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WO2012059932A1 - Dérivés de 2,4-diaminopyrimidine en tant qu'inhibiteurs de protéine kinases - Google Patents

Dérivés de 2,4-diaminopyrimidine en tant qu'inhibiteurs de protéine kinases Download PDF

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Publication number
WO2012059932A1
WO2012059932A1 PCT/IN2010/000718 IN2010000718W WO2012059932A1 WO 2012059932 A1 WO2012059932 A1 WO 2012059932A1 IN 2010000718 W IN2010000718 W IN 2010000718W WO 2012059932 A1 WO2012059932 A1 WO 2012059932A1
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alkyl
formula
compound
nitro
cycloalkyl
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Inventor
Saumitra Sengupta
Srinivasan Rajagopalan
Ningaraddi Belavagi
Muralidhara Ramachandra
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Aurigene Oncology Ltd
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Aurigene Discovery Technologies Ltd
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    • 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
    • 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
    • A61P37/00—Drugs for immunological or allergic disorders
    • 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
    • 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
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • 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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/645—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having two nitrogen atoms as the only ring hetero atoms
    • C07F9/6509—Six-membered rings
    • C07F9/6512—Six-membered rings having the nitrogen atoms in positions 1 and 3

Definitions

  • This invention relates to compounds useful as inhibitors of protein kinases.
  • This invention particularly relates to the compounds, processes for preparing the compounds of this invention, the isoforms of these compounds, and pharmaceutical compositions comprising the same as active ingredients.
  • the present invention further relates to the prodrugs, tautomeric forms, derivatives, analogues, stereo isomers, polymorphs, pharmaceutically acceptable salts, pharmaceutically acceptable solvates and pharmaceutically acceptable compositions containing compounds as described herein and their use in the treatment of various disorders.
  • Cancer is a group of varied diseases characterized by uncontrolled growth and spread of abnormal cells: Generally, all types of cancers involve some abnormality in the control of cell growth and division. The pathways regulating cell division and or cellular
  • cyclophosphamide, 5'- fluorouracil, and methotrexate rely upon a generalized damage to DNA and destabilization of chromosomal structure which eventually leads 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 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.
  • chemotherapeutic agents are 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 which may have differing properties and cellular targets, increases the effectiveness of chemotherapy and limits the generation of drug resistance.
  • Protein kinases constitute a large family of structurally related enzymes that are responsible for the control of a variety of signal transduction processes within the cell.
  • Protein kinases are thought to have evolved from a common ancestral gene due to the conservation of their structure and catalytic function. Almost all kinases contain a similar 250- 300 amino acid catalytic domain.
  • the kinases may be categorized into families by the substrates they phosphorylate (e.g. protein- tyrosine, protein- serine/ threonine, lipids, etc.). Sequence motifs have been identified that generally correspond to each of these kinase families (for example Hanks, S .K-, Hunter, T., FASEB J .
  • the protein kinases may be broadly divided into two groups; those that phosphorylate serine or threonine residues (serine /threonine kinases, STK) which are inclusive of but not limited to the likes of AKT, P70 S6, J K, AURORA, P38, ERK, IKK, AMPK, CHK, CDKs, GSK, PKC, Raf, PLK,
  • PTK protein tyrosine kinases
  • receptor types such as EGFR, PDGFR, JAK, C-Kit, and the non -receptor types which include C-SRC, FLT3, Abl, FGFR1 , KDR/ (VEGFR2), Ret, c-MET, JAK2, Syk ,FAK and dual Kinase inhibitors such as MEK.
  • kinases such as those selected from the likes of Aurora, CDK2, EGFR, C-SRC, FGFR, VEGFR, C-MET, JAK and FAK while retaining a sufficient therapeutic window.
  • Aurora kinase is involved in mitosis, and has been demonstrated to be a putative oncoprotein overexpressed in several cancer cells of breast, colon, pancreas and ovarian cancer (Carvajal RD et al., Clin. Cancer Res., 12(23), 6869-75, 2006).
  • Aurora kinase inhibitors have been reported so far and some of them have been discussed previously in this document.
  • Cycline-dependent kinase is known to play a prominent role in Gl/S transition and G2 M transition in cell cycle (Kim Nasmyth, Science, 21 A, 1643-1677, 1996) to regulate cell growth.
  • CDK Cycline-dependent kinase
  • the epidermal growth factor receptor (EGFR) family comprises four closely related receptors (HERl/EGFR, HER2, HER3 and HER4) involved in cellular responses such as differentiation and proliferation.
  • EGFR kinase or its ligand TGF-alpha, is frequently associated with many cancers, including breast, lung, colorectal, ovarian, renal cell, bladder, head and neck cancers, glioblastomas and astrocytomas, and is believed to contribute to the malignant growth of these tumors.
  • Recent reports have shown that the sensitivity of cell lines to growth inhibition by EGFR inhibitors is dependent on the down-regulation of the PI3K-PDK1-Akt pathway.
  • Non-receptor tyrosine kinases belonging to the Src family are key effectors of signal transduction.
  • C-src was initially discovered as the oncogenic protein of the retrovirus Rous sarcoma virus, and it is now well established that the family of src kinases play an important role in cell cycle control, cell adhesion, proliferation and differentiation, as well as lymphokine-mediated cell survival and angiogenesis (Schlessinger, Cell, 2000, 100, 293- 296).
  • the kinase activity of several members of the Src family, including c-src, fyn, and lyk is negatively regulated by phosphorylation by c-src tyrosine kinase.
  • C-src tyrosine kinase phosphorylates c-src on tyrosine 527 which induces intramolecular interactions between phosphotyrosine sites that leads to a conformational change which maintains c-src in a catalytically inactive conformation.
  • c-src tyrosine kinase holds a pivotal role in many signal transduction pathways that regulate the cell cycle (Latour and Veillette, Curr. Opin. Immunol, 2001, 13, 299306).
  • the Janus kinases are a family of non receptor tyrosine kinases consisting of JAK1, JAK2, JAK3 and TYK2.
  • the JA s play a critical role in cytokine signaling.
  • the downstream substrates of the JAK family of kinases include the signal transducer and activator of transcription (STAT) proteins.
  • STAT signal transducer and activator of transcription
  • JAK/STAT signaling has been implicated in the mediation of many abnormal immune responses such as allergies, asthma, autoimmune diseases such as transplant rejection, rheumatoid arthritis, amyotrophic lateral sclerosis and multiple sclerosis as well as in solid and hematological malignancies such as leukemias and lymphomas.
  • the pharmaceutical intervention in the JAK/STAT pathway has been reviewed ( Frank Molt Med. 5: 432-456 1999 & Seidel, et al, Oncogene 19: 2645- 2656).
  • c-Met is also known as hepatocyte growth factor receptor or scatter factor receptor. c-Met is thought to play a role in primary tumor growth and metastasis and compounds modulating this target have been discussed in US7250417.
  • VEGF acts through two high affinity tyrosine kinase receptors, VEGFRl or Fms-related tyrosine kinase, Flt-1), and VEGFR2 (also known as kinase domain receptor or kinase insert domain-containing receptor, KDR).
  • VEGFR1 binds VEGF with a 50- fold higher affinity than KDR, KDR appears to be the major transducer of VEGF angiogenic effects, i.e.
  • angiogenesis and tumor inhibition has been achieved by using agents that either interrupt VEGF/KI)R interaction and/or block the KDR signal transduction pathway,
  • FGFR binds the angiogenic growth factors aFGF and bFGF and mediates subsequent intracellular signal transduction. It has been suggested that growth factors such as bFGF may play a critical role in inducing angiogenesis in solid tumors that have reached a certain size; Yoshiji et al., Cancer Research, 57, 3924-3928 (1997).
  • FGF-R is expressed in a number of different cell types throughout the body and may or may not play important roles in other normal physiological processes in the adult, Nonetheless, systemic administration of a small molecule inhibitor of the kinase activity of FGF-R has been reported to block bFGF-induced angiogenesis in mice without apparent toxicity; Mohammad et al, EMBO Journal, 17, 5996-5904 (1998).
