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• • 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
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
  • A61K31/5375—1,4-Oxazines, e.g. morpholine
  • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents

Definitions

• Protein kinases are important in cellular signal pathways that regulate various cell functions, including differentiation, proliferation, migration, and apoptosis. Deregulation of protein kinases is implicated in cancer and a number of other diseases.
• Heterocyclic compounds have been extensively studied as potent protein kinase inhibitors.
• aminothiazoles appear as a recurring structural motif in many biologically active compounds.
• aminothiazoles present several challenges. First, they generally lack adequate in vivo exposure to exert desirable efficacy in pre-clinical or clinical studies. Further, being promiscuous protein kinase inhibitors, aminothiazoles possess poor kinase selectivity. Moreover, they often cause animal death in toxicity studies, raising safety concerns.
• the present invention is based on unexpected discoveries that certain aminothiazole compounds inhibit multiple protein kinases effectively, exert high in vivo anti-cancer efficacy, and show great safety.
• this invention relates to aminothiazole com ounds of Formula (I):
• Ri is H
• X is O or NR a , R a being H or Ci_6 alkyl
• Y is CR b R c or NR d , in which each of R b and R c , independently, is H, halo, Ci_ 6 alkyl, Ci_ 6 alkoxyl, or amino, and R d is H or Ci-6 alkyl; or 3 ⁇ 4, together with R a , the carbon atom bonded to 3 ⁇ 4, and the nitrogen atom bonded to R a , is C 3 _io heterocycloalkyl, or R d , together with R a and the nitrogen atoms bonded to R d and R a , is C 3 -1 0 heterocycloalkyl;
• R2 is -Cf ⁇ Cf ⁇ R e or NR f R g , in which R e is H, halo, Ci-6 alkyl, or OR h , each of R f and R g , independently,
• heterocycloalkyl aryl, or heteroaryl
• m is 1, 2, 3, or 4
• n is 1 or 2.
• this invention relates to aminothiazole compounds of Formula (I), in which Ri is Ci_6 alkyl or Ci_6 thioalkyl; X is O or NR a , R a being H or Ci_6 alkyl; Y is CR b R c or NR d , in which each of R b and R c , independently, is H, halo, Ci_6 alkyl, Ci_6 alkoxyl, or amino, and R d is H or Ci_6 alkyl; or R b , together with R a , the carbon atom bonded to R b , and the nitrogen atom bonded to R a , is C 3 _io heterocycloalkyl, or R d , together with R a and the nitrogen atoms bonded to R d and R a , is C 3 -1 0 heterocycloalkyl; R2 is -Cf ⁇ Cf ⁇ R e or NR f R g , in
• alkyl herein refers to a saturated, linear or branched hydrocarbon moiety, such as -CH 3 or branched -C 3 H7.
• cycloalkyl refers to a non-aromatic, monocyclic, bicyclic, tricyclic, or tetracyclic hydrocarbon moiety, such as cyclohexyl, cyclohexen-3-yl, or adamantyl.
• alkoxyl refers to an -O-alkyl radical.
• alkoxyl examples include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy, sec-butoxy, and tert-butoxy.
• thioalkyl refers to an -S-alkyl radical. Examples of thioalkyl include, but are not limited to, methylthiol, ethylthiol, and benzylthiol.
• heterocycloalkyl refers to a non-aromatic, monocyclic, bicyclic, tricyclic, or tetracyclic moiety having one or more ring heteroatoms (e.g., N, O, or S).
• heterocycloalkyl examples include, but are not limited to, 4-morpholinyl, 1-piperazinyl, 4- tetrahydropyranyl, and 4-pyranyl.
• aryl refers to a hydrocarbon moiety having one or more aromatic rings. Examples of aryl moieties include phenyl (Ph), phenylene, naphthyl, naphthylene, pyrenyl, anthryl, and phenanthryl.
• heteroaryl refers to a moiety having one or more aromatic rings that contain at least one heteroatom (e.g., N, O, or S).
