WO2019140953A1 - 用于抑制激酶活性的二苯氨基嘧啶类化合物 - Google Patents

用于抑制激酶活性的二苯氨基嘧啶类化合物 Download PDF

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WO2019140953A1
WO2019140953A1 PCT/CN2018/109043 CN2018109043W WO2019140953A1 WO 2019140953 A1 WO2019140953 A1 WO 2019140953A1 CN 2018109043 W CN2018109043 W CN 2018109043W WO 2019140953 A1 WO2019140953 A1 WO 2019140953A1
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compound
disease
pharmaceutically acceptable
mmol
acceptable salt
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PCT/CN2018/109043
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French (fr)
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王义汉
李焕银
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深圳市塔吉瑞生物医药有限公司
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Priority to JP2020539273A priority Critical patent/JP7169005B2/ja
Priority to EP18901461.6A priority patent/EP3578555B1/en
Priority to US16/492,994 priority patent/US11384069B2/en
Publication of WO2019140953A1 publication Critical patent/WO2019140953A1/zh

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Definitions

  • the invention belongs to the technical field of medicine, and in particular relates to a substituted diphenylaminopyrimidine compound and a composition comprising the same and use thereof. More specifically, the present invention relates to certain anthracene substituted N-(tert-butyl)-3-((5-methyl-2-((4-(2-(pyrrolidin-1-yl))ethoxy) Phenyl)amino)pyrimidin-4-yl)amino)benzenesulfonamides, these guanidine substituted compounds exhibit JAK2 protein tyrosine kinase inhibition and are useful for the treatment of JAK2 kinase mediated diseases, and these quinone substituted compounds Has more excellent pharmacokinetic properties.
  • JAK family of cellular protein tyrosinase includes four kinase subtypes of JAK 1 - JAK 3 and TYK 2, which are highly homologous. They have seven homologous domains (JK homology domain, JH) from the carboxy terminus (C-terminus) to the amino terminus (N-terminus) and are usually divided into four functional domains.
  • JH1 is the active kinase catalytic domain
  • the JH 2 structural region is a region unique to the JAK family, known as the pseudokinase domain or the pseudokinase domain. Although it has no catalytic function, it can play an indispensable key regulation through cooperation.
  • the SH 2 domain consisting of JH 3 and JH 4 plays a role in stabilizing JAK mainly in the kinase structure, while the JH 5 to JH 7 part (FERM domain) directly interacts with the intracellular structure of the cytokine receptor. The role also interacts with the JH1 domain.
  • JAK 2 has a unique cytokine profile in the JAK family.
  • g-chain (gc) family cytokines In addition to being activated by g-chain (gc) family cytokines, it can also be used by many other cytokines (such as bc family cytokines, erythropoietin and platelets).
  • bc family cytokines Activation of blood-related cytokines such as pheromone, its activity is essential for the process of hematopoiesis. Therefore, JAK2 can affect some basic functions such as erythropoietin (EPO) and granulocyte-macrophage colony-stimulating factor (GM-CSF), and polycythemia vera (PV), anemia, and primary platelets.
  • EPO erythropoietin
  • GM-CSF granulocyte-macrophage colony-stimulating factor
  • PV polycythemia vera
  • the JAK pathway has been shown to be complementary in cell survival and proliferation.
  • CML chronic myelogenous leukemia
  • JAK2 inhibitors can be applied to CML, where it has been confirmed that the Philadelphia chromosome produces a hybrid Bcr-Abl, thereby maintaining the constitutive activity of the cells.
  • JAK 2 pathway-based BCR-ABL mutant eg, A JAK 2 inhibitor of the BCR-ABL (T315I) mutation.
  • JAK 2 inhibitors can be used to treat patients with resistance to known therapies, where BCR-ABL is directly targeted, and drug resistance has now been shown to dominate all of the resistance in patients with failed existing therapies. (50%-90%).
  • Fedratinib (SAR-302503, TG-101348) was acquired by Sanofi in 2010 and advanced Fedratinib to advanced clinical stages. The drug was later taken over by a startup, Impact Biopharmaceuticals. Development, the company has been acquired by Celgene.
  • Fedratinib is a highly selective oral inhibitor of JAK 2 protein kinase with the chemical name (N-(tert-butyl)-3-((5-methyl-2-((4-(2-(pyrrolidine)- 1-yl)ethoxy)phenyl)amino)pyrimidin-4-yl)amino)benzenesulfonamide.
  • the clinical indications for Fedratinib are myelofibrosis (MF) and polycythemia vera (PV), which are shown early in the clinic. Very good clinical benefit, but in 2013, Fedratinib was found to have serious neurological side effects.
  • the present invention provides a novel JAK2 inhibitor for deuterated modification with Fedratinib as a parent compound, which reduces or eliminates undesirable metabolites by a deuteration strategy; increases the half-life of the parent compound; reduces the dosage required to achieve the desired effect Number; reduces the amount of dose required to achieve the desired effect; increases the formation of active metabolites (if formed); reduces the production of harmful metabolites in specific tissues; produces drugs that are more effective for multiple administrations and/or Safer drugs (regardless of whether the multiple drugs are intentional).
  • the present invention discloses a novel anthracene-substituted diphenylpyrimidine compound and a composition and use thereof, which have better JAK2 kinase and JAK2/V617F kinase inhibitory activity, lower side effects, and more Good pharmacodynamic/pharmacokinetic properties for the treatment of JAK2 kinase mediated diseases.
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , Y 6 , Y 7 , Y 8 and Y 9 are each independently selected from hydrogen or hydrazine;
  • X 1 , X 2 , X 3 and X 4 are each independently selected from CH 3 , CD 3 , CHD 2 and CH 2 D;
  • the invention provides a pharmaceutical composition comprising a compound of the invention and a pharmaceutically acceptable excipient.
  • a compound of the invention is provided in the pharmaceutical composition in an effective amount.
  • the compounds of the invention are provided in a therapeutically effective amount.
  • the compounds of the invention are provided in a prophylactically effective amount.
  • the present invention provides a process for the preparation of a pharmaceutical composition as described above, comprising the steps of: mixing a pharmaceutically acceptable excipient with a compound of the present invention to form a pharmaceutical composition.
  • the invention is also a method of treating a disease mediated at least in part by JAK 2 comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the invention.
  • a compound of the invention in the manufacture of a medicament for the treatment of a disease mediated by JAK 2 in a subject in need thereof.
  • the compound is administered orally, subcutaneously, intravenously or intramuscularly.
  • the compound is administered chronically.
  • the JAK 2 mediated disease is selected from the group consisting of a myeloproliferative disorder, polycythemia vera, idiopathic thrombocytosis, myelofibrosis, any other bone marrow-related disorder, proliferative diabetic retinopathy, cancer , eye disease, inflammation, psoriasis, any disease or viral infection associated with angiogenesis.
  • deuterated means that one or more hydrogens in the compound or group are replaced by deuterium; deuteration may be monosubstituted, disubstituted, polysubstituted or fully substituted.
  • deuteration may be monosubstituted, disubstituted, polysubstituted or fully substituted.
  • deuterated is used interchangeably with “one or more deuterated”.
  • non-deuterated compound means a compound containing a proportion of germanium atoms not higher than the natural helium isotope content (0.015%).
  • the invention also includes isotopically labeled compounds, equivalent to the original compounds disclosed herein.
  • isotopes which may be listed as compounds of the present invention include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine isotopes such as 2 H, 3 H, 13 C, 14 C, 15 N, 17 O, 18 O, respectively. , 31 P, 32 P, 35 S, 18 F and 36 Cl. a compound, or an enantiomer, a diastereomer, an isomer, or a pharmaceutically acceptable salt or solvate of the present invention, wherein an isotope or other isotopic atom containing the above compound is within the scope of the present invention .
  • isotopically-labeled compounds of the present invention such as the radioisotopes of 3 H and 14 C, are also among them, useful in tissue distribution experiments of drugs and substrates. ⁇ , ie 3 H and carbon 14, ie 14 C, are easier to prepare and detect and are preferred in isotopes.
  • isotopically labeled compounds can be prepared in a conventional manner by substituting a readily available isotopically labeled reagent with a non-isotopic reagent using the protocol of the examples.
  • the compounds of the invention may include one or more asymmetric centers, and thus may exist in a variety of "stereoisomer" forms, for example, enantiomeric and/or diastereomeric forms.
  • the compounds of the invention may be in the form of individual enantiomers, diastereomers or geometric isomers (e.g., cis and trans isomers), or may be in the form of a mixture of stereoisomers, A racemic mixture and a mixture rich in one or more stereoisomers are included.
  • the isomers can be separated from the mixture by methods known to those skilled in the art, including: chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of a chiral salt; or preferred isomers can be passed Prepared by asymmetric synthesis.
  • HPLC high pressure liquid chromatography
  • compound of the invention refers to a compound of formula (I).
  • the term also encompasses pharmaceutically acceptable salts, prodrugs, hydrates or solvate compounds, N-oxides, crystal forms, stereoisomers, isotopic variations or various diastereomeric forms of the compounds of formula (I). Structure.
  • the term "pharmaceutically acceptable salt” means that, within the scope of sound medical judgment, it is suitable for contact with tissues of humans and lower animals without excessive toxicity, irritation, allergies, etc., and reasonable The benefits/hazard ratios are proportional to those salts.
  • Pharmaceutically acceptable salts are well known in the art. For example, Berge et al., pharmaceutically acceptable salts as described in detail in J. Pharmaceutical Sciences (1977) 66: 1-19.
  • Pharmaceutically acceptable salts of the compounds of the invention include those derived from suitable inorganic and organic acids and inorganic and organic bases.
  • suitable inorganic and organic acids and inorganic and organic bases include those derived from suitable inorganic and organic acids and inorganic and organic bases.
  • pharmaceutically acceptable non-toxic acid addition salts are salts with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid, or salts with organic acids such as acetic acid, oxalic acid, Maleic acid, tartaric acid, citric acid, succinic acid or malonic acid.
  • adipic acid salts alginate, ascorbate, aspartate, besylate, benzoate, disulfate, borate, butyrate, camphor Acid salt, camphor sulfonate, citrate, cyclopentanoate, digluconate, lauryl sulfate, ethanesulfonate, formate, fumarate, gluconate, glycerol Phosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate , malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate Salt, pectin
  • Pharmaceutically acceptable salts derived from suitable bases include the alkali metal, alkaline earth metal, ammonium and N + (C 1-4 alkyl) 4 salts.
  • Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium salts, and the like.
  • other pharmaceutically acceptable salts include non-toxic ammonium salts, quaternary ammonium salts and amine cations formed with counterions, counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, Nitrate, lower alkyl sulfonate and aryl sulfonate.
  • solvate refers to a complex of a compound of the invention that is coordinated to a solvent molecule to form a specific ratio.
  • Hydrophilate means a complex formed by the coordination of a compound of the invention with water.
  • prodrug includes a compound of the formula (I) which is biologically active or inactive, which, when taken by a suitable method, is metabolized or chemically reacted in the human body, or converted into a compound of the formula (I), or a formula a salt or solution of a compound of (I).
  • the prodrug includes, but is not limited to, the following compounds: an amino acid residue or a polypeptide chain consisting of one or more (eg, 2, 3 or 4) amino acid residues covalently linked by an amide or ester linkage in the present invention The free amino, hydroxyl or carboxyl group of the compound.
  • Amino acid residues include, but are not limited to, 20 natural amino acids usually represented by 3 letter symbols, but also 4-hydroxyproline, hydroxyl lysine, Demosine, isodemosine, 3-methylhistidine, n-amylamine Acid, ornithine and azide sulfones.
  • Other types of prodrugs are also included.
  • a free carboxyl group can be derivatized as an amide or an alkyl ester.
  • free hydroxyl groups are derivatized by the use of groups including, but not limited to, hemisuccinates, phosphates, dimethylaminoacetates, and phosphoryl groups. Oxymethoxymethyl group.
  • Hydroxyl and amino carbamate prodrugs as well as hydroxy carbonate prodrugs, sulfonates and sulfates, are also included. Also included are derivatized hydroxyl groups such as (acyloxy)methyl and (acyloxy)ethyl ethers, wherein the acyl group can be an alkyl ester, optionally including, but not limited to, ether, amine, and carboxylic acid functional groups. The group is substituted, or wherein the acyl group is an amino acid ester as described above. Prodrugs of this type are described in the following literature: J. Med. Chem. 1996, 39, 10. Free presses can also be derivatized to amides, sulfonamides or phosphoramides. All of these other moieties can incorporate groups including, but not limited to, ether, amine, and carboxylic acid functional groups.
  • crystalline form refers to a different arrangement of chemical drug molecules, generally expressed as the presence of a pharmaceutical material in a solid state.
  • a drug may exist in a plurality of crystalline forms, and different crystal forms of the same drug may have different dissolution and absorption in the body, thereby affecting the dissolution and release of the formulation.
  • the term "subject” includes, but is not limited to, a human (ie, a male or female of any age group, eg, a pediatric subject (eg, an infant, a child, adolescent) or an adult subject (eg, Young adults, middle-aged adults or older adults) and/or non-human animals, for example, mammals, for example, primates (eg, cynomolgus monkeys, rhesus monkeys), cattle, pigs, horses , sheep, goats, rodents, cats and/or dogs.
  • the subject is a human.
  • the subject is a non-human animal.
  • treatment includes the effect of a subject having a particular disease, disorder, or condition that reduces the severity of the disease, disorder, or condition, or delays or slows the disease, disorder. Or the development of a condition ("therapeutic treatment"), but also the effect that occurs before the subject begins to have a particular disease, disorder or disease (“prophylactic treatment”).
  • an "effective amount" of a compound refers to an amount sufficient to cause a target biological response.
  • an effective amount of a compound of the invention can vary depending on, for example, the biological target, the pharmacokinetics of the compound, the condition being treated, the mode of administration, and the age of the subject. Health conditions and symptoms. Effective amounts include therapeutically and prophylactically effective amounts.
  • a “therapeutically effective amount” of a compound, as used herein, is a quantity sufficient to provide a therapeutic benefit, or one or more associated with a disease, disorder, or condition, in the course of treating a disease, disorder, or condition, unless otherwise stated. Symptoms are delayed or minimized.
  • a therapeutically effective amount of a compound refers to the amount of a therapeutic agent used alone or in combination with other therapies that provides a therapeutic benefit in the treatment of a disease, disorder or condition.
  • the term "therapeutically effective amount” can include an amount that improves overall treatment, reduces or avoids the symptoms or causes of a disease or condition, or enhances the therapeutic efficacy of other therapeutic agents.
  • a “prophylactically effective amount” of a compound is an amount sufficient to prevent a disease, disorder, or condition, or a quantity sufficient to prevent one or more symptoms associated with a disease, disorder, or condition, or to prevent disease, unless otherwise stated. The number of relapses of a disorder or condition.
  • a prophylactically effective amount of a compound refers to the amount of a therapeutic agent used alone or in combination with other agents that provides a prophylactic benefit in the prevention of a disease, disorder or condition.
  • the term “prophylactically effective amount” can include an amount that improves the overall amount of prevention, or enhances the prophylactic efficacy of other prophylactic agents.
  • Combination and related terms mean the simultaneous or sequential administration of a therapeutic agent of the invention.
  • a compound of the invention may be administered simultaneously or sequentially with another therapeutic agent in separate unit dosage forms, or together with another therapeutic agent in a single unit dosage form.
