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WO2017205762A1 - Inhibiteurs de la kinase associée au récepteur de l'interleukine 1 - Google Patents

Inhibiteurs de la kinase associée au récepteur de l'interleukine 1 Download PDF

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Publication number
WO2017205762A1
WO2017205762A1 PCT/US2017/034717 US2017034717W WO2017205762A1 WO 2017205762 A1 WO2017205762 A1 WO 2017205762A1 US 2017034717 W US2017034717 W US 2017034717W WO 2017205762 A1 WO2017205762 A1 WO 2017205762A1
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WO
WIPO (PCT)
Prior art keywords
substituted
unsubstituted
alkyl
cycloalkyl
membered heteroaryl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/US2017/034717
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English (en)
Inventor
Wei Chen
Zhaozhong J. Jia
William D. Thomas
David Wone
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Pharmacyclics LLC
Original Assignee
Pharmacyclics LLC
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Pharmacyclics LLC filed Critical Pharmacyclics LLC
Publication of WO2017205762A1 publication Critical patent/WO2017205762A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems

Definitions

  • heterocycloalkyl substituted or unsubstituted Ce-C ⁇ aryl, substituted or unsubstituted 5- to 7-membered heteroaryl, halo, CN, -NO2, -OR 10 , -SR 10 , -NR n R 12 , -
  • compositions formulated for administration by an appropriate route and means containing effective concentrations of one or more of the compounds provided herein that deliver amounts effective for the treatment, prevention, or amelioration of one or more symptoms of dieases, disorders or conditions that are modulated or otherwise affected by IRAK activity, or in which IRAK activity is implicated, are provided.
  • the effective amounts and concentrations are effective for ameliorating any of the symptoms of any of the diseases, disorders or conditions disclosed herein.
  • IRAK protein kinase such as IRAK4
  • pharmaceutically acceptable derivative thereof which is effective for inhibiting the activity of IRAK protein kinase, such as IRAK4, within the packaging material, and a label that indicates that the compound or composition thereof is used for inhibiting the activity of IRAK protein kinase(s), such as IRAK4, are provided.
  • Cyano refers to the -CN radical.
  • Carboxy means a -C(0)OH radical.
  • Rings refers to any covalently closed structure. Rings include, for example, carbocycles (e.g., aryls and cycloalkyls), heterocycles (e.g., heteroaryls and non-aromatic heterocycles), aromatics (e.g. aryls and heteroaryls), and non-aromatics (e.g., cycloalkyls and non-aromatic heterocycles). Rings can be optionally substituted. Rings can be monocyclic or polycyclic.
  • an "effective amount” or “therapeutically effective amount,” as used herein, refer to a sufficient amount of an agent or a compound being administered which will relieve to some extent one or more of the symptoms of the disease or condition being treated or prevent to some extent the onset or progression of the disease or condition or a symptom thereof. The result can be reduction and/or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system.
  • an "effective amount” for therapeutic uses is the amount of the composition including a compound as disclosed herein required to to achieve a desired pharmacologic effect or therapeutic improvement or provide a clinically significant decrease in disease symptoms without undue adverse side effects.
  • module means to interact with a target either directly or indirectly so as to alter the activity of the target, including, by way of example only, to enhance the activity of the target, to inhibit the activity of the target, to limit the activity of the target, or to extend the activity of the target.
  • the methods described herein can be used to treat hetero immune conditions or diseases, which include, but are not limited to graft versus host disease, transplantation, transfusion, anaphylaxis, allergies (e.g., allergies to plant pollens, latex, drugs, foods, insect poisons, animal hair, animal dander, dust mites, or cockroach calyx), type I hypersensitivity, allergic conjunctivitis, allergic rhinitis, asthma, and atopic dermatitis.
  • hetero immune conditions or diseases include, but are not limited to graft versus host disease, transplantation, transfusion, anaphylaxis, allergies (e.g., allergies to plant pollens, latex, drugs, foods, insect poisons, animal hair, animal dander, dust mites, or cockroach calyx), type I hypersensitivity, allergic conjunctivitis, allergic rhinitis, asthma, and atopic dermatitis.
  • compositions that include at least one such compound or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, pharmaceutically active metabolite or pharmaceutically acceptable prodrug of such compound, are provided.
  • compounds disclosed herein when compounds disclosed herein contain an oxidizable nitrogen atom, the nitrogen atom can be converted to an N-oxide by methods well known in the art.