• heteroaryl moieties include furyl, furylene, fluorenyl, pyrrolyl, thienyl, oxazolyl, imidazolyl, thiazolyl, pyridyl, pyrimidinyl, quinazolinyl, quinolyl, isoquinolyl and indolyl.
• Alkyl, thioalkyl, alkoxyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl mentioned herein include both substituted and unsubstituted moieties, unless specified otherwise.
• Possible substituents on cycloalkyl, heterocycloalkyl, aryl, and heteroaryl include Ci_io alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-20 cycloalkyl, C3-20 cycloalkenyl, Ci-20 heterocycloalkyl, Ci-20 heterocycloalkenyl, Ci_io alkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, amino, Ci_io alkylamino, Ci-2 0 dialkylamino, arylamino, diarylamino, hydroxyl, halogen, thio, Ci_io alkylthio, arylthio, Ci_io alkylsulfonyl, arylsulfonyl, acylamino, aminoacyl, aminothioacyl, amidino, guanidine, ureido, cyano, nitro, acyl, thioacyl, acy
• heterocycloalkyl aryl, and heteroaryl can also be fused with each other.
• aminothiazole compounds described above include the compounds themselves, as well as their salts, prodrugs, and solvates, if applicable.
• a salt for example, can be formed between an anion and a positively charged group (e.g., amino) on an aminothiazole compound.
• Suitable anions include chloride, bromide, iodide, sulfate, nitrate, phosphate, citrate, methanesulfonate, trifluoroacetate, acetate, malate, tosylate, tartrate, fumurate, glutamate, glucuronate, lactate, glutarate, and maleate.
• a salt can also be formed between a cation and a negatively charged group (e.g., carboxylate) on an aminothiazole compound.
• Suitable cations include sodium ion, potassium ion, magnesium ion, calcium ion, and an ammonium cation such as tetramethylammonium ion.
• the aminothiazole compounds also include those salts containing quaternary nitrogen atoms.
• prodrugs include esters and other pharmaceutically acceptable derivatives, which, upon administering to a subject, are capable of providing active aminothiazole compounds.
• a solvate refers to a complex formed between an active aminothiazole compound and a pharmaceutically acceptable solvent. Examples of a pharmaceutically acceptable solvent include water, ethanol, isopropanol, ethyl acetate, acetic acid, and ethanolamine.
• this invention relates to a method for inhibiting a protein kinase.
• the method includes contacting the protein kinase with an effective amount of one or more of the above-described aminothiazole compounds.
• Also within the scope of this invention is a method for treating cancer associated with a protein kinase.
• the method includes administering to a subject in need thereof an effective amount of one or more of the aminothiazole compounds of Formula (I) described above.
• the protein kinase can be a wild type or mutant.
• protein kinase examples include FMS-like tyrosine kinase 3 (FLT3), FMS-like tyrosine kinase 4 (FLT4), aurora kinase (AURK) A, AURK B, vascular endothelial growth factor receptor (VEGFR), platelet- derived growth factor receptor (PDGFR) A, PDGFR B, c-Src (SRC), tyrosine -protein kinase Lyn (LYN) A, LYN B, rearranged during transfection tyrosine kinase (RET), colony stimulating factor 1 receptor (CSF1R), lymphocyte-specific protein tyrosine kinase (LCK), Gardner-Rasheed feline sarcoma viral (v-fgr) oncogene homolog (FGR), discoidin domain receptor 1 (DDRl), kinase insert domain receptor (KDR), tropomyosin receptor kina
• cancers include acute myeloid leukemia, chloroma, chronic myelogenous leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, Hodgkin's disease, non-Hodgkin' s lymphoma, B-cell lymphoma, multiple myeloma,
• composition containing one or more of the above-described amino thiazole compounds of Formula (I).
• the pharmaceutical composition can be used for treating cancer.
• This invention also encompasses use of one or more of the above-described aminothiazole compounds of Formula (I) for the manufacture of a medicament for treating cancer.
• treating refers to administering one or more of the aminothiazole compounds to a subject, who has an above-described disease, i.e., cancer, a symptom of such a disease, or a predisposition toward such a disease, with the purpose to confer a therapeutic effect, e.g., to cure, relieve, alter, affect, ameliorate, or prevent the above-described disease, the symptom of it, or the predisposition toward it.