  • the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof, crystal form, N-oxide and various diastereomers:
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , Y 6 , Y 7 , Y 8 and Y 9 are each independently selected from hydrogen or hydrazine;
  • X 1 , X 2 , X 3 and X 4 are each independently selected from CH 3 , CD 3 , CHD 2 and CH 2 D;
  • the compound of the formula (I) contains at least one halogen atom, more preferably one germanium atom, more preferably two germanium atoms, more preferably three germanium atoms, more preferably four germanium atoms. More preferably five helium atoms, more preferably six helium atoms, more preferably seven helium atoms, more preferably eight helium atoms, more preferably nine helium atoms, more preferably ten helium atoms, more Preferably, the earth has eleven atoms, more preferably twelve helium atoms, more preferably thirteen helium atoms, and more preferably fourteen helium atoms.
  • the cerium isotope content of cerium in the deuterated position is at least 0.015%, preferably greater than 30%, more preferably greater than 50%, more preferably greater than 75%, more preferably greater than the natural strontium isotope content.
  • the ground is greater than 95%, more preferably greater than 99%.
  • the strontium isotope content in each deuterated position is at least 5%, preferably greater than 10%, more preferably more than 15%, more preferably more than 20%, more preferably more than 25%, more preferably more than 30%, more preferably more than 35%, more preferably more than 40%, more preferably more than 45 More preferably, more than 50%, more preferably more than 55%, more preferably more than 60%, more preferably more than 65%, more preferably more than 70%, more preferably more than 75%, more preferably more than 80% More preferably, it is
  • At least one of Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , Y 6 , Y 7 , Y 8 , Y 9 , X 1 , X 2 , X 3 and X 4 contains ruthenium, more preferably two ⁇ , preferably three ⁇ , preferably four ⁇ , more preferably five ⁇ , more preferably six ⁇ , more preferably seven ⁇ , more preferably eight ⁇ More preferably, nine contain sputum, more preferably ten sputum, more preferably eleven sputum, more preferably twelve sputum, more preferably thirteen sputum, more preferably fourteen ⁇ , preferably fifteen ⁇ , more preferably sixteen ⁇ , more preferably seventeen ⁇ , more preferably
  • the compound of the formula (I) contains at least one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, ten Three, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, twenty, twenty-one, twenty-two, twenty-three, twenty-four Twenty-five, twenty-six, twenty-seven, twenty-eight, twenty-nine, thirty, thirty-one, thirty-two, thirty-three atomic atoms.
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 and R 12 are each independently Selected from hydrogen or helium.
  • R 1 and R 2 are deuterium.
  • R 3 and R 4 are deuterium.
  • R 1 , R 2 , R 3 and R 4 are deuterium.
  • R 5 , R 6 , R 7 and R 8 are deuterium.
  • R 9 , R 10 , R 11 and R 12 are deuterium.
  • R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 and R 12 are deuterium.
  • X 1 , X 2 , X 3 and X 4 are each independently selected from the group consisting of CH 3 , CD 3 , CHD 2 and CH 2 D.
  • X 1 is CD 3 .
  • X 2 is CD 3 .
  • X 3 is CD 3 .
  • X 4 is CD 3 .
  • both X 1 and X 2 are CD 3 .
  • X 1 , X 2 and X 3 are both CD 3
  • Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , Y 6 , Y 7 , Y 8 and Y 9 are each independently selected from hydrogen or deuterium.
  • Y 5 is deuterium
  • One embodiment of the invention provides a compound of formula (II):
  • R 1 , R 2 are selected from the group consisting of ruthenium, R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 And Y 5 are each independently selected from hydrogen or hydrazine, and X 1 , X 2 , X 3 and X 4 are each independently selected from the group consisting of CH 3 , CD 3 , CHD 2 and CH 2 D.
  • R 1 , R 2 are selected from the group consisting of ruthenium, R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 and Y 5 , respectively.
  • R 1 , R 2 are selected from the group consisting of ruthenium, R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 and Y 5 , respectively.
  • Independently selected from hydrogen or hydrazine, X 1 , X 2 , X 3 and X 4 are each independently selected from CH 3 or CD 3 .
  • R 1 , R 2 , R 3 , R 4 are selected from the group consisting of ruthenium, R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 and Y 5 are each Independently selected from hydrogen or hydrazine, X 1 , X 2 , X 3 and X 4 are each independently selected from CH 3 or CD 3 .
  • Y 5 is selected from the group consisting of ruthenium, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 And R 12 are each independently selected from hydrogen or hydrazine, and X 1 , X 2 , X 3 and X 4 are each independently selected from the group consisting of CH 3 , CD 3 , CHD 2 and CH 2 D.
  • Y 5 is selected from the group consisting of ruthenium, each of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 and R 12 Independently selected from hydrogen or hydrazine, X 1 , X 2 , X 3 and X 4 are each independently selected from CH 3 or CD 3 .
  • Y 5 is selected from the group consisting of fluorene
  • X 4 is selected from the group consisting of CD 3 , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9.
  • R 10 , R 11 and R 12 are each independently selected from hydrogen or hydrazine
  • X 1 , X 2 and X 3 are each independently selected from the group consisting of CH 3 , CD 3 , CHD 2 and CH 2 D.
  • Y 5 is selected from the group consisting of ruthenium
  • X 4 is selected from the group consisting of CD 3
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 R 11 and R 12 are each independently selected from hydrogen or hydrazine
  • X 1 , X 2 and X 3 are each independently selected from CH 3 and CD 3 .
  • X 4 is selected from the group consisting of CD 3 , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 and Y 5 are each independently selected from hydrogen or hydrazine, and X 1 , X 2 and X 3 are each independently selected from CH 3 , CD 3 , CHD 2 and CH 2 D.
  • X 4 is selected from the group consisting of CD 3 , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 And Y 5 are each independently selected from hydrogen or hydrazine, and X 1 , X 2 and X 3 are each independently selected from CH 3 and CD 3 .
  • X 1 is selected from the group consisting of CD 3 , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 and Y 5 are each independently selected from hydrogen or hydrazine, and X 2 , X 3 and X 4 are each independently selected from the group consisting of CH 3 , CD 3 , CHD 2 and CH 2 D.
  • X 1 is selected from the group consisting of CD 3 , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 And Y 5 are each independently selected from hydrogen or hydrazine, and X 2 , X 3 and X 4 are each independently selected from CH 3 and CD 3 .
  • X 1 and X 3 are selected from CD 3 , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 and Y 5 are each independently selected from hydrogen or hydrazine, and X 2 and X 4 are each independently selected from the group consisting of CH 3 , CD 3 , CHD 2 and CH 2 D.
  • X 1 and X 3 are selected from the group consisting of CD 3 , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 R 12 and Y 5 are each independently selected from hydrogen or hydrazine, and X 3 and X 4 are each independently selected from CH 3 and CD 3 .
  • X 1 , X 2 and X 3 are selected from CD 3 , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 and Y 5 are each independently selected from hydrogen or hydrazine, and X 4 is each independently selected from the group consisting of CH 3 , CD 3 , CHD 2 and CH 2 D.
  • X 1 , X 2 and X 3 are selected from the group consisting of CD 3 , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 And R 11 , R 12 and Y 5 are each independently selected from hydrogen or hydrazine, and each of X 4 is independently selected from CH 3 and CD 3 .
  • R 5 , R 6 , R 7 or R 8 is selected from the group consisting of ruthenium, R 1 , R 2 , R 3 , R 4 , R 9 , R 10 , R 11 , R 12 And Y 5 are each independently selected from hydrogen or hydrazine, and X 1 , X 2 , X 3 and X 4 are each independently selected from the group consisting of CH 3 , CD 3 , CHD 2 and CH 2 D.
  • R 5 , R 6 , R 7 or R 8 is selected from the group consisting of ruthenium, each of R 1 , R 2 , R 3 , R 4 , R 9 , R 10 , R 11 , R 12 , Y 5 Independently selected from hydrogen or hydrazine, X 1 , X 2 , X 3 and X 4 are each independently selected from CH 3 and CD 3 .
  • R 9 , R 10 , R 11 and R 12 are selected from the group consisting of ruthenium, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 Or Y 5 are each independently selected from hydrogen or hydrazine, and X 1 , X 2 , X 3 and X 4 are each independently selected from CH 3 , CD 3 , CHD 2 and CH 2 D.
  • R 9 , R 10 , R 11 and R 12 are selected from the group consisting of ruthenium, each of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 or Y 5 Independently selected from hydrogen or hydrazine, X 1 , X 2 , X 3 and X 4 are each independently selected from CH 3 and CD 3 .
  • R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 and R 12 are selected from the group consisting of ruthenium, R 1 , R 2 , R 3 , R 4 Or Y 5 are each independently selected from hydrogen or hydrazine, and X 1 , X 2 , X 3 and X 4 are each independently selected from the group consisting of CH 3 , CD 3 , CHD 2 and CH 2 D.
  • R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 and R 12 are selected from the group consisting of ruthenium, each of R 1 , R 2 , R 3 , R 4 and Y 5 Independently selected from hydrogen or hydrazine, X 1 , X 2 , X 3 and X 4 are each independently selected from CH 3 and CD 3 .
  • the compound is selected from the group consisting of the compounds or pharmaceutically acceptable salts thereof:
  • the compound does not include a non-deuterated compound.
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the invention (also referred to as "active ingredient") and a pharmaceutically acceptable excipient.
  • the pharmaceutical composition comprises an effective amount of the active component.
  • the pharmaceutical composition comprises a therapeutically effective amount of the active component.
  • the pharmaceutical composition comprises a prophylactically effective amount of the active component.
  • compositions of the present invention comprise a safe or effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier.
  • safe and effective amount it is meant that the amount of the compound is sufficient to significantly improve the condition without causing serious side effects.
  • the pharmaceutical compositions contain from 0.5 to 2000 mg of the compound of the invention per agent, more preferably from 1 to 500 mg of the compound of the invention per agent.
  • the "one dose" is a capsule or tablet.
  • “Pharmaceutically acceptable excipient” means a non-toxic carrier, adjuvant or vehicle that does not destroy the pharmacological activity of the compound formulated together.
  • Pharmaceutically acceptable carriers, adjuvants, or vehicles that can be used in the compositions of the present invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (eg, human serum albumin) ), buffer substances (such as phosphate), glycine, sorbic acid, potassium sorbate, a mixture of partial glycerides of saturated plant fatty acids, water, salt or electrolyte (such as protamine sulfate), disodium hydrogen phosphate, potassium hydrogen phosphate, Sodium chloride, zinc salt, silica gel, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based material, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylate, wax, polyethylene-polyoxypropylene-embedded Seg
  • compositions of the present invention can be prepared by combining the compounds of the present invention with suitable pharmaceutically acceptable excipients, for example, as solid, semi-solid, liquid or gaseous preparations such as tablets, pills, capsules. , powders, granules, ointments, emulsions, suspensions, solutions, suppositories, injections, inhalants, gels, microspheres and aerosols.
  • suitable pharmaceutically acceptable excipients for example, as solid, semi-solid, liquid or gaseous preparations such as tablets, pills, capsules. , powders, granules, ointments, emulsions, suspensions, solutions, suppositories, injections, inhalants, gels, microspheres and aerosols.
  • Typical routes of administration of a compound of the invention or a pharmaceutical composition thereof include, but are not limited to, oral, rectal, transmucosal, enteral administration, or topical, transdermal, inhalation, parenteral, sublingual, intravaginal, intranasal, ocular Internal, intramuscular, intramuscular, subcutaneous, intravenous administration.
  • the pharmaceutical composition of the present invention can be produced by a method well known in the art, such as a conventional mixing method, a dissolution method, a granulation method, a drag coating method, a grinding method, an emulsification method, a freeze drying method, and the like.
  • the pharmaceutical composition can be formulated by mixing the active compound with pharmaceutically acceptable excipients which are well known in the art. These excipients enable the compounds of the present invention to be formulated into tablets, pills, troches, dragees, capsules, liquids, gels, slurries, suspensions and the like for oral administration to a patient.
  • Solid oral compositions can be prepared by conventional methods of mixing, filling or tabletting. For example, it can be obtained by mixing the active compound with a solid excipient, optionally milling the resulting mixture, adding other suitable adjuvants if necessary, and then processing the mixture into granules. The core of a tablet or dragee.
  • Suitable excipients include, but are not limited to, binders, diluents, disintegrants, lubricants, glidants, sweeteners or flavoring agents, and the like.
  • microcrystalline cellulose glucose solution, gum arabic, gelatin solution, sucrose and starch paste; talc, starch, calcium stearate or stearic acid; lactose, sucrose, starch, mannitol, sorbitol or phosphoric acid Calcium; silica; cross-linked hydroxymethylcellulose sodium, pre-treated starch, sodium starch glycolate, alginic acid, corn starch, potato starch, methyl cellulose, agar, hydroxymethyl cellulose, cross-linked poly Vinyl pyrrolidone and the like.
  • the core of the dragee may optionally be coated according to methods well known in the ordinary pharmaceutical practice, especially using enteric coatings.
  • compositions may also be suitable for parenteral administration, such as sterile solutions, suspensions or lyophilized products in a suitable unit dosage form.
  • suitable excipients such as fillers, buffers or surfactants can be used.
  • the compounds of the invention may be administered by any route and method of administration, for example by oral or parenteral (e.g., intravenous) administration.
  • a therapeutically effective amount of a compound of the invention is from about 0.0001 to 20 mg/kg body weight per day, such as from 0.001 to 10 mg/kg body weight per day.
  • the dosage frequency of the compounds of the invention is determined by the needs of the individual patient, for example, once or twice daily, or more times per day. Administration may be intermittent, for example, wherein the patient receives a daily dose of a compound of the invention over a period of several days, followed by a patient's daily dose of the compound of the invention for a period of several days or more. .
  • the compounds of the invention exhibit JAK2 protein tyrosine kinase inhibition, and the compounds are useful in the treatment of various diseases, either alone or in combination with other active agents, such as the chemotherapeutic or protein therapeutics described below, including, but not limited to: For example, bone marrow tissue proliferative disorders, proliferative diabetic retinopathy and other conditions associated with the formation of blood vessels, including solid tumors and other types of cancer, eye diseases, inflammation, psoriasis and viral infections.
  • Types of cancer that can be treated include, but are not limited to, digestive/gastrointestinal cancer, colon cancer, liver cancer, skin cancer, breast cancer, ovarian cancer, prostate cancer, lymphoma, leukemia (including acute myeloid leukemia and chronic myelogenous leukemia), kidney Cancer, lung cancer, muscle cancer, bone cancer, bladder cancer or brain cancer.
  • digestive/gastrointestinal cancer colon cancer
  • liver cancer skin cancer
  • breast cancer ovarian cancer
  • prostate cancer lymphoma
  • leukemia including acute myeloid leukemia and chronic myelogenous leukemia
  • kidney Cancer including acute myeloid leukemia and chronic myelogenous leukemia
  • lung cancer muscle cancer
  • bone cancer bone cancer
  • bladder cancer or brain cancer.
