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WO2022015670A1 - Dérivés de pyrido[2,3-d]pyrimidin-7(8h)-one utilisés en tant qu'inhibiteurs de kinase 2 dépendant de la cycline - Google Patents

Dérivés de pyrido[2,3-d]pyrimidin-7(8h)-one utilisés en tant qu'inhibiteurs de kinase 2 dépendant de la cycline Download PDF

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WO2022015670A1
WO2022015670A1 PCT/US2021/041331 US2021041331W WO2022015670A1 WO 2022015670 A1 WO2022015670 A1 WO 2022015670A1 US 2021041331 W US2021041331 W US 2021041331W WO 2022015670 A1 WO2022015670 A1 WO 2022015670A1
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alkyl
compound
cancer
hydroxy
halo
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Jiping Fu
Yan Lou
Yigang He
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Nikang Therapeutics Inc
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Nikang Therapeutics Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • the present disclosure provides certain pyrido[2,3-d]pyrimidin-7(8H)-one derivaties that are Cy clin-dependent kinase 2 (CDK2) inhibitors and are therefore useful for the treatment of diseases treatable by inhibition of CDK2. Also provided are pharmaceutical compositions containing such compounds and processes for preparing such compounds.
  • CDK2 Cy clin-dependent kinase 2
  • Cyclin-dependent kinases are cellular kinases that are critical for orchestrating signaling events such as DNA replication and protein synthesis to ensure faithful eukaryotic cell division and proliferation.
  • the cyclin-dependent kinase catalytic units of CDK often require binding with regulatory subunits known as cyclins.
  • the activity of CDK is also controlled by its phosphorylation status, as well as by binding of inhibitory proteins.
  • at least twenty-one mammalian CDKs have been identified (see Malumbres M. Genome Biol. (2014) 15:122).
  • CDKl/Cyclin B, CDK2/Cyclin E, CDK2/Cyclin A, CDK4/Cyclin D, CDK6/Cyclin D complexes are known to be important regulators of cell cycle progression; while other CDKs are important in regulating gene transcription, DNA repair, differentiation, and apoptosis (see Morgan, D. O. Annu. Rev. Cell. Dev. Biol. (1997) 13: 261-291).
  • CDKs Due to their key roles in regulating cell cycle and other essential cellular processes, increased activity or temporally abnormal activation of CDKs has been shown to result in the development of various types of cancer. Human tumor development is commonly associated with alterations in either the CDK proteins themselves or their regulators (see Cordon-Cardo C. Am. J. Pathol. (1995) 147:545-560; Karp JE, Broder S. Nat. Med. (1995) 1:309-320; and Hall M, Peters G. Adv. Cancer Res. (1996) 68:67-108).
  • CDK 4/6 inhibitors have changed the therapeutic management of hormone receptor-positive (HR+) metastatic breast cancer (MBC).
  • Palbociclib, ribociclib, and abemaciclib, selective reversible inhibitors of CDK4 and CDK6, are approved for hormone receptor-positive (FIR+) metastatic breast cancer in combination with endocrine therapies.
  • Additional clinical trials with these CDK4/6 inhibitors are ongoing in both breast and other cancers, either as single agents or in combination with other therapeutics, (see O'Leary et al. Nature Reviews (2016) 13:417-430). While CDK4/6 inhibitors have shown significant clinical efficacy in ER-positive metastatic breast cancer, the clinical benefit may be limited over time due to the development of primary or acquired resistance.
  • CDK4/6 inhibitors One important mechanism of resistance to CDK4/6 inhibitors is the abnormal activation of CDK2. It has been reported that high Cyclin E expression leads to overactivated CDK2/Cyclin E complex, which bypasses the requirement for CDK4/6 for cell cycle reentry (see Asghar, U. et al. Clin. Cancer Res. (2017) 23:5561). In addition, it has been found that when CDK4/6 is inhibited, there is a noncanonical CDK2/cyclin D1 complex formation that promotes pRb phosphorylation recovery and drives cell cycle progression (see Herrera-Abreu MT et al, Cancer Res. (2006) 15: 2301).
  • CDK2/Cyclin E complex plays an important role in regulation of the Gl/S transition, histone biosynthesis and centrosome duphcation. Following the initial phosphorylation of Rb by Cdk4/6/cyclin D, Cdk2/Cyclin E further hyper-phosphoiylates p-RB, releases E2F to transcribe genes required for S-phase entry. During S-phase, Cyclin E is degraded and CDK2 forms a complex with Cyclin A to promote phosphorylation of substrates that permit DNA replication and inactivation of E2F, for S-phase completion. ( see Asghar et al. Nat. Rev. Drug. Discov. (2015) 14: 130-146).
  • CDK2 In addition to cyclin bindings, the activity of CDK2 is also tightly regulated through its interaction with negative regulators, such as p21 and p27. In response to mitogenic stimulation, which signals optimal environment for cell cycle, p21 and p27 are phosphorylated and degraded, releasing the break on CDK2/Cyclin activation.
  • Cyclin E the regulatory cyclin for CDK2
  • Cyclin E2 is frequently overexpressed in cancer, and its overexpression correlates with poor prognosis.
  • Cyclin E amplification or overexpression has been shown to associate with poor outcomes in breast cancer (see Keyomarsi et al., N Engl JMed. (2002) 347:1566-75).
  • Cyclin E2 (CCNE2) overexpression is associated with endocrine resistance in breast cancer cells and CDK2 inhibition has been reported to restore sensitivity to tamoxifen or CDK4/6 inhibitors in tamoxifen resistant and CCNE2 overexpressing cells, (see Caldon et al., Mol Cancer Ther. (2012) 11:1488-99; and Herrera-Abreu et al., Cancer Res.
  • Cyclin E amplification also reportedly contributes to trastuzumab resistance in HER2+ breast cancer, (see Scaltriti et al. Proc Natl Acad Sci. (2011) 108:3761-6). Cyclin E overexpression has also been reported to play a role in basal-like and triple negative breast cancer (TNBC), as well as inflammatory breast cancer (see Elsawaf Z. et al. Breast Care (2011) 6:273-278; and Alexander A. et al. Oncotarget (2017) 8:14897-14911.)
  • CCNE1 cyclin E1
  • loss-of-function mutations in FBXW7 a component of SCF Fbw7 ubiquitin E3 ligase responsible for cyclin E degradation, also leads to cyclin E overexpression and CDK2 activation.
  • certain cancer cells express a hyperactive, truncated form of cyclin E.
  • cyclin A amplification and overexpression have also been reported in various cancers such as hepatocellular carcinomas, colorectal and breast cancers.
  • CDK2 In contrast to the frequent upregulation of Cyclin E, the inhibitory regulators of CDK2, p21 and p27 are often abnormally downregulated in cancers. It is postulated that the loss or decrease of these key endogenous inhibitors leads to high and/or abnormal temporal activation of CDK2, thereby promoting oncogenic growth.
  • CDK2 protein phosphatases responsible for the dephosphorylations that activate the CDK2
  • CDK2/cyclin E phosphorylates oncogenic Myc to oppose ras-induced senescence, highlighting the importance of CDK2 in myc/ras-induced tumorigenesis. Inactivation of CDK2 has been shown to be synthetically lethal to myc over-expressing cancer cells.
  • CDK2 inhibition can also be used as a promising preventive treatment for noise-, cisplatin-, or antibiotic-induced or age-related hearing loss, for which no Food and Drug Administration approved drugs are currently available.
  • CDK2 inhibitors in early phase of clinical trials.
  • Dinaciclib MK-7965 which inhibits CDK1, CDK2, CDK5 and CDK9 is in clinical development for solid tumors and hematological cancers in combination with other agents
  • CYC065, which potently inhibits CDK2, CDK3, CDK4, CDK9 and moderately inhibits CDK1, CDK5 and CDK7 is being investigated for the treatment of refractory CLL and other cancers
  • PF-06873600 a CDK2 inhibitor with activities against other CDKs, is in clinical trial for the treatment of breast cancer either as single agent or in combination with endocrine therapies.
