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WO2018081204A1 - N-(5-((4-éthylpipérazine-1-yl)méthyl) pyridin-2-yl)-5-fluoro-4-(4-fluoro-1-isopropyl-2-méthyl-1h-benzo[d]imidazol-6-yl)pyrimidin-2-amine deutéré - Google Patents

N-(5-((4-éthylpipérazine-1-yl)méthyl) pyridin-2-yl)-5-fluoro-4-(4-fluoro-1-isopropyl-2-méthyl-1h-benzo[d]imidazol-6-yl)pyrimidin-2-amine deutéré Download PDF

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WO2018081204A1
WO2018081204A1 PCT/US2017/058191 US2017058191W WO2018081204A1 WO 2018081204 A1 WO2018081204 A1 WO 2018081204A1 US 2017058191 W US2017058191 W US 2017058191W WO 2018081204 A1 WO2018081204 A1 WO 2018081204A1
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compound
deuterium
hydrogen
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formula
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George Y. Li
Duanjle Hou
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings

Definitions

  • the present invention relates io an isoiopologue of Compound 1 substituted with one or more deuteriums;
  • the isotopoiogues of this invention are selective CDK4 6 kinase inhibitors and possess unique biopharroaceutical and metabolic properties compared io Compound 1. They may also be used to accurately determine the concentration of Compound 1 in bioiogicai fluids and io determine metabolic patterns of Compound 1 and its isotopoiogues.
  • the invention further provides compositions comprising these deuterated isotopoiogues and methods for treating a variety of p-Rb positive tumor types including HR (hormone-receptor)- positive and HER2 (human epidermal growth factor receptor 2) ⁇ negative breast cancer, melanoma, liposarcoma and non-small-cell lung cancer, alone or in combination with additional agents.
  • HR hormone-receptor
  • HER2 human epidermal growth factor receptor 2 ⁇ negative breast cancer
  • melanoma human epidermal growth factor receptor 2
  • non-small-cell lung cancer alone or in combination with additional agents.
  • HR hormone-receptor
  • HER2 human epidermal growth factor receptor 2
  • Compound 1 salts, solvates, hydrates, and polymorph thereof, are known as selective- CDK4/6 inhibitors.
  • This compound and pharmaceutical compositions comprising h may have utility in the treatment of pRb-positive tumor types including HR ! HER2 " breast cancer melanoma, liposarcoma and non-small-cell. lung cancer, alone or in combination with additional agents.
  • Compound 1 also known as abemacic ib (LY283521 ), selectively binds to cyclin- dependent kinases 4 and 6 (CDK4/6) and inhibits the activity of CDK4/6 thereby inhibiting retinoblastoma (Rb) protein phosphorylation, inhibition of Rb phosphorylation prevents CDK-mediated Gl-S phase transition, therefore arresting the cell cycle in the G phase, suppressing DNA synthesis and inhibiting cancer cell, growth.
  • Increased cyciin or CDK expression or decreased levels of endogenous CDK inhibitors such as ⁇ ⁇ 4 or CfP/KiP, as seen in certain types of cancer, causes cell cycle deregulation and uncontrolled cellular proliferation:.
  • the emergence of a new generation o f selective CD 4/6 inhibitors has enabled tumor types in which CD 4/6 has a pivotal role in the Gt-to-S-phase cell- cycle transition to be targeted with improved effectiveness, and fewer adverse effects.
  • Abemaciclib is one of this type of drugs currently in clinical development. See Shapiro GL "Cydiii dependent kinase pathways as targets for cancer treatment " Clin Oncol
  • the antitumor activity of LY28352I9 was assessed in mice bearing colo-205 human xenografts 24 h after oral dosing. It significantly inhibited the growth of colo-205 xenografts at doses from 12.5 mg kg up to 100 rag/kg, and correlated with in vivo inhibition of ph ⁇ R dose dependently. The antitumor activity was further confirmed in several additional human xenografts representing different human histologies, and was dose-dependent. Finally, antitumor activity of LY2835219 was sustained for up to 56 days with continuous or intermittent dosing schedules in mice bearing colo-205 xenografts.
  • the MONARCH 1 results confirmed objective response (ORR), durability of response (DoR), clinical benefit rate (CBR) and progression-free survival (PFS), At the .final analysis of response (minimum of 12 months follow-up), patients treated with abemaciclib achieved art ORR of 19.7 % with a median time to response of 3.7 months and a median DoR of 8,6 months.
  • the median PFS was six months with a CBR (defined as patients who achieved complete response, partial response or stable disease for si mon ths or longer) of 42.4%. Of the 13 patients who remained on treatment at the time of this analysis, nine were responders and four had stable disease (SD). See Announcement; Results from MONARCH i Trial of Abemaciclib Monotherapy, 03, 201 , Eli Lilly and Company. Also see: fattp:// ww,pr3 ⁇ 4ewsw ⁇ re.oom
  • Abemaciclib has now entered into Phase If f development with two trials in HR.+ breast cancer patients, as well as a Phase 111 trial in lung cancer.
