINGOLD, J. CHEM. SOC., 1951, pages 612
COLIGAN ET AL.: "Remington's Pharmaceutical Sciences", 1990, MACK PUBLISHING CO.
CULIG, JOURNAL OF CELL PHYSIOLOGY, vol. 231, no. 2, 2016, pages 270
DANCYCOLE, CHEMICAL REVIEWS, vol. 115, no. 6, 2015, pages 2419
DI MARTILECO-WORKERS, ONCOTARGET, vol. 7, no. 34, 2016, pages 55789
DOYLEGRIFFITHS: "Cell and Tissue Culture: Laboratory Procedures in Biotechnology", 1998, JOHN WILEY & SONS
DUTTACO-WORKERS, MOLECULAR GENETICS AND METABOLISM, vol. 119, no. 1-2, 2016, pages 37
EDEN E. ET AL., BMC BIOINFORMATICS, vol. 10, 2009, pages 48
EMBO JOURNAL, vol. 17, 1998, pages 3124
FAIVRE, E. ET AL., NATURE, vol. 578, no. 7794, 2020, pages 3060310
FERACO-WORKERS, BIOCHEMISTRY, vol. 51, no. 47, 2012, pages 9524
FINGL ET AL., PHARMACOLOGICAL BASIS OF THERAPEUTICS, 1975
FROST ET AL., J. BIOL. CHEM., vol. 266, 1991, pages 18082
GOODMANSMOLIK, GENES & DEVELOPMENT, vol. 14, no. 13, 2000, pages 1553
J. MED. CHEM., vol. 39, 1996, pages 10
JACQUES ET AL.: "Enantiomers, Racemates, and Resolutions", 1981, JOHN WILEY & SONS
JIN, L. ET AL., CANCER RES, vol. 77, no. 20, 2017, pages 5564 - 5575
KAMEICO-WORKERS, CELL, vol. 85, 1996, pages 403
KRATZ ET AL., EXP. CELL RES., vol. 202, 1992, pages 381
KUSHALCO-WORKERS, PNAS, vol. 110, no. 39, 2013, pages 15602
LAOCO-WORKERS, PNAS, vol. 111, no. 21, 2014, pages 7531
LASKO LM ET AL., NATURE, vol. 550, no. 7674, 5 October 2017 (2017-10-05), pages 128 - 132
LASKO, L. ET AL., ACS MED CHEM LETT, vol. 9, no. 1, 2017, pages 28 - 33
LEECO-WORKERS, ONCOGENE, vol. 16, 1998, pages 2695
LEROY ET AL., HUMAN MUTATION, vol. 35, no. 6, 2014, pages 672 - 688
LI ET AL., PROC NATL ACAD SCI USA., vol. 100, no. 5, 2003, pages 2674 - 8
MASOUDLI, ACTA PHARMACOLOGICA SINICA B, vol. 5, no. 5, 2015, pages 378
NYQUIST, MD ET AL.: "Combined TP53 and RB1 Loss Promotes Prostate Cancer Resistance to a Spectrum of Therapeutics and Confers Vulnerability to Replication Stress", CELL REP, vol. 31, no. 8, 26 May 2020 (2020-05-26), pages 107669
OGIWARA H. ET AL., CANCER DISCOV, vol. 6, no. 4, April 2016 (2016-04-01), pages 430 - 45
PATELCO-WORKERS, THE EMBO JOURNAL, vol. 18, no. 18, 1999, pages 5061
PEARSON ET AL., PNAS, vol. 85, April 1988 (1988-04-01), pages 2444 - 2448
PEGG, N. ET AL., POSTER #3991 AACR, 2018
S. M. BERGE ET AL., J. PHARMACEUTICAL SCIENCES, vol. 66, 1977, pages 1 - 19
SAMBROOK ET AL.: "Molecular Cloning, A Laboratory Manual", 2000, COLD SPRING HARBOR PRESS
SAMBROOK ET AL.: "Molecular Cloning: A Laboratory Manual", 2001, HARBOR LABORATORY PRESS
SAULNIER ET AL., BIOORGANIC AND MEDICINAL CHEMISTRY LETTERS, vol. 4, 1994, pages 1985
SOOD RAMAN ET AL: "Role of RUNX1 in hematological malignancies", BLOOD, vol. 129, no. 15, 13 April 2017 (2017-04-13), pages 2070 - 2082, XP055793761, DOI: 10.1182/blood-2016-10- *
STAUFFERCO-WORKERS, JOURNAL OF BIOLOGICAL CHEMISTRY, vol. 282, no. 13, 2007, pages 9678 - 9687
T. W. GREENE: "Protecting Groups in Organic Chemistry", 1999, JOHN WILEY AND SONS, INC.
TORNESELLOCO-WORKERS, CANCERS (BASEL, vol. 10, no. 7, 2018, pages E213
WUCHANO YUANGIORDANO, ONCOGENE, vol. 21, 2002, pages 2253 - 2260
XIECO-WORKERS, ONCOGENE, vol. 33, no. 8, 2014, pages 1037

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US12012393B2 (en) 2017-12-15 2024-06-18 Inthera Bioscience AG Oxopiperazine derivatives
WO2021255239A1 (fr) * 2020-06-19 2021-12-23 Inthera Bioscience AG Dérivés d'oxopipérazine pour le traitement du cancer
WO2024245974A1 (fr) * 2023-05-26 2024-12-05 Inthera Bioscience AG Dérivés d'oxopipérazine pour le traitement du cancer

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