• An effective amount refers to the amount of an active compound that is required to confer the therapeutic effect. Effective doses will vary, as recognized by those skilled in the art, depending on the types of disease treated, route of administration, excipient usage, and the possibility of co- usage with other therapeutic treatment.
• a composition having one or more of the above-described aminothiazole compounds can be administered parenterally, orally, nasally, rectally, topically, or buccally.
• parenteral refers to subcutaneous, intracutaneous, intravenous, intraperitoneal, intramuscular, intraarticular, intraarterial, intrasynovial, intrasternal, intrathecal, intralesional, or intracranial injection, as well as any suitable infusion technique.
• a sterile injectable composition can be a solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1,3-butanediol.
• a non-toxic parenterally acceptable diluent or solvent such as a solution in 1,3-butanediol.
• acceptable vehicles and solvents that can be employed are mannitol, water, Ringer's solution, and isotonic sodium chloride solution.
• fixed oils are conventionally employed as a solvent or suspending medium (e.g., synthetic mono- or di-glycerides).
• Fatty acid, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically acceptable oils, such as olive oil and castor oil, especially in their polyoxyethylated versions.
• oil solutions or suspensions can also contain a long chain alcohol diluent or dispersant, carboxymethyl cellulose, or similar dispersing agents.
• a long chain alcohol diluent or dispersant carboxymethyl cellulose, or similar dispersing agents.
• Other commonly used surfactants such as Tweens and Spans or other similar emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms can also be used for the purpose of formulation.
• a composition for oral administration can be any orally acceptable dosage form including capsules, tablets, emulsions and aqueous suspensions, dispersions, and solutions.
• commonly used carriers include lactose and corn starch.
• Lubricating agents such as magnesium stearate, are also typically added.
• useful diluents include lactose and dried corn starch.
• a nasal aerosol or inhalation composition can be prepared according to techniques well known in the art of pharmaceutical formulation.
• such a composition can be prepared as a solution in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other solubilizing or dispersing agents known in the art.
• composition having one or more of the above-described aminothiazole compounds can also be administered in the form of suppositories for rectal administration.
• the carrier in the pharmaceutical composition must be "acceptable” in the sense that it is compatible with the active ingredient of the composition (and preferably, capable of stabilizing the active ingredient) and not deleterious to the subject to be treated.
• One or more solubilizing agents can be utilized as pharmaceutical excipients for delivery of an active 1,5- diphenyl-penta-l,4-dien-3-one compound.
• examples of other carriers include colloidal silicon oxide, magnesium stearate, cellulose, sodium lauryl sulfate, and D&C Yellow # 10.
• two sets of aminothiazole compounds include (i) those in which Ri is H; X is O or NR a , R a being H or Ci_6 alkyl; Y is CRbR c or NRd, in which each of Rb and R c , independently, is H, halo, Ci_6 alkyl, Ci_6 alkoxyl, or amino, and Rd is H or Ci_6 alkyl; or R b , together with R a , the carbon atom bonded to R b , and the nitrogen atom bonded to R a , is C 3 -1 0 heterocycloalkyl, or Rd, together with R a and the nitrogen atoms bonded to Rd and R a , is C 3 _io heterocycloalkyl; R 2 is -CH 2 CH 2 R e or NR f R g , in which R e is H, halo, Ci_ 6 alkyl, or OR h , each
• n 1 or 2.
• aminothiazole compounds set forth above are compounds of Formula (II):
• Ri, R2, R3, R ⁇ , X, and Y are defined as those described in Formula (I) above, both sets.
• compounds of Formula (II) have Ri as H and X as O.
• Y is NR d and R2 is -CH 2 CH 2 R e , in which R e is OR h , R h , together with R d , the oxygen atom bonded to R h , and the nitrogen atom bonded to R d , being C 3 -1 0 heterocycloalkyl; R3 is H, halo,
• compounds of Formula (II) have R ! as H and X as NR a , R a being H or Ci-6 alkyl.