  • Two Phase 3 clinical trials MONARCH 2 to evaluate the combination of abemaciclib and Mvestrant for treatment of HR+, HER2- advanced or metastatic breast cancer in postmenopausal women, and MONARCH 3 to evaluate (he combination of abemaciciib and a nonsteroidal aromatase inhibitor in H +, HER2- ioeoregionally recurrent o metastatic breast cancer in postmenopausal, women. See Jason M. Broderick ''Abemaciciib Active Against
  • Y ! ⁇ Y ⁇ Y 4 , Y 4 ⁇ Y Y 5 Y 6 , Y 6 ', Y ⁇ Y 7 ', Y S , Y* Y ' Y* Y 10 , Y I , Y ! ⁇ 5 Y N , Y ! ⁇ Y» Y' 4 , Y m Y i , Y iS ; ⁇ 1 ⁇ ; ⁇ ⁇ 6 ⁇ ⁇ ' ⁇ ⁇ !7 , Y ir , and Y 3 is deuterium; and each carbon is independently optionally replaced with L, C.
  • compound of formul I may fee primarily metabolized by CYP3A and other drug metabolizing enzymes.
  • the primary metabolic pathways for compound of ormula I may involve oxidation, presumably at the benxylic carbon and/or at the electron rich nitrogen and/or a ⁇ earbons of the piperazine ring, including N-oxidation, oxidative N-dealkylation, ring oxidation, and ring opening.
  • a radiolabeled disposition study with 150 rag oral dose of C-LY28352.I in healthy subjects has found 5 metabolites denoted as Ml, M2, M.I 8, M20, and M22 in. the plasma it* addition to parent drag abemariclib.
  • Various deuteration patterns can be used to a) reduce or eliminate unwanted.
  • metabolites b) increase the half-life of t he parent drug, c) decrease the number of doses needed to achieve a desired effect, d) decrease the amount of a dose needed to achieve a desired effect, e) increase the formation of active metabolites, if any are formed, and/or f) decrease the production of deleterious metabolites in specific tissues and/or create more effective drug and/or a safer drug for polypharmacy, whether the polypharmacy be intentional or not.
  • the deuteration approach has strong potential to slow the metabolism via various oxidative and other modification mechanisms.
  • the compounds and compositions of this invention are also useful as analytical.
  • Compound 1 refers to a compound wherein all hydrogen and all carbon atoms are present at their natural isotopic abundance percentages. It is recognized that some variation of natural isotopic abundance occurs depending upon the origin of chemical materials. The concentration of naturally abundant stable hydrogen and carbon isotopes, not withstanding this variation, is small and .immaterial with respect to the degree of stable isotopic substitution of compounds of this invention. (See for instance Wada E and Hanba ⁇ , Seikagaku .1 94 66; 15; Ganes L Z et al. f Cotnp. Biochem. Physiol. A Mol. Integr.
  • the altered properties of the compounds of this invention will not obliterate their ability to bind to their protein target. This is. because such binding is primarily dependent upon non-covalent binding between the protein and the inhibitor which may be impacted both positively and. negatively by isotopic substitution, depending on the specific
  • the compounds of this invention possess molecular topology that is very similar to Compound 1, since exchange of deuterium for hydrogen does not alter molecular shape and exchange of ! j C for n C is conformational! ⁇ ' neutral (HoltzerM E et. al, Biophys. J. 2001 80: 939). Deuterium replacement does cause a slight decrease in Van der Waals radius (Wade D. Chem. Biol, interact. 1999 1 17; 191): hut applicant believes that such decrease will not greatly reduce binding affinity between the molecule and its receptor. Furthermore, the slightly smaller size of the deuterated compounds of this invention prevents their being involved in new undesirable stertc clashes with the binding protei relative to the Compound 1.
  • deuterium nor ! 3 C atoms in the compounds of this invention contribute significantly to hydrogen bonding or ionic interactions with the protein receptors. This is because the major hydrogen bond and ionic interactions formed by Compound 1 with serotonin uptake proteins are mediated by the oxygens, nitrogens, and the amine-bound hydrogens within Compound i . Any deuterium atoms attached to the amine nitrogen, will be rapidly exchanged wi th balk solvent protons under physiological conditions.. Protein reorganization or side chain movement- will be identical between a compound of this invention and Compound 1. Desoivatian energy of a compound of this .invention 3 ⁇ 4it!
  • a compound of this invention advantageously retains substantial selective CD 4/6 inhibitory acti vity with reduced rate of metabolite generation.
  • the compounds and compositions of this invention are also useful as analytical reagents for determining the concentration of the Compound 1 in solution.
  • Y I , Y I 7 , Y 17' , and Y N" are selected from the group consisting of hydrogen or - deuterium, whereto at least one of Y ⁇ Y ⁇ , Y*, Y 4 , Y ⁇
  • ⁇ of the- compounds of -formula (I) are each deuterium, wherein Y ,
  • Y 3 of the compounds of formula (1) is a deuterium, wherein Y 2 , Y ⁇ Y , Y 4 ', Y 5 , Y > , Y 6 , Y 6 Y Y 7 ⁇ Y ⁇ Y , Y !> 5 Y , Y 50 , Y I , Y JR , and Y IT ⁇ are each hydrogen.