  • diseases and conditions that can be treated include ocular neovascularization, infant hemangioma; organ hypoxia, vascular proliferation, organ transplant rejection, lupus, multiple sclerosis, rheumatoid arthritis, psoriasis, 1 Type 2 diabetes and complications caused by diabetes, inflammatory diseases, acute pancreatitis, chronic pancreatitis, asthma, rhinitis, atopic dermatitis, autoimmune thyroid disease, ulcerative colitis, Crohn's disease, metastatic black Oncoma, Kaposi's sarcoma, multiple myeloma, cytokine-related disorders and other autoimmune gastritis, autoimmune hemolytic disease, autoimmune neutropenia, thrombocytopenia, atopy
  • allergic asthma, atopic dermatitis or allergic rhinitis chronic active hepatitis, myasthenia gravis, multiple sclerosis, inflammatory bowel disease, graft versus host disease, neurodegenerative diseases,
  • Examples of certain additional diseases and conditions that can be treated include cell-mediated hypersensitivity (allergic contact dermatitis, hypersensitivity pneumonitis), rheumatic diseases (eg, systemic lupus erythematosus, rheumatoid arthritis, juvenile joints) Inflammation, Sjogren's syndrome, scleroderma, polymyositis, ankylosing spondylitis, psoriatic arthritis), viral disease (EB virus, hepatitis B, hepatitis C, HIV, HTLV1, chickenpox - ribbon) Herpes virus, human papillomavirus), food allergies, skin inflammation and immunosuppression induced by solid tumors.
  • cell-mediated hypersensitivity allergic contact dermatitis, hypersensitivity pneumonitis
  • rheumatic diseases eg, systemic lupus erythematosus, rheumatoid arthritis, juvenile joints
  • Inflammation Sjogren's syndrome, scleroderma,
  • the compounds of the invention or the compositions described can be used to treat primary myelofibrosis. In some embodiments, the compounds of the invention or the compositions described are useful for treating myelofibrosis following polycythemia vera. In some embodiments, the compounds of the invention or the compositions described are useful for treating myelofibrosis following idiopathic thrombocythemia. In some embodiments, the compounds of the invention or the compositions described can be used to treat high-risk myelofibrosis. In some embodiments, a compound of the invention or the composition described can be used to treat a moderate risk of myelofibrosis (eg, a moderate risk level 2).
  • a moderate risk of myelofibrosis eg, a moderate risk level 2.
  • the compounds of the invention are useful for treating mutations in the mutation of valine 617 to phenylalanine (ie, V617F) of JAK 2 to positive for myelofibrosis. In some embodiments, the compounds of the invention are useful for treating mutations in the mutation of valine 617 to phenylalanine (ie, V617F) of JAK 2 to negative myelofibrosis.
  • the compounds of the invention are administered to a subject in need of such treatment with an anti-inflammatory, antihistamine, chemotherapeutic, immunomodulatory, therapeutic antibody or protein kinase inhibitor, such as a tyrosine kinase inhibitor.
  • chemotherapeutic agents include antimetabolites such as methotrexate, DNA crosslinkers such as cisplatin/carboplatin; alkylating agents such as canbusil; topoisomerase I inhibitors such as dactinomycin Microtubule inhibitors such as Taxol (paclitaxol) and the like.
  • chemotherapeutic agents include, for example, vinca alkaloids, mitomycin-like antibiotics, bleomycin-like antibiotics, antifolates, colchicine, demecoline, etoposide, taxanes, anthracyclines , doxorubicin, daunorubicin, erythromycin, epirubicin, idarubicin, mitoxanthrone, 4-dimethoxy-danomycin, 11-deoxyred red ,13-deoxydaunorubicin, doxorubicin-14-benzoate, doxorubicin-14-octanoate, doxorubicin-14-naphthyl acetate, ampicillin, carmust Tetamine, cyclophosphamide, cytarabine, etoposide, lovastatin, melphalan, topotecan, oxalaplatin, chlorambucil, methotrexate Methtrexate),
  • therapeutic antibodies include antibodies directed against the HER2 protein, such as trastuzumab; antibodies directed to growth factors or growth factor receptors, such as bevacizumab and targets targeting vascular endothelial growth factor.
  • OSI-774 to epidermal growth factor; an antibody that targets the integrin receptor, such as Vitaxin (also known as MEDI-522) and the like.
  • Types of anticancer drugs suitable for use in the compositions and methods of the invention include, but are not limited to: 1) alkaloids, including microtubule inhibitors (eg, vincristine, vinblastine, and vindesine, etc.), microtubule stabilizers (eg, Paclitaxel [taxol] and docetaxel, taxotere, etc.) and chromatin function inhibitors, including topoisomerase inhibitors, such as epipodophyllotoxin (eg, etoposide [VP-16] and teniposide Glycosides [VM-26], etc.
  • alkaloids including microtubule inhibitors (eg, vincristine, vinblastine, and vindesine, etc.), microtubule stabilizers (eg, Paclitaxel [taxol] and docetaxel, taxotere, etc.) and chromatin function inhibitors, including topoisomerase inhibitors, such as epipodophyllotoxin (eg, etopo
  • topoisomerase I eg, camptothecin and irinotecan [CPT-11], etc.
  • covalent DNA-binding agents include nitrogen mustard (eg, nitrogen mustard, chlorambucil, cyclophosphamide, ifosfamide, and busulfan [Maliland], etc.), nitrosoureas (eg, carmustine, lovastatin) And other alkylating agents (such as dacarbazine, methylol melamine, thiotepa and Mitocycin, etc.); 3) non-covalent DNA-binding agents [antitumor antibiotics], including nucleic acids Inhibitors (eg actinomycin D [actinomycin D], etc.), anthracyclines (eg daunorubicin [danomycin and n-mycin], doxorubicin [doxorubicin] and Darbystar [demethoxydaun
  • nucleic acids Inhibitors eg
  • interleukin eg IL-2, etc.
  • IL-2 interleukin-2
  • 10) adoptive immunotherapy 11) hematopoietic growth factors; 12) active agents that induce tumor cell differentiation ( For example, all-trans retinoic acid, etc.); 13) gene therapy techniques; 14) antisense therapy techniques; 15) tumor vaccines; 16) metastase-directed therapies (eg, Batimistat et al); and 17) angiogenesis inhibitors.
  • compositions and methods of the present invention may further comprise other therapeutically active compounds as described herein which are commonly employed in the treatment of the above mentioned pathologies.
  • other therapeutic agents include the following: cyclosporins (e.g., cyclosporin A); CTLA4-Ig; antibodies such as ICAM-3, anti-IL-2 receptor (anti-Tac), anti-CD45RB, anti- -CD2, anti-CD3 (OKT-3), anti-CD4, anti-CD80, anti-CD86; an agent that blocks the interaction of CD40 with gp39, such as an antibody specific for CD40 and/or gp39 (ie CD154) , fusion proteins constructed by CD40 and gp39 (CD40Ig and CD8gp39), inhibitors of NF- ⁇ B function, such as nuclear translocation inhibitors, such as deoxyspermectin (DSG); cholesterol biosynthesis inhibitors, such as HMG CoA reduction Enzyme inhibitors (lovastatin and simvastatin); non-steroidal anti-
  • cytokine as used herein includes chemokines, interleukins, lymphokines, mononuclear factors, colony stimulating factors and receptor-associated proteins and functional fragments thereof.
  • functional fragment as used herein means a polypeptide or peptide having biological function or activity identified by a defined functional assay.
  • Cytokines include endothelial mononuclear cell activated polypeptide II (EMAP-II), granulocyte-macrophage-CSF (GM-CSF), granulocyte-CSF (G-CSF), macrophage-CSF (M-CSF) , IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-12 and IL-13, interferons, etc. and with specific biology, morphology or morphology in cellular or cellular mechanisms Phenotypic changes are related.
  • EAP-II endothelial mononuclear cell activated polypeptide II
  • GM-CSF granulocyte-macrophage-CSF
  • G-CSF granulocyte-CSF
  • M-CSF macrophage-CSF
  • a suitable dosage level is generally from about 0.01 to about 1000 mg per 1 kg of patient body weight per day, which may be administered in single or multiple doses.
  • the dosage level can range from about 0.01 to about 250 mg/kg/day; more narrowly from about 0.5 to about 100 mg/kg/day.
  • Suitable dosage levels can range from about 0.01 to about 250 mg/kg/day, from about 0.05 to about 100 mg/kg/day or from about 0.1 to about 50 mg/kg/day or about 1.0 mg/kg/day.
  • the dosage can be from about 0.05 to about 0.5 mg/kg/day or from about 0.5 to about 5 mg/kg/day or from about 5 to about 50 mg/kg/day.
  • compositions are formulated to comprise from about 1.0 to about 1,000 mg of the active ingredient, for example, about 1.0, about 5.0, about 10.0, about 15.0, about 20.0, about 25.0, about 50.0, about 75.0, about 100.0 about 150.0, about 200.0, about 250.0, about 300.0, about 400.0, about 500.0, about 600.0, about 750.0, about 800.0, about 900.0 and about 1,000.0 mg of the active ingredient in tablet form to adjust for the symptoms of the patient being treated The dose.
  • the compound can be administered in a regimen of from 1 to 4 times per day, such as once or twice per day. There may be periods of no dosing followed by another dosing regimen.
  • the particular dosage level and dosage frequency for any particular patient may vary, and depending on various factors, including the activity of the particular compound employed, the metabolic stability and duration of action of the compound, age, weight, general health, Gender, diet, mode of administration and timing, rate of excretion, combination of drugs, severity of the specific condition, and ongoing therapy by the host.
  • the compounds of the invention may be used alone or in combination with an effective amount of a therapeutic antibody (or a therapeutic fragment thereof), a chemotherapeutic agent or an immunotoxic agent to treat a tumor.
  • chemotherapeutic agents that can be used for this purpose include doxorubicin, docetaxel or taxol.
  • combination therapies comprising a compound of the invention, including, but not limited to, vasculostatic agents, such as tyrosine, serine or threonine kinase inhibitors, and any chemotherapeutic or therapeutic antibody.
  • the compounds of the present invention have a number of advantages over non-deuterated compounds known in the art.
  • Advantages of the present invention include: First, the compounds and compositions employing the technical solutions of the present invention provide a more advantageous therapeutic tool for the treatment of JAK2-mediated diseases. Second, the metabolism of the compound in the organism is improved, giving the compound better pharmacokinetic parameter characteristics. In this case, the dosage can be changed and a long-acting preparation can be formed to improve the applicability. Third, the drug concentration of the compound in the animal is increased, and the drug efficacy is improved. Fourth, certain metabolites are inhibited and the safety of the compounds is increased.
  • each reaction is usually carried out in an inert solvent at room temperature to reflux temperature (e.g., 0 ° C to 100 ° C, preferably 0 ° C to 80 ° C).
  • the reaction time is usually from 0.1 to 60 hours, preferably from 0.5 to 24 hours.
  • JAK2, JAK2/V617F, ATP (Sigma, Cat. No. A7699-1G), DMSO (Sigma, Cat. No. D2650), 96-well plate (Corning, Cat. No. 3365), 384-well plate (Greiner, Cat. No. 784076), HTRF Kinase TK kit (Cisbio), 5x Kinase Buffer A (Life Technologies, Cat. No. PV3186), Kinase Tracer 199 (Life Technologies, Cat. No. PV5830), Eu-anti-GST antibody (Life Technologies, catalog number PV5594).
  • test compound was dissolved in DMSO to make a 20 mM mother liquor. Then, it was diluted 3 times in a medium gradient of DMSO and diluted 10 times. When dosing, dilute with buffer for 10 times.
  • JAK2 and JAK2 [V617F] Kinase Assay JAK2 or JAK2 [V617F] kinase was mixed with pre-diluted compounds of different concentrations in 5x Kinase Buffer A for 10 minutes at each concentration. The corresponding substrate and ATP were added and reacted at room temperature for 20 minutes (in which a negative positive control was set: a negative blank control and a positive erlotinib).
  • the detection reagent (the reagent in the HTRF Kinase TK kit) was added, and after incubation at room temperature for 30 minutes, the enzyme activity in the presence of the compound of the present invention at each concentration was measured by an Evnvision microplate reader, and the compound concentrations of different concentrations were calculated.
  • the inhibitory activity of the enzyme activity was then fitted according to the four-parameter equation, and the inhibitory activity of the enzyme activity under different concentrations of the compound was fitted according to Graphpad 5.0 software, and the IC 50 value was calculated.
  • the compound of the present invention and the undeuterated compound Fedratinib were tested in the above kinase inhibition assay, and the compounds of the present invention were found to have potent or comparable activities against JAK2 kinase and JAK2/V617F kinase.
  • the results of inhibition of kinase by representative example compounds are summarized in Table 1 below.
  • Example compound JAK2 IC 50 (nM) JAK2/V617F IC 50 (nM) Fedratinib 3.08 4.05 T-1 3.16 4.06 T-2 2.89 3.69 T-3 3.06 3.78 T-4 3.24 4.05 T-5 3.47 4.55
  • RPMI-1640 medium (GIBCO, catalog number A10491-01), fetal bovine serum (GIBCO, catalog number 10099-141), antibiotics (GIBCO, catalog number 10010-031), IL-3 (CST, catalog No. 8923SF), phosphate buffer solution PBS (GIBCO, catalog number 10010-0312), penicillin-streptomycin (GIBCO, catalog number 15140-122);
  • the compound of the present invention and the undeuterated compound Fedratinib were tested in the above cytotoxicity assay, and the compounds of the present invention were found to have potent or comparable activities against BaF3-EpoR-JAK2 cells and BaF3-EpoR-JAK2/V617F cells.
  • the results of inhibition of in vitro proliferation of cancer cells by representative example compounds are summarized in Table 2 below.
  • Microsomal experiments human liver microsomes: 0.5 mg/mL, Xenotech; rat liver microsomes: 0.5 mg/mL, Xenotech; mouse liver microsomes: 0.5 mg/mL, Xenotech; coenzyme (NADPH/NADH): 1 mM , Sigma Life Science; magnesium chloride: 5 mM, 100 mM phosphate buffer (pH 7.4).
  • phosphate buffer 100 mM, pH 7.4.
  • the pH of the solution was adjusted to 7.4, diluted 5 times with ultrapure water before use, and magnesium chloride was added to obtain a phosphate buffer (100 mM) containing 100 mM potassium phosphate, 3.3 mM magnesium chloride, and a pH of 7.4.
  • NADPH regeneration system containing 6.5 mM NADP, 16.5 mM G-6-P, 3 U/mL G-6-P D, 3.3 mM magnesium chloride was prepared and placed on wet ice before use.
  • the corresponding compound had a reaction concentration of 1 ⁇ M and a protein concentration of 0.5 mg/mL.
  • 100 ⁇ L of the reaction solution was taken at 10, 30, and 90 min, respectively, and added to the stopper, and the reaction was terminated by vortexing for 3 min.
  • the plate was centrifuged at 5000 x g for 10 min at 4 °C.
  • 100 ⁇ L of the supernatant was taken into a 96-well plate to which 100 ⁇ L of distilled water was previously added, mixed, and sample analysis was performed by LC-MS/MS.
  • the compound of the present invention and the undeuterated compound Fedratinib were tested in the above metabolic stability evaluation experiment, and the compound of the present invention was found to have a longer half-life and a shorter clearance rate, and more excellent metabolic stability.
  • the metabolic stability results of representative example compounds are summarized in Table 3.
  • Rats were fed a standard diet and given water. Fasting began 16 hours before the test.
  • the drug was dissolved with PEG400 and dimethyl sulfoxide. Blood was collected from the eyelids at a time point of 0.083 hours, 0.25 hours, 0.5 hours, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 12 hours, and 24 hours after administration.
  • Rats were briefly anesthetized after inhalation of ether, and 300 ⁇ L of blood samples were collected from the eyelids in test tubes. There was 30 ⁇ L of 1% heparin salt solution in the test tube. The tubes were dried overnight at 60 ° C before use. After the blood sample collection was completed at the last time point, the rats were anesthetized with ether and sacrificed.