  • Hy is a ring according to formula (i): where:
  • R is hydrogen or alkyl
  • X is CH orN
  • Y is CH, CMe, or N
  • at least one of X and Y is N
  • z is 0, 1, or 2
  • z’ and z are independently 0 or 1
  • at least one of z’ and z” is 1
  • R 5 is hydrogen, alkyl, cycloalkyl, or heterocyclyl, wherein alkyl, cycloalkyl, and heterocyclyl are optionally substituted with one or two substituents independently selected from alkyl, halo, hydroxy, cyano, alkoxy, haloalkyl, haloalkoxy, alkylsulfonyl, NR a R b , C(O)NR c R d , and NR e COR f [where R a , R b , R c
  • R 8 is hydrogen, alkyl, cycloalkyl, alkoxy, hydroxy, halo, -C(O)NR j R k , -NR w COR m , or heterocyclyl wherein alkyl, cycloalkyl, and heterocyclyl of R 8 are optionally substituted with one or two substituents independently selected from alkyl, halo, hydroxy, cyano, alkoxy, haloalkyl, haloalkoxy, NR n R o , S(O) 2 R p , C(O)NR q R r , SO 2 NR s R t , and NR u COR v [where R ⁇ , R k , R w , R m , R n ,
  • R o , R p , R q , R r , R s - R 1 , R u , and R v are independently hydrogen, alkyl, cycloalkyl, and heterocyclyl (where alkyl, cycloalkyl, and heterocyclyl are optionally substituted with one or two substituents independently selected from alkyl, hydroxy, cyano, alkoxy, haloalkyl, and haloalkoxy) or independently of each other, R n and R o , R q and R r , and R s and R t together with the nitrogen atom to which they are attached form heterocyclyl which can be optionally substituted with one or two substituents independently selected from alkyl, hydroxy, halo, cyano, alkoxy, alkylsulfonyl, and haloalkoxy]
  • R 1 is hydrogen, NH 2 , alkyl, halo, or haloalkyl
  • R 2 is hydrogen, halo, alkyl, haloalkyl, or cycloalkyl, where alkyl and cycloalkyl are optionally substituted with one or two substituents independently selected from alkyl, halo, hydroxy, cyano, alkoxy, and haloalkoxy;
  • R 3 is hydrogen, halo, NH 2 , alkyl, haloalkyl, cycloalkyl, aryl, or heterocyclyl, where alkyl, cycloalkyl, aryl, and heterocyclyl are optionally substituted with one or two substituents independently selected from alkyl, halo, hydroxy, cyano, alkoxy, haloalkyl, haloalkoxy, C(O)NH 2 , and C(O)OH; and
  • R 4 is alkyl, cycloalkyl, or heterocyclyl, where alkyl, cycloalkyl, and heterocyclyl are optionally substituted with one, two, or three substituents independently selected from alkyl, alkoxy, cyano, halo, and hydroxy; or a pharmaceutically acceptable salt thereof
  • a method of treating a disease treatable by inhibition of CDK2 in a patient preferably the patient is in need of such treatment, which method comprises administering to the patient, preferably a patient in need of such treatment, a therapeutically effective amount of a compound of Formula (I) (or any of the embodiments thereof described herein), or a pharmaceutically acceptable salt thereof.
  • the disease is cancer.
  • the disease is cancer selected from lung cancer (e.g., adenocarcinoma, small cell lung cancer and non-small cell lung carcinomas, parvicellular and non-parvicellular carcinoma, bronchial carcinoma, bronchial adenoma, pleuropulmonary blastoma), skin cancer (e.g.
  • lung cancer e.g., adenocarcinoma, small cell lung cancer and non-small cell lung carcinomas, parvicellular and non-parvicellular carcinoma, bronchial carcinoma, bronchial adenoma, pleuropulmonary blastoma
  • skin cancer e.g.
  • the cancers are those that are resistant to CDK4/6 inhibitors through CDK2- mediated mechanisms.
  • a method of treating noise-, cisplatin-, antibiotic- induced- or age-related hearing loss comprises administering to the patient, preferably a patient in need of such treatment, a a therapeutically effective amount of a compound of Formula (I) (or any of the embodiments thereof described herein), or a pharmaceutically acceptable salt thereof.
  • the amount of hearing loss is reduced when compared to an age-matched control.
  • the hearing loss is prevented when compared to an age-matched control.
  • a pharmaceutical composition comprising a compound of Formula (I) (or any of the embodiments thereof described herein), or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable excipient.
  • a compound of Formula (I) (or any embodiments thereof described herein), or a pharmaceutically acceptable salt thereof for use as a medicament.
  • the compound Formula (I) (and any embodiments thereof described herein), or a pharmaceutically acceptable salt thereof is useful for the treatment of one or more of diseases disclosed in the second aspect above.
  • a compound of Formula (I (and any embodiments thereof disclosed herein)), or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating a disease in a patient in which the activity of CDK2 contributes to the pathology and/or symptoms of the disease.
  • the disease is one or more of diseases disclosed in the second aspect above.
  • a method of inhibiting CDK2 comprises contacting CDK2 with a compound of Formula (I) (or any of the embodiments thereof described herein), or a pharmaceutically acceptable salt thereof; or contacting CDK2 with a pharmaceutical composition comprising a compound of Formula (I) (or any of the embodiments thereof described herein), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • any of the aforementioned aspects involving the treatment of cancer are further embodiments comprising administering the compound of Formula (I) (or any embodiments thereof disclosed herein), or a pharmaceutically acceptable salt thereof in combination with at least one additional anti cancer agent.
  • the agents can be administered simultaneously or sequentially.
  • Alkyl means a linear saturated monovalent hydrocarbon radical of one to six carbon atoms or a branched saturated monovalent hydrocarbon radical of three to six carbon atoms, e.g., methyl, ethyl, propyl, 2-propyl, butyl, pentyl, and the like. It will be recognized by a person skilled in the art that the term “alkyl” may include “alkylene” groups.
  • Alkylene means a linear saturated divalent hydrocarbon radical of one to six carbon atoms or a branched saturated divalent hydrocarbon radical of three to six carbon atoms unless otherwise stated; e.g., methylene, ethylene, propylene, 1-methylpropylene, 2-methylpropylene, butylene, pentylene, and the like.
  • Alkylsulfonyl means a -SO 2 R radical where R is alkyl as defined above, e.g., methylsulfonyl, ethylsulfonyl, and the like.
  • Alkoxy means a -OR radical where R is alkyl as defined above, e.g., methoxy, ethoxy, propoxy, or 2-propoxy, n-, iso-, or tert- butoxy, and the like.
  • Aryl means a monovalent monocyclic or bicyclic aromatic hydrocarbon radical of 6 to 10 ring atoms e.g., phenyl or naphthyl.
  • Cycloalkyl means a monocyclic saturated monovalent hydrocarbon radical of three to ten carbon atoms. Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
  • Cycloalkylene means a divalent saturated hydrocarbon radical of three to six carbon atoms, otherwise.g., 1,1 -cyclopropylene, and the like.
  • Halo means fluoro, chloro, bromo, or iodo, preferably fluoro or chloro.
  • Haloalkyl means alkyl radical as defined above, which is substituted with one or more halogen atoms, e.g., one to five halogen atoms, such as fluorine or chlorine, including those substituted with different halogens, e.g., -CH 2 CI, -CF 3 , -CHF 2 , -CH 2 CF 3 , -CF 2 CF 3 , -CF(CH 3 ) 2 , and the like.
  • halogen atoms e.g., one to five halogen atoms, such as fluorine or chlorine, including those substituted with different halogens, e.g., -CH 2 CI, -CF 3 , -CHF 2 , -CH 2 CF 3 , -CF 2 CF 3 , -CF(CH 3 ) 2 , and the like.
  • halogen atoms e.g., one to five halogen atoms, such as fluorine
  • Haloalkoxy means a -OR radical where R is haloalkyl as defined above e.g., -OCF 3 , -OCHF 2 , and the like.
  • R is haloalkyl where the alkyl is substituted with only fluoro, it is referred to in this Application as fluoroalkoxy.
  • Heterocyclyl means a saturated or unsaturated monovalent monocyclic group of 4 to 8 ring atoms in which one or two ring atoms are heteroatom independently selected from N, O, and S(O) n , where n is an integer from 0 to 2, the remaining ring atoms being C, unless stated otherwise. Additionally, one or two ring carbon atoms in the heterocyclyl ring can optionally be replaced by a -CO- group.
  • heterocyclyl includes, but is not limited to, pyrrolidino, piperidino, homopiperidino, 2-oxopyrrolidinyl, 2-oxopiperidinyl, morpholino, piperazino, tetrahydro-pyranyl, thiomorpholino, and the like.
  • heterocyclyl ring is unsaturated it can contain one or two ring double bonds provided that the ring is not aromatic.
  • heterocyclyl group contains at least one nitrogen atom, it is also referred to herein as heterocycloamino and is a subset of the heterocyclyl group.
  • Heterocyclylene means a saturated divalent group of 4 to 6 ring atoms in which one or two ring atoms are heteroatom independently selected from N, O, and S(O) n , where n is an integer from 0 to 2, the remaining ring atoms being C, unless stated otherwise. Additionally, one or two ring carbon atoms in the heterocyclyl ring can optionally be replaced by a -CO- group. More specifically the term heterocyclyl includes, but is not limited to, and the like.
  • the present disclosure also includes protected derivatives of compounds of Formula (I).
  • compounds of Formula (I) when compounds of Formula (I) contain groups such as hydroxy, carboxy, or any group containing a nitrogen atom(s), these groups can be protected with suitable protecting groups.
  • suitable protecting groups A comprehensive list of suitable protective groups can be found in T.W. Greene, Protective Groups in Organic Synthesis, 5 th Ed., John Wiley & Sons, Inc. (2014), the disclosure of which is incorporated herein by reference in its entirety.