• some compounds in this subgroup have Y as CR b R c , in which R b , together with R a , the carbon atom bonded to R b , and the nitrogen atom bonded to R a , is C 3 _io heterocycloalkyl, and R c is H, halo, Ci_ 6 alkyl, Ci_ 6 alkoxyl, or amino;
• R 2 as NR f R g , each of R f and R g , independently, being Ci_6 alkyl or C 3 -8 cycloalkyl;
• R 3 as H, halo, Ci_6 alkyl, or C 3 _io cycloalkyl; and R 4 as Ci_ 6 alkyl or C 3 _io cycloalkyl.
• R b together with R a , the carbon atom bonded to R b , and the nitrogen atom bonded to R a , is pyrrolidinyl or piperidinyl.
• Other compounds in this subgroup have Y as NR d , in which R d , together with R a and the nitrogen atoms bonded to R d and R a , is C 3 -1 0 heterocycloalkyl; R2 as -CH2CH2R e , in which R e is H, halo, Ci_6 alkyl, or OR h , R h being H or Ci_6 alkyl; R 3 as H, halo, Ci_6 alkyl, or C 3 -1 0 cycloalkyl; and R 4 as Ci_6 alkyl or C 3 -1 0 cycloalkyl.
• R d together with R a and the nitrogen atoms bonded to R d and R a , is
• compounds of Formula (II) have Ri as Ci_6 alkyl (e.g., -CH 3 ) or Ci_6 thioalkyl (e.g., -SCH 3 ) and X as O.
• compounds of Formula (II) have Ri as Ci_6 alkyl (e.g., - CH 3 ) or Ci_6 thioalkyl (e.g., -SCH 3 ) and X as NR a , R a being H or Ci_ 6 alkyl.
• some compounds in this additional subgroup have Y as CR b R c , in which R b , together with R a , the carbon atom bonded to R b , and the nitrogen atom bonded to R a , is C 3 -1 0 heterocycloalkyl, and R c is H, halo, Ci_ 6 alkyl, Ci_ 6 alkoxyl, or amino; R 2 as NR f R g , each of R f and R g , independently, being Ci_6 alkyl or C 3 -8 cycloalkyl; R 3 as H, halo, Ci_6 alkyl, or C 3 -1 0 cycloalkyl; and R 4 as Ci_6 alkyl or C 3 -1 0 cycloalkyl.
• R b together with R a , the carbon atom bonded to R b , and the nitrogen atom bonded to R a , is pyrrolidinyl or piperid
• R d together with R a and the nitrogen atoms bonded to R d and R a , is C 3 -1 0 heterocycloalkyl
• R2 as -Cf ⁇ Ci ⁇ R e , in which R e is halo, Ci_6 alkyl, or OR h , R h being H or Ci_6 alkyl
• R3 as H, halo, Ci_6 alkyl, or C 3 -1 0 cycloalkyl
• R 4 as Ci_6 alkyl or C 3 -1 0 cycloalkyl.
• R d together with R a and the nitrogen atoms bonded to R d and R a , is piperazinyl. Examples include
• compositions containing one or more of the aminothiazole compounds of Formula (I) for treating cancer are also covered by this invention.
• a method for treating cancer the method including administering to a subject in need thereof an effective amount of a compound of Formula (I).
• the compounds of Formula (I) thus prepared can be initially screened using biochemical assays, e.g., the kinase assay described in Example 21 below, for their potency in inhibiting protein kinases. They can be subsequently evaluated using in vivo assays, e.g., a xenograft animal model assay, for their activity in suppressing tumor growth in a mammal. The selected compounds can be further tested to verify their efficacy in treating cancer. For example, a compound can be administered to an animal (e.g., a mouse) having cancer and its therapeutic effect is then assessed. Based on the results, appropriate dosage ranges and administration routes can be investigated and determined.
• biochemical assays e.g., the kinase assay described in Example 21 below
• in vivo assays e.g., a xenograft animal model assay
• Examples 1-20 Shown in Examples 1-20 below are the structures of 20 exemplary compounds of Formula (I) and how they were prepared.