  • Focal Adhesion Kinase is a focal adhesion-associated protein kinase involved in cellular adhesion and spreading processes.
  • Focal adhesion kinase (FAK) is a 125 kDa, highly conserved, non-receptor tyrosine kinase originally identified as a substrate for the oncogene protein tyrosine kinase v-src (Guan, 1992 9 /id;Kanner, 1990 8 /id). This cytosolic kinase has been implicated in diverse cellular roles including cell locomotion, mitogen response and cell survival.
  • More than 800 compounds which are inhibitors of various kinases have been disclosed in clusters of highly similar patent applications WO2002/022601, WO2002/022602, WO2002/022603, WO2002/022604, WO2002/022605, WO2002022606, WO2002022607, WO2002022608, WO2002/50066, WO2002/0591 12, WO2002/50065 ,WO2002/62789 , WO2002/05911 1, WO2002/057259, WO05118544, WO06091737, WO06010915, WO06136442, WO20070731 17, WO 2004000833,
  • compounds of this invention are effective as inhibitors of protein kinases such as including but not limited to kinase inhibitors which belongs to the class of serine /threonine kinases and/ or protein tyrosine kinases (PTK) or dual kinase inhibitors such as kinases selected from the likes of Aurora, CDK2, EGFR, C-SRC, FGFR, VEGFR, C-MET, JAK and FAK.
  • protein kinases such as including but not limited to kinase inhibitors which belongs to the class of serine /threonine kinases and/ or protein tyrosine kinases (PTK) or dual kinase inhibitors such as kinases selected from the likes of Aurora, CDK2, EGFR, C-SRC, FGFR, VEGFR, C-MET, JAK and FAK.
  • kinases such as including but not limited to kinase inhibitors which belongs to the class of serine
  • R , A, and R are as described below.
  • the invention further includes the compounds as described herein, their tautomeric forms, their derivatives, their analogues, their stereo isomers, prodrugs, their polymorphs, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates and pharmaceutically acceptable compositions containing them for the treatment of tumors or for the treatment of cancers.
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula 1 or a salt, solvate, or a physiologically functional derivative thereof and one or more pharmaceutically acceptable carriers, diluents or excipients.
  • a method of treating a disorder in a mammal comprising administering to said mammal a therapeutically effective amount of a compound of formula 1 or a salt, solvate or a physiologically functional derivative thereof.
  • Said method may include preliminary testing to establish the need for such treatment and/or subsequent monitoring to determine the effect of such treatment, optionally by measurement of one or more biomarkers, optionally chemical biomarkers.
  • a compound of formula 1 or a salt, solvate, or a physiologically functional derivative thereof for use in therapy.
  • a compound of formula 1, or a salt, solvate, or a physiologically functional derivative thereof in the preparation of a medicament for use in the treatment of a disorder mediated by at least one of inappropriate Aurora, CDK2, EGFR, C-SRC, FGFR, VEGFR, C-MET , JAK and FAK activity.
  • a method of treating a disorder in a mammal comprising administering to said mammal therapeutically effective amounts of (i) a compound of formula 1 , or a salt, solvate or physiologically functional derivative thereof and (ii) an agent to inhibit growth factor receptor function.
  • a method of treating a disorder in a mammal comprising administering to said mammal a therapeutically effective amount of a compound of formula 1 , or a salt, solvate or physiologically functional derivative thereof.
  • An aspect of the present invention is also to provide a method of treating by enhancing immune response towards cancer, e.g. c-src and Jak, through inhibition of Stat3.
  • the compounds of formula 1 and pharmaceutically acceptable compositions thereof are useful for treating or preventing a variety of diseases, disorders or conditions in which proliferation, angiogenesis or immune response need to be modulated for therapeutic efficacy.
  • diseases, disorders or conditions include, but are not limited to, proliferative disorders such as cancer, defective wound healing, heart disease, diabetes, Alzheimer's disease, immunodeficiency disorders, inflammatory diseases, allergic diseases, autoimmune diseases, destructive bone disorders such as osteoporosis, infectious diseases,
  • compositions are also useful in inhibiting cell death and hyperplasia and due to which these compounds may be used to treat or prevent reperfusion/ischemia in stroke, heart attacks, and organ hypoxia.
  • the compounds provided by this invention are also useful for the evaluation of kinases in various biological processes including their role in intracellular signal transduction pathways. These compounds will also be useful as reference compounds in evaluation of new kinase inhibitors.
  • a molecular moiety may exist in a free species form, in which it is not associated with other molecules.
  • a compound may also exist as part of a larger aggregate, in which it is associated with other molecule(s), but nevertheless retains its chemical identity.
  • a solvate in which the molecular moiety of defined chemical structure ("compound") is associated with a molecule(s) of a solvent, is an example of such an associated form.
  • a hydrate is a solvate in which the associated solvent is water.
  • composition refers to the molecular moiety itself (of the recited structure), regardless whether it exists in a free form or and an associated forms.
  • composition as used herein is intended to encompass a product comprising the specified ingredients such as the said compound, their tautomeric forms, their derivatives, their analogues, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts, esters, ethers, metablolites, mixtures of isomers, their pharmaceutically acceptable solvates and pharmaceutically acceptable compositions in specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
  • compositions of the present invention are meant to encompass any composition made by admixing compounds of the present invention and their pharmaceutically acceptable carriers.
  • pharmaceutically acceptable means that the carrier, diluents or excipients are meant to be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
  • 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, by any mechanism of action, including, for example apoptosis.
  • treatment covers any treatment of a disease in a subject, particularly a human, and includes: (a) preventing the disease or symptom from occurring in a subject which may be predisposed to the disease or symptom, but has not yet been diagnosed as having it; (b) inhibiting the disease symptom, i.e. arresting its development; or (c) relieving the disease symptom, i.e. causing regression of the disease or symptom.
  • terapéuticaally effective amount refers to the amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system or patient that is being sought.
  • C x -C y refers to a chain of carbon atoms or a carbocyclic skeleton containing from x to y atoms, inclusive.
  • the designated range of carbon atoms may refer independently to the number of carbon atoms in the chain or the cyclic skeleton, or to the portion of a larger substituent in which the chain or the skeleton is included.
  • Ci-C 8 alkyl refers to an alkyl group having a carbon chain of 1 to 8 carbon atoms, inclusive of 1 and 8.
  • the chains of carbon atoms of the groups and substituents described and claimed herein may be saturated or unsaturated, straight chain or branched, substituted or
  • alkyl employed alone or in combination with other terms means both branched and straight-chain saturated or unsaturated aliphatic hydrocarbon group having a specified number of carbon atoms.
  • the alkyl groups of the invention are saturated. Preferably, they have from 1 to 10 carbon atoms, e.g. 1-6 carbon atoms or 1-3 carbon atoms. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl, are attached to a linear alkyl chain.
  • suitable alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, and t-butyl.
  • monoalkylamino is intended to include an amino group substituted one time with the above-defined “alkyl” group.
  • mono Ci-C 8 alkylamino group include methylamino, ethylamino, propylamino, and the like.
  • dialkylamino is intended to include an amino group substituted two times with the above-defined “alkyl” groups.
  • di Q-Q alkylamino groups include dimethylamino, diethylamino, methylethylamino, and the like.
  • cycloalkyl employed alone or in combination with other terms means a cyclic saturated akyl group having 3 to 15 carbon atoms, e.g. 3-8 carbon atoms, e.g. 3-6, especially 5 or 6 carbon atoms.
  • C 3 -C 8 cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, adamantyl, substituted adamantyl and the like.
  • cycloalkylalkyl is intended to include above defined “cycloalkyl” groups substituted with an above defined “alkyl” group.
  • C 3 -C 8 cycloalkyl Ci-C 8 alkyl groups are cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl, and the like.
  • alkoxy is intended to mean a chain of carbon atoms and is defined as 'alkyl-O-', wherein alkyl group is as defined above.