  • Y ! of the compounds of formula (I) is a deuterium, wherein Y ! ?
  • Y of the compounds of formula (I) is a deuterium, wherein Y 8 , Y 8" , Y 5 *, Y Y , Y» Y R , Y 10 ", Y U , Y R ⁇ Y U , Y U Y U Y 15 , Y 16 , Y 16' , Y 5 * " , Y 17 , Y S , and Y J are each hydrogen.
  • Y" of the compounds of formula (1) is a deuterium, wherein Y F , Y 2 , Y , Y , Y 9 , Y R , Y W , Y KI Y ' Y N , ⁇ ' ⁇ Y F4 , Y 14' , Y H ", Y' ⁇ Y 56 , Y 16 S6 Y 57 , Y IR , md Y T7" are each hydrogen.
  • Y 34 , Y F , artel Y ⁇ of the compounds of formula (I) are each deuterium, wherein Y ! , Y 8 , Y S' , Y 9 , Y 9> , Y 19 , and Y IR are each hydrogen.
  • Y" , Y * Y ' , Y ' , Y ' , Y ' , and ' of the compounds of formula (1) are each deuterium, wherein Y 1 , Y", Y -> , Y 4 , Y 4 ', Y', Y 5> , Y*, Y 6 Y Y 7 Y Y , Y 9 , Y* Y I0 , Y L Y 10 " * , Y H F Y 12 , Y L ⁇ Y I4 , Y S , and Y !4" are each hydrogen.
  • Y 4 , and Y 4 ' of the compounds of formula (I) are each deuterium, wherein Y 50 , Y I0 Y 50 ", Y", Y F2 , Y L ⁇ Y 14 , ⁇ , ' , Y 14" , Y 3S , Y' E , Y !I ⁇ Y ! , Y L Y IR , and Y V are each hydrogen.
  • Y ? ⁇ ⁇ % Y Y* ⁇ Y' ' , Y 7 Y H , and Y H' of the compounds of formula (I) are each deuieriitm, wherein Y 1 , Y".
  • Y ' Y 4 , Y 4 ', Y 9 , Y 9 ,, ⁇ ! ⁇ ', Y M Y I Y H , Y I2 , Y ] ⁇ Y , Y H Y U" , Y SI , Y 1 ⁇ 2 , Y IFT' , Y J 5 Y 3 ⁇ 47 , Y 57 and Y I are each hydrogen.
  • Y Y ⁇ , Y id , Y !) , and Y KL " of the compounds of formula (I) are each deuterium, wherein Y l , Y 2 , Y 3 , Y 4 Y 4* , Y S , Y S , Y 6 , Y 6 ⁇ Y 7 , Y 7 ', Y 's , Y 8' , Y U , Y i2 , Y B , Y 54 , Y L , Y f % Y 16 , Y I6' , Y i ⁇ ;" , Y 17 , Y 'i7' , and Y 5 are each hydrogen.
  • Y ! , Y ⁇ f Y 5 , and Y 11 of Che compounds of formula (I) are each deuterium, wherein Y 4 , Y 4 ', Y 5 , Y 5 ⁇ Y " ⁇ Y E ⁇ Y 7 , Y 7 ⁇ Y 8 , Y ( ⁇ Y 9" , Y ] Y w , Y l Y ⁇ ⁇ Y si , Y 14 5 Y 14 ', Y 54 ", Y !5 , Y Y L6> , Y 1 * * , Y 5 ', Y i , and Y !7" are each hydrogen.
  • Y ⁇ Y ⁇ , Y J , Y 4 , and Y * 'of the compounds of formula. (I) are each deuterium, wherein Y S , Y S ', Y", ⁇ ', ⁇ ', Y", Y , Y k , Y 9 , Y V , Y*°, Y KI Y n , Y 1T , and Y 17" are each hydrogen.
  • Y 3 , Y “ , Y ⁇ Y* t Y 3 ⁇ Y", Y° Y', Y 7 Y , and Y H of the compounds of formula (I) are each deuterium, wherein Y 4 , Y* Y x Y 9 , Y m , Y 10 Y I0» , Y n , Y u , Y l ⁇ Y ⁇ 4 , ⁇ ⁇ ' , Y 14" , Y l Y 16 , Y 16' , Y ! , Y 17 , Y ,? ⁇ arid Y 5 are each hydrogen.
  • Y ⁇ . Y 2 , Y 4 , Y '! , Y t0 . Y t0 , and Y h ' i! of the compounds of formula (1) are each deuterium.
  • Y 4 , Y 4 ', Y ⁇ Y S ⁇ Y* > Y* ⁇ ⁇ , Y' ⁇ Y 8 , Y 8> , Y u , Y 12 , and Y 5 are each hydrogen.
