US20140271460A1 - Highly Active Anti-Neoplastic and Anti-Proliferative Agents - Google Patents

Highly Active Anti-Neoplastic and Anti-Proliferative Agents Download PDF

Info

Publication number
US20140271460A1
US20140271460A1 US14/213,784 US201414213784A US2014271460A1 US 20140271460 A1 US20140271460 A1 US 20140271460A1 US 201414213784 A US201414213784 A US 201414213784A US 2014271460 A1 US2014271460 A1 US 2014271460A1
Authority
US
United States
Prior art keywords
alkylene
compound
substituted
alkyl
cycloalkyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
Application number
US14/213,784
Other languages
English (en)
Inventor
Norman E. Sharpless
Jay Copeland Strum
John Emerson Bisi
Patrick Joseph Roberts
Francis Xavier Tavares
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
G1 Therapeutics Inc
Original Assignee
G1 Therapeutics Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by G1 Therapeutics Inc filed Critical G1 Therapeutics Inc
Priority to US14/213,784 priority Critical patent/US20140271460A1/en
Publication of US20140271460A1 publication Critical patent/US20140271460A1/en
Priority to US15/201,286 priority patent/US20160310499A1/en
Assigned to G1 THERAPEUTICS, INC. reassignment G1 THERAPEUTICS, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: BISI, JOHN EMERSON, ROBERTS, PATRICK JOSEPH, STRUM, JAY COPELAND, TAVARES, FRANCIS XAVIER
Priority to US15/713,385 priority patent/US20180015096A1/en
Priority to US16/228,308 priority patent/US10709711B2/en
Priority to US16/926,035 priority patent/US20200345743A1/en
Assigned to G1 THERAPEUTICS, INC. reassignment G1 THERAPEUTICS, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: BISI, JOHN EMERSON, ROBERTS, PATRICK JOSEPH, STRUM, JAY COPELAND
Assigned to G1 THERAPEUTICS, INC. reassignment G1 THERAPEUTICS, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: TAVARES, FRANCIS X.
Assigned to G1 THERAPEUTICS, INC. reassignment G1 THERAPEUTICS, INC. CORRECTIVE ASSIGNMENT TO CORRECT THE ASSIGNEE ADDRESS PREVIOUSLY RECORDED AT REEL: 055725 FRAME: 0654. ASSIGNOR(S) HEREBY CONFIRMS THE ASSIGNMENT. Assignors: TAVARES, FRANCIS X.
Priority to US17/890,130 priority patent/US20230248733A1/en
Abandoned legal-status Critical Current

Links

Images

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/527—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim spiro-condensed
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings
    • C07D487/20—Spiro-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/529—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim forming part of bridged ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A61K47/48384—
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/545—Heterocyclic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
    • A61K47/6803—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
    • A61K47/6851—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell
    • A61K47/6867—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell the tumour determinant being from a cell of a blood cancer
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/041—Heterocyclic compounds
    • A61K51/044—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
    • A61K51/0459—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having six-membered rings with two nitrogen atoms as the only ring hetero atoms, e.g. piperazine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/041—Heterocyclic compounds
    • A61K51/044—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
    • A61K51/0463—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/041—Heterocyclic compounds
    • A61K51/044—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
    • A61K51/0468—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/10—Anti-acne agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings
    • C07D487/14—Ortho-condensed systems