  • the chains of carbon atoms of the alkoxy groups described and claimed herein are saturated or unsaturated (preferably saturated), and may be straight chain or branched.
  • “Ci-C 8 alkoxy” denotes an alkoxy group having carbon chain with from 1 to 8 carbon atoms, inclusive, straight chain or branched, substituted or unsubstituted.
  • Exemplary Ci-C 8 alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy and the like.
  • Aryl employed alone or in combination with other terms means an aromatic monocyclic or polycyclic ring system comprising about 6 to about 14 carbon atoms, preferably about 6 to about 10 carbon atoms.
  • suitable aryl groups include phenyl and naphthyl.
  • aryloxy is intended to mean 'aryl-O-', wherein aryl group is as defined above.
  • aryloxy include phenoxy, 1-naphthyloxy, and the like.
  • aralkyl herein used means the above mentioned “alkyl” substituted with the above mentioned “aryl” at any possible position. Examples of the aralkyl are benzyl, phenethyl (e.g., 2-phenethyl), phenylpropyl (e.g., 3-phenylpropyl), naphthylmethyl (e.g., 1- naphthylmethyl and 2-naphthylmethyl) and the like.
  • heteroaryl employed alone or in combination with other terms means an aromatic monocyclic or polycylic ring system comprising about 5 to about 14 ring atoms, preferably about 5 to about 10 ring atoms, in which one or more of the ring atoms is an element other than carbon, for example nitrogen, oxygen or sulfur, alone or in combination.
  • the prefix aza, oxa or thia before the heteroaryl root name means that at least a nitrogen, oxygen or sulfur atom respectively, is present as a ring atom.
  • a nitrogen atom of a heteroaryl can be optionally oxidized to the corresponding N-oxide.
  • Non-limiting examples of suitable heteroaryl groups include pyridyl, pyrazinyl, furanyl, thienyl, pyrimidinyl, isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, pyrrolyl, triazolyl, benzooxazolyl, benzothiazolyl and the like.
  • heteroarylkyl is intended to include the group wherein the above- mentioned “alkyl” group is substituted with the above-mentioned “heteroaryl”.
  • heteroarylalkyl examples include thienylmethyl (e.g., 2-thienylmethyl), thienylethyl (e.g., 2-(thiophen- 2-yl)ethyl), furylmethyl (e.g., 2-furylmethyl), furylethyl (e.g., 2-(furan-2-yl)ethyl), pyrrolylmethyl (e.g., 2-pyrrolylmethyl), pyrrolylethyl (e.g., 2-(pyrrol-2-yl)ethyl),
  • imidazolylmethyl e.g., 2-imidazolylmethyl, 4-imidazolylmethyl
  • imidazolylethyl e.g., 2- (imidazol-2-yl)ethyl
  • pyrazolylmethyl e.g., 3-pyrazolylmethyl
  • pyrazolylethyl e.g., 2- (pyrazol-3-yl)ethyl
  • thiazolylmethyl e.g., 2-thiazolylmethyl
  • thiazolylethyl e.g., 2-(thiazol- 2-yl)ethyl
  • isothiazolylmethyl e.g., 3 -thiazolylmethyl
  • isoxazolylmethyl e.g., 3- isoxazolylmethyl
  • oxazolylmethyl e.g., 2-oxazolylmethyl
  • oxazolylethyl e.g., 2-(oxazol-2- yl
  • heterocyclyl employed alone or in combination with other terms means an aromatic or non-aromatic monocyclic or polycylic ring system comprising about 5 to about 14 ring atoms, preferably about 5 to about 10 ring atoms, in which one or more of the ring atoms is an element other than carbon, for example nitrogen, oxygen or sulfur, alone or in combination.
  • aza, oxa, or thia before the heterocyclyl root name means that at least a nitrogen, oxygen, or sulfur atom respectively, is present as a ring atom.
  • a nitrogen atom of a heterocyclyl can be optionally oxidized to the corresponding N-oxide.
  • Non- limiting examples of suitable heterocylic groups include pyrrolidinyl (e.g., 1-pyrrolidinyl, 2- pyrrolidinyl), pyrrolinyl (e.g., 3-pyrrolinyl), imidazolidinyl (e.g., 2-imidazolidinyl), imidazolinyl (e.g., imidazolinyl), pyrazolidinyl (e.g., 1-pyrazolidinyl, 2-pyrazolidinyl), pyrazolinyl (e.g., pyrazolinyl), piperidinyl (e.g., piperidino, 2-piperidinyl), piperazinyl (e.g., 1 -piperazinyl), indolynyl (e.g., 1-indolynyl), isoindolinyl (e.g., isoindolinyl), morpholinyl (e.g., morph
  • heterocyclylalkyl is intended to include a group wherein the above- mentioned “alkyl” is substituted with the above-mentioned “heterocyclyl”.
  • heterocyclylalkyl examples include pyrrolidinylmethyl (e.g., 1-pyrrolidinylmethyl), pyrrolinylethyl (e.g., 3- pyrrolinylethyl), imidazolidinylmethyl (e.g., 2-imidazolidinylmethyl), pyrazolidinylethyl (e.g., 1 -pyrazolidinylethyl), piperidinylethyl (e.g., 2-piperidinylethyl), piperazinylmethyl (e.g., 1 -piperazinylmethyl), indolynylmethyl (e.g., 1 -indolynylmethyl), and the like.
  • acyl employed alone or in combination with other terms means alkylcarbonyl in which alkyl group is as defined above, and arylcarbonyl in which aryl group is as defined above.
  • examples of the acyl are acetyl, propionyl, benzoyl, and the like.
  • acylamino employed alone or in combination with other terms means amino group substituted with the above-mentioned "acyl” group.
  • examples of the acylamino include acetylamino, propionylamino, benzoylamino, and the like.
  • acyloxy is intended to include a group acyl-O, wherein acyl group is as defined above.
  • examples of the acyloxy group include acetyloxy, propionyloxy,
  • haloalkyl is intended to mean an above-defined “alkyl” group is substituted with the above defined “halogen” group at any one or more of the 1 to 8 carbon atoms of the alkyl group.
  • haloalkyl group are trifluoromethyl
  • perhaloalkyl refers to an alkyl group where all of the hydrogen atoms are replaced by halogen atoms.
  • substituted means that one or more hydrogens on the designated atom are replaced with a selection from the indicated groups, provided that the designated atom's normal valency is not exceeded, and that the substitution results in a stable compound.
  • inhibitor is intended to indicate a molecule that exhibits inhibition of the enzymatic activity of the indicated enzyme, such as from 1-100% inhibition.
  • an “inhibitor” is also intended to comprise active metabolites and prodrugs.
  • inhibitortors are also referred to as modulators or “effectors” that decrease or prevent a chemical reaction (e.g they prevent or decrease phosphorylation in the context of kinase inhibitors).
  • treatment is understood the management and care of a patient for the purpose of combating the disease condition or disorder and cancer in the present context.
  • halogen including when represented by "X”, means F, CI, Br, or I.
  • the present invention provides kinase inhibitors having Formula 1 HN
  • R 2 is -OH, -NH 2 , -O-alkyl or -O-cycloalkyl, -S-alkyl or -S-cycloalkyl, -CH 2 OH, -C3 ⁇ 40alkyl or -CH 2 0-cycloalkyl, -NHCO-alkyl or -NHCO-cycloalkyl, -NHCO-aryl, -CONH-alkyl or - CONH-cycloalkyl, -CONH-aryl, or -0-CO-NH 2 ;
  • 'A' is H, C]-C 6 straight or branched alkyl, d-C 6 alkenyl or C ⁇ -C 6 alkynyl, C 5 -C 8 cyclic, C 5 - C 8 heterocyclic, or halogen;
  • R 1 is a group represented by the following general formula 2;
  • Q is nitrogen or carbon and Q 1 independently is nitrogen or optionally substituted carbon; with a proviso that not both of Q and Q 1 are nitrogen; either T is R 4 and the other T is -L-R 3 where 'L' is a bond or a linker selected from -CO-, - CO-NH-, -0-(CH 2 ) 1.2 -, - (CH 2 ) 1-2 -0-, -S0 2 -, -S0 2 -NH-, -NH-S0 2 -, -N(R 9 )-S0 2 -, -CO- N(R 9 )-, -C 1 -C3 alkylene-, -NHCO-, and combinations thereof, where R 9 is as defined above; R 3 is selected from -H, -OH , -NH 2 , Ci- C straight or branched alkyl, Ci- Ci 2 straight or branched alkanol, Ci-C 3 alkylamide, C 5 - C &
  • R 4 is selected from H, C C 6 straight or branched alkyl , CrC 6 straight or branched alkanol, Ci-C 6 alkoxy, C,-C 6 haloalkyl,- CX 3 , CN, C 2 alkynyl, halogen; C
  • R 9 is H, or a Ci-C 6 alkyl
  • n 0, 1, or 2
  • the present disclosure relates to compounds described in formula 1 their
  • the disclosure also relates to compounds of interest in formula 1 , their polymorphs, and suitable formulations for oral dosage.