  • Y 4 , Y 4 ', Y*, Y , Y' W , Y 3 l , and Y I ⁇ IW of the compounds of formula (I) are each deuterium, wherein ⁇ ' ⁇ Y ⁇ , Y*, Y 5 , ⁇ '", Y f> , Y 6 ', ⁇ ⁇ and Y IT> are each, hydrogen,
  • Y* 5 Y 9 , Y 1 , Y L ° , Y K!,> , Y ' 4 , ⁇ ! " , and Y *4 of the conipoinids of formula (J) are each deuterium wherein Y ! , Y", Y * S Y 4 , Y 4* ,. Y ? , ⁇ 3 ⁇ 4 ', Y 6 , Y 6> , Y ? , Y 7 ', Yl Y s Y ! !
  • Y I2 , Y°, Y 1S , Y 3 ⁇ 4 , Y A6' S Y 5'6 ' ⁇ , ⁇ 5 ⁇ . and Y i7" are each hydrogen.
  • f orrnu la (1) are each deuterium, wherein Y 1 , Y ⁇ Y Y 4 , Y 4 ', Y 5 , Y J ⁇ Y ⁇ ⁇ * ⁇ ⁇ ' , Y 7 ', Y 8 , Y , ⁇ ", ⁇ ⁇ 2 , ⁇ 53 , ⁇ ⁇ , Y u and Y K" are each hydrogen.
  • ⁇ Y 9 Y li Y w , Y ⁇ Y' ⁇ Y u Y l4 Y ls , Y li Y'* , Y ,” S Y ! Y ] ' , and Y 17 ' of the compounds of formula (I) are each deuterium, wherein Y ! , Y ⁇ ⁇ ⁇ Y ', Y s , Y 5 ', Y* Y 6 ', ⁇ Y y ⁇ Y s' , Y ! ⁇ Y U , and ⁇ are each hydrogen .
  • Y Y 10 s a d Y 50 " of the eompoirads of formula (1) are each deiiterium, wherein Y 4 , Y 4 ', Y 55 , Y 12 S Y» Y , Y ', Y ,4> Y , S , Y 36 , Y 17 , Y 17' , and Y T are each hydrogen.
  • Y 4 , Y ', Y S , Y s ⁇ Y 6 , Y 6* , Y 7 , Y 7 ⁇ Y*, Y , Y S , Y 9 , Y*, Y K,' S and Y 10 " of the compounds of formula (I) are each deiiterium, wherein 15 Y i6" : , Y ! 7 , Y ⁇ ?> , and Y I are each hydrogen.
  • Y ⁇ . Y ⁇ ⁇ ⁇ ⁇ arid Y' ⁇ qf the compounds of formula (1) are each deuterium, wherein Y* Y 4 % Y ⁇ Y 5 ', Y* Y s ⁇ Y 7 , Y 7 ', Y s , Y* ⁇ and Y ! are 20 each hydrogen.
  • Y Y 2 , Y Y 5 ? , Y f f> , Y , Y tt! , Y ' '" , Y 1 ' , and Y 1 ' of the compoiinds of formula (I) are each de terirun, wherein Y 4 , Y " ' Y ? , Y 5> , Y", Y 6 ', Y 7 . Y 7 ', Y Y , Y 9 , Y 9' , Y K Y Hr , Y Y u , Y 12 , Y , Y U 5 Y 1 and Y !4" are each hydrogen.
  • Y ⁇ Y ' ⁇ and Y' ' of the compounds of formula 0 (1) are each deuteri m, wherein Y 1 , Y 2 , Y 3 ,. Y 9> ,
  • Y ! Y 14 , Y U , and Y '1** of the compounds of formula. (1) are each deuterium, wherein Y Y ⁇ , *, Y 4 , Y*', Y 5 ,. ⁇ Y 4 ', Y* * , ⁇ ', Y", Y*, Y ' , ⁇ ' Y , YTM Y W Y X Y N , ⁇ ⁇ ⁇ ⁇ 16 , Y W , Y W ⁇ ⁇ ? , Y I , and Y SR are each hydrogen.
  • Y 4 , Y Y 1 *, Y 14 , arid Y 54 of the compounds of formula (I) are each deuterium, wherein Y', Y I , Y*, Y ⁇ Y' Y FI , Y* ⁇ Y ⁇ Y' ⁇ Y , Y , Y ⁇ Y» Y M Y" Y L3 ⁇ 4 ⁇ Y N , Y , Y L' ⁇ Y IS , Y K Y H Y W Y* ⁇ Y IT , and Y ,R" are each hydrogen.
  • Y and Y of the compounds of formula ( ) are each deuterium, wherein Y 5 , Y 2 , Y ⁇ Y 4 , Y 4 ', Y 5 , Y* ⁇ Y 6 , Y F “, Y 7 , Y 7 ", Y S , Y* " , Y 9 , Y 9> , Y 10 , Y 10* , Y !0 ", Y , Y !4 , Y W , Y Y S 5 , Y I6 , Y S Y I7 , Y I , and Y I?” are each hydrogen.