  • stereoisomers such as enantiomers or E/Z isomers, and chemically protected forms of compounds having a structure represented by any of Formula are also provided.
  • L 1 is a covalent bond and Cy 2 is spiro C7-Ci2Cycloalkyl. In some embodiments, L 1 is a covalent bond and Cy 2 is spiro C3-C?cyclo alkyl fused with a 5 - or 6-membered heteroaryl.
  • Cy 2 is Cy 3 -NR 5a R 5b or Cy 4 ;
  • Cy 3 is C 3 -Ci 2 Cycloalkyl
  • A is a 5-membered heteroaryl
  • heterocycloalkyl phenyl, and 5- to 7-membered heteroaryl; or R 11 and R 12 together with the nitrogen to which they are attached form a 3- to 7-membered heterocycloalkyl ring;
  • R 6 is C1-C3 alkyl optionally substituted with OH, OCH 3 , CN, NH 2 , NHCH 3 or CONH 2 .
  • R 4 is NR 7a R 7b .
  • R 7a is H or CH3, and R 7b is C1-C3 alkyl optionally substituted with OH, OCH3, CN, NH 2 , NHCH3 or CONH2.
  • R 4 is halogen.
  • R 4 is F or CI.
  • R 2 is selected from H, or substituted and unsubstituted Ci-C3alkyl
  • each R 8 is independently selected from C1-C4 alkyl, Ci-C4 haloalkyl, halo, CN, and -NO2;
  • R 11 and R 12 are independently selected from H, C 1 -C 4 alkyl, C 3 -C 8 cycloalkyl, 3- to 7-membered
  • n 0, 1 or 2;
  • R 4 is selected from
  • R 2 is selected from H, or substituted and unsubstituted Ci-C3alkyl
  • heterocycloalkyl phenyl, and 5- to 7-membered heteroaryl
  • Cy 3 is C 3 -Ci 2 Cycloalkyl
  • R 6 is selected from substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted 3- to 7-membered heterocycloalkyl, substituted or unsubstituted Ce-Ci2 aryl, and substituted or unsubstituted 5- to 7-membered heteroaryl; each of R 7a and R 7b is independently selected from H, and substituted or unsubstituted C 1 -C3 alkyl; or R 7a and R 7b together with the N to which they are attached, are combined to form a substituted or unsubstituted 3- to 7-heterocycloalkyl ring;
  • heterocycloalkyl phenyl, and 5- to 7-membered heteroaryl; or R 11 and R 12 together with the nitrogen to which they are attached form a 3- to 7-membered heterocycloalkyl ring;
  • n 0, 1 or 2;
  • R 5a and R 5b together with the N to which they are attached, are combined to form a substituted or unsubstituted 3- to 7-membered
  • the cancer is carcinoma of the brain, kidney, liver, adrenal gland, bladder, breast, stomach, gastric tumors, ovaries, colon, rectum, prostate, pancreas, lung, vagina, cervix, testis, genitourinary tract, esophagus, larynx, skin, bone or thyroid, sarcoma, glioblastomas, neuroblastomas, multiple myeloma, gastrointestinal cancer, especially colon carcinoma or colorectal adenoma, a tumor of the neck and head, an epidermal hyperproliferation, a neoplasia, a neoplasia of epithelial character, adenoma, adenocarcinoma, keratoacanthoma, epidermoid carcinoma, large cell carcinoma, non-small-cell lung carcinoma, lymphomas, Hodgkins and Non-Hodgkins, a mammary carcinoma, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma
  • prodrugs refers to an agent that is converted into the parent drug in vivo. Prodrugs are often useful because, in some situations, they may be easier to administer than the parent drug. They may, for instance, be bioavailable by oral administration whereas the parent is not. The prodrug may also have improved solubility in pharmaceutical compositions over the parent drug.
  • Compounds described herein may be formed as, and/or used as, pharmaceutically acceptable salts.
  • the type of pharmaceutical acceptable salts include, but are not limited to: (1) acid addition salts, formed ) by reacting the free base form of the compound with a pharmaceutically acceptable: inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, metaphosphoric acid, and the like; or with an organic acid such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, trifluoroacetic acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1 ,
  • compositions including a compound described herein may be manufactured in a conventional manner, such as, by way of example only, by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or compression processes.
  • Antioxidants include, for example, butylated hydroxytoluene (BHT), sodium ascorbate, ascorbic acid, sodium metabisulfite and tocopherol. In certain embodiments, antioxidants enhance chemical stability where required.
  • BHT butylated hydroxytoluene
  • antioxidants enhance chemical stability where required.
  • hydroxypropylmethylcellulose hydroxyethylcellulose, hydroxypropylcellulose (e.g., Klucel ® ), ethylcellulose (e.g., Ethocel ® ), and microcrystalline cellulose (e.g., Avicel ® ); microcrystalline dextrose; amylose;
  • magnesium aluminum silicate polysaccharide acids; bentonites; gelatin; polyvinylpyrrolidone/vinyl acetate copolymer; crosspovidone; povidone; starch; pregelatinized starch; tragacanth, dextrin, a sugar, such as sucrose (e.g., Dipac ® ), glucose, dextrose, molasses, mannitol, sorbitol, xylitol (e.g., Xylitab ® ), and lactose; a natural or synthetic gum such as acacia, tragacanth, ghatti gum, mucilage of isapol husks,