  • Q is nitrogen or carbon and Q 1 independently is nitrogen or optionally substituted carbon; with a proviso that not both of Q and Q 1 are nitrogen; either T is R 4 and the other T is -L-R 3 where 'L' is a bond and R 3 is as defined above or more preferably is an amide of the formula -CO-NH-R', or -NH-CO-R' wherein R' is selected from C,-C 6 alkyl, Ci-C 6 alkanol, C C 6 alkanediol C r C 6 alkoxy, and N-(R 5 R 6 ) , wherein, R 5 and R 6 are independently selected from H, C ! -C alkyl , straight or branched Ci-C 6 alkanol, C r C 6 alkanediol, Ci-C 6 alkoxy with the proviso that R 5 and R 6 are not both H;
  • R 4 is as defined above or more preferably is H, Ci-C 6 alkyl , C]-C haloalkyl , C 2 alkynyl, or CX 3 (e.g. CF 3 ).
  • Q may preferably be carbon and Q 1 may preferably then be nitrogen or may be optionally substituted carbon.
  • Q may be carbon and Q 1 may be optionally substituted carbon.
  • R 4 is H, (Ci-C 6 ) alkyl (e.g. CH 3 ), CX 3 (e.g. CF 3 ), CN, or C 2 alkynyl,
  • 'L' is a bond or a linker as defined above, preferably selected from the likes of CO, - CO-NH-, -, -O- (CH 2 ) m , -(CH 2 ) m -0-, -CH 2 ) m - and -S0 2 ; and
  • R is a heterocyclic or heteroaryl ring exemplified by the following non limiting representative groups
  • R is as defined above, but may preferably be selected from H, straight or branched C,-C 6 alkyl, C C 6 alkanol, d-Q alkoxy, -S0 2 -R', halogen , C r C 6 haloalkyl, C r C 6 alkyl, Ci-C 6 hydroxy alkyl, CO-NH-R', alkoxy, ester, cycloalkyl or heteroaryl
  • R' is H or lower alkyl such as methyl;
  • Representative compounds of the second subsidiary aspect of the invention include not limited to those exemplified in table -II below;
  • a third subsidiary aspect of the present invention provides compounds of formula 1 containing as R 1 the moiety as represented by the formula 2a, but wherein R 4 is H,
  • R is a N- bicyclic bridgehead group optionally substituted by R , and further exemplified by the following representative groups;
  • R is as defined above but is preferably selected from H, Cj-C alkyl, OH, Ci-C 6 alkanol, C
  • Representative compounds of the third subsidiary aspect of the invention include but are not limited to those illustrated below in table -III ;
  • a fourth subsidiary aspect of the present invention provides compounds of Formula 1 containing the moiety represented by the followin formula 2b;
  • R 4 is as defined above but is preferably H, or halogen
  • R 8 is as defined above but is preferably selected from H, hydroxyl, Ci-C 6 alkyl, OH, Ci-C ⁇ 5 alkanol, C C 6 alkoxy ; amide;
  • a fifth subsidiary aspect of the present invention provides compounds of formula 1
  • R 3 is H; and Q 1 is as described for Formula 1;
  • R 4 is represented by the following fragments
  • R 9 isH,Xor ad-C 6 alkyl.
  • Representative compounds of the fifth subsidiary aspect of the invention include but are not limited to those illustrated below in table -V below; TABLE -V
  • R 3 is H
  • 'L' is a bond or a linker selected from -(CH 2 )- m , -O- , -(CH 2 ) m -NH-CO- , -(CH 2 ) m - CO-NH-, S0 2 ;
  • R 4 is group selected from the groups selected from; Ci-C 6 alkyl; Ci-C 8 cycloalkyl,
  • R is selected from H, one or more Ci-C 6 straight or branched alkyl; Ci-C 6 straight branched alkanol, Ci-C 6 alkoxy; and
  • R 9 is H, X or a Q-Q alkyl
  • Representative compounds of the sixth subsidiary aspect of the invention include but are not limited to those illustrated below in table -VI below;
  • R is selected from H, CF 3 , one or more Q-Q straight or branched alky 1; Ci-C straight or branched alkanol, Ci-C 6 alkoxy;
  • R 10 is H or C,-C 6 alkyl
  • R 4 is selected from H, C 3 -C 6 alkyl, X, CN, -C 2 alkynyl;
  • Ring 'B' is selected from a carbocyclic, heterocyclic, aryl, heteroaryl ring wherein the heterocyclic or heteroaryl rings contain one or more heteroatoms; and is optionally substituted, e.g. with -CF 3 ;
  • Representative compounds of the seventh subsidiary aspect of the invention include not limited to those illustrated below in VII below; TABLE -VII
  • R 8 is selected from H , one or more C[-C 6 straight or branched alkyl; Ci-C straight or branched alkanol, Ci-C 6 alkoxy, cycloalkyl, or heterocycloalkyl;
  • R 10 is H or Ci-C 6 alkyl
  • ⁇ ' when present is one or more of N, O, or combinations thereof;
  • each n independently 0, 1, or 2.
  • the compounds of the present invention encompass stereoisomers.
  • optical isomer defines a compound having a defined optical configuration at least one optical center. This principle applies for each structural genus described herein, as well as for each subgenus and for individual structures.
  • the compounds of the invention will exist as cis- and trans- isomers with respect to the adamantyl group. In our tests we have found that typically trans- isomers show better activity in terms of IC50 values, but cis- isomers show better activity in terms of EC50 values.
  • the present invention also relates to useful forms of compounds such as disclosed herein, such as freebase forms and pharmaceutically acceptable salts.
  • pharmaceutically acceptable salts and the term 'veterinarily acceptable salts' as used herein include those obtained by reacting the main compound functioning as a base with an inorganic or organic acid to form a salt for example, salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric, and methane sulfonic acid, camphor sulfonic acid, oxalic acid, maleic acid, acetic acid, succinic acid, tartaric acid, para-toluene sulfonic acid, citric acid, benzoic acid, salicylic acid, mandelic acid and carbonic acid
  • compositions containing the active ingredient may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs.
  • compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations.
  • Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets.
  • excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc.
  • the tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • a time delay material such as glyceryl monostearate or glyceryl distearate may be employed.
  • Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin, or olive oil.
  • Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethyl cellulose, methylcellulose, hydroxy-propylmethyl cellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia;
  • dispersing or wetting agents may be a naturally-occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol mono oleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate.
  • a naturally-occurring phosphatide for example lecithin
  • condensation products of an alkylene oxide with fatty acids for example polyoxyethylene stearate
  • condensation products of ethylene oxide with long chain aliphatic alcohols for example heptadecaethyleneoxycetanol
  • the aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl, p- hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.
  • Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin.
  • the oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or acetyl alcohol.
  • Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
  • Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives.
  • a dispersing or wetting agent e.g., glycerol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerin, glycerin, glycerin, glycerin, glycerin, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerol
  • the emulsions may also contain sweetening and flavoring agents.
  • Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, preservative and flavoring and coloring agent.