Definitions

  • This invention is in the area of improved compounds and methods for treating selected cancers and hyperproliferative disorders.
  • Cancer is a group of diseases categorized by uncontrolled growth and spread. In the United States in 2013, approximately 1.6 million new cases of cancer were expected to be diagnosed, and over 500,000 people in the U.S. were expected to die from the disease, which is about 1,600 per day. Cancer Facts and Figures 2013 , American Cancer Society.
  • cancers involve a malfunction of genes that control cell growth and division. Although all cancers share that characteristic, cancers vary greatly according to tissue or cell type, which specific genes are down or upregulated, which aspect of the cell cycle is implicated, whether and which cell surface receptors accelerate growth, types of altered metabolism, and which drugs the cancer cells respond to with a therapeutically acceptable effect. Therefore, one of the key goals of cancer research is to identify drugs that show high activity against certain specific target cancers. Non-cancerous cellular hyperproliferation presents a similar problem.
  • Lymphoid neoplasms are broadly categorized into precursor lymphoid neoplasms and mature T-cell, B-cell or natural killer cell (NK) neoplasms.
  • Chronic leukemias are those likely to exhibit primary manifestations in blood and bone marrow, whereas lymphomas are typically found in extramedullary sites, with secondary events in the blood or bone.
  • Some mature B-cell disorders exhibit dominant immunosecretory manifestations.
  • Lymphoma is a cancer of lymphocytes, which are a type of white blood cell. Lymphomas are categorized as Hodgkin or non-Hodgkin. Over 48,000 new cases of leukemias were expected in 2013. They are classified into four main groups according to cell type and rate of growth: acute lymphocytic (ALL), chronic lymphocytic (CLL), acute myeloid (AML), and chronic myeloid (CML).
  • ALL acute lymphocytic
  • CLL chronic lymphocytic
  • AML acute myeloid
  • CML chronic myeloid
  • WO 2012/061156 filed by Francis Tavares and assigned to G1 Therapeutics describes CDK inhibitors. Also see WO 2013/148748 filed by Francis Tavares and assigned to G1 Therapeutics, directed to Lactam Kinase Inhibitors.
  • the present invention includes the use of an effective amount of a compound described herein, or its pharmaceutically acceptable salt, prodrug, or isotopic variant, optionally in a pharmaceutical composition, to treat a host, typically a human, with a selected cancer, tumor, hyperproliferative condition, or an inflammatory or immune disorder as described further herein.
  • a host typically a human
  • Some of the disclosed compounds are highly active against T-cell proliferation and/or B-cell proliferation and/or NK-cell proliferation.
  • Disorders include, but are not limited to those involving T-cell proliferation, maintenance of peripheral tolerance, those involving the inappropriate differentiation of Th2 cells, maturation or survival of T and/or B cells, natural killer cell development, or regulation of immunoglobulin class switching in B cells.
  • a compound/method of the present invention is used in combination with another therapy to treat the T, B or NK abnormal cellular proliferation, cancer or disorder.
  • the second therapy can be an immunotherapy.
  • the compound can be conjugated to an antibody, radioactive agent or other targeting agent that directs the compound to the diseased or abnormally proliferating cell.
  • the compound is used in combination with another pharmaceutical or a biologic agent (for example an antibody) to increase the efficacy of treatment with a combined or a synergistic approach.
  • the compound can be used with T-cell vaccination, which typically involves immunization with inactivated autoreactive T cells to eliminate a pathogenic autoreactive T cell population.
  • the compound is used in combination with a bispecific T-cell Engager (BiTE), which is an antibody designed to simultaneously bind to specific antigens on endogenous T cells and malignant cells, linking the two types of cells.
  • BiTE bispecific T-cell Engager
  • the present invention includes the following features:
  • FIGS. 1-3 illustrate exemplary embodiments of R 2 of compounds useful in the described invention.
  • FIGS. 4A-4C , 5 A- 5 D, 6 A- 6 C, 7 A-B, and 8 A- 8 F illustrate exemplary embodiments of the core structure of the compounds useful in the described invention.
  • FIG. 9 is a graph showing the cellular proliferation of SupT1 cells (human T-cell lymphoblastic leukemia) treated with PD0332991 (circles) or Compound T (Table 1; squares).
  • SupT1 cells human T-cell lymphoblastic leukemia
  • PD0332991 circles
  • Compound T Table 1; squares.
  • the SupT1 cells were seeded in Costar (Tewksbury, Mass.) 3093 96 well tissue culture treated white walled/clear bottom plates.
  • a nine point dose response dilution series from 10 uM to 1 nM was performed and cell viability was determined after four days as indicated using the CellTiter-Glo® assay (CTG; Promega, Madison, Wis., United States of America) following the manufacturer's recommendations.
  • CTG CellTiter-Glo® assay
  • FIG. 10 is a graph showing the cellular proliferation of SupT1 cells (human T-cell lymphoblastic leukemia) treated with Compound Q (Table 1; circles) or Compound GG (Table 1; squares).
  • SupT1 cells were seeded in Costar (Tewksbury, Mass.) 3093 96 well tissue culture treated white walled/clear bottom plates.
  • a nine point dose response dilution series from 10 uM to 1 nM was performed and cell viability was determined after four days as indicated using the CellTiter-Glo® assay (CTG; Promega, Madison, Wis., United States of America) following the manufacturer's recommendations.
  • CTG CellTiter-Glo® assay
  • the present invention includes compounds and methods that are highly active against certain cancers and hyperproliferative conditions.
  • compounds and methods are provided to treat cancers and proliferative disorders of hematopoietic cells, and in particular, T cells, B cells and NK cells.
  • Selected active compounds are also useful to treat inflammatory disorders, auto-immune conditions, and immune disorders.
  • the invention is directed to compounds or the use of such compounds of Formula I, II, III, IV, or V:
  • Z is —(CH 2 ) x — wherein x is 1, 2, 3 or 4 or —O—(CH 2 ) z — wherein z is 2, 3 or 4; each X is independently CH or N; each X′ is independently, CH or N; X′′ is independently CH 2 , S or NH, arranged such that the moiety is a stable 5-membered ring; R, R 8 , and R 11 are independently H, C 1 -C 3 alkyl or haloalkyl, cycloalkyl or cycloalkyl containing one or more heteroatoms selected from N, O or S; -(alkylene)m-C 3 -C 8 cycloalkyl, -(alkylene) m -aryl, -(alkylene) m -heterocyclo, -(alkylene) m -heteroaryl, -(alkylene) m -NR 3 R 4
  • the compound is of Formula I or Formula II and R 6 is absent.
  • the compound is of Formula III:
  • R x is not further substituted.
  • R 2 is -(alkylene) m -heterocyclo, -(alkylene) m -heteroaryl, -(alkylene) m -NR 3 R 4 , -(alkylene) m -C(O)—NR 3 R 4 ; -(alkylene) m -O—R 5 , -(alkylene) m -S(O) n —R 5 , or -(alkylene) m -S(O) n —NR 3 R 4 any of which may be optionally independently substituted with one or more R x groups as allowed by valance, and wherein two R x groups bound to the same or adjacent atom may optionally combine to form a ring and wherein m is 0 or 1 and n is 0, 1 or 2.
  • R 8 is hydrogen or C 1 -C 3 alkyl.
  • R is hydrogen or C 1 -C 3 alkyl.
  • R 2 is -(alkylene) m -heterocyclo, -(alkylene) m -NR 3 R 4 , -(alkylene) m -C(O)—NR 3 R 4 , -(alkylene) m -C(O)—O-alkyl or -(alkylene) m -OR 5 any of which may be optionally independently substituted with one or more R x groups as allowed by valance, and wherein two R x groups bound to the same or adjacent atom may optionally combine to form a ring.
  • R 2 is -(alkylene) m -heterocyclo, -(alkylene) m -NR 3 R 4 , -(alkylene) m -C(O)—NR 3 R 4 , -(alkylene) m -C(O)—O-alkyl or -(alkylene) m -OR 5 without further substitution.
  • n in R 2 is 1. In a further aspect, the alkylene in R 2 is methylene.
  • R 2 is
  • R 2 * is a bond, alkylene, -(alkylene) m -O-(alkylene) m -, -(alkylene) m -C(O)-(alkylene) m -, -(alkylene) m -S(O) 2 -(alkylene) m - and -(alkylene) m -NH-(alkylene) m - wherein each m is independently 0 or 1; P is a 4- to 8-membered mono- or bicyclic saturated heterocyclyl group; each R x1 is independently -(alkylene) m -(C(O)) m -(alkylene) m -(N(R N )) m -(alkyl) m wherein each m is independently 0 or 1 provided at least one m is 1, -(C(O))—O-alkyl, -(alkylene) m -cycloalky
  • R N is H, C 1 to C 4 alkyl or C 1 to C 6 heteroalkyl
  • each R x1 is only optionally substituted by unsubstituted alkyl, halogen or hydroxy.
  • R x1 is hydrogen or unsubstituted C 1 -C 4 alkyl.
  • At least one R x1 is -(alkylene) m -heterocyclyl wherein m is 0 or 1.
  • R 2 is
  • P* is a 4- to 8-membered mono- or bicyclic saturated heterocyclyl group.
  • R 2 is
  • R 2 is
  • R 2 is
  • R 2* is a bond, alkylene, -(alkylene) m -O-(alkylene) m -, -(alkylene) m -C(O)-(alkylene) m -, -(alkylene) m -S(O) 2 -(alkylene) m - and -(alkylene) m -NH-(alkylene) m - wherein each m is independently 0 or 1; P is a 4- to 8-membered mono- or bicyclic saturated heterocyclyl group; P1 is a 4- to 6-membered monocyclic saturated heterocyclyl group; each R X2 is independently hydrogen or alkyl; and s is 0, 1 or 2.
  • R 2 is
  • P1 includes at least one nitrogen.
  • any alkylene in R 2 * in any previous aspect is not further substituted.
  • R 2 is selected from the structures depicted in FIGS. 1-3 .
  • R 2 is
  • the compound has general Formula I and more specifically one of the general structures in FIGS. 4-8 wherein the variables are as previously defined.
  • the compound has general Formula Ia:
  • R 1 , R 2 , R and y are as previously defined.
  • the compound has Formula Ia and R is alkyl.
  • the compound has Formula Ia and R is H.
  • the compound has Formula Ia and R 2 is
  • P* is a 4- to 8-membered mono- or bicyclic saturated heterocyclyl group and R 2* , R x1 and t are as previously defined.
  • the compound has Formula Ia and R 2 is
  • P* is a 4- to 8-membered mono- or bicyclic saturated heterocyclyl group
  • R x1 is hydrogen or unsubstituted C 1 -C 4 alkyl and R 2* is as previously defined.
  • the compound has Formula Ib:
  • R 2 and R are as previously defined.
  • the compound has Formula Ib and R is alkyl.
  • the compound has Formula Ib and R is H.
  • the compound has Formula Ib and R 2 is
  • P* is a 4- to 8-membered mono- or bicyclic saturated heterocyclyl group and R 2* , R x1 and t are as previously defined.
  • the compound has Formula Ib and R 2 is
  • P* is a 4- to 8-membered mono- or bicyclic saturated heterocyclyl group
  • R x1 is hydrogen or C 1 -C 4 alkyl
  • R 2* is as previously defined.
  • the compound has Formula Ic:
  • R 2 and R are as previously defined.
  • the compound has Formula Ic and R is alkyl.
  • the compound has Formula Ic and R is H.
  • the compound has Formula Ic and R 2 is
  • P* is a 4- to 8-membered mono- or bicyclic saturated heterocyclyl group and R 2* , R x1 and t are as previously defined.
  • the compound has Formula Ic and R 2 is
  • P* is a 4- to 8-membered mono- or bicyclic saturated heterocyclyl group
  • R x1 is hydrogen or C 1 -C 4 alkyl
  • R 2* is as previously defined.
  • the compound has Formula Id:
  • R 2 and R are as previously defined.
  • the compound has Formula Id and R is alkyl.
  • the compound has Formula Id and R is H.
  • the compound has Formula Id and R 2 is
  • P* is a 4- to 8-membered mono- or bicyclic saturated heterocyclyl group and R 2* , R x1 and t are as previously defined.
  • the compound has Formula Id and R 2 is
  • P* is a 4- to 8-membered mono- or bicyclic saturated heterocyclyl group
  • R x1 is hydrogen or C 1 -C 4 alkyl
  • R 2* is as previously defined.
  • the compound has Formula Ie:
  • the compound has Formula Ie and R is alkyl.
  • the compound has Formula Ie and R is H.
  • the compound has Formula Ie and R 2 is
  • P* is a 4- to 8-membered mono- or bicyclic saturated heterocyclyl group and R 2* , R x1 and t are as previously defined.
  • the compound has Formula Ie and R 2 is
  • P* is a 4- to 8-membered mono- or bicyclic saturated heterocyclyl group
  • R x1 is hydrogen or C 1 -C 4 alkyl
  • R 2* is as previously defined.
  • the compound has Formula If:
  • the compound has Formula If and R is alkyl.
  • the compound has Formula If and R is H.
  • the compound has Formula If and R 2 is
  • P* is a 4- to 8-membered mono- or bicyclic saturated heterocyclyl group and R 2* , R x1 and t are as previously defined.
  • the compound has Formula If and R 2 is
  • P* is a 4- to 8-membered mono- or bicyclic saturated heterocyclyl group
  • R x1 is hydrogen or C 1 -C 4 alkyl
  • R 2* is as previously defined.
  • the compound has Formula Ig:
  • the compound has Formula Ig and R is alkyl.
  • the compound has Formula Ig and R is H.
  • the compound has Formula Ig and R 2 is
  • P* is a 4- to 8-membered mono- or bicyclic saturated heterocyclyl group and R 2* , R x1 and t are as previously defined.
  • the compound has Formula Ig and R 2 is
  • P* is a 4- to 8-membered mono- or bicyclic saturated heterocyclyl group
  • R x1 is hydrogen or C 1 -C 4 alkyl
  • R 2* is as previously defined.
  • the compound has Formula Ih:
  • the compound has Formula Ih and R is alkyl.
  • the compound has Formula Ih and R is H.
  • the compound has Formula Ih and R 2 is
  • P* is a 4- to 8-membered mono- or bicyclic saturated heterocyclyl group and R 2* , R x1 and t are as previously defined.
  • the compound has Formula Ih and R 2 is
  • P* is a 4- to 8-membered mono- or bicyclic saturated heterocyclyl group
  • R x1 is hydrogen or C 1 -C 4 alkyl
  • R 2* is as previously defined.
  • the compound has Formula Ii:
  • the compound has Formula Ii and R is alkyl.
  • the compound has Formula Ii and R is H.
  • the compound has Formula Ii and R 2 is
  • P* is a 4- to 8-membered mono- or bicyclic saturated heterocyclyl group and R 2* , R x1 and t are as previously defined.
  • the compound has Formula Ii and R 2 is
  • P* is a 4- to 8-membered mono- or bicyclic saturated heterocyclyl group
  • R x1 is hydrogen or C 1 -C 4 alkyl
  • R 2* is as previously defined.
  • the compound has Formula Ij:
  • the compound has Formula Ij and R is alkyl.
  • the compound has Formula Ij and R is H.
  • the compound has Formula Ij and R 2 is
  • P* is a 4- to 8-membered mono- or bicyclic saturated heterocyclyl group.
  • the compound has Formula Ij and R 2 is
  • P* is a 4- to 8-membered mono- or bicyclic saturated heterocyclyl group
  • R x1 is hydrogen or C 1 -C 4 alkyl.
  • the compound has Formula Ij and R is H, and both X are N.
  • the compound has the structure:
  • the compound has Formula Ik and R 2 is
  • P* is a 4- to 8-membered mono- or bicyclic saturated heterocyclyl group.
  • the compound has Formula Ik and R 2 is
  • P* is a 4- to 8-membered mono- or bicyclic saturated heterocyclyl group
  • R x1 is hydrogen or C 1 -C 4 alkyl.
  • the compound has Formula Il:
  • the compound has Formula Il and R 2 is
  • P* is a 4- to 8-membered mono- or bicyclic saturated heterocyclyl group.
  • the compound has Formula Il and R 2 is
  • P* is a 4- to 8-membered mono- or bicyclic saturated heterocyclyl group
  • R x1 is hydrogen or C 1 -C 4 alkyl.
  • the compound has Formula Im:
  • the compound has Formula Im and R 2 is
  • P* is a 4- to 8-membered mono- or bicyclic saturated heterocyclyl group.
  • the compound has Formula Im and R 2 is
  • P* is a 4- to 8-membered mono- or bicyclic saturated heterocyclyl group
  • R x1 is hydrogen or C 1 -C 4 alkyl.
  • the compound has Formula IIa:
  • the compound has Formula IIa and R 2 is
  • P* is a 4- to 8-membered mono- or bicyclic saturated heterocyclyl group.
  • the compound has Formula IIa and R 2 is