  • the protected derivatives of compounds of the present disclosure can be prepared by methods well known in the art.
  • the present disclosure also includes polymorphic forms and deuterated forms of the compound of Formula (I) or a pharmaceutically acceptable salt thereof.
  • prodrug refers to a compound that is made more active in vivo.
  • Certain compounds Formula (I) may also exist as prodrugs, as described in Hydrolysis in Drug and Prodrug Metabolism: Chemistry, Biochemistry, and Enzymology ( see Testa, Bernard and Mayer, Joachim M. Wiley -VHCA, Zurich, Switzerland 2003).
  • Prodrugs of the compounds described herein are structurally modified forms of the compound that readily undergo chemical changes under physiological conditions to provide the active compound. Prodrugs are often useful because, in some situations, they may be easier to administer than the compound, or parent drug. They may, for instance, be bioavailable by oral administration whereas the parent drug is not.
  • prodrug derivatives are known in the art, such as those that rely on hydrolytic cleavage or oxidative activation of the prodrug.
  • An example, without limitation, of a prodrug would be a compound which is administered as an ester (the “prodrug”), but then is metabolically hydrolyzed to the carboxylic acid, the active entity. Additional examples include peptidyl derivatives of a compound.
  • a “pharmaceutically acceptable salt” of a compound means a salt that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound.
  • Such salts include: acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as formic acid, acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxy ethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid,
  • the compounds of Formula (I) may have asymmetric centers.
  • Compounds of Formula (I) containing an asymmetrically substituted atom may be isolated in optically active or racemic forms.
  • Individual stereoisomers of compounds can be prepared synthetically from commercially available starting materials which contain chiral centers or by preparation of mixtures of enantiomeric products followed by separation such as conversion to a mixture of diastereomers followed by separation or recrystallization, chromatographic techniques, direct separation of enantiomers on chiral chromatographic columns, or any other appropriate method known in the art. All chiral, diastereomeric, all mixtures of chiral or diasteromeric forms, and racemic forms are within the scope of this disclosure, unless the specific stereochemistry or isomeric form is specifically indicated.
  • the compounds of Formula (I) may also contain unnatural amounts of isotopes at one or more of the atoms that constitute such compounds.
  • Unnatural amounts of an isotope may be defined as ranging from the amount found in nature to an amount 100% of the atom in question, that differ only in the presence of one or more isotopically enriched atoms.
  • Exemplary isotopes that can be incorporated into compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 32 P, 33 P, 35 S, 18 F, 36 Cl, 123 I, and 125 l, respectively.
  • Isotopically labeled compounds e.g., those labeled with 3 H and 14 C
  • Tritiated (i.e., 3 H) and carbon-14 (i.e., 14 C) isotopes can be useful for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium (i.e., 2 H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements).
  • substituents such as deuterium (i.e., 2 H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements).
  • compounds of Formula (I) including in Table I below one or more hydrogen atoms are replaced by 2 H or 3 H, or one or more carbon atoms are replaced by 13 C- or 14 C -enriched carbon.
  • Positron emitting isotopes such as 15 O, 13 N, 11 C, and 15 F are useful for positron emission tomography (PET) studies to examine substrate receptor occupancy.
  • Isotopically labeled compounds can generally be prepared by following procedures analogous to those disclosed in the Schemes or in the Examples herein, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.
  • a “pharmaceutically acceptable carrier or excipient” means a carrier or an excipient that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes a carrier or an excipient that is acceptable for veterinary use as well as human pharmaceutical use.
  • “A pharmaceutically acceptable carrier/excipient” as used in the specification and claims includes both one and more than one such excipient.
  • the term “about,” as used herein, is intended to qualify the numerical values which it modifies, denoting such a value as variable within a margin of error.
  • Hy is optionally substituted with R 6 , R 7 , and/or R 8 independently selected from hydrogen, alkyl, haloalkyl, haloalkoxy, alkoxy, hydroxy, halo, and ... ,” in the definition of Hy in Formula (I) (and similar phrases used to define other groups in Formula (I)) is intended to cover Hy that is unsubstituted and Hy that is substituted with any one, or two, or all three, of R 6 , R 7 , and R 8 .
  • disease as used herein is intended to be generally synonymous, and is used interchangeably with, the terms “disorder,” “syndrome,” and “condition” (as in medical condition), in that all reflect an abnormal condition of the human or animal body or of one of its parts that impairs normal functioning, is typically manifested by distinguishing signs and symptoms, and causes the human or animal to have a reduced duration or quality of life.
  • combination therapy means the administration of two or more therapeutic agents to treat a disease or disorder described in the present disclosure. Such administration encompasses co-administration of these therapeutic agents in a substantially simultaneous manner, such as in a single capsule having a fixed ratio of active ingredients or in multiple, separate capsules for each active ingredient. In addition, such administration also encompasses use of each type of therapeutic agent in a sequential manner. In either case, the treatment regimen will provide beneficial effects of the drug combination in treating the conditions or disorders described herein.
  • patient is generally synonymous with the term “subject” and includes all mammals including humans. Examples of patients include humans, livestock such as cows, goats, sheep, pigs, and rabbits, and companion animals such as dogs, cats, rabbits, and horses. Preferably, the patient is a human.
  • Treating” or “treatment” of a disease includes:
  • treating or treatment of a disease includes inhibiting the disease, i.e., delaying, arresting or reducing the development or severity of the disease or its clinical symptoms; or relieving the disease, i.e., causing regression of the disease or its clinical symptoms.
  • a “therapeutically effective amount” means the amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof that, when administered to a patient for treating a disease, is sufficient to affect such treatment for the disease.
  • the “therapeutically effective amount” will vary depending on the compound, the disease and its severity and the age, weight, etc., of the mammal to be treated.
  • inhibiting and “reducing,” or any variation of these terms in relation to CDK2, includes any measurable decrease or complete inhibition to achieve a desired result. For example, there may be a decrease of about, at most about, or at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or more, or any range derivable therein, reduction of CDK2activity compared to itsnormal activity.
  • the present disclosure includes:
  • the compound of Formula (I) or a pharmaceutically acceptable salt thereof is as described in the first aspect of the Summary above.
  • the compound of embodiment 1 or a pharmaceutically acceptable salt thereof is wherein R 1 and R 2 are hydrogen.
  • the compound of embodiment 1 or a pharmaceutically acceptable salt thereof is wherein R 4 is cycloalkyl optionally substituted with one or two substituents independently selected from alkyl, alkoxy, cyano, halo, and hydroxy.
  • R 4 is unsubstituted cycloalkyl.
  • R 4 is cycloalkyl substituted with hydroxy or alkyl, or with both hydroxyl and alkyl.
  • R 4 is cyclopentyl optionally substituted with one or two substituents independently selected from alkyl, alkoxy, cyano, halo, and hydroxy.
  • R 4 is unsubstituted cyclopentyl.
  • R 4 is a group of structure:
  • the compound of any one of embodiments 1 to 3, or a pharmaceutically acceptable salt thereof is wherein R 3 is hydrogen, halo, haloalkyl, or alkyl optionally substituted with hydroxy.
  • the compound or a pharmaceutically acceptable salt thereof is wherein R 3 is hydrogen.
  • the compound or a pharmaceutically acceptable salt thereof is wherein R 3 is haloalkyl, preferably R 3 is difluoromethyl.
  • the compound or a pharmaceutically acceptable salt thereof is wherein R 3 is alkyl substituted with hydroxy, preferably R 3 is 2-hydroxyethyl.
  • Hy is a ring of formula: where Hy is substituted with R 6 , R 7 , and/or R 8 as defined in the Summary.
  • Hy is a ring of formula: where z is 1 or 2 and Hy is substituted with R 6 , R 7 , and/or R 8 as defined in the Summary.
  • Hy is a ring of formula: where Hy is substituted with R 6 , R 7 , and/or R 8 as defined in the Summary.
  • X and Y are N.
  • X is N and Y is CH.
  • Y is N and X is CH.
  • the compound of any one of embodiments 1 to 5 or a pharmaceutically acceptable salt thereof, is wherein R 5 is hydrogen.
  • the compound of any one of embodiments 1 to 5 or a pharmaceutically acceptable salt thereof is wherein R 5 is alkyl optionally substituted with one or two substituents independently selected from hydroxy, alkoxy, halo, and alkylsulfonyl.
  • R 5 is methyl, ethyl, 2-methoxy ethyl, or 2-hydroxyethyl.
  • the compound of any one of embodiments 1 to 5 or a pharmaceutically acceptable salt thereof is wherein R 5 is heterocyclyl optionally substituted with one or two substituents independently selected from hydroxy, alkoxy, halo, and alkylsulfonyl.
  • R 5 is oxetane, tetrahydrofuran, or tetrahydropyranyl.
  • the compound of any one of embodiments 1 to 5 or a pharmaceutically acceptable salt thereof is wherein R 5 is cycloalkyl optionally substituted with one or two substituents independently selected from hydroxy, alkoxy, and halo.