  • the pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1,3-butane diol.
  • the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono-or diglycerides.
  • fatty acids such as oleic acid find use in the preparation of injectables.
  • the compounds of the present invention may also be administered in the form of suppositories for rectal administration of the drug.
  • These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • Such materials are cocoa butter and polyethylene glycols.
  • topical use creams, ointments, jellies, solutions or suspensions, etc. containing the compounds of the present invention are employed. (For purposes of this application, topical application shall include mouth washes and gargles.)
  • an appropriate dosage level will generally be about 0.01 to 100 mg per kg patient body weight per day which can be administered in single or multiple doses.
  • the precise dosage of the agents of the invention to be employed for treating conditions mediated by inhibition of protein kinase depends upon several factors, including the host, the nature and the severity of the condition being treated, the mode of
  • an agent of the invention is administered enterally, e.g. orally, or parenterally, e.g. intravenously, preferably orally, at a daily dosage of from about 0.002 mg/kg to about 10 mg/kg, preferably of from about 0.02 mg/kg to about 2.5 mg/kg body weight or, for most larger primates, a daily dosage of from about 0.1 mg to about 250 mg, preferably from about 1 mg to about 100 mg.
  • a typical oral dosage unit is from about 0.01 mg/kg to about 0.75 mg/kg, one to three times a day.
  • a small dose is administered initially and the dosage is gradually increased until the optimal dosage for the host under treatment is determined.
  • the upper limit of dosage is that imposed by side effects and can be determined by trial for the host being treated.
  • the agents of the invention may be formulated into enteral and parenteral
  • compositions containing an amount of the active substance that is effective for treating or preventing disease or disorder conditions mediated by inhibition of protein kinases such compositions in unit dosage form and such compositions comprising a pharmaceutically acceptable carrier.
  • Agents of the invention may be administered in enantiomerically pure forms or as racemic mixtures.
  • the above dosage ranges are based on the compounds of formula 1.
  • This dosage regimen may be adjusted to provide the optimal therapeutic response. It will be understood, however, that the specific dose level and frequency of dosage for any particular patient may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of
  • the compounds of the present invention may be used in combination with one or more other drugs in the treatment, prevention, suppression or amelioration of diseases or conditions for which compounds of Formula 1 or the other drugs may have utility, where the combination of the drugs together are safer or more effective than either drug alone.
  • Such other drug (s) may be administered, by a route and in an amount commonly used thereof, contemporaneously or sequentially with a compound of Formula 1.
  • a pharmaceutical composition in unit dosage form containing such other drugs and the compound of Formula 1 is preferred.
  • the combination therapy may also include therapies in which the compound of Formula 1 and one or more other drugs are administered on different overlapping schedules.
  • compositions of the present invention include those that contain one or more other active ingredients, in addition to a compound of Formula 1.
  • An embodiment of the present invention provides preparation of the novel compounds of formula 1 according to the procedure of the following schemes, using appropriate materials. Those skilled in the art will readily understand that known variations of the conditions and processes of the following preparative procedures can be used to prepare these compounds. Moreover, by utilizing the procedures described in detail, one of ordinary skill in the art can readily prepare additional compounds of the present invention claimed herein.
  • compositions of the present invention comprising compounds of Formula 1 or pharmaceutically acceptable salt, solvate or pro-drug thereof, may be manufactured in a manner that is known in the art, e.g. by means of conventional mixing, ' encapsulating, dissolving, granulating, emulsifying, entrapping, dragee-making, or lyophilizing processes.
  • These pharmaceutical preparations can be formulated with therapeutically inert, inorganic or organic carriers. Lactose, corn starch or derivatives thereof, talc, steric acid or its salts can be used as such carriers for tablets, coated tablets, dragees and hard gelatin capsules.
  • Suitable carriers for soft gelatin capsules include vegetable oils, waxes and fats.
  • Suitable carriers for the manufacture of solutions and syrups are water, polyols, saccharose, invert sugar and glucose.
  • Suitable carriers for injection are water, alcohols, polyols, glycerine, vegetable oils, phospholipids and surfactants.
  • Suitable carriers for suppositories are natural or hardened oils, waxes, fats and semi-liquid polyols.
  • Step-IA 5 -Hydroxy adamantan-2-one : Suitable mineral acid such as fuming nitric acid is added to 2-adamantanone and the mixture is optionally heated. Excess acid is then distilled under reduced pressure and the resultant residual mass is treated with water along with mineral acid such as conc.H 2 S0 4 . The resultant is heated, cooled and neutralized with inorganic bases such as dil. NaOH, KOH, K 2 C0 3 and the like. The aqueous layer is extracted with a suitable organic solvent such as DCM, CHC1 3 and the like and the combined organic layer is concentrated under reduced pressure. The residue is then dissolved in a minimum amount of solvent such as DCM, CHC1 3 and the like and the required product is precipitated with solvents selected from hexane, petroleum ether etc. Step-1 B:
  • Ammonium formate is added to 5-hydroxyadamantan-2-one in an organic solvent such methanol and the like.
  • Reducing agent such as 10% Pd-C (2.5g) is then added and the resultant is allowed to react at about 60° for about 15mins to 3hrs. Susequenly the reaction mixture is cooled to ambient temperature, filtered and concentrated under reduced pressure. The residue is dissolved in a minimum amount of water, basified with a base such as NaOH and extracted with an organic solvent such as ethylacetate. The organic layer is concentrated under reduced pressure and the product obtained is washed with a suitable organic solvent such as hexane to yield a mixture of cis/trans isomers of the 4-Aminoadamantan-l-ol.
  • 5-hydro yadamantan-2-one is added to ammonia in methanol and molecular sieves.
  • 'A' is selected from atoms or groups such as H, C ! -C 6 straight or branched alkyl, alkenyl or alkynyl, C 5 -C 8 cyclic, heterocyclic,halogen;
  • 4-Aminoadamantan-l-ol is added to a solution of a suitable amino pyrimidine such as for example, 5-bromo-2,4-dichloropyrimidine in a solvent such as n-butanol, or ethanol followed by ⁇ , ⁇ -diisopropyl ethyl amine, TEA, and the like.
  • a suitable amino pyrimidine such as for example, 5-bromo-2,4-dichloropyrimidine in a solvent such as n-butanol, or ethanol followed by ⁇ , ⁇ -diisopropyl ethyl amine, TEA, and the like.
  • a suitable amino pyrimidine such as for example, 5-bromo-2,4-dichloropyrimidine
  • a solvent such as n-butanol, or ethanol
  • TEA ⁇ , ⁇ -diisopropyl ethyl amine
  • the cis and trans isomers are separated by methods such as preparative HPLC to afford the cis- and trans-isomers of 4-(5-bromo-2-chloropyrimidin-4-ylamino) adamantan-l- ol.
  • the cis and trans isomers are separated by methods such as preparative HPLC or silcagel column chromatography to afford the cis- and trans-isomers of 4-(5-Bromo-2- chloropyrimidin-4-ylamino) adamantan-l-ol in about 95-99% pure form.
  • Step-3B Synthesis of the final adamantanol compounds
  • Step-1 A 5-Methoxyadamantan-2-one
  • Suitable base such as sodium hydride, potassium carbonate, or potassium hydride is added to solvents such as THF, DMSO or DMF at 0°C and the resultant is stirred for 15min at 0°C.
  • solvents such as THF, DMSO or DMF at 0°C
  • methyl iodide dropwise over a period of 5-10mins and stirring is continued for further lhr at 0°C.
  • To the resulting reaction mixture is added ice cold water and the mixture is extracted with solvents such as ethylacetate, ether, DCM, chloroform etc. The organic layers are combined, dried and concentrated to afford the 5-methoxyadamantan-2-one as the required product.
  • Step-IB 4-Aminoadamantyl methyl ether
  • Ammonium formate is added to a solution of 5-methoxyadamantan-2-one in solvent such as methanol or ethanol and the resultant is stirred for 15 mins at the ambient temperature. To this residual mass is added a suitable catalyst such as Pd/C and the reaction mixture is heated to about 40-60°C for 2hrs. The resulting reaction mixture is cooled to ambient temperature, filtered through a celite bed and concentrated under reduced pressure to afford 4-aminoadamantyl methyl ether.