  • Plasma samples were centrifuged at 5000 rpm for 5 minutes at 4 ° C to separate plasma from red blood cells. Pipette 100 ⁇ L of plasma into a clean plastic centrifuge tube, indicating the name and time of the compound. Plasma was stored at -80 °C prior to analysis. The concentration of the compound of the invention in plasma was determined by LC-MS/MS. Pharmacokinetic parameters were calculated based on the plasma concentration of each animal at different time points.
  • the compound of the present invention and the undeuterated compound Fedratinib were tested in the above rat pharmacokinetic experiments, and the compounds of the present invention were found to have better oral availability.
  • the oral availability results for the representative example compounds are summarized in Table 4.

Abstract

本发明提供了一种取代的二苯氨基嘧啶类化合物的药物组合物及其用途，所述的化合物如式(I)所示化合物，或其药学上可接受的盐、前药、水合物或溶剂化合物、晶型、N-氧化物和各种非对映体。本发明化合物可用于治疗可用JAK2激酶抑制剂治疗的疾病。

Description

用于抑制激酶活性的二苯氨基嘧啶类化合物 技术领域
本发明属于医药技术领域，尤其涉及一种取代的二苯氨基嘧啶类化合物及包含该化合物的组合物及其用途。更具体而言，本发明涉及某些氘取代的N-(叔丁基)-3-((5-甲基-2-((4-(2-(吡咯烷-1-基)乙氧基)苯基)氨基)嘧啶-4-基)氨基)苯磺酰胺，这些氘取代的化合物显示JAK2蛋白酪氨酸激酶抑制，且可用于治疗JAK2激酶介导疾病的用途，且这些氘取代的化合物具有更优良的药代动力学性质。
背景技术
JAK家族细胞蛋白酪氨酸酶包括JAK 1～JAK 3和TYK 2四个激酶亚型，这四个家族成员具有高度同源性。它们从羧基末端(C端)到氨基末端(N端)有着七个同源域(JAK homology domain,JH)，通常又被划分成为四个功能结构域。其中JH1是活性激酶催化结构域，而JH 2结构区是JAK家族特有的区域，被称为假激酶结构域或伪激酶域，虽然它无催化功能，但能通过协作发挥不可或缺的关键调节作用，JH 3和JH 4组成的SH 2结构域主要是在激酶结构上起着稳定JAK的作用，而JH 5～JH 7部分(FERM结构域)则与细胞因子受体的细胞内结构直接相互作用，也与JH1结构域有着相互作用。
其中，JAK 2在JAK家族中有着独特的细胞因子谱，它除了可以被g链(gc)家族细胞因子激活外，也可以被许多其它细胞因子(如bc家族细胞因子，***和血小板生成素等血液相关细胞因子)激活，它的活性对于造血这一过程是必不可少的。因此，JAK2可以影响有***(EPO)和粒细胞-巨噬细胞集落刺激因子(GM-CSF)等调节的一些基本功能，与真性红细胞增多症(PV)、贫血、原发性血小板增多(ET)等血液疾病息息相关。若其严重损伤则对生物体有着致死性的威胁。
已经证实JAK途径可在细胞存活和增殖中得到补充。例如，就为导致慢性髓性白血病(CML)的费城染色体阳性的细胞而言，存在JAK 2途径在组成型活化中得到补充的证据。因此，使用JAK2抑制剂可以应用于CML，其中已经证实费城染色体产生杂种Bcr-Abl，由此保持细胞的组成型活性。
更显著地在于就基于BCR-ABL特异性抑制剂产生的抗性突变而言，如就T315I看门基因突变 或任何其它突变而言，可能使用基于JAK 2途径的BCR-ABL突变体(如就BCR-ABL(T315I)突变而言)的JAK 2抑制剂。因此，JAK 2抑制剂可以用于治疗具有对已知疗法产生抗性的患者，其中直接靶向BCR-ABL，并且目前已经将抗药性证实为现存疗法失败的患者中的所有抗性中占主导的(50％-90％)。
因此，由于可利用治疗上述JAK 2信号传导途径失调或得到直接或简介补充的疾病的疗法不足，所以对研发用作激酶，特别是JAK 2激酶的抑制剂的化合物存在需求。
Fedratinib(SAR-302503,TG-101348)由TargeGene公司研发的，在2010年被赛诺菲(Sanofi)收购，并将Fedratinib推进到了晚期临床阶段，后来该药被一家创业公司Impact生物医药公司接手继续开发，目前该公司已被新基(Celgene)收购。Fedratinib是一款高度选择性的JAK 2蛋白激酶口服抑制剂，化学名为(N-(叔丁基)-3-((5-甲基-2-((4-(2-(吡咯烷-1-基)乙氧基)苯基)氨基)嘧啶-4-基)氨基)苯磺酰胺。Fedratinib的临床适应症为骨髓纤维化(MF)和真性红细胞增多症(PV)，临床早期表现出非常优异的临床收益，但是2013年，Fedratinib被发现出严重的神经***副作用。
因此，本领域仍需开发对适用作治疗剂的JAK 2激酶介导疾病具有选择性抑制活性或更好地药效学/药代动力学的化合物。本发明提供一款新型的以Fedratinib为母体化合物进行氘代修饰的JAK2抑制剂，通过氘代策略降低或消除不希望的代谢物；增加母体化合物的半衰期；减少实现所希望的效果所需要的剂量数目；减少实现所希望的效果所需要的剂量数量；增加活性代谢物的形成(如果形成的话)；减少在特定组织中有害代谢物的产生；产生对于多重用药而言更有效的药物和/或更安全的药物(不论该多重用药是否有意向的)。
发明概述
针对以上技术问题，本发明公开了一种新的氘取代的二苯基嘧啶类化合物及其组合物和用途，其具有更好地JAK2激酶和JAK2/V617F激酶抑制活性、更低的副作用、更好地药效学/药代动力学性能，可用于治疗JAK2激酶介导的疾病。
对此，本发明采用以下技术方案：
本发明的第一方面，提供了式(I)化合物：
Figure PCTCN2018109043-appb-000001
Figure PCTCN2018109043-appb-000002
其中，
R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8、R 9、R 10、R 11、R 12、Y 1、Y 2、Y 3、Y 4、Y 5、Y 6、Y 7、Y 8和Y 9各自独立地选自自氢或氘；
X 1、X 2、X 3和X 4各自独立地选自CH 3、CD 3、CHD 2和CH 2D；
条件是如果X 1、X 2、X 3和X 4每个都是CH 3，那么R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8、R 9、R 10、R 11、R 12、Y 1、Y 2、Y 3、Y 4、Y 5、Y 6、Y 7、Y 8和Y 9中至少一个是氘。
在另一方面，本发明提供了含有本发明化合物和药学上可接受的赋形剂的药物组合物。在具体实施方案中，本发明化合物以有效量提供在所述药物组合物中。在具体实施方案中，本发明化合物以治疗有效量提供。在具体实施方案中，本发明化合物以预防有效量提供。
在另一方面，本发明提供了一种如上所述的药物组合物的制备方法，包括以下步骤：将药学上可接受的赋形剂与本发明化合物进行混合，从而形成药物组合物。
在另一方面，本发明还涉及治疗至少部分由JAK 2介导的疾病的方法，包括向需要的受试者给药治疗有效剂量的本发明化合物。在具体实施方案包括本发明化合物在制备用于需要的受试者中治疗由JAK 2介导的疾病的药物中的用途。在具体实施方案包括本发明化合物在制备用于需要的受试者中治疗由JAK2/V617F介导的疾病的药物中的用途。在具体实施方案中，口服、皮下、静脉内或肌肉内给药所述化合物。在具体实施方案中，长期给药所述化合物。在具体的实施方案中，JAK 2介导的疾病选自骨髓组织增殖病症，真性红细胞增多症，特发性血小板增多，骨髓纤维化，任何其它与骨髓相关的病症，增生型糖尿病视网膜病变，癌症，眼病，炎症，银屑病，与血管发生相关的任何疾病或病毒感染。
由随后的具体实施方式、实施例和权利要求，本发明的其它目的和优点将对于本领域技术人员显而易见。
发明详述
术语和定义
本文中，如无特别说明，“氘代”指化合物或基团中的一个或多个氢被氘所取代；氘代可以是一取代、二取代、多取代或全取代。术语“一个或多个氘代的”与“一次或多次氘代”可互换使用。
本文中，如无特别说明，“非氘代的化合物”是指含氘原子比例不高于天然氘同位素含量(0.015％)的化合物。
本发明还包括同位素标记的化合物，等同于原始化合物在此公开。可以列为本发明的化合物同位素的例子包括氢，碳，氮，氧，磷，硫，氟和氯同位素，分别如 2H， 3H， 13C， 14C， 15N， 17O， 18O， 31P， 32P， 35S， 18F以及 36Cl。本发明中的化合物，或对映体，非对映体，异构体，或药学上可接受的盐或溶剂化物，其中含有上述化合物的同位素或其他其他同位素原子都在本发明的范围之内。本发明中某些同位素标记化合物，例如 3H和 14C的放射性同位素也在其中，在药物和底物的组织分布实验中是有用的。氚，即 3H和碳14，即 14C，它们的制备和检测比较容易，是同位素中的首选。同位素标记的化合物可以用一般的方法，通过用易得的同位素标记试剂替换为非同位素的试剂，用示例中的方案可以制备。
本发明化合物可包括一个或多个不对称中心，且因此可以存在多种“立体异构体”形式，例如，对映异构体和/或非对映异构体形式。例如，本发明化合物可为单独的对映异构体、非对映异构体或几何异构体(例如顺式和反式异构体)，或者可为立体异构体的混合物的形式，包括外消旋混合物和富含一种或多种立体异构体的混合物。异构体可通过本领域技术人员已知的方法从混合物中分离，所述方法包括：手性高压液相色谱法(HPLC)以及手性盐的形成和结晶；或者优选的异构体可通过不对称合成来制备。
如本文所用，术语“本发明化合物”指式(I)所示的化合物。该术语还包括及式(I)化合物的药学上可接受的盐、前药、水合物或溶剂化合物、N-氧化物、晶型、立体异构体、同位素变体或各种非对映异构体。
如本文所用，术语“药学上可接受的盐”是指，在可靠的医学判断范围内，适合与人和低等动物的组织接触而没有过度毒性、刺激性、***反应等等，并且与合理的益处/危险比例相称的那些盐。药学上可接受的盐在本领域是众所周知的。例如，Berge等人在J.Pharmaceutical Sciences(1977)66:1-19中详细描述的药学上可接受的盐。
本发明化合物的药学上可接受的盐包括衍生自合适的无机和有机酸和无机和有机碱的盐。药学上可接受的无毒的酸加成盐的实例是与无机酸形成的盐，例如盐酸、氢溴酸、磷酸、硫酸和高氯酸，或与有机酸形成的盐，例如乙酸、草酸、马来酸、酒石酸、枸橼酸、琥珀酸或丙二酸。也包括使用本领域常规方法形成的盐，例如，离子交换方法。其它药学上可接受的盐包括：已二酸盐、海藻酸盐、抗坏血酸盐、天冬氨酸盐、苯磺酸盐、苯甲酸盐、重硫酸盐、硼酸盐、丁酸盐、樟脑酸盐、樟脑磺酸盐、柠檬酸盐、环戊丙酸盐、二葡糖酸盐、十二烷基硫酸盐、乙磺酸盐、甲酸盐、富马酸盐、葡萄糖酸盐、甘油磷酸盐、葡糖酸盐、半硫酸盐、庚酸盐、己酸盐、氢碘酸盐、2-羟基-乙磺酸盐、乳糖酸盐、乳酸盐、月桂酸盐、月桂基硫酸盐、苹果酸盐、马来酸盐、丙二酸盐、甲磺酸盐、2-萘 磺酸盐、烟酸盐、硝酸盐、油酸盐、草酸盐、棕榈酸盐、双羟萘酸盐、果胶酯酸盐、过硫酸盐、3-苯丙酸盐、磷酸盐、苦味酸盐、特戊酸盐、丙酸盐、硬脂酸盐、琥珀酸盐、硫酸盐、酒石酸盐、硫氰酸盐、对甲苯磺酸盐、十一烷酸盐、戊酸盐，等等。衍生自合适的碱的药学上可接受的盐包括碱金属、碱土金属、铵和N +(C 1-4烷基) 4盐。代表性的碱金属或碱土金属盐包括钠、锂、钾、钙、镁盐，等等。如果合适的话，其它的药学上可接受的盐包括与反离子形成的无毒的铵盐、季铵盐和胺阳离子，反离子例如卤离子、氢氧根、羧酸根、硫酸根、磷酸根、硝酸根、低级烷基磺酸根和芳基磺酸根。
术语“溶剂合物”指本发明化合物与溶剂分子配位形成特定比例的配合物。“水合物”指本发明化合物与水进行配位形成的配合物。
术语“前药”包括其本身可以是具有生物活性的或非活性的，当用适当的方法服用后，其在人体内进行代谢或化学反应而转变成式(I)的一类化合物，或式(I)的一个化合物所组成的盐或溶液。所述的前药包括(但不限于)以下化合物：氨基酸残基或由一个或多个(如2、3或4个)氨基酸残基组成的多肽链通过酰胺或酯键共价连接在本发明化合物的游离氨基、羟基或羧基上。氨基酸残基包括但不限于20个通常用3个字母符号表示的天然氨基酸，而且还包括4-羟基脯氨酸、羟基赖氨酸、Demosine、isodemosine、3-甲基组氨酸、正缬氨酸、鸟氨酸和氮氨酸砜。也包括其他类型的前药。例如，游离羧基可衍生为酰胺或烷基酯。如Advanced Drug Delivery Reviews 1996,19,115中所述，游离羟基通过使用以下基团来进行衍生化，所述基团包括但不限于半琥珀酸酯、磷酸酯、二甲基氨基乙酸酯和磷酰基氧基甲氧基碳基。羟基和氨基的氨基甲酸酯前药，以及羟基的碳酸酯前药、磺酸酯和硫酸酯，也包括在内。还包括羟基的衍生化如(酰基氧基)甲基和(酰基氧基)乙基醚，其中所述酰基可以是烷基酯，任选被包括但不限于醚、胺和羧酸官能团的基团取代，或者其中所述酰基是如上述的氨基酸酯。该类型的前药描述在以下文献中：J.Med.Chem.1996,39,10.游离按也可以被衍生化为酰胺、磺酰胺或磷酰胺。所有这些其他部分可掺入包括但不限于醚、胺和羧酸官能团的基团。
术语“晶型”是指化学药物分子的不同排列方式，一般表现为药物原料在固体状态下的存在形式。一种药物可以多种晶型物质状态存在，同一种药物的不同晶型，在体内的溶解和吸收可能不同，从而会对制剂的溶出和释放产生影响。
如本文所用，术语“受试者”包括但不限于：人(即，任何年龄组的男性或女性，例如，儿科受试者(例如，婴儿、儿童、青少年)或成人受试者(例如，年轻的成人、中年的成人或年长的成人))和/或非人的动物，例如，哺乳动物，例如，灵长类(例如，食蟹猴、恒河猴)、牛、猪、马、绵羊、 山羊、啮齿动物、猫和/或狗。在一些实施方案中，受试者是人。在另一些实施方案中，受试者是非人动物。
“疾病”、“障碍”和“病症”在本文中可以互换地使用。
除非另作说明，否则，本文使用的术语“治疗”包括受试者患有具体疾病、障碍或病症时所发生的作用，它降低疾病、障碍或病症的严重程度，或延迟或减缓疾病、障碍或病症的发展(“治疗性治疗”)，还包括受试者开始患有具体疾病、障碍或疾病之前发生的作用(“预防性治疗”)。