  • Y S , Y , Y U" , Y IS , Y ! «, ⁇ ⁇ 3 ⁇ 4 Y 16" , Y 1 , and Y I? of the compounds of formula (!) are each deuterium;
  • At least one of the positions represented as D independently lias deuterium enrichment of no less than abou t 1%, no less than about 5%, no less than about 10%, no less than about 20%, no less than about 50%, no less than about 70%, no less than about 80%, no less than about 90%, or no less than about 98%.
  • the deuierated compound as disclosed herei may also contain less prevalent isotopes for other elements, including, but not limited to, °C or U C for carbon, ! ⁇ ⁇ for nitrogen, and i7 0 or !S 0 for oxygen.
  • the deuierated compounds disclosed herein maintain the beneficial aspects of fhe corresponding non-isotopicaily enriched molecules while substantially increasing the maximum tolerated dose, decreasing toxicity, increasing the half-life (Tj . ), lowering the maximum plasma concentration (C mstx ) of the minimum efficacious dose (MED), lowering the efficacious dose and thus decreasing the non- mechanism- elated toxicity, and/or lowering the probability of drug-drag interactions.
  • compound as used herein, is intended to include salts, prodrugs, and prodrug salts of a compound of formul I.
  • the term also includes any solvates, hydrates, and polymorphs of any of the foregoing.
  • T he specific recitation o prodrug,” “prodrug salt,” “solvate “ “hydrate,” or “polymorph” in certain aspects of the invention described in this application shall not be interpreted as an intended omission of these forms hi other aspects .of the invention where the term, "compound” is used without recitation of these other forms.
  • a salt of a compound of this invention is formed between an acid and a basic group of the compound, such as an amino functional group, or a base and an acidic group of the compound, such as a carboxyl functional group.
  • the compound is a pharmaceutically acceptable acid addition salt.
  • prodrug means a derivative of a compound that can hydro!yze, oxidize, or otherwise react under biological conditions (in vitro or in vivo) to provide a compound of this invention.
  • Prodrugs may only become active upon such reaction under bioiogicai conditions, or they may have activity in their unreached forms. Examples of prodrugs contemplated in this invention include, but.
  • biohydrolyzabie moieties such as biohydrolyzabie amides, biohydrolyzabie esters, biohydrolyzabie carbamates, biohydrolyzabie carbonates, biohydrolyzabie ureides, and biohydrolyzabie phosphate analogues.
  • Other examples of prodrugs include derivatives of compounds of an one of the formulae disclosed herein that comprise—NO, ⁇ NO.sub.2, --ONO, or -ONO.sub.2 moieties.
  • Prodrugs can typically be prepared using well-known methods, such as those described by Burger's Medicinal Chemistry and Drug Discovery (1995) 172-178, 49-982 (Manfred E. Wolff ed.,, 5th ed) see also Goodman and Oilman's, The Pharmacological basis of Therapeutics, 8th ed., McGraw-Hill, Int. Ed. 1992, "Biotransformation of Drugs”.
  • biohydrolyzabie amide ''biohydrolyzabie ester
  • biohydrolyzabie carbamate a biohydrolyzabie carbonate
  • biohydrolyzabie ureide a biohydrolyzabie phosphate analogue
  • biohydrolyzabie amides incl ude are no limited to, lower alkyl amides, .alpha. -amino acid amides, alkoxyaey! amides, and alkylaniinoalkylcarbonyl amides.
  • biohydrolyzabie esters include, but are not limited to, lower alkyl esters, alkoxyacyloxy esters, alkyl acykmmo.alky! -esters, and choline esters.
  • biohydrolyzable carbamates include, but- are not limited to, lower alky lamines, substituted ethylenedia ines, amino acids, hydroxyalkylamines, heterocyclic arid heteroaromatic amines, sod polyether amines.
  • a prodrug salt is a compound formed between an acid and a basic group of the prodrug, such as an ami no functional group, or a base and an acidic group of the prodrug, such as a carboxyi functional group, in a preferred embodiment, the prodrug salt is a pharmaceutically acceptable salt.
  • the counterfoil to the saltable prodrug of the compound of formula J is pharmaceutically acceptable.
  • Pharmaceutically acceptable eoun tenons include, for instance, those acids and bases noted herein as being suitable to form pharmaceutically acceptable salts.
  • Particularly favored prodrugs and prodrug salts are those that increase the bioavailability of the compounds of this invention when such compounds are administered to a mammal (e.g., by allowing an orally administered compound to be more readily absorbed into the blood) or which enhance delivery of the parent compound to a biological compartment (e.g., the brain or central nervous system) relative to the parent species.
  • Preferred prodrugs include derivatives where a group that enhances aqueous solubility or active transport through the gut membrane is appended to the structure of formulae described herein. See, e.g., Alexander, I et al. Journal of Medicinal Chemistry 1 88, 31, 318-322; Bundgaard, H.