  • the compound of any one of embodiments 1 to 9 or a pharmaceutically acceptable salt thereof is wherein R 6 , R 7 , and R 8 are hydrogen.
  • the compound of any one of embodiments 1 to 9 or a pharmaceutically acceptable salt thereof is wherein Hy is substituted with R 7 and R 8 , optionally where one or both of R 7 and R 8 are not hydrogen.
  • R 8 is alkyl, alkoxy, hydroxy, or halo wherein alkyl of R 8 is optionally substituted with one or two substituents independently selected from alkyl, halo, hydroxy, alkoxy, NR n R o , and S(O) 2 R p [where R n , R o , and R p are independently hydrogen, alkyl, cycloalkyl, and heterocyclyl (where alkyl, cycloalkyl, and heterocyclyl are optionally substituted with one or two substituents independently selected from alkyl, hydroxy, cyano, alkoxy, haloalkyl, and haloalkoxy) or R n and R o together with the nitrogen atom
  • the compound of any one of embodiments 1 to 9 or a pharmaceutically acceptable salt thereof is wherein Hy is substituted with R 8 , where R 8 is not hydrogen.
  • R 8 is alkyl, alkoxy, hydroxy, or halo wherein alkyl of R 8 is optionally substituted with one or two substituents independently selected from alkyl, halo, hydroxy, alkoxy, NR n R o , and S(O) 2 R P
  • R n , R o , and R p are independently hydrogen, alkyl, cycloalkyl, and heterocyclyl (where alkyl, cycloalkyl, and heterocyclyl are optionally substituted with one or two substituents independently selected from alkyl, hydroxy, cyano, alkoxy, haloalkyl, and haloalkoxy) or R n and R o together with the nitrogen atom to which they are attached form heterocyclyl which can be
  • R 8 listed in the second sub-embodiment of embodiment 12 can independently be combined with one or more of the embodiments 1-11 and/or subembodiments contained therein.
  • the starting materials and reagents used in preparing these compounds are either available from commercial suppliers such as Aldrich Chemical Co., (Milwaukee, Wis.), Bachem (Torrance, Calif.), or Sigma (St. Louis, Mo.) or are prepared by methods known to those skilled in the art following procedures set forth in references such as Fieser and Fieser’s Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd’s Chemistry of Carbon Compounds, Volumes 1-5 and Supplemental (Elsevier Science Publishers, 1989); Organic Reactions,
  • the reactions described herein take place at atmospheric pressure over a temperature range from about -78 °C to about 150 °C, such as from about 0 °C to about 125 °C and further such as at about room (or ambient) temperature, e.g., about 20 °C.
  • Coupling reaction between a compound of formula 1-c, where z is 0, 1, or 2, and a compound of formula 1-d under acid condition such as phosphomolybdic acid provides a compound of formula 1-e.
  • the alkylene and/or alkenylene chain can be optionally substituted with R 6 , R 7 and/or R 8 , where R 6 , R 7 and/or R 8 is as defined in the Summary.
  • Compounds of formula 1-c and 1-d are commercially available or they can be prepared by methods well known the art.
  • 3-(N-phthaloyl)propionaldehyde is commercially available and N-(but-3-en-1-yl)-4-methylbenzenesulfonamide can be synthesized by reaction between TsCl and homoallylamine in the presence of a base such as pyridine or TEA. Protection of the hydroxyl group in compound of formula 1-e with a suitable protecting group such as a TBS group provides a compound of formula 1-f. Treatment of compound 1-f with hydrazine, followed by reacting the resulting primary amine 1-g with sodium and naphthalene in DME provides a diamine compound of formula 1-h. Treatment of 1-h with sulfuric diamide in pyridine provides a compound of formula 1-i.
  • TBS protecting group in 1-i under acidic reaction conditions such as HC1 in dioxane provides an alcohol of formula 1-j, which can be oxidized with a suitable oxidizing reagent such as Dess-Martin reagent to provide a compound of formula 1-k
  • a suitable oxidizing reagent such as Dess-Martin reagent to provide a compound of formula 1-k
  • Ketone 1-k can be converted to compound of formula 1-a under reductive amination conditions such as NH 4 OAc and NaBH 3 CN in MeOH solvent.
  • Reduction of the ester group in 2-d with a suitable reducing reagent such LiA1H 4 provides a hydroxy compound of formula 2-e, which can be converted to corresponding aldehyde of formula 2-f with an oxidizing agent such as MnO 2 .
  • Olefmation of 2-f with ethyl 2-(triphenyl- ⁇ 5 - phosphanylidene)acetate provides a compound of formula 2g, which can undergo cyclization in the presence of a base such as DBU under heating condition to provide a compound of formula 2-h.
  • Compound 2-h can then be converted to a compound of formula 2-a where LG is SO 2 Me by treatment with an oxidant such as m-CPBA.
  • CDK2/Cylin E kinase activity of CDK2/Cylin E or CDK2/Cyclin A complexes is elevated via several mechanisms in human cancers.
  • Cyclin E has been found to be frequently amplified in human malignancies, for example, in ovarian cancer and breast cancer.
  • loss-of-function mutations in FBXW7 a component of SCF Fbw7 ubiquitin E3 ligase responsible for cyclin E degradation, also leads to cyclin E overexpression and CDK2 activation.
  • certain cancer cells express a hyperactive, truncated form of cyclin E.
  • cyclin A amplification and overexpression have also been reported in various cancers such as hepatocellular carcinomas, colorectal and breast cancers.
  • catalytic activity of CDK2 is increased following loss of the expression or alteration of the location of the endogenous CDK2 inhibitor p27 or p21.
  • CDC25A and CDC25B protein phosphatases responsible for the dephosphorylations that activate the CDK2, are overexpressed in various tumors.
  • CDK2/cyclin E phosphorylates oncogenic Myc to oppose ras-induced senescence, highlighting the importance of CDK2 in myc/ras-induced tumorigenesis. Inactivation of CDK2 has been shown to be synthetically lethal to myc over-expressing cancer cells. Therefore, a compound of the invention may be useful for treating tumors characterized by 1) overexpression of CDK2, 2) amplification of cyclin E or cyclin A, 3) loss-of-function of mutation in FBXW7, 4) expression of truncated cylclin E, 5) dysregulation of p21 or p27, and 6) hyperactive MYC/RAS.
  • CDK2 activation as a result of cyclin E amplification or overexpression has also been identified as a key primary or acquired resistance pathway to tumors treated by CDK4/6 inhibitors or trastuzumab.
  • the cancer is hepatocellular carcinomas, colorectal and breast cancers.
  • the cancer is ovarian cancer.
  • the ovarian cancer is characterized by amplification or overexpression of CCNE1 and/or CCNE2.
  • the cancer is breast cancer, including, e.g., ER-positiive/HR-positive breast cancer, HER2-negative breast cancer; ER-positiive/HR-positive breast cancer, HER2-positive breast cancer; triple negative breast cancer (TNBC); or inflammatory breast cancer.
  • the breast cancer is endocrine resistant breast cancer, trastuzumab resistant breast cancer, or breast cancer demonstrating primary or acquired resistance to CDK4/CDK6 inhibition.
  • the breast cancer is advanced or metastatic breast cancer. In some embodiments of each of the foregoing, the breast cancer is characterized by amplification or overexpression of CCNE1 and/or CCNE2.
  • CDK2 inhibitory activity of the compounds of the present disclosure can be tested using the in vitro assay described in Biological Examples 1 below.
  • the compounds Formula (I) (unless stated otherwise, reference to compound/compounds of Formula (I) herein includes any embodiments thereof described herein or a pharmaceutically acceptable salt thereof) will be administered in a therapeutically effective amount by any of the accepted modes of administration for agents that serve similar utilities.
  • Therapeutically effective amounts of compounds Formula (I) may range from about 0.01 to about 500 mg per kg patient body weight per day, which can be administered in single or multiple doses.
  • a suitable dosage level may be from about 0.1 to about 250 mg/kg per day; about 0.5 to about 100 mg/kg per day.
  • a suitable dosage level may be about 0.01 to about 250 mg/kg per day, about 0.05 to about 100 mg/kg per day, or about 0.1 to about 50 mg/kg per day.
  • the dosage can be about 0.05 to about 0.5, about 0.5 to about 5 or about 5 to about 50 mg/kg per day.
  • the compositions can be provided in the form of tablets containing about 1.0 to about 1000 milligrams of the active ingredient, particularly about 1, 5, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 400, 500, 600, 750, 800, 900, and 1000 milligrams of the active ingredient.
  • the actual amount of the compound Formula (I), i.e., the active ingredient will depend upon numerous factors such as the severity of the disease to be treated, the age and relative health of the patient, the potency of the compound being utilized, the route and form of administration, and other factors.
  • compositions will be administered as pharmaceutical compositions by any one of the following routes: oral, systemic (e.g., transdermal, intranasal or by suppository), or parenteral (e.g., intramuscular, intravenous or subcutaneous) administration.