  • P* is a 4- to 8-membered mono- or bicyclic saturated heterocyclyl group
  • R x1 is hydrogen or C 1 -C 4 alkyl.
  • the compound has Formula IIb:
  • the compound has Formula Im and R 2 is
  • P* is a 4- to 8-membered mono- or bicyclic saturated heterocyclyl group.
  • the compound has Formula Im and R 2 is
  • P* is a 4- to 8-membered mono- or bicyclic saturated heterocyclyl group
  • R x1 is hydrogen or C 1 -C 4 alkyl.
  • the active compound is:
  • the present invention includes compounds and the use of compounds with desired isotopic substitutions of atoms, at amounts above the natural abundance of the isotope, i.e., enriched.
  • Isotopes are atoms having the same atomic number but different mass numbers, i.e., the same number of protons but a different number of neutrons.
  • isotopes of hydrogen for example, deuterium ( 2 H) and tritium ( 3 H) may be used anywhere in described structures.
  • isotopes of carbon e.g., 13 C and 14 C, may be used.
  • a preferred isotopic substitution is deuterium for hydrogen at one or more locations on the molecule to improve the performance of the drug.
  • the deuterium can be bound in a location of bond breakage during metabolism (an ⁇ -deuterium kinetic isotope effect) or next to or near the site of bond breakage (a ⁇ -deuterium kinetic isotope effect).
  • substitution with isotopes such as deuterium can afford certain therapeutic advantages resulting from greater metabolic stability, such as, for example, increased in vivo half-life or reduced dosage requirements.
  • Substitution of deuterium for hydrogen at a site of metabolic break down can reduce the rate of or eliminate the metabolism at that bond.
  • the hydrogen atom can be any isotope of hydrogen, including protium ( 1 H), deuterium ( 2 H) and tritium ( 3 H).
  • isotopically-labeled refers to an analog that is a “deuterated analog”, a “ 13 C-labeled analog,” or a “deuterated/ 13 C-labeled analog.”
  • deuterated analog means a compound described herein, whereby a H-isotope, i.e., hydrogen/protium ( 1 H), is substituted by a H-isotope, i.e., deuterium ( 2 H).
  • Deuterium substitution can be partial or complete. Partial deuterium substitution means that at least one hydrogen is substituted by at least one deuterium.
  • the isotope is 90, 95 or 99% or more enriched in an isotope at any location of interest. In some embodiments it is deuterium that is 90, 95 or 99% enriched at a desired location.
  • alkyl either alone or within other terms such as “haloalkyl” and “alkylamino,” embraces linear or branched radicals having one to about twelve carbon atoms. “Lower alkyl” radicals have one to about six carbon atoms. Examples of such radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isoamyl, hexyl and the like.
  • alkylene embraces bridging divalent linear and branched alkyl radicals. Examples include methylene, ethylene, propylene, isopropylene and the like.
  • alkenyl embraces linear or branched radicals having at least one carbon-carbon double bond of two to about twelve carbon atoms. “Lower alkenyl” radicals having two to about six carbon atoms. Examples of alkenyl radicals include ethenyl, propenyl, allyl, propenyl, butenyl and 4-methylbutenyl.
  • alkenyl and lower alkenyl embrace radicals having “cis” and “trans” orientations, or alternatively, “E” and “Z” orientations.
  • alkynyl denotes linear or branched radicals having at least one carbon-carbon triple bond and having two to about twelve carbon atoms. “Lower alkynyl” radicals having two to about six carbon atoms. Examples of such radicals include propargyl, butynyl, and the like.
  • Alkyl, alkenyl, and alkynyl radicals may be optionally substituted with one or more functional groups such as halo, hydroxy, nitro, amino, cyano, haloalkyl, aryl, heteroaryl, heterocyclo and the like.
  • alkylamino embraces “N-alkylamino” and “N,N-dialkylamino” where amino groups are independently substituted with one alkyl radical and with two alkyl radicals, respectively.
  • “Lower alkylamino” radicals have one or two alkyl radicals of one to six carbon atoms attached to a nitrogen atom.
  • Suitable alkylamino radicals may be mono or dialkylamino such as N-methylamino, N-ethylamino, N.N-dimethylamino, N,N-diethylamino and the like.
  • halo means halogens such as fluorine, chlorine, bromine or iodine atoms.
  • haloalkyl embraces radicals wherein any one or more of the alkyl carbon atoms is substituted with one or more halo as defined above. Examples include monohaloalkyl, dihaloalkyl and polyhaloalkyl radicals including perhaloalkyl.
  • a monohaloalkyl radical for one example, may have an iodo, bromo, chloro or fluoro atom within the radical.
  • Dihalo and polyhaloalkyl radicals may have two or more of the same halo atoms or a combination of different halo radicals.
  • “Lower haloalkyl” embraces radicals having 1-6 carbon atoms.
  • haloalkyl radicals include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl.
  • Perfluoroalkyl means an alkyl radical having all hydrogen atoms replaced with fluoro atoms. Examples include trifluoromethyl and pentafluoroethyl.
  • aryl alone or in combination, means a carbocyclic aromatic system containing one or two rings wherein such rings may be attached together in a fused manner.
  • aryl embraces aromatic radicals such as phenyl, naphthyl, indenyl, tetrahydronaphthyl, and indanyl. More preferred aryl is phenyl.
  • Said “aryl” group may have 1 or more substituents such as lower alkyl, hydroxyl, halo, haloalkyl, nitro, cyano, alkoxy, lower alkylamino, and the like.
  • An aryl group may be optionally substituted with one or more functional groups such as halo, hydroxy, nitro, amino, cyano, haloalkyl, aryl, heteroaryl, heterocyclo and the like.
  • heterocyclyl (or “heterocyclo”) embraces saturated, and partially saturated heteroatom-containing ring radicals, where the heteroatoms may be selected from nitrogen, sulfur and oxygen.
  • Heterocyclic rings comprise monocyclic 6-8 membered rings, as well as 5-16 membered bicyclic ring systems (which can include bridged fused and spiro-fused bicyclic ring systems). It does not include rings containing —O—O—, —O—S— or —S—S— portions.
  • Said “heterocyclyl” group may have 1 to 3 substituents such as hydroxyl, Boc, halo, haloalkyl, cyano, lower alkyl, lower aralkyl, oxo, lower alkoxy, amino, lower alkylamino, and the like.
  • saturated heterocyclo groups include saturated 3- to 6-membered heteromonocyclic groups containing 1 to 4 nitrogen atoms [e.g. pyrrolidinyl, imidazolidinyl, piperidinyl, pyrrolinyl, piperazinyl]; saturated 3 to 6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g. morpholinyl]; saturated 3 to 6-membered heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms [e.g., thiazolidinyl].
  • partially saturated heterocyclyl radicals include dihydrothienyl, dihydropyranyl, dihydrofuryl, dihydrothiazolyl, and the like.
  • Particular examples of partially saturated and saturated heterocyclo groups include pyrrolidinyl, imidazolidinyl, piperidinyl, pyrrolinyl, pyrazolidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, thiazolidinyl, dihydrothienyl, 2,3-dihydro-benzo[1,4]dioxanyl, indolinyl, isoindolinyl, dihydrobenzothienyl, dihydrobenzofuryl, isochromanyl, chromanyl, 1,2-dihydroquinolyl, 1,2,3,4-tetrahydro-isoquinolyl, 1,2,3,4-tetrahydro-quinolyl, 2,3,4,4a,9,9a-hexahydro-1H-3-aza-fluorenyl, 5,6,7-trihydro-1,2,4-triazolo[3,4-a]isoquinolyl, 3,4-
  • Heterocyclo groups also includes radicals where heterocyclic radicals are fused/condensed with aryl radicals: unsaturated condensed heterocyclic group containing 1 to 5 nitrogen atoms, for example, indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl, tetrazolopyridazinyl [e.g., tetrazolo[1,5-b]pyridazinyl]; unsaturated condensed heterocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g.
  • benzoxazolyl, benzoxadiazolyl unsaturated condensed heterocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms
  • benzothiazolyl, benzothiadiazolyl unsaturated condensed heterocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms
  • saturated, partially unsaturated and unsaturated condensed heterocyclic group containing 1 to 2 oxygen or sulfur atoms e.g. benzofuryl, benzothienyl, 2,3-dihydro-benzo[1,4]dioxinyl and dihydrobenzofuryl].
  • heteroaryl denotes aryl ring systems that contain one or more heteroatoms selected from the group O, N and S, wherein the ring nitrogen and sulfur atom(s) are optionally oxidized, and nitrogen atom(s) are optionally quarternized.
  • Examples include unsaturated 5 to 6 membered heteromonocyclyl group containing 1 to 4 nitrogen atoms, for example, pyrrolyl, imidazolyl, pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl [e.g., 4H-1,2,4-triazolyl, IH-1,2,3-triazolyl, 2H-1,2,3-triazolyl]; unsaturated 5- to 6-membered heteromonocyclic group containing an oxygen atom, for example, pyranyl, 2-furyl, 3-furyl, etc.; unsaturated 5 to 6-membered heteromonocyclic group containing a sulfur atom, for example, 2-thienyl, 3-thienyl, etc.; unsaturated 5- to 6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen
  • heteroarylalkyl denotes alkyl radicals substituted with a heteroaryl group. Examples include pyridylmethyl and thienylethyl.
  • sulfonyl whether used alone or linked to other terms such as alkylsulfonyl, denotes respectively divalent radicals —SO 2 —.
  • carbonyl whether used alone or with other terms, such as “aminocarbonyl”, denotes —C(O)—.
  • aminocarbonyl denotes an amide group of the Formula —C(O)—NH 2 .
  • heterocycloalkyl embrace heterocyclic-substituted alkyl radicals. Examples include piperidylmethyl and morpholinylethyl.
  • arylalkyl embraces aryl-substituted alkyl radicals. Examples include benzyl, diphenylmethyl and phenylethyl. The aryl in said aralkyl may be additionally substituted with halo, alkyl, alkoxy, halkoalkyl and haloalkoxy.
  • cycloalkyl includes saturated carbocyclic groups of 3 to 10 carbons.
  • Lower cycloalkyl groups include C 3 -C 6 rings. Examples include cyclopentyl, cyclopropyl, and cyclohexyl.
  • Cycloalkyl groups may be optionally substituted with one or more functional groups such as halo, hydroxy, nitro, amino, cyano, haloalkyl, aryl, heteroaryl, heterocyclo and the like.
  • cycloalkylalkyl embraces cycloalkyl-substituted alkyl radicals.
  • “Lower cycloalkylalkyl” radicals are cycloalkyl radicals attached to alkyl radicals having one to six carbon atoms. Examples of include cyclohexylmethyl.
  • the cycloalkyl in said radicals may be additionally substituted with halo, alkyl, alkoxy and hydroxy.
  • cycloalkenyl includes carbocyclic groups having one or more carbon-carbon double bonds including “cycloalkyldienyl” compounds. Examples include cyclopentenyl, cyclopentadienyl, cyclohexenyl and cycloheptadienyl.
  • oxo as used herein contemplates an oxygen atom attached with a double bond.
  • nitro as used herein contemplates —NO 2 .
  • cyano as used herein contemplates —CN.
  • the term “prodrug” means a compound which when administered to a host in vivo is converted into the parent drug.
  • parent drug means any of the presently described chemical compounds that are useful to treat any of the disorders described herein, or to control or improve the underlying cause or symptoms associated with any physiological or pathological disorder described herein in a host, typically a human.
  • Prodrugs can be used to achieve any desired effect, including to enhance properties of the parent drug or to improve the pharmaceutic or pharmacokinetic properties of the parent.
  • Prodrug strategies exist which provide choices in modulating the conditions for in vivo generation of the parent drug, all of which are deemed included herein.
  • Nonlimiting examples of prodrug strategies include covalent attachment of removable groups, or removable portions of groups, for example, but not limited to acylation, phosphorylation, phosphonylation, phosphoramidate derivatives, amidation, reduction, oxidation, esterification, alkylation, other carboxy derivatives, sulfoxy or sulfone derivatives, carbonylation or anhydride, among others.
  • the term “host” refers to an individual, preferably a mammal such as a human.
  • the term “host” can include domesticated animals, such as cats, dogs, etc., livestock (e.g., cattle, horses, pigs, sheep, goats, etc.), laboratory animals (e.g., mouse, monkey, rabbit, rat, guinea pig, etc.) and birds.
  • the invention includes the use of an effective amount of a compound described herein, or its pharmaceutically acceptable salt, prodrug or isotopic variant optionally in a pharmaceutical composition, to treat a host, typically a human, with a selected cancer, tumor, hyperproliferative condition or an inflammatory or immune disorder.
  • a host typically a human
  • a selected cancer, tumor, hyperproliferative condition or an inflammatory or immune disorder typically a selected cancer, tumor, hyperproliferative condition or an inflammatory or immune disorder.
  • T-cells, B-cells, and/or NK-cells can result in a wide range of diseases such as cancer, proliferative disorders and inflammatory/immune diseases.
  • a host for example a human, afflicted with any of these disorders can be treated with an effective amount of a compound as described herein to achieve a decrease in symptoms (a palliative agent) or a decrease in the underlying disease (a disease modifying agent).
  • T-cell or NK-cell lymphoma examples include T-cell or NK-cell lymphoma, for example, but not limited to: peripheral T-cell lymphoma; anaplastic large cell lymphoma, for example anaplastic lymphoma kinase (ALK) positive, ALK negative anaplastic large cell lymphoma, or primary cutaneous anaplastic large cell lymphoma; angioimmunoblastic lymphoma; cutaneous T-cell lymphoma, for example mycosis fungoides, Sézary syndrome, primary cutaneous anaplastic large cell lymphoma, primary cutaneous CD30+ T-cell lymphoproliferative disorder; primary cutaneous aggressive epidermotropic CD8+ cytotoxic T-cell lymphoma; primary cutaneous gamma-delta T-cell lymphoma; primary cutaneous small/medium CD4+ T-cell lymphoma, and lymphomatoid papulosis; Adult T-cell Leukemia/Lymphoma (
  • a compound disclosed herein, or its salt, prodrug, or isotopic variant can be used in an effective amount to treat a host, for example a human, with a lymphoma or lymphocytic or myelocytic proliferation disorder or abnormality.
  • a host for example a human
  • the compounds as described herein can be administered to a host suffering from a Hodgkin Lymphoma or a Non-Hodgkin Lymphoma.
  • the host can be suffering from a Non-Hodgkin Lymphoma such as, but not limited to: an AIDS-Related Lymphoma; Anaplastic Large-Cell Lymphoma; Angioimmunoblastic Lymphoma; Blastic NK-Cell Lymphoma; Burkitt's Lymphoma; Burkitt-like Lymphoma (Small Non-Cleaved Cell Lymphoma); Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma; Cutaneous T-Cell Lymphoma; Diffuse Large B-Cell Lymphoma; Enteropathy-Type T-Cell Lymphoma; Follicular Lymphoma; Hepatosplenic Gamma-Delta T-Cell Lymphoma; Lymphoblastic Lymphoma; Mantle Cell Lymphoma; Marginal Zone Lymphoma; Nasal T-Cell Lymphoma; Pediatric Lymphoma; Peripheral
  • a compound disclosed herein, or its salt, prodrug, or isotopic variant can be used in an effective amount to treat a host, for example a human, with a Hodgkin Lymphoma, such as, but not limited to: Nodular Sclerosis Classical Hodgkin's Lymphoma (CHL); Mixed Cellularity CHL; Lymphocyte-depletion CHL; Lymphocyte-rich CHL; Lymphocyte Predominant Hodgkin Lymphoma; or Nodular Lymphocyte Predominant HL.
  • CHL Nodular Sclerosis Classical Hodgkin's Lymphoma
  • Mixed Cellularity CHL Lymphocyte-depletion CHL
  • Lymphocyte-rich CHL Lymphocyte Predominant Hodgkin Lymphoma
  • Lymphocyte Predominant Hodgkin Lymphoma or Nodular Lymphocyte Predominant HL.