  • pharmaceutically acceptable refers to a component that is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and other mammals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefi i/risk ratio.
  • pharmaceutically acceptable salt means any non-toxic salt that, upon administration to a recipient, is capable of providing, either directly or indirectly, a compound or a prodrug of compound of this invention.
  • pharmaceutically acceptable ⁇ eountsrion is an ionic portion of a salt that is not toxic when released from the sail ⁇ » administration to a recipient.
  • Acids commonly employed to form baraiaceuticaily acceptable salts include
  • inorganic acids such as hydrogen bisulfide, hydrochloric, bydrobromic, hydroiodic, sulfuric and phosphoric acid, a well as organic acids such as para-tolueuesuifenic, salicylic, tartaric, bitartarie, ascorbic, rnaleie, besyiic. fiiniaric, gluconic, glucuronic, formic, glutamic, meihanesuifonic, ethanesulfonic, benzsnesulfomc, lactic, oxalic, para- bromophenylsulfonic, carbonic, succinic, citric, benzoic and acetic acid, and related inorganic and organic acids.
  • Such pharmaceutically acceptable salts thus include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate,
  • dihydrogenphosphate metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, aery late, formate, isobittyrate, caprate, heptanoale, propsolate, oxalate, malonate, succinate, suberate, sebacaie, fumarate, maieate, butyne-1,4- dioate, hexyne-1 5 6 ⁇ dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phtbalate, terephathaS te, sulfonate, xylenesulfonate, phenylaceiate, phenylpropionate, phenylburyrate, citrate, lactate, .beta.-hydrexybutyrate, glycolate, maieate, tartrate,
  • hydrochloric acid and bydrobromic acid and especially those formed with organic acids such as raateic acid.
  • hydrate means a compound which further includes a stoichiometric or non-stoichiometrie amount of water bound by non-covalem
  • solvate means a compound which further includes a stoichiometric or non-stoichiometrie amount of solvent such as water, acetone, emanoi, methanol, dichloromethane, 2-propanol, or the like, bound by non-covalent intermolecular forces.
  • polymorph As used herein, the term "polymorph” .means solid crystalline forms of a compoun o comple thereof which may be characterized by physical means such as, for instance, X- ray powder diffraction patterns or infrared spectroscopy. Different polymorphs of the same compound can exhibit different physical, chemical and/or spectroscopic properties.
  • Different physical properties include, but are not limited to stability (e.g., to heat, light or moisture), compressibi!ity and density (important in formulation and product manufacturing), hygroscopicity, solubility, and dissolution rates and solubiiiiy (which can affect bioavailability). Differences in stability can. result from changes in chemical reactivity (e.g., differential oxidation, such that a dosage form discolors more rapidly when comprised of one polymorph than when comprised of another polymorph) or mechanical characteristics (e.g., tablets crumble on storage as a kiueiically favored polymorph converts to thennodynamically more stable polymorph) or both (e.g., tablets of one polymorph are more susceptible to breakdown at high humidity).
  • Different physical properties of polymorphs can affect their processing. For example, one polymorph might be more likely to form solvates or might be more difficult to filter or wash free of impurities than another due to, for example, the shape or size distribution of particles of it,
  • any range of numbers recited in the specification or paragraphs hereinafter describing or claiming various aspects of the invention, such as that representing a particular set of properties, units of measure, conditions, physical states or percentages, is intended to literally incorporate expressly herein by reference or otherwise, any number falling within such range, including any subset of numbers or ranges subsumed within any range so recited.
  • the compounds of .formula I may be prepared by the processes described herein in the following reaction scheme (Scheme A). Examples of suitable reagents and procedures for conducting these reactions appear hereinafter and in the working examples included therein. Protection and deprotection in the schemes herein may be carried out by procedures generally known in the art [See, for example, T.W. Greene ⁇ & P.O. M.Wuts, Protecting Groups in Organic Synthesis, 4th Edition, Wiley, (2007) J.
  • the reaction can be carried out in an organic solvent, preferably DME, ia the presence of a palladium catalyst such as PdC3 ⁇ 4(dppf ⁇ and a base such as 2 COs at an elevated temperature preferably at 80 °C.
  • Reaction of the compound of formula Hi can be efficiently coupled with aqueous ammonia in the presence of Cu-acetylacetonate as a catalyst to generate the compound of formula IV.
  • Reaction of the compound of formula IV and me compound of formula V to form the compound of formula I can be achieved through an animation reaction.
  • the reaction can be carried out in an organic solvent such as dioxane, in the presence of a capper catalyst such as Cul and a base such as K.2OO3 at an elevated tempemtore preferably at 1 10 °C.
  • Method B Shiffia i GC-2010/GCMS-QP2010S. Primary eoltmiti S ' LB-5ms 30m x 0.25 mm, 0.25 urn; GC oven temperature program total 15 min, 45 °C to 300 °C at 40 °C /min with 10 mm-hold at 300 °C; Carrier gas He; Inlet pressore 50 kPa; Column flow rate 1.0 ml/min. Product detected by electron ionization mode.