  • routes oral, systemic (e.g., transdermal, intranasal or by suppository), or parenteral (e.g., intramuscular, intravenous or subcutaneous) administration.
  • parenteral e.g., intramuscular, intravenous or subcutaneous
  • compositions can take the form of tablets, pills, capsules, semisolids, powders, sustained release formulations, solutions, suspensions, elixirs, aerosols, or any other appropriate compositions.
  • formulations in the form of tablets, pills or capsules, including enteric coated or delayed release tablets, pills or capsules are preferred.
  • compositions are comprised of in general, a compound of Formula (I) in combination with at least one pharmaceutically acceptable excipient.
  • Acceptable excipients are generally nontoxic, aid administration, and do not adversely affect the therapeutic benefit of the compound of Formula (I).
  • excipient may be any solid, liquid, semi-solid or, in the case of an aerosol composition, gaseous excipient that is generally available to one of skill in the art.
  • Solid pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, dried skim milk and the like.
  • Liquid and semisolid excipients may be selected from glycerol, propylene glycol, water, ethanol and various oils, including those of petroleum, animal, vegetable or synthetic origin, e.g., peanut oil, soybean oil, mineral oil, sesame oil, etc.
  • Preferred liquid carriers, particularly for injectable solutions include water, saline, aqueous dextrose, and glycols.
  • the compounds of Formula (I) may be formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion.
  • Formulations for injection may be presented in unit dosage form, e.g, in ampoules or in multi-dose containers, with an added preservative.
  • the compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
  • the formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in powder form or in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example, saline or sterile pyrogen-free water, immediately prior to use.
  • sterile liquid carrier for example, saline or sterile pyrogen-free water
  • Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.
  • Formulations for parenteral administration include aqueous and non-aqueous (oily) sterile injection solutions of the active compounds which may contain antioxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.
  • Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes.
  • Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran.
  • the suspension may also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.
  • the compounds of Formula (I) may also be formulated as a depot preparation.
  • Such long-acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection.
  • the compounds may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
  • compositions may take the form of tablets, lozenges, pastilles, or gels formulated in conventional manner.
  • Such compositions may comprise the active ingredient in a flavored basis such as sucrose and acacia or tragacanth.
  • the compounds of Formula (I) may also be formulated in rectal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter, polyethylene glycol, or other glycerides.
  • Certain compounds of Formula (I) may be administered topically, that is by non- systemic administration. This includes the application of a compound of Formula (I) externally to the epidermis or the buccal cavity and the instillation of such a compound into the ear, eye and nose, such that the compound does not significantly enter the blood stream.
  • systemic administration refers to oral, intravenous, intraperitoneal and intramuscular administration.
  • Formulations suitable for topical administration include liquid or semi-liquid preparations suitable for penetration through the skin to the site of inflammation such as gels, liniments, lotions, creams, ointments or pastes, and drops suitable for administration to the eye, ear or nose.
  • the active ingredient for topical administration may comprise, for example, from 0.001% to 10% w/w (by weight) of the formulation. In certain embodiments, the active ingredient may comprise as much as 10% w/w. In other embodiments, it may comprise less than 5% w/w. In certain embodiments, the active ingredient may comprise from 2% w/w to 5% w/w. In other embodiments, it may comprise from 0.1% to 1% w/w of the formulation.
  • compounds of Formula (I) may be conveniently delivered from an insufflator, nebulizer pressurized packs or other convenient means of delivering an aerosol spray.
  • Pressurized packs may comprise a suitable propellant such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • the dosage unit may be determined by providing a valve to deliver a metered amount.
  • the compounds of Formula (I) may take the form of a dry powder composition, for example a powder mix of the compound and a suitable powder base such as lactose or starch.
  • the powder composition may be presented in unit dosage form, in for example, capsules, cartridges, gelatin or blister packs from which the powder may be administered with the aid of an inhalator or insufflator.
  • suitable pharmaceutical excipients and their formulations are described in Remington’s Pharmaceutical Sciences, edited by E. W. Martin (Mack Publishing Company, 20th ed., 2000).
  • the level of the compound of Formula (I) in a formulation can vary within the full range employed by those skilled in the art.
  • the formulation will contain, on a weight percent (wt. %) basis, from about 0.01-99.99 wt. % of a compound of Formula (I) based on the total formulation, with the balance being one or more suitable pharmaceutical excipients.
  • the compound is present at a level of about 1-80 wt. %.
  • the compounds of Formula (I) may be used in combination with one or more other drugs in the treatment of diseases or conditions for which compounds of Formula (I) or the other drugs may have utility. Such other drug(s) may be administered, by a route and in an amount commonly used therefore, contemporaneously or sequentially with a compound of Formula (I).
  • a pharmaceutical composition in unit dosage form containing such other drugs and the compound of Formula (I) is preferred.
  • the combination therapy may also include therapies in which the compound of Formula (I) and one or more other drugs are administered on different overlapping schedules. It is also contemplated that when used in combination with one or more other active ingredients, the compounds of Formula (I) and the other active ingredients may be used in lower doses than when each is used singly.
  • compositions of the present disclosure also include those that contain one or more other drugs, in addition to a compound of of Formula (I).
  • the above combinations include combinations of a compound of Formula (I) not only with one other drug, but also with two or more other active drugs.
  • a compound of Formula (I) may be used in combination with other drugs that are used in the prevention, treatment, control, amelioration, or reduction of risk of the diseases or conditions for which a compound of Formula (I) is useful.
  • Such other drugs may be administered, by a route and in an amount commonly used therefore, contemporaneously or sequentially with a compound of Formula (I).
  • compositions of the present disclosure also include those that also contain one or more other active ingredients, in addition to a compound of Formula (I).
  • the weight ratio of the compound of this disclosure to the second active ingredient may be varied and will depend upon the effective dose of each ingredient. Generally, an effective dose of each will be used.
  • the subject in need is suffering from or at risk of suffering from cancer
  • the subject can be treated with a compound of of Formula (I) in any combination with one or more other anti- cancer agents including but not limited to: MAP kinase pathway (RAS/RAF/MEK/ERK) inhibitors including but not limited to: Vemurafanib (PLX4032), Dabrafenib, Encorafenib (LGX818), TQ-B3233, XL-518 (Cas No.
  • trametinib trametinib, selumetinib (AZD6244), TQ-B3234, PD184352, PD325901, TAK-733, pimasertinib, binimetinib, refametinib, cobimetinib (GDC-0973), AZD8330, BVD-523, LTT462, Ulixertinib, AMG510, ARS853, and any RAS inhibitors disclosed in patents WO2016049565,
  • CSF1R inhibitors PLX3397, LY3022855, etc.
  • CSF1R antibodies IMC-054, RG7155
  • TGF beta receptor kinase inhibitor such as LY2157299;
  • BTK inhibitor such as ibrutinib;BCR-ABL inhibitors: Imatinib (Gleevec®); Inilotinib hydrochloride; Nilotinib (Tasigna®); Dasatinib (BMS-345825); Bosutinib (SKI-606); Ponatinib (AP24534); Bafetinib (INNO406); Danusertib (PHA-739358), AT9283 (CAS 1133385-83-7);
  • Saracatinib (AZD0530); and N-[2-[(15,4R)-6-[[4-(cyclobutylarmno)-5-(trifluoromethyl)-2 - pyrimidinyl] amino] -1, 2,3,4- tetrahy dronaphthalen-1,4-imin-9-yl]-2-oxoethyl]-acetamide (PF- 03814735, CAS 942487-16-3); ALK inhibitors: PF-2341066 (XALKOPJ ® ; crizotinib); 5-chloro-N4-(2- (isopropylsulfonyl)phenyl)-N2-(2-methoxy-4-(4-(4-methylpiper azin-1-yl)piperidin-1- yl)phenyl)pyrimidine-2,4-diamine; GSK1838705 A; CH5424802; Ceritinib (ZYKADIA); TQ- B31
  • VEGF receptor inhibitors Bevacizumab (sold under the trademark Avastin® by Genentech/Roche), axitinib, (N-methy 1-2- [ [3 - [(E)-2-pyridin-2- y letheny 1] -1H-indazol-6-yl] sulfany 1] benzamide, also known as AG013736, and described in PCT Publication No.
  • Brivanib Alaninate ((S)-((R)-1-(4-(4-fluoro-2-methyl-1H-indol- 5-yloxy)-5-methylpyrrolo[2,1-f] [1,2,4]triazin-6-yloxy)propan -2-yl)2-aminopropanoate, also known as BMS-582664), motesanib (N-(2,3-dihydro-3,3-dimethyl-1H-indol-6-yl)-2-[(4- pyridinylmethyl)amino]-3-pyridinecarboxamide, and described in PCT Publication No.
