US20080021020A1 - 2,4-Pyrimidinediamine Compounds And Uses As Anti-Proliferative Agents - Google Patents

2,4-Pyrimidinediamine Compounds And Uses As Anti-Proliferative Agents Download PDF

Info

Publication number
US20080021020A1
US20080021020A1 US11/567,817 US56781706A US2008021020A1 US 20080021020 A1 US20080021020 A1 US 20080021020A1 US 56781706 A US56781706 A US 56781706A US 2008021020 A1 US2008021020 A1 US 2008021020A1
Authority
US
United States
Prior art keywords
hydrogen
methyl
group
ome
lower alkyl
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
US11/567,817
Inventor
Ankush Argade
Rajinder Singh
Hui Li
David Carroll
Susan Catalano
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.)
Rigel Pharmaceuticals Inc
Original Assignee
Rigel Pharmaceuticals 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 Rigel Pharmaceuticals Inc filed Critical Rigel Pharmaceuticals Inc
Priority to US11/567,817 priority Critical patent/US20080021020A1/en
Assigned to RIGEL PHARMACEUTICALS, INC. reassignment RIGEL PHARMACEUTICALS, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: CATALANO, SUSAN, ARGADE, ANKUSH, CARROLL, DAVID, LI, HUI, SINGH, RAJINDER
Publication of US20080021020A1 publication Critical patent/US20080021020A1/en
Abandoned legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic 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
    • A61K31/495—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
    • 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
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • 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
    • A61P35/04—Antineoplastic agents specific for metastasis
    • 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
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/48—Two nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • the present invention relates to 2,4 pyrimidinediamine compounds that exhibit antiproliferative activity, prodrugs of the compounds, intermediates and methods of synthesis for making the compounds and/or prodrugs, pharmaceutical compositions comprising the compounds acid the use of the compounds in a variety of contexts, including for the treatment of proliferative disorders) such as, for example, tumors and cancers.
  • Cancer is a group of varied diseases characterized by uncontrolled growth and spread of abnormal cells. Generally, all types of cancers involve some abnormality hi the control of cell growth and division. The pathways regulating cell division and/or cellular communication become altered in cancer cells such that the effects of these regulatory mechanisms in controlling and limiting cell growth fails or is bypassed.
  • a group of abnormal cells generally originating from a single mutant cell, accumulates additional mutations that provide selective growth advantage over other cells, and thus evolves into a cell type that predominates in the cell mass. This process of mutation and natural selection is enhanced by genetic instability displayed by many types of cancer cells, an instability which is gained either from somatic mutations or by inheritance from the germ line.
  • the enhanced mutability of cancerous cells increases the probability of their progression towards formation of malignant cells.
  • chemotherapeutic treatments have been developed based on knowledge of how cancer cells develop, for example, the anti-estrogen compound tamoxifen, the effectiveness of all chemotherapeutic treatments are subject to development of resistance to the drugs.
  • the increased expression of cell membrane bound transporters, such as MdrI produces a multidrug resistance phenotype characterized by increased efflux of drugs from the cell.
  • MdrI cell membrane bound transporters
  • identification of other chemotherapeutic agents is critical for establishing therapies effective for attacking the heterogeneous nature of proliferative disease and for overcoming any resistance that may develop over the course of therapy with other compounds.
  • use of combinations of chemotherapeutic agents with differing properties and cellular targets increases the effectiveness of chemotherapy and limits the generation of drug resistance.
  • the present invention provides 2,4-pyrimidinediamine compounds that exhibit antiproliferative activity against a variety of different cell types, including a variety of different types of tumor cells.
  • the compounds are generally 2,4-pyrimidinediamine compounds according to structural formula (I):
  • the present invention provides prodrugs of the 2,4-pyrimidinediamine compounds.
  • Such prodrugs may be active in their prodrug form, or may be inactive until converted under physiological or other conditions of use to an active drug form.
  • one or more functional groups of the 2,4-pyrimidinediamine compounds are included in promoieties that cleave from the molecule under the conditions of use, typically by way of hydrolysis, enzymatic cleavage or some other cleavage mechanism, to yield the functional groups.
  • promoieties that cleave from the molecule under the conditions of use, typically by way of hydrolysis, enzymatic cleavage or some other cleavage mechanism, to yield the functional groups.
  • primary or secondary amino groups may be included in an amide promoiety that cleaves under conditions of use to generate the primary or secondary amino group.
  • the prodrugs include special types of protecting groups, termed “progroups,” masking one or more functional groups of the 2,4-pyrimidinediamine compounds that cleave under the conditions of use to yield an active 2,4-pyrimidinediamine drug compound.
  • Functional groups within the 2,4-pyrimidinediamine compounds that may be masked with progroups for inclusion in a promoiety include, but are not limited to, amines (primary and secondary), hydroxyls, sulfanyls (thiols), carboxyls, carbonyls, phenols, catechols, diols, alkynes, phosphates, etc.
  • promoieties suitable for masking such functional groups to yield promoieties that are cleavable under the desired conditions of use are known in the art. All of these progroups, alone or in combinations, may be included in the prodrugs. Specific examples of promoieties that yield primary or secondary amine groups that can be included in the prodrugs include, but are not limited to amides, carbamates, imines, ureas, phosphenyls, phosphoryls and sulfenyls.
  • promoieties that yield sulfanyl groups that can be included in the prodrugs include, but are not limited to, thioethers, for example S-methyl derivatives (monothio, dithio, oxythio, aminothio acetals), silyl thioethers, thioesters, thiocarbonates, thiocarbamates, asymmetrical disulfides, etc.
  • promoieties that cleave to yield hydroxyl groups that can be included in the prodrugs include, but are not limited to, sulfonates, esters and carbonates.
  • promoieties that yield carboxyl groups include, but are not limited to, esters (including silyl esters, oxamic acid esters and thioesters), amides and hydrazides.
  • the present invention provides compositions comprising one or more 2,4-pyrimidinediamine compounds and/or prodrugs and an appropriate carrier, excipient and/or diluent.
  • an appropriate carrier, excipient and/or diluent will depend upon the desired use for the composition, and may range from being suitable or acceptable for veterinary uses to being suitable or acceptable for human use.
  • the 2,4-pyrimidinediamine compounds are potent inhibitors of proliferation abnormal cells, such as tumor cell proliferation, in in vitro assays.
  • the present invention provides methods of inhibiting proliferation of abnormal cells, in particular tumor cells.
  • the method generally involves contacting an abnormal cell such as a tumor cells with an amount of a 2,4-pyrimidinediamine compound or prodrug, or an acceptable salt, hydrate, solvate, N-oxide and/or composition thereof effective to inhibit its proliferations
  • the method may be practiced in in vitro contexts or in in vivo contexts as a therapeutic approach towards the treatment or prevention of proliferative disorders, such as tumorigenic cancers.
  • the present invention provides methods of treating proliferative disorders.
  • the methods may be practiced in animals in veterinary contexts or in humans.
  • the methods generally involve administering to an animal or human subject an amount of a 2,4-pyrimidinediamine compound or prodrug, or an acceptable salt, hydrate, solvate, N-oxide and/or composition thereof, effective to treat the disorder.
  • Proliferative disorders that can be treated according to the methods include, but are not limited to, tumorigenic cancers.
  • Alkyl by itself or as part of another substituent refers to a saturated or unsaturated branched, straight-chain or cyclic monovalent hydrocarbon radical having the stated number of carbon atoms (i.e., C1-C6 means one to six carbon atoms) that is derived by the removal of one hydrogen atom from a single carbon atom of a parent alkane, alkene or alkyne.
  • Typical alkyl groups include, but are not limited to, methyl; ethyls such as ethanyl, ethenyl, ethynyl; propyls such as propan-1-yl, propan-2-yl, cyclopropan-1-yl, prop-1-en-1-yl, prop-1-en-2-yl, prop-2-en-1-yl, cycloprop-1-en-1-yl; cycloprop-2-en-1-yl, prop-1-yl-1-yl, prop-2-yn-1-yl, etc.; butyls such as butan-1-yl, butan-2-yl, 2-methyl-propan-1-yl, 2-methyl-propan-2-yl, cyclobutan-1-yl, but-1-en-1-yl, but-1-en-2-yl, 2-methyl-prop-1-en-1-yl, but-2-en-2-yl, buta-1,3-die
  • alkanyl alkenyl
  • alkynyl alkynyl
  • Alkanyl by itself or as pail of another substituent refers to a saturated branched, straight-chain or cyclic alkyl derived by the removal of one hydrogen atom from a single carbon atom of a parent alkane.
  • Typical alkanyl groups include, but are not limited to, methanyl; ethanyl; propanyls such as propan-1-yl, propan-2-yl (isopropyl), cyclopropan-1-yl, etch; butanyls such as butan-1-yl, butan-2-yl (sec-butyl), 2-methyl-propan-1-yl (isobutyl), 2-methyl-propan-2-yl (t-butyl), cyclobutan-1-yl, etc.; and the like.
  • Alkenyl by itself or as part of another substituent refers to an unsaturated branched, straight-chain or cyclic alkyl having at least one carbon-carbon double bond derived by the removal of one hydrogen atom from a single carbon atom of a parent alkene.
  • the group may be in either the cis or trans conformation about the double bond(s).
  • Typical alkenyl groups include, but are not limited to, ethenyl; propenyls such as prop-1-en-1-yl, prop-1-en-2-yl, prop-2-en-1-yl, prop-2-en-2-yl, cycloprop-1-en-1-yl; cycloprop-2-en-1-yl; butenyls such as but-1-en-1-yl, but-1-en-2-yl, 2-methyl-prop-1-en-1-yl, but-2-en-1-yl, but-2-en-2-yl, buta-1,3-dien-1-yl, buta-1,3-dien-2-yl, cyclobut-1-en-1-yl, cyclobut-1-en-3-yl, cyclobuta-1,3-dien-1-yl, etc.; and the like.
  • Alkynyl by itself or as part of another substituent refers to an unsaturated branched, straight-chain or cyclic alkyl having at least one carbon-carbon triple bond derived by the removal of one hydrogen atom from a single carbon atom of a parent alkyne.
  • Typical alkynyl groups include, but are not limited to, ethynyl; propynyls such as prop-1-yn-1-yl, prop-2-yn-1-yl, etc.; butynyls such as but-1-yn-1-yl, but-1-yn-3-yl, but-3-yn-1-yl, etc.; and the like.
  • Alkyldiyl by itself or as part of another substituent refers to a saturated or unsaturated, branched, straight-chain or cyclic divalent hydrocarbon group having the stated number of carbon atoms (i.e., C1-C6 means from one to six carbon atoms) derived by the removal of one hydrogen atom from each of two different carbon atoms of a parent alkane, alkene or alkyne, or by the removal of two hydrogen atoms from a single carbon atom of a parent alkane, alkene or alkyne.
  • the two monovalent radical centers or each valency of the divalent radical center can form bonds with the same or different atoms.
  • Typical alkyldiyl groups include, but are not limited to, methandiyl; ethyldiyls such as ethan-1,1-diyl, ethan-1,2-diyl, ethen-1,1-diyl, ethen-1,2-diyl; propyldiyls such as propan-1,1-diyl, propan-1,2-diyl, propan-2,2-diyl, propan-1,3-diyl, cyclopropan-1,1-diyl, cyclopropan-1,2-diyl, prop-1-en-1,1-diyl, prop-1-en-1,2-diyl, prop-2-en-1,2-diyl, prop-1-en-1,3-diyl, cycloprop-1-en-1,2-diyl, cycloprop-2-en-1,2-diyl, cycloprop-2-en-1,2-d
  • alkanyldiyl alkenyldiyl and/or alkynyldiyl
  • alkylidene alkylidene
  • the alkyldiyl groups are saturated acyclic alkaniyldiyl groups in which the radical centers are at the terminal carbons, e.g., methandiyl (methano); ethan-1,2-diyl (ethano); propan-1,3-diyl (propano); butan-1,4-diyl (butano); and the like (also referred to as alkylenes, defined infra).
  • Alkylene by itself or as part of another substituent refers to a straight-chain saturated or unsaturated alkyldiyl group having two terminal monovalent radical centers derived by the removal of one hydrogen atom from each of the two terminal carbon atoms of straight-chain parent alkane, alkene or alkyne.
  • the locant of a double bond or triple bond, if present, in a particular alkylene is indicated in square brackets.
  • Typical alkylene groups include, but are not limited to, methylene (methano); ethylenes such as ethano, etheno, ethyno; propylenes such as propano, prop[1]eno, propa[1,2]dieno, prop[1]yno, etc.; butylenes such as butano, but[1]eno, but[2]eno, buta[1,3]dieno, but[1]yno, but[2]yno, buta[1,3]diyno, etc.; and the like. Where specific levels of saturation are intended, the nomenclature alkano, alkeno and/or alkyno is used.
  • the alkylene group is (C1-C6) or (C1-C3) alkylene. Also preferred are straight-chain saturated alkano groups, e.g., methanol ethano, propano, butano, and the like.
  • Cycloalkyl by itself or as part of another substituent refers to a cyclic version of an “alkyl” group.
  • Typical cycloalkyl groups include, but are not limited to, cyclopropyl; cyclobutyls such as cyclobutanyl and cyclobutenyl; cyclopentyls such as cyclopentanyl and cyclopentenyl; cyclohexyls such as cyclohexanyl and cyclohexenyl; and the like, “Lower cycloalkyl” refers to a cycloalkyl group having from 3 to 8 ring carbon atoms.
  • Cycloalkylalkyl by itself or as part of another substitutent refers to an alkyl group that comprises a linear or branched portion and a cyclic portion.
  • Typical cycloalkylalkyl groups include, but are not limited to, cyclopropylmethyl, 1-cyclopropyleth-1-yl, 2-cyclopropyleth-1-yl, cyclobutylmethyl, 1-cyclobytyleth-1-yl, 2-cyclobutyleth-1-yl, cyclopentylmethyl, 1-cyclopentyleth-1-yl, 2-cyclopentyleth-1-yl, cyclohexylmethyl, 1-cyclohexyleth-1-yl, 2-cyclohexteth-1-yl, and the like.
  • “Lower cycloalkylalkyl” refers to a cycloalkylalkyl group in which the linear or branched portion contains from 1 to 4 carbon atoms and the cycl
  • Heteroalkyl by itself or as part of another substituent refers to an alkyl group in which at least one of the carbon atoms is replaced with a heteroatom, for example, a heteroatom selected from O, S and N. In heteroalkyl groups including more than one heteroatom, the heteroatoms may be the same or they may be different. Like an alkyl group, a heteroalkyl can be linear, branched or cyclic in structure, and can be saturated or unsaturated. Typical heteralkyl groups include, but are not limited to, and the like. Where specific levels of saturation are intended, the nomenclature “heteroalkanyl,” “heteroalkenyl,” and heteroalkynyl” is used. “Lower heteroalkyl” refers to a heteroalkyl group having from 1 to 8 carbon and heteroatoms.
  • Cycloheteroalkyl by itself or as part of another substituent refers to a cyclic version of a heteroalkyl. Typical examples of cycloheteroalkyl groups include, but are not limited to, and the like. “Lower cycloheteroalkyl” refers to a cycloheteroalkyl group having from 3 to 8 ring atoms.
  • Parent aromatic Ring System refers to an unsaturated cyclic or polycyclic ring system having a conjugated ⁇ electron system.
  • parent aromatic ring system fused ring systems in which one or more of the rings are aromatic and one or more of the rings are saturated or unsaturated, such as, for example, fluorene, indane, indene, phenalene, tetrahydronaphthalene, etc.
  • Typical parent aromatic ring systems include, but are not limited to, aceanthrylene, acenaphthylene, acephenanthlylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexylene, indacene, s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene, tetrahydronaphthalene, triphenylene, trinaphthalene, and the like, as well as
  • Aryl by itself or as part of another substituent refers to a mionovalenit aromatic hydrocarbon group having the stated number of carbon atoms (i.e., C5-C15 means from 5 to 15 carbon atoms) derived by the removal of one hydrogen atom from a single carbon atom of a parent aromatic ring system.
  • Typical aryl groups include, but are not limited to, groups derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexylene, as-indacene, s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene, trinaphthalene, and the like, as well as the various hydro isomers
  • Halogen or “Halo” by themselves or as part of another substituent, unless otherwise stated, refer to fluoro, chloro, bromo and iodo.
  • Haloalkyl by itself or as part of another substituent refers to an alkyl group in which one or more of the hydrogen atoms is replaced with a halogen.
  • haloalkyl is meant to include monohaloalkyls, dihaloalkyls, trihaloalkyls, etc. up to perhaloalkyls.
  • (C1-C2) haloalkyl includes fluoromethyl, difluoromethyl, trifluoromethyl, 1-fluoroethyl, 1,1-difluoroethyl, 1,2-difluoroethyl, 1,1,1-trifluoroethyl, perfluoroethyl, etc.
  • alkyloxy or “alkoxy” refers to a group of the formula —OR
  • alkylamine refers to a group of the formula —NHR
  • dialkylamine refers to a group of the formula —NRR, where each R is independently an alkyl.
  • haloalkoxy or “haloalkyloxy” refers to a group of the formula —OR′, where R′ is a haloalkyl.
  • Prodrug refers to a derivative of an active 2,4-pyrimidinediamine compound (drug) that may require a transformation under the conditions of use, such as within the body, to release the active 2,4-pyrimidinediamine drug.
  • Prodrugs are frequently, but not necessarily, pharmacologically inactive until converted into the active drug.
  • Prodrugs are typically obtained by masking a functional group in the 2,4-pyrimidinediamine drug believed to be in part required for activity with a progroup (defined below) to form a promoiety which undergoes a transformation, such as cleavage, under the specified conditions of use to release the functional group, and hence the active 2,4-pyrimidinediamine drug.
  • the cleavage of the promoiety may proceed spontaneously, such as by way of a hydrolysis reaction, or it may be catalyzed or induced by another agent, such as by an enzyme, by light, by acid or base, or by a change of or exposure to a physical or environmental parameter, such as a change of temperature.
  • the agent may be endogenous to the conditions of use, such as an enzyme present in the cells to which the prodrug is administered or the acidic conditions of the stomach, or it may be supplied exogenously.
  • progroups as well as the resultant promoieties, suitable for masking functional groups in the active 2,4-pyrimidinediamines compounds to yield prodrugs are well-known in the art.
  • a hydroxyl functional group may be masked as a sulfonate, ester or carbonate promoiety, which may be hydrolyzed in vivo to provide the hydroxyl group.
  • An amino functional group may be masked as an amide, carbamate, imine, urea, phosphenyl, phosphoryl or sulfenyl promoiety, which may be hydrolyzed in viva to provide the amino group.
  • a carboxyl group may be masked as an ester (including silyl esters and thioesters), amide or hydrazide promoiety, which may be hydrolyzed in vivo to provide the carboxyl group.
  • ester including silyl esters and thioesters
  • amide or hydrazide promoiety which may be hydrolyzed in vivo to provide the carboxyl group.
  • suitable progroups and their respective promoieties will be apparent to those of skill in the art.
  • Progroup refers to a type of protecting group that, when used to mask a functional group within an active 2,4-pyrimidinediamine drug to form a promoiety, converts the drug into a prodrug.
  • Progroups are typically attached to the functional group of the drug via bonds that are cleavable under specified conditions of use.
  • a progroup is that portion of a promoiety that cleaves to release the functional group under the specified conditions of use.
  • an amide promoiety of the formula —NH—C(O)CH 3 comprises the progroup —C(O)CH 3 .
  • Proliferative disorder refers to a disease or disorder characterized by aberrant cell proliferation, for example where cells divide more than their counterpart normal cells.
  • the aberrant proliferation may be caused by any mechanism of action or combination of mechanisms of action.
  • the cell cycle of one or more cells may be affected such that cell(s) divide more frequently than their counterpart normal cells, or alternatively, one or more cells may bypass inhibitory signals which would normally limit their number of divisions.
  • Proliferative diseases include, but are not limited to, slow or fast growing tumors and cancers.
  • Antiproliferative compound refers to a compound that inhibits the proliferation of a cell as compared to an untreated control cell of a similar type.
  • the inhibition can be brought about by any mechanism or combination of mechanisms, and may operate to inhibit proliferation cytostatically or cytotoxically.
  • inhibition as used herein includes, but is not limited to, arrest of cell division, a reduction in the rate of cell division, proliferation and/or growth and/or induction of cell death.
  • “Pharmaceutically effective amount” or “therapeutically effective amount” refers to an amount of a compound sufficient to treat a specified disorder or disease or one or more of its symptoms and/or to prevent the occurrence of the disease or disorder.
  • a pharmaceutically or therapeutically effective amount comprises an amount sufficient to, among other things, cause the tumor to shrink or to decrease the growth rate of the tumor.
  • the antiproliferative compounds are generally 2,4-pyrimidinediamine compounds according to structural formula (I):
  • An important class of compounds of structural formula (I) includes compounds in which L 1 and L 2 are each a covalent bond, such that the compound is a 2,4-pyrimidine diamine according to structural formula (II):
  • An important class of compounds of structural formulae (I) and/or (II) and the salts, hydrates, solvates and N-oxides thereof, includes compounds in which R 5 is fluoro.
  • Another important class of compounds of structural formulae (I) and/or (II) and the salts, hydrates, solvates and N-oxides thereof, includes compounds in which R 2 ′ is hydrogen.
  • R 2 ′ and R 4 ′ are each, independently of one another, selected from hydrogen and methyl.
  • Another important class of compounds of structural formulae (I) and/or (II) and the salts, hydrates, solvates and N-oxides thereof, includes compounds in which R 4 ′ is methyl.
  • R 9 and R 10 are not both simultaneously lower alkoxy or methoxy. In other embodiments, R 8 , R 9 and R 10 are not each simultaneously lower alkoxy or methoxy. In still other embodiments R 8 , R 9 and R 10 are each methoxy or lower alkoxy.
  • R 9 is selected from hydrogen, lower alkyl, lower alkoxy, —OR a , halo, —CF 3 and —OCF 3 and one of R 9 or R 10 is selected from In a specific embodiment, the other one of R 9 or R 10 is other than In yet other embodiments, R 8 is selected from hydrogen, lower alkyl, —OR a , halo, —CF 3 and —OCF 3 and one of R 9 or R 10 is selected from —OCH 2 C(O)R a , —OCH 2 C(O)OR a , —OCH 2 C(O)NHR d , —OCH 2 C(O)NHR d and —OCH 2 C(O)NR c R c .
  • the other one of R 9 or R 10 is other than —OCH 2 C(O)R a , OCH 2 C(O)OR a , —OCH 2 C(O)NHR a , —OCH 2 C(O)NHR d or —OCH 2 C(O)NR c R c .
  • R 8 and R 9 are each, independently of one another, selected from hydrogen, lower alkyl, —OR a , halo, —CF 3 and OR a and R 10 is In yet other embodiments R 9 is hydrogen and R 8 and R 10 are each, independently of one another, selected from the group consisting of lower alkyl, methyl, lower alkoxy, methoxy, —CF 3 and —OCF 3 . Specific combinations of R 8 and R 10 when R 9 is hydrogen are as follows:
  • R 9 is hydroxy, methoxy or chloro and R 8 and R 10 are each, independently of one another, selected from the group consisting of lower alkyl, methyl, lower alkoxy, methoxy and chloro.
  • R 8 , R 9 and R 10 are as follows:
  • R 2 and R 4 are each in the compounds described herein, such as, for example, the compounds of structural formulae (I)-(V), in some embodiments no more than one of R 8 , R 9 and R 10 of the R 4 phenyl is hydrogen unless at least one of R 8 , R 9 or R 10 of the R 2 phenyl is —O(CH 2 ) n —NR c R c , In other embodiments, the substitution patterns of the R 2 and R 4 phenyl rings are different from each other such that the compound is not a N2,N4-bis(3,4,5-substituted phenyl)pyrimidinediamine.
  • the compound is a compound according to structural formula (VI): including the salts, hydrates, solvates and N-oxides thereof wherein R 4 ′, R 8 , R 9 and R 10 are as previously defined for structural formula (I).
  • R 2 and R 4 are each R 8 , R 9 and R 10 are selected such that each R 2 and R 4 phenyl ring is mono-substituted.
  • R 2 and R 4 are each R 8 , R 9 and R 10 are selected such that each R 2 and R 4 phenyl ring is di-substituted. In one specific embodiment, each R 2 and R 4 phenyl ring is substituted with an ethylenedioxy acetal group.
  • R 2 and R 4 when R 2 and R 4 are each R 10 of the R 2 or R 4 ring is other than 1,3-oxazolyl or 1,3-oxazol-5-yl when the R 8 and R 9 of the same ring are each hydrogen.
  • R 8 , R 9 and R 10 are as defined in the preceeding sentence when R 5 is fluoro and L 2 is a lower alkylene.
  • R 2 is other than 3-(1,3-oxazolyl)phenyl or 3-(1,3-oxazol-5-yl)phenyl when R 4 is 2-(trifluoromethyl)benzyl.
  • the compound is other than N2-[3-(1,3-oxazolyl)phenyl]-N4-[2-trifluoromethy)lbenzyl]-5-fluoro-2,4-pyrimidinediamine.
  • R 10 is an oxazolyl
  • the oxazolyl is not connected at the 5 position.
  • the oxazole is connected at the 2 position.
  • the compound is not any compound described in WO 03/040141, the disclosure of which is incorporated herein by reference.
  • R 9 or R 10 is selected from where R 12 is as previously defined for structural formula (I) and the other one of R 9 or R 10 is other than
  • R 8 is selected from hydrogen, lower alkyl, methyl, lower alkoxy, methoxy and halo and one of R 9 or R 10 is —OCH 2 —R b , where R b is selected from —C(O)NR a and —C(O)NHR a , and the other one of R 9 or R 10 is selected from hydrogen, lower alkyl, methyl, lower alkoxy, methoxy and halo.
  • R 2 is where R 8 is hydrogen, fluoro or CF 3 .
  • R 2 is
  • R 8 and R 9 are each independently selected from hydrogen, lower alkyl, methyl, lower alkoxy, methoxy, halo and chloro.
  • R 8 , R 9 and R 13 are each independently selected from halo, lower alkyl, methyl, lower alkoxy, and methoxy.
  • R 2 is selected from
  • R 4 is selected from where D is as previously defined for structural formula (I).
  • R 4 is where Z 1 , Z 2 and R 16 , R 17 , R 18 , R 19 and R 20 are as previously described for structural formula (I).
  • R 12 is methyl.
  • R 12 is —C(O)R a or —C(O)OR a , where R a is lower alkyl, ethyl or methyl.
  • each R 13 is, independently or the other, selected from lower alkyl, methyl, hydroxy, lower alkoxy and methoxy; and/or (ii) R 4 is selected from where Z 1 , Z 2 and R 16 , R 17 , R 18 , R 19 and R 20 are as previously described for structural formula (I).
  • R 4 is where Z 1 is CH, R 16 is hydrogen R 17 and R 18 are taken together to form an oxo ( ⁇ O) group and R 19 and R 20 are each hydrogen or methyl; and R 2 is where each R 13 is, independently of the other, selected from lower alkyl, methyl, hydroxy, lower alkoxy and methoxy.
  • R 4 is where D is as previously defined for structural formula (I)
  • R 11 is selected from the group consisting of hydroxy, methoxy, ethoxy, —NHCH 3 , —NHCH 2 CH 2 OH, —NHCH 2 CH(OH)CH 2 OH, —NHCH 2 CH(OH)(CH 3 ) 2 , —N(CH 3 )CH 2 CH 2 OH and —N(CH 3 )C(CH 3 ) 2 CH 2 OH and Y is as previously defined.
  • R 2 is in the compounds described herein, such as the compounds of structural formulae (I)-(V), in some embodiments the ring is connected to the remainder of the molecule at the 5-position In other embodiments, it is connected to the remainder of the molecule at the 6-position
  • R 16 is selected from lower n-alkanyl, lower branched alkanyl, lower cycloalkanyl and lower cycloalkanylmethyl.
  • R 4 is selected from
  • R 4 is selected from lower cycloalkyl and lower cycloheteroalkyl optionally substituted at one or more ring carbon or heteroatoms with an R a or an R b group.
  • R 4 is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, where R e and R f are selected from (C1-C3) alkanyl and methyl and R g is benzyl.
  • each R e is methyl.
  • R f is ethyl.
  • R 4 is selected from lower alkyl, isopropyl, t-butyl, lower cycloalkyl, in the compounds described herein, such as, for example, the compounds of structural formulae (I)-(V), in some embodiments R 2 is selected from where R 8 , R 9 , R 10 and R 13 are as previously defined for structural formula (I). In a specific embodiment, R 2 is selected from any of the above-described embodiments of these substituted phenyls. In other embodiments, R 2 is where R 8 and R 9 are a previously defined for structural formula (I).
  • R 4 is where R 15 is lower branched alkyl or t-butyl, and R 2 is in the compounds described herein, such as, for example, the compounds of structural formulae (I)-(V), in some embodiments at least one of R 8 or R 10 is other than hydrogen. In other embodiments, at least two of R 8 , R 9 and R 10 are other than hydrogen. In still other embodiments, at least two of R 8 , R 9 and R 13 are other than hydrogen.
  • R 10 is hydrogen.
  • R 9 is hydrogen.
  • R 10 is other than lower branched alkyl, t-butyl or —O(CH 2 ) n R b , where n is as previously defined for structural formula (I) and R b is selected from NRCRA, —C(O)OR a , —C(O)NR c R c and —C(O)NR a R d .
  • R 8 is other than —O(CH 2 ) n R b , where it is as previously defined for structural formula (I) and R b is —NR c R c .
  • the compound is not any compound described in WO 01/64656, WO 03/026665 or WO 03/026666, the disclosures of which are incorporated herein by reference.
  • R 4 is —(CH 2 ) n —R b in the compounds described herein, such as, for example, the compounds of structural formulae (II)-(V), in some embodiments R b is selected from the group consisting of —OR a , —NR c R c , —C(O)R a and —C(O)NR c R c , where each R c is independently selected from hydrogen and lower alkyl.
  • R 4 is in the compounds described herein, such as, for example, the compounds of structural formulae (I)-(V) in some embodiments
  • R 2 is where R 9 is selected from the group consisting of —OR a , methoxy, isopropoxy, OCH 2 C(O)OR a , —OCH 2 C(O)NHR a , —OCH 2 C(O)NR a R a and —OCH 2 CH 2 NR a R a ; and R 8 and R 10 are as previously defined for structural formula (I).
  • R 8 and R 10 are selected from one of the following combinations:
  • R 4 is selected from lower alkyl optionally monosubstituted with an R b group, a lower cycloalkyl optionally monosubstituted with an R b group and C(R a R a ) n —R b , where, R a and R b are as previously defined for structural formula (I), and/or L 2 is a lower alkylene linker in the compounds described herein, in some embodiments, R 2 is other than mono-substituted phenyl, 3-hydroxyphenyl, 3-halophenyl, 3-chlorophenyl, 3-bromophenyl, 4-halophenyl, 4-chlorophenyl, 4-bromophenyl, 3,4-dihalophenyl, 3,4-dichlorophenyl or 3,4-dichlorophenyl.
  • R 2 is other than these defined groups in compounds in which R 5 is —CF 3 .
  • the compound is not any compound described in US 2003/0171359 and/or WO 03/032997, the disclosures of which are incorporated herein by reference.
  • R 9 and R 9 are non-bulky substitutents.
  • R 9 is other than and R 10 is other than
  • R 8 , R 9 and R 10 are each, independently of one another, selected from hydrogen lower alkyl, methyl hydroxy, lower alkoxy, methoxy, halo, fluoro and chloro.
  • R 8 is selected from hydrogen, lower alkyl, methyl, lower alkoxy and methoxy
  • R 9 is selected from hydrogen, lower alkoxy and methoxy
  • R 10 is selected from lower alkyl, methyl, lower alkoxy, methoxy, halo, fluoro and
  • R 4 is in some embodiments D is selected from the group consisting of —CH 2 —, —CF 2 —, —CH 2 CH 2 —, —CF 2 —CF 2 — and —CH 2 —CH 2 —CH 2 —.
  • the lower alkyl substituent or group is a saturated straight-chained, branched or cyclic alkyl (i.e., an alkanyl).
  • Type R 21 R 22 R 23 R 4′ A549 H1299 191 A H H H 192 A H H H 193 A H H H 194 A H H H 195 A H H H 196 A H H H 197 A H H H 198 A H H H H
  • Type A Type B No. Type R 4 R 21 R 22 R 23 A549 H1299 215 A i-propyl H H + + 216 A i-propyl H Cl + + 217 A i-propyl H Me + + 218 A i-propyl H CF 3 + + 219 A i-propyl H H + + 220 A t-butyl H H + + 221 A t-butyl H H + + 222 A t-butyl H Cl + + 223 A t-butyl H Me + + + 224 A t-butyl H CF 3 + + 225 B i-propyl H — + + 226 B t-butyl H — + + 227 B i-propyl Me — + + + + +
  • Type A Type B No. Type R 4′ R 4 Y R 11 A549 HTC116 H1299 617 A H NH OEt ⁇ 618 A H NH OEt + 619 A H O OMe ⁇ 620 A H O OMe 621 A H NH OH ⁇ 622 A H O OH ⁇ 623 A H O OMe ⁇ 624 A H O ⁇ 625 A H O + + 626 A H O ⁇ /+ + 627 A H O NHMe ⁇ 628 A H O NHMe ⁇ 629 A H O NHMe + + 630 A H O NH(CH 2 ) 2 OH ⁇ 631 A H O NH(CH 2 ) 2 OH + + 632 A H O + + 633 A H O + + 634 A H O + ⁇ 635 A H O + 636 A H O OMe + ⁇ 637 A H NH OEt 638 A H O OMe ⁇ 639 A H O OH ⁇ 640 A H O O
  • Type A Type B Type C Type D No. Type R 16 R 31 R 32 R 33 A549 H1299 1066 B ethyl H OMe Cl 1067 B ethyl H Cl Cl 1068 B ethyl — — — 1069 B ethyl H F OMe 1070 A ethyl H OMe Cl 1071 A ethyl H Cl Cl 1072 C ethyl — — — 1073 A ethyl H F OMe 1074 B n-propyl H OMe Cl + + 1075 B n-propyl H Cl Cl ⁇ ⁇ 1076 D n-propyl — — + + 1077 A n-propyl H F OMe + + 1078 B n-propyl H OMe Cl + + 1079 B n-propyl H Cl Cl + + 1080 C n-propyl — — + + + 1081 A n-propyl H F OM
  • the 2,4-pyrimidinediamine compounds described herein may include functional groups that can be masked with progroups to create prodrugs.
  • prodrugs are usually, but need not be, pharmacologically inactive until converted into their active drug form.
  • ester groups commonly undergo acid-catalyzed hydrolysis to yield the parent carboxylic acid when exposed to the acidic conditions of the stomach, or base-catalyzed hydrolysis when exposed to the basic conditions of the intestine or blood.
  • 2,4-pyimidinediamines that include ester moieties may be considered prodrugs of their corresponding carboxylic acid, regardless of whether the ester form is pharmacologically active.
  • any available functional moiety may be masked with a progroup to yield a prodrug.
  • Functional groups within the 2,4-pyrimidinediamine compounds that may be masked with progroups for inclusion in a promoiety include, but are not limited to, amines (primary and secondary), hydroxyls, sulfanyls (thiols), carboxyls, etc.
  • Myriad progroups suitable for masking such functional groups to yield promoieties that are cleavable under the desired conditions of use are known in the art. All of these progroups, alone or in combinations, may be included in the prodrugs of the invention.
  • the prodrugs are compounds according to structural formulae (I)-(VI) in which R a R b and R c may be, in addition to their previously-defined alternatives, a progroup.
  • the prodrugs are compounds according to structural formulae (I)-(VI) in which R 2 ′ and R 4 ′ are each, independently of one another, a progroup.
  • Specific examples of progroups according to this embodiment of the invention include, but are not limited to, —C(O)CH 3 , —C(O)NHR h and —S(O) 2 R h , where R h is selected from the group consisting of lower alyl, (C5-C15) aryl and (C3-C8) cycloalkyl.
  • the compounds and prodrugs described herein, as well as the various compound species specifically described and/or illustrated herein, may exhibit the phenomena of tautomerism, conformational isomerism, geometric isomerism and/or optical isomerism.
  • the compounds and prodrugs may include one or more chiral centers and/or double bonds and as a consequence may exist as stereoisomers, such as double-bond isomers (i.e., geometric isomers), enantiomers and diasteromers and mixtures thereof, such as racemic mixtures.
  • the compounds and prodrugs may exist in several tautomeric forms, including the enol form, the keto form and mixtures thereof.
  • the 2,4-pyrimidinediamine compounds and prodrugs may be in the form of salts.
  • Such salts include salts suitable for pharmaceutical uses (“pharmaceutically-acceptable salts”), salts suitable for veterinary uses, etc.
  • Such salts may be derived from acids or bases, as is well-known in the art.
  • the salt is a pharmaceutically acceptable salt.
  • pharmaceutically acceptable salts are those salts that retain substantially one or more of the desired pharmacological activities of the parent compound and which are suitable for administration to humans.
  • Pharmaceutically acceptable salts include acid addition salts formed with inorganic acids or organic acids.
  • Inorganic acids suitable for forming pharmaceutically acceptable acid addition salts include, by way of example and not limitation, hydrohalide acids (e.g., hydrochloric acid, hydrobromic acid, hydriodic, etc.), sulfuric acid, nitric acid, phosphoric acid, and the like.
  • Organic acids suitable for forming pharmaceutically acceptable acid addition salts include, by way of example and not limitation, acetic acid, trifluoroacetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, oxalic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, palmitic acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, alkylsulfonic acids (e.g., methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, etc.), arylsulfonic acids (e.g., benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenes
  • Pharmaceutically acceptable salts also include salts formed when an acidic proton present in the parent compound is either replaced by a metal ion (egg, an alkali metal ion, an alkaline earth metal ion or an aluminum ion) or coordinates with an organic base (e.g., ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, morpholine, piperidine, dimethylamine, diethylamine, etc.).
  • a metal ion egg, an alkali metal ion, an alkaline earth metal ion or an aluminum ion
  • organic base e.g., ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, morpholine, piperidine, dimethylamine, diethylamine, etc.
  • the 2,4-pyrimidinediamine compounds and prodrugs, as well as the salts thereof, may also be in the form of hydrates, solvates and N-oxides, as are well-known in the art.
  • the 2,4-pyrimidinediamine compounds and prodrugs may be synthesized via a variety of different synthetic routes using commercially available starting materials and/or starting materials prepared by conventional synthetic methods. Suitable exemplary methods that may be routinely adapted to synthesize the 2,4-pyrimidinediamine compounds and prodrugs are found in U.S. Pat. No. 5,958,935, the disclosure of which is incorporated herein by reference. Specific examples describing the synthesis of numerous 2,4-pyrimidinediamine compounds and prodrugs, as well as intermediates therefor, are described in copending U.S. application Ser. No. 10/355,543, filed Jan. 31, 2003 (US 2004-0029902 published Feb. 12, 2004), WO 03/63794, copending U.S. application Ser.
  • the compounds can be synthesized from substituted or unsubstituted uracils or thiouracils as illustrated in Scheme (I), below:
  • R 2 , R 4 , R 5 , R 6 , L 1 and L 2 are as previously defined for structural formulae (I),
  • X is a halogen (e.g., F, Cl, Br or I) and G and G′ are each, independently of one another, selected from the group consisting of O and S.
  • uracil or thiouracil 2 is dihalogenated at the 2- and 4-positions using standard halogenating agent POX 3 (or other standard halogenating agent) under standard conditions to yield 2,4-bishalo pyrimidine 4, Depending upon the R 5 substituent, in pyrimidine 4, the halide at the C4 position is more reactive towards nucleophiles than the halide at the C2 position.
  • standard halogenating agent POX 3 or other standard halogenating agent
  • the C4 halide is more reactive towards nucleophiles, as illustrated in the Scheme,
  • the identity of the R 5 substituent may alter this reactivity.
  • R 5 is trifluoromethyl
  • a 50:50 mixture of 4N-substituted-4-pyrimidineamine 8 and the corresponding 2N-substituted-2-pyrimidineamine is obtained Regardless of the identity of the R 5 substituent, the regioselectivity of the reaction can be controlled by adjusting the solvent and other synthetic conditions (such as temperature), as is well-known in the art.
  • the uracil or thiouracil 2 starting materials may be purchased from commercial sources or prepared using standard techniques of organic chemistry, Commercially available uracils and thiouracils that can be used as starting materials in Scheme (I) include, by way of example and not limitation, uracil (Aldrich #13,078-8; CAS Registry 66-22-8); 2-thio-uracil (Aldrich #11,558-4; CAS Registry 141-90-2); 2,4-dithiouracil (Aldrich #15,846-1; CAS Registry 2001-93-6); 5-bromouracil (Aldrich #85,247-3; CAS Registry 51-20-7; 5-fluorouracil (Aldrich #85,847-1; CAS Registry 51-21-8); 5-iodouracil (Aldrich #85,785-8; CAS Registry 696-07-1); 5-nitrouracil (Aldrich #85,276-7; CAS Registry 611-08-5); 5-(trifluoromethyl)-ura
  • Additional 5-substituted uracils and/or thiouracils are available from General Intermediates of Canada, Inc., Edmonton, Calif. (www.generalintermediates.com) and/or Interchim, Cedex, France (www.interchim.com), or may be prepared using standard techniques. Myriad textbook references teaching suitable synthetic methods are provided infra.
  • Amines 6 and 10 may be purchased from commercial sources or, alternatively, may be synthesized utilizing standard techniques. For example, suitable amines may be synthesized from nitro precursors using standard chemistry. Specific exemplary reactions are provided in the Examples section. See also Vogel, 1989 , Practical Organic Chemistry , Addison Wesley Longman, Ltd. and John Wiley & Sons, Inc.
  • amines 6 and 10 and/or substituents R 5 and/or R 6 on uracil or thiouracil 2 may include functional groups that require protection during synthesis.
  • the exact identity of any protecting group(s) used will depend upon the identity of the functional group being protected, and will be apparent to these of skill in the art.
  • Guidance for selecting appropriate protecting groups, as well as synthetic strategies for their attachment and removal, may be found, for example, in Greene & Wuts, Protective Groups in Organic Synthesis, 3d Edition, John Wiley & Sons, Inc., New York (1999) and the references cited therein (hereinafter “Greene & Wuts”).
  • non-bis-2N,4N-disubstituted-5-fluoro-2,4-pyrimidinediamine 9 may be obtained by reacting 2,4-dichloro-5-fluoropyrimidine 5 with one equivalent of amine 10 (to yield 2-chloro-N4-substituted-5-fluoro-4-pyrimidineamine 7) followed by one or more equivalents of amine 6.
  • 2,4-pyrimidinediamine compounds of the invention may be synthesized from substituted or unstibstituted cytosines as illustrated in Schemes (IIa) and (IIb), below:
  • Protected cytosine 22 is halogenated at the C2 position using a standard halogenation reagent under standard conditions to yield 2-chloro-4N-protected-4-pyrimidineamine 24 Reaction with amine 6 followed by deprotection of the C4 exocyclic amine and reaction with amine 10 yields a 2,4-pyrimidinediamine according to structural formulae (I).
  • cytosine 20 may be reacted with amine 10 or protected amine 21 to yield N4-substituted cytosine 23 or 27, respectively.
  • substituted cytosines may then be halogenated as previously described, deprotected (in the case of N4-substituted cytosine 27) and reacted with amine 6 to yield a 2,4-pyrimidinediamine according to structural formulae (I).
  • cytosines that may be used as starting materials in Schemes (IIa) and (IIb) include, but are not limited to, cytosine (Aldrich #14,201-8; CAS Registry 71-30-7); N 4 -acetylcytosine (Aldrich #37,791-0; CAS Registry 14631-20-0); 5-fluorocytosine (Aldrich #27,159-4; CAS Registry 2022-85-7); and 5-(trifluoromethyl)-cytosine.
  • suitable cytosines useful as starting materials in Schemes (IIa) are available from General Intermediates of Canada, Inc., Edmonton, Calif. (www.generalintermediates.com) and/or Interchim, Cedex, France (www.interchim.com), or may be prepared using standard techniques, Myriad textbook references teaching suitable synthetic methods are provided infra.
  • the 2,4-pyrimidinediamine compounds may be synthesized from substituted or unsubstituted 2-amino-4-pyrimidinols as illustrated in Scheme (III), below:
  • Suitable commercially-available 2-amino-4-pyrimidinols 30 that can be used as starting materials in Scheme (III) are available from General Intermediates of Canada, Inc, Edmonton, Calif. (www.generalintermediates.com) and/or Interchim, Cedex, France (www.interchim.com), or may be prepared using standard techniques. Myriad textbook references teaching suitable synthetic methods are provided infra.
  • 2,4-pyrimidinediamine compounds may be prepared from substituted or unsubstituted 4-amino-2-pyrimidinols as illustrated in Scheme (IV), below:
  • Compound 44 may include virtually any leaving group that can be displaced by the C4-amino of N2-substituted-2,4-pyrimidinediamine 42, Suitable leaving groups Z include, but are not limited to, halogens, methanesulfonyloxy (mesyloxy; “OMs”), trifluoromethanesulfonyloxy (“OTf”) and p-toluenesulfonyloxy (tosyloxy; “OTs”), benzene sulfonyloxy (“besylate”) and metanitro benzene sulfonyloxy (“nosylate”).
  • OMs methanesulfonyloxy
  • OTf trifluoromethanesulfonyloxy
  • OTs p-toluenesulfonyloxy
  • benzene sulfonyloxy besylate
  • metanitro benzene sulfonyloxy metanitro
  • Substituted 4-amino-2-pyrimidinol starting materials may be obtained commercially or synthesized using standard techniques. Myriad textbook references teaching suitable synthetic methods are provided infra.
  • the 2,4-pyrimidinediamine compounds can be prepared from 2-chloro-4-aminopyrimidines or 2-amino-4-chloropyrimidines as illustrated in Scheme (V), below:
  • pyrimidines 50 and 54 suitable for use as starting materials in Scheme (V) are commercially available from General Intermediates of Canada, Inc., Edmonton, Calif. (www.generalintermediates.com) and/or Interchim, Cedex, France (www.interchim.com), or may be prepared using standard techniques Myriad textbook references teaching suitable synthetic methods are provided infra.
  • 4-chloro-2-pyrimidineamines 50 may be prepared as illustrated in Scheme (Va):
  • R 5 and R 6 are as previously defined for structural formulae (I).
  • dicarbonyl 53 is reacted with guanidine to yield 2-pyrimidineamine 51
  • Reaction with peracids like m-chloroperbenzoic acid, trifluoroperacetic acid or urea hydrogen peroxide complex yields N-oxide 55, which is then halogenated to give 4-chloro-2-pyrimidineamine 50.
  • the corresponding 4-halo-2-pyrimidineamines may be obtained by using suitable halogenation reagents.
  • the 2,4-pyrimidinediamine compounds can be prepared from substituted or unsubstituted uridines as illustrated in Scheme (VI) below:
  • R 2 , R 4 , R 5 , R 6 , L 1 , L 2 and X are as previously defined for Scheme (I) and the superscript PG represents a protecting group, as discussed in connection with Scheme (IIb).
  • uridine 60 has a C4 reactive center such that reaction with amine 10 or protected amine 21 yields N4-substituted cytidine 62 or 64, respectively.
  • Acid-catalyzed deprotection of N4-substituted 62 or 64 yields N4-substituted cytosine 28, which may be subsequently halogenated at the C2-position and reacted with amine 6 to yield a 2,4-pyrimidinediamine according to structural formulae (I).
  • uridines and cytidines useful as starting materials in Schemes (VI) and (VII) are known in the art, and include, by way of example and not limitation, 5-trifluoromethyl-2′-deoxycytidine (Chem, Sources #ABCR F07669; CAS Registry 66,384-66-5); 5-bromouridine (Chem.
  • R 4 , R 5 , R 6 , L 1 , L 2 , Y, R a and R c are as previously defined for structural formulae (I).
  • Each R a ′ is independently an R 5 , and may be the same or different from the illustrated R a .
  • carboxylic acid or ester 100 may be converted to amide 104 by reaction with amine 102.
  • R a ′ may be the same or different than R a of acid or ester 100.
  • carbonate ester 106 may be converted to carbamate 108.
  • Prodrugs as described herein may be prepared by routine modification of the above-described methods, Alternatively, such prodrugs may be prepared by reacting a suitably protected 2,4-pyrimidinediamine of structural formula (I), (II), (III), (IV) and/or (V) with a suitable progroup. Conditions for carrying out such reactions and for deprotecting the product to yield a prodrugs as described herein are well-known.
  • Active 2,4-pyrimidinediamine compounds typically inhibit proliferation of desired cells, such as tumor cells, with an IC 50 in the range of about 1 mM or less, as measured in a standard in vitro cellular proliferation assay.
  • desired cells such as tumor cells
  • IC 50 in the range of about 1 mM or less, as measured in a standard in vitro cellular proliferation assay.
  • compounds which exhibit lower IC 50 s for example on the order of 100 P, 20 ⁇ M, 10 ⁇ M, 1 ⁇ M, 100 nM, 10 mM, 1 nM, or even lower, may be particularly useful in therapeutic applications.
  • the antiproliferative activity may be cytostatic or it may be cytotoxic.
  • the compound may be assayed for activity with the desired cell type and counter-screened for a lack of activity against other cell types.
  • the desired degree of “inactivity” in such counter screens, or the desired ratio of activity vs. inactivity may vary for different situations, and may be selected by the user.
  • the antiproliferative 2,4-pyrimidinediamine compounds may be used to inhibit cell proliferation in a variety of contexts.
  • a cell or population of cells is contacted with an amount of such a compound effective to inhibit proliferation of the cell or cell population.
  • the compound may act cytotoxically to kill the cell, or cytostatically to inhibit proliferation without killing the cell.
  • the methods may be practiced as a therapeutic approach towards the treatment of proliferative disorders.
  • the 2,4-pyrimidinediamine compounds may be used to treat proliferative disorders in animal subjects, including humans.
  • the method generally comprises administering to the subject an amount of a compound of the invention, or a salt, prodrug, hydrate or N-oxide thereof, effective to treat the disorder.
  • the subject is a mammal, including, but not limited to, bovine, horse, feline, canine, rodent, or primate.
  • the subject is a human.
  • a variety of cellular proliferative disorders may be treated with the compounds of the present invention.
  • the compounds are used to treat various cancers in afflicted subjects. Cancers are traditionally classified based on the tissue and cell type from which the cancer cells originate. Carcinomas are considered cancers arising from epithelial cells while sarcomas are considered cancers arising from connective tissues or muscle. Other cancer types include leukemias, which arise from hematopoietic cells, and cancers of nervous system cells, which arise from neural tissue. For non-invasive tumors, adenomas are considered benign epithelial tumors with glandular organization while chondomas are benign tumor arising from cartilage. In the present invention, the described compounds may be used to treat proliferative disorders encompassed by carcinomas, sarcomas, leukemias, neural cell tumors, and non-invasive tumors.
  • the compounds are used to treat solid tumors arising from various tissue types, including, but not limited to, cancers of the bone, breast, respiratory tract (e.g., bladder), brain reproductive organs, digestive tract, urinary tract, eye, liver, skin, head, neck, thyroid, parathyroid, and mestastatic forms thereof.
  • various tissue types including, but not limited to, cancers of the bone, breast, respiratory tract (e.g., bladder), brain reproductive organs, digestive tract, urinary tract, eye, liver, skin, head, neck, thyroid, parathyroid, and mestastatic forms thereof.
  • proliferative disorders include the following: a) proliferative disorders of the breast include, but are not limited to, invasive ductal carcinoma, invasive lobular carcinoma, ductal carcinoma, lobular carcinoma in situ, and metastatic breast cancer; b) proliferative disorders of the skin include, but are not limited to, basal cell carcinoma, squamous cell carcinoma, malignant melanoma, and Karposi's sarcoma; c) proliferative disorders of the respiratory tract include, but are not limited to, small cell and non-small cell lung carcinoma, bronchial adema, pleuropulmonary blastoma, and malignant mesothelioma; d) proliferative disorders of the brain include, but are not limited to, brain stem and hyptothalamic glioma, cerebellar and cerebral astrocytoma, medullablastoma, ependymal tumors, oligodendroglial, meningiomas, and neuroecto
  • proliferative disorders is not limited to the conditions described above, but encompasses other disorders characterized by uncontrolled growth and malignancy. It is further understood that proliferative disorders include various metastatic forms of the tumor and cancer types described herein.
  • the compounds of the present invention may be tested for effectiveness against the disorders described herein, and a therapeutically effective regimen established Effectiveness, as further described below, includes reduction or remission of the tumor, decreases in the rate of cell proliferation, or cytostatic or cytotoxic effect on cell growth.
  • the compounds of the present invention may be used alone, in combination with one another, or as an adjunct to, or in conjunction with, other established antiproliferative therapies.
  • the compounds of the present invention may be used with traditional cancer therapies, such as ionization radiation in the form of ⁇ -rays and x-rays, delivered externally or internally by implantation of radioactive compounds, and as a follow-up to surgical removal of tumors.
  • the compounds of the present invention may be used with other chemotherapeutic agents useful for the disorder or condition being treated. These compounds may be administered simultaneously, sequentially, by the same route of administration, or by a different route.
  • the present compounds may be used with other anti-cancer or cytotoxic agents.
  • Various classes of anti-cancer and anti-neoplastic compounds include, but are not limited to, alkylating agents, antimetabolites, vinca alkyloids, taxanes, antibiotics, enzymes, cytokines, platinum coordination complexes, substituted ureas, tyrosine kinase inhibitors, hormones and hormone antagonists.
  • Exemplary alkylating agents include, by way of example and not limitation, mechlorothamine, cyclophosphamide, ifosfamide, melphalan, chlorambucil, ethyleneimines, methylmelamines, alkyl sulfonates (egg, busulfan), and carmustine.
  • Exemplary antimetabolites include, by way of example and not limitation, folic acid analog methotrexate; pyrimidine analog fluorouracil, cytosine arbinoside; purine analogs mercaptopurine, thioguanine, and azathioprine.
  • Exemplary vinca alkyloids include, by way of example and not limitation, vinblastine, vincristine, paclitaxel, and colchicine.
  • Exemplary antibiotics include, by way of example and not limitation, actinomycin D, daunorubicin, and bleomycin.
  • An exemplary enzyme effective as anti-neoplastic agents include L-asparaginase.
  • Exemplary coordination compounds include, by way of example and not limitation, cisplatin and carboplatin.
  • hormones and hormone related compounds include, by way of example and not limitation, adrenocorticosteroids prednisone and dexamethasone; aromatase inhibitors amino glutethlimide, formestane, and anastrozole; progestin compounds hydroxyprogesteron caproate, medroxyprogesterone; and anti-estrogen compound tamoxifen.
  • Additional anti-proliferative compounds useful in combination with the compounds of the present invention include, by way of example and not limitation, antibodies directed against growth factor receptors (erg, anti-Her2); antibodies for activating T cells (e.g., anti-CTLA-4 antibodies); and cytokines such as interferon- ⁇ and interferon- ⁇ , interleukin-2, and GM-CSF.
  • growth factor receptors erg, anti-Her2
  • T cells e.g., anti-CTLA-4 antibodies
  • cytokines such as interferon- ⁇ and interferon- ⁇ , interleukin-2, and GM-CSF.
  • the active compounds When used to treat or prevent such diseases, the active compounds may be administered singly, as mixtures of one or more active compounds or in mixture or combination with other agents useful for treating such diseases and/or the symptoms associated with such diseases.
  • the active compounds may also be administered in mixture or in combination with agents useful to treat other disorders or maladies, such as steroids, membrane stabilizers.
  • the active compounds or prodrugs may be administered per se, or as pharmaceutical compositions, comprising an active compound or prodrug.
  • compositions comprising the active compounds of the invention (or prodrugs thereof) may be manufactured by means of conventional mixing, dissolving, granulating, dragee-making levigating, emulsifying, encapsulating, entrapping or lyophilization processes.
  • the compositions may be formulated in conventional manner using one or more physiologically acceptable carriers, diluents, excipients or auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically (see Remington's Pharmaceutical Sciences, 15 th Ed, Hoover, J. E. ed., Mack Publishing Co. (2003)
  • the active compound or prodrug may be formulated in the pharmaceutical compositions per se, or in the form of a hydrate, solvate, N-oxide or pharmaceutically acceptable salt, as previously described Typically, such salts are more soluble in aqueous solutions than the corresponding free acids and bases, but salts having lower solubility than the corresponding free acids and bases may also be formed.
  • compositions of the invention may take a form suitable for virtually any mode of administration, including, for example, topical, ocular, oral, buccal, systemic, nasal, injection, transdermal, rectal, vaginal, etc., or a form suitable for administration by inhalation or insufflation.
  • the active compound(s) or prodrug(s) may be formulated as solutions, gels, ointments, creams, suspensions, etc, as are well-known in the art.
  • Systemic formulations include those designed for administration by injection, e.g., subcutaneous, intravenous, intramuscular, intrathecal or intraperitoneal injection, as well as those designed for transdermal, transmucosal oral or pulmonary administration.
  • Useful injectable preparations include sterile suspensions, solutions or emulsions of the active compound(s) in aqueous or oily vehicles.
  • the compositions may also contain formulating agents, such as suspending, stabilizing and/or dispersing agent.
  • the formulations for injection may be presented in unit dosage form, e.g., in ampules or in multidose containers, and may contain added preservatives.
  • the injectable formulation may be provided in powder form for reconstitution with a suitable vehicle, including but not limited to sterile pyrogen free water, buffer, dextrose solution, etc., before use.
  • a suitable vehicle including but not limited to sterile pyrogen free water, buffer, dextrose solution, etc.
  • the active compound(s) may be dried by any art-known technique, such as lyophilization, and reconstituted prior to use.
  • penetrants appropriate to the barrier to be permeated are used in the formulation.
  • penetrants are known in the art.
  • the pharmaceutical compositions may take the form of, for example, lozenges, tablets or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g., pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (e.g., lactose, microcrystalline cellulose or calcium hydrogen phosphate); lubricants (e.g., magnesium stearate, talc or silica); disintegrants (e.g., potato starch or sodium starch glycolate); or wetting agents (e.g., sodium lauryl sulfate, lecithin).
  • binding agents e.g., pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose
  • fillers e.g., lactose, microcrystalline cellulose or calcium hydrogen phosphate
  • lubricants e.g., magnesium stearate, talc or silica
  • Liquid preparations for oral administration may take the form of, for example, elixirs, solutions, syrups or suspensions, or they may be presented as a dry product for constitution with water or other suitable vehicle before use.
  • Such liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (e.g., sorbitol syrup, cellulose derivatives or hydrogenated edible fats); emulsifying agents (e.g., lecithin or acacia); non-aqueous vehicles (e.g., almond oil, oily esters, ethyl alcohol, cremophoreTM or fractionated vegetable oils); and preservatives (e.g., methyl or propyl-p-hydroxybenzoates or sorbic acid).
  • the preparations may also contain buffer salts, preservatives, flavoring, coloring and sweetening agents as appropriate.
  • Preparations for oral administration may be suitably formulated to give controlled release of the active compound or prodrug, as is well known.
  • compositions may take the form of tablets or lozenges formulated in conventional manner.
  • the active compound(s) may be formulated as solutions (for retention enemas) suppositories or ointments containing conventional suppository bases such as cocoa butter or other glycerides.
  • the active compound(s) or prodrug(s) can be conveniently delivered in the form of an aerosol spray from pressurized packs or a nebulizer with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, fluorocarbons, carbon dioxide or other suitable gas.
  • a suitable propellant e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, fluorocarbons, carbon dioxide or other suitable gas.
  • the dosage unit may be determined by providing a valve to deliver a metered amount.
  • Capsules and cartridges for use in an inhaler or insufflator may be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.
  • the active compound(s) or prodrug(s) may be formulated as a solution, emulsion, suspension, etc, suitable for administration to the eye.
  • a variety of vehicles suitable for administering compounds to the eye are known in the art. Specific none limiting examples are described in U.S. Pat. No. 6,261,547; U.S. Pat. No. 6,197,934; U.S. Pat. No. 6,056,950; U.S. Pat. No. 5,800,807; U.S. Pat. No. 5,776,445; U.S. Pat. No. 5,698,219; U.S. Pat. No. 5,521,222; U.S. Pat. No. 5,403,841; U.S. Pat. No. 5,077,033; U.S. Pat. No. 4,882,150; and U.S. Pat. No. 4,738,851.
  • the active compound(s) or prodrug(s) can be formulated as a depot preparation for administration by implantation or intramuscular injection.
  • the active ingredient may be formulated with suitable polymeric or hydrophobic materials (e.g., as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, e.g., as a sparingly soluble salt.
  • transdermal delivery systems manufactured as an adhesive disc or patch which slowly releases the active compound(s) for percutaneous absorption may be used.
  • permeation enhancers may be used to facilitate transdermal penetration of the active compound(s), Suitable transdermal patches are described in for example, U.S. Pat. No.
  • Liposomes and emulsions are well-known examples of delivery vehicles that may be used to deliver active compound(s) or prodrug(s).
  • Certain organic solvents such as dimethylsulfoxide (DMSO) may also be employed, although usually at the cost of greater toxicity.
  • DMSO dimethylsulfoxide
  • compositions may, if desired, be presented in a pack or dispenser device which may contain one or more unit dosage forms containing the active compound(s).
  • the pack may, for example, comprise metal or plastic foil, such as a blister pack.
  • the pack or dispenser device may be accompanied by instructions for administration.
  • the active compound(s) or prodrug(s) of the invention, or compositions thereof will generally be used in an amount effective to achieve the intended result, for example in an amount effective to treat or prevent the particular disease being treated.
  • the compound(s) may be administered therapeutically to achieve therapeutic benefit.
  • therapeutic benefit is meant eradication or amelioration of the underlying disorder being treated and/or eradication or amelioration of one or more of the symptoms associated with the underlying disorder such that the patient reports an improvement in feeling or condition, notwithstanding that the patient may still be afflicted with the underlying disorder.
  • Therapeutic benefit also includes halting or slowing the progression of the disease, regardless of whether improvement is realized.
  • the amount of compound administered will depend upon a variety of factors, including, for example, the particular indication being treated, the mode of administration, the severity of the indication being treated and the age and weight of the patient, the bioavailability of the particular active compound, etc. Determination of an effective dosage is well within the capabilities of those skilled in the art.
  • Effective dosages may be estimated initially from in vitro assays.
  • an initial dosage for use in animals may be formulated to achieve a circulating blood or serum concentration of active compound that is at or above an IC 50 of the particular compound as measured in an in vitro assay, such as the in vitro assays described in the Examples section.
  • Calculating dosages to achieve such circulating blood or serum concentrations talking into account the bioavailability of the particular compound is well within the capabilities of skilled artisans.
  • the reader is referred to Fingl & Woodbury, “General Principles,” In: Goodman and Gilman's The Pharmaceutical Basis of Therapeutics , Chapter 1, pp. 1-46, latest edition, Pagamonon Press, and the references cited therein.
  • Initial dosages may also be estimated from in vivo data, such as animal models. Animal models useful for testing the efficacy of compounds to treat or prevent the various diseases described above are well-known in the art. Dosage amounts will typically be in the range of from about 0.0001 or 0.001 or 0.01 mg/kg/day to about 100 mg/kg/day, but may be higher or lower, depending upon, among other factors, the activity of the compound, its bioavailability, the mode of administration and various factors discussed above. Dosage amount and interval may be adjusted individually to provide plasma levels of the compound(s) which are sufficient to maintain therapeutic or prophylactic effect.
  • the compounds may be administered once per week, several times per week (e.g., every other day), once per day or multiple times per day, depending upon, among other things, the mode of administration, the specific indication being treated and the judgment of the prescribing physician.
  • the effective local concentration of active compound(s) may not be related to plasma concentration Skilled artisans will be able to optimize effective local dosages without undue experimentation.
  • the compound(s) will provide therapeutic or prophylactic benefit without causing substantial toxicity.
  • Toxicity of the compound(s) may be determined using standard pharmaceutical procedures.
  • the dose ratio between toxic and therapeutic (or prophylactic) LD 50 /ED 50 effect is the therapeutic index (LD 50 is the dose lethal to 50% of the population and ED 50 is the dose therapeutically effective in 50% of the population).
  • Compounds(s) that exhibit high therapeutic indices are preferred.
  • kits The compounds and/or prodrugs described herein may be assembled in the form of kits.
  • the kit provides the compound(s) and reagents to prepare a composition for administration.
  • the composition may be in a dry or lyophilized form, or in a solution, particularly a sterile solution.
  • the reagent may comprise a pharmaceutically acceptable diluent for preparing a liquid formulation.
  • the kit may contain a device for administration or for dispensing the compositions, including, but not limited to syringe, pipette, transdermal patch, or inhalant.
  • kits may include other therapeutic compounds for use in conjunction with the compounds described herein.
  • the therapeutic agents are other anti-cancer and anti-neoplastic compounds. These compounds may be provided in a separate form, or mixed with the compounds of the present invention.
  • kits will include appropriate instructions for preparation and administration of the composition, side effects of the compositions, and any other relevant information.
  • the instructions may be in any suitable format, including, but not limited to, printed matter, videotape, computer readable disk, or optical disc.
  • the IC 50 values of various compounds against a various different tumor cell lines were determined using standard in vitro antiproliferation assays.
  • the tumor cell lines tested were as follows: A549 (lung); H1299 (lung), ACHN (kidney/p53 wt), CAKI (renal cell carcinoma), NCI-H460 (lung); HCT116 (colon/p53 wt); HELA (cervix/p53 wt), HUH7 (liver/p53 wt), HUVEC (primary endothelial), LNCAP (prostate), HT-29 (colon); MCF-7 (breast); MCF-7 (breast/ER positive), MDA MB435S (breast); MDA MB231 (breast/ER negative), DU145 (prostate); BxPC-3 (pancreatic); SKOV-3 (ovarian); HepG2 (hepatic), NDHF primary normal human dermal fibroblast), SKMEL28 (breas
  • a value of “+/ ⁇ ” indicates that the specific compound exhibited an IC 50 of ⁇ 20 ⁇ M in a 3-point assay, but exhibited an IC 50 of >20 ⁇ M in a higher-point (e.g., 6-point) assay.
  • a blank indicates the specified compound was not tested against the specified cell line. Many of the compounds tested exhibited IC50s against A549 and/or H1299 cells in the nanomolar range.
  • tumor size 107 A549 25 mg/kg and Bid daily 16% Cremophor/ Compound No significant 50 mg/kg And 16% EtOH/ crashed out of reduction in Bid 4 days w/8 68% Saline solution when tumor size seen days rest saline was with either added dose 858 A549 25 mg/kg Bid, daily 5% EtOH/ No No significant 15% Cremophor/ precipitation reduction in 80% Saline was noted tumor size seen 164, 211 A549 25 mg/kg R563-5 days bid 100% DMSO No 23.2% with 2 days of precipitation reduction in rest was noted tumor size in R565 - bid, daily mice treated with 211. Compound 164 showed no significant reduction in tumor size.