  • a compound disclosed herein, or its salt, prodrug, or isotopic variant can be used in an effective amount to treat a host, for example a human with a specific B-cell lymphoma or proliferative disorder such as, but not limited to: multiple myeloma; Diffuse large B cell lymphoma; Follicular lymphoma; Mucosa-Associated Lymphatic Tissue lymphoma (MALT); Small cell lymphocytic lymphoma; Mediastinal large B cell lymphoma; Nodal marginal zone B cell lymphoma (NMZL); Splenic marginal zone lymphoma (SMZL); Intravascular large B-cell lymphoma; Primary effusion lymphoma; or Lymphomatoid granulomatosis; B-cell prolymphocytic leukemia; Hairy cell leukemia; Splenic lymphoma/leukemia, unclassifiable; Splenic diffuse red pulp small B-cell lymphoma; Hairy cell
  • a compound disclosed herein, or its salt, prodrug, or isotopic variant can be used in an effective amount to treat a host, for example a human with leukemia.
  • the host may be suffering from an acute or chronic leukemia of a lymphocytic or myelogenous origin, such as, but not limited to: Acute lymphoblastic leukemia (ALL); Acute myelogenous leukemia (AML); Chronic lymphocytic leukemia (CLL); Chronic myelogenous leukemia (CML); juvenile myelomonocytic leukemia (JMML); hairy cell leukemia (HCL); acute promyelocytic leukemia (a subtype of AML); large granular lymphocytic leukemia; or Adult T-cell chronic leukemia.
  • ALL Acute lymphoblastic leukemia
  • AML Acute myelogenous leukemia
  • CLL Chronic lymphocytic leukemia
  • CML Chronic myelogenous leuk
  • the patient suffers from an acute myelogenous leukemia, for example an undifferentiated AML (M0); myeloblastic leukemia (M1; with/without minimal cell maturation); myeloblastic leukemia (M2; with cell maturation); promyelocytic leukemia (M3 or M3 variant [M3V]); myelomonocytic leukemia (M4 or M4 variant with eosinophilia [M4E]); monocytic leukemia (M5); erythroleukemia (M6); or megakaryoblastic leukemia (M7).
  • M0 undifferentiated AML
  • M1 myeloblastic leukemia
  • M2 myeloblastic leukemia
  • M3V promyelocytic leukemia
  • M4 or M4 variant with eosinophilia [M4E] myelomonocytic leukemia
  • M5 monocytic leukemia
  • M6
  • a compound disclosed herein, or its salt, prodrug, or isotopic variant can be used in an effective amount to treat a host, for example a human with an autoimmune disorder.
  • a host for example a human with an autoimmune disorder.
  • Examples include, but are not limited to: Acute disseminated encephalomyelitis (ADEM); Addison's disease; Agammaglobulinemia; Alopecia areata; Amyotrophic lateral sclerosis (Also Lou Gehrig's disease; Motor Neuron Disease); Ankylosing Spondylitis; Antiphospholipid syndrome; Antisynthetase syndrome; Atopic allergy; Atopic dermatitis; Autoimmune aplastic anemia; Autoimmune arthritis; Autoimmune cardiomyopathy; Autoimmune enteropathy; Autoimmune granulocytopenia; Autoimmune hemolytic anemia; Autoimmune hepatitis; Autoimmune hypoparathyroidism; Autoimmune inner ear
  • a compound disclosed herein, or its salt, prodrug, or isotopic variant can be used in an effective amount to treat a host, for example a human with a disease involving the immune system.
  • a compound disclosed herein can be used to prevent organ transplant rejection (e.g., allograft rejection and graft versus host disease).
  • a compound disclosed herein, or its salt, prodrug, or isotopic variant can be used in an effective amount to treat a host, for example a human with a skin disorders such as psoriasis (for example, psoriasis vulgaris), atopic dermatitis, skin rash, skin irritation, skin sensitization (e.g., contact dermatitis or allergic contact dermatitis).
  • a skin disorder such as psoriasis (for example, psoriasis vulgaris), atopic dermatitis, skin rash, skin irritation, skin sensitization (e.g., contact dermatitis or allergic contact dermatitis).
  • certain substances including some pharmaceuticals when topically applied can cause skin sensitization.
  • the skin disorder is treated by topical administration of compounds known in the art in combination with the compounds disclosed herein.
  • a compound disclosed herein, or its salt, prodrug, or isotopic variant can be used in an effective amount to treat a host, for example a human with a proliferative condition such as a myeloproliferative disorder (MPD), polycythemia vera (PV), essential thrombocythemia (ET), myeloid metaplasia with myelofibrosis (MMM), chronic myelomonocytic leukemia (CMML), hypereosinophilic syndrome (HES), systemic mast cell disease (SMCD), and the like.
  • MPD myeloproliferative disorder
  • PV polycythemia vera
  • ET essential thrombocythemia
  • MMM myeloid metaplasia with myelofibrosis
  • CMML chronic myelomonocytic leukemia
  • HES hypereosinophilic syndrome
  • SMCD systemic mast cell disease
  • a compound disclosed herein, or its salt, prodrug, or isotopic variant can be used in an effective amount to treat a host, for example a human with an inflammatory disorder.
  • Example inflammatory diseases include inflammatory diseases of the eye (e.g., ulceris, uveitis, conjunctivitis, or related disease), inflammatory diseases of the respiratory tract (e.g., the upper respiratory tract including the nose and sinuses such as rhinitis or sinusitis or the lower respiratory tract including bronchitis, chronic obstructive pulmonary disease, and the like), inflammatory myopathy such as myocarditis, and other inflammatory diseases.
  • a compound disclosed herein, or its salt, prodrug, or isotopic variant can be used in an effective amount to treat a host, for example a human with an inflammatory ischemic event such as stroke or cardiac arrest.
  • the compounds provided herein is useful for the treatment of primary myelofibrosis, post-polycythemia vera myelofibrosis, post-essential thrombocythemia myelofibrosis, and secondary acute myelogenous leukemia.
  • the compounds provided herein can be used to treat patients with intermediate or high-risk myelofibrosis, including primary myelofibrosis, post-polycythemia vera myelofibrosis and post-essential thrombocythemia myelofibrosis.
  • the host to be treated (e.g., a human) is determined to be non-responsive or resistant to one or more therapies for myeloproliferative disorders.
  • a method of treating a myeloproliferative neoplasm in a host in need thereof comprising administering to the host an effective amount of a composition comprising a compound described herein, or a pharmaceutically acceptable salt thereof
  • the compounds disclosed herein can be beneficially administered in combination with another therapeutic regimen for beneficial, additive or synergistic effects.
  • a compound/method of the present invention is used in combination with another therapy to treat the T, B or NK abnormal cellular proliferation including cancer or disorder.
  • the second therapy can be an immunotherapy.
  • the compound can be conjugated to an antibody, radioactive agent or other targeting agent that directs the compound to the diseased or abnormally proliferating cell.
  • the compound is used in combination with another pharmaceutical or a biologic agent (for example an antibody) to increase the efficacy of treatment with a combined or a synergistic approach.
  • the compound can be used with T-cell vaccination, which typically involves immunization with inactivated autoreactive T cells to eliminate a pathogenic autoreactive T cell population.
  • the compound is used in combination with a bispecific T-cell Engager (BiTE), which is an antibody designed to simultaneously bind to specific antigens on endogenous T cells and malignant cells, linking the two types of cells.
  • BiTE bispecific T-cell Engager
  • the additional therapy is a monoclonal antibody (MAb).
  • MAbs stimulate an immune response that destroys cancer cells. Similar to the antibodies produced naturally by B cells, these MAbs “coat” the cancer cell surface, triggering its destruction by the immune system.
  • FDA-approved MAbs of this type include rituximab, which targets the CD20 antigen found on non-Hodgkin lymphoma cells, and alemtuzumab, which targets the CD52 antigen found on B-cell chronic lymphocyticleukemia (CLL) cells.
  • Rituximab may also trigger cell death (apoptosis) directly.
  • MAbs stimulates an anticancer immune response by binding to receptors on the surface of immune cells and inhibiting signals that prevent immune cells from attacking the body's own tissues, including cancer cells.
  • Other MAbs interfere with the action of proteins that are necessary for tumor growth.
  • bevacizumab targets vascular endothelial growth factor (VEGF), a protein secreted by tumor cells and other cells in the tumor's microenvironment that promotes the development of tumor blood vessels.
  • VEGF vascular endothelial growth factor
  • VEGF vascular endothelial growth factor
  • trastuzumab targets the human epidermal growth factor receptor 2 (HER-2).
  • MAbs that bind to cell surface growth factor receptors prevent the targeted receptors from sending their normal growth-promoting signals. They may also trigger apoptosis and activate the immune system to destroy tumor cells.
  • Another group of cancer therapeutic MAbs are the immunoconjugates. These MAbs, which are sometimes called immunotoxins or antibody-drug conjugates, consist of an antibody attached to a cell-killing substance, such as a plant or bacterial toxin, a chemotherapy drug, or a radioactive molecule.
  • the antibody latches onto its specific antigen on the surface of a cancer cell, and the cell-killing substance is taken up by the cell.
  • FDA-approved conjugated MAbs that work this way include 90 Y-ibritumomab tiuxetan, which targets the CD20 antigen to deliver radioactive yttrium-90 to B-cell non-Hodgkin lymphoma cells; 131 I-tositumomab, which targets the CD20 antigen to deliver radioactive iodine-131 to non-Hodgkin lymphoma cells; and ado-trastuzumab emtansine, which targets the HER-2 molecule to deliver the drug DM1, which inhibits cell proliferation, to HER-2 expressing metastatic breast cancer cells.
  • Immunotherapies with T cells engineered to recognize cancer cells via bispecific antibodies (bsAbs) or chimeric antigen receptors (CARs) are particularly promising approaches with potential to ablate both dividing and non/slow-dividing subpopulations of cancer cells.
  • Bispecific antibodies by simultaneously recognizing target antigen and an activating receptor on the surface of an immune effector cell, offer an opportunity to redirect immune effector cells to kill cancer cells.
  • the other approach is the generation of chimeric antigen receptors by fusing extracellular antibodies to intracellular signaling domains. Chimeric antigen receptor-engineered T cells are able to specifically kill tumor cells in a MHC-independent way.
  • General anticancer pharmaceutical agents include: Vincristine (Oncovin®) or liposomal vincristine (Marqibo®), Daunorubicin (daunomycin or Cerubidine®) or doxorubicin (Adriamycin®), Cytarabine (cytosine arabinoside, ara-C, or Cytosar®), L-asparaginase (Elspar®) or PEG-L-asparaginase (pegaspargase or Oncaspar®), Etoposide (VP-16), Teniposide (Vumon®), 6-mercaptopurine (6-MP or Purinethol®), Methotrexate, Cyclophosphamide (Cytoxan®), Prednisone, Dexamethasone (Decadron), imatinib (Gleevec®), dasatinib (Sprycel®), nilotinib (Tasigna®), bosutinib (Bosul
  • chemotherapeutic drugs used to treat AML are cytarabine (cytosine arabinoside or ara-C) and the anthracycline drugs (such as daunorubicin/daunomycin, idarubicin, and mitoxantrone).
  • cytarabine cytosine arabinoside or ara-C
  • anthracycline drugs such as daunorubicin/daunomycin, idarubicin, and mitoxantrone.
  • chemo drugs that may be used to treat AML include: Cladribine (Leustatin®, 2-CdA), Hudarabine (Fludara®), Topotecan, Etoposide (VP-16), 6-thioguanine (6-TG), Hydroxyurea (Hydrea®), Corticosteroid drugs, such as prednisone or dexamethasone (Decadron®), Methotrexate (MTX), 6-mercaptopurine (6-MP), Azacitidine (Vidaza®), Decitabine (Dacogen®)
  • Current chemotherapeutic drugs for CU and other lymphomas include: purine analogs such as fludarabine (Fludara®), pentostatin (Nipent®), and cladribine (2-CdA, Leustatin®), and alkylating agents, which include chlorambucil (Leukeran®) and cyclophosphamide (Cytoxan®) and bendamustine (Treanda®).
  • Other drugs sometimes used for CLL include doxorubicin (Adriamycin®), methotrexate, oxaliplatin, vincristine (Oncovin®), etoposide (VP-16), and cytarabine (ara-C).
  • chemotherapies for CML include: Interferon, imatinib (Gleevec), the chemo drug hydroxyurea (Hydrea®), cytarabine (Ara-C), busulfan, cyclophosphamide (Cytoxan®), and vincristine (Oncovin®).
  • Oxydrea® the chemo drug hydroxyurea
  • cytarabine the cytarabine
  • Busulfan cyclophosphamide
  • Cytoxan® cyclophosphamide
  • Oncovin® vincristine
  • CMML is now treated with Deferasirox (Exjade®), cytarabine with idarubicin, cytarabine with topotecan, and cytarabine with fludarabine, Hydroxyurea (hydroxycarbamate, Hydrea®), azacytidine (Vidaza®) and decitabine (Dacogen®).
  • Erythropoietin (Epo® or Procrit®), a growth factor that promotes red blood cell production, can help avoid transfusions of red blood cells in some patients. Recently it has been found that combining erythropoietin with a growth factor for white blood cells (G-CSF, Neupogen®, or filgrastim) improves the patient's response to the erythropoietin.
  • G-CSF white blood cells
  • Neupogen® or filgrastim
  • Darbepoetin (Aranesp®) is a long-acting form of erythropoietin. It works in the same way but can be given less often.
  • Oprelvekin (Neumega®, interleukin-11, or IL-11) can be used to stimulate platelet production after chemotherapy and in some other diseases.
  • Therapies for multiple myeloma include Pomalidomide (Pomalyst®), Carfilzomib (KyprolisTM), Everolimus (Afinitor®), dexamethasone (Decadron), prednisone and methylprednisolone (Solu-medrol®) and hydrocortisone.
  • Therapies for Hodgkins disease include Brentuximab vedotin (AdcetrisTM): anti-CD-30, Rituximab, Adriamycint® (doxorubicin), Bleomycin, Vinblastine, dacarbazine (DTIC).
  • Monoclonal antibodies for Non-Hodgkins disease include Rituximab (Rituxan®), Ibritumomab (Zevalin®), tositumomab (Bexxar®), Alemtuzumab (Campath®) (CD52 antigen), Ofatumumab (Arzerra®), Brentuximab vedotin (Adcetris®) and Lenalidomide (Revlimid®).
  • B-cell Lymphoma approved therapies include:
  • chemotherapeutic agents include, but are not limited to, radioactive molecules, toxins, also referred to as cytotoxins or cytotoxic agents, which includes any agent that is detrimental to the viability of cells, agents, and liposomes or other vesicles containing chemotherapeutic compounds.
  • chemotherapeutic agents include but are not limited to 1-dehydrotestosterone, 5-fluorouracil decarbazine, 6-mercaptopurine, 6-thioguanine, actinomycin D, adriamycin, aldesleukin, alkylating agents, allopurinol sodium, altretamine, amifostine, anastrozole, anthramycin (AMC)), anti-mitotic agents, cis-dichlorodiamine platinum (II) (DDP) cisplatin), diamino dichloro platinum, anthracyclines, antibiotics, antis, asparaginase, BCG live (intravesical), betamethasone sodium phosphate and betamethasone acetate, bicalutamide, bleomycin sulfate, busulfan, calcium leucouorin, calicheamicin, capecitabine, carboplatin, lomustine (CCNU), carmustine (BSNU), Chlorambuci
  • Additional therapeutic agents that can be administered in combination with the compounds disclosed herein can include bevacizumab, sutinib, sorafenib, 2-methoxyestradiol, finasunate, vatalanib, vandetanib, aflibercept, volociximab, etaracizumab, cilengitide, erlotinib, cetuximab, panitumumab, gefitinib, trastuzumab, atacicept, rituximab, alemtuzumab, aldesleukine, atlizumab, tocilizumab, temsirolimus, everolimus, lucatumumab, dacetuzumab, atiprimod, natalizumab, bortezomib, carfilzomib, marizomib, tanespimycin, saquinavir mesylate, ritonavir, n
  • the compounds disclosed herein are combined with at least one immunosuppressive agent.