  • Step J 6 ⁇ ' 2-bromo ⁇ 5-fluoropyrimidm- -yl)-4-fluoro- 1 -isoprop l ⁇ 2 ⁇ methyl- 1 H- ben3 ⁇ 4o[d]imida3 ⁇ 4ole
  • the reaction mixture was then cooled to ambient temperature and diluted -with water ( 100 mL) and stirred for 20 mm. After separation the aqueous layer was extracted with EiOAc (3 x 150 mL). The combined organic layers were washed with brine (50 mL) and dried over MgS0 4 . The organic phase was concentrated under reduced pressure, and the crude product was purified by flash chromatography on silica gei using a mixture of hexane/ethyl acetate (8:1 ) as eluent. White solid. Yield: 4.0 g, 39.8%.
  • Step 2 5-fl «oro-4-(4-fluoro-l-isopropyi-2-methyl-lH-ben o[djimida !:ol-6- yl)pyrimidm-2-amme
  • aqueous phase was extracted with EiOAc (3 X 200 ML), the combined organic phases were washed with brine (100 mL), dried over MgS04, filtered, concentrated under reduced pressure, and the crude product was purified by flash chromatography on silica gel using a mixture of hexane/ethyi acetate (8: 1) as eluent to afford an ⁇ -white solid (3.0 g, 91 % Yield).
  • Step 3 l ⁇ ((6-BronK ⁇ pyridi.n ⁇ 3 ⁇ y ⁇
  • Step 4 N-(5 ⁇ ((4 ⁇ (eihyl-ds)piperazin- 1 ⁇ yl)n hy1)pyrid ⁇ 2 ⁇ yl-3 ( 4,6 ⁇ dj) ⁇ 3 ⁇ flu ⁇ ro- ⁇ (4-fiuoro- i-isopropyl-2-meihyi-lH-
  • Example 3 was prepared from 5-i]uoro-4-(4-fluoro-l -isopropyi-2-m
  • Example 4 was prepared from 5-flitoro-4-(4-flttoro- 1 -isopropyl-2-meth !- 1 H-benzo[d] imidazoi-6-y i)pytimidin-2-amine (260 mg, 0.86 mraol), Pd(dha) 2 (24 mg, 0.042 mmoi), BINAP (82 mg, 0.13 mmoi), CS2CO3 (650 mg, 1.7 mmoi), dioxane (6 mL), and i-((6-bromopyridk-3-yl-2 ?
  • Example 5 was prepared from
  • Step 1 i -(2-chlar0 ⁇ 5 ⁇ i3 ⁇ 4Km ⁇ yr ⁇
  • Example 7 Aecording to the procedures described for Example 6, Example 7 was prepared .from
  • Example 8 (4- ' flu.of t> ⁇ I -isoprop l ⁇ 2 ⁇ mef hyl- ⁇ H-benm d ⁇ imida/ol- ⁇ -y1)pyriTi «dm ⁇ > ⁇ 2-amii3 ⁇ 4e
  • Example 8 was prepared from 6 ⁇ (2 ⁇ chSoro ⁇ 5 ⁇ fiimropyrM
  • Example 9 was prepared from
  • Microsomal Assay Certain in viiro liver metabolism studies have been described previously in the following references: Obach, R. S. Drag Metab Disp 1999, 27, p. 1350 "Prediction of human clearance of twenty-nine drugs from hepatic microsomal intrinsic clearance data: An examination of in vitro half-life approach and nonspecific binding to microsomes"; Houston,, J. B. el al., Drug Metab Rev 1997, 29, p. 891 "Prediction of hepatic clearance from microsomes, hepatocytes, and liver slices"; Houston, I. B.
  • Biochem Pharmacol 1 94, 47, p. 1469 "Utility of in vitro drag metabolism data in predicting in vivo metabolic clearance”: Iwatsubo, T et al., Pharmacol Ther 1 97, 73, p. 1.47 "Prediction of in vivo drug metabolism in the human liver from in vitro metabolism data”; and Lave, T. et al, Pharm Res 1997, ! 4, p. 152 "The use of human hepatocytes to select compounds based on their expected hepatic extraction ratios in humans”.
  • the objectives of the present study were to determine the metabolic stability of the test compounds in pooled liver and rat microsomal incubations. Samples of the test compounds, exposed to pooled human and rat liver microsomes, were analyzed using UPLC LC-MS/ S detection.
  • NADPH ⁇ Nicotinamide Adenine Dmucleoti.de 2' ⁇ Phasphate Reduced Tetrasodiom Salt
  • human liver and rat microsomes Disodium hydrogen phosphate; Sodium dihydrogen phosphate; Deionized water; Midazolam.
  • Buffer B l ,0 L of 0.1 M Dibasic Potassium Phosphate .buffer c n ainin 1 ,0 reM EDTA.
  • Buffer C 0.1 M Potassium Phosphate buffer, 1,0 mM EDTA, pH 7.4 by titrating 700 mL of buffer B with buffer A while monitoring with the pH meter.