  • pasireotide also known as SOM230, and described in PCT Publication No. WO 02/010192
  • sorafenib sold under the tradename Nexavar®
  • AL-2846 MET inhibitor such as foretinib, carbozantinib, or crizotinib
  • FLT3 inhibitors - sunitinib malate (sold under the tradename Sutent® by Pfizer); PKC412 (midostaurin); tanutinib, sorafenib, lestaurtinib, KW-2449, quizartinib (AC220) and crenolanib;
  • Epidermal growth factor receptor (EGFR) inhibitors Gefitnib (sold under the tradename Iressa®), N-[4- [(3 -chloro-4-fluorophenyl)amino] -7- [[(3 S)-tetrahy dro- 3-furanyl]oxy]-6- quinazolinyl]-4(dimethylamino)-2-butenamide, sold under the tradename Tovok® by Boehringer Ingelheim), cetuximab (sold under the tradename Erbitux® by Bristol-Myers Squibb), panitumumab (sold under the tradename Vectibix® by Amgen);
  • HER2 receptor inhibitors Trastuzumab (sold under the trademark Herceptin® by Genentech/Roche), neratinib (also known as HKI-272, (2E)-N-[4-[[3-chloro-4-[(pyridin-2- yl)methoxy]phenyl]amino]-3-cyano-7-ethoxyquinolin-6-yl]-4-(dimethylamino)but-2-enamide, and described PCT Publication No.
  • lapatinib or lapatinib ditosylate sold under the trademark Tykerb® by GlaxoSmithKline
  • Trastuzumab emtansine in the United States, ado- trastuzumab emtansine, trade name Kadcyla
  • an antibody -drug conjugate consisting of the monoclonal antibody trastuzumab (Herceptin) linked to the cytotoxic agent mertansine (DM1)
  • HER dimerization inhibitors Pertuzumab (sold under the trademark Omnitarg®, by
  • CD20 antibodies Rituximab (sold under the trademarks Riuxan® and MabThera® by Genentech/Roche), tositumomab (sold under the trademarks Bexxar® by GlaxoSmithKline), ofatumumab (sold under the trademark Arzerra® by GlaxoSmithKline);
  • Tyrosine kinase inhibitors Erlotinib hydrochloride (sold under the trademark Tarceva® by Genentech/Roche), Linifanib (N-[4-(3-amino-1H-indazol-4-yl)phenyl]-N'-(2-fluoro-5- methylphenyl)urea, also known as ABT-869, available from Genentech), sunitinib malate (sold under the tradename Sutent® by Pfizer), bosutinib (4-[(2,4-dichloro-5-methoxyphenyl)amino]-6- methoxy-7-[3-(4-methylpiperazin-1-yl)propoxy] quinoline-3 -carbonitrile, also known as SKI-606, and described in US Patent No.
  • dasatinib (sold under the tradename Sprycel® by Bristol-Myers Squibb), armala (also known as pazopanib, sold under the tradename Votrient® by GlaxoSmithKline), imatinib and imatinib mesylate (sold under the tradenames Gilvec® and Gleevec® by Novartis).
  • DNA Synthesis inhibitors Capecitabine (sold under the trademark Xeloda® by Roche), gemcitabine hydrochloride (sold under the trademark Gemzar® by Eli Lilly and Company), nelarabine ((2R3S,4R,5R)-2-(2-amino-6-methoxy-purin-9-yl)-5-(hydroxymethyl)oxolane-3,4- diol, sold under the tradenames Arranon® and Atriance® by GlaxoSmithKline);
  • Antineoplastic agents oxaliplatin (sold under the tradename Eloxatin® ay Sanofi- Aventis and described in US Patent No. 4,169,846);
  • G-CSF modulators Filgrastim (sold under the tradename Neupogen® by Amgen).
  • Immunomodulators Afutuzumab (available from Roche®), pegfilgrastim (sold under the tradename Neulasta® by Amgen), lenalidomide (also known as CC-5013, sold under the tradename Revlimid®), thalidomide (sold under the tradename Thalomid®);
  • CD40 inhibitors Dacetuzumab (also known as SGN-40 or huS2C6, available from Seattle Genetics, Inc); Pro-apoptotic receptor agonists (PARAs): Dulanermin (also known as AMG-951, available from Amgen/Genentech);
  • Hedgehog antagonists 2-chloro-N-[4-chloro-3-(2-pyridinyl)phenyl]-4-(methylsulfonyl)- benzamide (also known as GDC-0449, and described in PCT Publication No. WO 06/028958);
  • Phospholipase A2 inhibitors Anagrelide (sold under the tradename Agrylin®);
  • BCL-2 inhibitors 4-[4-[[2-(4-chlorophenyl)-5,5-dimethyl-1-cyclohexen-1-yl]methyl]-1- piperazinyl]-N-[[4-[[(lR)-3-(4-morpholinyl)-1-[(phenylthio)m ethyl] propyl] amino] -3 - [(trifluoromethyl)sulfonyl]phenyl]sulfonyl]benzamide (also known as ABT-263 and described in PCT Publication No. WO 09/155386);
  • MCl-1 inhibitors MIK665, S64315, AMG 397, and AZD5991;
  • Aromatase inhibitors Exemestane (sold under the trademark Aromasin® by Pfizer), letrozole (sold under the tradename Femara® by Novartis), anastrozole (sold under the tradename Arimidex®);
  • Topoisomerase I inhibitors Irinotecan (sold under the trademark Camptosar® by Pfizer), topotecan hydrochloride (sold under the tradename Hycamtin® by GlaxoSmithKline);
  • Topoisomerase II inhibitors etoposide (also known as VP- 16 and Etoposide phosphate, sold under the tradenames Toposar®, VePesid® and Etopophos®), teniposide (also known as VM-26, sold under the tradename Vumon®); mTOR inhibitors: Temsirolimus (sold under the tradename Torisel® by Pfizer), ridaforolimus (formally known as deferolimus, (lR,2R,4S)-4-[(2R)-2- [(1R,9S,12S,15R,16E,18R,19R,21R, 23S,24E,26E,28Z,30S,32S,35R)-1,18-dihydroxy-19,30- dimethoxy-15,17,21,23, 29,35-hexamethyl-2,3,10,14,20-pentaoxo-11,36-dioxa-4- azatricyclo[30.3.1.
  • Proteasome inhibitor such as carfilzomib, MLN9708, delanzomib, or bortezomib;
  • BET inhibitors such as INCB054329, OTX015, and CPI-0610;
  • ESDI inhibitors such as GSK2979552, and INCB059872;
  • HIF-2 ⁇ inhibitors such as PT2977 and PT2385;
  • Osteoclastic bone resorption inhibitors l-hydroxy-2-imidazol-1-yl-phosphonoethyl) phosphonic acid monohydrate (sold under the tradename Zometa® by Novartis); CD33 Antibody Drug Conjugates: Gemtuzumab ozogamicin (sold under the tradename Mylotarg® by Pfizer/Wyeth);
  • CD22 Antibody Drug Conjugates Inotuzumab ozogamicin (also referred to as CMC-544 and WAY-207294, available from Hangzhou Sage Chemical Co., Ltd.);
  • CD20 Antibody Drug Conjugates Ibritumomab tiuxetan (sold under the tradename Zevalin®);
  • octreotide also known as octreotide acetate, sold under the tradenames Sandostatin® and Sandostatin LAR®
  • Synthetic Interleukin- 11 IL-11
  • oprelvekin sold under the tradename Neumega® by
  • RANK Nuclear Factor ⁇ B
  • Thrombopoietin mimetic peptibodies Romiplostim (sold under the tradename Nplate® by
  • Cell growth stimulators Palifermin (sold under the tradename Kepivance® by Amgen); Anti-insulin-like Growth Factor- 1 receptor (IGF-1R) antibodies: Figitumumab (also known as CP-751,871, available from ACC Corp), robatumumab (CAS No. 934235-44-6); Anti-CSl antibodies: Elotuzumab (HuLuc63, CAS No. 915296-00-3);
  • CD52 antibodies Alemtuzumab (sold under the tradename Campath®);
  • Histone deacetylase inhibitors Voninostat (sold under the tradename Zolinza® by Merck);
  • Alkylating agents Temozolomide (sold under the tradenames Temodar® and Temodal® by Schering-Plough/Merck), dactinomycin (also known as actinomycin-D and sold under the tradename Cosmegen®), melphalan (also known as L-PAM, L-sarcolysin, and phenylalanine mustard, sold under the tradename Alkeran®), altretamine (also known as hexamethylmelamine (HMM), sold under the tradename Hexalen®), carmustine (sold under the tradename BiCNU®), bendamustine (sold under the tradename Treanda®), busulfan (sold under the tradenames Busulfex® and Myleran®), carboplatin (sold under the tradename Paraplatin®), lomustine (also known as CCNU, sold under the tradename CeeNU®), cisplatin (also known as CDDP, sold under the tradenames Platinol® and Platinol