Abstract

The present invention provides 2,4-pyrimidinediamine compounds having antiproliferative activity, compositions comprising the compounds and methods of using the compounds to inhibit cellular proliferation and to treat proliferative diseases such as tumorigenic cancers.

Description

    1. CROSS-REFERENCE TO RELATED APPLICATIONS
  • This application is a continuation of U.S. patent application Ser. No. 10/913,270 filed Aug. 6, 2004, which claims benefit to U.S. Provisional Application No. 60/494,008 filed Aug. 7, 2003 and U.S. Provisional Application No. 60/572,534 filed May 18, 2004.
    • 2. FIELD
  • The present invention relates to 2,4 pyrimidinediamine compounds that exhibit antiproliferative activity, prodrugs of the compounds, intermediates and methods of synthesis for making the compounds and/or prodrugs, pharmaceutical compositions comprising the compounds acid the use of the compounds in a variety of contexts, including for the treatment of proliferative disorders) such as, for example, tumors and cancers.
    • 3. BACKGROUND
  • Cancer is a group of varied diseases characterized by uncontrolled growth and spread of abnormal cells. Generally, all types of cancers involve some abnormality hi the control of cell growth and division. The pathways regulating cell division and/or cellular communication become altered in cancer cells such that the effects of these regulatory mechanisms in controlling and limiting cell growth fails or is bypassed. Through successive rounds of mutation and natural selection, a group of abnormal cells, generally originating from a single mutant cell, accumulates additional mutations that provide selective growth advantage over other cells, and thus evolves into a cell type that predominates in the cell mass. This process of mutation and natural selection is enhanced by genetic instability displayed by many types of cancer cells, an instability which is gained either from somatic mutations or by inheritance from the germ line. The enhanced mutability of cancerous cells increases the probability of their progression towards formation of malignant cells. As the cancer cells father evolve, some become locally invasive and then metastasize to colonize tissues other than the cancer cell's tissue of origin. This property along with the heterogeneity of the tumor cell population makes cancer a particularly difficult disease to treat and eradicate.
  • Traditional cancer treatments take advantage of the higher proliferative capacity of cancer cells and their increased sensitivity to DNA damage Ionizing radiation, including γ-rays and x-rays, and cytotoxic agents, such as bleomycin, cis-platin, vinblastine, cyclophosphamide, 5′-fluorouracil, and methotrexate rely upon a generalized damage to DNA and destabilization of chromosomal structure which eventually lead to destruction of cancer cells. These treatments are particularly effective for those types of cancers that have defects in cell cycle checkpoint, which limits the ability of these cells to repair damaged DNA before undergoing cell division. The non-selective nature of these treatments, however, often results in severe and debilitating side effects. The systemic use of these drugs may result in damage to normally healthy organs and tissues, and compromise the long term health of the patient.
  • Although more selective chemotherapeutic treatments have been developed based on knowledge of how cancer cells develop, for example, the anti-estrogen compound tamoxifen, the effectiveness of all chemotherapeutic treatments are subject to development of resistance to the drugs. In particular, the increased expression of cell membrane bound transporters, such as MdrI, produces a multidrug resistance phenotype characterized by increased efflux of drugs from the cell. These types of adaptation by cancer cells severely limit the effectiveness of certain classes of chemotherapeutic agents. Consequently, identification of other chemotherapeutic agents is critical for establishing therapies effective for attacking the heterogeneous nature of proliferative disease and for overcoming any resistance that may develop over the course of therapy with other compounds. Moreover, use of combinations of chemotherapeutic agents with differing properties and cellular targets increases the effectiveness of chemotherapy and limits the generation of drug resistance.
    • 4. SUMMARY
  • In one aspect, the present invention provides 2,4-pyrimidinediamine compounds that exhibit antiproliferative activity against a variety of different cell types, including a variety of different types of tumor cells. The compounds are generally 2,4-pyrimidinediamine compounds according to structural formula (I):
    Figure US20080021020A1-20080124-C00001
  • including salts, hydrates, solvates and N-oxides thereof wherein:
      • L1 and L2 are each, independently of one another, selected from a lower alkyldiyl linker, a lower alkylene linker and a covalent bond;
      • R2 is selected from the group consisting of lower alkyl optionally substituted with an Rb group,
        Figure US20080021020A1-20080124-C00002
        where Y is NH, O or CH2;
      • R2′ is hydrogen, methyl or lower alkyl;
      • R4′ is hydrogen, methyl or lower alkyl;
      • R4 is selected from the group consisting of lower alkyl optionally monosubstituted with an Ra or Rb group, lower cycloalkyl optionally monosubstituted with an Ra or Rb group, lower cycloheteroalkyl optionally substituted at one or more ring carbon and/or heteroatoms with an Ra or Rb group, —(CRaRa)n—Rb,
        Figure US20080021020A1-20080124-C00003
        where D is —(CR7R7)m—,
        Figure US20080021020A1-20080124-C00004
        where Z1 is N or CH and Z2 is O, S, NH, 8(O) or 8(O)2;
      • R5 is selected from the group consisting of halo, fluoro and —CF3;
      • R6 is hydrogen;
      • each R7 is independently selected from the group consisting of hydrogen, methyl, lower alkyl and halo;
      • each R8 is independently selected from the group consisting of hydrogen, lower alkyl, —(CH2)n—OH, —ORa, —(CH2)n—NRcRc, —O(CH2)n—Ra, —O(CH2)n—Rb, —C(O)ORa, —C(S)ORa, halo, —CF3 and —OCF3;
      • each R9 is independently selected from the group consisting of hydrogen, lower alkyl, —ORa, —(CH2)n—RcRc, —O(CH2)n—Ra, O(CH2)n—Rb, —C(O)—NRcRc, C(S)—NRcRc, S(O)2—NRcRc, —NHC(O)Ra, —NHC(S)Ra, —C(O)—NH—(CH2)n—NRcRc, —C(S)—NH—(CH2)n—NRcRc, halo, —CF3, —OCF3,
        Figure US20080021020A1-20080124-C00005
      • each R10 is independently selected from the group consisting of hydrogen, lower alkyl, —(CH2)n—OH, (CH2)n, —NRcRc, —ORa, O(CH2)n—Ra, —O(CH2)n—Rb, halo, —CF3, —OCF3,
        Figure US20080021020A1-20080124-C00006
      • each R11 is independently selected from the group consisting of —ORa, —NRcRc and —NRaRd;
      • each R12 is independently selected from the group consisting of lower alkyl, arylalkyl, —ORa, —NRcRc, C(O)Ra, —C(O)ORa and —C(O)NRcRc;
      • each R13 is independently selected from the group consisting of lower alkyl, hydroxy, lower alkoxy, methoxy, —C(O)NRcRc and —C(O)NH2;
      • each R15 is independently selected from the group consisting of hydrogen, lower alkyl, lower cycloakyl and phenyl;
      • each R16 is independently selected from the group consisting of hydrogen, methyl, lower alkyl, lower cycloalkyl, lower branched alkyl and lower cycloalkylmethyl;
      • each R17 is independently selected from the group consisting of hydrogen, lower alkyl, methyl and Rd or, alternatively, R17 may be taken together with R18 to form an oxo (═O) group;
      • each R18 is independently selected from the group consisting of hydrogen, lower alkyl and methyl or, alternatively, R18 may be taken together with R17 to form an oxo (═O) group;
      • each R19 is independently selected form the group consisting of hydrogen, lower alkyl, methyl and Rd;
      • each R20 is independently selected from the group consisting of hydrogen, lower alkyl, methyl and Rd;
      • each m is independently an integer from 1 to 3;
      • each n is independently an integer from 1 to 3;
      • each Ra is independently selected from the group consisting of hydrogen, lower alkyl, lower cycloalkyl, lower cycloalkylalkyl, phenyl and benzyl;
      • each Rb is independently selected from the group consisting of —ORa, —CF3, —OCF3, —NRcRc, —C(O)Ra, —C(S)Ra, —C(O)ORa, —C(S)ORa, —C(O)NRcRc, —C(S)NRcRc, S(O)2NRcRc, —C(O)NRaRd, —C(S)NRaRd and S(O)2NRaRd;
      • each Rc is independently selected from the group consisting of hydrogen, lower alkyl and lower cycloalkyl, or, alternatively, two Rcs may be taken together with the nitrogen atom to which they are bonded to form a 5-7 membered saturated ring which optionally includes 1-2 additional heteroatomic groups selected from O, NRa, NRa—C(O)Ra, NRa—C(O)ORa and NRa—C(O)NRa; and
      • each Rd is independently selected from lower mono-hydroxyalkyl and lower di-hydroxyalkyl.
  • In another aspect, the present invention provides prodrugs of the 2,4-pyrimidinediamine compounds. Such prodrugs may be active in their prodrug form, or may be inactive until converted under physiological or other conditions of use to an active drug form. In the prodrugs, one or more functional groups of the 2,4-pyrimidinediamine compounds are included in promoieties that cleave from the molecule under the conditions of use, typically by way of hydrolysis, enzymatic cleavage or some other cleavage mechanism, to yield the functional groups. For example, primary or secondary amino groups may be included in an amide promoiety that cleaves under conditions of use to generate the primary or secondary amino group. Thus, the prodrugs include special types of protecting groups, termed “progroups,” masking one or more functional groups of the 2,4-pyrimidinediamine compounds that cleave under the conditions of use to yield an active 2,4-pyrimidinediamine drug compound. Functional groups within the 2,4-pyrimidinediamine compounds that may be masked with progroups for inclusion in a promoiety include, but are not limited to, amines (primary and secondary), hydroxyls, sulfanyls (thiols), carboxyls, carbonyls, phenols, catechols, diols, alkynes, phosphates, etc. Myriad progroups suitable for masking such functional groups to yield promoieties that are cleavable under the desired conditions of use are known in the art. All of these progroups, alone or in combinations, may be included in the prodrugs. Specific examples of promoieties that yield primary or secondary amine groups that can be included in the prodrugs include, but are not limited to amides, carbamates, imines, ureas, phosphenyls, phosphoryls and sulfenyls. Specific examples of promoieties that yield sulfanyl groups that can be included in the prodrugs include, but are not limited to, thioethers, for example S-methyl derivatives (monothio, dithio, oxythio, aminothio acetals), silyl thioethers, thioesters, thiocarbonates, thiocarbamates, asymmetrical disulfides, etc. Specific examples of promoieties that cleave to yield hydroxyl groups that can be included in the prodrugs include, but are not limited to, sulfonates, esters and carbonates. Specific examples of promoieties that yield carboxyl groups that can be included in the prodrugs include, but are not limited to, esters (including silyl esters, oxamic acid esters and thioesters), amides and hydrazides.
  • In another aspect, the present invention provides compositions comprising one or more 2,4-pyrimidinediamine compounds and/or prodrugs and an appropriate carrier, excipient and/or diluent. The exact nature of the carrier, excipient and/or diluent will depend upon the desired use for the composition, and may range from being suitable or acceptable for veterinary uses to being suitable or acceptable for human use.
  • The 2,4-pyrimidinediamine compounds are potent inhibitors of proliferation abnormal cells, such as tumor cell proliferation, in in vitro assays. Thus, in still another aspect, the present invention provides methods of inhibiting proliferation of abnormal cells, in particular tumor cells. The method generally involves contacting an abnormal cell such as a tumor cells with an amount of a 2,4-pyrimidinediamine compound or prodrug, or an acceptable salt, hydrate, solvate, N-oxide and/or composition thereof effective to inhibit its proliferations The method may be practiced in in vitro contexts or in in vivo contexts as a therapeutic approach towards the treatment or prevention of proliferative disorders, such as tumorigenic cancers.
  • In still another aspect, the present invention provides methods of treating proliferative disorders. The methods may be practiced in animals in veterinary contexts or in humans. The methods generally involve administering to an animal or human subject an amount of a 2,4-pyrimidinediamine compound or prodrug, or an acceptable salt, hydrate, solvate, N-oxide and/or composition thereof, effective to treat the disorder. Proliferative disorders that can be treated according to the methods include, but are not limited to, tumorigenic cancers.
  • Other aspects of the present invention include, but are not limited to, intermediates and methods useful for synthesizing the compound and prodrugs, as will be described in more detail herein below.
    • 5. DETAILED DESCRIPTION
  • 5.1 Definitions
  • As used herein, the following terms are intended to have the following meanings:
  • “Alkyl” by itself or as part of another substituent refers to a saturated or unsaturated branched, straight-chain or cyclic monovalent hydrocarbon radical having the stated number of carbon atoms (i.e., C1-C6 means one to six carbon atoms) that is derived by the removal of one hydrogen atom from a single carbon atom of a parent alkane, alkene or alkyne. Typical alkyl groups include, but are not limited to, methyl; ethyls such as ethanyl, ethenyl, ethynyl; propyls such as propan-1-yl, propan-2-yl, cyclopropan-1-yl, prop-1-en-1-yl, prop-1-en-2-yl, prop-2-en-1-yl, cycloprop-1-en-1-yl; cycloprop-2-en-1-yl, prop-1-yl-1-yl, prop-2-yn-1-yl, etc.; butyls such as butan-1-yl, butan-2-yl, 2-methyl-propan-1-yl, 2-methyl-propan-2-yl, cyclobutan-1-yl, but-1-en-1-yl, but-1-en-2-yl, 2-methyl-prop-1-en-1-yl, but-2-en-1-yl, but-2-en-2-yl, buta-1,3-dien-1-yl, buta-1,3-dien-2-yl, cyclobut-1-en-1-yl, cyclobut-1-en-3-yl, cyclobuta-1,3-dien-1-yl, but-1-yn-1-yl, but-1-yn-3-yl, but-3-yn-1-yl, etc.; and the like. Where specific levels of saturation are intended, the nomenclature “alkanyl,” “alkenyl” and/or “alkynyl” is used, as defined below, “Lower alkyl” refers to alkyl groups having from 1 to 8 carbon atoms.
  • “Alkanyl” by itself or as pail of another substituent refers to a saturated branched, straight-chain or cyclic alkyl derived by the removal of one hydrogen atom from a single carbon atom of a parent alkane. Typical alkanyl groups include, but are not limited to, methanyl; ethanyl; propanyls such as propan-1-yl, propan-2-yl (isopropyl), cyclopropan-1-yl, etch; butanyls such as butan-1-yl, butan-2-yl (sec-butyl), 2-methyl-propan-1-yl (isobutyl), 2-methyl-propan-2-yl (t-butyl), cyclobutan-1-yl, etc.; and the like.
  • “Alkenyl” by itself or as part of another substituent refers to an unsaturated branched, straight-chain or cyclic alkyl having at least one carbon-carbon double bond derived by the removal of one hydrogen atom from a single carbon atom of a parent alkene. The group may be in either the cis or trans conformation about the double bond(s). Typical alkenyl groups include, but are not limited to, ethenyl; propenyls such as prop-1-en-1-yl, prop-1-en-2-yl, prop-2-en-1-yl, prop-2-en-2-yl, cycloprop-1-en-1-yl; cycloprop-2-en-1-yl; butenyls such as but-1-en-1-yl, but-1-en-2-yl, 2-methyl-prop-1-en-1-yl, but-2-en-1-yl, but-2-en-2-yl, buta-1,3-dien-1-yl, buta-1,3-dien-2-yl, cyclobut-1-en-1-yl, cyclobut-1-en-3-yl, cyclobuta-1,3-dien-1-yl, etc.; and the like.
  • “Alkynyl” by itself or as part of another substituent refers to an unsaturated branched, straight-chain or cyclic alkyl having at least one carbon-carbon triple bond derived by the removal of one hydrogen atom from a single carbon atom of a parent alkyne. Typical alkynyl groups include, but are not limited to, ethynyl; propynyls such as prop-1-yn-1-yl, prop-2-yn-1-yl, etc.; butynyls such as but-1-yn-1-yl, but-1-yn-3-yl, but-3-yn-1-yl, etc.; and the like.
  • “Alkyldiyl” by itself or as part of another substituent refers to a saturated or unsaturated, branched, straight-chain or cyclic divalent hydrocarbon group having the stated number of carbon atoms (i.e., C1-C6 means from one to six carbon atoms) derived by the removal of one hydrogen atom from each of two different carbon atoms of a parent alkane, alkene or alkyne, or by the removal of two hydrogen atoms from a single carbon atom of a parent alkane, alkene or alkyne. The two monovalent radical centers or each valency of the divalent radical center can form bonds with the same or different atoms. Typical alkyldiyl groups include, but are not limited to, methandiyl; ethyldiyls such as ethan-1,1-diyl, ethan-1,2-diyl, ethen-1,1-diyl, ethen-1,2-diyl; propyldiyls such as propan-1,1-diyl, propan-1,2-diyl, propan-2,2-diyl, propan-1,3-diyl, cyclopropan-1,1-diyl, cyclopropan-1,2-diyl, prop-1-en-1,1-diyl, prop-1-en-1,2-diyl, prop-2-en-1,2-diyl, prop-1-en-1,3-diyl, cycloprop-1-en-1,2-diyl, cycloprop-2-en-1,2-diyl, cycloprop-2-en-1,1-diyl, prop-1-yn-1,3-diyl, etc.; butyldiyls such as, butan-1,1-diyl, butan-1,2-diyl, butan-1,3-diyl, butan-1,4-diyl, butan-2,2-diyl, 2-methyl-propan-1,1-diyl, 2-methyl-propan-1,2-diyl, cyclobutan-1,1-diyl; cyclobutan-1,2-diyl, cyclobutan-1,3-diyl, but-1-en-1,1-diyl, but-1-en-1,2-diyl, but-1-en-1,3-diyl, but-1-en-1,4-diyl, 2-methyl-prop-1-en-1,1-diyl, 2-methanylidene-propan-1,1-diyl, buta-1,3-dien-1,1-diyl, buta-1,3-dien-1,2-diyl, buta-1,3-dien-1,3-diyl, buta-1,3-dien-1,4-diyl, cyclobut-1-en-1,2-diyl, cyclobut-1-en-1,3-diyl, cyclobut-2-en-1,2-diyl, cyclobuta-1,3-dien-1,2-diyl, cyclobuta-1,3 dien-1,3-diyl, but-1-yn-1,3-diyl, but-1-yn-1,4-diyl, buta-1,3-diyn-1,4-diyl, etc.; and the like. Where specific levels of saturation are intended, the nomenclature alkanyldiyl, alkenyldiyl and/or alkynyldiyl is used. Where it is specifically intended that the two valencies are on the same carbon atom, the nomenclature “alkylidene” is used. A “lower alkyldiyl” is an alkyldiyl group having from 1 to 6 carbon atoms. In preferred embodiments the alkyldiyl groups are saturated acyclic alkaniyldiyl groups in which the radical centers are at the terminal carbons, e.g., methandiyl (methano); ethan-1,2-diyl (ethano); propan-1,3-diyl (propano); butan-1,4-diyl (butano); and the like (also referred to as alkylenes, defined infra).
  • “Alkylene” by itself or as part of another substituent refers to a straight-chain saturated or unsaturated alkyldiyl group having two terminal monovalent radical centers derived by the removal of one hydrogen atom from each of the two terminal carbon atoms of straight-chain parent alkane, alkene or alkyne. The locant of a double bond or triple bond, if present, in a particular alkylene is indicated in square brackets. Typical alkylene groups include, but are not limited to, methylene (methano); ethylenes such as ethano, etheno, ethyno; propylenes such as propano, prop[1]eno, propa[1,2]dieno, prop[1]yno, etc.; butylenes such as butano, but[1]eno, but[2]eno, buta[1,3]dieno, but[1]yno, but[2]yno, buta[1,3]diyno, etc.; and the like. Where specific levels of saturation are intended, the nomenclature alkano, alkeno and/or alkyno is used. In preferred embodiments, the alkylene group is (C1-C6) or (C1-C3) alkylene. Also preferred are straight-chain saturated alkano groups, e.g., methanol ethano, propano, butano, and the like.
  • “Cycloalkyl” by itself or as part of another substituent refers to a cyclic version of an “alkyl” group. Typical cycloalkyl groups include, but are not limited to, cyclopropyl; cyclobutyls such as cyclobutanyl and cyclobutenyl; cyclopentyls such as cyclopentanyl and cyclopentenyl; cyclohexyls such as cyclohexanyl and cyclohexenyl; and the like, “Lower cycloalkyl” refers to a cycloalkyl group having from 3 to 8 ring carbon atoms.
  • “Cycloalkylalkyl” by itself or as part of another substitutent refers to an alkyl group that comprises a linear or branched portion and a cyclic portion. Typical cycloalkylalkyl groups include, but are not limited to, cyclopropylmethyl, 1-cyclopropyleth-1-yl, 2-cyclopropyleth-1-yl, cyclobutylmethyl, 1-cyclobytyleth-1-yl, 2-cyclobutyleth-1-yl, cyclopentylmethyl, 1-cyclopentyleth-1-yl, 2-cyclopentyleth-1-yl, cyclohexylmethyl, 1-cyclohexyleth-1-yl, 2-cyclohexteth-1-yl, and the like. “Lower cycloalkylalkyl” refers to a cycloalkylalkyl group in which the linear or branched portion contains from 1 to 4 carbon atoms and the cyclic portion contains from 3 to 8 carbon atoms.
  • “Heteroalkyl” by itself or as part of another substituent refers to an alkyl group in which at least one of the carbon atoms is replaced with a heteroatom, for example, a heteroatom selected from O, S and N. In heteroalkyl groups including more than one heteroatom, the heteroatoms may be the same or they may be different Like an alkyl group, a heteroalkyl can be linear, branched or cyclic in structure, and can be saturated or unsaturated. Typical heteralkyl groups include, but are not limited to,
    Figure US20080021020A1-20080124-C00007
    and the like. Where specific levels of saturation are intended, the nomenclature “heteroalkanyl,” “heteroalkenyl,” and heteroalkynyl” is used. “Lower heteroalkyl” refers to a heteroalkyl group having from 1 to 8 carbon and heteroatoms.
  • “Cycloheteroalkyl” by itself or as part of another substituent refers to a cyclic version of a heteroalkyl. Typical examples of cycloheteroalkyl groups include, but are not limited to,
    Figure US20080021020A1-20080124-C00008
    and the like. “Lower cycloheteroalkyl” refers to a cycloheteroalkyl group having from 3 to 8 ring atoms.
  • “Parent Aromatic Ring System” refers to an unsaturated cyclic or polycyclic ring system having a conjugated π electron system. Specifically included within the definition of “parent aromatic ring system” are fused ring systems in which one or more of the rings are aromatic and one or more of the rings are saturated or unsaturated, such as, for example, fluorene, indane, indene, phenalene, tetrahydronaphthalene, etc. Typical parent aromatic ring systems include, but are not limited to, aceanthrylene, acenaphthylene, acephenanthlylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexylene, indacene, s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene, tetrahydronaphthalene, triphenylene, trinaphthalene, and the like, as well as the various hydro isomers thereof.
  • “Aryl” by itself or as part of another substituent refers to a mionovalenit aromatic hydrocarbon group having the stated number of carbon atoms (i.e., C5-C15 means from 5 to 15 carbon atoms) derived by the removal of one hydrogen atom from a single carbon atom of a parent aromatic ring system. Typical aryl groups include, but are not limited to, groups derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexylene, as-indacene, s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene, trinaphthalene, and the like, as well as the various hydro isomers thereof. In preferred embodiments, the aryl group is (C5-C15) aryl, with (C5-C10) being even more preferred, Particularly preferred aryls are phenyl and naphthyl.
  • “Halogen” or “Halo” by themselves or as part of another substituent, unless otherwise stated, refer to fluoro, chloro, bromo and iodo.
  • “Haloalkyl” by itself or as part of another substituent refers to an alkyl group in which one or more of the hydrogen atoms is replaced with a halogen. Thus, the term “haloalkyl” is meant to include monohaloalkyls, dihaloalkyls, trihaloalkyls, etc. up to perhaloalkyls. For example, the expression “(C1-C2) haloalkyl” includes fluoromethyl, difluoromethyl, trifluoromethyl, 1-fluoroethyl, 1,1-difluoroethyl, 1,2-difluoroethyl, 1,1,1-trifluoroethyl, perfluoroethyl, etc.
  • The above-defined groups may include prefixes and/or suffixes that are commonly used in the art to create additional well-recognized substituent groups. As non-limiting examples, “alkyloxy” or “alkoxy” refers to a group of the formula —OR, “alkylamine” refers to a group of the formula —NHR and “dialkylamine” refers to a group of the formula —NRR, where each R is independently an alkyl. As another non-limiting example, “haloalkoxy” or “haloalkyloxy” refers to a group of the formula —OR′, where R′ is a haloalkyl.
  • “Prodrug” refers to a derivative of an active 2,4-pyrimidinediamine compound (drug) that may require a transformation under the conditions of use, such as within the body, to release the active 2,4-pyrimidinediamine drug. Prodrugs are frequently, but not necessarily, pharmacologically inactive until converted into the active drug. Prodrugs are typically obtained by masking a functional group in the 2,4-pyrimidinediamine drug believed to be in part required for activity with a progroup (defined below) to form a promoiety which undergoes a transformation, such as cleavage, under the specified conditions of use to release the functional group, and hence the active 2,4-pyrimidinediamine drug. The cleavage of the promoiety may proceed spontaneously, such as by way of a hydrolysis reaction, or it may be catalyzed or induced by another agent, such as by an enzyme, by light, by acid or base, or by a change of or exposure to a physical or environmental parameter, such as a change of temperature. The agent may be endogenous to the conditions of use, such as an enzyme present in the cells to which the prodrug is administered or the acidic conditions of the stomach, or it may be supplied exogenously.
  • A wide variety of progroups, as well as the resultant promoieties, suitable for masking functional groups in the active 2,4-pyrimidinediamines compounds to yield prodrugs are well-known in the art. For example, a hydroxyl functional group may be masked as a sulfonate, ester or carbonate promoiety, which may be hydrolyzed in vivo to provide the hydroxyl group. An amino functional group may be masked as an amide, carbamate, imine, urea, phosphenyl, phosphoryl or sulfenyl promoiety, which may be hydrolyzed in viva to provide the amino group. A carboxyl group may be masked as an ester (including silyl esters and thioesters), amide or hydrazide promoiety, which may be hydrolyzed in vivo to provide the carboxyl group. Other specific examples of suitable progroups and their respective promoieties will be apparent to those of skill in the art.
  • “Progroup” refers to a type of protecting group that, when used to mask a functional group within an active 2,4-pyrimidinediamine drug to form a promoiety, converts the drug into a prodrug. Progroups are typically attached to the functional group of the drug via bonds that are cleavable under specified conditions of use. Thus, a progroup is that portion of a promoiety that cleaves to release the functional group under the specified conditions of use. As a specific example, an amide promoiety of the formula —NH—C(O)CH3 comprises the progroup —C(O)CH3.
  • “Proliferative disorder” refers to a disease or disorder characterized by aberrant cell proliferation, for example where cells divide more than their counterpart normal cells. The aberrant proliferation may be caused by any mechanism of action or combination of mechanisms of action. For example, the cell cycle of one or more cells may be affected such that cell(s) divide more frequently than their counterpart normal cells, or alternatively, one or more cells may bypass inhibitory signals which would normally limit their number of divisions. Proliferative diseases include, but are not limited to, slow or fast growing tumors and cancers.
  • “Antiproliferative compound” refers to a compound that inhibits the proliferation of a cell as compared to an untreated control cell of a similar type. The inhibition can be brought about by any mechanism or combination of mechanisms, and may operate to inhibit proliferation cytostatically or cytotoxically. As a specific example, inhibition as used herein includes, but is not limited to, arrest of cell division, a reduction in the rate of cell division, proliferation and/or growth and/or induction of cell death.
  • “Pharmaceutically effective amount” or “therapeutically effective amount” refers to an amount of a compound sufficient to treat a specified disorder or disease or one or more of its symptoms and/or to prevent the occurrence of the disease or disorder. In reference to tumorigenic proliferative disorders, a pharmaceutically or therapeutically effective amount comprises an amount sufficient to, among other things, cause the tumor to shrink or to decrease the growth rate of the tumor.
  • 5.2 Antiproliferative 2,4-Pyrimidinediamine Compounds
  • The antiproliferative compounds are generally 2,4-pyrimidinediamine compounds according to structural formula (I):
    Figure US20080021020A1-20080124-C00009
  • including salts, hydrates, solvates and N-oxides thereof; wherein:
      • L1 and L2 are each, independently of one another, selected from a lower alkyldiyl linker; a lower alkylene linker and a covalent bond;
      • R2 is selected from the group consisting of lower alkyl optionally substituted with an Rb group,
        Figure US20080021020A1-20080124-C00010
        where Y is NH, O or CH2;
      • R2′ is hydrogen, methyl or lower alkyl;
      • R4′ is hydrogen, methyl or lower alkyl;
      • R4 is selected from the group consisting of lower alkyl optionally monosubstituted with an Ra or Rb group, lower cycloalkyl optionally monosubstituted with an Ra or Rb group, lower cycloheteroalkyl optionally substituted at one or more ring carbon and/or heteroatoms with an Ra or Rb group, —(CRaRa)n—Rb,
        Figure US20080021020A1-20080124-C00011
        where D is —(CR7R7)m—,
        Figure US20080021020A1-20080124-C00012
        where Z1 is N or CH and Z2 is O, S, NH, S(O) or S(O)2;
      • R5 is selected from the group consisting of halo, fluoro and —CF3;
      • R6 is hydrogen;
      • each R7 is independently selected from the group consisting of hydrogen, methyl, lower alkyl and halo;
      • each R8 is independently selected from the group consisting of hydrogen, lower alkyl, —(CH2)n—OH, —ORa, (CH2)n—NRcRc, —O(CH2)n—Ra, —O(CH2)n—Rb, —C(O)ORa, —C(S)ORa halo, —CF3 and —OCF3;
      • each R9 is independently selected from the group consisting of hydrogen, lower alkyl, —ORa, —(CH2)n—NRcRc, —O(CH2)n—Ra, —O(CH2)n—Rb, —C(O)—NRcRc, —C(S)—NRcRc, —S(O)2—NRcRc, —NHC(O)Ra, —NHC(S)Ra, —C(O)—NH—(CH2)n—NRcRc, —C(S)—NH—(CH2)n—NRcRc, halo, —CF3, —OCF3,
        Figure US20080021020A1-20080124-C00013
      • each R10 is independently selected from the group consisting of hydrogen, lower alkyl, —(CH2)n—OH, —(CH2)n—NRcRc, —ORa, —O(CH2)n—Ra, —O(CH2)n—Rb, halo, —CF3, —OCF3,
        Figure US20080021020A1-20080124-C00014
      • each R11 is independently selected from the group consisting of —ORa, —NRcRc and —NRaRd;
      • each R12 is independently selected from the group consisting of lower alkyl, arylalkyl, —ORa, —NRcRc, —C(O)Ra, —C(O)ORa and —C(O)NRcRc;
      • each R13 is independently selected from the group consisting of lower alkyl, hydroxy, lower alkoxy, methoxy, —C(O)NRcRc and —C(O)NH2;
      • each R15 is independently selected from the group consisting of hydrogen, lower alkyl, lower cyclo alkyl and phenyl;
      • each R16 is independently selected from the group consisting of hydrogen, methyl, lower alkyl, lower cycloalkyl, lower branched alkyl and lower cycloalkylmethyl;
      • each R17 is independently selected from the group consisting of hydrogen, lower alkyl, methyl and Rd or, alternatively, R17 may be taken together with R18 to form an oxo (═O) group;
      • each R18 is independently selected from the group consisting of hydrogen, lower alkyl and methyl or, alternatively, R18 may be taken together with R17 to form an oxo (═O) group;
      • each R19 is independently selected form the group consisting of hydrogen, lower alkyl, methyl and Rd;
      • each R20 is independently selected from the group consisting of hydrogen, lower alkyl, methyl and Rd;
      • each m is independently an integer from 1 to 3;
      • each n is independently an integer from 1 to 3;
      • each Ra is independently selected from the group consisting of hydrogen, lower alkyl, lower cycloalkyl, lower cycloalkylalkyl, phenyl and benzyl;
      • each Rb is independently selected from the group consisting of —ORa, —CF3, —OCF3, —NRcRc, —C(O)Ra, C(S)Ra, —C(O)ORa, —C(S)ORa, —C(O)NRcRc, —C(S)NRcRc, —S(O)2NRcRc, —C(O)NRaRd, —C(S)NRaRd and —S(O)2NRaRd;
      • each Rc is independently selected from the group consisting of hydrogen, lower alkyl and lower cycloalkyl, or, alternatively, two Rcs may be taken together with the nitrogen atom to which they are bonded to form a 5-7 membered saturated ring which optionally includes 1-2 additional heteroatomic groups selected from O, NRa, NRa—C(O)Ra, NRa—C(O)ORa and NRa—C(O)NRa; and
      • each Rd is independently selected from lower mono-hydroxyalkyl and lower di-hydroxyalkyl.
  • An important class of compounds of structural formula (I) includes compounds in which L1 and L2 are each a covalent bond, such that the compound is a 2,4-pyrimidine diamine according to structural formula (II):
    Figure US20080021020A1-20080124-C00015
      • including salts, hydrates, solvates and N-oxides thereof, wherein R2, R2, R2′, R4, R4′, R5 and R6 are as previously defined for structural formula (I).
  • An important class of compounds of structural formulae (I) and/or (II) and the salts, hydrates, solvates and N-oxides thereof, includes compounds in which R5 is fluoro.
  • Another important class of compounds of structural formulae (I) and/or (II) and the salts, hydrates, solvates and N-oxides thereof, includes compounds in which R2′ is hydrogen.
  • Another important class of compounds of structural formulae (J) and/or (II) and the salts, hydrates, solvates and N-oxides thereof, includes compounds in which R2′ and R4′ are each, independently of one another, selected from hydrogen and methyl.
  • Another important class of compounds of structural formulae (I) and/or (II) and the salts, hydrates, solvates and N-oxides thereof, includes compounds in which R4′ is methyl.
  • Other important classes of compounds of structural formulae (I) and/or (II) include compounds according to structural formulae (III)-(V):
    Figure US20080021020A1-20080124-C00016
      • and salts, hydrates, solvates and N-oxides thereof, wherein R2, R2′, R4 and R4′, are as previously defined for structural formula (I).
  • When R2 and/or R4 is
    Figure US20080021020A1-20080124-C00017
    in the compounds described herein, for example, the compounds of structural formulae (I)-(V), in some embodiments, R9 and R10 are not both simultaneously lower alkoxy or methoxy. In other embodiments, R8, R9 and R10 are not each simultaneously lower alkoxy or methoxy. In still other embodiments R8, R9 and R10 are each methoxy or lower alkoxy. In yet other embodiments, R9 is selected from hydrogen, lower alkyl, lower alkoxy, —ORa, halo, —CF3 and —OCF3 and one of R9 or R10 is selected from
    Figure US20080021020A1-20080124-C00018
    In a specific embodiment, the other one of R9 or R10 is other than
    Figure US20080021020A1-20080124-C00019
    In yet other embodiments, R8 is selected from hydrogen, lower alkyl, —ORa, halo, —CF3 and —OCF3 and one of R9 or R10 is selected from —OCH2C(O)Ra, —OCH2C(O)ORa, —OCH2C(O)NHRd, —OCH2C(O)NHRd and —OCH2C(O)NRcRc. In a specific embodiment, the other one of R9 or R10 is other than —OCH2C(O)Ra, OCH2C(O)ORa, —OCH2C(O)NHRa, —OCH2C(O)NHRd or —OCH2C(O)NRcRc.
  • In yet other embodiments, R8 and R9 are each, independently of one another, selected from hydrogen, lower alkyl, —ORa, halo, —CF3 and ORa and R10 is
    Figure US20080021020A1-20080124-C00020
    In yet other embodiments R9 is hydrogen and R8 and R10 are each, independently of one another, selected from the group consisting of lower alkyl, methyl, lower alkoxy, methoxy, —CF3 and —OCF3. Specific combinations of R8 and R10 when R9 is hydrogen are as follows:
      • R8 and R10 are each the same lower alkyl or methyl;
      • R8 and R10 are each the same lower alkoxy or methoxy;
      • R8 is lower alkyl or methyl and R10 is —CF3;
      • R8 is lower alkoxy or methoxy and R10 is —CF3; and
      • R8 is lower alkyl or methyl and R10 is —OCF3.