  • disintegrate includes both the dissolution and dispersion of the dosage form when contacted with gastrointestinal fluid.
  • disintegration agents or disintegrants facilitate the breakup or disintegration of a substance.
  • disintegration agents include a starch, e.g., a natural starch such as corn starch or potato starch, a pregelatinized starch such as National 1551 or Amijel ® , or sodium starch glycolate such as Promogel ® or Explotab ® , a cellulose such as a wood product, methylcrystalline cellulose, e.g., Avicel ® , Avicel ® PH101, Avicel ® PH102, Avicel ® PH105, Elcema ® P100, Emcocel ® , Vivacel ® , Ming Tia ® , and Solka-Floc ® , methylcellulose, croscarmellose, or a cross-linked cellulose, such as cross-linked sodium carboxymethyl
  • Step state is when the amount of drug administered is equal to the amount of drug eliminated within one dosing interval resulting in a plateau or constant plasma drug exposure.
  • pharmaceutical formulation is administered in two, or three, or four, capsules or tablets.
  • microcrystalline cellulose cellulose powder, dextrose, dextrates, dextran, starches, pregelatinized starch, hydroxypropylmethy cellulose (HPMC), hydroxypropylmethy cellulose phthalate,
  • a powder including the formulations with a compound described herein may be formulated to include one or more pharmaceutical excipients and flavors.
  • a powder may be prepared, for example, by mixing the formulation and optional pharmaceutical excipients to form a bulk blend composition. Additional embodiments also include a suspending agent and/or a wetting agent. This bulk blend is uniformly subdivided into unit dosage packaging or multi-dosage packaging units.
  • the formulations described herein are solid dispersions. Methods of producing such solid dispersions are known in the art and include, but are not limited to, for example, U.S. Patent Nos. 4,343,789, 5,340,591, 5,456,923, 5,700,485, 5,723,269, and U.S. Published Application 2004/0013734, each of which is specifically incorporated by reference.
  • the formulations described herein are solid solutions. Solid solutions incorporate a substance together with the active agent and other excipients such that heating the mixture results in dissolution of the drug and the resulting composition is then cooled to provide a solid blend which can be further formulated or directly added to a capsule or compressed into a tablet. Methods of producing such solid solutions are known in the art and include, but are not limited to, for example, U.S. Patent Nos. 4,151,273, 5,281,420, and 6,083,518, each of which is specifically incorporated by reference.
  • Controlled release refers to the release of the compound described herein from a dosage form in which it is incorporated according to a desired profile over an extended period of time.
  • Controlled release profiles include, for example, sustained release, prolonged release, pulsatile release, and delayed release profiles.
  • immediate release compositions controlled release compositions allow delivery of an agent to a subject over an extended period of time according to a predetermined profile.
  • Such release rates can provide therapeutically effective levels of agent for an extended period of time and thereby provide a longer period of pharmacologic response while minimizing side effects as compared to conventional rapid release dosage forms.
  • Such longer periods of response provide for many inherent benefits that are not achieved with the corresponding short acting, immediate release preparations.
  • Suitable preservatives for the aqueous suspensions or dispersions described herein include, for example, potassium sorbate, parabens (e.g., methylparaben and propylparaben), benzoic acid and its salts, other esters of parahydroxybenzoic acid such as butylparaben, alcohols such as ethyl alcohol or benzyl alcohol, phenolic compounds such as phenol, or quaternary compounds such as benzalkonium chloride.
  • Preservatives, as used herein, are incorporated into the dosage form at a concentration sufficient to inhibit microbial growth.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Cette invention concerne des inhibiteurs de la protéine kinase IRAK. L'invention concerne également des compositions pharmaceutiques qui comprennent ces composés. L'invention concerne enfin des procédés d'utilisation des inhibiteurs d'IRAK, seuls ou en combinaison avec d'autres agents thérapeutiques, pour le traitement de maladies ou d'affections auto-immunes, de maladies ou d'affections hétéro-immunes, du cancer, y compris du lymphome, et de maladies ou d'affections inflammatoires.
PCT/US2017/034717 2016-05-27 2017-05-26 Inhibiteurs de la kinase associée au récepteur de l'interleukine 1 Ceased WO2017205762A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US201662342463P 2016-05-27 2016-05-27
US62/342,463 2016-05-27