  • solvent such as methanol or ethanol
  • Steps 2( 2A) and 3 are the same as for Series I
  • Step- 1 A 4-Oxoadamantan- 1 -carboxylic acid
  • 4-Oxoadamantane-l-carboxylic acid is added to a solution of ammonium formate in solvent such as methanol or ethanol and the reaction mixture is stirred at ambient temperature for 15min. Suitable catalyst such as Pd/C is then added and the reaction mixture is heated to reflux for about lh. The resulting reaction mixture is cooled to ambient temperature, filtered through celite and concentrated to give 4-aminoadamantan-l-carboxylic acid as the pure product (as a mixture of cis/trans isomers).
  • Step 1 A is the same as for Series III
  • Step-B Synthesis of 4-Oxo-adamantane-l-carboxylic acid cyclopropylamide.
  • Step-C Synthesis of 4-Amino-adamantane-l-carboxylic acid cyclopropylamide.
  • 4-oxo-adamantane-l-carboxylic acid cyclopropylamide is added to a solution of ammonium formate in methanol and is stirred at the ambient temperature for about 1 Omin.
  • a suitable catalyst such as Pd/C is added to the residual reaction mass and is heated to about 40-60°C for about 2hrs.
  • the reaction is monitored by TLC.
  • the resulting reaction mixture is cooled to ambient temperature, filtered through celite bed and concentrated to afford 4- amino-adamantane-l-carboxylic acid cyclopropylamide as the required product.
  • Step 1A is the same as for Series III
  • Step-IB Synthesis of (4-Oxo-adamantan-l-yI)-carbamic acid tert-butyl ester.
  • DPPA and bases such as N-ethyldiisopropylamine or TEA are added to a solution of 4-oxo-adamantane-l-carboxylic acid in tert-butanol and the resultant is heated to reflux for about 18hrs.
  • the reaction is monitored by TLC.
  • the residual mass is cooled to ambient temperature, followed by the addition of saturated solution of bases such as NaHC0 3 or Na 2 C0 3 or 2 C0 3 and the resulting reaction mixture is extracted with suitable solvents such as DCM or ethylacetate and the like.
  • Step-lC Synthesis of 5-Amino-adamantan-2-one hydrochloride.
  • Cyclopropane carbonyl chloride is added dropwise over a period of 5-10mins to a stirred solution of 5-amino-adamantan-2-one hydrochloride and DIPEA in solvents such as DCM or THF at about 0-5°C.
  • the resulting reaction mixture is stirred at about 0-5°C for 2hrs.
  • the reaction is monitored by TLC.
  • the residual reaction mixture is quenched with ice cold water and the organic layer obtained is washed with dil. HC1, saturated NaHC0 3 and brine solution.
  • Step-IE Synthesis of Cyclopropanecarboxylic acid (4-amino-adamantan-l-yl)-amide.
  • Cyclopropanecarboxylic acid (4-oxo-adamantan-l-yl)-amide is added to a solution of ammonium formate in solvent such as methanol or ethanol and is stirred at the ambient temperature for about lOmin.
  • a suitable catalyst such as Pd/C is added to the residual reaction mass and is heated to about 40-60°C for 2hrs. The reaction is monitored by TLC. The resulting reaction mixture is cooled to ambient temperature, filtered through celite bed and concentrated to afford cyclopropane carboxylic acid (4-amino-adamantan-l-yl)-amide as the required product.
  • Steps 1 and 2A are the same as for Series I
  • Trichloroacetylisocyanate is added to a solution of 5-substituted 4-(2-chloro- pyrimidin-4-ylamino)-adamantan-l-ol in a suitable solvents such as dichloromethane or THF at -about 0°C and the resultant is stirred for about 20mins to 2h at about 0°C. Then the temperature of the reaction mixture is gradually increased to ambient temperature and stirring is continued for about another 2hrs. The reaction is monitored by TLC. The solvent is removed by distillation and suitable solvents such as ethanol or methanol are added, followed by the addition of a saturated solution of a suitable base such as K 2 C0 3 or Na 2 C0 3 and the like.
  • a suitable solvents such as dichloromethane or THF
  • the residual reaction mixture is heated to about 40-50°C and maintained for 4-6h. The reaction is again monitored by TLC. Solvent is distilled out. Water is added to the residual mixture, the resultant is filtered, washed with water and dried to afford 5-substituted 4-(2- chloro-pyrimidin-4-ylamino)-adamantan-l-yl ester as the required product.
  • Room temperature is defined as an ambient temperature range, typically from about 20°C to about 35°C, specifically it can in each instance be 25 °C.
  • An ice bath (crushed ice and water) temperature is defined as a range, typically from about -5°C to about 0 °C.
  • Temperature at reflux is defined as ⁇ 15°C of the boiling point of the primary reaction solvent. Overnight is defined as a time range of from about 8 to about 16 hours and can specifically be 12 hours.
  • Vacuum filtration (water aspirator) is defined as occurring over a range of pressures, typically from about 5 mm Hg to about 15 mm Hg.
  • Dried under vacuum is defined as using a high vacuum pump at a range of pressures, typically from about 0.1 mm Hg to about 5 mm Hg.
  • Neutralization is defined as a typical acid-based neutralization method and measured to a pH range of from about pH 6 to about pH 8, using pH-indicating paper.
  • Brine is defined as a saturated aqueous sodium chloride.
  • Nitrogen atmosphere is defined as positive static pressure of nitrogen gas passed through a DrieriteTM column with an oil bubbler system. Concentrated ammonium hydroxide is defined as an approximately 15 M solution. Melting points were measured against a mercury thermometer and are not corrected.
  • crushed ice quantity typically ranged from about 10 g to about 1000 g depending on reaction scale
  • silica gel quantity used in column chromatography depended on material quantity, complexity of mixture, and size of chromatography column employed and typically ranged from about 5 g to about 1000 g
  • extraction solvent volume typically ranged from about 10 mL to about 500 mL, depending upon the reaction size
  • washes employed in compound isolation ranged from about 10 mL to about 100 mL of solvent or aqueous reagent, depending on scale of reaction
  • drying reagents potassium carbonate, sodium carbonate, sodium sulphate or magnesium sulfate
  • TMS tetramethylsilane
  • Step-IA 5-Hydroxyadamantan-2-one :
  • Fuming nitric acid (900 ml) was added to 2-adamantanone (lOOg, 0.66mole) and the mixture heated at 60° for 16h.
  • Excess nitric acid was distilled under reduced pressure at 60° and the residual mass was treated with water (350ml) and conc.H 2 S0 4 (120 ml), heated at 95- 100° for 2h, cooled to ambient temperature and neutralized with 10% NaOH.
  • the resultant was partitioned using water and CHC1 3 and the combined organic layer was concentrated under reduced pressure. The residual mass was dissolved in a minimum amount of CHC1 3 and precipitated using hexane. The precipitate was collected to yield 56g (51%) of 5- Hydroxyadamantan-2-one as the required compound.
  • Step-1 B
  • Step-3A Synthesis of amine intermediate R 1 -NH 2 for coupling with pyrido-adamantyl compound in the last step ( 3B) .
  • Step3A-l Synthesis of N-(2-Dimethylamino-ethyl)-4-nitro-benzamide.
  • EDCI.HCI (2.29g, 0.01 196mmol), followed by HOBt.H 2 0 (161mg, 0.00119mol), DIPEA (3.12ml, 0.0179mol) and N,N-dimethyl-ethane-l,2-diamine (0.65ml, 0.00598mol) were added to a solution of 4-nitro-benzoic acid (lg, 0.00598mmol) in DMF (10ml) at 0°C. The resultant was stirred overnight at RT. The reaction was monitored by the TLC (10% methanol: chloroform).