  • In still other embodiments, R9 is hydroxy, methoxy or chloro and R8 and R10 are each, independently of one another, selected from the group consisting of lower alkyl, methyl, lower alkoxy, methoxy and chloro. Specific combinations of R8, R9 and R10 according to this embodiment are as follows:
      • R8 and R10 are each methyl and R9 is hydroxy, methoxy or chloro;
      • R8 and R10 are each chloro and R9 is hydroxy or methoxy; and
      • R8 is chloro, R10 is methyl and R9 is hydroxy or methoxy.
  • When R2 and R4 are each
    Figure US20080021020A1-20080124-C00021
    in the compounds described herein, such as, for example, the compounds of structural formulae (I)-(V), in some embodiments no more than one of R8, R9 and R10 of the R4 phenyl is hydrogen unless at least one of R8, R9 or R10 of the R2 phenyl is —O(CH2)n—NRcRc,
    Figure US20080021020A1-20080124-C00022
    In other embodiments, the substitution patterns of the R2 and R4 phenyl rings are different from each other such that the compound is not a N2,N4-bis(3,4,5-substituted phenyl)pyrimidinediamine.
  • In still other embodiments, the compound is a compound according to structural formula (VI):
    Figure US20080021020A1-20080124-C00023
    including the salts, hydrates, solvates and N-oxides thereof wherein R4′, R8, R9 and R10 are as previously defined for structural formula (I).
  • In still other embodiments when R2 and R4 are each
    Figure US20080021020A1-20080124-C00024
    R8, R9 and R10 are selected such that each R2 and R4 phenyl ring is mono-substituted.
  • In yet other embodiments when R2 and R4 are each
    Figure US20080021020A1-20080124-C00025
    R8, R9 and R10 are selected such that each R2 and R4 phenyl ring is di-substituted. In one specific embodiment, each R2 and R4 phenyl ring is substituted with an ethylenedioxy acetal group.
  • In still other embodiments when R2 and R4 are each
    Figure US20080021020A1-20080124-C00026
    R10 of the R2 or R4 ring is other than 1,3-oxazolyl or 1,3-oxazol-5-yl when the R8 and R9 of the same ring are each hydrogen. In one specific embodiment, R8, R9 and R10 are as defined in the preceeding sentence when R5 is fluoro and L2 is a lower alkylene. In another specific embodiment, R2 is other than 3-(1,3-oxazolyl)phenyl or 3-(1,3-oxazol-5-yl)phenyl when R4 is 2-(trifluoromethyl)benzyl. In another specific embodiment, the compound is other than N2-[3-(1,3-oxazolyl)phenyl]-N4-[2-trifluoromethy)lbenzyl]-5-fluoro-2,4-pyrimidinediamine. In compounds where R10 is an oxazolyl, the oxazolyl is not connected at the 5 position. In a specific embodiment, the oxazole is connected at the 2 position. In still another specific embodiment, the compound is not any compound described in WO 03/040141, the disclosure of which is incorporated herein by reference.
  • When R2 is
    Figure US20080021020A1-20080124-C00027
    in the compounds described herein, such as, for example, the compounds of structural formulae (I)-(VI), in some embodiments one of R9 or R10 is selected from
    Figure US20080021020A1-20080124-C00028
    where R12 is as previously defined for structural formula (I) and the other one of R9 or R10 is other than
    Figure US20080021020A1-20080124-C00029
    In still other embodiments, R8 is selected from hydrogen, lower alkyl, methyl, lower alkoxy, methoxy and halo and one of R9 or R10 is —OCH2—Rb, where Rb is selected from —C(O)NRa and —C(O)NHRa, and the other one of R9 or R10 is selected from hydrogen, lower alkyl, methyl, lower alkoxy, methoxy and halo. In still other embodiments R2 is
    Figure US20080021020A1-20080124-C00030
    where R8 is hydrogen, fluoro or CF3. In a specific embodiment, R2 is
    Figure US20080021020A1-20080124-C00031
  • When 12 is
    Figure US20080021020A1-20080124-C00032
    in the compounds described herein, such as, for example, the compounds according to structural formulae (I)-(V), in some embodiments, R8 and R9 are each independently selected from hydrogen, lower alkyl, methyl, lower alkoxy, methoxy, halo and chloro. One specific embodiment, R8, R9 and R13 are each independently selected from halo, lower alkyl, methyl, lower alkoxy, and methoxy. In another specific embodiment, R2 is selected from
    Figure US20080021020A1-20080124-C00033
  • In some embodiments of compounds in which R2 is
    Figure US20080021020A1-20080124-C00034
    including any of the above-described specific embodiments, R4 is selected from
    Figure US20080021020A1-20080124-C00035
    where D is as previously defined for structural formula (I).
  • When R2 is 3,4,5-trimethoxyphenyl or 3,4,5-tri(loweralkoxy)phenyl in the compounds described herein, such as, for example the compounds of structural formulae (I)-(V), in some embodiments, R4 is
    Figure US20080021020A1-20080124-C00036
    where Z1, Z2 and R16, R17, R18, R19 and R20 are as previously described for structural formula (I).
  • When R9 or R10 is
    Figure US20080021020A1-20080124-C00037
    in the compounds described herein, such as, for example, the compounds of structural formulae (I)-(VI), in some embodiments R12 is methyl. In other embodiments, R12 is —C(O)Ra or —C(O)ORa, where Ra is lower alkyl, ethyl or methyl.
  • When R2 is
    Figure US20080021020A1-20080124-C00038
    in the compounds described herein, such as, for example, the compounds of structural formulae (I)-(V), in some embodiments (i) each R13 is, independently or the other, selected from lower alkyl, methyl, hydroxy, lower alkoxy and methoxy; and/or (ii) R4 is selected from
    Figure US20080021020A1-20080124-C00039
    where Z1, Z2 and R16, R17, R18, R19 and R20 are as previously described for structural formula (I). In a specific embodiment, R4 is
    Figure US20080021020A1-20080124-C00040
    where Z1 is CH, R16 is hydrogen R17 and R18 are taken together to form an oxo (═O) group and R19 and R20 are each hydrogen or methyl; and R2 is
    Figure US20080021020A1-20080124-C00041
    where each R13 is, independently of the other, selected from lower alkyl, methyl, hydroxy, lower alkoxy and methoxy.
  • When R2 is lower alkyl in the compounds described herein, such as, for example, the compounds of structural formulae (I)-(V), in some embodiments, R4 is
    Figure US20080021020A1-20080124-C00042
    where D is as previously defined for structural formula (I)
  • When R2 is
    Figure US20080021020A1-20080124-C00043
    in the compounds described herein, such as, for example, the compounds of structural formulae (I)-(V), in some embodiments, R11 is selected from the group consisting of hydroxy, methoxy, ethoxy, —NHCH3, —NHCH2CH2OH, —NHCH2CH(OH)CH2OH, —NHCH2CH(OH)(CH3)2, —N(CH3)CH2CH2OH and —N(CH3)C(CH3)2CH2OH and Y is as previously defined.
  • When R2 is
    Figure US20080021020A1-20080124-C00044
    in the compounds described herein, such as the compounds of structural formulae (I)-(V), in some embodiments the ring is connected to the remainder of the molecule at the 5-position
    Figure US20080021020A1-20080124-C00045
    In other embodiments, it is connected to the remainder of the molecule at the 6-position
    Figure US20080021020A1-20080124-C00046
    In some embodiments, R16 is selected from lower n-alkanyl, lower branched alkanyl, lower cycloalkanyl and lower cycloalkanylmethyl. In some embodiments, R4 is selected from
    Figure US20080021020A1-20080124-C00047
  • When R2 is
    Figure US20080021020A1-20080124-C00048
    in the compounds described herein, such as, for example, the compound of structural formulae (I)-(V), in some embodiments, R4 is selected from lower cycloalkyl and lower cycloheteroalkyl optionally substituted at one or more ring carbon or heteroatoms with an Ra or an Rb group. In a specific embodiment, R4 is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
    Figure US20080021020A1-20080124-C00049
    where Re and Rf are selected from (C1-C3) alkanyl and methyl and Rg is benzyl. In some embodiments, each Re is methyl. In some embodiments, Rf is ethyl.
  • When R4 is selected from lower alkyl, isopropyl, t-butyl, lower cycloalkyl,
    Figure US20080021020A1-20080124-C00050
    in the compounds described herein, such as, for example, the compounds of structural formulae (I)-(V), in some embodiments R2 is selected from
    Figure US20080021020A1-20080124-C00051
    where R8, R9, R10 and R13 are as previously defined for structural formula (I). In a specific embodiment, R2 is selected from any of the above-described embodiments of these substituted phenyls. In other embodiments, R2 is
    Figure US20080021020A1-20080124-C00052
    where R8 and R9 are a previously defined for structural formula (I).
  • When R4 is
    Figure US20080021020A1-20080124-C00053
    where R15 is lower branched alkyl or t-butyl, and R2 is
    Figure US20080021020A1-20080124-C00054
    in the compounds described herein, such as, for example, the compounds of structural formulae (I)-(V), in some embodiments at least one of R8 or R10 is other than hydrogen. In other embodiments, at least two of R8, R9 and R10 are other than hydrogen. In still other embodiments, at least two of R8, R9 and R13 are other than hydrogen.
  • In still other embodiments, either: (i) R9 is
    Figure US20080021020A1-20080124-C00055
    and R10 is other than
    Figure US20080021020A1-20080124-C00056
    or (ii) R10 is
    Figure US20080021020A1-20080124-C00057
    and R9 is other than
    Figure US20080021020A1-20080124-C00058
  • In a specific embodiment of alternative (i), R10 is hydrogen. In a specific embodiment of alternative (ii), R9 is hydrogen.
  • In still other embodiments, when R2 is
    Figure US20080021020A1-20080124-C00059
    where R8 and R9 are each hydrogen, then R10 is other than lower branched alkyl, t-butyl or —O(CH2)nRb, where n is as previously defined for structural formula (I) and Rb is selected from NRCRA, —C(O)ORa, —C(O)NRcRc and —C(O)NRaRd.
  • In still other embodiments, when R2 is
    Figure US20080021020A1-20080124-C00060
    where R9 is hydrogen and R13 is selected from hydrogen, lower alkyl and methyl, then R8 is other than —O(CH2)nRb, where it is as previously defined for structural formula (I) and Rb is —NRcRc. In still other embodiments, the compound is not any compound described in WO 01/64656, WO 03/026665 or WO 03/026666, the disclosures of which are incorporated herein by reference.
  • When R4 is —(CH2)n—Rb in the compounds described herein, such as, for example, the compounds of structural formulae (II)-(V), in some embodiments Rb is selected from the group consisting of —ORa, —NRcRc, —C(O)Ra and —C(O)NRcRc, where each Rc is independently selected from hydrogen and lower alkyl.
  • When R4 is
    Figure US20080021020A1-20080124-C00061
    in the compounds described herein, such as, for example, the compounds of structural formulae (I)-(V) in some embodiments R2 is
    Figure US20080021020A1-20080124-C00062
    where R9 is selected from the group consisting of —ORa, methoxy, isopropoxy, OCH2C(O)ORa, —OCH2C(O)NHRa, —OCH2C(O)NRaRa and —OCH2CH2NRaRa; and R8 and R10 are as previously defined for structural formula (I). In a specific embodiment, R8 and R10 are selected from one of the following combinations:
      • R8 and R10 are each the same lower alkyl or methyl;
      • R8 is lower alkyl or methyl and R10 is halo, fluoro or chloro; and
      • R9 and R10 are each the same halo, fluoro or chloro.
  • When R4 is selected from lower alkyl optionally monosubstituted with an Rb group, a lower cycloalkyl optionally monosubstituted with an Rb group and C(RaRa)n—Rb, where, Ra and Rb are as previously defined for structural formula (I), and/or L2 is a lower alkylene linker in the compounds described herein, in some embodiments, R2 is other than mono-substituted phenyl, 3-hydroxyphenyl, 3-halophenyl, 3-chlorophenyl, 3-bromophenyl, 4-halophenyl, 4-chlorophenyl, 4-bromophenyl, 3,4-dihalophenyl, 3,4-dichlorophenyl or 3,4-dichlorophenyl. In a specific embodiment, R2 is other than these defined groups in compounds in which R5 is —CF3. In another specific embodiment, the compound is not any compound described in US 2003/0171359 and/or WO 03/032997, the disclosures of which are incorporated herein by reference.
  • When R4 is
    Figure US20080021020A1-20080124-C00063
    and R2 is
    Figure US20080021020A1-20080124-C00064
    in the compounds described herein, such as, for example, the compounds of structural formulae (I)-(V), in some embodiments, R9 and R9 are non-bulky substitutents. In a specific embodiment, R9 is other than
    Figure US20080021020A1-20080124-C00065
    and R10 is other than
    Figure US20080021020A1-20080124-C00066
    In another specific embodiment, R8, R9 and R10 are each, independently of one another, selected from hydrogen lower alkyl, methyl hydroxy, lower alkoxy, methoxy, halo, fluoro and chloro. In another specific embodiment, R8 is selected from hydrogen, lower alkyl, methyl, lower alkoxy and methoxy, R9 is selected from hydrogen, lower alkoxy and methoxy and R10 is selected from lower alkyl, methyl, lower alkoxy, methoxy, halo, fluoro and
    Figure US20080021020A1-20080124-C00067
  • In all of the compounds described herein in which R4 is
    Figure US20080021020A1-20080124-C00068
    in some embodiments D is selected from the group consisting of —CH2—, —CF2—, —CH2CH2—, —CF2—CF2— and —CH2—CH2—CH2—.
  • In all of the compounds described herein having lower alkyl substitutents or substituents including lower alkyl groups (e.g., lower alkoxy groups, etc.), in some embodiments the lower alkyl substituent or group is a saturated straight-chained, branched or cyclic alkyl (i.e., an alkanyl).
  • Additional exemplary embodiments of the compounds described herein are illustrated in the following TABLES 1-14, below
    TABLE IA
    Type A Type B
    Figure US20080021020A1-20080124-C00069
    Figure US20080021020A1-20080124-C00070
    No. Type n R21 R22 R23 R4′ A549 H1299
    101 A 1 H
    Figure US20080021020A1-20080124-C00071
         		H H +
    102 A 1 H H
    Figure US20080021020A1-20080124-C00072
         		H + +
    103 A 1 H H
    Figure US20080021020A1-20080124-C00073
         		H + +
    104 A 1 H
    Figure US20080021020A1-20080124-C00074
         		H H + +
    105 A 1 H
    Figure US20080021020A1-20080124-C00075
         		H H + +
    106 A 1 H H
    Figure US20080021020A1-20080124-C00076
         		H + +
    107 A 2 H
    Figure US20080021020A1-20080124-C00077
         		H H + +
    108 A 2 H
    Figure US20080021020A1-20080124-C00078
         		H H + +
    109 A 2 H H
    Figure US20080021020A1-20080124-C00079
         		H + +
    110 A 2 H H
    Figure US20080021020A1-20080124-C00080
         		H + +
    111 A 2 H Cl Cl H + +
    112 A 2 H OMe Cl H + +
    113 A 2 H H
    Figure US20080021020A1-20080124-C00081
         		H + +
    114 A 2 Cl OMe Cl H + +
    115 A 2 H H
    Figure US20080021020A1-20080124-C00082
         		H + +
    116 A 2 Me H Me H + +
    117 A 2 OMe H OMe H + +
    118 A 2 OMe H CF3 H − +
    119 A 2 H H
    Figure US20080021020A1-20080124-C00083
         		H + +
    120 A 2 H H
    Figure US20080021020A1-20080124-C00084
         		H + +
    121 A 2 H
    Figure US20080021020A1-20080124-C00085
         		H H + +
    122 A 2 H
    Figure US20080021020A1-20080124-C00086
         		H H + +
    123 A 2 H
    Figure US20080021020A1-20080124-C00087
         		H Me + +
    124 A 2 H
    Figure US20080021020A1-20080124-C00088
         		H Me + +
    125 A 2 H
    Figure US20080021020A1-20080124-C00089
         		H Me + +
    126 (HCl salt) A 2 H
    Figure US20080021020A1-20080124-C00090
         		H Me + +
    127 A 2 H H
    Figure US20080021020A1-20080124-C00091
         		Me + +
    128 A 2 H H
    Figure US20080021020A1-20080124-C00092
         		Me + +
    129 A 2 H H
    Figure US20080021020A1-20080124-C00093
         		Me + +
    130 A 2 H H
    Figure US20080021020A1-20080124-C00094
         		Me + +
    131 A 2 H
    Figure US20080021020A1-20080124-C00095
         		H H + +
    132 A 2 H
    Figure US20080021020A1-20080124-C00096
         		H H + +
    133 A 3 H
    Figure US20080021020A1-20080124-C00097
         		H H + +
    134 A 3 H
    Figure US20080021020A1-20080124-C00098
         		H H + +
    135 A 3 H H
    Figure US20080021020A1-20080124-C00099
         		H + +
    136 A 3 H H
    Figure US20080021020A1-20080124-C00100
         		H + +
    137 A 3 H H
    Figure US20080021020A1-20080124-C00101
         		H + +
    138 A 3 H H
    Figure US20080021020A1-20080124-C00102
         		H + +
    139 A 4 H
    Figure US20080021020A1-20080124-C00103
         		H H + +
    140 A 4 H
    Figure US20080021020A1-20080124-C00104
         		H H + +
    141 A 4 H
    Figure US20080021020A1-20080124-C00105
         		H H + +
    142 A 4 H
    Figure US20080021020A1-20080124-C00106
         		H H + +
    143 A 4 H H
    Figure US20080021020A1-20080124-C00107
         		H + +
    144 A 4 H H
    Figure US20080021020A1-20080124-C00108
         		H + +
    145 A 4 H H
    Figure US20080021020A1-20080124-C00109
         		H + +
    146 A 4 H H
    Figure US20080021020A1-20080124-C00110
         		H + +
    147 A 3 H
    Figure US20080021020A1-20080124-C00111
         		H H + +
    148 A 3 H
    Figure US20080021020A1-20080124-C00112
         		H H + +
    149 A 4 H
    Figure US20080021020A1-20080124-C00113
         		H H + +
    150 A 4 H
    Figure US20080021020A1-20080124-C00114
         		H H + +
    151 A 2 H H
    Figure US20080021020A1-20080124-C00115
         		Me + +
    152 A 2 H
    Figure US20080021020A1-20080124-C00116
         		Cl H + +
    153 A 4 H
    Figure US20080021020A1-20080124-C00117
         		Cl H + +
    154 (HCl salt) A 2 H
    Figure US20080021020A1-20080124-C00118
         		H H + +
    155 (TsOH salt) A 4 H
    Figure US20080021020A1-20080124-C00119
         		H H + +
    156 (HCl salt) A 4 H
    Figure US20080021020A1-20080124-C00120
         		H H + +
    157 A 3 H
    Figure US20080021020A1-20080124-C00121
         		Cl H + +
    158 A 2 H
    Figure US20080021020A1-20080124-C00122
         		Cl H + +
    159 A 4 H
    Figure US20080021020A1-20080124-C00123
         		Cl H + +
    160 A 2 H
    Figure US20080021020A1-20080124-C00124
         		Me H + +
    161 A 3 H
    Figure US20080021020A1-20080124-C00125
         		Me H + +
    162 A 4 H
    Figure US20080021020A1-20080124-C00126
         		Me H + +
    163 A 2 H
    Figure US20080021020A1-20080124-C00127
         		CF3 H + +
    164 A 2 H
    Figure US20080021020A1-20080124-C00128
         		CF3 H + +
    165 A 4 H
    Figure US20080021020A1-20080124-C00129
         		CF3 H + +
    166 A 2 H
    Figure US20080021020A1-20080124-C00130
         		Me H + +
    167 B 2 H
    Figure US20080021020A1-20080124-C00131
         		— H + +
    168 B 3 H
    Figure US20080021020A1-20080124-C00132
         		— H + +
    169 B 4 H
    Figure US20080021020A1-20080124-C00133
         		— H + +
    170 A 2 H
    Figure US20080021020A1-20080124-C00134
         		CH2OH H
    171 B 2 Me
    Figure US20080021020A1-20080124-C00135
         		— H + +
    172 B 3 Me
    Figure US20080021020A1-20080124-C00136
         		— H + +
    173 B 4 Me
    Figure US20080021020A1-20080124-C00137
         		— H + +
    174 A 2 H
    Figure US20080021020A1-20080124-C00138
         		CH2OH H + +
    175 A 3 H
    Figure US20080021020A1-20080124-C00139
         		H H + −
    176 A 3 H
    Figure US20080021020A1-20080124-C00140
         		H H + +
    177 A 3 H
    Figure US20080021020A1-20080124-C00141
         		H H + +
    TABLE 1B
    Type A Type B
    Figure US20080021020A1-20080124-C00142
    Figure US20080021020A1-20080124-C00143
    No. Type R21 R22 R23 R4′ A549 H1299
    178 A H
    Figure US20080021020A1-20080124-C00144
         		H H + +
    179 A H H
    Figure US20080021020A1-20080124-C00145
         		H + +
    180 A H
    Figure US20080021020A1-20080124-C00146
         		Cl H + +
    181 A H
    Figure US20080021020A1-20080124-C00147
         		Me H + +
    182 A H
    Figure US20080021020A1-20080124-C00148
         		CF3 H + +
    183 B H
    Figure US20080021020A1-20080124-C00149
         		— H + +
    184 B Me
    Figure US20080021020A1-20080124-C00150
         		— H + +
    TABLE 1C
    Type A Type B
    Figure US20080021020A1-20080124-C00151
    Figure US20080021020A1-20080124-C00152
    No. Type R21 R22 R23 R4′ A549 H1299
    185 A H
    Figure US20080021020A1-20080124-C00153
         		H H + +
    186 A H H
    Figure US20080021020A1-20080124-C00154
         		H + +
    187 A H
    Figure US20080021020A1-20080124-C00155
         		Cl H + +
    188 A H
    Figure US20080021020A1-20080124-C00156
         		Me H + +
    189 A H
    Figure US20080021020A1-20080124-C00157
         		CF3 H + +
    190 B H
    Figure US20080021020A1-20080124-C00158
         		— H + +
    TABLE 1D
    Type A Type B
    Figure US20080021020A1-20080124-C00159
    Figure US20080021020A1-20080124-C00160
    No. Type R21 R22 R23 R4′ A549 H1299
    191 A H
    Figure US20080021020A1-20080124-C00161
         		H H
    192 A H
    Figure US20080021020A1-20080124-C00162
         		H H
    193 A H
    Figure US20080021020A1-20080124-C00163
         		H H
    194 A H
    Figure US20080021020A1-20080124-C00164
         		H H
    195 A H H
    Figure US20080021020A1-20080124-C00165
         		H
    196 A H H
    Figure US20080021020A1-20080124-C00166
         		H
    197 A H H
    Figure US20080021020A1-20080124-C00167
         		H
    198 A H H
    Figure US20080021020A1-20080124-C00168
         		H
  • TABLE 2
    Figure US20080021020A1-20080124-C00169
    No. R15 R21 R22 R23 A549 H1299
    199 t-butyl H H
    Figure US20080021020A1-20080124-C00170
         		+
    200 t-butyl H H
    Figure US20080021020A1-20080124-C00171
         		+ +
    201 t-butyl H H
    Figure US20080021020A1-20080124-C00172
         		+ +
    202 t-butyl H
    Figure US20080021020A1-20080124-C00173
         		H + +
    203 t-butyl H
    Figure US20080021020A1-20080124-C00174
         		H + +
    204 t-butyl H
    Figure US20080021020A1-20080124-C00175
         		H + +
    205 cyclopropyl H H
    Figure US20080021020A1-20080124-C00176
         		+ +
    206 cyclopropyl H
    Figure US20080021020A1-20080124-C00177
         		H + +
    207 cyclopropyl H H
    Figure US20080021020A1-20080124-C00178
         		+ +
    208 cyclopropyl H H
    Figure US20080021020A1-20080124-C00179
    209 cyclopropyl H
    Figure US20080021020A1-20080124-C00180
         		H + +
    210 cyclopropyl H
    Figure US20080021020A1-20080124-C00181
         		H + −
    211 cyclopropyl H H
    Figure US20080021020A1-20080124-C00182
         		+ +
    212 cyclopropyl H
    Figure US20080021020A1-20080124-C00183
         		Cl + +
    213 cyclopropyl H
    Figure US20080021020A1-20080124-C00184
         		Me + +
    214 cyclopropyl H
    Figure US20080021020A1-20080124-C00185
         		CF3 + +
  • TABLE 3
    Type A Type B
    Figure US20080021020A1-20080124-C00186
    Figure US20080021020A1-20080124-C00187
    No. Type R4 R21 R22 R23 A549 H1299
    215 A i-propyl H
    Figure US20080021020A1-20080124-C00188
         		H + +
    216 A i-propyl H
    Figure US20080021020A1-20080124-C00189
         		Cl + +
    217 A i-propyl H
    Figure US20080021020A1-20080124-C00190
         		Me + +
    218 A i-propyl H
    Figure US20080021020A1-20080124-C00191
         		CF3 + +
    219 A i-propyl H H
    Figure US20080021020A1-20080124-C00192
         		+ +
    220 A t-butyl H
    Figure US20080021020A1-20080124-C00193
         		H + +
    221 A t-butyl H H
    Figure US20080021020A1-20080124-C00194
         		+ +
    222 A t-butyl H
    Figure US20080021020A1-20080124-C00195
         		Cl + +
    223 A t-butyl H
    Figure US20080021020A1-20080124-C00196
         		Me + +
    224 A t-butyl H
    Figure US20080021020A1-20080124-C00197
         		CF3 + +
    225 B i-propyl H
    Figure US20080021020A1-20080124-C00198
         		— + +
    226 B t-butyl H
    Figure US20080021020A1-20080124-C00199
         		— + +
    227 B i-propyl Me
    Figure US20080021020A1-20080124-C00200
         		— + +
  • TABLE 4
    Figure US20080021020A1-20080124-C00201
    No. Z1 Z2 R16 R19 R20 R21 R22 R23 R4′ A549 H1299
    228 CH O H Me (R) H H OMe Cl H
    229 CH O H Me (S) H Me H Me H + +
    230 CH O H Me (R) H Me H Me H − +
    231 CH O H Me (R) H Cl OMe H H − −
    232 CH O H Me (R) H Cl OMe H H + −
    233 CH O H Me (R) H Cl OMe H H
    234 CH O H Me (R) H Cl OMe H H
    235 CH O H Me (R) H Cl OMe H H
    236 CH O H H H H H
    Figure US20080021020A1-20080124-C00202
         		H + +
    237 CH O H CH2CH2OH H H H
    Figure US20080021020A1-20080124-C00203
         		H + +
    238 CH O H CH2CH2OH H H H
    Figure US20080021020A1-20080124-C00204
         		H + +
    239 CH O H H H H H
    Figure US20080021020A1-20080124-C00205
         		H − +
    240 CH O H Me (S) H H H
    Figure US20080021020A1-20080124-C00206
         		H + −
    241 CH O H Me (R) H H H
    Figure US20080021020A1-20080124-C00207
         		H
    242 CH O H Me (S) H H H
    Figure US20080021020A1-20080124-C00208
         		H
    243 CH S H H H H H
    Figure US20080021020A1-20080124-C00209
         		H
    244 CH S H H H OMe H OMe H
    245 CH S H H H H OMe Cl H
    246 CH S Me H H H H
    Figure US20080021020A1-20080124-C00210
         		H
    247 CH S Me H H OMe H OMe H
    248 CH O H H H H H C(S)NH2 H
    249 CH O H CH2CH2OH H H H C(S)NH2 H
    250 CH S(O)2 H Me H OMe H OMe H + +
    251 CH S(O)2 H Me H Me H Me H + +
    252 CH S(O)2 H Me H OMe OMe OMe H
    253 CH O H H H H H
    Figure US20080021020A1-20080124-C00211
         		H
    254 CH O H H H H H OH H +
    255 CH O Me H H H H OH H
    256 CH O H Me H H H
    Figure US20080021020A1-20080124-C00212
         		H +
    257 CH O H Me (S) H Cl OMe Cl H
    258 CH O H Me (R) H Cl OMe Cl H
    259 CH O H CH2CH2OH H OMe H OMe H
    260 CH O H CH2CH2OH H Cl OMe H H
    261 CH O H Me (S) H OMe H OMe H
    262 CH O H Me (R) H OMe H OMe H
    263 CH S(O)2 H Me Me OMe H OMe H − −
    264 CH S(O)2 H Me Me Me H Me H − +
    265 CH S(O)2 H Me Me OMe OMe OMe H + +
    266 CH S H Me H OMe H OMe
    267 CH S H Me H Me H Me H
    268 CH S H Me H OMe OMe OMe H
    269 CH S(O)2 H Me Me H H
    Figure US20080021020A1-20080124-C00213
         		H
    270 CH S(O)2 H Me Me H OMe Cl H
    271 CH S H Me H H H
    Figure US20080021020A1-20080124-C00214
         		H
    272 CH S H Me H H OMe Cl H
    273 CH S H H H H H OH H
    274 CH S H Me H H H OH H
    275 CH S(O)2 H Me Me H H OH H
    276 CH S(O)2 H Me H H H OH H
    277 CH S(O)2 H Me H H H
    Figure US20080021020A1-20080124-C00215
         		H
    278 CH S(O)2 H Me H H OMe Cl H
    279 CH S H H H OMe OMe OMe H
    280 CH S H Me Me H OMe Cl H
    281 CH S H Me Me OMe H OMe H
    282 CH S H Me Me Me H Me H
    283 CH S H Me Me OMe OMe OMe H
    284 CH S H Me Me H H CH H
    285 CH S H Me Me H H
    Figure US20080021020A1-20080124-C00216
         		H
    286 CH S(O)2 H Me H H OMe F H
    287 CH S(O)2 H Me Me H OMe F H + +
    288 CH S H Me H H OMe F H + +
    289 CH S H Me Me H OMe F H + +
    290 CH S H H H H OMe F H + +
    291 CH S H H H Me O Me H − +
    292 CH S(O)2 H H H Me O Me H
    293 CH S(O)2 H H H OMe H OMe H
    294 CH S(O)2 H H H H OMe Cl H
    295 CH S(O)2 H H H H H
    Figure US20080021020A1-20080124-C00217
         		H
    296 CH S(O)2 H H H OMe OMe OMe H
    297 CH S(O)2 H H H H H OH H
    298 CH S(O)2 H H H H OMe F H
    299 CH O Me H H H H
    Figure US20080021020A1-20080124-C00218
         		H + −
    300 CH O H Me (S) H H H
    Figure US20080021020A1-20080124-C00219
         		H +
    301 CH O H Me (R) H H H
    Figure US20080021020A1-20080124-C00220
         		H
    302 CH O H Me (S) H Cl OMe H H
    303 CH O H Me (R) H Cl OMe H H
    304 CH O H Me Me OMe Me Me H
    305 CH O H Me Me OMe H OMe H +
    306 CH O H Me Me Cl Me Cl H + +
    307 CH O H Me Me Cl OMe Cl H +
    308 CH O H Me Me Cl H Cl H
    309 CH O H Me Me OMe H CF3 H +
    310 CH O H Me Me Me H Me H +
    311 CH O H Me Me OMe H OMe H +
    312 CH O H Me Me OMe H OMe H +
    313 CH O H Me Me OMe H OMe H +
    314 CH O H Me Me OMe H OMe H +
    315 CH O H Me Me OMe H OMe H
    316 CH O H Me Me Me H Me H
    317 CH O H Me Me Me H Me H
    318 CH O H Me Me H OMe Cl H
    319 CH O H Me Me Me Cl Me H
    320 CH O H Me Me CH2OH H CH2OH H + +
    321 CH O H Me Me Cl H OMe H + +
    322 CH O H Me Me H OMe Cl H
    323 CH O H Me Me OMe H OMe Me + +
    324 CH O Me Me Me Me H Me Me + −
    325 CH O Me Me Me H OMe Cl Me + +
    326 CH O Me Me Me OMe H OMe Me + +
    327 CH O H Me Me H OMe Cl Me + +
    328 CH O Me Me Me Me H Me H
    329 CH O Me Me Me OMe H OMe H
    330 CH O H Me Me H C(O)NHMe Cl H
    331 CH O H Me Me H S(O)2NHMe OMe H
    332 CH O H Me Me H H
    Figure US20080021020A1-20080124-C00221
         		H
    333 CH O H Me Me C(O)OMe H
    Figure US20080021020A1-20080124-C00222
         		H − −
    334 CH O H Me Me CF3 H
    Figure US20080021020A1-20080124-C00223
         		H + −
    335 N O H Me Me Me OMe Me H
    336 N O H Me Me Me OMe Me H
    337 N O H Me Me Me OMe Me H
    338 CH O H Me Me OMe OMe OMe H + +
    339 CH O H Me Me Me
    Figure US20080021020A1-20080124-C00224
         		Me H + +
    340 N O H Me Me OMe OMe OMe H
    341 N O H Me Me OMe OMe OMe H
    342 N O H Me Me OMe OMe OMe H
    343 N O H Me Me OMe OMe OMe H
    344 N O H Me Me OMe OMe OMe H
    345 N O H Me Me OMe OMe OMe H
    346 N O H Me Me OMe OMe OMe H
    347 N O H Me Me OMe OMe OMe H
    348 N O H Me Me OMe OMe OMe H
    349 N O H Me Me OMe OMe OMe H
    350 N O H Me Me Me Cl Me H
    351 N O H Me Me OMe OMe OMe H
    352 N O H Me Me Cl OH Cl H + +
    353 N O Me Me Me OMe OMe OMe H
    354 N O H Me Me OMe
    Figure US20080021020A1-20080124-C00225
         		OMe H + +
    355 CH O H Me Me H H
    Figure US20080021020A1-20080124-C00226
         		H + +
    356 CH O H Me Me H H OH H + −
    357 N O H Me Me H H
    Figure US20080021020A1-20080124-C00227
         		H
    358 CH O H Me Me Me OH Cl H +
    359 CH O H Me Me Me OMe Cl H + +
    360 N O H Me Me H H
    Figure US20080021020A1-20080124-C00228
         		H
    361 N O H Me Me H H
    Figure US20080021020A1-20080124-C00229
         		H
    362 N O H Me Me H OMe Cl H
    363 N O H Me Me OMe H OMe H
    364 N O H Me Me H Cl Cl H
    365 (HCl salt) N O H Me Me H H
    Figure US20080021020A1-20080124-C00230
         		H
    366 (bis HCl salt) N O H Me Me H H
    Figure US20080021020A1-20080124-C00231
         		H
    367 (nitrate salt) N O H Me Me H H
    Figure US20080021020A1-20080124-C00232
         		H
    368 (bis nitrate salt) N O H Me Me H H
    Figure US20080021020A1-20080124-C00233
         		H
    369 (mesylate salt) N O H Me Me H H
    Figure US20080021020A1-20080124-C00234
         		H
    370 N O H Me Me H H
    Figure US20080021020A1-20080124-C00235
         		H
    371 N O H Me Me H H t-butyl H + +
    372 N O H Me Me H H OH H
    373 N O H Me Me H H
    Figure US20080021020A1-20080124-C00236
         		H
    374 N O H Me Me H OMe F H − −
    375 N O H Me Me H H Cl H − −
    376 N O H Me Me Cl H Cl H + +
    377 CH O H Me Me Me OMe Cl H
    378 N O H Me Me H OCF3 Cl H − −
    379 N O H Me Me Me OMe Cl H
    380 N O H Me Me H H
    Figure US20080021020A1-20080124-C00237
         		H
    381 N O H Me Me Me OH Cl H
    382 N O H Me Me Me OMe Me H − −
    383 N O H Me Me H H i-propyl H
    384 N O H Me Me OMe OMe OMe H + +
    385 CH O H Me Me Cl OEt Me H + −
    386 N O Me Me Me Me OMe Cl H
    387 N O H Me Me Cl OEt Me H − −
    388 N O Me Me Me H H
    Figure US20080021020A1-20080124-C00238
         		H + +
    389 CH O H Me Me Me
    Figure US20080021020A1-20080124-C00239
         		Cl H
    390 N O Me Me Me H H
    Figure US20080021020A1-20080124-C00240
         		H
    391 CH O H Me Me H H
    Figure US20080021020A1-20080124-C00241
         		H + +
    392 N O Me Me Me H H
    Figure US20080021020A1-20080124-C00242
         		H
    393 CH O H Me Me Me
    Figure US20080021020A1-20080124-C00243
         		Cl H
    394 CH O Me Me Me H H
    Figure US20080021020A1-20080124-C00244
         		H + −
    395 CH O H Me Me H H
    Figure US20080021020A1-20080124-C00245
         		Me − +
    396 CH O H Me Me H H
    Figure US20080021020A1-20080124-C00246
         		H
    397 CH O Me Me Me H H
    Figure US20080021020A1-20080124-C00247
         		Me + +
    398 N O H Me Me Me
    Figure US20080021020A1-20080124-C00248
         		Cl H − −
    399 N O H Me Me H H
    Figure US20080021020A1-20080124-C00249
         		H
    400 N O H Me Me H H
    Figure US20080021020A1-20080124-C00250
         		H
    401 CH O Me Me Me H H
    Figure US20080021020A1-20080124-C00251
         		Me + +
    402 CH O Me Me Me Me OMe Me Me + −
    403 CH O Me Me Me Me
    Figure US20080021020A1-20080124-C00252
         		Cl Me + −
    404 N O Me Me Me Me OMe Me H
    405 N O Me Me Me Me
    Figure US20080021020A1-20080124-C00253
         		Cl H + +
    406 N O H Me Me H H
    Figure US20080021020A1-20080124-C00254
         		H
    407 CH O H Me Me H H
    Figure US20080021020A1-20080124-C00255
         		H + +
    408 N O H Me Me Me
    Figure US20080021020A1-20080124-C00256
         		Cl H
    409 N O H Me Me Me
    Figure US20080021020A1-20080124-C00257
         		Me H
    410 CH O H Me Me Me i-propoxy Cl H
    411 N O H Me Me Me i-propoxy Cl H
    412 N O H Me Me Me
    Figure US20080021020A1-20080124-C00258
         		Me H
    413 N O H Me Me Me
    Figure US20080021020A1-20080124-C00259
         		Cl H
    414 N O H Me Me Me
    Figure US20080021020A1-20080124-C00260
         		Cl H − −
    415 N O H Me Me Me
    Figure US20080021020A1-20080124-C00261
         		Me H
    416 CH O H Me Me H H
    Figure US20080021020A1-20080124-C00262
         		H
    417 N O H Me Me H C(O)NHMe Cl H
    418 N O H H H H H
    Figure US20080021020A1-20080124-C00263
         		H
    419 N O H H H H
    Figure US20080021020A1-20080124-C00264
         		H H
    420 N O H H H H
    Figure US20080021020A1-20080124-C00265
         		H H
    421 N O H H H H Cl Cl H
    422 N O H H H H OMe Cl H
    423 N O H H H Cl OMe Cl H
    424 N O H H H OMe H OMe H
    425 N O H H H H OMe F H
    426 N O H H H H OMe H H
    427 N O H H H H OCF3 H H
    428 N O H H H H OEt H H
    429 N O H H H H OBu H
    430 N O H H H H
    Figure US20080021020A1-20080124-C00266
         		H H
    431 N O H H H H O-iPr H H
    432 N O H Me Me H
    Figure US20080021020A1-20080124-C00267
         		H H
    433 N O H H H H OMe OMe H
    434 N O H Me Me H
    Figure US20080021020A1-20080124-C00268
         		H H
    435 N O H H H H
    Figure US20080021020A1-20080124-C00269
         		H H + +
    436 N O H Me Me H
    Figure US20080021020A1-20080124-C00270
         		H H +
    437 N O H H H Me H Me M
    436 N O H Me Me Me H Me H
    439 N O H H H H H i-propyl H − −
    440 N O H H H H Me Cl H − −
    441 N O H H H CF3 H OMe H − −
    442 N O H H H Cl H Cl H − −
    443 N O H H H H H Br H − −
    444 N O H H H H H t-butyl H − −
    445 N O H H H OMe OMe OMe H
    446 N O H H H H F F H − −
    447 N O H H H Me OMe Me H
    448 N O H H H Me OH Me H + +
    449 N O H H H H H
    Figure US20080021020A1-20080124-C00271
         		H + +
    450 N O H H H H H
    Figure US20080021020A1-20080124-C00272
         		H + +
    451 N O H H H H
    Figure US20080021020A1-20080124-C00273
         		H H − −
    452 N O H H H H H
    Figure US20080021020A1-20080124-C00274
         		H
    453 N O H H H H H
    Figure US20080021020A1-20080124-C00275
         		H + +
    454 N O H Me Me H H
    Figure US20080021020A1-20080124-C00276
         		H − −
    455 N O H Me Me H H
    Figure US20080021020A1-20080124-C00277
         		H + +
    456 N O H Me Me H
    Figure US20080021020A1-20080124-C00278
         		H H + +
    457 N O H Me Me H H
    Figure US20080021020A1-20080124-C00279
         		H
    458 N O H Me Me H
    Figure US20080021020A1-20080124-C00280
         		H + +
    459 N O H Me (S) H H OMe Cl H
    460 N O H Me (S) H OMe OMe OMe H
    461 N O H Me (S) H Me H Me H
    462 CH O H Me (R) H H C(O)NH2 H H — +
    463 CH O H Me (S) H CH2NHBOC H H H
    464 CH O H Me (R) H CH2NHBOC H H H
    465 CH O H Me (S) H CH2NH2 H H H
    466 CH O H Me (R) H CH2NH2 H H H
    467 CH O H Me Me H H
    Figure US20080021020A1-20080124-C00281
         		H
    468 CH O H Me (S) H H H
    Figure US20080021020A1-20080124-C00282
         		H
    469 CH O H Me (R) H H H
    Figure US20080021020A1-20080124-C00283
         		H
    470 CH O H Me Me H
    Figure US20080021020A1-20080124-C00284
         		H H − −
    471 CH O H Me (S) H H
    Figure US20080021020A1-20080124-C00285
         		H H + −
    472 N O H Me Me H C(O)NH2 H H + +
    473 N → O O H Me Me OMe OMe OMe H + +