  • the immunosuppressive agent may be selected from the group consisting of a calcineurin inhibitor, e.g. a cyclosporin or an ascomycin, e.g. Cyclosporin A (NEORAL®), tacrolimus, a mTOR inhibitor, e.g. rapamycin or a derivative thereof, e.g. Sirolimus (RAPAMUNE®), Everolimus (Certican®), temsirolimus, biolimus-7, biolimus-9, a rapalog, e.g. azathioprine, campath 1H, a S1P receptor modulator, e.g.
  • fingolimod or an analogue thereof an anti IL-8 antibody, mycophenolic acid or a salt thereof, e.g. sodium salt, or a prodrug thereof, e.g. Mycophenolate Mofetil (CELLCEPT®), OKT3 (ORTHOCLONE OKT3®), Prednisone, ATGAM®, THYMOGLOBULIN®, Brequinar Sodium, 15-deoxyspergualin, tresperimus, Leflunomide ARAVA®, anti-CD25, anti-IL2R, Basiliximab (SIMULECT®), Daclizumab (ZENAPAX®), mizorbine, methotrexate, dexamethasone, pimecrolimus (Elidel®), abatacept, belatacept, etanercept (Enbrel®), adalimumab (Humira®), infliximab (Remicade®), an anti-LFA-1 antibody, natalizum
  • Drugs sometimes used to treat autoimmune disorders include: methylprednisolone oral, Kenalog inj, Medrol oral, Medrol (Pak) oral, Depo-Medrol inj, prednisolone oral, Solu-Medrol inj, Solu-Medrol IV, Cortef oral, hydrocortisone oral, cortisone oral, Celestone Soluspan inj, Orapred oral, Orapred ODT oral, methylprednisolone acetate inj, betamethasone acet & sod phos inj, Veripred 20 oral, Solu-Medrol (PF) inj, methylprednisolone sodium succ IV, Solu-Medrol (PF) IV, methylprednisolone sodium succ inj, Solu-Cortef inj, Pediapred oral, Millipred oral, Aristospan Intra-Articular inj, hydrocortisone sod succinate inj, prednisolone sodium phosphate oral
  • the activity of an active compound for a purpose described herein can be augmented through conjugation to an agent that targets the diseased or abnormally proliferating cell or otherwise enhances activity, delivery, pharmacokinetics or other beneficial property.
  • the compound can be administered as an antibody-drug conjugates (ADC).
  • ADC antibody-drug conjugates
  • a selected compound described herein can be administered in conjugation or combination with an antibody or antibody fragment.
  • Fragments of an antibody can be produced through chemical or genetic mechanisms.
  • the antibody fragment is an antigen binding fragment.
  • the antigen binding fragment can be selected from an Fab, Fab′, (Fab′)2, or Fv.
  • the antibody fragment is a Fab.
  • Monovalent F(ab) fragments have one antigen binding site.
  • the antibody is a divalent (Fab′)2 fragment, which has two antigen binding regions that are linked by disulfide bonds.
  • the antigen fragment is a (Fab′). Reduction of F(ab′)2 fragments produces two monovalent Fab′ fragments, which have a free sulfhydryl group that is useful for conjugation to other molecules.
  • a selected compound described herein can be administered in conjugation or combination with a Fv fragment.
  • Fv fragments are the smallest fragment made from enzymatic cleavage of IgG and IgM class antibodies.
  • Fv fragments have the antigen-binding site made of the VH and VC regions, but they lack the CH1 and CL regions. The VH and VL chains are held together in Fv fragments by non-covalent interactions.
  • a selected compound as described herein can be administered in combination with an antibody fragment selected from the group consisting of an ScFv, diabody, triabody, tetrabody, Bis-scFv, minibody, Fab2, or Fab3 antibody fragment.
  • the antibody fragment is a ScFv.
  • ScFv single chain variable fragments
  • the linker is at least 12 residues long, the ScFv fragments are primarily monomeric.
  • the antibody fragment administered in combination with a selected compound described herein is a bivalent diabody. If the linker length is less than three residues, scFv molecules associate into triabodies or tetrabodies. In one embodiment, the antibody fragment is a triabody. In one embodiment, the antibody fragment is a tetrabody.
  • Multivalent scFvs possess greater functional binding affinity to their target antigens than their monovalent counterparts by having binding to two more target antigens, which reduces the off-rate of the antibody fragment.
  • the antibody fragment is a minibody. Minibodies are scFv-CH3 fusion proteins that assemble into bivalent dimers.
  • the antibody fragment is a Bis-scFv fragment. Bis-scFv fragments are bispecific. Miniaturized ScFv fragments can be generated that have two different variable domains, allowing these Bis-scFv molecules to concurrently bind to two different epitopes.
  • a selected compound described herein is administered in conjugation or combination with a bispecific dimer (Fab2) or trispecific dimer (Fab3). Genetic methods are also used to create bispecific Fab dimers (Fab2) and trispecific Fab trimers (Fab3). These antibody fragments are able to bind 2 (Fab2) or 3 (Fab3) different antigens at once.
  • Fab2 bispecific dimer
  • Fab3 trispecific dimer
  • a selected compound described herein is administered in conjugation or combination with an rIgG antibody fragment.
  • rIgG antibody fragments refers to reduced IgG (75,000 daltons) or half-IgG. It is the product of selectively reducing just the hinge-region disulfide bonds. Although several disulfide bonds occur in IgG, those in the hinge-region are most accessible and easiest to reduce, especially with mild reducing agents like 2-mercaptoethylamine (2-MEA).
  • Half-IgG are frequently prepared for the purpose of targeting the exposing hinge-region sulfhydryl groups that can be targeted for conjugation, either antibody immobilization or enzyme labeling.
  • a selected active compound described herein can be linked to a radioisotope to increase efficacy, using methods well known in the art.
  • Any radioisotope that is useful against the T, B or NK abnormal cells can be incorporated into the conjugate, for example, but not limited to 131 I, 123 I, 192 Ir, 32 P, 90 Sr, 198 Au, 226 Ra, 90 Y, 241 Am, 252 Cf, 60 Co, or 137 Cs.
  • the linker chemistry can be important to efficacy and tolerability of the drug conjugates.
  • the thio-ether linked T-DM1 increases the serum stability relative to a disulfide linker version and appears to undergo endosomal degradation, resulting in intra-cellular release of the cytotoxic agent, thereby improving efficacy and tolerability, See, Barginear, M. F. and Budman, D. R., Trastuzumab-DM1: A review of the novel immune-conjugate for HER2-overexpressing breast cancer, The Open Breast Cancer Journal, 1:25-30, 2009.
  • the active compounds described herein, or their salt or prodrug can be administered to the host using any suitable approach which achieves the desired therapeutic result.
  • the amount and timing of active compound administered will, of course, be dependent on the host being treated, the instructions of the supervising medical specialist, on the time course of the exposure, on the manner of administration, on the pharmacokinetic properties of the particular active compound, and on the judgment of the prescribing physician.
  • the dosages given below are a guideline and the physician can titrate doses of the compound to achieve the treatment that the physician considers appropriate for the host.
  • the physician can balance a variety of factors such as age and weight of the host, presence of preexisting disease, as well as presence of other diseases.
  • compositions can be prepared for any desired route of administration including, but not limited to, systemic, topical, oral, intravenous, subcutaneous, transdermal, buccal, sublingual, intraaortal, intranasal, parenteral, or aerosol administration, as discussed in greater detail below.
  • the therapeutically effective dosage of any active compound described herein will be determined by the health care practitioner depending on the condition, size and age of the patient as well as the route of delivery.
  • a dosage from about 0.1 to about 200 mg/kg has therapeutic efficacy, with all weights being calculated based upon the weight of the active compound, including the cases where a salt is employed.
  • the dosage can be the amount of compound needed to provide a serum concentration of the active compound of up to between about 1 and 5, 10, 20, 30, or 40 ⁇ M.
  • a dosage from about 10 mg/kg to about 50 mg/kg can be employed for oral administration.
  • a dosage from about 0.5 mg/kg to 5 mg/kg can be employed for intramuscular injection.
  • dosages can be from about 1 ⁇ mol/kg to about 50 ⁇ mol/kg, or, optionally, between about 22 ⁇ mol/kg and about 33 ⁇ mol/kg of the compound for intravenous or oral administration.
  • An oral dosage form can include any appropriate amount of active material, including for example from 5 mg to, 50, 100, 200, or 500 mg per tablet or other solid dosage form.
  • pharmaceutically active compounds as described herein can be administered orally as a solid or as a liquid, or can be administered intramuscularly, intravenously, or by inhalation as a solution, suspension, or emulsion.
  • the compounds or salts also can be administered by inhalation, intravenously, or intramuscularly as a liposomal suspension.
  • the active compound or salt can be in the form of a plurality of solid particles or droplets having any desired particle size, and for example, from about 0.01, 0.1 or 0.5 to about 5, 10, 20 or more microns, and optionally from about 1 to about 2 microns.
  • Compounds as disclosed in the present invention have demonstrated good pharmacokinetic and pharmacodynamics properties, for instance when administered by the oral or intravenous routes.
  • the pharmaceutical formulations can comprise an active compound described herein or a pharmaceutically acceptable salt thereof, in any pharmaceutically acceptable carrier.
  • water may be the carrier of choice for water-soluble compounds or salts.
  • an organic vehicle such as glycerol, propylene glycol, polyethylene glycol, or mixtures thereof, can be suitable. In the latter instance, the organic vehicle can contain a substantial amount of water.
  • the solution in either instance can then be sterilized in a suitable manner known to those in the art, and for illustration by filtration through a 0.22-micron filter. Subsequent to sterilization, the solution can be dispensed into appropriate receptacles, such as depyrogenated glass vials. The dispensing is optionally done by an aseptic method. Sterilized closures can then be placed on the vials and, if desired, the vial contents can be lyophilized.
  • the pharmaceutical formulations can contain other additives, such as pH-adjusting additives.
  • useful pH-adjusting agents include acids, such as hydrochloric acid, bases or buffers, such as sodium lactate, sodium acetate, sodium phosphate, sodium citrate, sodium borate, or sodium gluconate.
  • the formulations can contain antimicrobial preservatives.
  • Useful antimicrobial preservatives include methylparaben, propylparaben, and benzyl alcohol. An antimicrobial preservative is typically employed when the formulations is placed in a vial designed for multi-dose use.
  • the pharmaceutical formulations described herein can be lyophilized using techniques well known in the art.
  • a pharmaceutical composition can take the form of solutions, suspensions, tablets, pills, capsules, powders, and the like.
  • Tablets containing various excipients such as sodium citrate, calcium carbonate and calcium phosphate may be employed along with various disintegrants such as starch (e.g., potato or tapioca starch) and certain complex silicates, together with binding agents such as polyvinylpyrrolidone, sucrose, gelatin and acacia.
  • binding agents such as polyvinylpyrrolidone, sucrose, gelatin and acacia.
  • lubricating agents such as magnesium stearate, sodium lauryl sulfate, and talc are often very useful for tableting purposes.
  • Solid compositions of a similar type may be employed as fillers in soft and hard-filled gelatin capsules.
  • compositions in this connection also include lactose or milk sugar as well as high molecular weight polyethylene glycols.
  • lactose or milk sugar as well as high molecular weight polyethylene glycols.
  • the compounds of the presently disclosed host matter can be combined with various sweetening agents, flavoring agents, coloring agents, emulsifying agents and/or suspending agents, as well as such diluents as water, ethanol, propylene glycol, glycerin and various like combinations thereof.
  • injectable, stable, sterile formulations comprising an active compound as described herein, or a salt thereof, in a unit dosage form in a sealed container.
  • the compound or salt is provided in the form of a lyophilizate, which is capable of being reconstituted with a suitable pharmaceutically acceptable carrier to form liquid formulation suitable for injection thereof into a host.
  • a sufficient amount of emulsifying agent which is physiologically acceptable, can be employed in sufficient quantity to emulsify the compound or salt in an aqueous carrier.
  • Particularly useful emulsifying agents include phosphatidyl cholines and lecithin.
  • Additional embodiments provided herein include liposomal formulations of the active compounds disclosed herein.
  • the technology for forming liposomal suspensions is well known in the art.
  • the compound is an aqueous-soluble salt, using conventional liposome technology, the same can be incorporated into lipid vesicles.
  • the active compound due to the water solubility of the active compound, the active compound can be substantially entrained within the hydrophilic center or core of the liposomes.
  • the lipid layer employed can be of any conventional composition and can either contain cholesterol or can be cholesterol-free.
  • the active compound of interest is water-insoluble, again employing conventional liposome formation technology, the salt can be substantially entrained within the hydrophobic lipid bilayer that forms the structure of the liposome.
  • the liposomes that are produced can be reduced in size, as through the use of standard sonication and homogenization techniques.
  • the liposomal formulations comprising the active compounds disclosed herein can be lyophilized to produce a lyophilizate, which can be reconstituted with a pharmaceutically acceptable carrier, such as water, to regenerate a liposomal suspension.
  • compositions which are suitable for administration as an aerosol by inhalation. These formulations comprise a solution or suspension of a desired compound described herein or a salt thereof, or a plurality of solid particles of the compound or salt.
  • the desired formulations can be placed in a small chamber and nebulized. Nebulization can be accomplished by compressed air or by ultrasonic energy to form a plurality of liquid droplets or solid particles comprising the compounds or salts.
  • the liquid droplets or solid particles may for example have a particle size in the range of about 0.5 to about 10 microns, and optionally from about 0.5 to about 5 microns.
  • the solid particles can be obtained by processing the solid compound or a salt thereof, in any appropriate manner known in the art, such as by micronization.
  • the size of the solid particles or droplets can be from about 1 to about 2 microns.
  • commercial nebulizers are available to achieve this purpose.
  • the compounds can be administered via an aerosol suspension of respirable particles in a manner set forth in U.S. Pat. No. 5,628,984, the disclosure of which is incorporated herein by reference in its entirety.
  • the formulations suitable for administration as an aerosol can comprise a water-soluble active compound in a carrier that comprises water.
  • a surfactant can be present, which lowers the surface tension of the formulations sufficiently to result in the formation of droplets within the desired size range when hosted to nebulization.
  • pharmaceutically acceptable salts refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with hosts (e.g., human hosts) without 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 presently disclosed host matter.