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WO2017205762A1 true WO2017205762A1 (fr) 2017-11-30

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Cited By (29)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10336762B2 (en) 2017-02-16 2019-07-02 Gilead Sciences, Inc. Pyrrolo[1,2-b]pyridazine derivatives
WO2019192962A1 (fr) * 2018-04-05 2019-10-10 Merck Patent Gmbh Composés hétéroaryle en tant qu'inhibiteurs d'irak de type ii et leurs utilisations
WO2020001449A1 (fr) 2018-06-25 2020-01-02 南京明德新药研发有限公司 Composé d'isothiazolo [5,4-d] pyrimidine en tant qu'inhibiteur d'irak
CN111662295A (zh) * 2019-03-05 2020-09-15 珠海宇繁生物科技有限责任公司 一种irak4激酶抑制剂及其制备方法
US10874743B2 (en) 2017-12-26 2020-12-29 Kymera Therapeutics, Inc. IRAK degraders and uses thereof
US10875866B2 (en) 2018-07-13 2020-12-29 Gilead Sciences, Inc. Pyrrolo[1,2-B]pyridazine derivatives
EP3800188A1 (fr) 2019-10-02 2021-04-07 Bayer AG Pyrazolopyrimidines substituées en tant qu'inhibiteurs d'irak4
WO2021092239A1 (fr) * 2019-11-05 2021-05-14 Dermira, Inc. Compositions topiques comprenant des inhibiteurs d'irak4 pour une utilisation dans le traitement d'états dermatologiques caractérisés par une inflammation
WO2021158495A1 (fr) * 2020-02-03 2021-08-12 Bristol-Myers Squibb Company Composés de benzo[5,6] [1,4]dioxino[2,3-b]pyridine utiles en tant qu'inhibiteurs de l'irak4
US11117889B1 (en) 2018-11-30 2021-09-14 Kymera Therapeutics, Inc. IRAK degraders and uses thereof
US11292792B2 (en) 2018-07-06 2022-04-05 Kymera Therapeutics, Inc. Tricyclic CRBN ligands and uses thereof
US11358948B2 (en) 2017-09-22 2022-06-14 Kymera Therapeutics, Inc. CRBN ligands and uses thereof
US11485743B2 (en) 2018-01-12 2022-11-01 Kymera Therapeutics, Inc. Protein degraders and uses thereof
US11512080B2 (en) 2018-01-12 2022-11-29 Kymera Therapeutics, Inc. CRBN ligands and uses thereof
US11591332B2 (en) 2019-12-17 2023-02-28 Kymera Therapeutics, Inc. IRAK degraders and uses thereof
US11623932B2 (en) 2017-09-22 2023-04-11 Kymera Therapeutics, Inc. Protein degraders and uses thereof
WO2023075479A1 (fr) * 2021-10-28 2023-05-04 재단법인 대구경북첨단의료산업진흥재단 Nouveau dérivé de thiéno [2,3-d] pyrimidine, son procédé de préparation et composition pharmaceutique pour la prévention ou le traitement du cancer ou d'une maladie auto-immune le comprenant en tant que principe actif
KR20230061269A (ko) * 2021-10-28 2023-05-08 재단법인 대구경북첨단의료산업진흥재단 신규한 티에노[2,3-d]피리미딘 유도체, 이의 제조방법 및 이를 유효성분으로 포함하는 암 또는 자가면역질환의 예방 또는 치료용 약학적 조성물
US11685750B2 (en) 2020-06-03 2023-06-27 Kymera Therapeutics, Inc. Crystalline forms of IRAK degraders
WO2023121207A1 (fr) * 2021-12-20 2023-06-29 재단법인 대구경북첨단의료산업진흥재단 Composition pharmaceutique inhibant aak1, pour prévenir ou traiter des maladies virales ou des maladies cérébrales
US11707457B2 (en) 2019-12-17 2023-07-25 Kymera Therapeutics, Inc. IRAK degraders and uses thereof
RU2810338C2 (ru) * 2018-04-05 2023-12-27 Мерк Патент Гмбх Гетероарильные соединения в качестве ингибиторов irak ii типа и их применения
US12091411B2 (en) 2022-01-31 2024-09-17 Kymera Therapeutics, Inc. IRAK degraders and uses thereof
US12097261B2 (en) 2021-05-07 2024-09-24 Kymera Therapeutics, Inc. CDK2 degraders and uses thereof
WO2024217522A1 (fr) * 2023-04-21 2024-10-24 正大天晴药业集团股份有限公司 Utilisation d'un composé isothiazolo[5,4-d]pyrimidine dans le traitement de maladies inflammatoires
US12150995B2 (en) 2020-12-30 2024-11-26 Kymera Therapeutics, Inc. IRAK degraders and uses thereof
US12171768B2 (en) 2021-02-15 2024-12-24 Kymera Therapeutics, Inc. IRAK4 degraders and uses thereof
US12187744B2 (en) 2021-10-29 2025-01-07 Kymera Therapeutics, Inc. IRAK4 degraders and synthesis thereof
US12454520B2 (en) 2018-07-06 2025-10-28 Kymera Therapeutics, Inc. Protein degraders and uses thereof

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