    ††In TABLE 4, compounds having chirality at the carbon labeled with an asterisk (*) that, through substituent R19, designate a specified stereochemistry were synthesized and tested as the substantially pure enantiomer; compounds that do not designate a specified stereochemistry at this carbon atom were synthesized and, if tested, were tested as the racemate.
  • TABLE 5
    Figure US20080021020A1-20080124-C00286
    No. m R7 R21 R22 R23 R4′ A549 H1299
    474 1 H H
    Figure US20080021020A1-20080124-C00287
         		H H −
    475 1 H H
    Figure US20080021020A1-20080124-C00288
         		H H −
    476 0 F H H
    Figure US20080021020A1-20080124-C00289
         		H
    477 1 H H hexoxy H H −
    478 1 H H OEt H H +
    479 1 H H butoxy H H −
    480 1 H H
    Figure US20080021020A1-20080124-C00290
         		H H −
    481 1 H H H
    Figure US20080021020A1-20080124-C00291
         		H −
    482 1 H H H OH H −
    483 1 H H OEt H H −
    484 1 H H OMe OMe H
    485 1 H H F Cl H −
    486 1 H H t-butyl H H
    487 1 H H F H H −
    488 1 H H H F H
    489 1 H H Et H H −
    490 1 H H
    Figure US20080021020A1-20080124-C00292
         		H H −
    491 1 H H H
    Figure US20080021020A1-20080124-C00293
         		H − +
    492 1 H H H
    Figure US20080021020A1-20080124-C00294
         		H −
    493 1 H H H
    Figure US20080021020A1-20080124-C00295
         		H −/+ +
    494 1 H H H
    Figure US20080021020A1-20080124-C00296
         		H + +
    495 1 H H H
    Figure US20080021020A1-20080124-C00297
         		H −/+ +
    496 1 H H H
    Figure US20080021020A1-20080124-C00298
         		H +
    497 1 H H H
    Figure US20080021020A1-20080124-C00299
         		H +
    498 1 H H H
    Figure US20080021020A1-20080124-C00300
         		H −
    499 1 H H H
    Figure US20080021020A1-20080124-C00301
         		H
    500 1 H H H
    Figure US20080021020A1-20080124-C00302
         		H +
    501 1 H H
    Figure US20080021020A1-20080124-C00303
         		H H −
    502 1 H H
    Figure US20080021020A1-20080124-C00304
         		H H −
    503 1 F H H
    Figure US20080021020A1-20080124-C00305
         		H −/+
    504 1 H H H
    Figure US20080021020A1-20080124-C00306
         		H +
    505 1 H H Me
    Figure US20080021020A1-20080124-C00307
         		H
    506 1 H OMe OMe OMe H +
    507 1 H CF OH Cl H +
    508 1 H H H
    Figure US20080021020A1-20080124-C00308
         		H −
    509 1 H H H
    Figure US20080021020A1-20080124-C00309
         		H −
    510 1 H H H
    Figure US20080021020A1-20080124-C00310
         		H −
    511 1 H H i-propyl H H −
    512 1 H OMe H OMe H + +
    513 0 F H H Cl H + +
    514 1 H H H CF3 H −
    515 1 H H H
    Figure US20080021020A1-20080124-C00311
         		H + +
    516 1 H H H
    Figure US20080021020A1-20080124-C00312
         		H +
    517 1 H H H
    Figure US20080021020A1-20080124-C00313
         		H
    518 1 H H OMe
    Figure US20080021020A1-20080124-C00314
         		H
    519 1 H H H
    Figure US20080021020A1-20080124-C00315
         		H
    520 1 H H H
    Figure US20080021020A1-20080124-C00316
         		H +
    521 1 H Me H OH H + −
    522 1 H F H CF3 H − −
    523 1 H Me H CF3 H − +
    524 1 H F H F H − −
    525 1 H H OMe Cl H
    526 1 H H OCF2 Cl H + −
    527 1 H Me H Me H +
    528 1 H Me Cl Me H +
    529 1 H CH2OH H CH2OH H + +
    530 1 H Cl H Cl H + +
    531 1 H OMe H CF3 H − +
    532 1 F OMe H OMe H + +
    533 1 F Me Cl Me H − +
    534 1 F CH2OH H CH2OH H +
    535 1 F Cl H Cl H + +
    536 1 F OMe H CF3 H + +
    537 1 F Me H Me H + +
    538 1 F Me H CF3 H + −
    539 1 H Cl H OMe H + +
    540 0 H OMe H OMe H
    541 0 H OMe H CF3 H + +
    542 0 H Me H CF3 H − −
    543 0 H Cl H Cl H + +
    544 0 H Me H Me H − −
    545 0 H H H
    Figure US20080021020A1-20080124-C00317
         		Me
    546 1 H OMe H OMe Me + −
    547 1 H Me H Me Me + +
    548 1 H H H
    Figure US20080021020A1-20080124-C00318
         		Me
    549 1 H H H
    Figure US20080021020A1-20080124-C00319
         		Me + +
    550 1 H H H
    Figure US20080021020A1-20080124-C00320
         		H + +
    551 1 H H H H + +
    552 1 F H H
    Figure US20080021020A1-20080124-C00321
         		H + +
    553 1 F H
    Figure US20080021020A1-20080124-C00322
         		H H + +
    554 1 H H C(O)NHMe Cl H + +
    555 1 H H C(O)NHMe Cl Me
    556 1 H H S(O)2NHMe OMe H
    557 1 H H H
    Figure US20080021020A1-20080124-C00323
         		H
    558 1 H C(O)OMe H
    Figure US20080021020A1-20080124-C00324
         		H + +
    559 1 H CF3 H
    Figure US20080021020A1-20080124-C00325
         		H +
    560 0 F OMe OMe OMe H + +
    561 0 F OMe H OMe H + +
    562 0 F Me H Me H + +
    563 0 F Cl OH Cl H + +
    564 0 F Cl H Cl H + +
    565 0 F Me Cl Me H − −
    566 0 F Me OH Cl H + +
    567 0 F OMe H CF3 H + +
    568 0 F Me H CF3 H − +
    569 1 H Me
    Figure US20080021020A1-20080124-C00326
         		Me H + +
    570 0 H Me
    Figure US20080021020A1-20080124-C00327
         		Me H + +
    571 1 F H H
    Figure US20080021020A1-20080124-C00328
         		H + +
    572 1 F H H
    Figure US20080021020A1-20080124-C00329
         		Me + +
    573 1 H Me
    Figure US20080021020A1-20080124-C00330
         		Me Me + +
    574 1 F Me
    Figure US20080021020A1-20080124-C00331
         		Me Me + +
    575 1 F Me
    Figure US20080021020A1-20080124-C00332
         		Me H + +
    576 1 H H H
    Figure US20080021020A1-20080124-C00333
         		H +
    577 2 H H
    Figure US20080021020A1-20080124-C00334
         		H H
    578 2 H H
    Figure US20080021020A1-20080124-C00335
         		H H
    579 2 H H
    Figure US20080021020A1-20080124-C00336
         		H H
    580 2 H H H
    Figure US20080021020A1-20080124-C00337
         		H −
    581 2 H H H
    Figure US20080021020A1-20080124-C00338
         		H +
    582 2 H H H
    Figure US20080021020A1-20080124-C00339
         		H
    583 1 H Me OH Cl H
    584 1 H Me OMe Me H
    585 1 H Me OMe Cl H
    586 1 H H H
    Figure US20080021020A1-20080124-C00340
         		H −
    587 1 H H
    Figure US20080021020A1-20080124-C00341
         		H H +
  • TABLE 6
    Figure US20080021020A1-20080124-C00342
    No. Y1 Y2 Z3 R17 R18 R19 R20 R21 R22 R23 R4′ A549 H1299
    588 N O CH Me Me H H OMe H OMe H + +
    589 N O CH H H H H H H
    Figure US20080021020A1-20080124-C00343
         		H + +
    590 N O CH Me Me H H H H
    Figure US20080021020A1-20080124-C00344
         		H + +
    591 N O CH H H H H H H
    Figure US20080021020A1-20080124-C00345
         		H + +
    592 N O CH Me Me H H H H
    Figure US20080021020A1-20080124-C00346
         		H — —
    593 N O CH H H H CH2CH2OH OMe H OMe H
    594 N O CH H H H CH2CH2OH Me H Me H
    595 N S CH H H H H H H
    Figure US20080021020A1-20080124-C00347
         		H
    596 N O CH H H Me Me H H
    Figure US20080021020A1-20080124-C00348
         		H
    597 N O CH H H Me Me Me OMe Cl H + +
    598 N O CH H H Me Me OMe H OMe H
    599 N O N H H Me Me H H
    Figure US20080021020A1-20080124-C00349
         		H
    600 N O N H H H H H H
    Figure US20080021020A1-20080124-C00350
         		H
    601 N O N H H H H H
    Figure US20080021020A1-20080124-C00351
         		H H
    602 N O N H H H H H H
    Figure US20080021020A1-20080124-C00352
         		H
    603 N O N H H H H H
    Figure US20080021020A1-20080124-C00353
         		H H + +
    604 N O N H H H H H
    Figure US20080021020A1-20080124-C00354
         		H H − +
    605 N O N H H H H H H
    Figure US20080021020A1-20080124-C00355
         		H + +
    606 N O N H H H H H H
    Figure US20080021020A1-20080124-C00356
         		H + +
    607 N O N H H H H H H
    Figure US20080021020A1-20080124-C00357
         		H + +
    608 N O N H H H H H
    Figure US20080021020A1-20080124-C00358
         		H H + +
    609 N O N H H H H H H
    Figure US20080021020A1-20080124-C00359
         		H + +
    610 N O N H H H H H H
    Figure US20080021020A1-20080124-C00360
         		H + +
    611 N O N H H H H OMe OMe OMe H + +
    612 N O N H H H H H OMe Cl H − −
    613 N O N H H H H H H
    Figure US20080021020A1-20080124-C00361
         		H + +
    614 N O N H H H H H H
    Figure US20080021020A1-20080124-C00362
         		H + +
    615 N O N H H H H H
    Figure US20080021020A1-20080124-C00363
         		Cl H + +
    616 N O N H H H H H
    Figure US20080021020A1-20080124-C00364
         		Me H + +
  • TABLE 7
    Type A Type B
    Figure US20080021020A1-20080124-C00365
    Figure US20080021020A1-20080124-C00366
    No. Type R4′ R4 Y R11 A549 HTC116 H1299
    617 A H
    Figure US20080021020A1-20080124-C00367
         		NH OEt −
    618 A H
    Figure US20080021020A1-20080124-C00368
         		NH OEt +
    619 A H
    Figure US20080021020A1-20080124-C00369
         		O OMe −
    620 A H
    Figure US20080021020A1-20080124-C00370
         		O OMe
    621 A H
    Figure US20080021020A1-20080124-C00371
         		NH OH −
    622 A H
    Figure US20080021020A1-20080124-C00372
         		O OH −
    623 A H
    Figure US20080021020A1-20080124-C00373
         		O OMe −
    624 A H
    Figure US20080021020A1-20080124-C00374
         		O
    Figure US20080021020A1-20080124-C00375
         		−
    625 A H
    Figure US20080021020A1-20080124-C00376
         		O
    Figure US20080021020A1-20080124-C00377
         		+ +
    626 A H
    Figure US20080021020A1-20080124-C00378
         		O
    Figure US20080021020A1-20080124-C00379
         		−/+ +
    627 A H
    Figure US20080021020A1-20080124-C00380
         		O NHMe −
    628 A H
    Figure US20080021020A1-20080124-C00381
         		O NHMe −
    629 A H
    Figure US20080021020A1-20080124-C00382
         		O NHMe + +
    630 A H
    Figure US20080021020A1-20080124-C00383
         		O NH(CH2)2OH −
    631 A H
    Figure US20080021020A1-20080124-C00384
         		O NH(CH2)2OH + +
    632 A H
    Figure US20080021020A1-20080124-C00385
         		O
    Figure US20080021020A1-20080124-C00386
         		+ +
    633 A H
    Figure US20080021020A1-20080124-C00387
         		O
    Figure US20080021020A1-20080124-C00388
         		+ +
    634 A H
    Figure US20080021020A1-20080124-C00389
         		O
    Figure US20080021020A1-20080124-C00390
         		+ −
    635 A H
    Figure US20080021020A1-20080124-C00391
         		O
    Figure US20080021020A1-20080124-C00392
         		+
    636 A H
    Figure US20080021020A1-20080124-C00393
         		O OMe + −
    637 A H
    Figure US20080021020A1-20080124-C00394
         		NH OEt
    638 A H
    Figure US20080021020A1-20080124-C00395
         		O OMe −
    639 A H
    Figure US20080021020A1-20080124-C00396
         		O OH −
    640 A H
    Figure US20080021020A1-20080124-C00397
         		O
    Figure US20080021020A1-20080124-C00398
         		−
    641 A H
    Figure US20080021020A1-20080124-C00399
         		O OMe −
    642 A H
    Figure US20080021020A1-20080124-C00400
         		O NHMe +
    643 A H
    Figure US20080021020A1-20080124-C00401
         		O N(Me)2 −
    644 A H
    Figure US20080021020A1-20080124-C00402
         		O
    Figure US20080021020A1-20080124-C00403
         		+ +
    645 A H
    Figure US20080021020A1-20080124-C00404
         		O
    Figure US20080021020A1-20080124-C00405
         		+ +
    646 B H
    Figure US20080021020A1-20080124-C00406
         		NH OEt + + +
    647 B H
    Figure US20080021020A1-20080124-C00407
         		NH OEt + +
    648 B H
    Figure US20080021020A1-20080124-C00408
         		NH OEt + +
    649 B H
    Figure US20080021020A1-20080124-C00409
         		NH NHMe + +
    650 A H
    Figure US20080021020A1-20080124-C00410
         		O OMe
    651 A H
    Figure US20080021020A1-20080124-C00411
         		O OMe −
    652 A H
    Figure US20080021020A1-20080124-C00412
         		O OMe −
    653 B H
    Figure US20080021020A1-20080124-C00413
         		NH NHMe + +
    654 B H
    Figure US20080021020A1-20080124-C00414
         		NH NHMe + +
    655 B H
    Figure US20080021020A1-20080124-C00415
         		NH NHMe + +
    656 A H
    Figure US20080021020A1-20080124-C00416
         		O OMe − −
    657 A H
    Figure US20080021020A1-20080124-C00417
         		O OH − −
    658 A H
    Figure US20080021020A1-20080124-C00418
         		NH Me − +
    659 B H
    Figure US20080021020A1-20080124-C00419
         		NH N(Me)CH2CH2OH + + +
    660 B H
    Figure US20080021020A1-20080124-C00420
         		NH NHC(Me)2CH2OH + + +
    661 B Me
    Figure US20080021020A1-20080124-C00421
         		O OMe − −
    662 A Me
    Figure US20080021020A1-20080124-C00422
         		O OMe − +
    663 B Me
    Figure US20080021020A1-20080124-C00423
         		NH NHMe + +
    664 B H
    Figure US20080021020A1-20080124-C00424
         		NH OEt + +
    665 B H
    Figure US20080021020A1-20080124-C00425
         		NH NHMe + +
    666 B Me
    Figure US20080021020A1-20080124-C00426
         		NH OEt + +
    667 B H CH2CH2OH NH OEt − − −
    668 B H
    Figure US20080021020A1-20080124-C00427
         		NH NHMe − +
    669 B H
    Figure US20080021020A1-20080124-C00428
         		NH NHMe + +
    670 B H
    Figure US20080021020A1-20080124-C00429
         		NH NHMe − −
    671 A Me
    Figure US20080021020A1-20080124-C00430
         		O OMe − −
    672 A Me
    Figure US20080021020A1-20080124-C00431
         		O OMe − −
    673 A H
    Figure US20080021020A1-20080124-C00432
         		O OMe
    674 A H
    Figure US20080021020A1-20080124-C00433
         		O OMe
    675 A H
    Figure US20080021020A1-20080124-C00434
         		O NHMe −
    676 A H
    Figure US20080021020A1-20080124-C00435
         		O OMe +
    677 A H
    Figure US20080021020A1-20080124-C00436
         		O OMe + −
    678 B H
    Figure US20080021020A1-20080124-C00437
         		NH OEt − −
  • TABLE 8
    Figure US20080021020A1-20080124-C00438
    No. R4′ R21 R22 R23
    679 H Cl H H
    680 H Me Me H
    681 H H H Br
    682 H Cl H H
    683 H Me Me H
    684 H H Cl H
    685 H H OEt H
    686 H H OMe H
    687 H H H H
    688 H Me H H
    689 H H Br H
    690 H H H H
    691 H H H Br
    692 H Me H H
    693 H H H
    Figure US20080021020A1-20080124-C00439
    694 H H
    Figure US20080021020A1-20080124-C00440
    695 H H H
    Figure US20080021020A1-20080124-C00441
    696 H H H
    Figure US20080021020A1-20080124-C00442
    697 H H H
    Figure US20080021020A1-20080124-C00443
    698 H H H
    Figure US20080021020A1-20080124-C00444
    699 H H H
    Figure US20080021020A1-20080124-C00445
    700 H H H Me
    701 H H CF3 H
    702 H H OMe H
    703 H H CF3 F
    704 H H OEt H
    705 H H H OCF3
    706 H H Cl CF3
    707 H H H OEt
    708 H H H OMe
    709 H H OMe OMe
    710 H H OMe OMe
    711 H H H OH
    712 H H OMe OMe
    713 H H OEt H
    714 H H H OH
    715 H H H OH
    716 H H Cl H
    717 H H H Cl
    718 H H t-butyl H
    719 H H F Cl
    720 H H F H
    721 H H Me H
    722 H H Et H
    723 H H
    Figure US20080021020A1-20080124-C00446
         		H
    724 H H H
    Figure US20080021020A1-20080124-C00447
    725 H H OMe OH
    726 H H Me OH
    727 H H
    Figure US20080021020A1-20080124-C00448
         		H
    728 H H
    Figure US20080021020A1-20080124-C00449
         		H
    729 H H
    Figure US20080021020A1-20080124-C00450
         		H
    730 H H OH H
    731 H H OH Me
    732 H H H
    Figure US20080021020A1-20080124-C00451
    733 H H
    Figure US20080021020A1-20080124-C00452
         		H
    734 H H
    Figure US20080021020A1-20080124-C00453
         		H
    735 H H
    Figure US20080021020A1-20080124-C00454
         		H
    736 H H
    Figure US20080021020A1-20080124-C00455
         		H
    737 H H
    Figure US20080021020A1-20080124-C00456
         		H
    738 H H
    Figure US20080021020A1-20080124-C00457
         		H
    739 H H
    Figure US20080021020A1-20080124-C00458
         		H
    740 H H OH Cl
    741 H H
    Figure US20080021020A1-20080124-C00459
         		Cl
    742 H H OH F
    743 H OMe OMe OMe
    744 H H
    Figure US20080021020A1-20080124-C00460
         		H
    745 H H i-propoxy H
    746 H H H OH
    747 H H
    Figure US20080021020A1-20080124-C00461
         		H
    748 H H H
    Figure US20080021020A1-20080124-C00462
    749 H H H
    Figure US20080021020A1-20080124-C00463
    750 H H H
    Figure US20080021020A1-20080124-C00464
    751 H H H
    Figure US20080021020A1-20080124-C00465
    752 H H H
    Figure US20080021020A1-20080124-C00466
    753 H H H
    Figure US20080021020A1-20080124-C00467
    754 H H H
    Figure US20080021020A1-20080124-C00468
    755 H H H
    Figure US20080021020A1-20080124-C00469
    756 H H H
    Figure US20080021020A1-20080124-C00470
    757 H H Me
    Figure US20080021020A1-20080124-C00471
    758 H H Me
    Figure US20080021020A1-20080124-C00472
    759 H H Me
    Figure US20080021020A1-20080124-C00473
    760 H OMe OMe OMe
    761 H H H
    Figure US20080021020A1-20080124-C00474
    762 H H H
    Figure US20080021020A1-20080124-C00475
    763 H H H OH
    764 H H i-pr H
    765 H OMe H OMe
    766 H H H
    Figure US20080021020A1-20080124-C00476
    767 H H H
    Figure US20080021020A1-20080124-C00477
    768 H H H OH
    769 H OMe H OMe
    770 H H H
    Figure US20080021020A1-20080124-C00478
    771 H OMe H OMe
    772 H H H
    Figure US20080021020A1-20080124-C00479
    773 H H OMe
    774 H H H
    Figure US20080021020A1-20080124-C00480
    775 H H H
    Figure US20080021020A1-20080124-C00481
    776 H H H
    Figure US20080021020A1-20080124-C00482
    777 H H H
    Figure US20080021020A1-20080124-C00483
    778 H H H
    Figure US20080021020A1-20080124-C00484
    779 H H H
    Figure US20080021020A1-20080124-C00485
    780 H H H
    Figure US20080021020A1-20080124-C00486
    781 H H OCF3 Cl
    782 H Br H CF3
    783 H H H
    Figure US20080021020A1-20080124-C00487
    784 H H H
    Figure US20080021020A1-20080124-C00488
    785 H H H
    Figure US20080021020A1-20080124-C00489
    786 H H H OH
    787 H Cl OH Me
    788 H H H
    Figure US20080021020A1-20080124-C00490
    789 H H H
    Figure US20080021020A1-20080124-C00491
    790 H H H
    Figure US20080021020A1-20080124-C00492
    791 H H H
    Figure US20080021020A1-20080124-C00493
    792 H H H
    Figure US20080021020A1-20080124-C00494
    793 H H H
    Figure US20080021020A1-20080124-C00495
    794 H H H
    Figure US20080021020A1-20080124-C00496
    795 H
    Figure US20080021020A1-20080124-C00497
         		H
    Figure US20080021020A1-20080124-C00498
    796 H OH H
    Figure US20080021020A1-20080124-C00499
    797 H OH H
    Figure US20080021020A1-20080124-C00500
    798 H
    Figure US20080021020A1-20080124-C00501
         		H
    Figure US20080021020A1-20080124-C00502
    799 H H H OH
    800 H H OMe Cl
    801 H Me OH Cl
    802 H Me OMe Cl
    803 H H H
    Figure US20080021020A1-20080124-C00503
    804 H H H
    Figure US20080021020A1-20080124-C00504
    805 H OMe H OMe
    806 H CF3 H OMe
    807 H H H
    Figure US20080021020A1-20080124-C00505
    808 H Cl H Cl
    809 H Me H Me
    810 H CF3 H OMe
    811 H Me Me Me
    812 H OMe H OMe
    813 H Me H Me
    814 H OMe H OMe
    815 H OMe H CF3
    816 H Me H CF3
    817 H Me H Me
    818 H OMe H OMe
    819 H CF3 H OMe
    820 H Me H CF3
    821 H OMe OMe OMe
    822 H Me OH Cl
    823 H Cl H Cl
    824 H CH2OH H CH2OH
    825 H Me Cl Me
    826 H H H
    Figure US20080021020A1-20080124-C00506
    827 H H H
    Figure US20080021020A1-20080124-C00507
    828 H Cl OH Cl
    829 H Cl OH Cl
    830 H H H
    Figure US20080021020A1-20080124-C00508
    831 H Cl OMe Cl
    832 H Cl OMe Cl
    833 H H H
    Figure US20080021020A1-20080124-C00509
    834 H Cl OMe Cl
    835 H OMe H OMe
    836 H OMe H OMe
    837 H OMe H OMe
    838 H Me H Me
    839 H OMe H OMe
    840 H OMe H OMe
    841 H Me H Me
    842 H CH2OH H CH2OH
    843 H CH2OH H CH2OH
    844 H CH2OH H CH2OH
    845 H Me Me Me
    846 H Me H Me
    847 H Cl H Cl
    848 H Me H CF3
    849 H OMe H CF3
    850 Me H H
    Figure US20080021020A1-20080124-C00510
    851 Me Me H Me
    852 Me OMe H OMe
    853 Me H OMe Cl
    854 Me H Cl OMe
    855 H Me H Me
    856 H OMe H OMe
    857 H H H
    Figure US20080021020A1-20080124-C00511
    858 H H H
    Figure US20080021020A1-20080124-C00512
    859 H H H
    Figure US20080021020A1-20080124-C00513
    860 H H OMe Cl
    861 H H H
    Figure US20080021020A1-20080124-C00514
    862 H H H
    Figure US20080021020A1-20080124-C00515
    863 H H
    Figure US20080021020A1-20080124-C00516
         		H
    864 Me Me H Me
    865 Me OMe H OMe
    866 H H
    Figure US20080021020A1-20080124-C00517
         		H
    867 Me H H
    Figure US20080021020A1-20080124-C00518
    868 Me H H
    Figure US20080021020A1-20080124-C00519
    869 Me H
    Figure US20080021020A1-20080124-C00520
         		H
    870 Me H H
    Figure US20080021020A1-20080124-C00521
    871 H H C(O)NHMe Cl
    872 H H C(O)NHMe Cl
    873 H H C(O)NHMe Cl
    874 H H C(O)NHMe Cl
    875 Me H C(O)NHMe Cl
    876 H OMe H OMe
    877 H Me H Me
    878 H H H
    Figure US20080021020A1-20080124-C00522
    879 H H S(O)2NHMe OMe
    880 H H S(O)2NHMe OMe
    881 H H S(O)2NHMe OMe
    882 H H S(O)2NHMe OMe
    883 H H S(O)2NHMe OMe
    884 H OMe H OMe
    885 H H H
    Figure US20080021020A1-20080124-C00523
    886 H H H
    Figure US20080021020A1-20080124-C00524
    887 H C(O)OMe H
    Figure US20080021020A1-20080124-C00525
    888 H C(O)Me H
    Figure US20080021020A1-20080124-C00526
    889 H CF3 H
    Figure US20080021020A1-20080124-C00527
    890 H H H
    Figure US20080021020A1-20080124-C00528
    891 H
    Figure US20080021020A1-20080124-C00529
         		H
    Figure US20080021020A1-20080124-C00530
    892 H CF3 H
    Figure US20080021020A1-20080124-C00531
    893 H Cl OH Cl
    894 H H
    Figure US20080021020A1-20080124-C00532
         		Me
    895 H OMe OMe OMe
    896 H Me Cl Cl
    897 H CH2OH H CH2OH
    898 H Cl H Cl
    899 H Cl Cl Cl
    900 H Me Cl Me
    901 H Me
    Figure US20080021020A1-20080124-C00533
         		Me
    902 H Me
    Figure US20080021020A1-20080124-C00534
         		Me
    903 Me OMe H OMe
    904 Me Me OMe Cl
    905 Me Me
    Figure US20080021020A1-20080124-C00535
         		Me
    906 Me H H
    Figure US20080021020A1-20080124-C00536
    907 Me H Me H
    908 Me OMe H OMe
    909 Me Me H Me
    910 Me H H
    Figure US20080021020A1-20080124-C00537
    911 Me OMe H OMe
    912 Me Me H Me
    913 Me H H
    Figure US20080021020A1-20080124-C00538
    914 Me H H
    Figure US20080021020A1-20080124-C00539
    915 H Me H Me
    916 H OMe H OMe
    917 H H OMe Cl
    918 H Me Cl Me
    919 H H C(O)NHMe Cl
    920 H H C(O)NHMe Cl
    921 Me H C(O)NHMe Cl
    922 H Me H Me
    923 H OMe H OMe
    924 H H OMe Cl
    925 H Me Cl Me
    926 H Me H Me
    927 H OMe H OMe
    928 H OMe Cl H
    929 H Me Cl Me
    930 H H Cl OMe
    931 H Me
    Figure US20080021020A1-20080124-C00540
         		Me
    932 H H H
    Figure US20080021020A1-20080124-C00541
    933 H H H
    Figure US20080021020A1-20080124-C00542
    934 H H
    Figure US20080021020A1-20080124-C00543
         		H
    935 H H H
    Figure US20080021020A1-20080124-C00544
    936 H H
    Figure US20080021020A1-20080124-C00545
         		H
    937 H H
    Figure US20080021020A1-20080124-C00546
         		H
    938 H H F Cl
    939 H H H OH
    940 H H H
    Figure US20080021020A1-20080124-C00547
    941 H Cl OH Cl
    942 H Me OH Cl
    943 H Cl OH Me
    944 H H H OH
    945 H H OMe OMe
    946 H Me OH Cl
    947 H H H
    Figure US20080021020A1-20080124-C00548
    948 H H H
    Figure US20080021020A1-20080124-C00549
    949 H H H
    Figure US20080021020A1-20080124-C00550
    950 H H H
    Figure US20080021020A1-20080124-C00551
    951 H H H t-Bu
    952 H H H
    Figure US20080021020A1-20080124-C00552
    953 H H H t-Bu
    954 H H H
    Figure US20080021020A1-20080124-C00553
    955 H H H t-Bu
    956 H H H t-Bu
    957 H H H
    Figure US20080021020A1-20080124-C00554
    958 H H H
    Figure US20080021020A1-20080124-C00555
    959 H Me OH Cl
    960 H H H
    Figure US20080021020A1-20080124-C00556
    961 H H H
    Figure US20080021020A1-20080124-C00557
    962 H H H
    Figure US20080021020A1-20080124-C00558
    963 H H H
    Figure US20080021020A1-20080124-C00559
    964 H H H OEt
    965 H H H
    Figure US20080021020A1-20080124-C00560
    966 H H H
    Figure US20080021020A1-20080124-C00561
    967 H H H
    Figure US20080021020A1-20080124-C00562
    968 H H H i-pr
    969 H H OMe OMe
    970 H H H
    Figure US20080021020A1-20080124-C00563
    971 H H
    Figure US20080021020A1-20080124-C00564
         		H
    972 H H
    Figure US20080021020A1-20080124-C00565
         		H
    973 H H
    Figure US20080021020A1-20080124-C00566
         		H
    974 H H H OH
    975 H H
    Figure US20080021020A1-20080124-C00567
         		H
    976 H H H
    Figure US20080021020A1-20080124-C00568
    977 H H H
    Figure US20080021020A1-20080124-C00569
    978 H H H
    Figure US20080021020A1-20080124-C00570
    979 H H H
    Figure US20080021020A1-20080124-C00571
    980 H H H
    Figure US20080021020A1-20080124-C00572
    981 H H H
    Figure US20080021020A1-20080124-C00573
    982 H H H
    Figure US20080021020A1-20080124-C00574
    983 H H H
    Figure US20080021020A1-20080124-C00575
    984 H H H
    Figure US20080021020A1-20080124-C00576
    985 H H H
    Figure US20080021020A1-20080124-C00577
    986 H H H
    Figure US20080021020A1-20080124-C00578
    987 H H H
    Figure US20080021020A1-20080124-C00579
    988 H H H
    Figure US20080021020A1-20080124-C00580
    989 H H H
    Figure US20080021020A1-20080124-C00581
    990 H H H
    Figure US20080021020A1-20080124-C00582
    991 H H H
    Figure US20080021020A1-20080124-C00583
    992 H H H
    Figure US20080021020A1-20080124-C00584
    993 H H H
    Figure US20080021020A1-20080124-C00585
    994 H H H
    Figure US20080021020A1-20080124-C00586
    995 H H H
    Figure US20080021020A1-20080124-C00587
    996 H H OH CF3
    997 H H H Me
    998 H H Me H
    999 H H H
    Figure US20080021020A1-20080124-C00588
    1000  H H H
    Figure US20080021020A1-20080124-C00589
    1001  H H H
    Figure US20080021020A1-20080124-C00590
    1002  H H H
    Figure US20080021020A1-20080124-C00591
    1003  H H H
    Figure US20080021020A1-20080124-C00592
    1004  H H H
    Figure US20080021020A1-20080124-C00593
    1005  H H H
    Figure US20080021020A1-20080124-C00594
    1006  H H H
    Figure US20080021020A1-20080124-C00595
    1007  Me Me H Me
    1008  Me H OMe Cl
    1009  Me OMe H OMe
    1010  Me Cl OMe Cl
    1011  Me H OCF3 Cl
    1012  H H CH2NHBoc H
    1013  H H CH2NH2 H
    1014  H H
    Figure US20080021020A1-20080124-C00596
         		H
    1015  H H H CH2NHBoc
    1016  H H H CH2NHBoc
    1017  H H H CH2NHBoc
    1018  H H H CH2NHBoc
    1019  H H
    Figure US20080021020A1-20080124-C00597
         		H
    1020  Me H
    Figure US20080021020A1-20080124-C00598
         		H
    1021  H H
    Figure US20080021020A1-20080124-C00599
         		H
    1022  H H C(O)NH2 H
    1023  H H CH2NHBoc H
    1024  H H CH2NHBoc H
    1025  H H
    Figure US20080021020A1-20080124-C00600
         		H
    1026  H H H OH
    1027  H Cl OH Cl
    1028  H H OMe Cl
    1029  H H C(O)NH2 H
    1030  Me H C(O)NH2 H
    1031  Me H
    Figure US20080021020A1-20080124-C00601
         		H
    1032  H H C(O)NH2 H
    1033  H H C(O)NH2 Cl
    1034  H H C(O)NH2 Cl
    1035  H H
    Figure US20080021020A1-20080124-C00602
         		H
    1036  H H C(O)NH2 H
    No. R31 R32 R33 A549 H1299
    679 Cl H H
    680 Me Me H
    681 H H Br
    682 Cl H H
    683 Me Me H
    684 H Cl H
    685 H OEt H
    686 H OMe H
    687 H H H
    688 Me H H
    689 H Br H
    690 H H H
    691 H H Br
    692 Me H H
    693 H H OH +
    694 H H
    Figure US20080021020A1-20080124-C00603
         		+ +
    695 H F F
    696 H Cl H
    697 H Cl Cl + +
    698 H H OCF3
    699 H OCF3 Cl +
    700 H OCF3 Cl
    701 H CF3 H − −
    702 H OMe H + +
    703 H CF3 F −
    704 H OEt H + +
    705 H H OCF3 −
    706 H Cl CF3 −
    707 H H OEt +
    708 H H OMe +
    709 H OEt H −
    710 H OMe OMe +
    711 H H H +
    712 H H H −
    713 H OMe OMe + +
    714 H OEt H −
    715 H OMe OMe +
    716 H Cl H −
    717 H H Cl +
    718 H t-butyl H − −
    719 H F Cl − −
    720 H F H + −
    721 H Me H − −
    722 H Et H −
    723 H
    Figure US20080021020A1-20080124-C00604
         		H +
    724 H H
    Figure US20080021020A1-20080124-C00605
         		− +
    725 H OMe OH +
    726 H Me OH
    727 H
    Figure US20080021020A1-20080124-C00606
         		H
    728 H H OH
    729 H H OH −
    730 H OH H +
    731 H OH Me −
    732 H H OH +
    733 H
    Figure US20080021020A1-20080124-C00607
         		H −
    734 H
    Figure US20080021020A1-20080124-C00608
         		H −
    735 H
    Figure US20080021020A1-20080124-C00609
         		H
    736 H H Cl −
    737 H
    Figure US20080021020A1-20080124-C00610
         		H −
    738 H
    Figure US20080021020A1-20080124-C00611
         		H −
    739 H
    Figure US20080021020A1-20080124-C00612
         		H −
    740 H OH Cl
    741 H Cl
    742 H OH F
    743 OMe OMe OMe −
    744 H H OH +
    745 H i-propoxy H −
    746 H
    Figure US20080021020A1-20080124-C00613
         		H −
    747 H t-Bu H −
    748 H t-Bu H −
    749 H t-Bu H −
    750 H t-Bu H −
    751 H i-propoxy H −/+
    752 H i-propoxy H −
    753 H OMe OMe −
    754 H OMe OMe −
    755 H H OMe +
    756 H Me OH
    757 H H OH
    758 H Me OH
    759 H Me
    Figure US20080021020A1-20080124-C00614
         		+ +
    760 H H OH −
    761 H H OH
    762 H H OH −
    763 H H
    Figure US20080021020A1-20080124-C00615
         		− +
    764 H H OH −
    765 H H OH +
    766 OMe H OMe − +
    767 OMe H OMe −
    768 OMe H OMe + +
    769 H H
    Figure US20080021020A1-20080124-C00616
         		− −
    770 H H CF3 +
    771 H H
    Figure US20080021020A1-20080124-C00617
         		+
    772 H OEt H + +
    773 H H OH
    774 H H OH
    775 H H Cl
    776 CF3 H OMe
    777 H OMe OH
    778 H OMe CF3
    779 H F CF3
    780 H Me Cl
    781 H H OH + +
    782 H H OH
    783 H OCF3 H
    784 H CF3 H
    785 H Cl CF3
    786 H H OCF3
    787 H H OH
    788 H OMe Cl +
    789 H OMe F
    790 H Me OMe +
    791 H H
    Figure US20080021020A1-20080124-C00618
         		+ +
    792 H H + +
    793 H Me CF3
    794 H F Me
    795 H H OH
    796 H H OH
    797 H H OH + −
    798 H H OH − −
    799 H OMe Cl
    800 H OMe Cl + −
    801 H OMe Cl
    802 H OMe Cl − −
    803 H O-iPr Cl
    804 H OMe Cl
    805 H
    Figure US20080021020A1-20080124-C00619
         		Cl
    806 H
    Figure US20080021020A1-20080124-C00620
         		Cl + +
    807 H OMe Cl
    808 H OMe Cl + +
    809 H OMe Cl
    810 H OMe Cl + −
    811 H OMe Cl + −
    812 H H OCF3 + +
    813 H H OCF3 − −
    814 Me H Me + +
    815 Me H Me + +
    816 Me H Me + +/−
    817 CF3 H OMe + +
    818 CF3 H OMe + +
    819 CF3 H OMe + +
    820 CF3 H OMe +/− +
    821 CF3 H OMe + +
    822 CF3 H OMe + +
    823 CF3 H OMe + +
    824 CF3 H OMe + −/+
    825 CF3 H OMe + +
    826 H Cl OMe
    827 H
    Figure US20080021020A1-20080124-C00621
         		Cl
    828 H OMe Cl + +
    829 H OCF3 Cl + +
    830 H
    Figure US20080021020A1-20080124-C00622
         		Cl
    831 H OMe Cl − −
    832 H OCF3 Cl + −
    833 Cl OMe Cl
    834 H Cl Cl + +
    835 H Cl Cl + +
    836 H OMe Cl
    837 H OCF3 Cl
    838 H Cl Cl + −
    839 OMe H OMe +
    840 OMe H OMe + +
    841 Me H Me + +
    842 OMe H OMe + +
    843 H OMe Cl + +
    844 H Cl Cl + +
    845 OMe H OMe + +
    846 OMe H OMe + +
    847 OMe H OMe +
    848 OMe H OMe +
    849 OMe H OMe + +
    850 OMe H OMe − −
    851 OMe H OMe + +
    852 OMe H OMe + +
    853 OMe H OMe − −
    854 OMe H OMe − −
    855 OMe H OMe + +
    856 H OMe OMe + +
    857 H OMe OMe
    858 H OMe OMe + +
    859 H OMe OMe + +
    860 H OMe OMe
    861 OMe H OMe + +
    862 H OMe OMe + +
    863 H OMe OMe + +
    864 H OMe OMe + +
    865 H OMe OMe + +
    866 OMe H OMe + +
    867 H OMe OMe − +
    868 H OMe OMe + +
    869 H OMe OMe + +
    870 H OMe OMe − −
    871 H OMe OMe + +
    872 OMe H OMe + +
    873 H OMe Cl
    874 H H OH
    875 H OMe OMe + +
    876 H C(O)NHMe Cl
    877 H C(O)NHMe Cl
    878 H C(O)NHMe Cl
    879 H OMe OMe + +
    880 OMe H OMe + +
    881 H Cl CF3
    882 H OCF3 Cl
    883 H H Cl
    884 H S(O)2NHMe OMe + +
    885 H H OH + +
    886 H OMe OMe + +
    887 H OMe OMe + +
    888 H H OH + +
    889 H OMe OMe + +
    890 H H OH + +
    891
    Figure US20080021020A1-20080124-C00623
         		H
    Figure US20080021020A1-20080124-C00624
         		− −
    892 CF3 H
    Figure US20080021020A1-20080124-C00625
         		+ +
    893 Cl OMe Cl
    894 H
    Figure US20080021020A1-20080124-C00626
         		Me + +
    895 Me H Me + +
    896 Me H Me + +
    897 Me H Me + +
    898 Me H Me − −
    899 Me H Me + +
    900 Me H Me − −
    901 H OMe Cl
    902 OMe H OMe + +
    903 H OMe Cl + +
    904 H OMe Cl − −
    905 H OMe Cl + +
    906 H OMe Cl + +
    907 H OMe Cl − +
    908 H Cl OMe
    909 H Cl OMe + +
    910 H Cl OMe + −
    911 Me Cl Me
    912 Me Cl Me − −
    913 Me Cl Me + +
    914 Me Cl Me − −
    915 H
    Figure US20080021020A1-20080124-C00627
         		Cl
    916 H
    Figure US20080021020A1-20080124-C00628
         		Cl
    917 H
    Figure US20080021020A1-20080124-C00629
         		Cl + +
    918 H
    Figure US20080021020A1-20080124-C00630
         		Cl
    919 H Cl OMe
    920 H Cl CF3
    921 Me Cl Me + +
    922 H
    Figure US20080021020A1-20080124-C00631
         		Cl
    923 H
    Figure US20080021020A1-20080124-C00632
         		Cl
    924 H
    Figure US20080021020A1-20080124-C00633
         		Cl
    925 H
    Figure US20080021020A1-20080124-C00634
         		Cl
    926 H
    Figure US20080021020A1-20080124-C00635
         		Cl
    927 H
    Figure US20080021020A1-20080124-C00636
         		Cl
    928 H
    Figure US20080021020A1-20080124-C00637
         		Cl
    929 H
    Figure US20080021020A1-20080124-C00638
         		Cl
    930 H
    Figure US20080021020A1-20080124-C00639
         		Cl
    931 OMe H OMe + +
    932 OMe OMe OMe + +
    933 OH OH
    Figure US20080021020A1-20080124-C00640
         		+ +
    934 H H OH +
    935 H i-pr H −
    936 H i-pr H −
    937 H i-pr H +
    938 H F Cl −
    939 H H
    Figure US20080021020A1-20080124-C00641
         		−
    940 OMe H OMe + +
    941 Cl OH Cl −
    942 Me OH Cl + +
    943 H H OH +
    944 Cl OH Me
    945 H
    Figure US20080021020A1-20080124-C00642
         		Me + +
    946 H
    Figure US20080021020A1-20080124-C00643
         		H
    947 Me OH Me − +
    948 Me OH Me −
    949 Me OH Me + +
    950 Me OH Me + +
    951 H H OH −
    952 Cl OH Me − +
    953 H OMe OMe −
    954 Cl OH Me −
    955 H H
    Figure US20080021020A1-20080124-C00644
         		− −
    956 H H
    Figure US20080021020A1-20080124-C00645
         		−
    957 Cl OH Me +
    958 H H t-Bu − −
    959 H H t-Bu −
    960 H H t-Bu −
    961 H H t-Bu −/+
    962 H H t-Bu − −
    963 H H t-Bu −
    964 H H i-pr −
    965 H H i-pr −
    966 H H i-pr +
    967 H CH2OH CH2OH −
    968 H H i-pr − +
    969 H H OH + +
    970 H H CH2NH2 + +
    971 H
    Figure US20080021020A1-20080124-C00646
         		H −
    972 H
    Figure US20080021020A1-20080124-C00647
         		H
    973 H
    Figure US20080021020A1-20080124-C00648
         		H −
    974 H
    Figure US20080021020A1-20080124-C00649
         		H + +
    975 H H OH
    976 H H OH −
    977 H i-propoxy H −
    978 H H OH −
    979 Me OH Me − +
    980 Me OH Me +
    981 Me OH Me +
    982 Me OH Me −
    983 Cl OH Me +
    984 Cl OH Me +
    985 Me OMe Me −
    986 Me OMe Me −
    987 Me OMe Me −
    988 H
    Figure US20080021020A1-20080124-C00650
         		H + +
    989 H
    Figure US20080021020A1-20080124-C00651
         		H + +
    990 H
    Figure US20080021020A1-20080124-C00652
         		H + +
    991 Me OH Cl +
    992 H
    Figure US20080021020A1-20080124-C00653
         		H − −
    993 H
    Figure US20080021020A1-20080124-C00654
         		H + +
    994 H H
    Figure US20080021020A1-20080124-C00655
    995 H H
    Figure US20080021020A1-20080124-C00656
         		+ +
    996 H OH CF3 −/+
    997 H H Me +
    998 H Me H −
    999 Cl OH Cl − −
    1000  Cl OH Cl
    1001  Cl OH Cl − −
    1002  H
    Figure US20080021020A1-20080124-C00657
         		H −
    1003  H
    Figure US20080021020A1-20080124-C00658
         		H −
    1004  H OH H −
    1005  H OMe CH2OH
    1006  H Cl Cl + +
    1007  H Cl Cl − −
    1008  H Cl Cl
    1009  H Cl Cl − −
    1010  H Cl Cl
    1011  H Cl Cl
    1012  H CH2NHBoc H + +
    1013  H CH2NH2 H + +
    1014  H Cl Cl
    1015  H H CH2NHBoc + +
    1016  H H CH2NHBoc + +
    1017  H Cl Cl
    1018  H Cl Cl
    1019  H Cl Cl
    1020  H Cl Cl
    1021  H OMe Cl + +
    1022  H OMe Cl + +
    1023  H OMe Cl + +
    1024  H OMe Cl + +
    1025  H OMe Cl − +
    1026  H C(O)NH2 H − +
    1027  H C(O)NH2 H + +
    1028  H C(O)NH2 H + +
    1029  H C(O)NH2 H − −
    1030  H Cl C + +
    1031  H Cl Cl + +
    1032  H Cl OMe − −
    1033  H OMe Cl + +
    1034  H Cl OMe − +
    1035  H Cl OMe + +
    1036  H H H + +
  • TABLE 9
    Figure US20080021020A1-20080124-C00659
    No. R4′ R2′ R2 A549 H1299
    1037 H H CH2CH═CH2 −
    1038 Me H Me + +
    1039 Me Me Me + +
    1040 Me H CH2CH2OH + +
    1041 Me H i-propyl + +
    1042 Me CH2CH2OH CH2CH2OH − +
    1043 Me H CH2CH═CH2 + +
    1044 H H Me − −
  • TABLE 10
    Figure US20080021020A1-20080124-C00660
    No. R4′ R40 R41 R42 A549 H1299
    1045 H H OMe OMe −
    1046 H H OMe Me + +
    1047 H OMe H Me + +
    1048 H Me H F + +
    1049 H OMe Cl OMe + +
  • TABLE 11
    Figure US20080021020A1-20080124-C00661
    No. R21 R22 R23 A549 H1299
    1050 Me OMe Me + +
    1051 H OMe F + +
    1052 Me H Me + +
    1053 OMe H OMe + +
    1054 H H
    Figure US20080021020A1-20080124-C00662
         		+ +
    1055 H H
    Figure US20080021020A1-20080124-C00663
         		− −
    1056 H
    Figure US20080021020A1-20080124-C00664
         		H − −
    1057 H
    Figure US20080021020A1-20080124-C00665
         		H − −
    1058 H
    Figure US20080021020A1-20080124-C00666
         		H − −
    1059 H H
    Figure US20080021020A1-20080124-C00667
         		− −
  • TABLE 12
    Figure US20080021020A1-20080124-C00668
    No. R13a R13b R19 R20 A549 H1299
    1060 Me OH Me Me + +
    1061 Me OMe Me Me + +
    1062 Me OMe H H + +
    1063 Me OH H H + +
    1064 Me OH Me Me + +
    1065 Me OMe Me Me + −
  • TABLE 13
    Type A
    Figure US20080021020A1-20080124-C00669
    Type B
    Figure US20080021020A1-20080124-C00670
    Type C
    Figure US20080021020A1-20080124-C00671
    Type D
    Figure US20080021020A1-20080124-C00672
    No. Type R16 R31 R32 R33 A549 H1299
    1066 B ethyl H OMe Cl
    1067 B ethyl H Cl Cl
    1068 B ethyl — — —
    1069 B ethyl H F OMe
    1070 A ethyl H OMe Cl
    1071 A ethyl H Cl Cl
    1072 C ethyl — — —
    1073 A ethyl H F OMe
    1074 B n-propyl H OMe Cl + +
    1075 B n-propyl H Cl Cl − −
    1076 D n-propyl — — — + +
    1077 A n-propyl H F OMe + +
    1078 B n-propyl H OMe Cl + +
    1079 B n-propyl H Cl Cl + +
    1080 C n-propyl — — — + +
    1081 A n-propyl H F OMe + +
    1082 B n-butyl H OMe Cl + −
    1083 B n-butyi H Cl Cl + +
    1084 D n-butyl — — — + +
    1085 B n-butyl H F OMe + +
    1086 A n-butyl H OMe Cl + +
    1087 A n-butyl H Cl Cl + +
    1088 C n-butyl — — — + +
    1089 A n-butyl H F OMe + +
    1090 B
    Figure US20080021020A1-20080124-C00673
         		H OMe Cl + +
    1091 B
    Figure US20080021020A1-20080124-C00674
         		H Cl Cl − −
    1092 D
    Figure US20080021020A1-20080124-C00675
         		— — — + +
    1093 B
    Figure US20080021020A1-20080124-C00676
         		H F OMe + +
    1094 A
    Figure US20080021020A1-20080124-C00677
         		H OMe Cl + +
    1095 A
    Figure US20080021020A1-20080124-C00678
         		H Cl Cl + +
    1096 C
    Figure US20080021020A1-20080124-C00679
         		— — — + +
    1097 A
    Figure US20080021020A1-20080124-C00680
         		H F OMe − +
    1098 B
    Figure US20080021020A1-20080124-C00681
         		H OMe Cl − +
    1099 B
    Figure US20080021020A1-20080124-C00682
         		H Cl Cl + +
    1100 D
    Figure US20080021020A1-20080124-C00683
         		— — — + +
    1101 B
    Figure US20080021020A1-20080124-C00684
         		H F OMe + +
    1102 A
    Figure US20080021020A1-20080124-C00685
         		H OMe Cl + +
    1103 A
    Figure US20080021020A1-20080124-C00686
         		H Cl Cl ° −
    1104 C
    Figure US20080021020A1-20080124-C00687
         		— — — + +
    1105 A
    Figure US20080021020A1-20080124-C00688
         		H F OMe + +
    1106 B
    Figure US20080021020A1-20080124-C00689
         		H OMe Cl + +
    1107 B
    Figure US20080021020A1-20080124-C00690
         		H Cl Cl − −
    1108 D
    Figure US20080021020A1-20080124-C00691
         		— — — + +
    1109 B
    Figure US20080021020A1-20080124-C00692
         		H F OMe + +
    1110 A
    Figure US20080021020A1-20080124-C00693
         		H OMe Cl + +
    1111 A
    Figure US20080021020A1-20080124-C00694
         		H Cl Cl + +
    1112 C
    Figure US20080021020A1-20080124-C00695
         		— — — + +
    1113 A
    Figure US20080021020A1-20080124-C00696
         		H F OMe + +
    1114 B
    Figure US20080021020A1-20080124-C00697
         		H OMe Cl
    1115 B
    Figure US20080021020A1-20080124-C00698
         		H Cl Cl + +
    1116 D
    Figure US20080021020A1-20080124-C00699
         		— — —
    1117 8
    Figure US20080021020A1-20080124-C00700
         		H F OMe + +
    1118 A
    Figure US20080021020A1-20080124-C00701
         		H OMe Cl + +
    1119 A
    Figure US20080021020A1-20080124-C00702
         		H Cl Cl + +
    1120 C
    Figure US20080021020A1-20080124-C00703
         		— — —
    1121 A
    Figure US20080021020A1-20080124-C00704
         		H F OMe + +
    1122 C methyl — — —
    1123 C methyl — — —
    1124 C methyl — — —
    1125 C methyl — — —
    1126 C methyl — — —
    1127 B i-propyl H OMe Cl
    1128 B i-propyl H Cl Cl
    1129 D i-propyl — — —
    1130 B i-propyl H F OMe
    1131 A i-propyl H OMe Cl
    1132 A i-propyl H Cl Cl
    1133 C i-propyl — — —
    1134 C methyl — — —
    1135 C H — — —
    1136 C H — — —
    1137 C ethyl — — —
    1138 C i-propyl — — —
  • TABLE 14
    No. Structure A549 H1299
    1139
    Figure US20080021020A1-20080124-C00705
         		+ −
    1140
    Figure US20080021020A1-20080124-C00706
         		− −
    1141
    Figure US20080021020A1-20080124-C00707
         		− −
    1142
    Figure US20080021020A1-20080124-C00708
         		+ −
    1143
    Figure US20080021020A1-20080124-C00709
    1144
    Figure US20080021020A1-20080124-C00710
    1145
    Figure US20080021020A1-20080124-C00711
         		+ +
    1146
    Figure US20080021020A1-20080124-C00712
         		+ −
    1147
    Figure US20080021020A1-20080124-C00713
         		+ +
    1148
    Figure US20080021020A1-20080124-C00714
    1149
    Figure US20080021020A1-20080124-C00715
    1150
    Figure US20080021020A1-20080124-C00716
    1151
    Figure US20080021020A1-20080124-C00717
    1152
    Figure US20080021020A1-20080124-C00718
    1153
    Figure US20080021020A1-20080124-C00719
    1154
    Figure US20080021020A1-20080124-C00720
    1155
    Figure US20080021020A1-20080124-C00721
    1156
    Figure US20080021020A1-20080124-C00722
    1157
    Figure US20080021020A1-20080124-C00723
    1158
    Figure US20080021020A1-20080124-C00724
         		+ +
    1159
    Figure US20080021020A1-20080124-C00725
         		+ +
    1160
    Figure US20080021020A1-20080124-C00726
         		+ +
    1161
    Figure US20080021020A1-20080124-C00727
         		+
    1162
    Figure US20080021020A1-20080124-C00728
         		+ +
    1163
    Figure US20080021020A1-20080124-C00729
         		+ +
    1164
    Figure US20080021020A1-20080124-C00730
         		+ +
  • Those of skill in the art will appreciate that the 2,4-pyrimidinediamine compounds described herein may include functional groups that can be masked with progroups to create prodrugs. Such prodrugs are usually, but need not be, pharmacologically inactive until converted into their active drug form. For example, ester groups commonly undergo acid-catalyzed hydrolysis to yield the parent carboxylic acid when exposed to the acidic conditions of the stomach, or base-catalyzed hydrolysis when exposed to the basic conditions of the intestine or blood. Thus, when administered to a subject orally, 2,4-pyimidinediamines that include ester moieties may be considered prodrugs of their corresponding carboxylic acid, regardless of whether the ester form is pharmacologically active.
  • In the prodrugs of the invention, any available functional moiety may be masked with a progroup to yield a prodrug. Functional groups within the 2,4-pyrimidinediamine compounds that may be masked with progroups for inclusion in a promoiety include, but are not limited to, amines (primary and secondary), hydroxyls, sulfanyls (thiols), carboxyls, etc. Myriad progroups suitable for masking such functional groups to yield promoieties that are cleavable under the desired conditions of use are known in the art. All of these progroups, alone or in combinations, may be included in the prodrugs of the invention.
  • In one illustrative embodiment, the prodrugs are compounds according to structural formulae (I)-(VI) in which RaRb and Rc may be, in addition to their previously-defined alternatives, a progroup.
  • In another illustrative embodiment, the prodrugs are compounds according to structural formulae (I)-(VI) in which R2′ and R4′ are each, independently of one another, a progroup. Specific examples of progroups according to this embodiment of the invention include, but are not limited to, —C(O)CH3, —C(O)NHRh and —S(O)2Rh, where Rh is selected from the group consisting of lower alyl, (C5-C15) aryl and (C3-C8) cycloalkyl.
  • Those of skill in the art will appreciate that many of the compounds and prodrugs described herein, as well as the various compound species specifically described and/or illustrated herein, may exhibit the phenomena of tautomerism, conformational isomerism, geometric isomerism and/or optical isomerism. For example, the compounds and prodrugs may include one or more chiral centers and/or double bonds and as a consequence may exist as stereoisomers, such as double-bond isomers (i.e., geometric isomers), enantiomers and diasteromers and mixtures thereof, such as racemic mixtures. As another example, the compounds and prodrugs may exist in several tautomeric forms, including the enol form, the keto form and mixtures thereof. As the various compound names, formulae and compound drawings within the specification and claims can represent only one of the possible tautomeric, conformational isomeric, optical isomeric or geometric isomeric forms, it should be understood that the invention encompasses any tautomeric, conformational isomeric, optical isomeric and/or geometric isomeric forms of the compounds or prodrugs having one or more of the utilities described herein, as well as mixtures of these various different isomeric forms. In cases of limited rotation around the 2,4-pyrimidinediamine core structure, atrop isomers are also possible and are also specifically included in the compounds and/or prodrugs of the invention.
  • Depending upon the nature of the various substituents, the 2,4-pyrimidinediamine compounds and prodrugs may be in the form of salts. Such salts include salts suitable for pharmaceutical uses (“pharmaceutically-acceptable salts”), salts suitable for veterinary uses, etc. Such salts may be derived from acids or bases, as is well-known in the art.
  • In some embodiments, the salt is a pharmaceutically acceptable salt. Generally, pharmaceutically acceptable salts are those salts that retain substantially one or more of the desired pharmacological activities of the parent compound and which are suitable for administration to humans. Pharmaceutically acceptable salts include acid addition salts formed with inorganic acids or organic acids. Inorganic acids suitable for forming pharmaceutically acceptable acid addition salts include, by way of example and not limitation, hydrohalide acids (e.g., hydrochloric acid, hydrobromic acid, hydriodic, etc.), sulfuric acid, nitric acid, phosphoric acid, and the like. Organic acids suitable for forming pharmaceutically acceptable acid addition salts include, by way of example and not limitation, acetic acid, trifluoroacetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, oxalic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, palmitic acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, alkylsulfonic acids (e.g., methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, etc.), arylsulfonic acids (e.g., benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, etc.), 4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like.
  • Pharmaceutically acceptable salts also include salts formed when an acidic proton present in the parent compound is either replaced by a metal ion (egg, an alkali metal ion, an alkaline earth metal ion or an aluminum ion) or coordinates with an organic base (e.g., ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, morpholine, piperidine, dimethylamine, diethylamine, etc.).
  • The 2,4-pyrimidinediamine compounds and prodrugs, as well as the salts thereof, may also be in the form of hydrates, solvates and N-oxides, as are well-known in the art.
  • 5.3 Methods of Synthesis
  • The 2,4-pyrimidinediamine compounds and prodrugs may be synthesized via a variety of different synthetic routes using commercially available starting materials and/or starting materials prepared by conventional synthetic methods. Suitable exemplary methods that may be routinely adapted to synthesize the 2,4-pyrimidinediamine compounds and prodrugs are found in U.S. Pat. No. 5,958,935, the disclosure of which is incorporated herein by reference. Specific examples describing the synthesis of numerous 2,4-pyrimidinediamine compounds and prodrugs, as well as intermediates therefor, are described in copending U.S. application Ser. No. 10/355,543, filed Jan. 31, 2003 (US 2004-0029902 published Feb. 12, 2004), WO 03/63794, copending U.S. application Ser. No. 10/631,029, filed Jul. 29, 2003, WO 2004/014312, copending application Ser. No. ______, filed Jul. 30, 2004 (identified by attorney docket no, 28575/US/US/US) and international application no. ______, filed Jul. 30, 2004 (identified by attorney docket no. 28575/US/US/PCT), the contents of which are incorporated herein by reference, All of the compounds described herein (including prodrugs) can be prepared according to, or by routine adaptation of, these various methods.
  • A variety of exemplary synthetic routes that can be used to synthesize the 2,4-pyrimidinediamine compounds and prodrugs are described in Schemes (I)-(XI), below. In Schemes (I)-(XI), like-numbered compounds have similar structures. These methods may be routinely adapted to synthesize the corresponding N2- and/or N4-alkylated compounds and prodrugs, as illustrated in Scheme (XII).