  • salts refers to inorganic and organic acid addition salts of compounds of the presently disclosed compounds.
  • These salts can be prepared by any means known in the art, including, without limitation, in situ during the final isolation and purification of the compounds or by separately reacting the purified compound in its free base form with a suitable organic or inorganic acid and isolating the salt thus formed.
  • the compounds of the presently disclosed host matter are basic compounds, they are all capable of forming a wide variety of different salts with various inorganic and organic acids.
  • Acid addition salts of the basic compounds are prepared by contacting the free base form with a sufficient amount of the desired acid to produce the salt in the conventional manner.
  • the free base form can be regenerated by contacting the salt form with a base and isolating the free base in the conventional manner.
  • the free base forms may differ from their respective salt forms in certain physical properties such as solubility in polar solvents.
  • Pharmaceutically acceptable base addition salts may be formed with metals or amines, such as alkali and alkaline earth metal hydroxides, or of organic amines. Examples of metals used as cations, include, but are not limited to, sodium, potassium, magnesium, calcium, and the like. Examples of suitable amines include, but are not limited to, N,N′-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, N-methylglucamine, and procaine.
  • the base addition salts of acidic compounds are prepared by contacting the free acid form with a sufficient amount of the desired base to produce the salt in the conventional manner.
  • the free acid form can be regenerated by contacting the salt form with an acid and isolating the free acid in a conventional manner.
  • the free acid forms may differ from their respective salt forms somewhat in certain physical properties such as solubility in polar solvents.
  • Salts can be prepared from inorganic acids sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide such as hydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydriodic, phosphorus, and the like.
  • Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate mesylate, glucoheptonate, lactobionate, laurylsulphonate and isethionate salts, and the like.
  • Salts can also be prepared from organic acids, such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, etc. and the like.
  • organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, etc. and the like.
  • Representative salts include acetate, propionate, caprylate, isobutyrate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalate, benzenesulfonate, toluenesulfonate, phenylacetate, citrate, lactate, maleate, tartrate, methanesulfonate, and the like.
  • Pharmaceutically acceptable salts can include cations based on the alkali and alkaline earth metals, such as sodium, lithium, potassium, calcium, magnesium and the like, as well as non-toxic ammonium, quaternary ammonium, and amine cations including, but not limited to, ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like. Also contemplated are the salts of amino acids such as arginate, gluconate, galacturonate, and the like. See, for example, Berge et al., J. Pharm. Sci., 1977, 66, 1-19, which is incorporated herein by reference.
  • Ref-1 is WO 2010/020675 A1
  • Ref-2 is White, J. D.; et al. J. Org. Chem. 1995, 60, 3600
  • Ref-3 Presser A. and Hufner, A. Monatshefte für Chemie 2004, 135, 1015.
  • Ref-1 is WO 2010/020675 A1
  • Ref-4 is WO 2005/040166 A1
  • Ref-5 is Schoenauer, K and Zbiral, E. Tetrahedron Letters 1983, 24, 573.
  • Ref-1 is WO 2010/020675 A1.
  • Ref-1 is WO 2010/020675 A1
  • Ref-2 is WO 2005/040166 A1
  • Ref-3 is Schoenauer, K and Zbiral, E. Tetrahedron Letters 1983, 24, 573.
  • the lactam can be generated by reacting the carboxylic acid with a protected amine in the presence of a strong acid and a dehydrating agent, which can be together in one moiety as a strong acid anhydride.
  • strong acid anhydrides include, but are not limited to, trifluoroacetic acid anhydride, tribromoacetic acid anhydride, trichloroacetic acid anhydride, or mixed anhydrides.
  • the dehydrating agent can be a carbodiimide based compound such as but not limited to DCC (N,N-dicyclohexylcarbodiimide), EDC (1-ethyl-3-(3-dimethylaminopropyl)carbodiimide or DIC (N,N-diisopropylcarbodiimide).
  • DCC N,N-dicyclohexylcarbodiimide
  • EDC 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide
  • DIC N,N-diisopropylcarbodiimide
  • amine intermediates and final amine compounds can be synthesized by those skilled in the art. It will be appreciated that the chemistry can employ reagents that comprise reactive functionalities that can be protected and de-protected and will be known to those skilled in the art at the time of the invention. See for example, Greene, T. W. and Wuts, P. G. M., Greene's Protective Groups in Organic Synthesis, 4 th edition, John Wiley and Sons.
  • This compound was prepared as described in WO 2010/020675 A1.
  • intermediate A tert-butyl N-[2-(benzyloxycarbonylamino)-3-methyl-butyl]carbamate, (6.1 g).
  • tert-butyl N-[[1-(benzyloxycarbonylamino)cyclopentyl]methyl]carbamate was synthesized in an analogous manner to tert-butyl N-[[1-(benzyloxycarbonylamino)cyclohexyl]methyl]carbamate.
  • 5-(4-morpholino-1-piperidyl)pyridin-2-amine was prepared in a manner similar to that used in the synthesis of 5-(4-methylpiperazin-1-yl)pyridin-2-amine.
  • LCMS ESI 263 (M+H).
  • 5-(1-piperidyl) pyridin-2-amine was prepared in a manner similar to that used in the synthesis of 5-(4-methylpiperazin-1-yl)pyridin-2-amine.
  • LCMS 178 (M+H).
  • 5-thiomorpholinopyridin-2-amine was prepared in a manner similar to that used in the synthesis of 5-(4-methylpiperazin-1-yl) pyridin-2-amine.
  • tert-butyl (4R)-5-(6-nitro-3-pyridyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate was synthesized in a manner similar to that used in the synthesis of 2-nitro-5-[4-(1-piperidyl)-1-piperidyl]pyridine.
  • tert-butyl (4R)-5-(6-amino-3-pyridyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate was prepared in a manner similar to that used in the synthesis of 5-(4-methylpiperazin-1-yl)pyridin-2-amine.
  • N,N-dimethyl-1-(6-nitro-3-pyridyl)piperidin-4-amine was synthesized in a manner similar to that used in the synthesis of 2-nitro-5-[4-(1-piperidyl)-1-piperidyl]pyridine.
  • 4-(6-nitro-3-pyridyl) morpholine was synthesized in a manner similar to that used in the synthesis of 2-nitro-5-[4-(1-piperidyl)-1-piperidyl]pyridine.
  • 5-morpholinopyridin-2-amine was prepared in a manner similar to that used in the synthesis of 5-(4-methylpiperazin-1-yl) pyridin-2-amine.
  • 1 HNMR 600 MHz, CHLOROFORM-d
  • 1-isobutyl-4-(6-nitro-3-pyridyl)piperazine was synthesized in a manner similar to that used in the synthesis of 2-nitro-5-[4-(1-piperidyl)-1-piperidyl]pyridine which was then converted 5-(4-isobutylpiperazin-1-yl)pyridin-2-amine in a manner similar to that used in the synthesis of 5-(4-methylpiperazin-1-yl)pyridin-2-amine.
  • 1-isopropyl-4-(6-nitro-3-pyridyl)piperazine was synthesized in a manner similar to that used in the synthesis of 2-nitro-5-[4-(1-piperidyl)-1-piperidyl]pyridine which was then converted to 5-(4-isopropylpiperazin-1-yl)pyridin-2-amine in a manner similar to that used in the synthesis of 5-(4-methylpiperazin-1-yl)pyridin-2-amine.
  • (2S,6R)-2,6-dimethyl-4-(6-nitro-3-pyridyl)morpholine was synthesized in a manner similar to that used in the synthesis of 2-nitro-5-[4-(1-piperidyl)-1-piperidyl]pyridine which was then converted to 5-[(2R,6S)-2,6-dimethylmorpholin-4-yl]pyridin-2-amine in a manner similar to that used in the synthesis of 5-(4-methylpiperazin-1-yl)pyridin-2-amine.
  • (3S,5R)-3,5-dimethyl-1-(6-nitro-3-pyridyl)piperazine was synthesized in a manner similar to that used in the synthesis of 2-nitro-5-[4-(1-piperidyl)-1-piperidyl]pyridine which was then converted to 5-[(3R,5S)-3,5-dimethylpiperazin-1-yl]pyridin-2-amine in a manner similar to that used in the synthesis of 5-(4-methylpiperazin-1-yl)pyridin-2-amine.
  • tert-butyl N-[2-[2-chloro-6-(diethoxymethyl)pyrrolo[2,3-d]pyrimidin-7-yl]-3-methyl-butyl]carbamate was synthesized by hosting tert-butyl N-[2-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]-3-methyl-butyl]carbamate to Sonogoshira conditions as described for tert-butyl N-[2-[[2-chloro-5-(3,3-diethoxyprop-1-ynyl)pyrimidin-4-yl]amino]ethyl]carbamate followed by subsequent treatment with TBAF as described in the synthesis of tert-butyl N-[2-[2-chloro-6-(diethoxymethyl)pyrrolo[2,3-d]pyrimidin-7-yl]ethyl]carbamate.
  • Compound 18 was hydrogenated with 10% Pd/C in ethanol under a blanket of hydrogen at 50 psi in a pressure bomb to afford tert-butyl N-[(2S)-2-amino-4-methyl-pentyl]carbamate which was then reacted with 5-bromo-2,4-dichloro-pyrimidine using analogous reaction conditions as described for tert-butyl N-[2-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]-3-methyl-butyl]carbamate to afford tert-butyl N-[(2S)-2-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]-4-methyl-pentyl]carbamate.
  • Compound 20 was hydrogenated using 10% Pd/C under hydrogen at 50 psi in a pressure vessel to afford tert-butyl N-[(2S)-2-amino-3-methyl-pentyl]carbamate which was reacted with 5-bromo-2,4-dichloro-pyrimidine using analogous reaction conditions as described for tert-butyl N-[2-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]-3-methyl-butyl]carbamate to afford tert-butyl N-[(2S)-2-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]-3-methyl-pentyl]carbamate.
  • tert-butyl N-[(2S)-2-[[2-chloro-5-(3,3-diethoxyprop-1-ynyl)pyrimidin-4-yl]amino]-3-methyl-pentyl]carbamate was synthesized using similar experimental conditions to that used in the synthesis of (2S)—N2-[2-chloro-5-(3,3-diethoxyprop-1-ynyl)pyrimidin-4-yl]-4-methyl-pentane-1,2-diamine.
  • Compound 21 was hydrogenated using 10% Pd/C under hydrogen at 50 psi in a pressure vessel to afford tert-butyl N-[(2S)-2-amino-3,3-dimethyl-butyl]carbamate which was then reacted with 5-bromo-2,4-dichloro-pyrimidine using analogous reaction conditions as described using analogous reaction conditions as described for tert-butyl N-[2-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]-3-methyl-butyl]carbamate to afford tert-butyl N-[(2S)-2-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]-3,3-dimethyl-butyl]carbamate.
  • Compound 21 was hydrogenated using 10% Pd/C under hydrogen at 50 psi in a pressure vessel to afford tert-butyl N-[(2S)-2-amino-2-phenyl-ethyl]carbamate which was then reacted with 5-bromo-2,4-dichloro-pyrimidine using analogous reaction conditions as described for tert-butyl N-[2-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]-3-methyl-butyl]carbamate to afford tert-butyl N-[(2S)-2-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]-2-phenyl-ethyl]carbamate.
  • tert-butyl N-[(2S)-2-[[2-chloro-5-(3,3-diethoxyprop-1-ynyl)pyrimidin-4-yl]amino]-2-phenyl-ethyl]carbamate was synthesized using similar experimental conditions to those used in the synthesis of (2S)—N2-[2-chloro-5-(3,3-diethoxyprop-1-ynyl)pyrimidin-4-yl]-4-methyl-pentane-1,2-diamine.
  • tert-butyl N-[(1S)-1-[[(5-bromo-2-chloro-pyrimidin-4-yl)amino]methyl]-2-methyl-propyl]carbamate was synthesized using 5-bromo-2,4-dichloro-pyrimidine and Intermediate E using analogous reaction conditions as described for tert-butyl N-[2-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]-3-methyl-butyl]carbamate.
  • tert-butyl N-[(1S)-1-[[[2-chloro-5-(3,3-diethoxyprop-1-ynyl)pyrimidin-4-yl]amino]methyl]-2-methyl-propyl]carbamate was synthesized using similar experimental conditions to those used in the synthesis (2S)—N2-[2-chloro-5-(3,3-diethoxyprop-1-ynyl)pyrimidin-4-yl]-4-methyl-pentane-1,2-diamine.
  • tert-butyl N-[2-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]-2-methyl-propyl]carbamate was synthesized using 5-bromo-2,4-dichloro-pyrimidine and tert-butyl N-(2-amino-2-methyl-propyl)carbamate using analogous reaction conditions as described for tert-butyl N-[2-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]-3-methyl-butyl]carbamate.
  • tert-butyl N-[2-[[2-chloro-5-(3,3-diethoxyprop-1-ynyl)pyrimidin-4-yl]amino]-2-methyl-propyl]carbamate was synthesized using similar experimental conditions to those used in the synthesis of (2S)—N2-[2-chloro-5-(3,3-diethoxyprop-1-ynyl)pyrimidin-4-yl]-4-methyl-pentane-1,2-diamine.
  • tert-butyl N-[[1-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]cyclohexyl]methyl]carbamate was synthesized using 5-bromo-2,4-dichloro-pyrimidine and Intermediate K using the analogous reaction conditions as described for tert-butyl N-[2-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]-3-methyl-butyl]carbamate.
  • tert-butyl N-[[1-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]cyclopentyl]methyl]carbamate was synthesized using 5-bromo-2,4-dichloro-pyrimidine and Intermediate L using analogous reaction conditions as described for tert-butyl N-[2-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]-3-methyl-butyl]carbamate.
  • tert-butyl N-[[1-[[2-chloro-5-(3,3-diethoxyprop-1-ynyl)pyrimidin-4-yl]amino]cyclopentyl]methyl]carbamate was synthesized using similar experimental conditions to that used in the synthesis of (2S)—N2-[2-chloro-5-(3,3-diethoxyprop-1-ynyl)pyrimidin-4-yl]-4-methyl-pentane-1,2-diamine.
  • tert-butyl N-[2-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]-4-methyl-pentyl]carbamate was synthesized using 5-bromo-2,4-dichloro-pyrimidine and Intermediate B using analogous reaction conditions as described for tert-butyl N-[2-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]-3-methyl-butyl]carbamate.
  • the analytical data is consistent with that described for the L-enantiomer.
  • tert-butyl N-[2-[[2-chloro-5-(3,3-diethoxyprop-1-ynyl)pyrimidin-4-yl]amino]-4-methyl-pentyl]carbamate was synthesized using similar experimental conditions to that used in the synthesis of tert-butyl N-[2-[ [2-chloro-5-(3,3-diethoxyprop-1-ynyl)pyrimidin-4-yl]amino]ethyl]carbamate.
  • Compound 60 was synthesized using an analogous synthetic sequence as that described for Compound 44.
  • the analytical data was consistent with that described for the L-isomer.
  • tert-butyl N-[(1S,2S)-2-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]cyclopentyl]carbamate was synthesized by treating tert-butyl N-[(1S,2S)-2-aminocyclopentyl]carbamate with 5-bromo-2,4-dichloro-pyrimidine using analogous reaction conditions as described for tert-butyl N-[2-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]-3-methyl-butyl]carbamate.
  • tert-butyl N-[(1S,2S)-2-[[2-chloro-5-(3,3-diethoxyprop-1-ynyl)pyrimidin-4-yl]amino]cyclopentyl]carbamate was synthesized using similar experimental conditions to that used in the synthesis of (2S)—N2-[2-chloro-5-(3,3-diethoxyprop-1-ynyl)pyrimidin-4-yl]-4-methyl-pentane-1,2-diamine.
  • Compound 108 was synthesized in a manner similar to that described for compounds 64 and 65 and was recovered as an HCl salt. The analytical data was consistent with that described for the antipode compound 75.
  • Compound 109 was synthesized in a manner similar to that described for compounds 64 and 65 and was recovered as an HCl salt. The analytical data was consistent with that described for the antipode compound 75.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Organic Chemistry (AREA)
  • Epidemiology (AREA)
  • Immunology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Optics & Photonics (AREA)
  • Physics & Mathematics (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Cell Biology (AREA)
  • Hematology (AREA)
  • Oncology (AREA)
  • Dermatology (AREA)
  • Transplantation (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Rheumatology (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
US14/213,784 2013-03-15 2014-03-14 Highly Active Anti-Neoplastic and Anti-Proliferative Agents Abandoned US20140271460A1 (en)