通常，化合物的“有效量”是指足以引起目标生物反应的数量。正如本领域普通技术人员所理解的那样，本发明化合物的有效量可以根据下列因素而改变：例如，生物学目标、化合物的药物动力学、所治疗的疾病、给药模式以及受试者的年龄健康情况和症状。有效量包括治疗和预防性治疗有效量。
除非另作说明，否则，本文使用的化合物的“治疗有效量”是在治疗疾病、障碍或病症的过程中足以提供治疗有益处的数量，或使与疾病、障碍或病症有关的一或多种症状延迟或最小化。化合物的治疗有效量是指单独使用或与其他疗法联用的治疗剂的数量，它在治疗疾病、障碍或病症的过程中提供治疗益处。术语“治疗有效量”可以包括改善总体治疗、降低或避免疾病或病症的症状或病因、或增强其他治疗剂的治疗效能的数量。
除非另作说明，否则，本文使用的化合物的“预防有效量”是足以预防疾病、障碍或病症的数量，或足以预防与疾病、障碍或病症有关的一或多种症状的数量，或防止疾病、障碍或病症复发的数量。化合物的预防有效量是指单独使用或与其它药剂联用的治疗剂的数量，它在预防疾病、障碍或病症的过程中提供预防益处。术语“预防有效量”可以包括改善总体预防的数量，或增强其它预防药剂的预防效能的数量。
“组合”以及相关术语是指同时或依次给药本发明的治疗剂。例如，本发明化合物可以与另一治疗剂以分开的单位剂型同时或依次给药，或与另一治疗剂一起呈单一单位剂型同时给药。
本发明的具体实施方案
化合物
本发明提供式(I)的化合物，或其药学上可接受的盐、前药、水合物或溶剂化合物、晶型、N-氧化物和各种非对映体：
Figure PCTCN2018109043-appb-000003
其中，
R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8、R 9、R 10、R 11、R 12、Y 1、Y 2、Y 3、Y 4、Y 5、Y 6、Y 7、Y 8和Y 9各自独立地选自自氢或氘；
X 1、X 2、X 3和X 4各自独立地选自CH 3、CD 3、CHD 2和CH 2D；
条件是如果X 1、X 2、X 3和X 4每个都是CH 3，那么R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8、R 9、R 10、R 11、R 12、Y 1、Y 2、Y 3、Y 4、Y 5、Y 6、Y 7、Y 8和Y 9中至少一个是氘；
作为本发明的优选实施方案，式(I)中化合物至少含有一个氘原子，更佳地一个氘原子，更佳地二个氘原子，更佳地三个氘原子，更佳地四个氘原子，更佳地五个氘原子，更佳地六个氘原子，更佳地七个氘原子，更佳地八个氘原子，更佳地九个氘原子，更佳地十个氘原子，更佳地十一个氘原子，更佳地十二个氘原子，更佳地十三个氘原子，更佳地十四个氘原子。
作为本发明的优选实施方案，氘在氘代位置的氘同位素含量至少是大于天然氘同位素含量0.015％，较佳地大于30％，更佳地大于50％，更佳地大于75％，更佳地大于95％，更佳地大于99％。
具体地说，在本发明中R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8、R 9、R 10、R 11、R 12、Y 1、Y 2、Y 3、Y 4、Y 5、Y 6、Y 7、Y 8、Y 9、X 1、X 2、X 3和X 4，各氘代位置中氘同位素含量至少是5％，较佳地大于10％，更佳地大于15％，更佳地大于20％，更佳地大于25％，更佳地大于30％，更佳地大于35％，更佳地大于40％，更佳地大于45％，更佳地大于50％，更佳地大于55％，更佳地大于60％，更佳地大于65％，更佳地大于70％，更佳地大于75％，更佳地大于80％，更佳地大于85％，更佳地大于90％，更佳地大于95％，更佳地大于99％。
在另一具体实施方案中，式(I)中化合物的R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8、R 9、R 10、R 11、R 12、Y 1、Y 2、Y 3、Y 4、Y 5、Y 6、Y 7、Y 8、Y 9、X 1、X 2、X 3和X 4至少其中一个含氘，更佳地两个含氘，更佳地三个含氘，更佳地四个含氘，更佳地五个含氘，更佳地六个含氘，更佳地七个含氘，更佳地八个含氘，更佳地九个含氘，更佳地十个含氘，更佳地十一个含氘，更佳地十二个含氘，更佳地十三个含氘，更佳地十四个含氘，更佳地十五个含氘，更佳地十六个含氘，更佳地十七个含氘，更佳地十八个含氘，更佳地十九个含氘，更佳地二十个含氘，更佳地二十一个含氘，更佳地二十二 个含氘，更佳地二十三个含氘，更佳地二十四个含氘，更佳地二十五个含氘，更佳地二十六个含氘，更佳地二十七个含氘，更佳地二十八个含氘，更佳地二十九个含氘，更佳地三十个含氘，更佳地三十一个含氘，更佳地三十二个含氘，更佳地三十三个含氘。具体而言，式(I)中化合物至少含有一个、两个、三个、四个、五个、六个、七个、八个、九个、十个、十一个、十二个、十三个、十四个、十五个、十六个、十七个、十八个、十九个、二十个、二十一个、二十二个、二十三个、二十四个、二十五个、二十六个、二十七个、二十八个、二十九个、三十个、三十一个、三十二个、三十三个氘原子。
在通式(I)的一个实施方案中，R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8、R 9、R 10、R 11和R 12各自独立地选自氢或氘。
在另一优选实施方案中，R 1和R 2是氘。
在另一优选实施方案中，R 3和R 4是氘。
在另一优选实施方案中，R 1、R 2、R 3和R 4是氘。
在另一优选实施方案中，R 5、R 6、R 7和R 8是氘。
在另一优选实施方案中，R 9、R 10、R 11和R 12是氘。
在另一优选实施方案中，R 5、R 6、R 7、R 8、R 9、R 10、R 11和R 12是氘。
在通式(I)的一个实施方案中，X 1、X 2、X 3和X 4各自独立地选自CH 3、CD 3、CHD 2和CH 2D。
在另一优选实施方案中，X 1是CD 3。
在另一优选实施方案中，X 2是CD 3。
在另一优选实施方案中，X 3是CD 3。
在另一优选实施方案中，X 4是CD 3。
在另一优选实施方案中，X 1和X 2均是CD 3。
在另一优选实施方案中，X 1、X 2和X 3均是CD 3
在通式(I)的一个实施方案中，Y 1、Y 2、Y 3、Y 4、Y 5、Y 6、Y 7、Y 8和Y 9各自独立地选自自氢或氘。
在另一优选实施方案中，Y 5是氘。
本发明的一个实施方案提供了通式(II)所示的化合物：
Figure PCTCN2018109043-appb-000004
其中，
R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8、R 9、R 10、R 11、R 12、Y 5、X 1、X 2、X 3和X 4的定义如上文所述；
或其药学上可接受的盐、前药、水合物或溶剂化合物、晶型、N-氧化物和各种非对映体。
在通式(II)的一个实施方案中，R 1、R 2选自氘，R 3、R 4、R 5、R 6、R 7、R 8、R 9、R 10、R 11、R 12、Y 5各自独立地选自氢或氘，X 1、X 2、X 3和X 4各自独立地选自CH 3、CD 3、CHD 2和CH 2D。
在另一优选实施方案中，R 1、R 2选自氘，R 3、R 4、R 5、R 6、R 7、R 8、R 9、R 10、R 11、R 12和Y 5各自独立地选自氢或氘，X 1、X 2、X 3和X 4各自独立地选自CH 3或CD 3。
在另一优选实施方案中，R 1、R 2、R 3、R 4选自氘，R 5、R 6、R 7、R 8、R 9、R 10、R 11、R 12和Y 5各自独立地选自氢或氘，X 1、X 2、X 3和X 4各自独立地选自CH 3或CD 3。
在通式(II)的一个实施方案中，Y 5选自氘，R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8、R 9、R 10、R 11、R 12各自独立地选自氢或氘，X 1、X 2、X 3和X 4各自独立地选自CH 3、CD 3、CHD 2和CH 2D。
在另一优选实施方案中，Y 5选自氘，R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8、R 9、R 10、R 11和R 12各自独立地选自氢或氘，X 1、X 2、X 3和X 4各自独立地选自CH 3或CD 3。
在通式(II)的一个实施方案中，Y 5选自氘，X 4选自CD 3，R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8、R 9、R 10、R 11和R 12各自独立地选自氢或氘，X 1、X 2和X 3各自独立地选自CH 3、CD 3、CHD 2和CH 2D。
在另一优选实施方案中，Y 5选自氘，X 4选自CD 3，R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8、R 9、R 10、R 11和R 12各自独立地选自氢或氘，X 1、X 2和X 3各自独立地选自CH 3和CD 3。
在通式(II)的一个实施方案中，X 4选自CD 3，R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8、R 9、R 10、R 11、R 12和Y 5各自独立地选自氢或氘，X 1、X 2和X 3各自独立地选自CH 3、CD 3、CHD 2和CH 2D。
在另一优选实施方案中，X 4选自CD 3，R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8、R 9、R 10、R 11、R 12和Y 5各自独立地选自氢或氘，X 1、X 2和X 3各自独立地选自CH 3和CD 3。
在通式(II)的一个实施方案中，X 1选自CD 3，R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8、R 9、R 10、R 11、R 12和Y 5各自独立地选自氢或氘，X 2、X 3和X 4各自独立地选自CH 3、CD 3、CHD 2和CH 2D。
在另一优选实施方案中，X 1选自CD 3，R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8、R 9、R 10、R 11、R 12和Y 5各自独立地选自氢或氘，X 2、X 3和X 4各自独立地选自CH 3和CD 3。
在通式(II)的一个实施方案中，X 1和X 3选自CD 3，R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8、R 9、R 10、R 11、R 12和Y 5各自独立地选自氢或氘，X 2和X 4各自独立地选自CH 3、CD 3、CHD 2和CH 2D。
在另一优选实施方案中，X 1和X 3选自CD 3，R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8、R 9、R 10、R 11、R 12和Y 5各自独立地选自氢或氘，X 3和X 4各自独立地选自CH 3和CD 3。
在通式(II)的一个实施方案中，X 1、X 2和X 3选自CD 3，R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8、R 9、R 10、R 11、R 12和Y 5各自独立地选自氢或氘，X 4各自独立地选自CH 3、CD 3、CHD 2和CH 2D。
在另一优选实施方案中，X 1、X 2和X 3选自CD 3，R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8、R 9、R 10、R 11、R 12和Y 5各自独立地选自氢或氘，X 4各自独立地选自CH 3和CD 3。
在通式(II)的一个实施方案中，R 5、R 6、R 7或R 8选自氘，R 1、R 2、R 3、R 4、R 9、R 10、R 11、R 12、Y 5各自独立地选自氢或氘，X 1、X 2、X 3和X 4各自独立地选自CH 3、CD 3、CHD 2和CH 2D。
在另一优选实施方案中，R 5、R 6、R 7或R 8选自氘，R 1、R 2、R 3、R 4、R 9、R 10、R 11、R 12、Y 5各自独立地选自氢或氘，X 1、X 2、X 3和X 4各自独立地选自CH 3和CD 3。
在通式(II)的一个实施方案中，R 9、R 10、R 11和R 12选自氘，R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8或Y 5各自独立地选自氢或氘，X 1、X 2、X 3和X 4各自独立地选自CH 3、CD 3、CHD 2和CH 2D。
在另一优选实施方案中，R 9、R 10、R 11和R 12选自氘，R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8或Y 5各自独立地选自氢或氘，X 1、X 2、X 3和X 4各自独立地选自CH 3和CD 3。
在通式(II)的一个实施方案中，R 5、R 6、R 7、R 8、R 9、R 10、R 11和R 12选自氘，R 1、R 2、R 3、R 4、或Y 5各自独立地选自氢或氘，X 1、X 2、X 3和X 4各自独立地选自CH 3、CD 3、CHD 2和CH 2D。
在另一优选实施方案中，R 5、R 6、R 7、R 8、R 9、R 10、R 11和R 12选自氘，R 1、R 2、R 3、R 4和Y 5各自独立地选自氢或氘，X 1、X 2、X 3和X 4各自独立地选自CH 3和CD 3。
作为本发明的优选实施方案中，所述化合物选自下组化合物或其药学上可接受的盐：
Figure PCTCN2018109043-appb-000005
Figure PCTCN2018109043-appb-000006
Figure PCTCN2018109043-appb-000007
Figure PCTCN2018109043-appb-000008
Figure PCTCN2018109043-appb-000009
在另一优选实施方案中，所述化合物不包括非氘代化合物。
药物组合物和施用方法
在另一方面，本发明提供了药物组合物，其包含本发明化合物(还称为“活性组分”)和药学上可接受的赋形剂。在一些实施方案中，所述药物组合物包含有效量的活性组分。在一些实施方案中，所述药物组合物包含治疗有效量的活性组分。在一些实施方案中，所述药物组合物包含预防有效量的活性组分。
本发明的药物组合物包含安全有效量范围内的本发明化合物或其药理上可接受的盐及药理上可以接受的赋形剂或载体。其中“安全有效量”指的是：化合物的量足以明显改善病情，而不至于产 生严重的副作用。通常，药物组合物含有0.5-2000mg本发明化合物/剂，更佳地，含有1-500mg本发明化合物/剂。较佳地，所述的“一剂”为一个胶囊或药片。