  • In one exemplary embodiment, the compounds can be synthesized from substituted or unsubstituted uracils or thiouracils as illustrated in Scheme (I), below:
    Figure US20080021020A1-20080124-C00731
  • In Scheme (I), R2, R4, R5, R6, L1 and L2 are as previously defined for structural formulae (I), X is a halogen (e.g., F, Cl, Br or I) and G and G′ are each, independently of one another, selected from the group consisting of O and S. Referring to Scheme (I), uracil or thiouracil 2 is dihalogenated at the 2- and 4-positions using standard halogenating agent POX3 (or other standard halogenating agent) under standard conditions to yield 2,4-bishalo pyrimidine 4, Depending upon the R5 substituent, in pyrimidine 4, the halide at the C4 position is more reactive towards nucleophiles than the halide at the C2 position. This differential reactivity can be exploited to synthesize 2,4-pyrimidinediamines according structural formulae (I by first reacting 2,4-bishalopyrimidine 4 with one equivalent of amine 10, yielding 4N-substituted-2-halo-4-pyiimidineamine 8, followed by amine 6 to yield a 2,4-pyrimidinediamine according structural formulae (U) 2N,4N-bis(substituted)-2,4-pyrimidinediamines 12 and 14 can be obtained by reacting 2,4-bishalopyrimidine 4 with excess 6 or 10, respectivel.
  • In most situations, the C4 halide is more reactive towards nucleophiles, as illustrated in the Scheme, However, as will be recognized by skilled artisans, the identity of the R5 substituent may alter this reactivity. For example, when R5 is trifluoromethyl, a 50:50 mixture of 4N-substituted-4-pyrimidineamine 8 and the corresponding 2N-substituted-2-pyrimidineamine is obtained Regardless of the identity of the R5 substituent, the regioselectivity of the reaction can be controlled by adjusting the solvent and other synthetic conditions (such as temperature), as is well-known in the art.
  • The reactions depicted in Scheme (1) may proceed more quickly when the reaction mixtures are heated via microwave. When heating in this fashion, the following conditions may be used: heat to 175° C. in ethanol for 5-20 min, in a Smith Reactor (Personal Chemistry) in a sealed tube (at 20 bar pressure).
  • The uracil or thiouracil 2 starting materials may be purchased from commercial sources or prepared using standard techniques of organic chemistry, Commercially available uracils and thiouracils that can be used as starting materials in Scheme (I) include, by way of example and not limitation, uracil (Aldrich #13,078-8; CAS Registry 66-22-8); 2-thio-uracil (Aldrich #11,558-4; CAS Registry 141-90-2); 2,4-dithiouracil (Aldrich #15,846-1; CAS Registry 2001-93-6); 5-bromouracil (Aldrich #85,247-3; CAS Registry 51-20-7; 5-fluorouracil (Aldrich #85,847-1; CAS Registry 51-21-8); 5-iodouracil (Aldrich #85,785-8; CAS Registry 696-07-1); 5-nitrouracil (Aldrich #85,276-7; CAS Registry 611-08-5); 5-(trifluoromethyl)-uracil (Aldrich #22,327-1; CAS Registry 54-20-6). Additional 5-substituted uracils and/or thiouracils are available from General Intermediates of Canada, Inc., Edmonton, Calif. (www.generalintermediates.com) and/or Interchim, Cedex, France (www.interchim.com), or may be prepared using standard techniques. Myriad textbook references teaching suitable synthetic methods are provided infra.
  • Amines 6 and 10 may be purchased from commercial sources or, alternatively, may be synthesized utilizing standard techniques. For example, suitable amines may be synthesized from nitro precursors using standard chemistry. Specific exemplary reactions are provided in the Examples section. See also Vogel, 1989, Practical Organic Chemistry, Addison Wesley Longman, Ltd. and John Wiley & Sons, Inc.
  • Skilled artisans will recognize that in some instances, amines 6 and 10 and/or substituents R5 and/or R6 on uracil or thiouracil 2 may include functional groups that require protection during synthesis. The exact identity of any protecting group(s) used will depend upon the identity of the functional group being protected, and will be apparent to these of skill in the art. Guidance for selecting appropriate protecting groups, as well as synthetic strategies for their attachment and removal, may be found, for example, in Greene & Wuts, Protective Groups in Organic Synthesis, 3d Edition, John Wiley & Sons, Inc., New York (1999) and the references cited therein (hereinafter “Greene & Wuts”).
  • A specific embodiment of Scheme (1) utilizing 5-fluorouracil (Aldrich #32,937-1) as a starting material is illustrated in Scheme (II), below.
    Figure US20080021020A1-20080124-C00732
  • In Scheme (II), R2, R4, L1 and L2 are as previously defined for Scheme (I). According to Scheme (II), 5-fluorouracil 3 is halogenated with POCl3 to yield 2,4-dichloro-5-fluoropyrimidine 5, which is then reacted with excess amine 6 or 10 to yield N2,N4-bis substituted 5-fluoro-2,4-pyrimidinediamine 11 or 13, respectively. Alternatively, non-bis-2N,4N-disubstituted-5-fluoro-2,4-pyrimidinediamine 9 may be obtained by reacting 2,4-dichloro-5-fluoropyrimidine 5 with one equivalent of amine 10 (to yield 2-chloro-N4-substituted-5-fluoro-4-pyrimidineamine 7) followed by one or more equivalents of amine 6.
  • In another exemplary embodiment, the 2,4-pyrimidinediamine compounds of the invention may be synthesized from substituted or unstibstituted cytosines as illustrated in Schemes (IIa) and (IIb), below:
    Figure US20080021020A1-20080124-C00733
    Figure US20080021020A1-20080124-C00734
  • In Schemes (IIa) and (IIb), R2, R4, R5, R6, L1, L2 and X are as previously defined for Scheme (I) and PG represents a protecting group. Referring to Scheme (IIa), the C4 exocyclic amine of cytosine 20 is first protected with a suitable protecting group PG to yield N4-protected cytosine 22. For specific guidance regarding protecting groups useful in this context, see Vorbrüggen and Ruh-Pohlenz, 2001, Handbook of Nucleoside Synthesis, John Wiley & Sons, NY, pp, 1-631 (“Vorbrüggen”). Protected cytosine 22 is halogenated at the C2 position using a standard halogenation reagent under standard conditions to yield 2-chloro-4N-protected-4-pyrimidineamine 24 Reaction with amine 6 followed by deprotection of the C4 exocyclic amine and reaction with amine 10 yields a 2,4-pyrimidinediamine according to structural formulae (I).
  • Alternatively, referring to Scheme (IIb), cytosine 20 may be reacted with amine 10 or protected amine 21 to yield N4-substituted cytosine 23 or 27, respectively. These substituted cytosines may then be halogenated as previously described, deprotected (in the case of N4-substituted cytosine 27) and reacted with amine 6 to yield a 2,4-pyrimidinediamine according to structural formulae (I).
  • Commercially-available cytosines that may be used as starting materials in Schemes (IIa) and (IIb) include, but are not limited to, cytosine (Aldrich #14,201-8; CAS Registry 71-30-7); N4-acetylcytosine (Aldrich #37,791-0; CAS Registry 14631-20-0); 5-fluorocytosine (Aldrich #27,159-4; CAS Registry 2022-85-7); and 5-(trifluoromethyl)-cytosine. Other suitable cytosines useful as starting materials in Schemes (IIa) are available from General Intermediates of Canada, Inc., Edmonton, Calif. (www.generalintermediates.com) and/or Interchim, Cedex, France (www.interchim.com), or may be prepared using standard techniques, Myriad textbook references teaching suitable synthetic methods are provided infra.
  • In still another exemplary embodiment, the 2,4-pyrimidinediamine compounds may be synthesized from substituted or unsubstituted 2-amino-4-pyrimidinols as illustrated in Scheme (III), below:
    Figure US20080021020A1-20080124-C00735
  • In Scheme (III), R2, R4, R5, R6, L1, L2 and X are as previously defined for Scheme (1) and Z is a leaving group as discussed in more detail in connection with Scheme IV, infra, Referring to Scheme (III), 2-amino-4-pyrimidinol 30 is reacted with amine 6 (or optionally protected amine 21) to yield N2-substituted-4-pyrimidinol 32, which is then halogenated as previously described to yield N2-substituted-4-halo-2-pyrimidineamine 34, Optional deprotection (for example if protected amine 21 was used in the first step) followed by reaction with amine 10 affords a 2,4-pyrimidinediamine according to structural formulae (I). Alternatively, pyrimidinol 30 can be reacted with acylating agent 31.
  • Suitable commercially-available 2-amino-4-pyrimidinols 30 that can be used as starting materials in Scheme (III) are available from General Intermediates of Canada, Inc, Edmonton, Calif. (www.generalintermediates.com) and/or Interchim, Cedex, France (www.interchim.com), or may be prepared using standard techniques. Myriad textbook references teaching suitable synthetic methods are provided infra.
  • Alternatively, the 2,4-pyrimidinediamine compounds may be prepared from substituted or unsubstituted 4-amino-2-pyrimidinols as illustrated in Scheme (IV), below:
    Figure US20080021020A1-20080124-C00736
  • In Scheme (IV), R2, R4, R5, R6, L1 and L2 awe as previously defined for Scheme (I) and Z represents a leaving group. Referring to Scheme (IV), the C2-hydroxyl of 4-amino-2-pyrimidinol 40 is more reactive towards nucleophiles than the C4-amino such that reaction with amine 6 yields N2-substituted-2,4-pyrimidinediamine 42. Subsequent reaction with compound 44, which includes a good leaving group Z, or amine 10 yields a 2,4-pyrimidinediamine according to structural formulae (I) Compound 44 may include virtually any leaving group that can be displaced by the C4-amino of N2-substituted-2,4-pyrimidinediamine 42, Suitable leaving groups Z include, but are not limited to, halogens, methanesulfonyloxy (mesyloxy; “OMs”), trifluoromethanesulfonyloxy (“OTf”) and p-toluenesulfonyloxy (tosyloxy; “OTs”), benzene sulfonyloxy (“besylate”) and metanitro benzene sulfonyloxy (“nosylate”). Other suitable leaving groups will be apparent to those of skill in the art.
  • Substituted 4-amino-2-pyrimidinol starting materials may be obtained commercially or synthesized using standard techniques. Myriad textbook references teaching suitable synthetic methods are provided infra.
  • In still another exemplary embodiment, the 2,4-pyrimidinediamine compounds can be prepared from 2-chloro-4-aminopyrimidines or 2-amino-4-chloropyrimidines as illustrated in Scheme (V), below:
    Figure US20080021020A1-20080124-C00737
  • In Scheme (V), R2, R4, R5, R6, L1, L2 and X are as defined for Scheme (I) and Z is as defined for Scheme (IV). Referring to Scheme (V), 2-amino-4-chloropyrimidine 50 is reacted with amino 10 to yield 4N-substituted-2-pyrimidineamine 52 which, following reaction with compound 31 or amine 6, yields a 2,4-pyrimidinediamine according to structural formulae (I). Alternatively, 2-chloro-4-amino-pyrimidine 54 may be reacted with compound 44 followed by amine 6 to yield a compound according to structural formulae (I).
  • A variety of pyrimidines 50 and 54 suitable for use as starting materials in Scheme (V) are commercially available from General Intermediates of Canada, Inc., Edmonton, Calif. (www.generalintermediates.com) and/or Interchim, Cedex, France (www.interchim.com), or may be prepared using standard techniques Myriad textbook references teaching suitable synthetic methods are provided infra.
  • Alternatively, 4-chloro-2-pyrimidineamines 50 may be prepared as illustrated in Scheme (Va):
    Figure US20080021020A1-20080124-C00738
  • In Scheme (Va), R5 and R6 are as previously defined for structural formulae (I). In Scheme (Va), dicarbonyl 53 is reacted with guanidine to yield 2-pyrimidineamine 51, Reaction with peracids like m-chloroperbenzoic acid, trifluoroperacetic acid or urea hydrogen peroxide complex yields N-oxide 55, which is then halogenated to give 4-chloro-2-pyrimidineamine 50. The corresponding 4-halo-2-pyrimidineamines may be obtained by using suitable halogenation reagents.
  • In yet another exemplary embodiment, the 2,4-pyrimidinediamine compounds can be prepared from substituted or unsubstituted uridines as illustrated in Scheme (VI) below:
    Figure US20080021020A1-20080124-C00739
  • In Scheme (VI), R2, R4, R5, R6, L1, L2 and X are as previously defined for Scheme (I) and the superscript PG represents a protecting group, as discussed in connection with Scheme (IIb). According to Scheme (VI), uridine 60 has a C4 reactive center such that reaction with amine 10 or protected amine 21 yields N4-substituted cytidine 62 or 64, respectively, Acid-catalyzed deprotection of N4-substituted 62 or 64 (when “PG” represents an acid-labile protecting group) yields N4-substituted cytosine 28, which may be subsequently halogenated at the C2-position and reacted with amine 6 to yield a 2,4-pyrimidinediamine according to structural formulae (I).
  • Cytidines may also be used as starting materials in an analogous manner, as illustrated in Scheme (VII), below:
    Figure US20080021020A1-20080124-C00740
  • In Scheme (VII), R2, R4, R5, R6, L1, L2 and X are as previously defined in Scheme (I) and the superscript PG represents a protecting group as discussed above. Referring to Scheme (VII, like uridine 60, cytidine 70 has a C4 reactive center such that reaction with anine 10 or protected amine 21 yields N4-substituted cytidine 62 or 64, respectively. These cytidines 62 and 64 are then treated as previously described for Scheme (VI) to yield a 2,4-pyrimidinediamine according to structural formulae (I).
  • Although Schemes (VI) and (VII) are exemplified with ribosylnucleosides, skilled artisans will appreciate that the corresponding 2′-deoxyribo and 2′,3′-dideoxyribo nucleosides, as well as nucleosides including sugars or sugar analogs other than ribose, would also work.
  • Numerous uridines and cytidines useful as starting materials in Schemes (VI) and (VII) are known in the art, and include, by way of example and not limitation, 5-trifluoromethyl-2′-deoxycytidine (Chem, Sources #ABCR F07669; CAS Registry 66,384-66-5); 5-bromouridine (Chem. Sources Int'l 2000; CAS Registry 957-75-5); 5-iodo-2′-deoxyuridine (Aldrich #1-775-6; CAS Registry 54-42-2); 5-fluorouridine (Aldrich #32,937-1; CAS Registry 316-46-1); 5-iodouridine (Aldrich #85,259-7; CAS Registry 1024-99-3); 5-(trifluoromethyl)uridine (Chem. Sources Int'l 2000; CAS Registry 70-00-8); 5-trifluoromethyl-2′-deoxyuridine (Chem. Sources Int'l 2000; CAS Registry 70-00-8). Additional uridines and cytidines that can be used as starting materials in Schemes (VI) and (VII) are available from General Intermediates of Canada, Inc., Edmonton, Calif. (www.generalintermediates.com) and/or Interchim, Cedex, France (www.interchim.com), or may be prepared using standard techniques. Myriad textbook references teaching suitable synthetic methods are provided infra.
  • As will be recognized by skilled artisans, certain 2,4-pyrimidinediamines compounds synthesized via the exemplary methods described above, or by other well-known means, may also be utilized as starting materials and/or intermediates to synthesize additional 2,4-pyrimidinediamine compounds. A specific example is illustrated in Scheme (VIII), below:
    Figure US20080021020A1-20080124-C00741
  • In Scheme (VIII), R4, R5, R6, L1, L2, Y, Ra and Rc are as previously defined for structural formulae (I). Each Ra′ is independently an R5, and may be the same or different from the illustrated Ra. Referring to Scheme (VIII), carboxylic acid or ester 100 may be converted to amide 104 by reaction with amine 102. In amine 102, Ra′ may be the same or different than Ra of acid or ester 100. Similarly, carbonate ester 106 may be converted to carbamate 108.
  • A second specific example is illustrated in Scheme (IX), below:
    Figure US20080021020A1-20080124-C00742
  • In Scheme (IX) R4, R5, R6, L2, Y and Rc are as previously defined for structural formulae (I). Referring to Scheme (IX), amide 110 or 116 may be converted to amine 114 or 118, respectively, by borane reduction with borane methylsulfide complex 112. Other suitable reactions for synthesizing 2,4-pyrimidinediamine compounds from 2,4-pyrimidinediamine starting materials will be apparent to those of skill in the art.
  • Compounds including alkyl groups at the amine groups at the 2- and/or 4-position of the 2,4-pyrimidinediamine ring can be prepared using routine alkylation procedures. An exemplary scheme for selectively methylating the amine group at the 4-position of the 2,4-pyrimidinediamine is illustrated in Scheme (XII):
    Figure US20080021020A1-20080124-C00743
  • In Scheme (XII), L1, L2, R2, R4, R5 and R6 are as previously defined for structural formula (I). The above Scheme can be routinely adapted to synthesize other N-alkylated compounds.
  • Compounds that are entiomerically or diasteriomerically pure can be synthesized via chiral-specific syntheses utilizing enantiomerically or diasteriomerically pure starting reagents as is known in the art. Alternatively, specified enantiomers, diastereomers and/or mixtures thereof can be isolated utilizing conventional chiral separation techniques.
  • Although many of the synthetic schemes discussed above do not illustrate the use of protecting groups, skilled artisans will recognize that in some instances certain substituents, such as, for example, R2 and/or R4, may include functional groups requiring protection. The exact identity of the protecting group used will depend upon, among other things, the identity of the functional group being protected and the reaction conditions used in the particular synthetic scheme, and will be apparent to those of skill in the art Guidance for selecting protecting groups and chemistries for their attachment and removal suitable for a particular application can be found, for example, in Greene & Wuts, supra.
  • Prodrugs as described herein may be prepared by routine modification of the above-described methods, Alternatively, such prodrugs may be prepared by reacting a suitably protected 2,4-pyrimidinediamine of structural formula (I), (II), (III), (IV) and/or (V) with a suitable progroup. Conditions for carrying out such reactions and for deprotecting the product to yield a prodrugs as described herein are well-known.
  • Myriad references teaching methods useful for synthesizing pyrimidines generally, as well as starting materials described in Schemes (I)-(IX), are known in the art. For specific guidance, the reader is referred to Brown, D. J., “The Pyrimidines”, in The Chemistry of Heterocyclic Compounds, Volume 16 (Weissberger, A., Ed.), 1962, Interscience Publishers, (A Division of John Wiley & Sons), New York (“Brown I”); Brown, D. J., “The Pyrimidines”, in The Chemistry of Heterocyclic Compounds, Volume 16, Supplement I (Weissberger, A. and Taylor, E. C., Ed.), 1970, Wiley-Interscience, (A Division of John Wiley & Sons), New York (Brown II”); Brown, D. J., “The Pyrimidines”, in The Chemistry of Heterocyclic Compounds, Volume 16, Supplement II (Weissberger, A, and Taylor, E. C., Ed.), 1985, An Interscience Publication (John Wiley & Sons), New York (“Brown III”); Brown, D. J., “The Pyrimidines” in The Chemistry of Heterocyclic Compounds, Volume 52 (Weissberger, A. and Taylor; E. C., Ed.), 1994, John Wiley & Sons, Inc., New York, pp. 1-1509 (Brown IV”); Kenner, G. W. and Todd, A., in Heterocyclic Compounds, Volume 6, (Elderfield, R. C., Ed.), 1957, John Wiley, New York, Chapter 7 (pyrimidines); Paquette, L, A., Principles of Modern Heterocyclic Chemistry, 1968, W. A. Benjamin, Inc., New York, pp. 1-401 (uracil synthesis pp. 313, 315; pyrimidine synthesis pp. 313-316; amino pyrimidine synthesis pp. 315); Joule, J. A., Mills, K. and Smith, G. F., Heterocyclic Chemistry, 3rd Edition, 1995, Chapman and Hall, London, U-K, pp. 1-516; Vorbrüggen, H. and Ruh-Pohlenz, C., Handbook of Nucleoside Synthesis, John Wiley & Sons, New York, 2001, pp. 1-631 (protection of pyrimidines by acylation pp. 90-91; silylation of pyrimidines pp. 91-93); Joule, J. A., Mills, K. and Smith, G. F., Heterocyclic Chemistry, 4th Edition, 2000, Blackwell Science, Ltd, Oxford, UK., pp. 1-589; and Comprehensive Organic Synthesis, Volumes 1-9 (Trost, B. M. and Fleming, I., Ed.), 1991, Pergamon Press, Oxford, UK.
  • 5.4 Activity of the Antiproliferative Compounds
  • Active 2,4-pyrimidinediamine compounds typically inhibit proliferation of desired cells, such as tumor cells, with an IC50 in the range of about 1 mM or less, as measured in a standard in vitro cellular proliferation assay. Of course, skilled artisans will appreciate that compounds which exhibit lower IC50s, for example on the order of 100 P, 20 μM, 10 μM, 1 μM, 100 nM, 10 mM, 1 nM, or even lower, may be particularly useful in therapeutic applications. The antiproliferative activity may be cytostatic or it may be cytotoxic. In instances where antiproliferative activity specific to a particular cell type is desired, the compound may be assayed for activity with the desired cell type and counter-screened for a lack of activity against other cell types. The desired degree of “inactivity” in such counter screens, or the desired ratio of activity vs. inactivity may vary for different situations, and may be selected by the user.
  • 5.5 Uses of the Antiproliferative Compounds
  • The antiproliferative 2,4-pyrimidinediamine compounds, including the various salts, prodrugs, hydrates and N-oxide forms thereof, may be used to inhibit cell proliferation in a variety of contexts. According to some embodiments of the method, a cell or population of cells is contacted with an amount of such a compound effective to inhibit proliferation of the cell or cell population. The compound may act cytotoxically to kill the cell, or cytostatically to inhibit proliferation without killing the cell.
  • In some embodiments, the methods may be practiced as a therapeutic approach towards the treatment of proliferative disorders. Thus, in a specific embodiment, the 2,4-pyrimidinediamine compounds (and the various forms described herein) may be used to treat proliferative disorders in animal subjects, including humans. The method generally comprises administering to the subject an amount of a compound of the invention, or a salt, prodrug, hydrate or N-oxide thereof, effective to treat the disorder. In one embodiment, the subject is a mammal, including, but not limited to, bovine, horse, feline, canine, rodent, or primate. In another embodiment, the subject is a human.
  • A variety of cellular proliferative disorders may be treated with the compounds of the present invention. In one embodiment, the compounds are used to treat various cancers in afflicted subjects. Cancers are traditionally classified based on the tissue and cell type from which the cancer cells originate. Carcinomas are considered cancers arising from epithelial cells while sarcomas are considered cancers arising from connective tissues or muscle. Other cancer types include leukemias, which arise from hematopoietic cells, and cancers of nervous system cells, which arise from neural tissue. For non-invasive tumors, adenomas are considered benign epithelial tumors with glandular organization while chondomas are benign tumor arising from cartilage. In the present invention, the described compounds may be used to treat proliferative disorders encompassed by carcinomas, sarcomas, leukemias, neural cell tumors, and non-invasive tumors.
  • In a specific embodiment, the compounds are used to treat solid tumors arising from various tissue types, including, but not limited to, cancers of the bone, breast, respiratory tract (e.g., bladder), brain reproductive organs, digestive tract, urinary tract, eye, liver, skin, head, neck, thyroid, parathyroid, and mestastatic forms thereof.
  • Specific proliferative disorders include the following: a) proliferative disorders of the breast include, but are not limited to, invasive ductal carcinoma, invasive lobular carcinoma, ductal carcinoma, lobular carcinoma in situ, and metastatic breast cancer; b) proliferative disorders of the skin include, but are not limited to, basal cell carcinoma, squamous cell carcinoma, malignant melanoma, and Karposi's sarcoma; c) proliferative disorders of the respiratory tract include, but are not limited to, small cell and non-small cell lung carcinoma, bronchial adema, pleuropulmonary blastoma, and malignant mesothelioma; d) proliferative disorders of the brain include, but are not limited to, brain stem and hyptothalamic glioma, cerebellar and cerebral astrocytoma, medullablastoma, ependymal tumors, oligodendroglial, meningiomas, and neuroectodermal and pineal tumors; e) proliferative disorders of the male reproductive organs include, but are not limited to, prostate cancer, testicular cancer, and penile cancer f) proliferative disorders of the female reproductive organs include, but are not limited to, uterine cancer (endometrial), cervical, ovarian, vaginal, vulval cancers, uterine sarcoma, ovarian germ cell tumor; g) proliferative disorders of the digestive tract include, but are not limited to, anal, colon, colorectal, esophageal, gallbladder, stomach (gastric), pancreatic cancer, pancreatic cancer-Islet cell, rectal, small-intestine, and salivary gland cancers; h) proliferative disorders of the liver include, but are not limited to, hepatocellular carcinoma, cholangiocarcinioma, mixed hepatocellular cholangiocarcinoma, and primary liver cancer; i) proliferative disorders of the eye include, but are not limited to, intraocular melanoma, retinoblastoma, and rhabdomyosarcoma; j) proliferative disorders of the head and cancers include, but are not limited to, laryngeal, hypopharyngeal, nasopharyngeal, oropharyngeal cancers, and lip and oral cancer, squamous neck cancer, metastatic paranasal sinus cancer; k) proliferative disorders of the lymphomas include, but are not limited to, various T cell and B cell lymphomas, non-Hodgkins lymphoma, cutaneous T cell lymphoma, Hodgkins disease, and lymphoma of the central nervous system; 1) leukemias include, but are not limited to, acute myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, and hair cell leukemia, m) proliferative disorders of the thyroid include thyroid cancer, thymoma, and malignant thymoma; n) proliferative disorders of the urinary tract include, but are not limited to, bladder cancer; o) sarcomas include, but are not limited to, sarcoma of the soft tissue, osteosarcoma, malignant fibrous histiocytoma, lymphosarcoma, and rhabdomyosarcoma.
  • It is to be understood that the descriptions of proliferative disorders is not limited to the conditions described above, but encompasses other disorders characterized by uncontrolled growth and malignancy. It is further understood that proliferative disorders include various metastatic forms of the tumor and cancer types described herein. The compounds of the present invention may be tested for effectiveness against the disorders described herein, and a therapeutically effective regimen established Effectiveness, as further described below, includes reduction or remission of the tumor, decreases in the rate of cell proliferation, or cytostatic or cytotoxic effect on cell growth.
  • 5.6 Combination Therapies
  • The compounds of the present invention may be used alone, in combination with one another, or as an adjunct to, or in conjunction with, other established antiproliferative therapies. Thus, the compounds of the present invention may be used with traditional cancer therapies, such as ionization radiation in the form of γ-rays and x-rays, delivered externally or internally by implantation of radioactive compounds, and as a follow-up to surgical removal of tumors.
  • In another aspect, the compounds of the present invention may be used with other chemotherapeutic agents useful for the disorder or condition being treated. These compounds may be administered simultaneously, sequentially, by the same route of administration, or by a different route.
  • In one embodiment, the present compounds may be used with other anti-cancer or cytotoxic agents. Various classes of anti-cancer and anti-neoplastic compounds include, but are not limited to, alkylating agents, antimetabolites, vinca alkyloids, taxanes, antibiotics, enzymes, cytokines, platinum coordination complexes, substituted ureas, tyrosine kinase inhibitors, hormones and hormone antagonists. Exemplary alkylating agents include, by way of example and not limitation, mechlorothamine, cyclophosphamide, ifosfamide, melphalan, chlorambucil, ethyleneimines, methylmelamines, alkyl sulfonates (egg, busulfan), and carmustine. Exemplary antimetabolites include, by way of example and not limitation, folic acid analog methotrexate; pyrimidine analog fluorouracil, cytosine arbinoside; purine analogs mercaptopurine, thioguanine, and azathioprine. Exemplary vinca alkyloids include, by way of example and not limitation, vinblastine, vincristine, paclitaxel, and colchicine. Exemplary antibiotics include, by way of example and not limitation, actinomycin D, daunorubicin, and bleomycin. An exemplary enzyme effective as anti-neoplastic agents include L-asparaginase. Exemplary coordination compounds include, by way of example and not limitation, cisplatin and carboplatin. Exemplary hormones and hormone related compounds include, by way of example and not limitation, adrenocorticosteroids prednisone and dexamethasone; aromatase inhibitors amino glutethlimide, formestane, and anastrozole; progestin compounds hydroxyprogesteron caproate, medroxyprogesterone; and anti-estrogen compound tamoxifen.
  • These and other useful anti-cancer compounds are described in Merck Index, 13th Ed, (O'Neil M. J, et al., ed) Merck Publishing Group (2001) and Goodman and Gilmans The Pharmacological Basis of Therapeutics, 10th Edition, Hardman, J. G. and Limbird, L. E. eds., pg. 1381-1287, McGraw Hill, (1996), both of which are incorporated by reference herein.
  • Additional anti-proliferative compounds useful in combination with the compounds of the present invention include, by way of example and not limitation, antibodies directed against growth factor receptors (erg, anti-Her2); antibodies for activating T cells (e.g., anti-CTLA-4 antibodies); and cytokines such as interferon-α and interferon-γ, interleukin-2, and GM-CSF.
  • 5.7 Formulations and Administration
  • When used to treat or prevent such diseases, the active compounds may be administered singly, as mixtures of one or more active compounds or in mixture or combination with other agents useful for treating such diseases and/or the symptoms associated with such diseases. The active compounds may also be administered in mixture or in combination with agents useful to treat other disorders or maladies, such as steroids, membrane stabilizers. The active compounds or prodrugs may be administered per se, or as pharmaceutical compositions, comprising an active compound or prodrug.
  • Pharmaceutical compositions comprising the active compounds of the invention (or prodrugs thereof) may be manufactured by means of conventional mixing, dissolving, granulating, dragee-making levigating, emulsifying, encapsulating, entrapping or lyophilization processes. The compositions may be formulated in conventional manner using one or more physiologically acceptable carriers, diluents, excipients or auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically (see Remington's Pharmaceutical Sciences, 15th Ed, Hoover, J. E. ed., Mack Publishing Co. (2003)
  • The active compound or prodrug may be formulated in the pharmaceutical compositions per se, or in the form of a hydrate, solvate, N-oxide or pharmaceutically acceptable salt, as previously described Typically, such salts are more soluble in aqueous solutions than the corresponding free acids and bases, but salts having lower solubility than the corresponding free acids and bases may also be formed.
  • Pharmaceutical compositions of the invention may take a form suitable for virtually any mode of administration, including, for example, topical, ocular, oral, buccal, systemic, nasal, injection, transdermal, rectal, vaginal, etc., or a form suitable for administration by inhalation or insufflation.
  • For topical administration, the active compound(s) or prodrug(s) may be formulated as solutions, gels, ointments, creams, suspensions, etc, as are well-known in the art.
  • Systemic formulations include those designed for administration by injection, e.g., subcutaneous, intravenous, intramuscular, intrathecal or intraperitoneal injection, as well as those designed for transdermal, transmucosal oral or pulmonary administration.
  • Useful injectable preparations include sterile suspensions, solutions or emulsions of the active compound(s) in aqueous or oily vehicles. The compositions may also contain formulating agents, such as suspending, stabilizing and/or dispersing agent. The formulations for injection may be presented in unit dosage form, e.g., in ampules or in multidose containers, and may contain added preservatives.
  • Alternatively, the injectable formulation may be provided in powder form for reconstitution with a suitable vehicle, including but not limited to sterile pyrogen free water, buffer, dextrose solution, etc., before use. To this end, the active compound(s) may be dried by any art-known technique, such as lyophilization, and reconstituted prior to use.
  • For transmucosal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are known in the art.
  • For oral administration, the pharmaceutical compositions may take the form of, for example, lozenges, tablets or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g., pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (e.g., lactose, microcrystalline cellulose or calcium hydrogen phosphate); lubricants (e.g., magnesium stearate, talc or silica); disintegrants (e.g., potato starch or sodium starch glycolate); or wetting agents (e.g., sodium lauryl sulfate, lecithin). The tablets may be coated by methods well known in the art with, for example, sugars, films or enteric coatings.
  • Liquid preparations for oral administration may take the form of, for example, elixirs, solutions, syrups or suspensions, or they may be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (e.g., sorbitol syrup, cellulose derivatives or hydrogenated edible fats); emulsifying agents (e.g., lecithin or acacia); non-aqueous vehicles (e.g., almond oil, oily esters, ethyl alcohol, cremophore™ or fractionated vegetable oils); and preservatives (e.g., methyl or propyl-p-hydroxybenzoates or sorbic acid). The preparations may also contain buffer salts, preservatives, flavoring, coloring and sweetening agents as appropriate.
  • Preparations for oral administration may be suitably formulated to give controlled release of the active compound or prodrug, as is well known.
  • For buccal administration, the compositions may take the form of tablets or lozenges formulated in conventional manner.
  • For rectal and vaginal routes of administration, the active compound(s) may be formulated as solutions (for retention enemas) suppositories or ointments containing conventional suppository bases such as cocoa butter or other glycerides.
  • For nasal administration or administration by inhalation or insufflation, the active compound(s) or prodrug(s) can be conveniently delivered in the form of an aerosol spray from pressurized packs or a nebulizer with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, fluorocarbons, carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the dosage unit may be determined by providing a valve to deliver a metered amount. Capsules and cartridges for use in an inhaler or insufflator (for example capsules and cartridges comprised of gelatin) may be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.
  • For ocular administration, the active compound(s) or prodrug(s) may be formulated as a solution, emulsion, suspension, etc, suitable for administration to the eye. A variety of vehicles suitable for administering compounds to the eye are known in the art. Specific none limiting examples are described in U.S. Pat. No. 6,261,547; U.S. Pat. No. 6,197,934; U.S. Pat. No. 6,056,950; U.S. Pat. No. 5,800,807; U.S. Pat. No. 5,776,445; U.S. Pat. No. 5,698,219; U.S. Pat. No. 5,521,222; U.S. Pat. No. 5,403,841; U.S. Pat. No. 5,077,033; U.S. Pat. No. 4,882,150; and U.S. Pat. No. 4,738,851.
  • For prolonged delivery, the active compound(s) or prodrug(s) can be formulated as a depot preparation for administration by implantation or intramuscular injection. The active ingredient may be formulated with suitable polymeric or hydrophobic materials (e.g., as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, e.g., as a sparingly soluble salt. Alternatively, transdermal delivery systems manufactured as an adhesive disc or patch which slowly releases the active compound(s) for percutaneous absorption may be used. To this end, permeation enhancers may be used to facilitate transdermal penetration of the active compound(s), Suitable transdermal patches are described in for example, U.S. Pat. No. 5,407,713; U.S. Pat. No. 5,352,456; U.S. Pat. No. 5,332,213; U.S. Pat. No. 5,336,168; U.S. Pat. No. 5,290,561; U.S. Pat. No. 5,254,346; U.S. Pat. No. 5,164,189; U.S. Pat. No. 5,163,899; U.S. Pat. No. 5,088,977; U.S. Pat. No. 5,087,240; U.S. Pat. No. 5,008,110; and U.S. Pat. No. 4,921,475.
  • Alternatively, other pharmaceutical delivery systems may be employed. Liposomes and emulsions are well-known examples of delivery vehicles that may be used to deliver active compound(s) or prodrug(s). Certain organic solvents such as dimethylsulfoxide (DMSO) may also be employed, although usually at the cost of greater toxicity.
  • The pharmaceutical compositions may, if desired, be presented in a pack or dispenser device which may contain one or more unit dosage forms containing the active compound(s). The pack may, for example, comprise metal or plastic foil, such as a blister pack. The pack or dispenser device may be accompanied by instructions for administration.
  • 5.8 Effective Dosages
  • The active compound(s) or prodrug(s) of the invention, or compositions thereof will generally be used in an amount effective to achieve the intended result, for example in an amount effective to treat or prevent the particular disease being treated. The compound(s) may be administered therapeutically to achieve therapeutic benefit. By therapeutic benefit is meant eradication or amelioration of the underlying disorder being treated and/or eradication or amelioration of one or more of the symptoms associated with the underlying disorder such that the patient reports an improvement in feeling or condition, notwithstanding that the patient may still be afflicted with the underlying disorder. Therapeutic benefit also includes halting or slowing the progression of the disease, regardless of whether improvement is realized.
  • The amount of compound administered will depend upon a variety of factors, including, for example, the particular indication being treated, the mode of administration, the severity of the indication being treated and the age and weight of the patient, the bioavailability of the particular active compound, etc. Determination of an effective dosage is well within the capabilities of those skilled in the art.
  • Effective dosages may be estimated initially from in vitro assays. For example, an initial dosage for use in animals may be formulated to achieve a circulating blood or serum concentration of active compound that is at or above an IC50 of the particular compound as measured in an in vitro assay, such as the in vitro assays described in the Examples section. Calculating dosages to achieve such circulating blood or serum concentrations talking into account the bioavailability of the particular compound is well within the capabilities of skilled artisans. For guidance, the reader is referred to Fingl & Woodbury, “General Principles,” In: Goodman and Gilman's The Pharmaceutical Basis of Therapeutics, Chapter 1, pp. 1-46, latest edition, Pagamonon Press, and the references cited therein.
  • Initial dosages may also be estimated from in vivo data, such as animal models. Animal models useful for testing the efficacy of compounds to treat or prevent the various diseases described above are well-known in the art. Dosage amounts will typically be in the range of from about 0.0001 or 0.001 or 0.01 mg/kg/day to about 100 mg/kg/day, but may be higher or lower, depending upon, among other factors, the activity of the compound, its bioavailability, the mode of administration and various factors discussed above. Dosage amount and interval may be adjusted individually to provide plasma levels of the compound(s) which are sufficient to maintain therapeutic or prophylactic effect. For example, the compounds may be administered once per week, several times per week (e.g., every other day), once per day or multiple times per day, depending upon, among other things, the mode of administration, the specific indication being treated and the judgment of the prescribing physician. In cases of local administration or selective uptake, such as local topical administration, the effective local concentration of active compound(s) may not be related to plasma concentration Skilled artisans will be able to optimize effective local dosages without undue experimentation.
  • Preferably, the compound(s) will provide therapeutic or prophylactic benefit without causing substantial toxicity. Toxicity of the compound(s) may be determined using standard pharmaceutical procedures. The dose ratio between toxic and therapeutic (or prophylactic) LD50/ED50 effect is the therapeutic index (LD50 is the dose lethal to 50% of the population and ED50 is the dose therapeutically effective in 50% of the population). Compounds(s) that exhibit high therapeutic indices are preferred.
  • 5.9 Kits
  • The compounds and/or prodrugs described herein may be assembled in the form of kits. In some embodiments, the kit provides the compound(s) and reagents to prepare a composition for administration. The composition may be in a dry or lyophilized form, or in a solution, particularly a sterile solution. When the composition is in a dry form, the reagent may comprise a pharmaceutically acceptable diluent for preparing a liquid formulation. The kit may contain a device for administration or for dispensing the compositions, including, but not limited to syringe, pipette, transdermal patch, or inhalant.
  • The kits may include other therapeutic compounds for use in conjunction with the compounds described herein. In some embodiments, the therapeutic agents are other anti-cancer and anti-neoplastic compounds. These compounds may be provided in a separate form, or mixed with the compounds of the present invention.
  • The kits will include appropriate instructions for preparation and administration of the composition, side effects of the compositions, and any other relevant information. The instructions may be in any suitable format, including, but not limited to, printed matter, videotape, computer readable disk, or optical disc.
    • 6. EXAMPLES 6.1 In vitro Cellular Experiments
  • The compounds illustrated in TABLES 1-14, supra, were synthesized using the methods described herein. Salts of the compounds were prepared using standard techniques.
  • The IC50 values of various compounds against a various different tumor cell lines were determined using standard in vitro antiproliferation assays. The tumor cell lines tested were as follows: A549 (lung); H1299 (lung), ACHN (kidney/p53 wt), CAKI (renal cell carcinoma), NCI-H460 (lung); HCT116 (colon/p53 wt); HELA (cervix/p53 wt), HUH7 (liver/p53 wt), HUVEC (primary endothelial), LNCAP (prostate), HT-29 (colon); MCF-7 (breast); MCF-7 (breast/ER positive), MDA MB435S (breast); MDA MB231 (breast/ER negative), DU145 (prostate); BxPC-3 (pancreatic); SKOV-3 (ovarian); HepG2 (hepatic), NDHF primary normal human dermal fibroblast), SKMEL28 (breast/p53mut), SKMEL5 (breast/p53 wt), U2OS (bone) and PCS3 (prostate). The activity of the compounds against A549 cells and H1299 cells is reported in TABLES 1-14, supra. In the tables, a “+” indicates an IC50 of 20 μM or less, a “−” indicates an IC50 of >20 μM. A value of “−/+” indicates that the specific compound exhibited an IC50 of ≧20 μM in a 3-point assay, but exhibited an IC50 of ≦20 μM in a higher-point (e.g., 6-point) assay. A value of “+/−” indicates that the specific compound exhibited an IC50 of ≦20 μM in a 3-point assay, but exhibited an IC50 of >20 μM in a higher-point (e.g., 6-point) assay. A blank indicates the specified compound was not tested against the specified cell line. Many of the compounds tested exhibited IC50s against A549 and/or H1299 cells in the nanomolar range.
  • Many of the compounds were tested against other cell lines. Their activity is reported in TABLE 15, below, where +”, “−”, “−/+” or “+/−” values are as described for TABLES 1-14. Where the cell line includes a value in a parenthetical, the value indicates the seeding density at which the assay was performed
    TABLE 15
    No ACHN CAKI HCT116 HELA HUH7 HUVEC LNCAP MCF7(2K) MCF7(4K)
    254
    256
    300 +
    697 +
    699
    710 +
    717 −
    493 −/+
    494 +
    534 +
    626 +
    495 +
    629 +
    631 +
    632 +
    633 +
    634 −
    496 −
    497 −
    732 +
    500 +
    636 −
    742
    501
    502
    746
    747
    642
    748
    643
    749
    750
    751
    752
    503 +
    753
    754
    755 +
    504 +
    506 −
    507 −
    508
    509
    644 +
    645 +
    510
    761
    762
    763
    764
    765
    511
    512 + − + + + +
    766
    767
    646 + + − + + + +
    647 +
    649 − + + + +
    516 +
    523 + − + + + +
    790
    651 −
    652 −
    305 +
    306 −
    307 +
    835 +
    +
    309 +
    310 +
    311 +
    312 +
    313 −/+
    314 −/+
    838 −
    527 +
    528 +
    839 +
    841 +
    529 +
    845 +
    846 + + + +
    847 +
    848 +
    654 + +
    851 + +
    858 + + + + +
    868 + + +
    869 +
    933 +
    938
    940 +
    580
    581 +
    942 + + + + + + +
    947
    948
    949 +
    950 +
    954
    955
    956
    957
    958
    959
    960
    961
    962
    355 − +
    356 −
    676
    677 −
    358 −/+
    359 +/− +
    978
    979 +
    980 +
    981
    982
    983
    984
    985
    986
    987
    418
    101 + + +
    102 + + +
    103 + + +
    991 +
    104 −
    105 +
    106 + + +
    107 + + − + + + + + +
    419 +
    420 −
    110 +
    111 +
    112 +
    113 +
    114 +
    432 +
    435 +
    436 +
    211 + + + +
    125 + + + +
    141 + + + +
    1006  +
    1007  −
    1009  +
    No MDA-MB-231(2K) MDA-MB-231(4K) NDHF PC3 SKMEL28 SKMEL5 U20S
    254 +
    256 +
    300
    697
    699 −
    710
    717
    493
    494
    534
    626
    495
    629
    631
    632
    633
    634
    496
    497
    732
    500 −
    636
    742 +
    501 −
    502 −
    746 −
    747 +
    642 +
    748 −
    643 −
    749 −
    750 +
    751 −
    752 −
    503 −
    753 −
    754 −
    755
    504
    506
    507
    508 −
    509 −
    644 −
    645 −
    510 −
    761 −
    762 +
    763 −
    764 −
    765 +
    511 +
    512 + − + + +
    766 −
    767 −
    646 + + + +
    647
    649 + +
    516 +
    523 + + + +
    790 +
    651
    652
    305
    306
    307
    835
    +
    309
    310
    311
    312
    313
    314
    838
    527
    528
    839
    841
    529
    845
    846 + +
    847
    848
    654 + +
    851 +
    858 + + + + +
    868 + + +
    869 + +
    933
    938 −
    940 +
    580 −
    581
    942 + + + +
    947 +
    948 +
    949 + +
    950 +
    954 −
    955 −
    956 −
    957 +
    958 −
    959 −
    960 −
    961 −
    962 −
    355 +
    356
    676 +
    677
    358
    359
    978 −
    979 −
    980 −
    981 +
    982 −
    983 −
    984 +
    985 −
    986 −
    987 +
    418 +
    101 + +
    102 + +
    103 + +
    991
    104
    105
    106 + +
    107 + + + + + +
    419
    420
    110
    111
    112
    113
    114
    432
    435
    436
    211 + +
    125 + +
    141 + +
    1006 
    1007 
    1009 
    • 6.2 In Vivo Xenograft Experiments
  • Compounds 107, 858, 164, 211 and 156 were tested for their ability to shrink tumors generated from A549 cells in standard xenograft experiments. Compounds 141 and 211 were tested against H1299 tumors. When palpable tumors appeared and were of a preselected volume (approximately 40-150 mm3), the mice were administered test compounds as specified in TABLE 16, below. Preliminary results are reported in TABLE 16,
    TABLE 16
    Test Preliminary
    Compound Cell Type Dose Dose Schedule Formulation Comments Results
    107 A549 40 mg/kg 3x a day for 4 Liposome No No significant
    days followed by Vehicle (DMPC) precipitation reduction in
    5 days rest. was noted tumor size
    107 A549 25 mg/kg and Bid, daily 16% Cremophor/ Compound No significant
    50 mg/kg And 16% EtOH/ crashed out of reduction in
    Bid 4 days w/8 68% Saline solution when tumor size seen
    days rest saline was with either
    added dose
    858 A549 25 mg/kg Bid, daily 5% EtOH/ No No significant
    15% Cremophor/ precipitation reduction in
    80% Saline was noted tumor size seen
    164, 211 A549 25 mg/kg R563-5 days bid 100% DMSO No 23.2%
    with 2 days of precipitation reduction in
    rest was noted tumor size in
    R565 - bid, daily mice treated
    with 211.
    Compound 164
    showed no
    significant
    reduction in
    tumor size.
    141, 211 H1299 25 mg/kg Bid, daily 100% DMSO Compound 141 No significant
    precipitated out reduction in
    on day 2. tumor size was
    Compound was seen with
    prepared fresh either
    for days 3, 4, compound.
    and 5. No
    precipitation
    was noted for
    Compound 211
    156 A549 25 mg/kg and Bid, daily 0.9% Saline No 60.4%
    50 mg/kg precipitation reduction in
    was noted tumor size was
    observed in
    mice treated
    with 50 mg/kg.
    No significant
    reduction was
    seen at the
    lower dose.
  • Although the foregoing inventions have been described in some detail to facilitate understanding, it will be apparent that certain changes and modifications may be practiced within the scope of the appended claims. Accordingly, the described embodiments are to be considered as illustrative and not restrictive, and the invention is not to be limited to the details given herein, but may be modified within the scope and equivalents of the appended claims.
  • It is to be understood that when ranges of integers are described herein, the description is intended to include the endpoints and each intervening integer as though each integer were explicitly delineated. As a specific example, the description “an integer from 1 to 6,” is intended to explicitly describe 1, 2, 3, 4, 5 and 6.
  • All literature and patent references cited throughout the application are incorporated by reference into the application for all purposes.