Priority Applications (6)

Application Number Priority Date Filing Date Title
US14/213,784 US20140271460A1 (en) 2013-03-15 2014-03-14 Highly Active Anti-Neoplastic and Anti-Proliferative Agents
US15/201,286 US20160310499A1 (en) 2013-03-15 2016-07-01 Highly Active Anti-Neoplastic and Anti-Proliferative Agents
US15/713,385 US20180015096A1 (en) 2013-03-15 2017-09-22 Highly active anti-neoplastic and anti-proliferative agents
US16/228,308 US10709711B2 (en) 2013-03-15 2018-12-20 Highly active anti-neoplastic and anti-proliferative agents
US16/926,035 US20200345743A1 (en) 2013-03-15 2020-07-10 Highly active anti-neoplastic and anti-proliferative agents
US17/890,130 US20230248733A1 (en) 2013-03-15 2022-08-17 Highly active anti-neoplastic and anti-proliferative agents

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
US201361798772P 2013-03-15 2013-03-15
US201361861374P 2013-08-01 2013-08-01
US201361911354P 2013-12-03 2013-12-03
US201461949795P 2014-03-07 2014-03-07
US14/213,784 US20140271460A1 (en) 2013-03-15 2014-03-14 Highly Active Anti-Neoplastic and Anti-Proliferative Agents

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US15/201,286 Division US20160310499A1 (en) 2013-03-15 2016-07-01 Highly Active Anti-Neoplastic and Anti-Proliferative Agents

Publications (1)

Publication Number Publication Date
US20140271460A1 true US20140271460A1 (en) 2014-09-18

Family

ID=51527866

Family Applications (6)

Application Number Title Priority Date Filing Date
US14/213,784 Abandoned US20140271460A1 (en) 2013-03-15 2014-03-14 Highly Active Anti-Neoplastic and Anti-Proliferative Agents
US15/201,286 Abandoned US20160310499A1 (en) 2013-03-15 2016-07-01 Highly Active Anti-Neoplastic and Anti-Proliferative Agents
US15/713,385 Abandoned US20180015096A1 (en) 2013-03-15 2017-09-22 Highly active anti-neoplastic and anti-proliferative agents
US16/228,308 Active US10709711B2 (en) 2013-03-15 2018-12-20 Highly active anti-neoplastic and anti-proliferative agents
US16/926,035 Abandoned US20200345743A1 (en) 2013-03-15 2020-07-10 Highly active anti-neoplastic and anti-proliferative agents
US17/890,130 Pending US20230248733A1 (en) 2013-03-15 2022-08-17 Highly active anti-neoplastic and anti-proliferative agents

Family Applications After (5)

Application Number Title Priority Date Filing Date
US15/201,286 Abandoned US20160310499A1 (en) 2013-03-15 2016-07-01 Highly Active Anti-Neoplastic and Anti-Proliferative Agents
US15/713,385 Abandoned US20180015096A1 (en) 2013-03-15 2017-09-22 Highly active anti-neoplastic and anti-proliferative agents
US16/228,308 Active US10709711B2 (en) 2013-03-15 2018-12-20 Highly active anti-neoplastic and anti-proliferative agents
US16/926,035 Abandoned US20200345743A1 (en) 2013-03-15 2020-07-10 Highly active anti-neoplastic and anti-proliferative agents
US17/890,130 Pending US20230248733A1 (en) 2013-03-15 2022-08-17 Highly active anti-neoplastic and anti-proliferative agents

Country Status (7)

Country Link
US (6) US20140271460A1 (he)
EP (1) EP2967050A4 (he)
JP (3) JP6435315B2 (he)
CN (2) CN107417691B (he)
CA (2) CA2906157C (he)
HK (1) HK1222766A1 (he)
WO (1) WO2014144740A2 (he)

Cited By (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9259399B2 (en) 2007-11-07 2016-02-16 Cornell University Targeting CDK4 and CDK6 in cancer therapy
US9464092B2 (en) 2013-03-15 2016-10-11 G1 Therapeutics, Inc. Transient protection of normal cells during chemotherapy
US9717735B2 (en) 2014-04-17 2017-08-01 G1 Therapeutics, Inc. Tricyclic lactams for use in HSPC-sparing treatments for RB-positive abnormal cellular proliferation
US9745316B2 (en) 2012-03-29 2017-08-29 G1 Therapeutics, Inc. Lactam kinase inhibitors
WO2018005533A1 (en) * 2016-07-01 2018-01-04 G1 Therapeutics, Inc. Antiproliferative pyrimidine-based compounds
WO2018129387A1 (en) * 2017-01-06 2018-07-12 G1 Therapeutics, Inc. Combination therapy for the treatment of cancer
US10231969B2 (en) 2014-09-12 2019-03-19 GI Therapeutics, Inc. Anti-neoplastic combinations and dosing regimens using CDK4/6 inhibitor compounds to treat RB-positive tumors
US20190119294A1 (en) * 2016-07-01 2019-04-25 G1 Therapeutics, Inc. Pyrimidine-based compounds for the treatment of cancer
WO2019133864A1 (en) * 2017-12-29 2019-07-04 Accutar Biotechnology DUAL INHIBITORS OF PARP1 and CDK
US10413547B2 (en) 2014-09-12 2019-09-17 G1 Therapeutics, Inc. Treatment of Rb-negative tumors using topoisomerase with cyclin dependent kinase 4/6 inhibitors
US10709711B2 (en) 2013-03-15 2020-07-14 G1 Therapeutics, Inc. Highly active anti-neoplastic and anti-proliferative agents
US10988479B1 (en) 2020-06-15 2021-04-27 G1 Therapeutics, Inc. Morphic forms of trilaciclib and methods of manufacture thereof
US11395821B2 (en) 2017-01-30 2022-07-26 G1 Therapeutics, Inc. Treatment of EGFR-driven cancer with fewer side effects
US11529352B2 (en) 2016-12-05 2022-12-20 G1 Therapeutics, Inc. Preservation of immune response during chemotherapy regimens
US11642342B2 (en) 2019-12-23 2023-05-09 Accutar Biotechnology Combinations of estrogen receptor degraders and cyclin-dependent kinase inhibitors for treating cancer
RU2810487C2 (ru) * 2017-01-06 2023-12-27 Г1 Терапьютикс, Инк. Комплексная терапия для лечения рака

Families Citing this family (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8691830B2 (en) 2010-10-25 2014-04-08 G1 Therapeutics, Inc. CDK inhibitors
EP3858835A1 (en) * 2016-07-01 2021-08-04 G1 Therapeutics, Inc. Pyrimidine-based antiproliferative agents
CA3028752A1 (en) * 2016-07-01 2018-01-04 G1 Therapeutics, Inc. Synthesis of n-(heteroaryl)-pyrrolo[3,2-d]pyrimidin-2-amines
AU2018291026B2 (en) * 2017-06-29 2022-09-01 G1 Therapeutics, Inc. Morphic forms of GIT38 and methods of manufacture thereof
WO2019136451A1 (en) 2018-01-08 2019-07-11 G1 Therapeutics, Inc. G1t38 superior dosage regimes
WO2021236650A1 (en) 2020-05-19 2021-11-25 G1 Therapeutics, Inc. Cyclin-dependent kinase inhibiting compounds for the treatment of medical disorders
MX2022015567A (es) * 2020-06-11 2023-01-19 Lunella Biotech Inc Productos terapeuticos contra el cancer de inhibidores selectivos de cdk4/6.

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20130237544A1 (en) * 2010-10-25 2013-09-12 G1 Therapeutics, Inc. Cdk inhibitors

Family Cites Families (70)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5591855A (en) 1994-10-14 1997-01-07 Cephalon, Inc. Fused pyrrolocarbazoles
US5628984A (en) 1995-07-31 1997-05-13 University Of North Carolina At Chapel Hill Method of detecting lung disease
JP2001509805A (ja) 1997-02-05 2001-07-24 ワーナー−ランバート・コンパニー 細胞増殖阻害剤としてのピリド〔２，３−ｄ〕ピリミジンおよび４−アミノピリミジン
GB9718913D0 (en) 1997-09-05 1997-11-12 Glaxo Group Ltd Substituted oxindole derivatives
US20040006074A1 (en) 1998-04-28 2004-01-08 The Government Of The United States Of America Cyclin dependent kinase (CDK)4 inhibitors and their use for treating cancer
CA2335115C (en) 1998-06-16 2009-01-27 The Government Of The United States Of America, Represented By The Secretary, Department Of Health And Human Services Fused azepinone cyclin dependent kinase inhibitors
AU3584200A (en) 1999-01-29 2000-08-18 Board Of Trustees Of The University Of Illinois, The P53 inhibitors and therapeutic use of the same
EP1557168B1 (en) 1999-07-26 2011-11-16 Msd K.K. Biarylurea Derivatives
US6387900B1 (en) 1999-08-12 2002-05-14 Pharmacia & Upjohn S.P.A. 3(5)-ureido-pyrazole derivatives process for their preparation and their use as antitumor agents
US6291504B1 (en) 1999-10-20 2001-09-18 Dupont Pharmaceuticals Company Acylsemicarbazides and their uses
AU2072201A (en) 1999-12-16 2001-06-25 Eli Lilly And Company Agents and methods for the treatment of proliferative diseases
US7053070B2 (en) 2000-01-25 2006-05-30 Warner-Lambert Company Pyrido[2,3-d]pyrimidine-2,7-diamine kinase inhibitors
CN100351253C (zh) 2000-06-26 2007-11-28 辉瑞产品公司 作为免疫抑制剂的吡咯并[2,3－d]嘧啶化合物
EP1325011B1 (en) 2000-09-29 2004-05-06 Eli Lilly And Company Methods and compounds for treating proliferative diseases
US6706718B2 (en) 2000-12-01 2004-03-16 Bristol-Myers Squibb Company 3-(2,4-dimethylthiazol-5-yl)indeno[1,2-c]pyrazol-4-one derivatives and their uses
JP4302986B2 (ja) 2001-02-28 2009-07-29 テンプル・ユニバーシティ−オブ・ザ・コモンウェルス・システム・オブ・ハイアー・エデュケイション 細胞及び組織をα，β不飽和アリールスルホンにより電離放射線から防護する方法
CN101172158A (zh) * 2001-05-11 2008-05-07 得克萨斯州立大学董事会 抗cd26单克隆抗体作为对与表达cd26的细胞相关疾病的治疗
SI1470124T1 (sl) 2002-01-22 2006-04-30 Warner Lambert Co 2-(piridin-2-ilamino)-pirido(2,3-d)pirimidin-7-oni
WO2003093469A2 (en) 2002-05-01 2003-11-13 Chromos Molecular Systems, Inc. Methods for delivering nucleic acid molecules into cells and assessment thereof
MXPA05007503A (es) 2003-01-17 2005-09-21 Warner Lambert Co Heterociclicos 2-aminopiridina sustituidos como inhibidores de proliferacion celular.
US7482354B2 (en) 2003-05-22 2009-01-27 Nerviano Medical Sciences S.R.L. Pyrazolo-quinazoline derivatives, process for their preparation and their use as kinase inhibitors
EP1648889B1 (en) 2003-07-11 2008-10-29 Warner-Lambert Company LLC Isethionate salt of a selective cdk4 inhibitor
JP4490434B2 (ja) 2003-10-23 2010-06-23 エフ．ホフマン−ラ ロシュ アーゲー 神経及び神経精神疾患の処置においてＧｌｙＴ−１阻害剤として使用するためのトリアザ−スピロピペリジン誘導体
GB0327380D0 (en) 2003-11-25 2003-12-31 Cyclacel Ltd Method
CA2561516A1 (en) 2004-03-30 2005-10-13 Pfizer Products Inc. Combinations of signal transduction inhibitors
US8603763B2 (en) 2004-04-08 2013-12-10 Cornell Research Foundation, Inc. Functional immunohistochemical cell cycle analysis as a prognostic indicator for cancer
ITMI20040874A1 (it) 2004-04-30 2004-07-30 Ist Naz Stud Cura Dei Tumori Derivati indolici ed azaindolici con azione antitumorale
US7947695B2 (en) 2005-01-14 2011-05-24 Janssen Pharmaceutica Nv 5-membered annelated heterocyclic pyrimidines as kinase inhibitors
WO2006077425A1 (en) 2005-01-21 2006-07-27 Astex Therapeutics Limited Combinations of pyrazole kinase inhibitors and further antitumor agents
ATE540948T1 (de) 2005-05-20 2012-01-15 Vertex Pharma Pyrrolopyridine als proteinkinasehemmer
US20070049591A1 (en) 2005-08-25 2007-03-01 Kalypsys, Inc. Inhibitors of MAPK/Erk Kinase
EP1779848A1 (en) 2005-10-28 2007-05-02 Nikem Research S.R.L. V-ATPase inhibitors for the treatment of inflammatory and autoimmune diseases
KR20080085014A (ko) 2005-12-09 2008-09-22 에프. 호프만-라 로슈 아게 비만 치료에 유용한 트라이사이클릭 아마이드 유도체
CA2631777A1 (en) 2005-12-22 2007-07-05 Wyeth Substituted isoquinoline-1,3(2h,4h)-diones, 1-thioxo-1,4-dihydro-2h-isoquinoline-3-ones and 1,4-dihydro-3(2h)-isoquinolones and use thereof as kinase inhibitor
EP2004163B1 (en) 2006-04-05 2014-09-17 Novartis Pharma AG Combination of everolimus and vinorelbine
US20070270362A1 (en) 2006-05-18 2007-11-22 The University Of Washington Methods and compositions for prevention or treatment of inflammatory-related diseases and disorders
AU2007269540B2 (en) 2006-07-05 2013-06-27 Exelixis, Inc. Methods of using IGF1R and Abl kinase modulators
EP2109450A2 (en) 2006-12-14 2009-10-21 Panacea Pharmaceuticals, Inc. Methods of neuroprotection by cyclin-dependent kinase inhibition
US20100048597A1 (en) 2006-12-22 2010-02-25 Novartis Ag Organic Compounds and Their Uses
MX2009013897A (es) 2007-06-25 2010-03-30 Neurogen Corp Piperacinil oxoalquil tetrahidro-beta-carbolinas y analogos relacionados.
US9259399B2 (en) 2007-11-07 2016-02-16 Cornell University Targeting CDK4 and CDK6 in cancer therapy
AU2008343932B2 (en) 2007-12-19 2013-08-15 Amgen Inc. Fused pyridine, pyrimidine and triazine compounds as cell cycle inhibitors
US8518930B2 (en) 2008-07-29 2013-08-27 Nerviano Medical Sciences S.R.L. Therapeutic combination comprising a CDKS inhibitor and an antineoplastic agent
PT2331547E (pt) * 2008-08-22 2014-10-29 Novartis Ag Compostos de pirrolopirimidina como inibidores de cdk
AU2009310352A1 (en) 2008-10-01 2010-05-06 The University Of North Carolina At Chapel Hill Hematopoietic protection against ionizing radiation using selective cyclin-dependent kinase 4/6 inhibitors
JP2012504646A (ja) 2008-10-01 2012-02-23 ザ ユニバーシティ オブ ノース カロライナ アット チャペル ヒル 選択的サイクリン依存性キナーゼ４／６阻害剤を用いた化学療法化合物に対する造血系の防護
JO2885B1 (en) 2008-12-22 2015-03-15 ايلي ليلي اند كومباني Protein kinase inhibitors
EP3025724B1 (en) 2009-05-13 2018-07-11 The University of North Carolina At Chapel Hill Cyclin dependent kinase inhibitors and methods of use
WO2011103485A1 (en) 2010-02-18 2011-08-25 Medivation Technologies, Inc. Fused tetracyclic pyrido[4,3-b]indole and pyrido[3,4-b]indole derivatives and methods of use
UY33227A (es) 2010-02-19 2011-09-30 Novartis Ag Compuestos de pirrolopirimidina como inhibidores de la cdk4/6
UY33226A (es) * 2010-02-19 2011-09-30 Novartis Ag Compuestos de pirrolopirimidina deuterada como inhibidores de la cdk4/6
US8691830B2 (en) 2010-10-25 2014-04-08 G1 Therapeutics, Inc. CDK inhibitors
CN103180324A (zh) 2010-11-02 2013-06-26 普罗美加公司 腔肠素衍生物及其使用方法
CA2818046A1 (en) 2010-11-17 2012-05-24 The University Of North Carolina At Chapel Hill Protection of renal tissues from ischemia through inhibition of the proliferative kinases cdk4 and cdk6
WO2012085244A1 (fr) 2010-12-23 2012-06-28 Sanofi Derives de pyrimidinone, leur preparation et leur utilisation pharmaceutique
KR101606250B1 (ko) * 2011-03-23 2016-03-24 암젠 인크 Cdk 4/6 및 flt3의 융합된 트리사이클릭 이중 저해제
AU2012279117A1 (en) 2011-07-01 2014-01-09 Novartis Ag Combination therapy comprising a CDK4/6 inhibitor and a PI3K inhibitor for use in the treatment of cancer
AU2013239816B2 (en) 2012-03-29 2017-08-24 G1 Therapeutics, Inc. Lactam kinase inhibitors
EP2841417A1 (en) 2012-04-26 2015-03-04 Francis Xavier Tavares Synthesis of lactams
US9241941B2 (en) 2012-09-20 2016-01-26 Memorial Sloan-Kettering Cancer Center Methods for treatment of lymphomas with mutations in cell cycle genes
EP2968291A4 (en) 2013-03-15 2016-09-28 G1 Therapeutics Inc HSPC-PROOF TREATMENTS FOR RB-POSITIVE ABNORMAL CELLULAR PROLIFERATION
US20140274896A1 (en) 2013-03-15 2014-09-18 G1 Therapeutics, Inc. Transient Protection of Hematopoietic Stem and Progenitor Cells Against Ionizing Radiation
WO2014144740A2 (en) 2013-03-15 2014-09-18 G1 Therapeutics, Inc. Highly active anti-neoplastic and anti-proliferative agents
EA201591656A1 (ru) 2013-04-08 2016-05-31 Фармасайкликс Элэлси Комбинированная терапия с ибрутинибом
WO2015061407A1 (en) 2013-10-24 2015-04-30 Francis Xavier Tavares Process for synthesis of lactams
US10314842B2 (en) 2013-12-02 2019-06-11 Cornell University Methods for treating B cell proliferative disorders
WO2015161287A1 (en) 2014-04-17 2015-10-22 G1 Therapeutics, Inc. Tricyclic lactams for use in the protection of normal cells during chemotherapy
EP3191098A4 (en) 2014-09-12 2018-04-25 G1 Therapeutics, Inc. Combinations and dosing regimes to treat rb-positive tumors
WO2016040848A1 (en) 2014-09-12 2016-03-17 G1 Therapeutics, Inc. Treatment of rb-negative tumors using topoisomerase inhibitors in combination with cyclin dependent kinase 4/6 inhibitors
US20160220569A1 (en) 2015-02-03 2016-08-04 G1 Therapeutics, Inc. CDK4/6 Inhibitor Dosage Formulations For The Protection Of Hematopoietic Stem And Progenitor Cells During Chemotherapy