“药学上可接受的赋形剂”是指不会破坏一起调配的化合物的药理学活性的无毒载体、佐剂或媒剂。可以用于本发明组合物中的药学上可接受的载体、佐剂或媒剂包括(但不限于)离子交换剂、氧化铝、硬脂酸铝、卵磷脂、血清蛋白(如人类血清白蛋白)、缓冲物质(如磷酸盐)、甘氨酸、山梨酸、山梨酸钾、饱和植物脂肪酸的偏甘油酯混合物、水、盐或电解质(如硫酸鱼精蛋白)、磷酸氢二钠、磷酸氢钾、氯化钠、锌盐、硅胶、三硅酸镁、聚乙烯吡咯烷酮、基于纤维素的物质、聚乙二醇、羧甲基纤维素钠、聚丙烯酸酯、蜡、聚乙烯-聚氧丙烯-嵌段聚合物、聚乙二醇以及羊毛脂。
本发明的药物组合物可通过将本发明的化合物与适宜的药学上可接受的赋形剂组合而制备，例如可配制成固态、半固态、液态或气态制剂，如片剂、丸剂、胶囊剂、粉剂、颗粒剂、膏剂、乳剂、悬浮剂、溶液剂、栓剂、注射剂、吸入剂、凝胶剂、微球及气溶胶等。
给予本发明的化合物或其药物组合物的典型途径包括但不限于口服、直肠、透黏膜、经肠给药，或者局部、经皮、吸入、肠胃外、舌下、***内、鼻内、眼内、抚摸内、肌内、皮下、静脉内给药。
本发明的药物组合物可以采用本领域众所周知的方法制造，如常规的混合法、溶解法、制粒法、制糖衣药丸法、磨细法、乳化法、冷冻干燥法等等。
对于口服给药，可以通过将活性化合物与本领域熟知的药学上可接受的赋形剂混合来配置该药物组合物。这些赋形剂能使本发明的化合物被配制成片剂、丸剂、锭剂、糖衣剂、胶囊剂、液体、凝胶剂、浆剂、悬浮剂等，用于对患者的口服给药。
可以通过常规的混合、填充或压片方法来制备固体口服组合物。例如，可通过下述方法获得：将所述的活性化合物与固体赋形剂混合，任选地碾磨所得的混合物，如果需要则加入其它合适的辅剂，然后将该混合物加工成颗粒，得到了片剂或糖衣剂的核心。适合的辅料包括但不限于：粘合剂、稀释剂、崩解剂、润滑剂、助流剂、甜味剂或矫味剂等。如微晶纤维素、葡萄糖溶液、***胶浆、明胶溶液、蔗糖和淀粉糊；滑石、淀粉、硬脂酸钙或硬脂酸；乳糖、蔗糖、淀粉、甘露糖醇、山梨糖醇或磷酸二钙；二氧化硅；交联羟甲基纤维素钠、预交化淀粉、淀粉羟乙酸钠、藻酸、玉米淀粉、马铃薯淀粉、甲基纤维素、琼脂、羟甲基纤维素、交联聚乙烯吡咯烷酮等。可以根据通常药物实践中公知的方法任选地对糖衣剂的核心进行包衣，尤其使用肠溶包衣。
药物组合物还可适用于肠胃外给药，如合适的单位剂型的无菌溶液剂、混悬剂或冻干产品。能够使用适当的赋形剂，例如填充剂、缓冲剂或表面活性剂。
本发明化合物可以通过任何使用途径和方法给药，例如通过口服或肠胃外(例如，静脉内)给 药。本发明化合物的治疗有效量为从约0.0001到20mg/kg体重/天，例如从0.001到10mg/kg体重/天。
本发明化合物的剂量频率由患者个体的需求决定，例如，每天1次或2次，或每天更多次。给药可以是间歇性的，例如，其中在若干天的期间内，患者接受本发明化合物的每日剂量，接着在若干天或更多天的期间，患者不接受式本发明化合物的每日剂量。
本发明化合物的治疗适应症
本发明化合物展现JAK2蛋白酪氨酸激酶抑制作用，且该化合物在单独或与其它活性剂(例如下述化疗剂或蛋白质治疗剂)联合给予时用于治疗各种疾病，包括，但不限于：例如，骨髓组织增殖病症，增生型糖尿病视网膜病变和其它与生成血管相关的病症，包括实体瘤和其它类型的癌症，眼病，炎症，银屑病和病毒感染。可以治疗癌症类型包括但不限于消化/胃肠道癌，结肠癌，肝癌，皮肤癌，乳腺癌，卵巢癌，***癌，淋巴瘤，白血病(包括急性髓性白血病和慢性髓性白血病)，肾癌，肺癌，肌肉癌，骨癌，膀胱癌或脑癌。
可以治疗的疾病和病症的某些实例还包括眼新生血管形成，婴儿血管瘤；器官缺氧，血管增生，器官移植物排斥，狼疮，多发性硬化，类风湿性关节炎，银屑病，1型糖尿病和因糖尿病导致的并发症，炎性疾病，急性胰腺炎，慢性胰腺炎，哮喘，鼻炎，特应性皮炎，自身免疫性甲状腺病，溃疡性结肠炎，克罗恩病，转移性黑素瘤，卡波西肉瘤，多发性骨髓瘤，与细胞因子相关的疾患和其它自身免疫性胃炎，自体免疫溶血性疾病，自身免疫性嗜中性白血球减少症，血小板减少症，特应性(例如过敏性哮喘，特应性皮炎或过敏性鼻炎)，慢性活动肝炎，重症肌无力，多发性硬化，炎性肠病，移植物抗宿主病，神经变性疾病，包括运动神经元疾病，阿尔茨海默病，帕金森病，肌萎缩性侧索硬化，亨廷顿舞蹈病，脑缺血症或因跌打损伤导致的神经变形疾病，中风，谷氨酸神经中毒或低氧；中风中的缺血性/再灌注损伤，心肌缺血，肾缺血，心脏病发作，心脏肥大，动脉粥样硬化和动脉硬化，器官缺氧和血小板聚集。
可以治疗的某些额外的疾病和病症的实例还包括细胞介导超敏反应(过敏性接触性皮炎，过敏性肺炎)，风湿性疾病(例如***性红斑狼疮，类风湿性关节炎，青少年关节炎，斯耶格仑综合征，硬皮病，多肌炎，强直性脊柱炎，牛皮癣性关节炎)，病毒疾病(EB病毒，乙型肝炎，丙型肝炎，HIV，HTLV1，水痘-带状疱疹病毒，人***瘤病毒)，食物过敏，皮肤炎症和因实体瘤诱导的免疫抑制。
在一些实施方案中，本发明的化合物或所述的组合物可用于治疗原发性骨髓纤维化。在一些实施方 案中，本发明化合物或所述的组合物可用于治疗真性红细胞增多症后骨髓纤维化。在一些实施方案中，本发明化合物或所述的组合物可用于治疗特发性血小板增多症后骨髓纤维化。在一些实施方案中，本发明化合物或所述的组合物可用于治疗高风险骨髓纤维化。在一些实施方案中，本发明化合物或所述的组合物可用于治疗中度风险骨髓纤维化(例如中度风险水平2)。在一些实施方案中，本发明化合物可用于治疗JAK 2的缬氨酸617向苯丙氨酸的突变(即V617F)的突变为阳性的骨髓纤维化。在一些实施方案中，本发明化合物可用于治疗JAK 2的缬氨酸617向苯丙氨酸的突变(即V617F)的突变为阴性的骨髓纤维化。
联合疗法
对有这类治疗需要的受试者给药本发明的化合物与抗炎药，抗组胺药，化疗剂，免疫调节剂，治疗抗体或蛋白激酶抑制剂，例如酪氨酸激酶抑制剂。尽管无需受到限制，但是化疗剂包括抗代谢药，诸如甲氨蝶呤，DNA交联剂，诸如顺铂/卡铂；烷化剂，诸如canbusil；拓扑异构酶I抑制剂，诸如更生霉素；微管抑制剂，诸如泰素(紫杉醇(paclitaxol))等。其它化疗剂包括，例如，长春花生物碱，丝裂霉素-类抗生素，博来霉素-类抗生素，抗叶酸剂，秋水仙碱，demecoline，依托泊苷，紫杉烷，蒽环类抗生素，多柔比星，柔红霉素，洋红霉素，表柔比星，伊达比星，米托蒽醌(mithoxanthrone)，4-二甲氧基-道诺霉素，11-脱氧柔红霉素，13-脱氧柔红霉素，阿霉素-14-苯甲酸盐，阿霉素-14-辛酸盐，阿霉素-14-萘乙酸盐，安吖啶，卡莫司汀，环磷酰胺，阿糖胞苷，依托泊苷，洛伐他汀，美法仑，托泊替康(topetecan)，奥沙利铂(oxalaplatin)，苯丁酸氮芥，甲氨蝶呤(methtrexate)，洛莫司汀，硫鸟嘌呤，天冬酰胺酶，长春碱，长春地辛，他莫昔芬或氮芥。尽管无需受到限制，但是治疗抗体包括定向于HER2蛋白的抗体，诸如曲妥珠单抗；定向于生长因子或生长因子受体的抗体，诸如靶向血管内皮生长因子的贝伐珠单抗和靶向表皮生长因子的OSI-774；靶向整联蛋白受体的抗体，诸如Vitaxin(也称作MEDI-522)等。适用于本发明组合物和方法的抗癌药类型包括，但不限于:1)生物碱，包括微管抑制剂(例如长春新碱，长春碱和长春地辛等)，微管稳定剂(例如紫杉醇[泰素]和多西他赛，泰索帝等)和染色质功能抑制剂，包括拓扑异构酶抑制剂，诸如表鬼臼毒素(例如依托泊苷[VP-16]和替尼泊苷[VM-26]等)和靶向拓扑异构酶I的活性剂(例如喜树碱和伊立替康(Isirinotecan)[CPT-11]等)；2)共价DNA-结合剂[烷化剂]，包括氮芥(例如氮芥，苯丁酸氮芥，环磷酰胺，异环磷酰胺和白消安[马利兰]等)，亚硝基脲类(例如卡莫司汀，洛莫司汀和司莫司汀等)和其它烷化剂(例如达卡巴嗪，羟甲基蜜胺，塞替派和Mitocycin等)；3)非共价DNA-结合剂[抗肿瘤抗生素]，包括核酸抑制剂(例如放线菌素D[放线菌素D]等)，蒽环类(例如柔红霉素[道诺 霉素和正定霉素]，多柔比星[阿霉素]和伊达比星[去甲氧柔红霉素]等)，蒽二酮类(例如蒽环类抗生素类似物，诸如，[米托蒽醌]等)，博来霉素(博来霉素)等和普卡霉素(光辉霉素)等；4)抗代谢药，包括抗叶酸剂(例如甲氨蝶呤，富血铁-叶酸和甲氨蝶呤钠等)，嘌呤抗代谢药(例如6-巯基嘌呤[6-MP，巯嘌呤]，6-硫鸟嘌呤[6-TG]，硫唑嘌呤，阿昔洛韦，更昔洛韦，氯脱氧腺苷，2-氯脱氧腺苷[CdA]和2＇-去氧肋间型霉素[喷司他丁]等)，嘧啶拮抗剂(例如氟嘧啶类[例如5-氟尿嘧啶(Adrucil)，5-氟脱氧尿苷(FdUrd)(氟尿苷)]等)和胞嘧啶阿糖核苷(例如赛德萨[ara-C]和氟达拉滨等)；5)酶，包括L-天冬酰胺酶；6)激素，包括糖皮质激素，诸如，抗***药(例如他莫昔芬等)，非类固醇类抗雄激素药(例如氟他胺等)和芳香酶抑制剂(例如阿那曲唑[瑞宁得]等)；7)铂化合物(例如顺铂和卡铂等)；8)与抗癌药，毒素和/或放射性核素缀合的单克隆抗体等；9)生物反应修饰剂(例如干扰素[例如IFN-.α.等]和白细胞介素[例如IL-2等]等)；10)过继免疫疗法；11)造血生长因子；12)诱导肿瘤细胞分化的活性剂(例如全反式视黄酸等)；13)基因疗法技术；14)反义疗法技术；15)肿瘤疫苗；16)定向于转移瘤的疗法(例如Batimistat等)；和17)血管发生抑制剂。
本发明的药物组合物和方法可以进一步包括本文所述常应用于治疗上述病理学情况的其它治疗活性化合物。其它治疗剂的实例包括如下:环孢菌素类(例如环孢素A)；CTLA4-Ig；抗体，诸如ICAM-3，抗-IL-2受体(抗-Tac)，抗-CD45RB，抗-CD2，抗-CD3(OKT-3)，抗-CD4，抗-CD80，抗-CD86；阻断CD40与gp39相互作用的活性剂，诸如对CD40和/或gp39具有特异性的抗体(即CD154)，由CD40和gp39构建的融合蛋白(CD40Ig和CD8gp39)，NF-κB功能抑制剂，诸如核易位抑制剂，诸如脱氧精胍菌素(DSG)；胆固醇生物合成抑制剂，诸如HMG CoA还原酶抑制剂(洛伐他汀和辛伐他汀)；非类固醇抗炎药(NSAIDs)，诸如布洛芬和环加氧酶抑制剂，诸如罗非昔布；类固醇，诸如***或***；金化合物；抗增殖药，诸如甲氨蝶呤，FK506(他克莫司，普乐可复)，麦考酚酸吗乙酯，细胞毒性药物，诸如硫唑嘌呤和环磷酰胺；TNF-a抑制剂，诸如替尼达普；抗-TNF抗体或可溶性TNF受体和雷帕霉素(西罗莫司或雷帕鸣)或其衍生物。
可以与本发明化合物联合给药的其它活性剂包括蛋白质治疗剂，诸如细胞因子，免疫调节剂和抗体。本文所用的术语“细胞因子”包括趋化因子，白细胞介素，淋巴因子，单核因子，集落刺激因子和受体相关蛋白及其功能片段。本文所用的术语＂功能片段＂意指具有通过确定的功能测定法鉴定的生物功能或活性的多肽或肽。
细胞因子包括内皮单核细胞活化多肽II(EMAP-II)，粒细胞-巨噬细胞-CSF(GM-CSF)，粒细胞-CSF(G-CSF)，巨噬细胞-CSF(M-CSF)，IL-1，IL-2，IL-3，IL-4，IL-5，IL-6，IL-12和IL-13，干扰素等并且与细胞或细胞机制中的特定生物学，形态或表型改变相关。
当将其它治疗剂与本发明的化合物联用时，例如，可以以Physician Desk Reference(PDR)中所述的用量使用它们，否则就由本领域技术人员确定。
在涉及细胞增殖的疾患的治疗或预防中，适当的剂量水平一般在约0.01-约1000mg/1kg患者体重/天，可以将其以单或多次剂量给药。例如，该剂量水平可以在约0.01-约250mg/kg/天；更窄的是在约0.5-约100mg/kg/天。适当的剂量水平可以在约0.01-约250mg/kg/天，约0.05-约100mg/kg/天或约0.1-约50mg/kg/天或约1.0mg/kg/天。例如，在该范围内，剂量可以在约0.05-约0.5mg/kg/天或约0.5-约5mg/kg/天或约5-约50mg/kg/天。就口服给药而言，将组合物制成包含约1.0-约1,000mg活性组分，例如，约1.0，约5.0，约10.0，约15.0，约20.0，约25.0，约50.0，约75.0，约100.0约150.0，约200.0，约250.0，约300.0，约400.0，约500.0，约600.0，约750.0，约800.0，约900.0和约1,000.0mg活性组分的片剂形式，以便根据所治疗的患者的症状调整该剂量。可以以1-4次/天，诸如一次或两次/天的方案给药化合物。可有不给药时期，随后进行另一种给药方案。
然而，可以理解针对任何特定患者的具体剂量水平和剂量频次可以改变，并且取决于各种因素，包括所用具体化合物的活性，该化合物的代谢稳定性和作用期限，年龄，体重，一般健康状况，性别，膳食，给药方式和时间，***速率，药物组合，具体病情的严重性和宿主正在进行的疗法。
可以将本发明的化合物单独使用或与有效量的治疗抗体(或其治疗片段)，化疗剂或免疫毒性剂联用以便***。可以用于该目的的化疗剂的例证性实例包括多柔比星，多西他赛或泰素。进一步应理解本发明包括包含本发明化合物，包括，但不限于vasculostatic agents，诸如酪氨酸，丝氨酸或苏氨酸激酶抑制剂和任何化疗剂或治疗抗体的联合疗法。
本发明的化合物与现有技术中已知的非氘代化合物相比，具有一系列优点。本发明的优点包括：第一，采用本发明技术方案的化合物和组合物为JAK2介导的疾病的治疗提供了更有利的治疗工具。第二，改进了化合物在生物体中的代谢，使化合物具有更好的药代动力学参数特性。在这种情况下，可以改变剂量并形成长效制剂，改善适用性。第三，提高了化合物在动物体内的药物浓度，提高了药物疗效。第四，抑制了某些代谢产物，提高化合物的安全性。
实施例
下面结合具体实施例，作进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件，或按照制造厂商所建议的条件。除非另外说明，否则份数和百分比为重量份和重量百分比。
通常，在制备流程中，各反应通常在惰性溶剂中，在室温至回流温度(如0℃～100℃，优选0℃～80℃)下进行。反应时间通常为0.1-60小时，优选地为0.5-24小时。
实施例1 N-(叔丁基)-3-((5-甲基-2-((4-(2-(吡咯烷-1-基)乙氧基-1,1,2,2-d4)苯基)氨基)嘧啶-4-基) 氨基)苯磺酰胺(化合物T-1)的制备。
Figure PCTCN2018109043-appb-000010
采用以下路线进行合成：
Figure PCTCN2018109043-appb-000011
步骤1 化合物3的合成。
依次往配有磁力搅拌的250mL单口烧瓶中加入化合物1(10.0g，45.12mmol)和THF(100mL)，搅拌溶清，冰水浴下缓慢滴加入叔丁胺(9.9g，135.37mmol)的THF溶液(20mL)，滴毕，拆去冰水，氮气氛下室温搅拌反应1小时。减压蒸除有机溶剂，加水(50mL)，二氯甲烷萃取(50mLx3)，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩，硅胶柱层析分离得白色固体9.5g，收率81.6％。LC-MS(APCI):m/z＝259.1(M+1) +。 1H NMR(500MHz,CDCl 3)δppm:8.75(t,J＝2.0Hz, 1H),8.40(dd,J＝8.0Hz,J＝2.0Hz,1H),8.24(dd,J＝8.0Hz,J＝2.0Hz,1H),7.73(t,J＝8.0Hz,1H),4.99(s,1H),1.27(s,9H).