Claims (101)

1. A method of inhibiting proliferation of a cancer cell, comprising contacting the cancer cell with an effective amount of a 2,4-pyrimidinediamine compound according to structural formula (I):
Figure US20080021020A1-20080124-C00744
including prodrugs, salts, hydrates, solvates and N-oxides thereof, wherein:
L1 and L2 are each, independently of one another, selected from a lower alkyldiyl linker, a lower allylene linker and a covalent bond;
R2 is selected from the group consisting of lower alkyl optionally substituted with an Rb group,
Figure US20080021020A1-20080124-C00745
 where Y is NH, O or CH2;
R2′ is hydrogen, methyl or lower alkyl;
R4′ is hydrogen, methyl or lower alkyl;
R4 is selected from the group consisting of lower alkyl optionally monosubstituted with an Ra or Rb group, lower cycloalkyl optionally monosubstituted with an Ra or Rb group, lower cycloheteroalkyl optionally substituted at one or more ring carbon and/or heteroatoms with an Ra or Rb group, —(CRaRa)n—Rb,
Figure US20080021020A1-20080124-C00746
 where D is —(CR7R7)m—,
Figure US20080021020A1-20080124-C00747
 where Z1 is N or CH and Z2 is O, S, NH, S(O) or S(O)2;
R5 is selected from the group consisting of halo, fluoro and —CF3;
R6 is hydrogen;
each R7 is independently selected from the group consisting of hydrogen, methyl, lower alkyl and halo;
each R8 is independently selected from the group consisting of hydrogen, lower allyl, —(CH2)nOH, —ORa, —(CH2)n—NRcRc, —O(CH2)n—Ra, —O(CH2)n—Rb, —C(O)ORa, —C(S)ORa, halo, —CF3 and —OCF3;
each R9 is independently selected from the group consisting of hydrogen, lower alkyl, —ORa, —(CH2)n—NRcRc, O(CH2)n—Ra, —O(CH2)n—Rb, —C(O)—NRcRc, —C(S)—NRcRc, —S(O)2NRcRc, —NHC(O)Ra, —NHC(S)Ra, —C(O)—NH—(CH2), —NRcRc, —C(S)—NH—(CH2), —NRcRc, halo, —CF3, —OCF3,
Figure US20080021020A1-20080124-C00748
each R10 is independently selected from the group consisting of hydrogen, lower alkyl, —(CH2)n—OH, —(CH2)n—NRcRc, ORa, O(CH2)n—Ra, —O(CH2)n—Rb, e halo, —CF3, —OCF3,
Figure US20080021020A1-20080124-C00749
each R11 is independently selected from the group consisting of —ORa, —NRcRc and NRaRd;
each R12 is independently selected from the group consisting of lower alkyl, arylalkyl, —ORa, —NRcRc, —C(O)Ra, —C(O)ORa and —C(O)NRcRc;
each R13 is independently selected from the group consisting of lower alkyl, hydroxy, lower alkoxy, methoxy, —C(O)NRcRc and —C(O)NH2;
each R15 is independently selected from the group consisting of hydrogen, lower alkyl, lower cycloakyl and phenyl;
each R16 is independently selected from the group consisting of hydrogen, methyl, lower alkyl, lower cycloalkyl, lower branched alkyl and lower cycloalkylmethyl;
each R17 is independently selected from the group consisting of hydrogen, lower alkyl, methyl and Rd or, alternatively, R17 may be taken together with R18 to form an oxo (═O) group;
each R18 is independently selected on the group consisting of hydrogen, lower alkyl and methyl or, alternatively, R18 may be taken together with R17 to form all oxo (═O) group;
each R19 is independently selected form the group consisting of hydrogen, lower alkyl, methyl and Rd;
each R20 is independently selected from the group consisting of hydrogen, lower alkyl, methyl and Rd;
each m is independently an integer from 1 to 3;
each n is independently an integer from 1 to 3;
each Ra is independently selected from the group consisting of hydrogen, lower alkyl, lower cycloalkyl, lower cycloalkylalkyl, phenyl and benzyl;
each Rb is independently selected from the group consisting of —ORa, —CF3, —OCF3, NRcRc, C(O)Ra, —C(S)Ra, —C(O)ORa, —C(S)ORa, —C(O)NRcRc, —C(S)NRcRc, S(O)2NRcRC, —C(O)NRaRd, —C(S)NRaRd and —S(O)2NRaRd;
each Rc is independently selected from the group consisting of hydrogen, lower alkyl and lower cycloalkyl, or, alternatively, two Rcs may be taken together with the nitrogen atom to which they are bonded to form a 5-7 membered saturated ring which optionally includes 1-2 additional heteroatomic groups selected from O, NRa, NRa—C(O)Ra, NRa—C(O)ORa and NRa—C(O)NRa; and
each Rd is independently selected from lower mono-hydroxyalkyl and lower di-hydroxyalkyl,
with the provisos that:
(i) when R2 is
Figure US20080021020A1-20080124-C00750
 then R9 and R10 are not both simultaneously lower alkoxy or methoxy, or when R2 is 3,4,5-trimethoxyphenyl or 3,4,5-tri(loweralkoxy)phenyl, then R4 is
Figure US20080021020A1-20080124-C00751
(ii) when R2 is lower alkyl, then R4 is
Figure US20080021020A1-20080124-C00752
(iii) when R4 is
Figure US20080021020A1-20080124-C00753
 and L2 is lower alkylene, then R2 is other than 3-(1,3-oxazolyl)phenyl;
(iv) when R4 is
Figure US20080021020A1-20080124-C00754
 where R15 is t-butyl and R2 is
Figure US20080021020A1-20080124-C00755
 then at least two of R8, R9 and R10 or R8, R9 and R13 are other than hydrogen;
(v) when R4 is
Figure US20080021020A1-20080124-C00756
 where R15 is t-butyl and R2 is
Figure US20080021020A1-20080124-C00757
where R1 and R9 are each hydrogen, then R10 is other than —(CH2)n—OH or —O(CH2)n—Rb where Rb is selected from NRcRc, —C(O)Ra, —C(O)NRcRc and —C(O)NRaRd.
2. The method of claim 1 in which L1 and L2 are each a covalent bond.
3. The method of claim 2 in which R5 is fluoro.
4. The method of claim 3 in which R2′ and R4′ are each hydrogen.
5. The method of claim 3 in which R2′ is hydrogen and R4′ is methyl.
6. The method of claim 3 in which R2 is
Figure US20080021020A1-20080124-C00758
7. The method of claim 6 in which R4 is selected from unsubstituted cyclopropyl, unsubstituted cyclobutyl, unsubstituted cyclopentyl, unsubstituted cyclohexyl
Figure US20080021020A1-20080124-C00759
where Re and Rf are selected from (C1-C3) alkanyl and methyl and Rg is benzyl.
8. The method of claim 7 in which R8 is hydrogen; R9 is selected from
Figure US20080021020A1-20080124-C00760
and R10 is other than
Figure US20080021020A1-20080124-C00761
9. The method of claim 8 in which R10 is selected from hydrogen, methyl, methoxy, hydroxymethyl, trifluoromethyl and chloro.
10. The method of claim 8 in which R12 is selected from methyl, —C(O)CH3, —C(O)OCH3 and —C(O)OCH2CH3.
11. The method of claim 8 in which R8 is hydrogen; R9 is other than
Figure US20080021020A1-20080124-C00762
and R10 is selected from
Figure US20080021020A1-20080124-C00763
12. The method of claim 11 in which R9 is selected from hydrogen, methyl, methoxy, hydroxymethyl, trifluoromethyl and chloro.
13. The method of claim 11 in which R12 is selected from methyl, —C(O)CH3, —C(O)OCH3 and —C(O)Cl2CH3.
14. The method of claim 8 in which R9 is other than
Figure US20080021020A1-20080124-C00764
and R10) is other than
Figure US20080021020A1-20080124-C00765
15. The method of claim 14 in which R8 and R9 are each hydrogen and R10 is —OCH2NHRa.
16. The method of claim 14 in which R8, R9 and R10 are each, independently of one another, selected from hydrogen, methyl, methoxy, hydroxymethyl, trifluoromethyl and chloro, with the proviso that at least two of R8, R9 and R10 are other than hydrogen.
17. The method of claim 7 in which the 2,4-pyrimidinediamine compound is selected from any compound in any one of TABLEs 1A-1D having an IC50 of ≦20 μM against at least one tumor cell line in an in vitro antiproliferation assay.
18. The method of claim 3 in which R4 is
Figure US20080021020A1-20080124-C00766
19. The method of claim 18 in which R1 is hydrogen and R15 is selected from lower branched alkyl and lower cycloalkyl.
20. The method of claim 18 in which R15 is t-butyl or cyclopropyl.
21. The method of claim 18 in which R2 is
Figure US20080021020A1-20080124-C00767
22. The method of claim 21 in which R8 is hydrogen; R9 is selected from
Figure US20080021020A1-20080124-C00768
and R10 is other than
Figure US20080021020A1-20080124-C00769
23. The method of claim 22 in which R10 is selected from methyl, trifluoromethyl and chloro.
24. The method of claim 22 in which R12 of R9 is selected from methyl, —C(O)CH3, —C(O)OCH3 and —C(O)CH2CH3.
25. The method of claim 21 in which R8 is hydrogen; R9 is other than
Figure US20080021020A1-20080124-C00770
and R10 is selected from
Figure US20080021020A1-20080124-C00771
26. The method of claim 25 in which R9 is selected from hydrogen, methyl, trifluoromethyl and chloro.
27. The method of claim 25 in which R12 of R10 is selected from methyl, —C(O)CH3, —C(O)OCH3 and —C(O)CH2CH3.
28. The method of claim 18 in which the 2,4-pyrimidinediamine compound is selected from any compound in TABLE 2 having an IC50 of ≦20 μM against at least one tumor cell line in an in vitro antiproliferation assay.
29. The method of claim 3 in which R4 is lower alkyl.
30. The method of claim 29 in which the lower alkyl is branched.
31. The method of claim 30 in which Re4 is i-propyl or t-butyl.
32. The method of claim 30 in which R2 is
Figure US20080021020A1-20080124-C00772
33. The method of claim 32 in which R8 is hydrogen; R9 is selected from
Figure US20080021020A1-20080124-C00773
and R10 is other than
Figure US20080021020A1-20080124-C00774
34. The method of claim 33 in which R10 is selected from hydrogen, methyl, trifluoromethyl and chloro.
35. The method of claim 33 in which R2 of R9 is methyl.
36. The method of claim 32 in which R8 is hydrogen; R9 is hydrogen and R10 is selected from
Figure US20080021020A1-20080124-C00775
37. The method of claim 36 in which R12 is methyl.
38. The method of claim 18 in which the 2,4-pyrimidinediamine compound is selected from any compound in TABLE 3 having an IC50 of ≦20 μM against at least one tumor cell line in an in vitro antiproliferation assay.
39. The method of claim 3 in which R4 is selected from
Figure US20080021020A1-20080124-C00776
40. The method of claim 39 in which R19 and R20 are different from one another such that the carbon atom to which they are bonded is chiral.
41. The method of claim 40 in which the 2,4-pyrimidinediamine compound is a racemate of R and S enantiomers.
42. The method of claim 40 which the 2,4-pyrimidinediamine compound is enriched in the R enantiomer.
43. The method of claim 42 in which the 2,4-pyrimidinediamine compound is substantially free of the S enantiomer.
44. The method of claim 40 in which the 2,4-pyrimidinediamine compound is enriched in the S enantiomer.
45. The method of claim 44 in which the 2,4-pyrimidinediamine compound is substantially free of the R enantiomer.
46. The method of claim 39 in which R2 is
Figure US20080021020A1-20080124-C00777
47. The method of claim 46 in which R8, R9 and R10 are each, independently of one another, selected from hydrogen, lower alkyl, methyl, lower alkoxy, methoxy, halo, chloro and OCH2C(O)NHRa, with the proviso that at least one of R8, R9 or R10 is other than hydrogen.
48. The method of claim 46 in which R8 is hydrogen; R9 is selected from
Figure US20080021020A1-20080124-C00778
and R10 is selected from hydrogen, methyl and chloro.
49. The method of claim 48 in which R12 is selected from methyl, —C(O)CH3, —C(O)OCH3 and —C(O)OCH2CH3.
50. The method of claim 46 in which R8 is hydrogen, R9 is selected from hydrogen, methyl and chloro; and R10 is selected from
Figure US20080021020A1-20080124-C00779
51. The method of claim 50 in which R12 is selected from methyl, —C(O)CH3, —C(O)OCH3 and —C(O)OCH2CH3.
52. The method of claim 46 in which the substituents on the R4 and R2 groups are independently selected from any combinations described in TABLE 4 or TABLE 6.
53. The method of claim 46 in which the 2,4-pyrimidinediamine compound is selected from any compound in TABLE 4 or TABLE 6 having an IC50 of ≦20 μM against at least one tumor cell line in an in vitro antiproliferation assay.
54. The method of claim 3 in which R4 is
Figure US20080021020A1-20080124-C00780
55. The method of claim 54 in which D is selected from —CH2—CH2—, —CF2—CF2, —CH2—, and —CF2—.
56. The method of claim 54 in which R2 is
Figure US20080021020A1-20080124-C00781
57. The method of claim 56 in which R8, R9 and R10 are each, independently of one another, selected from hydrogen, lower alkyl, methyl, hydroxy, lower alkoxy, methoxy, halo, chloro, fluoro, —OCH2C(O)NHRa, —OCH2C(O)NRcRc, —OCH2C(O)ORa, trifluoromethyl and —O(CH2)nOH, with the proviso that at least one of R8, R9 or R10 (is other than hydrogen.
58. The method of claim 54 which is selected from any compound in TABLE 5 having an IC50 of ≦20 μM against at least one tumor cell line in an in vitro antiproliferation assay.
59. The method of claim 3 in which R2 is
Figure US20080021020A1-20080124-C00782
60. The method of claim 59 in which R11 is selected from any R11 group listed in TABLE 7.
61. The method of claim 59 in which the 2,4-pyrimidinediamine compound is selected from any compound in TABLE 7 having an IC50 of ≦20 μM against at least one tumor cell line in an in vitro antiproliferation assay.
62. The method of claim 3 in which R4 is
Figure US20080021020A1-20080124-C00783
63. The method of claim 62 in which R2 is
Figure US20080021020A1-20080124-C00784
64. The method of claim 63 in which each R8, R9 and R10 is selected such that the compound is not an N2,N4-bis(substituted phenyl)-2,4-pyrimidinediamine.
65. The method of claim 63 in which each R8, R9 and R10 is, independently of the others, selected from hydrogen, lower alkyl, methyl, hydroxy, trifluoromethoxy, lower linear alkoxy, halo, —O(CH2)nNRcRc, —OCH2C(O)NRa, —OCH2C(O)NRcRc and —OCH2C(O)ORa.
66. The method of claim 65 in which R8, R9 and R10 are each, independently of one another; selected from hydrogen, methyl, trifluoromethyl, methoxy, trifluoromethoxy, and chloro, with the proviso that at least one of R8, R9 and R10 on both of R2 and R4 is other than hydrogen.
67. The method of claim 66 in which at least two of R8, R9 and R10 on both of R2 and R4 are other than hydrogen.
68. The method of claim 63 in which R8 and R9 of R2 are each hydrogen; R10 of R2 is —OCH2C(O)NRcRc or —OCH2C(O)NHRa; R8 and R10 of 10 are, independently of one another, selected from hydrogen, methyl and chloro; and R9 of R4 is selected from hydroxy,
Figure US20080021020A1-20080124-C00785
69. The method of claim 63 in which the 2,4-pyrimidinediamine compound is selected from any compound in TABLE 8 having an IC50 of ≦20 μM against at least one tumor cell line in an in vitro antiproliferation assay.
70. The method of claim 3 in which R2 is
Figure US20080021020A1-20080124-C00786
71. The method of claim 70 in which R4 is
Figure US20080021020A1-20080124-C00787
where D is —CH2CH2—.
72. The method of claim 71 in which R8, R9 and R10 are each, independently of one another, selected from hydrogen, methyl, methoxy, fluoro and chloro.
73. The method of claim 71 which is selected from any compound in TABLE 10 having an IC50 of ≦20 μM against at least one tumor cell line in an in vitro antiproliferation assay.
74. The method of claim 3 in which R2 is
Figure US20080021020A1-20080124-C00788
75. The method of claim 74 in which R4 is
Figure US20080021020A1-20080124-C00789
76. The method of claim 75 in which R16 is selected from hydrogen, lower linear alkanyl, lower branched alkanyl, lower cyclic alkanyl and lower cyclicalkanylmethyl.
77. The method of claim 75 in which the 2,4-pyrimidinediamine compound is selected from any compound in TABLE 13 having an IC50 of ≦20 μM against at least one tumor cell line in an in vitro antiproliferation assay.
78. The method of claim 1 in which the 2,4-pyrimidinediamine compound is selected from any compound illustrated in TABLES 1-14 having an IC50 of ≦20 μM against at least one tumor cell line in an in vitro antiproliferation assay.
79. The method of claim 1 in which the 2,4-pyrimidinediamine compound is compound according to structural formula (Ia):
Figure US20080021020A1-20080124-C00790
including prodrugs, salts, hydrates, solvates and N-oxides thereof, wherein:
m is as integer ranging from 1 to 3;
R21 is selected from hydrogen, lower alkyl, methyl, lower alkoxy, methoxy, halogen and chloro;
R22 is selected from hydrogen, lower alkoxy, methoxy, halogen, chloro,
Figure US20080021020A1-20080124-C00791
R23 is selected from hydrogen, methyl, lower alkyl, lower alkoxy, methoxy, halogen, chloro, trifluomethyl, —OCH2C(O)NHRa,
Figure US20080021020A1-20080124-C00792
 and
R24 is selected from hydrogen and methyl,
with the provisos that (i) when R22 is
Figure US20080021020A1-20080124-C00793
 then R23 is other than
Figure US20080021020A1-20080124-C00794
 and (ii) when R23 is
Figure US20080021020A1-20080124-C00795
 then R22 is other than
Figure US20080021020A1-20080124-C00796
80. The method of claim 79 in which R21 and R22 are each hydrogen and R23 is selected from —OCH2C(O)NHRa,
Figure US20080021020A1-20080124-C00797
81. The method of claim 79 in which R22 is selected from hydrogen methoxy, chloro,
Figure US20080021020A1-20080124-C00798
82. The method of claim 81 in which R12 is methyl.
83. The method of claim 79 in which R21 is hydrogen and R22 is
Figure US20080021020A1-20080124-C00799
where R12 is methyl.
84. The method of claim 1 in which the 2,4-pyrimidinediamine compound is a compound according to structural formula (Ib):
Figure US20080021020A1-20080124-C00800
including prodrugs, salts, hydrates, solvates and N-oxides thereof, wherein:
R15 is selected from t-butyl and cyclopropyl;
R21, R22 and R23 are as defined in claim 79.
85. The method of claim 1 in which the 2,4-pyrimidinediamine compound is a compound according to structural formula (Ic):
Figure US20080021020A1-20080124-C00801
including prodrugs, salts, hydrates, solvates and N-oxides thereof, wherein:
R14 is selected from i-propyl and t-butyl; and
R21, R22 and R23 are as defined in claim 79.
86. The method of claim 1 in which the 2,4-pyrimidinediamine compound is a compound according to structural formula (Id):
Figure US20080021020A1-20080124-C00802
including prodrugs, salts, hydrates, solvates and N-oxides thereof, wherein:
Z1 is selected from N and CH;
Z2 is selected from NH, O, S and S(O)2;
R16 is selected from hydrogen and methyl;
R19 is as defined in claim 1;
R20 is as defined in claim 1;
R24 is as defined in claim 79;
R41 is selected from hydrogen, lower alkyl, methyl; hydroxy, lower alkoxy, methoxy, halo, chloro, trifluoromethyl and —CH2OH;
R42 is selected from hydrogen, lower alkyl, methyl, hydroxy, lower alkoxy, methoxy, halo, chloro, trifluoromethyl, trifluoromethoxy, —OCH2C(O)NHRa,
Figure US20080021020A1-20080124-C00803
 where R12 is as defined in claim 1; and
R43 is selected from hydrogen, lower alkyl, methyl, hydroxy, lower alkoxy, methoxy, halo, chloro, trifluoromethyl, trifluoromethoxy, —OCH2C(O)NHRa, —OCH2C(O)ORa,
Figure US20080021020A1-20080124-C00804
 where R12 is as defined in claim 1,
with the provisos that:
(i) when R42 is
Figure US20080021020A1-20080124-C00805
 then R43 is other than
Figure US20080021020A1-20080124-C00806
 and
(ii) when R43 is
Figure US20080021020A1-20080124-C00807
 then R42 is other than
Figure US20080021020A1-20080124-C00808
87. The method of claim 1 in which the 2,4-pyrimidinediamine compound is a compound according to structural formula (Ie):
Figure US20080021020A1-20080124-C00809
including prodrugs, salts, hydrates, solvates and N-oxides thereof, wherein Z1, Z2, R16, R19, R20, R24, R41, R42 and R43 are as defined in claim 86.
88. The method of claim 1 in which the 2,4-pyrimidinediamine compound is a compound according to structural formula (If):
Figure US20080021020A1-20080124-C00810
including prodrugs, salts, hydrates, solvates and N-oxides thereof, wherein:
Z3 is selected from N and CH;
p is 0 or 1;
R7 is selected from hydrogen and fluoro;
R24 is as defined in claim 79;
R51 is selected from hydrogen, lower alkyl, methyl, lower alkoxy, methoxy, halo, trifluoromethyl, CH2OH and —C(O)OCH3;
R52 is selected from hydrogen, lower alkyl, methyl, hydroxy, lower alkoxy, methoxy, halo, trifluoromethyl, CH2OH and —OCH2C(O)NRaRa where Ra is as defined in claim 1; and
R53 is selected from hydrogen, lower alkyl, methyl, lower alkoxy, methoxy, halo, trifluoromethyl, CH2OH, —OCH2C(O)ORa and OCH2C(O)NHRa where Ra is as defined in claim 1.
89. The method of claim 1 in which the 2,4-pyrimidinediamine compound is a compound according to structural formula (Ig):
Figure US20080021020A1-20080124-C00811
including prodrugs, salts, hydrates, solvates and N-oxides thereof, wherein:
R28 is hydrogen or methyl;
R16 is as defined in claim 86; and
R21, R22, R23 and R24 are as defined in claim 79.
90. The method of claim 1 in which the 2,4-pyrimidinediamine compound is a compound according to structural formula (Ih):
Figure US20080021020A1-20080124-C00812
including prodrugs, salts, hydrates, solvates and N-oxides thereof, wherein:
R24 is as defined in claim 79;
R61 is selected from H and Cl;
R62 is selected from —CH2NHBoc, —CH2NH2, —C(O)NH2, —C(O)NH—CH2—C(O)OH, —C(O)NH—CH2—C(O)OMe and —C(O)NH—CH2CH2—N(Et)2;
R63 is selected from H and Cl;
R71 is H;
R72 is selected from H, OMe, Cl and —C(O)NH2; and
R73 is selected from H, OMe and Cl.
91. The method of claim 1 in which the 2,4-pyrimidinediamine compound is a compound according to structural formula (Ii):
Figure US20080021020A1-20080124-C00813
including prodrugs, salts, hydrates, solvates and N-oxides thereof, wherein:
each R24 is independently as defined in claim 79; and
R30 is selected from alkanyl and alkenyl.
92. The method of claim 1 in which the 2,4-pyrimidinediamine compound is a compound according to structural formula (Ij):
Figure US20080021020A1-20080124-C00814
including prodrugs, salts, hydrates, solvates and N-oxides thereof, wherein:
R24 is as defined in claim 79;
R81 is selected from hydrogen, methyl and methoxy;
R82 is selected from hydrogen, methoxy and chloro; and
R83 is selected from methyl, methoxy, halo and fluoro.
93. The method of claim 1 in which the 2,4-pyrimidinediamine compound is a compound according to structural formula (Ik), (Il), (Im) or (In):
Figure US20080021020A1-20080124-C00815
including prodrugs, salts, hydrates, solvates and N-oxides thereof, wherein:
R91, if present, is hydrogen;
R92, if present, is selected from lower alkoxy, methoxy, halo, chloro and fluoro;
R93, if present, is selected from lower alkoxy, methoxy, halo and chloro; and
R96 is selected from hydrogen, lower linear alkanyl, lower branched alkanyl, lower cycloalkanyl and lower cycloalkanylmethyl.
94. The method of claim 1 in which the cancer cell is a tumor cell.
95. The method of claim 94 in which the tumor cell is a bladder, lung, colon, breast, prostate, pancreatic, ovarian or hepatic tumor cell.
96. The method of claim 1 which is practiced in vivo as a therapeutic approach towards the treatment of cancer.
97. The method of claim 96 in which the cancer is a metastatic tumor.
98. The method of claim 97 in which the cancer is selected from the group consisting of breast, colon, pancreatic, lung, neural, esophageal, gastric, and melanoma.
99. The method of claim 96 in which the compound is administered in the form of a pharmaceutical composition.
100. The method of claim 99 in which the compound is administered orally or intravenously.
101. The method of claim 100 in which the subject is a human.
US11/567,817 2003-08-07 2006-12-07 2,4-Pyrimidinediamine Compounds And Uses As Anti-Proliferative Agents Abandoned US20080021020A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
US11/567,817 US20080021020A1 (en) 2003-08-07 2006-12-07 2,4-Pyrimidinediamine Compounds And Uses As Anti-Proliferative Agents