  • Anti-microtubule agents Estramustine (sold under the tradename Emcyl®);
  • Cathepsin K inhibitors Odanacatib (also know as MK-0822, N-(1-cyanocyclopropyl)-4- fluoro-N2- ⁇ ( 1 S)-2,2,2-trifluoro-1 - [4'-(methy lsulfonyl)biphenyl-4-yl]ethyl ⁇ -L-leucinamide, available from Lanzhou Chon Chemicals, ACC Corp., and ChemieTek, and described in PCT Publication no. WO 03/075836); Epothilone B analogs: Ixabepilone (sold under the tradename Lxempra® by Bristol- Myers Squibb);
  • HSP Heat Shock Protein
  • TpoR agonists Eltrombopag (sold under the tradenames Promacta® and Revolade® by GlaxoSmithKline);
  • Anti-mitotic agents Docetaxel (sold under the tradename Taxotere® by Sanofi- Aventis); Adrenal steroid inhibitors: aminoglutethimide (sold under the tradename Cytadren®);
  • Anti-androgens Nilutamide (sold under the tradenames Nilandron® and Anandron®), bicalutamide (sold under tradename Casodex®), flutamide (sold under the tradename Fulexin TM ); Androgens: Fluoxymesterone (sold under the tradename Halotestin®);
  • CDK (CDK1, CDK2, CDK3, CDK5, CDK7, CDK8, CDK9, CDKll/12, or CDK16) inhibitors including but not limited to Alvocidib (pan-CDK inhibitor, also known as flovopirdol or HMR-1275, 2-(2-chlorophenyl)-5,7-dihydroxy-8-[(3S,4R)-3-hydroxy-1-methyl-4-piperidinyl]-4- chromenone, and described in US Patent No. 5,621,002);
  • CDK4/6 inhibitors pabociclib, ribociclib, abemaciclib, and Trilaciclib; CDK9 inhibtiors AZD 4573, P276-00, AT7519M, TP-1287; CDK2/4/6 inhibitor such as PF-06873600;
  • SHP-2 inhibitor such as TN0155
  • MDM2/MDMX, MDM2/p53 and/or MDMX/p53 modulators Gonadotropin-releasing hormone (GnRH) receptor agonists: Leuprolide or leuprolide acetate (sold under the tradenames Viadure® by Bayer AG, Eligard® by Sanofi-Aventis and Lupron® by Abbott Lab);
  • Taxane anti-neoplastic agents Cabazitaxel (l-hydroxy-7,10 -dimethoxy-9-oxo-5,20- epoxytax-11-ene-2a,4,13a-triyl-4-acetate-2-benzoate-13-[(2R,3S)-3- ⁇ [(tert-butoxy)carbonyl] - amino ⁇ -2-hydroxy-3-phenylpropanoate), larotaxel ((2 ⁇ ,3 ⁇ ,4 ⁇ ,5 ⁇ ,7 ⁇ ,10 ⁇ ,13 ⁇ )- 4,10- bis(acetyloxy)- 13 -( ⁇ (2R,3S)-3- [(tert-butoxycarbonyl) amino] -2-hydroxy-3- phenylpropanoyl ⁇ - oxy)-1- hydroxy-9-oxo-5,20-epoxy-7,19-cyclotax-11-en-2-yl benzoate);
  • 5HT1a receptor agonists Xaliproden (also known as SR57746, 1- [2-(2-naphthyl)ethyl] -4- [3-(trifluoromethyl)phenyl]-1,2,3,6-tetrahydropyridine, and described in US Patent No.
  • HPC vaccines Cervarix® sold by GlaxoSmithKline, Gardasil® sold by Merck; Iron Chelating agents: Deferasinox (sold under the tradename Exjade® by Novartis);
  • Anti-metabolites Claribine (2-chlorodeoxy adenosine, sold under the tradename leustatin®), 5-fluorouracil (sold under the tradename Adrucil®), 6-thioguanine (sold under the tradename Purinethol®), pemetrexed (sold under the tradename Alimta®), cytarabine (also known as arabinosylcytosine (Ara-C), sold under the tradename Cytosar-U®), cytarabine liposomal (also known as Liposomal Ara-C, sold under the tradename DepoCyt TM ), decitabine (sold under the tradename Dacogen®), hydroxyurea (sold under the tradenames Hydrea®, Droxia TM and Mylocel TM ), fludarabine (sold under the tradename Fludara®), floxuridine (sold under the tradename FUDR®), cladribine (also known as 2-chloro
  • Bisphosphonates Pamidronate (sold under the tradename Aredia®), zoledronic acid (sold under the tradename Zometa®); Demethylating agents: 5-azacitidine (sold under the tradename Vidaza®), decitabine (sold under the tradename Dacogen®);
  • Plant Alkaloids Paclitaxel protein-bound (sold under the tradename Abraxane®), vinblastine (also known as vinblastine sulfate, vincaleukoblastine and VLB, sold under the tradenames Alkaban-AQ® and Velban®), vincristine (also known as vincristine sulfate, LCR, and VCR, sold under the tradenames Oncovin® and Vincas ar Pfs®), vinorelbine (sold under the tradename Navelbine®), paclitaxel (sold under the tradenames Taxol and Onxal TM );
  • Retinoids Alitretinoin (sold under the tradename Panretin®), tretinoin (all-trans retinoic acid, also known as ATRA, sold under the tradename Vesanoid®), Isotretinoin (13-cis-retinoic acid, sold under the tradenames Accutane®, Amnesteem®, Claravis®, Claras®, Decutan®, Isotane®, Izotech®, Oratane®, Isotret®, and Sotret®), bexarotene (sold under the tradename Targretin®);
  • Glucocorticosteroids Hydrocortisone (also known as cortisone, hydrocortisone sodium succinate, hydrocortisone sodium phosphate, and sold under the tradenames Ala-Cort®,
  • Cytokines interleukin-2 (also known as aldesleukin and IL-2, sold under the tradename Proleukin®), interleukin- 11 (also known as oprevelkin, sold under the tradename Neumega®), alpha interferon alfa (also known as IFN-alpha, sold under the tradenames Intron® A, and Roferon-A®); [00209] Estrogen receptor downregulators: Fulvestrant (sold under the tradename Faslodex®);
  • Anti-estrogens tamoxifen (sold under the tradename Novaldex®); Toremifene (sold under the tradename Fareston®);
  • SERMs selective estrogen receptor modulators
  • LHRH Leutinizing hormone releasing hormone
  • Goserelin sold under the tradename Zoladex®
  • Progesterones megestrol (also known as megestrol acetate, sold under the tradename Megace®);
  • Miscellaneous cytotoxic agents Arsenic trioxide (sold under the tradename Trisenox®), asparaginase (also known as L-asparaginase, Erwinia L-asparaginase, sold under the tradenames Elspar® and Kidrolase®);
  • One or more immune checkpoint inhibitors CD27, CD28, CD40, CD122, CD96, CD73, CD39, CD47, 0X40, GITR, CSF1R, JAK, PI3K delta, PI3K gamma, TAM kinase, arginase,
  • the immune checkpoint molecule is a stimulatory checkpoint molecule selected from CD27, CD28, CD40, ICOS, OX40, GITR, CD137 and STING.
  • the immune checkpoint molecule is an inhibitory checkpoint molecule selected from B7-H3, B7-H4, BTLA, CTLA-4, IDO, TDO, Arginase, KIR, LAG3, PD-1, TIM3, CD96, TIGIT and VISTA.
  • the compounds provided herein can be used in combination with one or more agents selected from KIR inhibitors, TIGIT inhibitors, LAIR1 inhibitors, CD 160 inhibitors, 2B4 inhibitors and TGFR beta inhibitors.
  • the inhibitor of an immune checkpoint molecule is an inhibitor of PD-1, e.g., an anti-PD-1 monoclonal antibody.
  • the anti-PD-1 monoclonal antibody is nivolumab, pembrolizumab (also known as MK-3475), pidilizumab, SHR-1210, PDR001, or AMP-224.
  • the anti-PD-1 monoclonal antibody is nivolumab, or pembrolizumab or PDR001.
  • the anti-PD1 antibody is pembrolizumab.
  • the inhibitor of an immune checkpoint molecule is an inhibitor of PD-L1, e.g., an anti-PD-L1 monoclonal antibody.
  • the anti-PD-L1 monoclonal antibody is BMS-935559, MEDI4736, MPDL3280A (also known as RG7446), or MSB0010718C.
  • the anti-PD-L1 monoclonal antibody is MPDL3280A
  • MEDI4736 durvalumab
  • the inhibitor of an immune checkpoint molecule is an inhibitor of CTLA-4, e.g., an anti-CTLA-4 antibody.
  • the anti-CTLA-4 antibody is ipilimumab or tremelimumab.
  • the inhibitor of an immune checkpoint molecule is an inhibitor of LAG3, e.g., an anti-LAG3 antibody.
  • the anti- LAG3 antibody is BMS-986016 or LAG525.
  • the inhibitor of an immune checkpoint molecule is an inhibitor of GITR, e.g., an anti-GITR antibody.