步骤2 化合物4的合成。
向配有磁力搅拌和冷凝管的100mL单口烧瓶中加入乙醇/水混合液(60mL，2/1)和化合物3(3.0g,11.66mmol)，搅拌下加入还原铁粉(6.51g,116.6mmol)和氯化铵(3.12g,58.3mmol)，氮气下升温到85℃，并保温搅拌反应1h。
冷却到室温，滤除不溶性固体，减压蒸除有机溶剂，加入饱和NaHCO 3水液(5mL)，乙酸乙酯萃取(50mLx3)，合并有机相，无水硫酸钠干燥，过滤，浓缩得白色固体2.55g，收率95.79％。LC-MS(APCI):m/z＝229.1(M+1) +。
步骤3 化合物6的合成。
室温下向配有磁力搅拌的50mL单口瓶中依次加化合物5(1.0g，6.13mmol)和甲醇/水混合液(15mL，1/1)，搅拌溶清，加入化合物4(1.26g，5.52mmol)，反应混合物氮气下升温到45℃并保温搅拌反应过夜。冷却到室温，析出大量白色固体，过滤，滤饼用甲醇/水(3.4mL/4.0mL)洗涤，抽干，50℃真空干燥得白色固体1.31g，收率60.17％。LC-MS(APCI):m/z＝354.1(M+1) +. 1H NMR(500MHz,DMSO-D 6)δppm:9.11(s,1H),8.11-8.09(m,2H),7.88-7.86(m,1H),7.55-7.52(m,3H),2.18(s,3H),1.12(s,9H).
步骤4 化合物9的合成。
向配有磁力搅拌的50mL单口瓶中依次加化合物7(300mg,2.16mmol)和DMF(6ml)，搅拌溶清，加入碳酸钾(894mg，6.47mmol)和化合物8(827mg，4.31mmol)，反应混合物氮气氛下升温到80℃并保温搅拌反应4小时。冷却到室温，加入水30mL，乙酸乙酯萃取(30mLx3)，合并有机相，水洗(60mLx3)，饱和食盐水洗(30mL)，无水硫酸钠干燥，过滤，浓缩并经硅胶柱分离得白色固体450mg，收率83.4％。LC-MS(APCI):m/z＝250.0和252.0(M+1) +.
步骤5 化合物10的合成。
向配有磁力搅拌的50mL单口瓶中依次加化合物9(450mg,1.8mmol)和DMF(6ml)，搅拌溶清，加入碳酸钾(746mg，5.4mmol)和吡咯烷(256mg，3.6mmol)，反应混合物氮气氛下升温到80℃并保温搅拌反应4小时。冷却到室温，加入水30mL，乙酸乙酯萃取(30mLx3)，合并有机相，水洗(60mLx3)，饱和食盐水洗(30mL)，无水硫酸钠干燥，过滤，浓缩并经硅胶柱分离得黄色油状物250mg，收率57.8％。LC-MS(APCI):m/z＝241(M+1) +.
步骤6 化合物11的合成。
向配有磁力搅拌50mL单口瓶中加入化合物10(250mg，1.04mmol)和甲醇(10mL)，搅拌溶清，加入Pd/C(25mg，10％)，氢气球下抽真空并置换3次，氢气氛下反应过夜。滤掉催化剂，甲醇(3mL)洗涤滤饼，合并滤液，浓缩得黄色油状物220mg，收率98.6％。LC-MS(APCI):m/z＝211.1(M+1) +.
步骤7 化合物T-1的合成。
向配有磁力搅拌跟冷凝管的25mL单口瓶中加入化合物6(200mg，0.56mmol)、化合物11(107mg，0.51mmol)和乙二醇单甲醚(6mL)，搅拌溶清，滴加入氯化氢的异丙醇溶液(1.41mmol，0.28mL，5M)，氮气氛下升温到120℃并保温搅拌反应过夜。冷却到室温，加入水(10mL)和饱和碳酸氢钠(5mL)，二氯甲烷萃取(15mLx3)，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩，残留物过硅胶柱得白色固体150mg，收率为50.3％。LC-MS(APCI):m/z＝529.2(M+1) +. 1H NMR(500MHz,CDCl 3)δppm:8.11(s,1H),7.92-7.89(m,2H),7.57(d,J＝8.0Hz,1H),7.41-7.38(m,3H),6.91(d,J＝8.0Hz,1H),6.81(s,1H),6.44(s,1H),4.60(s,1H),4.13(t,J＝6.0Hz,2H),2.94(t,J＝6.0Hz,2H),2.13(s,3H),1.22(s,9H).
实施例2 N-(叔丁基)-3-((5-(甲基-d 3)-2-((4-(2-(吡咯烷-1-基)乙氧基)苯基)氨基)嘧啶-4-基-6-d)氨 基)苯磺酰胺(化合物T-2)的制备。
Figure PCTCN2018109043-appb-000012
采用以下路线进行合成：
Figure PCTCN2018109043-appb-000013
步骤1 化合物13的合成。
向装有磁子的20mL微波管中加入化合物12(1.0g，7.93mmol)、Pd/C(200mg，10％)和重水(15mL)，通入氢气鼓泡2分钟，密封微波管并置于微波反应器中，升温到180℃反应1小时。冷却到室温，滤除催化剂，乙酸乙酯萃取(30mLx3)，合并有机相，无水硫酸钠干燥，过滤，浓缩并经硅胶柱分离得白色固体700mg，收率67.8％。LC-MS(APCI):m/z＝131.1(M+1) +。 1H NMR(300MHz,DMSO-d 6)δppm:11.00(s,1H),10.58(s,1H).
步骤2 化合物14的合成。
向配有磁力搅拌的50mL三口瓶中依次加化合物13(360mg,2.77mmol)和三氯氧磷(5mL,)，氮气氛下升温到110℃并保温搅拌反应过夜。减压蒸除未反应的三氯氧磷，残留物溶于乙酸乙酯(40mL)，加入饱和碳酸氢钠水液(10mL)，搅拌5分钟，分层，有机相无水硫酸钠干燥，过滤，浓缩并经硅胶柱分离得白色固体400mg，收率86.5％。LC-MS(APCI):m/z＝168.1(M+1) +。
步骤3 化合物15的合成。
室温下向配有磁力搅拌的50mL单口瓶中依次加化合物14(400mg，2.39mmol)和MeOD/重水混合液(10mL，1/1)，搅拌溶清，加入化合物4(382mg，1.68mmol)，反应混合物氮气下升温到45℃并保温搅拌反应过夜。冷却到室温，析出大量白色固体，过滤，滤饼用MeOD/重水(2mL/2mL)洗涤，抽干，50℃真空干燥得白色固体400mg，收率46.7％。LC-MS(APCI):m/z＝358.1(M+1) +. 1H NMR(400MHz,DMSO-D 6)δ/ppm:9.11(s,1H),8.11-8.09(m,1H),7.88-7.86(m,1H),7.55-7.52(m,3H),1.12(s,9H).
步骤4 化合物17的合成。
向配有磁力搅拌的50mL单口瓶中依次加化合物7(1.0g,7.19mmol)、化合物16(1.58g，9.35mmol)和DMF(20ml)，搅拌下加入Cs 2CO 3(碳酸铯，7.0g，21.6mmol)反应混合物氮气氛下升温到100℃并保温搅拌反应过夜。冷却到室温，加入水30mL，乙酸乙酯萃取(30mLx3)，合并有机相，水洗(60mLx3)，饱和食盐水洗(30mL)，无水硫酸钠干燥，过滤，浓缩并经硅胶柱分离得白色固体1.2g，收率70.4％。LC-MS(APCI):m/z＝237.1(M+1) +. 1H NMR(300MHz,CDCl 3)δppm:8.20(d,J＝9.0Hz,2H),6.98(d,J＝9.0Hz,2H),4.21(t,J＝6.0Hz,2H),2.96(t,J＝6.0Hz,2H),2.67-2.64(m,4H),1.88-1.82(m,4H).
步骤5 化合物18的合成。
向配有磁力搅拌50mL单口瓶中加入化合物17(250mg，1.04mmol)和甲醇(10mL)，搅拌溶清，加入Pd/C(25mg，10％)，氢气球下抽真空并置换3次，氢气氛下反应过夜。滤掉催化剂，甲醇(3mL)洗涤滤饼，合并滤液，浓缩得黄色油状物220mg，收率98.6％。 LC-MS(APCI):m/z＝207.1(M+1) +.
步骤6 化合物T-2的合成。
向配有磁力搅拌跟冷凝管的25mL单口瓶中加入化合物15(200mg，0.56mmol)、化合物18(107mg，0.51mmol)和乙二醇单甲醚(6mL)，搅拌溶清，滴加入氯化氢的异丙醇溶液(1.41mmol，0.28mL，5M)，氮气氛下升温到120℃并保温搅拌反应过夜。冷却到室温，加入水(10mL)和饱和碳酸氢钠(5mL)，二氯甲烷萃取(15mLx3)，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩，残留物过硅胶柱得白色固体150mg，收率为50.3％。LC-MS(APCI):m/z＝529.2(M+1) +. 1H NMR(500MHz,CDCl 3)δ/ppm:8.11(s,1H),7.90(dd,J＝8.0Hz,J＝1.0Hz,1H),7.57(d,J＝8.0Hz,1H),7.41-7.38(m,3H),6.91(d,J＝8.0Hz,1H),6.81(s,1H),6.44(s,1H),4.75(s,1H),4.13(t,J＝6.0Hz,2H),2.94(t,J＝6.0Hz,2H),2.69-2.64(m,4H),1.85-1.81(m,4H),1.22(s,9H).
实施例3 3-((5-甲基-2-((4-(2-(吡咯烷-1-基)乙氧基)苯基)氨基)嘧啶-4-基)氨基)-N-(2-甲基丙烷-2- 基-1,1,1,3,3,3-d 6)苯磺酰胺(化合物T-3)的制备。
Figure PCTCN2018109043-appb-000014
采用以下路线进行合成：
Figure PCTCN2018109043-appb-000015
步骤1 化合物20的合成。
向配有磁力搅拌和冷凝管的100mL三口瓶中依次加入化合物19(4.0g,62.39mmol)和***(40 mL)，氮气氛下冷却到-10℃，保温缓慢滴加入甲基溴化镁(20.80mL，62.39mmol，3M)，滴毕，缓慢升温到室温，再升温回流2小时。冷却到室温，冰浴下滴加入饱和NH 4Cl水液(10mL)淬灭反应，搅拌10分钟，分层，水层***萃取(20mLx2)，合并有机相，无水硫酸钠干燥，过滤，常温小心减压蒸馏得无色液体1.7g，收率33.99％。直接投下一步。
步骤2 化合物21的合成。
冰水浴下，浓硫酸(10g)缓慢滴加入水(10g)中，控制温度不超过5℃，缓慢分批加入叠氮化钠(1.52g，23.33mmol)，搅拌溶清，加入化合物20(1.7g，21.21mmol)，氮气氛下室温搅拌反应过夜。加入***(20mL)，静置分层，分出上层有机相，下层再次用***萃取(20mL)，合并有机相，饱和NaHCO 3(5mL)洗涤，无水硫酸钠干燥，常温小心蒸除溶剂，得黄色液体1.2g，收率53.80％。直接投下一步。
步骤3 化合物22的合成。
向配有磁力搅拌50mL单口瓶中加入化合物21(1.2g，11.41mmol)和甲醇(20mL)，搅拌溶清，加入Pd/C(120mg，10％)，氢气球下抽真空并置换3次，氢气氛下反应过夜。滤除催化剂，缓慢滴加入氯化氢异丙醇溶液(5M)，调pH～2，搅拌10分钟，减压蒸除溶剂，得黄色固体1.04g，收率79.23％。直接投下一步。
步骤4 化合物23的合成。
依次往配有磁力搅拌的50mL单口烧瓶中加入化合物1(2.0g，9.02mmol)和THF(30mL)，搅拌溶清，冰水浴下缓慢滴加入化合物22(1.04g，9.02mmol)和三乙胺(3.65g，36.08mmol)，加毕，拆去冰水，氮气氛下室温搅拌反应1小时。减压蒸除有机溶剂，加水(50mL)，二氯甲烷萃取(50mLx3)，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩，硅胶柱层析得白色固体700mg，收率29.34％。LC-MS(APCI):m/z＝265.1(M+1) +。 1H NMR(500MHz,CDCl 3)δ8.75(t,J＝2.0Hz,1H),8.40(dd,J＝8.0Hz,J＝2.0Hz,1H),8.24(dd,J＝8.0Hz,J＝2.0Hz,1H),7.73(t,J＝8.0Hz,1H),4.99(s,1H),1.27(s,3H).
步骤5 化合物24的合成。
向配有磁力搅拌和冷凝管的50mL单口烧瓶中加入乙醇/水混合液(15mL，2/1)和化合物23(300mg,1.17mmol)，搅拌下加入还原铁粉(651mg,11.67mmol)和氯化铵(0.31mg,5.83mmol)，氮气下升温到85℃，并保温搅拌反应1h。冷却到室温，滤除不溶性固体，减压蒸除有机溶剂，加入饱和NaHCO 3水液(5mL)，乙酸乙酯萃取(20mLx3)，合并有机相，无水硫酸钠干燥，过滤，浓缩得白色固体250mg，收率95.79％。LC-MS(APCI):m/z＝235.1(M+1) +。
步骤6 化合物25的合成。
室温下向配有磁力搅拌的50mL单口瓶中依次加化合物24(200mg，1.23mmol)和甲醇/水混合液(15mL，1/1)，搅拌溶清，加入化合物5(250mg，1.10mmol)，反应混合物氮气下升温到45℃并保温搅拌反应过夜。冷却到室温，析出大量白色固体，过滤，滤饼用甲醇/水(3.4mL/4.0mL)洗涤，抽干，50℃真空干燥得白色固体230mg，收率52.83％。LC-MS(APCI):m/z＝361.1(M+1) +. 1H NMR(500MHz,DMSO-d 6)δ9.11(s,1H),8.11-8.09(m,2H),7.88-7.86(m,1H),7.55-7.52(m,3H),2.18(s,3H),1.12(s,3H).