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20130237544A1 (en) * 2010-10-25 2013-09-12 G1 Therapeutics, Inc. Cdk inhibitors

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
Decker et al. BJH, 2004, Vol. 125, pgs. 141-148. *

Cited By (41)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9259399B2 (en) 2007-11-07 2016-02-16 Cornell University Targeting CDK4 and CDK6 in cancer therapy
US9745316B2 (en) 2012-03-29 2017-08-29 G1 Therapeutics, Inc. Lactam kinase inhibitors
US10464940B2 (en) 2012-03-29 2019-11-05 GI Therapeutics, Inc. Lactam kinase inhibitors
US9856268B2 (en) 2012-03-29 2018-01-02 G1 Therapeutics, Inc. Lactam kinase inhibitors
US10076523B2 (en) 2013-03-15 2018-09-18 G1 Therapeutics, Inc. HSPC-sparing treatments for RB-positive abnormal cellular proliferation
US10085992B2 (en) 2013-03-15 2018-10-02 G1 Therapeutics, Inc. Transient protection of normal cells during chemotherapy
US9527857B2 (en) 2013-03-15 2016-12-27 GI Therapeutics, Inc. HSPC-sparing treatments for RB-positive abnormal cellular proliferation
US11717523B2 (en) 2013-03-15 2023-08-08 G1 Therapeutics, Inc. Transient protection of normal cells during chemotherapy
US9931345B2 (en) 2013-03-15 2018-04-03 Presidents And Fellows Of Harvard College Transient protection of normal cells during chemotherapy
US11654148B2 (en) 2013-03-15 2023-05-23 G1 Therapeutics, Inc. HSPC-sparing treatments for RB-positive abnormal cellular proliferation
US10660896B2 (en) 2013-03-15 2020-05-26 GI Therapeutics, Inc. Transient protection of normal cells during chemotherapy
US9464092B2 (en) 2013-03-15 2016-10-11 G1 Therapeutics, Inc. Transient protection of normal cells during chemotherapy
US9487530B2 (en) 2013-03-15 2016-11-08 G1 Therapeutics, Inc. Transient protection of normal cells during chemotherapy
US11040042B2 (en) 2013-03-15 2021-06-22 G1 Therapeutics, Inc. Transient protection of normal cells during chemotherapy
US10966984B2 (en) 2013-03-15 2021-04-06 G1 Therapeutics, Inc. Transient protection of normal cells during chemotherapy
US10434104B2 (en) 2013-03-15 2019-10-08 G1 Therapeutics, Inc. HSPC-sparing treatments for Rb-positive abnormal cellular proliferation
US10925878B2 (en) 2013-03-15 2021-02-23 G1 Therapeutics, Inc. HSPC-sparing treatments for RB-positive abnormal cellular proliferation
US10709711B2 (en) 2013-03-15 2020-07-14 G1 Therapeutics, Inc. Highly active anti-neoplastic and anti-proliferative agents
US10376519B2 (en) 2014-04-17 2019-08-13 G1 Therapeutics, Inc. Tricyclic lactams for use in HSPC-sparing treatments for Rb-positive abnormal cellular proliferation
US9717735B2 (en) 2014-04-17 2017-08-01 G1 Therapeutics, Inc. Tricyclic lactams for use in HSPC-sparing treatments for RB-positive abnormal cellular proliferation
US11090306B2 (en) 2014-09-12 2021-08-17 G1 Therapeutics, Inc. Treatment of Rb-negative tumors using topoisomerase inhibitors in combination with cyclin dependent kinase 4/6 inhibitors
US10413547B2 (en) 2014-09-12 2019-09-17 G1 Therapeutics, Inc. Treatment of Rb-negative tumors using topoisomerase with cyclin dependent kinase 4/6 inhibitors
US11446295B2 (en) 2014-09-12 2022-09-20 G1 Therapeutics, Inc. Anti-neoplastic combinations and dosing regimens using CDK4/6 inhibitor compounds to treat Rb-positive tumors
US10231969B2 (en) 2014-09-12 2019-03-19 GI Therapeutics, Inc. Anti-neoplastic combinations and dosing regimens using CDK4/6 inhibitor compounds to treat RB-positive tumors
US20190119294A1 (en) * 2016-07-01 2019-04-25 G1 Therapeutics, Inc. Pyrimidine-based compounds for the treatment of cancer
US10618905B2 (en) * 2016-07-01 2020-04-14 G1 Therapeutics, Inc. Pyrimidine-based compounds for the treatment of cancer
US10654831B2 (en) 2016-07-01 2020-05-19 G1 Therapeutics, Inc. Antiproliferative pyrimidine-based compounds
WO2018005533A1 (en) * 2016-07-01 2018-01-04 G1 Therapeutics, Inc. Antiproliferative pyrimidine-based compounds
US11529352B2 (en) 2016-12-05 2022-12-20 G1 Therapeutics, Inc. Preservation of immune response during chemotherapy regimens
RU2810487C2 (ru) * 2017-01-06 2023-12-27 Г1 Терапьютикс, Инк. Комплексная терапия для лечения рака
TWI823845B (zh) * 2017-01-06 2023-12-01 美商G1治療公司 用於治療癌症的組合療法
WO2018129387A1 (en) * 2017-01-06 2018-07-12 G1 Therapeutics, Inc. Combination therapy for the treatment of cancer
CN110177554A (zh) * 2017-01-06 2019-08-27 G1治疗公司 用于治疗癌症的组合疗法
IL267795B (he) * 2017-01-06 2022-10-01 G1 Therapeutics Inc טיפול משולב לטיפול בסרטן
IL267795B2 (he) * 2017-01-06 2023-02-01 G1 Therapeutics Inc טיפול משולב לטיפול בסרטן
US11395821B2 (en) 2017-01-30 2022-07-26 G1 Therapeutics, Inc. Treatment of EGFR-driven cancer with fewer side effects
US10550103B2 (en) 2017-12-29 2020-02-04 Accutar Biotechnology Dual inhibitors of PARP1 and CDK
WO2019133864A1 (en) * 2017-12-29 2019-07-04 Accutar Biotechnology DUAL INHIBITORS OF PARP1 and CDK
US10519136B2 (en) 2017-12-29 2019-12-31 Accutar Biotechnology Dual inhibitors of PARP1 and CDK
US11642342B2 (en) 2019-12-23 2023-05-09 Accutar Biotechnology Combinations of estrogen receptor degraders and cyclin-dependent kinase inhibitors for treating cancer
US10988479B1 (en) 2020-06-15 2021-04-27 G1 Therapeutics, Inc. Morphic forms of trilaciclib and methods of manufacture thereof

Also Published As

Publication number Publication date
US20160310499A1 (en) 2016-10-27
JP2019094324A (ja) 2019-06-20
CN107417691A (zh) 2017-12-01
CA2906157A1 (en) 2014-09-18
US20180015096A1 (en) 2018-01-18
JP6703583B2 (ja) 2020-06-03
WO2014144740A3 (en) 2014-11-27
US20190125752A1 (en) 2019-05-02
JP2020128408A (ja) 2020-08-27
US10709711B2 (en) 2020-07-14
CN105407723A (zh) 2016-03-16
JP6435315B2 (ja) 2018-12-05
US20200345743A1 (en) 2020-11-05
CA3152117A1 (en) 2014-09-18
CN107417691B (zh) 2020-06-26
CA2906157C (en) 2022-05-17
WO2014144740A2 (en) 2014-09-18
EP2967050A4 (en) 2016-09-28
HK1222766A1 (zh) 2017-07-14
EP2967050A2 (en) 2016-01-20
JP2016518337A (ja) 2016-06-23
US20230248733A1 (en) 2023-08-10

Similar Documents

Publication Publication Date Title
US10709711B2 (en) Highly active anti-neoplastic and anti-proliferative agents
US11654148B2 (en) HSPC-sparing treatments for RB-positive abnormal cellular proliferation
US11090306B2 (en) Treatment of Rb-negative tumors using topoisomerase inhibitors in combination with cyclin dependent kinase 4/6 inhibitors
US11446295B2 (en) Anti-neoplastic combinations and dosing regimens using CDK4/6 inhibitor compounds to treat Rb-positive tumors
US20150297608A1 (en) Tricyclic Lactams for Use as Anti-Neoplastic and Anti-Proliferative Agents

Legal Events

Date Code Title Description
AS Assignment

Owner name: G1 THERAPEUTICS, INC., NORTH CAROLINA

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:STRUM, JAY COPELAND;BISI, JOHN EMERSON;ROBERTS, PATRICK JOSEPH;AND OTHERS;SIGNING DATES FROM 20140312 TO 20140313;REEL/FRAME:039068/0136

STCB Information on status: application discontinuation

Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION

AS Assignment

Owner name: G1 THERAPEUTICS, INC., NORTH CAROLINA

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:STRUM, JAY COPELAND;BISI, JOHN EMERSON;ROBERTS, PATRICK JOSEPH;REEL/FRAME:055650/0951

Effective date: 20210210

AS Assignment

Owner name: G1 THERAPEUTICS, INC., NORTH CAROLINA

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:TAVARES, FRANCIS X.;REEL/FRAME:055725/0654

Effective date: 20210322

AS Assignment

Owner name: G1 THERAPEUTICS, INC., NORTH CAROLINA

Free format text: CORRECTIVE ASSIGNMENT TO CORRECT THE ASSIGNEE ADDRESS PREVIOUSLY RECORDED AT REEL: 055725 FRAME: 0654. ASSIGNOR(S) HEREBY CONFIRMS THE ASSIGNMENT;ASSIGNOR:TAVARES, FRANCIS X.;REEL/FRAME:055748/0173

Effective date: 20210322