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US49400803P 2003-08-07 2003-08-07
US57253404P 2004-05-18 2004-05-18
US10/913,270 US20050113398A1 (en) 2003-08-07 2004-08-06 2,4-pyrimidinediamine compounds and uses as anti-proliferative agents
US11/567,817 US20080021020A1 (en) 2003-08-07 2006-12-07 2,4-Pyrimidinediamine Compounds And Uses As Anti-Proliferative Agents

Related Parent Applications (1)

Application Number Title Priority Date Filing Date
US10/913,270 Continuation US20050113398A1 (en) 2003-08-07 2004-08-06 2,4-pyrimidinediamine compounds and uses as anti-proliferative agents

Publications (1)

Publication Number Publication Date
US20080021020A1 true US20080021020A1 (en) 2008-01-24

Family

ID=34138795

Family Applications (6)

Application Number Title Priority Date Filing Date
US10/913,270 Abandoned US20050113398A1 (en) 2003-08-07 2004-08-06 2,4-pyrimidinediamine compounds and uses as anti-proliferative agents
US11/567,820 Active 2025-12-20 US7884111B2 (en) 2003-08-07 2006-12-07 2,4-pyrimidinediamine compounds and uses as anti-proliferative agents
US11/567,817 Abandoned US20080021020A1 (en) 2003-08-07 2006-12-07 2,4-Pyrimidinediamine Compounds And Uses As Anti-Proliferative Agents
US11/567,824 Abandoned US20080009484A1 (en) 2003-08-07 2006-12-07 2,4-Pyrimidinediamine Compounds And Uses As Anti-Proliferative Agents
US12/981,094 Active 2026-02-24 US8809341B2 (en) 2003-08-07 2010-12-29 2,4-pyrimidinediamine compounds and uses as anti-proliferative agents
US14/324,636 Active US9598432B2 (en) 2003-08-07 2014-07-07 2,4-pyrimidinediamine compounds and uses as anti-proliferative agents

Family Applications Before (2)

Application Number Title Priority Date Filing Date
US10/913,270 Abandoned US20050113398A1 (en) 2003-08-07 2004-08-06 2,4-pyrimidinediamine compounds and uses as anti-proliferative agents
US11/567,820 Active 2025-12-20 US7884111B2 (en) 2003-08-07 2006-12-07 2,4-pyrimidinediamine compounds and uses as anti-proliferative agents

Family Applications After (3)

Application Number Title Priority Date Filing Date
US11/567,824 Abandoned US20080009484A1 (en) 2003-08-07 2006-12-07 2,4-Pyrimidinediamine Compounds And Uses As Anti-Proliferative Agents
US12/981,094 Active 2026-02-24 US8809341B2 (en) 2003-08-07 2010-12-29 2,4-pyrimidinediamine compounds and uses as anti-proliferative agents
US14/324,636 Active US9598432B2 (en) 2003-08-07 2014-07-07 2,4-pyrimidinediamine compounds and uses as anti-proliferative agents

Country Status (9)

Country Link
US (6) US20050113398A1 (en)
EP (1) EP1663242B1 (en)
JP (1) JP4741491B2 (en)
AT (1) ATE506953T1 (en)
DE (1) DE602004032446D1 (en)
DK (1) DK1663242T3 (en)
ES (1) ES2365223T3 (en)
SI (1) SI1663242T1 (en)
WO (1) WO2005013996A2 (en)

Cited By (42)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20100029610A1 (en) * 2008-06-27 2010-02-04 Avila Therapeutics, Inc. Heteroaryl Compounds and Uses Thereof
US20100155402A1 (en) * 2008-02-27 2010-06-24 Pwp Industries, Inc. Display and storage container
US20100249092A1 (en) * 2008-06-27 2010-09-30 Avila Therapeutics, Inc. Heteroaryl compounds and uses thereof
US20110053082A1 (en) * 2009-08-31 2011-03-03 Sumitomo Chemical Company, Limited Resin, resist composition and method for producing resist pattern
US8481521B2 (en) 2005-04-18 2013-07-09 Rigel Pharmaceuticals, Inc. Methods of treating cell proliferative disorders
US8563217B2 (en) 2011-02-25 2013-10-22 Sumitomo Chemical Company, Limited Resist composition and method for producing resist pattern
US8563218B2 (en) 2011-02-25 2013-10-22 Sumitomo Chemical Company, Limited Resist composition and method for producing resist pattern
US8563219B2 (en) 2011-02-25 2013-10-22 Sumitomo Chemical Company, Limited Resist composition and method for producing resist pattern
US8563568B2 (en) 2010-08-10 2013-10-22 Celgene Avilomics Research, Inc. Besylate salt of a BTK inhibitor
US8568956B2 (en) 2011-02-25 2013-10-29 Sumitomo Chemical Company, Limited Resist composition and method for producing resist pattern
US8574812B2 (en) 2011-02-25 2013-11-05 Sumitomo Chemical Company, Limited Resist composition and method for producing resist pattern
US8574811B2 (en) 2010-08-30 2013-11-05 Sumitomo Chemical Company, Limited Resist composition and method for producing resist pattern
US8592132B2 (en) 2011-02-25 2013-11-26 Sumitomo Chemical Company, Limited Resist composition and method for producing resist pattern
US8652754B2 (en) 2011-07-19 2014-02-18 Sumitomo Chemical Company, Limited Resist composition and method for producing resist pattern
US8685619B2 (en) 2011-07-19 2014-04-01 Sumitomo Chemcial Company, Limited Resist composition and method for producing resist pattern
US8741543B2 (en) 2011-07-19 2014-06-03 Sumitomo Chemical Company, Limited Resist composition and method for producing resist pattern
US8778594B2 (en) 2011-07-19 2014-07-15 Sumitomo Chemical Company, Limited Resist composition and method for producing resist pattern
US8796255B2 (en) 2010-11-10 2014-08-05 Celgene Avilomics Research, Inc Mutant-selective EGFR inhibitors and uses thereof
US8835095B2 (en) 2011-02-25 2014-09-16 Sumitomo Chemical Company, Limited Resist composition and method for producing resist pattern
US8859182B2 (en) 2011-02-25 2014-10-14 Sumitomo Chemical Company, Limited Resist composition and method for producing resist pattern
US8927547B2 (en) 2010-05-21 2015-01-06 Noviga Research Ab Pyrimidine derivatives
US8940473B2 (en) 2011-02-25 2015-01-27 Sumitomo Chemical Company, Limited Resist composition and method for producing resist pattern
US8975249B2 (en) 2010-11-01 2015-03-10 Celgene Avilomics Research, Inc. Heterocyclic compounds and uses thereof
US9006241B2 (en) 2011-03-24 2015-04-14 Noviga Research Ab Pyrimidine derivatives
US9012462B2 (en) 2008-05-21 2015-04-21 Ariad Pharmaceuticals, Inc. Phosphorous derivatives as kinase inhibitors
US9052591B2 (en) 2011-07-19 2015-06-09 Sumitomo Chemical Company, Limited Resist composition and method for producing resist pattern
US9056839B2 (en) 2012-03-15 2015-06-16 Celgene Avilomics Research, Inc. Solid forms of an epidermal growth factor receptor kinase inhibitor
US9063414B2 (en) 2010-07-28 2015-06-23 Sumitomo Chemical Company, Limited Photoresist composition
US9108927B2 (en) 2012-03-15 2015-08-18 Celgene Avilomics Research, Inc. Salts of an epidermal growth factor receptor kinase inhibitor
US9126950B2 (en) 2012-12-21 2015-09-08 Celgene Avilomics Research, Inc. Heteroaryl compounds and uses thereof
US9145387B2 (en) 2013-02-08 2015-09-29 Celgene Avilomics Research, Inc. ERK inhibitors and uses thereof
US9238629B2 (en) 2010-11-01 2016-01-19 Celgene Avilomics Research, Inc. Heteroaryl compounds and uses thereof
US9273077B2 (en) 2008-05-21 2016-03-01 Ariad Pharmaceuticals, Inc. Phosphorus derivatives as kinase inhibitors
US9364476B2 (en) 2011-10-28 2016-06-14 Celgene Avilomics Research, Inc. Methods of treating a Bruton's Tyrosine Kinase disease or disorder
US9415049B2 (en) 2013-12-20 2016-08-16 Celgene Avilomics Research, Inc. Heteroaryl compounds and uses thereof
US9492471B2 (en) 2013-08-27 2016-11-15 Celgene Avilomics Research, Inc. Methods of treating a disease or disorder associated with Bruton'S Tyrosine Kinase
US9611283B1 (en) 2013-04-10 2017-04-04 Ariad Pharmaceuticals, Inc. Methods for inhibiting cell proliferation in ALK-driven cancers
US9834518B2 (en) 2011-05-04 2017-12-05 Ariad Pharmaceuticals, Inc. Compounds for inhibiting cell proliferation in EGFR-driven cancers
US9834571B2 (en) 2012-05-05 2017-12-05 Ariad Pharmaceuticals, Inc. Compounds for inhibiting cell proliferation in EGFR-driven cancers
US9908884B2 (en) 2009-05-05 2018-03-06 Dana-Farber Cancer Institute, Inc. EGFR inhibitors and methods of treating disorders
US10005760B2 (en) 2014-08-13 2018-06-26 Celgene Car Llc Forms and compositions of an ERK inhibitor
US11351168B1 (en) 2008-06-27 2022-06-07 Celgene Car Llc 2,4-disubstituted pyrimidines useful as kinase inhibitors