• the analytical data for the compounds thus prepared are also set forth in Examples 1-20 and the procedures for testing these compounds are described in Examples 21-25 that follow.
• Compound 1 was prepared according to the synthetic methods described in Chen et al., European Journal of Medicinal Chemistry, 2015, 100, 151-161.
• test compounds were screened in 160 nL of a 1% DMSO solution in the well of a 384-well plate; kinase/antibody mixtures (8 ⁇ ) were diluted to a 2-fold working concentration in an appropriate kinase buffer (3.84 ⁇ ) and a 4-fold AlexaFluor® labeled tracer (4 ⁇ ) was prepared in the kinase buffer; incubation of test solutions was conducted at room temperature for 60 minutes; and reatout on a fluorescence plate reader was recorded and analyzed. Table 1. Kinase inhibition data
• the number in the bracket indicates a IC 50 value.
• AC220 is a small molecule FLT3 inhibitor in clinical trials, which exerts high potency against FLT3-internal tandem duplication (FLT3-ITD) mutant.
• Clinically relevant AC220 resistance-conferring mutations have been restricted to residues in the FLT3 kinase domain, e.g., ITD-D835Y, ITD-D835V, ITD-D835F, ITD-F691L, and ITD-F691I.
• the five leukemic 32D cell lines were purchased from American Type Culture Collection (ATCC, Manassas, VA, USA).
• Murine pro-B lymphocyte 32D cell lines were stably transfected with expression vectors that encoded human FLT3 containing an ITD mutation (32D-ITD cells), ITD and D835Y (32D-ITD/D835Y cells), ITD and D835V (32D- ITD/D835V cells), ITD and D835F (32D-ITD/D835F cells), and ITD and F691L (32D- ITD/F691L cells) mutations, which lead to constitutive activation of the FLT3 downstream signaling proteins.
• ITD mutation 32D-ITD cells
• ITD and D835Y 32D-ITD/D835Y cells
• ITD and D835V 32D- ITD/D835V cells
• ITD and D835F 32D-ITD/D835F cells
• the cell viability was assessed with the MTS assay described in PLoS One, 2014, 9, e97116.
• 32D-ITD/D835Y, 32D-ITD/D835V, 32D-ITD/D835F, 32D- ITD/F691L, and 32D-ITD/F691I cells were seeded in 96-well plates at 1 x 10 4 cells/mL (100xL per well) for 24-h incubation.
• Test compounds at various concentrations in dimethyl sulfoxide (DMSO) were subsequently added to the culture medium for 72-h incubation.
• the cell viability was determined by the MTS assay (Promega, Madison, WI, USA).
• mice weighing 25-35 g each were obtained from BioLASCO (Taiwan Co., Ltd, Ilan, Taiwan). The animal studies were performed according to the National Health Research Institutes (NHRI) institutional animal care and committee-approved procedures.
• a single dose at 2.0 mg/kg of each of Compounds 2, 3, 5, and 6 was administered intravenously (IV) to a total of 33 male mice.
• IV intravenously
• a single dose at 10 mg/kg of each of these four compounds was administered orally (PO) to a total of 27 male mice.
• Each mouse was given 100 mL of the IV dosing solution by intravenous tail-vein injection and 200 mL of the PO dosing solution by oral gavage.
• TGI tumor growth inhibition
• mice Male nude mice (Nu-Foxl nu ) of 8 weeks old were purchased from BioLASCO (Taipei, Taiwan, R.O.C.). Human colorectal Colo205, pancreatic Mia-PaCa 2 tumor cells or MOLM- 13, 32D-ITD/D835Y leukemia cells were inoculated subcutaneously at lxlO 6 cells each in the nude mice. All human cancer cells were detected as free of Mycoplasma spp before they were injected into animals. The tumor cells grow as xenograft tumors and the tumor size reached approximately 200-250 mm 3 in the nude mice ready for dose treatments.
• Test compounds were dissolved in 20% 2-hydroxypropy- -cyclodextrin individually for oral gavage administrations to the nude mice.

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