  • Step-3B Synthesis of 4-[5-bromo-4-(5-hydroxy-adamantan-2-ylamino)-pyrimidin-2- yIamino]-N-(2-dimethylamino-ethyl)-benzamide
  • HC1 (0.3mL) was added to a mixture of 4-(5-bromo-2-chloro-pyrimidin-4- ylamino)-adamantan-l-ol (60mg, 0.167mmoles) and 4-amino-N-(2-dimethylamino-ethyl)- benzamide (45mg, 0.217mmoles) in n-butanol and the resultant was heated to 1 10°C for 16hrs. The reaction was monitored by the TLC (8:2, chloroform: methanol). The resulting reaction mixture was cooled to 80°C diluted with 5ml of n-butanol and filtered.
  • Step-1 A 5-Methoxyadamantan-2-one
  • Step-1 B 4-Aminoadamantyl methyl ether
  • Steps 2 and 3 were carried out in a manner similar to those for series I
  • Step-IA 4-Oxoadaniantan-l-carboxylic acid
  • 4-Oxoadamantane-l-carboxylic acid (2.75g, 14.17mmoles) was added to a-solution of ammonium formate (4.46g, 70.87mmoles) in methanol (50ml) and the reaction mixture was stirred at ambient temperature for 15min. 10% Pd-c (0.55g) was then added and the reaction mixture was heated under reflux for lhr. The resulting reaction mixture was cooled to ambient temperature, filtered through celite and the filterate was concentrated to afford 2.7g (98%o) of 4-aminoadamantan-l-carboxylic acid as a mixture of cis/trans isomers.
  • Steps 2 and 3 were carried out in a manner similar to those for series I
  • Step 1-A Was carried out in the same manner as for as for series III
  • Step-l-B Synthesis of 4-Oxo-adamantane-l-carboxylic acid cyclopropylamide.
  • Step-lC Synthesis of 4-Amino-adamantane-l-carboxylic acid cyclopropylamide.
  • 4-oxo-adamantane-l-carboxylic acid cyclopropylamide (lg, 4.28mmoles) was added to a solution of ammonium formate (1.35g, 21.4mmoles) in methanol and the resultant was stirred at the ambient temperature for lOmin. This was followed by the addition of 10% Pd/C (200mg) and the resultant was heated to 60°C for 2hrs, filtered through celite bed and the filterate was concentrated to afford 800mg (62% yield) of 4-amino-adamantane-l-carboxylic acid cyclopropylamide as the required product.
  • Step-1 E step-1 D Step 1A : Performed in a manner similar to what has been described previously for series HI
  • Step-IB Synthesis of (4-Oxo-adamantan-l-yl)-carbamic acid tert-butyl ester.
  • Step-ID Synthesis of Cyclopropanecarboxylic acid (4-oxo-adamantan-l-yl)-amide.
  • Step-IE Synthesis of Cyclopropanecarboxylic acid (4-amino-adamantan-l-yl)-amide.
  • Cyclopropanecarboxylic acid (4-oxo-adamantan-l-yl)-amide (158mg, 0.678mmol) was added to a solution of ammonium formate (171mg, 2.7mmol) in methanol (4ml) and was stirred at the ambient temperature for lOmin. 5% Pd/c (35mg) was added to the residual reaction mass and was heated to 60°C for 2hrs. The reaction was monitored by the TLC (100% ethylacetate).
  • Steps 2 and 3 are performed in a manner similar to what has been described previously in this document for series I
  • Trichloroacetylisocyanate (0.091ml, 0.7638mmol) was added to a solution of 4-(2,5- dichloro-pyrimidin-4-ylamino)-adamantan-l-ol (200mg, 0.7638mmol) in DCM (7ml) at 0°C and the resultant was stirred for 30mins at 0°C. Then the temperature of the reaction mixture was gradually increased to ambient temperature and with stirring being continued for a further 2hrs. The reaction was monitored by the TLC (10% methanol in chloroform). The solvent was removed by distillation and the residual mass was diluted with methanol and this was followed by the addition of a saturated solution of K 2 C0 3 (10ml).
  • step 3 A-2 is
  • reaction mixture was heated for a further 4hrs, diluted with ethylacetate, filtered through celite and the filterate was concentrated under reduced pressure.
  • the residue was partitioned between Ethyl acetate and water and the organic phase was washed with water, brine solution and concentrated under reduced pressure to get the crude product, which was purified by column chromatography (using silica gel of mesh size of 60-120, 100% ethylacetate as eluant) to afford 2g (36% yield) of l-Methyl-4-(3-nitro-phenyl)-piperazine.
  • reaction mixture was then filtered through celite, the filterate was concentrated and the crude product was purified through column chromatography (using silica gel of mesh size of 60- 120, 10% ethylacetate in hexane as eluant) to afford 1.8g (81 % yield) of 4-(3- nitro-phenyl)-thiomorpholine.
  • Step 3 B (synthesis of final compounds): Synthesis of //O#is-4-(5-Bromo-2- ⁇ 4-[4-(2- hydroxy-ethyl)-piperazin-l-yl]-phenylamino ⁇ -pyrimidin-4-ylamino)adamantan-l-ol:
  • the reaction mixture was quenched with crushed ice, and extracted with ethylacetate and the organic layer was washed with 10% HCl, brine solution, dried over Na 2 S0 4 and concentrated to get the crude product.
  • the crude product was purified by column chromatography (using silica gel of mesh size of 60-120, 50% EtOAc in hexane as eluant) to afford 600mg (48% yield) of N-(2-Hydroxy-ethyl)-4-nitro-benzamide.
  • Ammonium formate (2.226g, 0.035348mol) was added to a solution of 1 -Methyl- piperidin-4-one (lg, 0.008837mol) in MeOH and stirred for lOmins. 20% Pd-C was added to this and the reaction mixture was heated at 60°C for 2hrs. The reaction was monitored by the TLC (10% methanol in chloroform). The reaction mixture was filtered through celite bed, concentrated to afford lg (100% yield) of l-Methyl-piperidin-4-ylamine.
  • TEA 0.7 ml, 4.5122 moles
  • Morpholine 216mg, 2.48 lmmol
  • 4-Nitro-benzenesulfonyl chloride 50Omg, 2.256 lmmol
  • the reaction was monitored by the TLC (5% CHC1 3 in MeOH).
  • the resulting reaction mixture was taken partitioned with DCM and water .
  • the organic layer was concentrated, dried over Na 2 S0 4 to afford 500mg (81.3% yield) of 4-(4-Nitro-benzenesulfonyl)-morpholine.
  • Oxone (8.3g, 0.0136mol) was added to a solution of l-Methylsulfanylmethyl-3-nitro- benzene (lg, 0.00545) in DMF (10ml) at 0°C and the reaction flask was stirred at T for 2hrs. The reaction was monitored by the TLC (9: 1 CHC1 3 : MeOH). The resulting reaction mixture was quenched with crushed ice and the precipitate was collected, washed with ice cold water and dried to afford 0.8g (68.37% yield) of l-Methanesulfonylmethyl-3 -nitrobenzene.
  • CDI (6.35 g, 0.039 mol) was added to a solution of 4-Nitro-benzene- 1 ,2-diamine (2g, 0.013mol) in DMF and the flask was stirred for lhr at RT. The reaction was monitored by the TLC (10% methanol in chloroform). The resulting reaction mixture was quenched with crushed ice, stirred for lOmins, filtered and the filterate was dried under reduced pressure to afford 1.7 g ( 73.9 % yield) of 5-Nitro-l ,3-dihydro-benzoimidazol-2-one.
  • CDI (3.932g, 0.02425mol) was added to a stirred mixture of 2-Amino-4-nitro- phenol (1.245g, 0.00808mol) dissolved in DMF (12.45ml) and cooled to 0°C and the flask was stirred for lhr at T. The reaction was monitored by the TLC (10% CHC1 3 : MeOH). To the resulting reaction mixture was added ice cold water, filtered. The residue was washed with water and dried under reduced pressure to afford 1.11 lg (76.30% yield) of 5-Nitro-3H- benzooxazol-2-one.