Families Citing this family (110)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
TWI329105B (en) * 2002-02-01 2010-08-21 Rigel Pharmaceuticals Inc 2,4-pyrimidinediamine compounds and their uses
IL166241A (en) * 2002-07-29 2011-12-29 Rigel Pharmaceuticals Inc 2,4-pyrimidinediamine compounds for use in the treatment of autoimmune diseases
JP4886511B2 (en) * 2003-07-30 2012-02-29 ライジェル ファーマシューティカルズ， インコーポレイテッド Method for treating or preventing autoimmune diseases with 2,4-pyrimidinediamine compounds
EP1663242B1 (en) * 2003-08-07 2011-04-27 Rigel Pharmaceuticals, Inc. 2,4-pyrimidinediamine compounds and uses as anti-proliferative agents
TWI378923B (en) * 2003-08-15 2012-12-11 Novartis Ag Pyrimidine derivatives
MXPA06003054A (en) * 2003-09-18 2006-05-31 Novartis Ag 2,4-di (phenylamino) pyrimidines useful in the treatment of proliferative disorders.
JP4812763B2 (en) * 2004-05-18 2011-11-09 ライジェル ファーマシューティカルズ， インコーポレイテッド Cycloalkyl-substituted pyrimidinediamine compounds and uses thereof
GB2420559B (en) * 2004-11-15 2008-08-06 Rigel Pharmaceuticals Inc Stereoisomerically enriched 3-aminocarbonyl bicycloheptene pyrimidinediamine compounds and their uses
ES2380550T3 (en) 2004-11-24 2012-05-16 Rigel Pharmaceuticals, Inc. Spiro-2,4-pyrimidinediamine compounds and their uses
US7449458B2 (en) 2005-01-19 2008-11-11 Rigel Pharmaceuticals, Inc. Prodrugs of 2,4-pyrimidinediamine compounds and their uses
CN101166732B (en) 2005-04-28 2013-04-17 田边三菱制药株式会社 Cyanopyridine derivative and use thereof as medicine
US20060270694A1 (en) * 2005-05-03 2006-11-30 Rigel Pharmaceuticals, Inc. JAK kinase inhibitors and their uses
US7417066B2 (en) 2005-06-08 2008-08-26 Schering Ag Inhibitors of soluble adenylate cyclase
DE102005027274A1 (en) * 2005-06-08 2006-12-14 Schering Ag Inhibitors of soluble adenylate cyclase
WO2006133426A2 (en) 2005-06-08 2006-12-14 Rigel Pharmaceuticals, Inc. Compositions and methods for inhibition of the jak pathway
US20070203161A1 (en) * 2006-02-24 2007-08-30 Rigel Pharmaceuticals, Inc. Compositions and methods for inhibition of the jak pathway
CA2607901C (en) 2005-06-13 2016-08-16 Rigel Pharmaceuticals, Inc. Methods and compositions for treating degenerative bone disorders using a syk inhibitory 2,4-pyrimidinediamine
ATE352714T1 (en) * 2005-06-17 2007-02-15 Magneti Marelli Powertrain Spa FUEL INJECTION VALVE
JP2009501711A (en) * 2005-07-11 2009-01-22 サノフイ−アベンテイス Novel 2,4-dianilinopyrimidine derivatives, their preparation, pharmaceuticals, their use as pharmaceutical compositions, in particular as IKK inhibitors
FR2888239B1 (en) * 2005-07-11 2008-05-09 Sanofi Aventis Sa NOVEL 2,4-DIANILINOPYRIMIDINE DERIVATIVES, THEIR PREPARATION AS MEDICAMENTS, PHARMACEUTICAL COMPOSITIONS AND IN PARTICULAR AS INHIBITORS OF IKK
CA2626789A1 (en) 2005-10-21 2007-04-26 Exelixis, Inc. Pyrimidinones as casein kinase ii (ck2) modulators
EP1984357B1 (en) 2006-02-17 2013-10-02 Rigel Pharmaceuticals, Inc. 2,4-pyrimidinediamine compounds for treating or preventing autoimmune diseases
ES2622493T3 (en) 2006-02-24 2017-07-06 Rigel Pharmaceuticals, Inc. Compositions and methods for inhibiting the JAK route
PE20120006A1 (en) * 2006-05-15 2012-02-02 Boehringer Ingelheim Int COMPOUNDS DERIVED FROM PYRIMIDINE AS INHIBITORS OF KINASE AURORA
MX2008016007A (en) 2006-06-15 2009-01-16 Boehringer Ingelheim Int 2-anilino-4-aminoalkyleneaminopyrimidines.
JP2009540013A (en) 2006-06-15 2009-11-19 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング 2-anilino-4- (heterocyclic) amino-pyrimidine
AU2007286807B2 (en) 2006-08-21 2013-03-21 Genentech, Inc. Aza-benzothiophenyl compounds and methods of use
CL2007003049A1 (en) 2006-10-23 2008-05-16 Cephalon Inc Pharmacopeia Drug COMPOUNDS DERIVED FROM 2,4-DIAMINOPIRIMIDINE; PHARMACEUTICAL COMPOSITION, USEFUL TO TREAT PROLIFERATIVE DISORDERS.
WO2008061201A1 (en) * 2006-11-15 2008-05-22 Rigel Pharmaceuticals, Inc. Methods for treating renal tumors using 2,4-pyrimidinediamine drug and prodrug compounds
EP2537830A1 (en) 2006-12-08 2012-12-26 Irm Llc Compounds and compositions as protein kinase inhibitors
US20100144732A1 (en) * 2006-12-19 2010-06-10 Krueger Elaine B Pyrimidine kinase inhibitors
WO2008077885A2 (en) * 2006-12-22 2008-07-03 Boehringer Ingelheim International Gmbh 2- [(phenylamino) -pyrimidin-4ylamin0] -cyclopentane carboxamide derivatives and related compounds as inhibitors of kinases of the cell cycle for the treatment of cancer
MX2009006454A (en) 2006-12-22 2009-06-26 Hoffmann La Roche Spiro-piperidine derivatives.
DE102007010801A1 (en) 2007-03-02 2008-09-04 Bayer Cropscience Ag Use of new and known 2,4-diaminopyrimidine derivatives as fungicides, especially for controlling phytopathogenic fungi
US7834024B2 (en) 2007-03-26 2010-11-16 Rigel Pharmaceuticals, Inc. Compositions and methods for inhibition of the JAK pathway
JP5496877B2 (en) 2007-04-16 2014-05-21 アッヴィ・インコーポレイテッド 7-substituted indole Mcl-1 inhibitors
US20090012045A1 (en) * 2007-06-26 2009-01-08 Rigel Pharmaceuticals, Inc. Methods of Treating Cell Proliferative Disorders
BRPI0814432A2 (en) 2007-07-17 2017-05-09 Rigel Pharmaceuticals Inc cyclic amine substituted pyrimidinadiamines as pkc inhibitors
RU2010132728A (en) 2008-01-11 2012-02-20 Ф.Хоффманн-Ля Рош Аг (Ch) BETA AMYLOID MODULATORS
RU2010137300A (en) * 2008-02-22 2012-03-27 Ф. Хоффманн-Ля Рош Аг (Ch) BETA AMYLOID MODULATORS
AU2009233964B2 (en) * 2008-04-07 2012-06-07 Irm Llc Compounds and compositions as protein kinase inhibitors
CN102203083A (en) * 2008-06-25 2011-09-28 Irm责任有限公司 Compounds and compositions as kinase inhibitors
AU2013202496B2 (en) * 2008-06-27 2016-08-04 Celgene Car Llc Heteroaryl compounds and uses thereof
ES2426096T3 (en) 2008-07-01 2013-10-21 Genentech, Inc. Isoindolone derivatives as MEK kinase inhibitors and methods of use
RU2509078C2 (en) 2008-07-01 2014-03-10 Дженентек, Инк. Bicyclic heterocycles as mek kinase inhibitors
EP2161259A1 (en) 2008-09-03 2010-03-10 Bayer CropScience AG 4-Haloalkyl substituted Diaminopyrimidine
KR101324414B1 (en) 2008-10-09 2013-11-01 에프. 호프만-라 로슈 아게 Modulators for amyloid beta
AU2009312856A1 (en) 2008-11-10 2010-05-14 F. Hoffmann-La Roche Ag Heterocyclic gamma secretase modulators
JP5738196B2 (en) 2008-12-22 2015-06-17 ミレニアム ファーマシューティカルズ， インコーポレイテッドＭｉｌｌｅｎｎｉｕｍ Ｐｈａｒｍａｃｅｕｔｉｃａｌｓ， Ｉｎｃ． Combination of Aurora kinase inhibitor and anti-CD20 antibody
ES2624622T3 (en) 2008-12-30 2017-07-17 Rigel Pharmaceuticals, Inc. Pyrimidinediamine kinase inhibitors
WO2010083240A2 (en) * 2009-01-14 2010-07-22 Rigel Pharmaceuticals, Inc. Methods for treating inflammatory disorders using 2,4-pyrimidinediamine compounds
ES2555982T3 (en) * 2009-01-15 2016-01-12 Rigel Pharmaceuticals, Inc. Protein kinase C inhibitors and uses thereof
ES2635504T3 (en) 2009-01-21 2017-10-04 Rigel Pharmaceuticals, Inc. N2- (3-pyridyl or phenyl) -N4- (4-piperidyl) -2,4-pyrimidinadiamine derivatives useful in the treatment of inflammatory, toimmune or proliferative diseases
US20110071158A1 (en) * 2009-03-18 2011-03-24 Boehringer Ingelheim International Gmbh New compounds
CN102470135A (en) * 2009-07-28 2012-05-23 里格尔药品股份有限公司 Compositions and methods for inhibition of the JAK pathway
JP5681723B2 (en) 2009-11-20 2015-03-11 ライジェル ファーマシューティカルズ， インコーポレイテッド 2,4-pyrimidinediamine compounds and prodrugs thereof and uses thereof
EP2507227B1 (en) 2009-12-01 2014-10-08 Rigel Pharmaceuticals, Inc. Tetrazolones as protein kinase c inhibitors and uses thereof
US8486096B2 (en) * 2010-02-11 2013-07-16 Ethicon Endo-Surgery, Inc. Dual purpose surgical instrument for cutting and coagulating tissue
US8486967B2 (en) 2010-02-17 2013-07-16 Hoffmann-La Roche Inc. Heteroaryl substituted piperidines
CA2792278C (en) * 2010-04-13 2019-05-14 Rigel Pharmaceuticals, Inc. 2,4-pyrimidinediamine compounds and prodrugs thereof and their uses
EP2395001A1 (en) * 2010-05-21 2011-12-14 Chemilia AB Novel pyrimidine derivatives
US8354420B2 (en) 2010-06-04 2013-01-15 Genentech, Inc. Aminopyrimidine derivatives as LRRK2 inhibitors
JP6035238B2 (en) 2010-07-21 2016-11-30 ライジェル ファーマシューティカルズ， インコーポレイテッド Protein kinase C inhibitor and use thereof
CN103313978B (en) 2010-11-10 2015-04-15 霍夫曼-拉罗奇有限公司 Pyrazole aminopyrimidine derivatives as LRRK2 modulators
EP2489663A1 (en) 2011-02-16 2012-08-22 Almirall, S.A. Compounds as syk kinase inhibitors
US9249124B2 (en) 2011-03-30 2016-02-02 H. Lee Moffitt Cancer Center And Research Institute, Inc. Aurora kinase inhibitors and methods of making and using thereof
WO2012154518A1 (en) 2011-05-10 2012-11-15 Merck Sharp & Dohme Corp. Bipyridylaminopyridines as syk inhibitors
EP2707357B1 (en) 2011-05-10 2017-01-18 Merck Sharp & Dohme Corp. Pyridyl aminopyridines as syk inhibitors
MX2013013090A (en) 2011-05-10 2013-12-16 Merck Sharp & Dohme Aminopyrimidines as syk inhibitors.
KR102090440B1 (en) 2011-07-28 2020-03-17 리겔 파마슈티칼스, 인크. New (trimethoxyphenylamino)pyrimidinyl formulations
KR20140062079A (en) 2011-08-25 2014-05-22 에프. 호프만-라 로슈 아게 Serine/threonine pak1 inhibitors
EP2763974B1 (en) 2011-10-05 2016-09-14 Merck Sharp & Dohme Corp. Phenyl carboxamide-containing spleen tyrosine kinase (syk) inhibitors
US9216173B2 (en) 2011-10-05 2015-12-22 Merck Sharp & Dohme Corp. 2-Pyridyl carboxamide-containing spleen tyrosine kinase (SYK) inhibitors
EP2763975B1 (en) 2011-10-05 2016-04-06 Merck Sharp & Dohme Corp. 3-pyridyl carboxamide-containing spleen tyrosine kinase (syk) inhibitors
RU2014129740A (en) 2011-12-22 2016-02-10 Ф.Хоффманн-Ля Рош Аг 2,4-DIAMINOPYRIMIDINE DERIVATIVES AS SERIN / THREONIN KINASE INHIBITORS
US9487504B2 (en) 2012-06-20 2016-11-08 Merck Sharp & Dohme Corp. Imidazolyl analogs as syk inhibitors
EP2863914B1 (en) 2012-06-20 2018-10-03 Merck Sharp & Dohme Corp. Pyrazolyl derivatives as syk inhibitors
EP2863915B1 (en) 2012-06-22 2017-12-06 Merck Sharp & Dohme Corp. SUBSTITUTED DIAZINE AND TRIAZINE SPLEEN TYROSINE KINASE (Syk) INHIBITORS
WO2013192098A1 (en) 2012-06-22 2013-12-27 Merck Sharp & Dohme Corp. SUBSTITUTED PYRIDINE SPLEEN TYROSINE KINASE (Syk) INHIBITORS
KR101446742B1 (en) 2012-08-10 2014-10-01 한국화학연구원 N2,N4-bis(4-(piperazin-1-yl)phenyl)pyrimidine-2,4-diamine derivatives or pharmaceutically acceptable salt thereof, and pharmaceutical composition for the prevention or treatment of cancer containing the same as an active ingredient
WO2014031438A2 (en) 2012-08-20 2014-02-27 Merck Sharp & Dohme Corp. SUBSTITUTED PHENYL SPLEEN TYROSINE KINASE (Syk) INHIBITORS
US9586931B2 (en) 2012-09-28 2017-03-07 Merck Sharp & Dohme Corp. Triazolyl derivatives as Syk inhibitors
WO2014093191A1 (en) 2012-12-12 2014-06-19 Merck Sharp & Dohme Corp. AMINO-PYRIMIDINE-CONTAINING SPLEEN TYROSINE KINASE (Syk) INHIBITORS
WO2014100314A1 (en) 2012-12-21 2014-06-26 Merck Sharp & Dohme Corp. Thiazole-substituted aminopyridines as spleen tyrosine kinase inhibitors
WO2014176216A1 (en) 2013-04-26 2014-10-30 Merck Sharp & Dohme Corp. Thiazole-substituted aminopyrimidines as spleen tyrosine kinase inhibitors
WO2014176210A1 (en) 2013-04-26 2014-10-30 Merck Sharp & Dohme Corp. Thiazole-substituted aminoheteroaryls as spleen tyrosine kinase inhibitors
JP6525474B2 (en) 2013-12-06 2019-06-05 ミレニアム ファーマシューティカルズ， インコーポレイテッドＭｉｌｌｅｎｎｉｕｍ Ｐｈａｒｍａｃｅｕｔｉｃａｌｓ， Ｉｎｃ． Combination of Aurora kinase inhibitor and anti-CD30 antibody
US9670196B2 (en) 2013-12-20 2017-06-06 Merck Sharp & Dohme Corp. Thiazole-substituted aminoheteroaryls as Spleen Tyrosine Kinase inhibitors
EP3082807B1 (en) 2013-12-20 2018-07-04 Merck Sharp & Dohme Corp. Thiazole-substituted aminoheteroaryls as spleen tyrosine kinase inhibitors
EP3083559B1 (en) 2013-12-20 2021-03-10 Merck Sharp & Dohme Corp. Thiazole-substituted aminoheteroaryls as spleen tyrosine kinase inhibitors
US9775839B2 (en) 2014-03-13 2017-10-03 Merck Sharp & Dohme Corp. 2-pyrazine carboxamides as spleen tyrosine kinase inhibitors
CN105017159B (en) * 2014-04-28 2019-05-17 四川大学 Fluoro- 2,4- disubstituted amido pyrimidine derivatives of 5- and its preparation method and application
WO2016022460A1 (en) 2014-08-03 2016-02-11 H. Lee Moffitt Cancer Center And Research Institute, Inc. Potent dual brd4-kinase inhibitors as cancer therapeutics
WO2016029002A2 (en) * 2014-08-22 2016-02-25 Clovis Oncology, Inc. Growth factor receptor inhibitors
WO2017066428A1 (en) 2015-10-13 2017-04-20 H. Lee Moffitt Cancer Center & Research Institute, Inc. Brd4-kinase inhibitors as cancer therapeutics
US11203576B2 (en) * 2016-03-11 2021-12-21 H. Lee Moffitt Cancer Center And Research Institute, Inc. Aurora kinase and Janus kinase inhibitors for prevention of graft versus host disease
EP4285906A3 (en) * 2016-12-19 2024-03-13 Epizyme, Inc. Amine-substituted heterocyclic compounds as ehmt2 inhibitors and methods of use thereof
WO2018151681A1 (en) * 2017-02-15 2018-08-23 Nanyang Technological University Compounds for treating tuberculosis
WO2018195450A1 (en) 2017-04-21 2018-10-25 Epizyme, Inc. Combination therapies with ehmt2 inhibitors
EP3710006A4 (en) * 2017-11-19 2021-09-01 Sunshine Lake Pharma Co., Ltd. Substituted heteroaryl compounds and methods of use
WO2019195658A1 (en) 2018-04-05 2019-10-10 Dana-Farber Cancer Institute, Inc. Sting levels as a biomarker for cancer immunotherapy
MX2021013662A (en) 2019-05-10 2022-03-11 Deciphera Pharmaceuticals Llc Heteroarylaminopyrimidine amide autophagy inhibitors and methods of use thereof.
BR112021022504A2 (en) 2019-05-10 2022-04-12 Deciphera Pharmaceuticals Llc Phenylaminopyrimidine amide autophagy inhibitors and methods of using them
CA3143489A1 (en) 2019-06-17 2020-12-24 Deciphera Pharmaceuticals, Llc Aminopyrimidine amide autophagy inhibitors and methods of use thereof
EP3994132A1 (en) 2019-07-03 2022-05-11 Sumitomo Dainippon Pharma Oncology, Inc. Tyrosine kinase non-receptor 1 (tnk1) inhibitors and uses thereof
WO2021041532A1 (en) 2019-08-26 2021-03-04 Dana-Farber Cancer Institute, Inc. Use of heparin to promote type 1 interferon signaling
CN115304551A (en) * 2022-07-25 2022-11-08 南通大学 2- ((4-morpholinyl phenyl) amino) pyrimidine amino acid derivative and preparation method and application thereof
CN115232076A (en) * 2022-07-25 2022-10-25 南通大学 Phenylamino substituted pyrimidine amino acid derivative and preparation method and application thereof
CN115141150A (en) * 2022-07-25 2022-10-04 南通大学 2,4,5-trisubstituted pyrimidine hydroxylamine acyl derivative and preparation method and application thereof
CN115304550A (en) * 2022-07-25 2022-11-08 南通大学 Piperazine phenyl amino substituted pyrimidine amino acid derivative, preparation method and application

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5958935A (en) * 1995-11-20 1999-09-28 Celltech Therapeutics Limited Substituted 2-anilinopyrimidines useful as protein kinase inhibitors
US20050113398A1 (en) * 2003-08-07 2005-05-26 Ankush Argade 2,4-pyrimidinediamine compounds and uses as anti-proliferative agents
US20060276459A1 (en) * 2005-04-18 2006-12-07 Rigel Pharmaceuticals, Inc. Methods of treating cell proliferative disorders

Family Cites Families (41)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4921475A (en) 1983-08-18 1990-05-01 Drug Delivery Systems Inc. Transdermal drug patch with microtubes
US5087240A (en) 1983-08-18 1992-02-11 Drug Delivery Systems Inc. Transdermal drug patch with conductive fibers
US4738851A (en) 1985-09-27 1988-04-19 University Of Iowa Research Foundation, Inc. Controlled release ophthalmic gel formulation
US5163899A (en) 1987-03-20 1992-11-17 Drug Delivery Systems Inc. Transdermal drug delivery system
US5312325A (en) 1987-05-28 1994-05-17 Drug Delivery Systems Inc Pulsating transdermal drug delivery system
GB8804164D0 (en) 1988-02-23 1988-03-23 Tucker J M Bandage for administering physiologically active compound
US4882150A (en) 1988-06-03 1989-11-21 Kaufman Herbert E Drug delivery system
US5008110A (en) 1988-11-10 1991-04-16 The Procter & Gamble Company Storage-stable transdermal patch
US5088977A (en) 1988-12-21 1992-02-18 Drug Delivery Systems Inc. Electrical transdermal drug applicator with counteractor and method of drug delivery
US5521222A (en) 1989-09-28 1996-05-28 Alcon Laboratories, Inc. Topical ophthalmic pharmaceutical vehicles
PT96059B (en) 1989-12-04 1998-07-31 Searle & Co UNIQUE LAYER SYSTEM FOR ADMINISTRATION OF A TRANSDERMALIC DRUG
US5077033A (en) 1990-08-07 1991-12-31 Mediventures Inc. Ophthalmic drug delivery with thermo-irreversible gels of polxoxyalkylene polymer and ionic polysaccharide
EP0495421B1 (en) 1991-01-15 1996-08-21 Alcon Laboratories, Inc. Use of carrageenans in topical ophthalmic compositions
US5352456A (en) 1991-10-10 1994-10-04 Cygnus Therapeutic Systems Device for administering drug transdermally which provides an initial pulse of drug
EP0617665B1 (en) 1991-12-18 1999-03-31 Minnesota Mining And Manufacturing Company Multilayered barrier structures
ATE132381T1 (en) 1992-01-29 1996-01-15 Voelkl Franz Ski BALL GAME RACKETS, ESPECIALLY TENNIS RACKETS
IL114193A (en) 1994-06-20 2000-02-29 Teva Pharma Ophthalmic pharmaceutical compositions based on sodium alginate
ES2094688B1 (en) 1994-08-08 1997-08-01 Cusi Lab MANOEMULSION OF THE TYPE OF OIL IN WATER, USEFUL AS AN OPHTHALMIC VEHICLE AND PROCEDURE FOR ITS PREPARATION.
IT1283911B1 (en) 1996-02-05 1998-05-07 Farmigea Spa VISCOSIZED OPHTHALMIC SOLUTIONS WITH TAMARIND GUM POLYSACCHARIDES
US5800807A (en) 1997-01-29 1998-09-01 Bausch & Lomb Incorporated Ophthalmic compositions including glycerin and propylene glycol
US6432963B1 (en) * 1997-12-15 2002-08-13 Yamanouchi Pharmaceutical Co., Ltd. Pyrimidine-5-carboxamide derivatives
US6261547B1 (en) 1998-04-07 2001-07-17 Alcon Manufacturing, Ltd. Gelling ophthalmic compositions containing xanthan gum
US6197934B1 (en) 1998-05-22 2001-03-06 Collagenesis, Inc. Compound delivery using rapidly dissolving collagen film
GB9828511D0 (en) * 1998-12-24 1999-02-17 Zeneca Ltd Chemical compounds
DE122010000038I1 (en) * 2000-12-21 2011-01-27 Glaxosmithkline Llc PYRIMIDINAMINES AS ANGIOGENESIS MODULATORS
EP1392662B1 (en) * 2001-05-29 2009-01-07 Bayer Schering Pharma Aktiengesellschaft Cdk inhibiting pyrimidines, production thereof and their use as medicaments
WO2003030909A1 (en) * 2001-09-25 2003-04-17 Bayer Pharmaceuticals Corporation 2- and 4-aminopyrimidines n-substtituded by a bicyclic ring for use as kinase inhibitors in the treatment of cancer
WO2003026664A1 (en) * 2001-09-26 2003-04-03 Bayer Corporation 2-phenylamino-4- (5-pyrazolylamino) -pyramidine derivatives as kinase inhibitors, in particular, src kinase inhibitors
WO2003040141A1 (en) * 2001-09-28 2003-05-15 Bayer Pharmaceuticals Corporation Oxazolyl-phenyl-2,4-diamino-pyrimidine compounds and methods for treating hyperproliferative disorders
SE0104140D0 (en) * 2001-12-07 2001-12-07 Astrazeneca Ab Novel Compounds
WO2003055489A1 (en) * 2001-12-21 2003-07-10 Bayer Pharmaceuticals Corporation 2,4-diamino-pyrimidine derivative compounds as inhibitors of prolylpeptidase, inducers of apoptosis and cancer treatment agents
IL166241A (en) * 2002-07-29 2011-12-29 Rigel Pharmaceuticals Inc 2,4-pyrimidinediamine compounds for use in the treatment of autoimmune diseases
WO2004065378A1 (en) * 2003-01-17 2004-08-05 Warner-Lambert Company Llc 2-aminopyridine substituted heterocycles as inhibitors of cellular proliferation
US7514446B2 (en) * 2003-02-20 2009-04-07 Smithkline Beecham Corporation Pyrimidine compounds
GB0305929D0 (en) * 2003-03-14 2003-04-23 Novartis Ag Organic compounds
JP4886511B2 (en) * 2003-07-30 2012-02-29 ライジェル ファーマシューティカルズ， インコーポレイテッド Method for treating or preventing autoimmune diseases with 2,4-pyrimidinediamine compounds
JP4812763B2 (en) * 2004-05-18 2011-11-09 ライジェル ファーマシューティカルズ， インコーポレイテッド Cycloalkyl-substituted pyrimidinediamine compounds and uses thereof
US20060051406A1 (en) * 2004-07-23 2006-03-09 Manjeet Parmar Formulation of insoluble small molecule therapeutics in lipid-based carriers
WO2008061201A1 (en) * 2006-11-15 2008-05-22 Rigel Pharmaceuticals, Inc. Methods for treating renal tumors using 2,4-pyrimidinediamine drug and prodrug compounds
ES2635504T3 (en) * 2009-01-21 2017-10-04 Rigel Pharmaceuticals, Inc. N2- (3-pyridyl or phenyl) -N4- (4-piperidyl) -2,4-pyrimidinadiamine derivatives useful in the treatment of inflammatory, toimmune or proliferative diseases
EP2507227B1 (en) * 2009-12-01 2014-10-08 Rigel Pharmaceuticals, Inc. Tetrazolones as protein kinase c inhibitors and uses thereof

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5958935A (en) * 1995-11-20 1999-09-28 Celltech Therapeutics Limited Substituted 2-anilinopyrimidines useful as protein kinase inhibitors
US20050113398A1 (en) * 2003-08-07 2005-05-26 Ankush Argade 2,4-pyrimidinediamine compounds and uses as anti-proliferative agents
US20060276459A1 (en) * 2005-04-18 2006-12-07 Rigel Pharmaceuticals, Inc. Methods of treating cell proliferative disorders

Cited By (77)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8481521B2 (en) 2005-04-18 2013-07-09 Rigel Pharmaceuticals, Inc. Methods of treating cell proliferative disorders
US20100155402A1 (en) * 2008-02-27 2010-06-24 Pwp Industries, Inc. Display and storage container
US9273077B2 (en) 2008-05-21 2016-03-01 Ariad Pharmaceuticals, Inc. Phosphorus derivatives as kinase inhibitors
US9012462B2 (en) 2008-05-21 2015-04-21 Ariad Pharmaceuticals, Inc. Phosphorous derivatives as kinase inhibitors
US20100029610A1 (en) * 2008-06-27 2010-02-04 Avila Therapeutics, Inc. Heteroaryl Compounds and Uses Thereof
US9987276B2 (en) 2008-06-27 2018-06-05 Celgene Car Llc Substituted 2,4-diaminopyrimidines as kinase inhibitors
US8338439B2 (en) 2008-06-27 2012-12-25 Celgene Avilomics Research, Inc. 2,4-disubstituted pyrimidines useful as kinase inhibitors
US9212181B2 (en) 2008-06-27 2015-12-15 Celgene Avilomics Research, Inc. Substituted 2,4-diaminopyrimidines as kinase inhibitors
US8710222B2 (en) 2008-06-27 2014-04-29 Celgene Avilomics Research, Inc. 2,4-disubstituted pyrimidines useful as kinase inhibitors
US20100249092A1 (en) * 2008-06-27 2010-09-30 Avila Therapeutics, Inc. Heteroaryl compounds and uses thereof
US9296737B2 (en) 2008-06-27 2016-03-29 Celgene Avilomics Research, Inc. Substituted 2,4-diaminopyrimidines as kinase inhibitors
US8450335B2 (en) 2008-06-27 2013-05-28 Celgene Avilomics Research, Inc. 2,4-disubstituted pyrimidines useful as kinase inhibitors
US10010548B2 (en) 2008-06-27 2018-07-03 Celgene Car Llc 2,4-disubstituted pyrimidines useful as kinase inhibitors
US10596172B2 (en) 2008-06-27 2020-03-24 Celgene Car Llc 2,4-disubstituted pyrimidines useful as kinase inhibitors
US10828300B2 (en) 2008-06-27 2020-11-10 Celgene Car Llc Substituted 2,4-diaminopyrimidines as kinase inhibitors
US9409921B2 (en) 2008-06-27 2016-08-09 Celgene Avilomics Research, Inc. 2,4-disubstituted pyrimidines as kinase inhibitors
US8609679B2 (en) 2008-06-27 2013-12-17 Celgene Avilomics Research, Inc. 2,4-diaminopyrimidines useful as kinase inhibitors
US11351168B1 (en) 2008-06-27 2022-06-07 Celgene Car Llc 2,4-disubstituted pyrimidines useful as kinase inhibitors
US9908884B2 (en) 2009-05-05 2018-03-06 Dana-Farber Cancer Institute, Inc. EGFR inhibitors and methods of treating disorders
US9268226B2 (en) 2009-08-31 2016-02-23 Sumitomo Chemical Company, Limited Resin, resist composition and method for producing resist pattern
US8592129B2 (en) 2009-08-31 2013-11-26 Sumitomo Chemical Company, Limited Resin, resist composition and method for producing resist pattern
US20110053082A1 (en) * 2009-08-31 2011-03-03 Sumitomo Chemical Company, Limited Resin, resist composition and method for producing resist pattern
US8927547B2 (en) 2010-05-21 2015-01-06 Noviga Research Ab Pyrimidine derivatives
US9063414B2 (en) 2010-07-28 2015-06-23 Sumitomo Chemical Company, Limited Photoresist composition
US9604936B2 (en) 2010-08-10 2017-03-28 Celgene Car Llc Besylate salt of a BTK inhibitor
US8563568B2 (en) 2010-08-10 2013-10-22 Celgene Avilomics Research, Inc. Besylate salt of a BTK inhibitor
US8574811B2 (en) 2010-08-30 2013-11-05 Sumitomo Chemical Company, Limited Resist composition and method for producing resist pattern
US11096942B2 (en) 2010-11-01 2021-08-24 Celgene Car Llc Heterocyclic compounds and uses thereof
US8975249B2 (en) 2010-11-01 2015-03-10 Celgene Avilomics Research, Inc. Heterocyclic compounds and uses thereof
US10434101B2 (en) 2010-11-01 2019-10-08 Celgene Car Llc Heterocyclic compounds and uses thereof
US10081606B2 (en) 2010-11-01 2018-09-25 Celgene Car Llc Heteroaryl compounds and uses thereof
US9375431B2 (en) 2010-11-01 2016-06-28 Celgene Avilomics Research, Inc. 2,4-disubstituted pyrimidine compounds useful as kinase inhibtors
US9867824B2 (en) 2010-11-01 2018-01-16 Celgene Car Llc Heterocyclic compounds and uses thereof
US9765038B2 (en) 2010-11-01 2017-09-19 Celgene Car Llc Heteroaryl compounds and uses thereof
US9238629B2 (en) 2010-11-01 2016-01-19 Celgene Avilomics Research, Inc. Heteroaryl compounds and uses thereof
US9868723B2 (en) 2010-11-10 2018-01-16 Celgene Car Llc Mutant-selective EGFR inhibitors and uses thereof
US8796255B2 (en) 2010-11-10 2014-08-05 Celgene Avilomics Research, Inc Mutant-selective EGFR inhibitors and uses thereof
US9409887B2 (en) 2010-11-10 2016-08-09 Celgene Avilomics Research, Inc. Mutant-selective EGFR inhibitors and uses thereof
US8574812B2 (en) 2011-02-25 2013-11-05 Sumitomo Chemical Company, Limited Resist composition and method for producing resist pattern
US8940473B2 (en) 2011-02-25 2015-01-27 Sumitomo Chemical Company, Limited Resist composition and method for producing resist pattern
US8859182B2 (en) 2011-02-25 2014-10-14 Sumitomo Chemical Company, Limited Resist composition and method for producing resist pattern
US8835095B2 (en) 2011-02-25 2014-09-16 Sumitomo Chemical Company, Limited Resist composition and method for producing resist pattern
US8592132B2 (en) 2011-02-25 2013-11-26 Sumitomo Chemical Company, Limited Resist composition and method for producing resist pattern
US8568956B2 (en) 2011-02-25 2013-10-29 Sumitomo Chemical Company, Limited Resist composition and method for producing resist pattern
US8563219B2 (en) 2011-02-25 2013-10-22 Sumitomo Chemical Company, Limited Resist composition and method for producing resist pattern
US8563218B2 (en) 2011-02-25 2013-10-22 Sumitomo Chemical Company, Limited Resist composition and method for producing resist pattern
US8563217B2 (en) 2011-02-25 2013-10-22 Sumitomo Chemical Company, Limited Resist composition and method for producing resist pattern
US9006241B2 (en) 2011-03-24 2015-04-14 Noviga Research Ab Pyrimidine derivatives
US9834518B2 (en) 2011-05-04 2017-12-05 Ariad Pharmaceuticals, Inc. Compounds for inhibiting cell proliferation in EGFR-driven cancers
US8652754B2 (en) 2011-07-19 2014-02-18 Sumitomo Chemical Company, Limited Resist composition and method for producing resist pattern
US8685619B2 (en) 2011-07-19 2014-04-01 Sumitomo Chemcial Company, Limited Resist composition and method for producing resist pattern
US8741543B2 (en) 2011-07-19 2014-06-03 Sumitomo Chemical Company, Limited Resist composition and method for producing resist pattern
US8778594B2 (en) 2011-07-19 2014-07-15 Sumitomo Chemical Company, Limited Resist composition and method for producing resist pattern
US9052591B2 (en) 2011-07-19 2015-06-09 Sumitomo Chemical Company, Limited Resist composition and method for producing resist pattern
US9364476B2 (en) 2011-10-28 2016-06-14 Celgene Avilomics Research, Inc. Methods of treating a Bruton's Tyrosine Kinase disease or disorder
US10570099B2 (en) 2012-03-15 2020-02-25 Celgene Car Llc Salts of an epidermal growth factor receptor kinase inhibitor
US9056839B2 (en) 2012-03-15 2015-06-16 Celgene Avilomics Research, Inc. Solid forms of an epidermal growth factor receptor kinase inhibitor
US11292772B2 (en) 2012-03-15 2022-04-05 Celgene Car Llc Salts of an epidermal growth factor receptor kinase inhibitor
US10946016B2 (en) 2012-03-15 2021-03-16 Celgene Car Llc Solid forms of an epidermal growth factor receptor kinase inhibitor
US9540335B2 (en) 2012-03-15 2017-01-10 Celgene Avilomics Research, Inc. Salts of an epidermal growth factor receptor kinase inhibitor
US10005738B2 (en) 2012-03-15 2018-06-26 Celgene Car Llc Salts of an epidermal growth factor receptor kinase inhibitor
US9539255B2 (en) 2012-03-15 2017-01-10 Celgene Avilomics Research, Inc. Solid forms of an epidermal growth factor receptor kinase inhibitor
US10004741B2 (en) 2012-03-15 2018-06-26 Celgene Car Llc Solid forms of an epidermal growth factor receptor kinase inhibitor
US9108927B2 (en) 2012-03-15 2015-08-18 Celgene Avilomics Research, Inc. Salts of an epidermal growth factor receptor kinase inhibitor
US9834571B2 (en) 2012-05-05 2017-12-05 Ariad Pharmaceuticals, Inc. Compounds for inhibiting cell proliferation in EGFR-driven cancers
US9549927B2 (en) 2012-12-21 2017-01-24 Celgene Avilomics Research, Inc. Heteroaryl compounds and uses thereof
US9126950B2 (en) 2012-12-21 2015-09-08 Celgene Avilomics Research, Inc. Heteroaryl compounds and uses thereof
US9980964B2 (en) 2013-02-08 2018-05-29 Celgene Car Llc ERK inhibitors and uses thereof
US9504686B2 (en) 2013-02-08 2016-11-29 Celgene Avilomics Research, Inc. ERK inhibitors and uses thereof
US9145387B2 (en) 2013-02-08 2015-09-29 Celgene Avilomics Research, Inc. ERK inhibitors and uses thereof
US9561228B2 (en) 2013-02-08 2017-02-07 Celgene Avilomics Research, Inc. ERK inhibitors and uses thereof
US9796700B2 (en) 2013-02-08 2017-10-24 Celgene Car Llc ERK inhibitors and uses thereof
US9611283B1 (en) 2013-04-10 2017-04-04 Ariad Pharmaceuticals, Inc. Methods for inhibiting cell proliferation in ALK-driven cancers
US9492471B2 (en) 2013-08-27 2016-11-15 Celgene Avilomics Research, Inc. Methods of treating a disease or disorder associated with Bruton'S Tyrosine Kinase
US9415049B2 (en) 2013-12-20 2016-08-16 Celgene Avilomics Research, Inc. Heteroaryl compounds and uses thereof
US10202364B2 (en) 2014-08-13 2019-02-12 Celgene Car Llc Forms and compositions of an ERK inhibitor
US10005760B2 (en) 2014-08-13 2018-06-26 Celgene Car Llc Forms and compositions of an ERK inhibitor

Also Published As

Publication number Publication date
US7884111B2 (en) 2011-02-08
US8809341B2 (en) 2014-08-19
DE602004032446D1 (en) 2011-06-09
ES2365223T3 (en) 2011-09-26
WO2005013996A3 (en) 2005-06-09
US20050113398A1 (en) 2005-05-26
DK1663242T3 (en) 2011-08-01
ATE506953T1 (en) 2011-05-15
US20150011002A1 (en) 2015-01-08
WO2005013996A2 (en) 2005-02-17
SI1663242T1 (en) 2011-09-30
EP1663242B1 (en) 2011-04-27
JP4741491B2 (en) 2011-08-03
EP1663242A2 (en) 2006-06-07
US20080009484A1 (en) 2008-01-10
US9598432B2 (en) 2017-03-21
US20110190271A1 (en) 2011-08-04
JP2007501793A (en) 2007-02-01
US20080027045A1 (en) 2008-01-31

Similar Documents

Publication Publication Date Title
US9598432B2 (en) 2,4-pyrimidinediamine compounds and uses as anti-proliferative agents
US8044054B2 (en) Stereoisomerically enriched 3-aminocarbonyl bicycloheptene pyrimidinediamine compounds and their uses
US8546398B2 (en) Stereoisomerically enriched 3-aminocarbonyl bicycloheptene pyrimidinediamine compounds and their uses
US7482351B2 (en) 4-pyrimidineamine compounds and their uses as anti-proliferative agents

Legal Events

Date Code Title Description
AS Assignment

Owner name: RIGEL PHARMACEUTICALS, INC., CALIFORNIA

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:ARGADE, ANKUSH;SINGH, RAJINDER;LI, HUI;AND OTHERS;REEL/FRAME:018628/0397;SIGNING DATES FROM 20050104 TO 20050106

Owner name: RIGEL PHARMACEUTICALS, INC., CALIFORNIA

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:ARGADE, ANKUSH;SINGH, RAJINDER;LI, HUI;AND OTHERS;SIGNING DATES FROM 20050104 TO 20050106;REEL/FRAME:018628/0397

STCB Information on status: application discontinuation

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