  • the positive control compound. (Midazolam) was included in the assay. Any value of the compounds that was not within the specified limits was rejected and the experiment was repeated.
  • the negative control was used to exclude the misleading factor that resulted from instability of chemical itself.
  • the In peak area ratio (compound peak area/ internal standard peak area) was plotted against time and the gradien t of the line was determined.
  • test compounds were evaluated the human and rat liver microsome assay described above along with midazolam as a positive control and with no NADPH in reaction system as a negative control.
  • the columns of Table 1 labelled "% remaining" refer to the percentage of each test compound remaining after 0, 5, 15, 30, and 45 minute intervals in the human and rat microsomal assay.
  • Example 2 the deuieraied analogs (Example 2) of the invention displayed appreciable stability over time with y 2 extended to 11.24 min, from 1 .10 min, providing a S.1% increase in human liver microsome; and to 47.12 min. from 39.48 min, providing a 19% increase in rat liver microsome.
  • the deuterated analogs (Example 3) of the invention displayed appreciable stability over time with T ⁇ /2 extended to 13.33 min. from 10.10 min, providing a 32% increase in human liver microsome; and to 57.35 min. from 39.48 min, providing a 45% increase in rat live microsome.
  • the analog (Example 3) of the raventloa with 13 deuterium atom .replacements displayed appreciable stability over another deiuerated analog
  • Example 5 with only 5 deuterium atom replacements with ' !1 ⁇ 2 extended to 13.33 mm. from 1 1 ,1 1 mi «, providing a 20% racrease in human liver microsome; and to 57.35 mm. from 47.07 mm, providing a 22% increase in rat li ver microsome.
  • deuie aied compounds according to the invention may exhibit beneficial properties when administered to patients, e.g., improved metabolic liability.

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Abstract

La présente invention concerne des composés de Formule (I): (I) ou un sel pharmaceutiquement acceptable de ceux-ci; dans laquelle : Y1, Y2, Y3, Y4, Y4,, Y5, Y5,, Y6,Y6,, Y7, Y7,,Υ8, Y8', Y9, Y9', Y10, Y10', YI0", Y11, Y12, Y13, Y14, Y I4', Y14", Υ15, Y16, Υ16', Y16", Y17, Y17' and Y17" sont choisis dans le groupe constitué par l'hydrogène ou le deutérium, au moins l'un parmi Y1, Y2, Y3, Y4, Y4,,Y5 Y5,, Y6, Y6,, Y7, Y7,, Y8, Y8', Y9, Y9', Y10, Y10', Y10", Υ11, Y12, Y13, Y14, Y14', Y14", Y15, Y16, Y16', Y16", Y17, Y17', et Y17'' étant un deutérium ; et chaque carbone est éventuellement remplacé indépendamment par 13C. L'invention concerne également des compositions pharmaceutiques comprenant les composés de Formule (I) et l'utilisation de ces composés en tant que inhibiteurs sélectifs de CDK4/6 avec le potentiel pour le traitement de types de tumeurs pRb positifs comprenant le cancer du sein négatif au HER2 (récepteur du facteur de croissance épidermique humain-2) et positif au HR (récepteur hormonal), le mélanome, le liposarcome et le cancer bronchique non à petites cellules, seuls ou en combinaison avec d'autres agents.
PCT/US2017/058191 2016-10-26 2017-10-25 N-(5-((4-éthylpipérazine-1-yl)méthyl) pyridin-2-yl)-5-fluoro-4-(4-fluoro-1-isopropyl-2-méthyl-1h-benzo[d]imidazol-6-yl)pyrimidin-2-amine deutéré Ceased WO2018081204A1 (fr)

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WO2022063140A1 (fr) * 2020-09-23 2022-03-31 Shenzhen Ionova Life Science Co., Ltd. Dérivés de pyrimidine et de pyridine en tant que modulateurs de hpk1 et leurs procédés d'utilisation
WO2022113003A1 (fr) 2020-11-27 2022-06-02 Rhizen Pharmaceuticals Ag Inhibiteurs de cdk
WO2022149057A1 (fr) 2021-01-05 2022-07-14 Rhizen Pharmaceuticals Ag Inhibiteurs de cdk

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Publication number Priority date Publication date Assignee Title
WO2022063140A1 (fr) * 2020-09-23 2022-03-31 Shenzhen Ionova Life Science Co., Ltd. Dérivés de pyrimidine et de pyridine en tant que modulateurs de hpk1 et leurs procédés d'utilisation
CN116456985A (zh) * 2020-09-23 2023-07-18 深圳市原力生命科学有限公司 作为hpk1调节剂的嘧啶及吡啶衍生物和其使用方法
WO2022113003A1 (fr) 2020-11-27 2022-06-02 Rhizen Pharmaceuticals Ag Inhibiteurs de cdk
WO2022149057A1 (fr) 2021-01-05 2022-07-14 Rhizen Pharmaceuticals Ag Inhibiteurs de cdk

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