  • TEA (7.85ml, 0.0504mol) and Pd-c (0.183g) were added to a solution of (2,4-Dinitro- phenyl)-(2-methoxy-ethyl)-amine (3.4g, 0.0141mol) in CH 3 CN (20ml). At -15°C was added formic acid (2.07ml, 0.0505mol) and was maintained at RT for 2hrs. The reaction was monitored by the TLC (50% EtOAc in hexane). The resulting reaction mixture was filtered, washed the ethylacetate and partitioned between water and ethylacetate.
  • HCT116 primary cell line
  • MCF7 cells seeded at a density of 1 X 10 5 cells/well in a 6 well plate. Incubated in 37° C0 2 incubators overnight.
  • Fetal bovine serum (FBS) added to a final concentration of 2%.
  • VX680 was used as a reference inhibitor for the assay.
  • the compounds were initially screened at 100 nM and 1 ⁇ M.
  • IC 5 o values were determined for compounds that inhibited Aurora A more than 50% at 100 nM.
  • serial l/3 rd dilutions of compound were made in DMSO containing buffer.
  • IC 5 o values were obtained by fitting the dose-response data to sigmoidal equation using GraphPad Prism software.

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Abstract

La présente invention concerne de nouveaux dérivés de pyrimidine de formule (I) : pouvant être employés en tant qu'inhibiteurs de kinases. Plus particulièrement, la présente invention concerne de nouveaux composés de type pyrimidine, leurs méthodes de synthèse, les compositions pharmaceutiques les incluant et leur utilisation dans le traitement de troubles prolifératifs.
PCT/IN2010/000718 2010-11-01 2010-11-01 Dérivés de 2,4-diaminopyrimidine en tant qu'inhibiteurs de protéine kinases Ceased WO2012059932A1 (fr)

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US8314119B2 (en) 2006-11-06 2012-11-20 Abbvie Inc. Azaadamantane derivatives and methods of use
CN103232397A (zh) * 2013-04-28 2013-08-07 江苏双乐化工颜料有限公司 5-氨基-n-取代苯并咪唑酮的合成方法
WO2015123595A1 (fr) 2014-02-14 2015-08-20 The Regents Of The University Of California Peroxydes cycliques utilisés en tant que promédicaments pour l'administration sélective d'agents
US9464078B2 (en) 2010-09-23 2016-10-11 Abbvie Inc. Monohydrate of azaadamantane derivatives
JP2017510643A (ja) * 2014-03-28 2017-04-13 キャリター・サイエンシーズ・リミテッド・ライアビリティ・カンパニーＣａｌｉｔｏｒ Ｓｃｉｅｎｃｅｓ， Ｌｌｃ 置換されたヘテロアリール化合物および使用方法
WO2017162661A1 (fr) 2016-03-22 2017-09-28 Bayer Pharma Aktiengesellschaft 1h-benzo[de]isoquinoléine-1,3(2h)-diones
US9932344B2 (en) 2014-02-21 2018-04-03 Cancer Research Technology Limited Pyrazolo[1,5-A]pyrimidine-5,7-diamine compounds as CDK inhibitors and their therapeutic use
CN109096152A (zh) * 2018-07-31 2018-12-28 乐平市赛复乐医药化工有限公司 一种间甲磺酰胺基苯胺的制备方法
WO2020140054A1 (fr) 2018-12-28 2020-07-02 Spv Therapeutics Inc. Inhibiteurs de kinase cycline-dépendants
US11857552B2 (en) 2017-09-20 2024-01-02 Carrick Therapeutics Limited 4-[[(7-aminopyrazolo[1,5-a]pyrimidin-5-yl)amino]methyl]piperidin-3-ol compounds as CDK inhibitors
US12473303B2 (en) 2019-12-16 2025-11-18 Carrick Therapeutics Limited 4-[[(7-aminopyrazolo[1,5-a]pyrimidin-5-yl)amino methyl]piperidin-3-ol compounds and their therapeutic use

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US8314119B2 (en) 2006-11-06 2012-11-20 Abbvie Inc. Azaadamantane derivatives and methods of use
US9464078B2 (en) 2010-09-23 2016-10-11 Abbvie Inc. Monohydrate of azaadamantane derivatives
CN103232397A (zh) * 2013-04-28 2013-08-07 江苏双乐化工颜料有限公司 5-氨基-n-取代苯并咪唑酮的合成方法
CN103232397B (zh) * 2013-04-28 2016-04-20 江苏双乐化工颜料有限公司 5-氨基-n-取代苯并咪唑酮的合成方法
US10662215B2 (en) 2014-02-14 2020-05-26 The Regents Of The University Of California Cyclic peroxides as prodrugs for selective delivery of agents
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US11014955B2 (en) 2014-02-14 2021-05-25 The Regents Of The University Of California Cyclic peroxides as prodrugs for selective delivery of agents
WO2015123595A1 (fr) 2014-02-14 2015-08-20 The Regents Of The University Of California Peroxydes cycliques utilisés en tant que promédicaments pour l'administration sélective d'agents
US10414772B2 (en) 2014-02-21 2019-09-17 Imperial Innovations Limited Pyrazolo[1,5-A]pyrimidine-5,7-diamine compounds as CDK inhibitors and their therapeutic use
US10927119B2 (en) 2014-02-21 2021-02-23 Ip2Ipo Innovations Limited Pyrazolo[1,5-a]pyrimidine-5,7-diamine compounds as CDK inhibitors and their therapeutic use
US11566029B2 (en) 2014-02-21 2023-01-31 Ip2Ipo Innovations Limited Pyrazolo[1,5-a]pyrimidine-5,7-diamine compounds as CDK inhibitors and their therapeutic use
US9932344B2 (en) 2014-02-21 2018-04-03 Cancer Research Technology Limited Pyrazolo[1,5-A]pyrimidine-5,7-diamine compounds as CDK inhibitors and their therapeutic use
JP2017510644A (ja) * 2014-03-28 2017-04-13 キャリター・サイエンシーズ・リミテッド・ライアビリティ・カンパニーＣａｌｉｔｏｒ Ｓｃｉｅｎｃｅｓ， Ｌｌｃ 置換されたヘテロアリール化合物および使用方法
JP2017510643A (ja) * 2014-03-28 2017-04-13 キャリター・サイエンシーズ・リミテッド・ライアビリティ・カンパニーＣａｌｉｔｏｒ Ｓｃｉｅｎｃｅｓ， Ｌｌｃ 置換されたヘテロアリール化合物および使用方法
EP3122728A4 (fr) * 2014-03-28 2017-10-25 Calitor Sciences, LLC Composés hétéroaryle substitués et leurs méthodes d'utilisation
EP3327006A1 (fr) * 2014-03-28 2018-05-30 Calitor Sciences, LLC Composés d'hétéroaryle substitués et procédés d'utilisation
WO2017162661A1 (fr) 2016-03-22 2017-09-28 Bayer Pharma Aktiengesellschaft 1h-benzo[de]isoquinoléine-1,3(2h)-diones
US11857552B2 (en) 2017-09-20 2024-01-02 Carrick Therapeutics Limited 4-[[(7-aminopyrazolo[1,5-a]pyrimidin-5-yl)amino]methyl]piperidin-3-ol compounds as CDK inhibitors
CN109096152B (zh) * 2018-07-31 2021-01-08 乐平市赛复乐医药化工有限公司 一种间甲磺酰胺基苯胺的制备方法
CN109096152A (zh) * 2018-07-31 2018-12-28 乐平市赛复乐医药化工有限公司 一种间甲磺酰胺基苯胺的制备方法
WO2020140054A1 (fr) 2018-12-28 2020-07-02 Spv Therapeutics Inc. Inhibiteurs de kinase cycline-dépendants
US12473303B2 (en) 2019-12-16 2025-11-18 Carrick Therapeutics Limited 4-[[(7-aminopyrazolo[1,5-a]pyrimidin-5-yl)amino methyl]piperidin-3-ol compounds and their therapeutic use

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