  • the anti-GITR antibody is TRX518 or, MK-4166, INCAGN01876 or MK-1248.
  • the inhibitor of an immune checkpoint molecule is an inhibitor of 0X40, e.g., an anti-OX40 antibody or OX40L fusion protein.
  • the anti-OX40 antibody is MEDI0562 or, INCAGN01949, GSK2831781, GSK-3174998, MOXR-0916, PF-04518600 or LAG525.
  • the OX40L fusion protein is MEDI6383.
  • Compounds of the invention can also be used to increase or enhance an immune response, including increasing the immune response to an antigen; to improve immunization, including increasing vaccine efficacy; and to increase inflammation.
  • the compounds of the invention can be sued to enhance the immune response to vaccines including, but not limited, Listeria vaccines, oncolytic viral vaccines, and cancer vaccines such as GVAX® (granulocyte-macrophage colony -stimulating factor (GM-CF) gene-transfected tumor cell vaccine).
  • GVAX® granulocyte-macrophage colony -stimulating factor (GM-CF) gene-transfected tumor cell vaccine.
  • Anti-cancer vaccines include dendritic cells, synthetic peptides, DNA vaccines and recombinant viruses.
  • Other immune-modulatory agents also include those that block immune cell migration such as antagonists to chemokine receptors, including CCR2 and CCR4; Sting agonists and Toll receptor agonists.
  • anti-cancer agents also include those that augment the immune system such as adjuvants or adoptive T cell transfer.
  • Compounds of this application may be effective in combination with CAR (Chimeric antigen receptor) T cell treatment as a booster for T cell activation.
  • a compound of Formula (I) can also be used in combination with the following adjunct therapies: anti-nausea drugs: NK-1 receptor antagonists: Casopitant (sold under the tradenames Rezonic® and Zunrisa® by GlaxoSmithKline); and
  • Cytoprotective agents Amifostine (sold under the tradename Ethyol®), leucovorin (also known as calcium leucovorin, citrovorum factor and folinic acid).
  • Step 5 2-(4-((tert-butyldimethylsilyl)oxy)-1-tosylpiperidin-2-yl)ethan-1-amine
  • Step 6 2-(4-((tert-buty ldimethy lsily l)oxy)piperidin-2-yl)ethan-1-amine
  • naphthalene 3.42 g, 26.656 mmol, 10.00 equiv
  • DME 11 mL
  • metallic sodium 0.61 g, 26.656 mmol, 10.00 equiv
  • Step 7 6-((tert-butyldimethylsilyl)oxy)octahydropyrido[1,2-b][1,2,6]thiadiazine 1,1 -dioxide
  • Step 8 6-hydroxyoctahydropyrido[1,2-b][1,2,6]thiadiazine 1,1 -dioxide
  • Step 9 hexahy dropyrido[1,2-b] [1,2,6]thiadiazin-6(2H)-one 1,1 -dioxide
  • Step 10 6-aminooctahydropyrido[1,2-b] [1,2,6]thiadiazine 1,1 -dioxide
  • Step 11 tert-butyl (1,1 -dioxidooctahy dropyrido[1 ,2-b] [1,2,6]thiadiazin-6-yl)carbamate
  • Step 12 6-aminooctahydropyrido[1,2-b] [1 ,2,6]thiadiazine 1,1-dioxide
  • Step 13 rac-8-cyclopentyl-2-(((4aR,6R)-1,1-dioxidooctahydropyrido[1,2-b] [1,2,6]thiadiazin-6- yl)amino)pyrido[2,3-d]pyrimidin-7 (8H)-one [1] and rac-8-cyclopentyl-2-(((4aR,6S)-1,1- dioxidooctahydropyrido[1,2-b][1,2,6]thiadiazin-6-yl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one [2]
  • the compounds are either enantiomers 3 and 4 or 5 and 6.
  • the ability of the disclosed compounds to inhibit CDK2 was determined as follows.
  • the kinase reactions were carried out in 384- well white polystyrene plates (Greiner Bio-One, Cat #784075) using assay buffer containing 50 mM HEPES (pH7.5), 10 mM MgCl 2 , 1 mM EGTA, 0.01% Tween-20 and 2 mM DTT.
  • 0.05 nM full-length CDK2/Cyclin E complex (Cama Biosciences, Cat # 04-165) was co-incubated with various concentrations of test compounds in 8 ul of assay buffer for 2 hours at room temperature.
  • the reaction was initiated by addition of 4 ul substrate mixture containing 3 mM ATP and 150 nM of Ulight-MBP peptide (Perkin Emler, TRF0109) in assay buffer. After incubation at room temperature for 1 hour, the reaction was terminated by adding 4 ul detection solution containing 50 mM Tris (pH7.8), 150 mM NaCl, 0.05% BSA, 40 mM EDTA, and 4 nM Europium-conjugated anti-phospho-MBP antibody (Perkin Elmer, TRF0201).
  • Fluorescence signals were measured on ClarioSTAR plate reader (BMG Labtech) using the TR-FRET (time-resolved fluorescence resonance energy transfer) mode (Ex 332 nm, Em 620/665 nm).
  • TR-FRET time-resolved fluorescence resonance energy transfer
  • IC 50 Half maximal inhibitory concentration
  • CDK IC 50 data for selected compounds are provided in Table 2.
  • the compound with a CDK2 IC 50 of 0.068 is 3, then the compound with a CDK2 IC 50 of 5.9 is 4 or vice versa. Similarly, if the compound with a CDK2 IC 50 of 0.068 is 5, then the compound with a CDK2 IC 50 of 5.9 is 6.
  • Compound of the disclosure e.g., compound 1 in 2% HPMC, 1% Tween 80 in DI water, pH 2.2 with MSA, q.s. to at least 20 mg/mL
  • a pharmaceutical composition for inhalation delivery 20 mg of a compound disclosed herein is mixed with 50 mg of anhydrous citric acid and 100 mL of 0.9% sodium chloride solution. The mixture is incorporated into an inhalation delivery unit, such as a nebulizer, which is suitable for inhalation administration.
  • an inhalation delivery unit such as a nebulizer
  • a pharmaceutical topical gel composition 100 mg of a compound disclosed herein is mixed with 1.75 g of hydroxypropyl cellulose, 10 mL of propylene glycol, 10 mL of isopropyl myristate and 100 mL of purified alcohol USP. The resulting gel mixture is then incorporated into containers, such as tubes, which are suitable for topical administration.
  • a pharmaceutical ophthalmic solution composition 100 mg of a compound disclosed herein is mixed with 0.9 g of N aCl in 100 mL of purified water and filtered using a 0.2 micron filter. The resulting isotonic solution is then incorporated into ophthalmic delivery units, such as eye drop containers, which are suitable for ophthalmic administration.
  • a pharmaceutical nasal spray solution 10 g of a compound disclosed herein is mixed with 30 mL of a 0.05M phosphate buffer solution (pH 4.4). The solution is placed in a nasal administrator designed to deliver 100 ul of spray for each application.
  • a 0.05M phosphate buffer solution pH 4.4

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Abstract

La présente invention concerne certains pyrido[2,3-d]pyrimidin-7(8H)-one qui sont des inhibiteurs de la kinase 2 dépendant de la cycline (CDK2) et sont par conséquent utiles pour le traitement de maladies pouvant être traitées par inhibition de CDK2. L'invention concerne également des compositions pharmaceutiques contenant de tels composés et des procédés de préparation de tels composés.
PCT/US2021/041331 2020-07-14 2021-07-12 Dérivés de pyrido[2,3-d]pyrimidin-7(8h)-one utilisés en tant qu'inhibiteurs de kinase 2 dépendant de la cycline Ceased WO2022015670A1 (fr)

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WO2023249968A1 (fr) * 2022-06-22 2023-12-28 Nikang Therapeutics, Inc. Composés bifonctionnels contenant des dérivés de pyrido[2,3-djpyrimidin-7(8h)-one pour dégrader la kinase 2 dépendante des cyclines par l'intermédiaire d'une voie ubiquitine-protéasome
US12097261B2 (en) 2021-05-07 2024-09-24 Kymera Therapeutics, Inc. CDK2 degraders and uses thereof
EP4491055A1 (fr) 2023-07-10 2025-01-15 Crep Protect Limited Protection amovible de boite a orteil pour chaussures de sport

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Publication number Priority date Publication date Assignee Title
US12097261B2 (en) 2021-05-07 2024-09-24 Kymera Therapeutics, Inc. CDK2 degraders and uses thereof
WO2023249968A1 (fr) * 2022-06-22 2023-12-28 Nikang Therapeutics, Inc. Composés bifonctionnels contenant des dérivés de pyrido[2,3-djpyrimidin-7(8h)-one pour dégrader la kinase 2 dépendante des cyclines par l'intermédiaire d'une voie ubiquitine-protéasome
EP4491055A1 (fr) 2023-07-10 2025-01-15 Crep Protect Limited Protection amovible de boite a orteil pour chaussures de sport

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