步骤7 化合物T-2的合成。
向配有磁力搅拌跟冷凝管的25mL单口瓶中加入化合物25(200mg，0.56mmol)、化合物18(107mg，0.51mmol)和乙二醇单甲醚(6mL)，搅拌溶清，滴加入氯化氢异丙醇溶液(1.41mmol，0.28mL，5M)，氮气氛下升温到120℃并保温搅拌反应过夜。冷却到室温，加入水(10mL)和饱和碳酸氢钠(5mL)，二氯甲烷萃取(15mLx3)，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩，残留物过硅胶柱得白色固体150mg，收率为50.3％。LC-MS(APCI):m/z＝531.2(M+1) +. 1H NMR(300MHz,CDCl 3)δ8.11(s,1H),7.92-7.89(m,2H),7.57(d,J＝8.1Hz,1H),7.41-7.38(m,3H),6.91(d,J＝8.1Hz,1H),6.81(s,1H),6.44(s,1H),4.60(s,1H),4.13(t,J＝6.0Hz,2H),2.94(t,J＝6.0Hz,2H),2.69-2.64(m,4H),2.13(s,3H),1.85-1.81(m,4H),1.22(s,3H).
实施例4 3-((5-甲基-2-((4-(2-(吡咯烷-1-基)乙氧基)苯基)氨基)嘧啶-4-基)氨基)-N-(2-(甲基-d 3)丙 烷-2-基-1,1,1,3,3,3-d 6)苯磺酰胺(化合物T-4)的制备。
Figure PCTCN2018109043-appb-000016
采用以下路线进行合成：
Figure PCTCN2018109043-appb-000017
步骤1 化合物28的合成。
向配有磁力搅拌和冷凝管的100mL三口瓶中加入镁粉(1.80g，74.87mmol)，抽真空并氮气置换3次，氮气氛下加入***(30mL)和CD 3I(10.0g，68.96mmol)，滴毕，升温回流反应2小时。冷却到-10℃，滴加入化合物19(4.0g,62.39mmol)的***溶液(10mL)，滴毕，缓慢升温到室温，再升温回流2小时。冷却到室温，冰浴下滴加入饱和NH 4Cl水液(10mL)淬灭反应，搅拌10分钟，分层，水层***萃取(20mLx2)，合并有机相，无水硫酸钠干燥，过滤，常温小心减压蒸馏得无色液体1.7g，收率33.99％。直接投下一步。
步骤2 化合物29的合成。
冰水浴下，浓硫酸(10g)缓慢滴加入水(10g)中，控制温度不超过5℃，缓慢分批加入叠氮化钠(1.52g，23.33mmol)，搅拌溶清，加入化合物28(1.7g，21.21mmol)，氮气氛下室温搅拌反应过夜。加入***(20mL)，静置分层，分出上层有机相，下层再次用***萃取(20mL)，合并有机相，饱和NaHCO 3(5mL)洗涤，无水硫酸钠干燥，常温小心蒸除溶剂，得黄色液体1.2g，收率53.80％。直接投下一步。
步骤3 化合物30的合成。
向配有磁力搅拌50mL单口瓶中加入化合物29(1.2g，11.41mmol)和甲醇(20mL)，搅拌溶清，加入Pd/C(120mg，10％)，氢气球下抽真空并置换3次，氢气氛下反应过夜。滤除催化剂，缓慢滴加入氯化氢异丙醇溶液(5M)，调pH值约为2，搅拌10分钟，减压蒸除溶剂，得黄色固体1.04g，收率79.23％。直接投下一步。
步骤4 化合物31的合成。
依次往配有磁力搅拌的50mL单口烧瓶中加入化合物1(2.0g，9.02mmol)和THF(30mL)， 搅拌溶清，冰水浴下缓慢滴加入化合物30(1.04g，9.02mmol)和三乙胺(3.65g，36.08mmol)，加毕，拆去冰水，氮气氛下室温搅拌反应1小时。减压蒸除有机溶剂，加水(50mL)，二氯甲烷萃取(50mLx3)，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩，硅胶柱层析得白色固体700mg，收率29.34％。LC-MS(APCI):m/z＝268.1(M+1) +。 1H NMR(500MHz,CDCl 3)δ8.75(t,J＝2.0Hz,1H),8.40(dd,J＝8.0Hz,J＝2.0Hz,1H),8.24(dd,J＝8.0Hz,J＝2.0Hz,1H),7.73(t,J＝8.0Hz,1H),4.99(s,1H).
步骤5 化合物32的合成。
向配有磁力搅拌和冷凝管的50mL单口烧瓶中加入乙醇/水混合液(15mL，2/1)和化合物31(300mg,1.17mmol)，搅拌下加入还原铁粉(651mg,11.67mmol)和氯化铵(0.31mg,5.83mmol)，氮气下升温到85℃，并保温搅拌反应1h。冷却到室温，滤除不溶性固体，减压蒸除有机溶剂，加入饱和NaHCO 3水液(5mL)，乙酸乙酯萃取(20mLx3)，合并有机相，无水硫酸钠干燥，过滤，浓缩得白色固体250mg，收率95.79％。LC-MS(APCI):m/z＝238.1(M+1) +。
步骤6 化合物33的合成。
室温下向配有磁力搅拌的50mL单口瓶中依次加化合物32(200mg，1.23mmol)和甲醇/水混合液(15mL，1/1)，搅拌溶清，加入化合物5(250mg，1.10mmol)，反应混合物氮气下升温到45℃并保温搅拌反应过夜。冷却到室温，析出大量白色固体，过滤，滤饼用甲醇/水(3.4mL/4.0mL)洗涤，抽干，50℃真空干燥得白色固体230mg，收率52.83％。LC-MS(APCI):m/z＝364.1(M+1) +. 1H NMR(500MHz,DMSO-d 6)δ9.11(s,1H),8.11-8.09(m,2H),7.88-7.86(m,1H),7.55-7.52(m,3H),2.18(s,3H).
步骤7 化合物T-4的合成。
向配有磁力搅拌跟冷凝管的25mL单口瓶中加入化合物33(200mg，0.56mmol)、化合物18(107mg，0.51mmol)和乙二醇单甲醚(6mL)，搅拌溶清，滴加入氯化氢异丙醇溶液(1.41mmol，0.28mL，5M)，氮气氛下升温到120℃并保温搅拌反应过夜。冷却到室温，加入水(10mL)和饱和碳酸氢钠(5mL)，二氯甲烷萃取(15mLx3)，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩，残留物过硅胶柱得白色固体150mg，收率为50.3％。LC-MS(APCI):m/z＝534.2(M+1) +. 1H NMR(300MHz,CDCl 3)δ8.11(s,1H),7.92-7.89(m,2H),7.57(d,J＝8.1Hz,1H),7.41-7.38(m,3H),6.91(d,J＝8.1Hz,1H),6.81(s,1H),6.44(s,1H),4.60(s,1H),4.13(t,J＝6.0Hz,2H),2.94(t,J＝6.0Hz,2H),2.69-2.64(m,4H),2.13(s,3H),1.85-1.81(m,4H).
实施例5 N-(叔丁基)-3-((5-甲基-2-((4-(2-(吡咯烷-1-基-d8)乙氧基)苯基)氨基)嘧啶-4-基)氨基)苯 磺酰胺(化合物T-5)的制备。
Figure PCTCN2018109043-appb-000018
采用以下路线进行合成：
Figure PCTCN2018109043-appb-000019
步骤1 化合物36的合成。
依次往配有磁力搅拌的50mL三口烧瓶中加入NaH(595mg，14.88mmol，60％)，抽真空并氮气置换3次，氮气氛下加入无水THF(20mL)，冰水浴下滴加入2-乙醇胺(909mg，14.88mmol)的无水THF(2mL)溶液，搅拌反应10分钟，再次滴加入化合物34(2.0g，14.17mmol)的无水THF(3mL)溶液，滴毕，拆去冰浴，室温搅拌反应2小时。加入饱和水的乙酸乙酯(50mL)淬灭反应，过滤，滤液无水硫酸钠干燥，过滤，浓缩并过硅胶柱得黄色油状物1.6g，收率61.69％。LC-MS(APCI):m/z＝183.1(M+1) +。 1H NMR(300MHz,CDCl 3)δ8.21(d,J＝9.3Hz,2H),6.97(d,J＝9.3Hz,2H),4.09(t,J＝5.1Hz,2H),3.15(t,J＝5.1Hz,2H).
步骤2 化合物38的合成。
冰水浴下，向配有磁力搅拌和冷凝管的50mL单口烧瓶中加入氢溴酸水溶液(7.57g，93.57mmol，48％)和浓硫酸(3.67g)，搅拌均匀，滴加入化合物37(3.0g，37.43mmol)，滴毕，反应混合物升温到90℃并保温搅拌反应2小时。冷却到室温，乙酸乙酯(20mLx2)萃取，合并有机 相，无水硫酸钠干燥，浓缩并过硅胶柱得无水油状物1.5g，收率17.89％。
步骤3 化合物39的合成。
向配有磁力搅拌和冷凝管的50mL单口烧瓶中加入化合物36(420mg，2.31mmol)、化合物38(640mg，2.86mmol)和乙腈(15mL)，搅拌溶清，加入碘化钾(76mg，0.46mmol)和碳酸钾(382mg，2.77mmol)，反应混合物氮气氛下升温回流并保温反应过夜。冷却到室温，减压蒸除溶剂，加入水(15mL)和乙酸乙酯(20mL)，分出有机层，水层乙酸乙酯萃取(20mLx2)，合并有机相，无水硫酸钠干燥，过滤，浓缩并过硅胶柱得黄色油状物250mg，收率44.2％。LC-MS(APCI):m/z＝245.1(M+1) +。 1H NMR(300MHz,CDCl 3)δ8.20(d,J＝9.0Hz,2H),6.98(d,J＝9.0Hz,2H),4.21(t,J＝6.0Hz,2H),2.96(t,J＝6.0Hz,2H)。
步骤4 化合物40的合成。
向配有磁力搅拌50mL单口瓶中加入化合物39(250mg，1.04mmol)和甲醇(10mL)，搅拌溶清，加入Pd/C(25mg，10％)，氢气球下抽真空并置换3次，氢气氛下反应过夜。滤掉催化剂，甲醇(3mL)洗涤滤饼，合并滤液，浓缩得黄色油状物220mg，收率98.6％。LC-MS(APCI):m/z＝215.1(M+1) +.
步骤5 化合物T-5的合成。
向配有磁力搅拌跟冷凝管的25mL单口瓶中加入化合物40(200mg，0.56mmol)、化合物6(107mg，0.51mmol)和乙二醇单甲醚(6mL)，搅拌溶清，滴加入氯化氢异丙醇溶液(1.41mmol，0.28mL，5M)，氮气氛下升温到120℃并保温搅拌反应过夜。冷却到室温，加入水(10mL)和饱和碳酸氢钠(5mL)，二氯甲烷萃取(15mLx3)，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩，残留物过硅胶柱得白色固体150mg，收率为50.3％。LC-MS(APCI):m/z＝533.2(M+1) +. 1H NMR(500MHz,CDCl 3)δ8.11(s,1H),7.92-7.89(m,2H),7.57(d,J＝8.0Hz,1H),7.41-7.38(m,3H),6.91(d,J＝8.0Hz,1H),6.81(s,1H),6.44(s,1H),4.60(s,1H),4.13(t,J＝5.5Hz,2H),2.94(t,J＝5.5Hz,2H),2.13(s,3H),1.22(s,9H).
生物活性测试。
(1)激酶抑制作用
试剂和耗材：
JAK2，JAK2/V617F，ATP(Sigma,目录号A7699-1G)，DMSO(Sigma,目录号D2650)，96孔板(Corning,目录号3365)，384孔板(Greiner,目录号784076)，HTRF Kinase TK试剂盒(Cisbio)，5x 激酶缓冲液A(Life Technologies,目录号PV3186)，激酶示踪剂199(Life Technologies,目录号PV5830)，
Figure PCTCN2018109043-appb-000020
Eu-anti-GST抗体(Life Technologies,目录号PV5594)。
具体实验方法：
化合物配制：将受试化合物溶于DMSO配成20mM母液。然后，在DMSO中等梯度3倍稀释，稀释十次。加药时再用缓冲液稀释10倍。
JAK2及JAK2[V617F]激酶检测：在5x激酶缓冲液A中，将JAK2或JAK2[V617F]激酶与预先稀释配制的不同浓度的化合物混合10分钟，每个浓度双复孔。加入对应底物及ATP，室温反应20分钟(其中设置阴阳性对照：阴性为空白对照，阳性为厄洛替尼)。反应完毕加入检测试剂(HTRF Kinase TK试剂盒内的试剂)，室温孵育30分钟后，通过Evnvision酶标仪检测，测定在各浓度的本发明化合物存在下的酶活力，并计算不同浓度的化合物对酶活力的抑制活性，之后根据四参数方程，根据Graphpad 5.0软件对不同浓度化合物下酶活力的抑制活性进行拟合，计算出IC 50值。
在上述激酶抑制实验中测试了本发明化合物和未经氘代的化合物Fedratinib，发现本发明化合物对JAK2激酶和JAK2/V617F激酶具有更强效或相当的活性。代表性实施例化合物对激酶的抑制作用的结果归纳于如下表1中。
表1
实施例化合物 JAK2 IC 50(nM) JAK2/V617F IC 50(nM)
Fedratinib 3.08 4.05
T-1 3.16 4.06
T-2 2.89 3.69
T-3 3.06 3.78
T-4 3.24 4.05
T-5 3.47 4.55
(2)细胞毒性实验
检测实施例化合物对BaF3-EpoR-JAK2、BaF3-EpoR-JAK2/V617F细胞活性的抑制效应。
耗材及试剂：RPMI-1640培养基(GIBCO，目录号A10491-01)、胎牛血清(GIBCO，目录号10099-141)、抗生素(GIBCO，目录号10010-031)，IL-3(CST，目录号8923SF)，磷酸盐缓冲溶液PBS(GIBCO，，目录号10010-0312)，青霉素-链霉素(Penicillin-Streptomycin)(GIBCO，目录号15140-122)；
细胞系：BaF3-EpoR-JAK2细胞(Pharmaron)，BaF3-EpoR-JAK2/V617F细胞(Pharmaron)，活细胞检测试剂盒CellTiter-Glo4(Promega，目录号G7572)，96孔黑壁透明平底细胞培养板(Corning，目录号3340)。
实验方法：1.制备细胞板将BaF3-EpoR-JAK2细胞，BaF3-EpoR-JAK2/V617F细胞分别种于96孔板中，并在Ba/F3细胞中加入1ng/ml IL-3，细胞板置于二氧化碳培养箱中过夜培养。2.用DMSO溶解被测化合物并进行3倍梯度稀释，9个化合物浓度，设置复孔实验。3.化合物处理细胞将化合物转移到细胞板中，化合物起始浓度为10μM。细胞板置于二氧化碳培养箱中培养3天。4.检测向细胞板中加入CellTiter-Glo试剂，室温孵育30分钟使发光信号稳定。采用PerkinElmer Envision多标记分析仪读数。
在上述细胞毒性实验中测试了本发明化合物和未经氘代的化合物Fedratinib，发现本发明化合物对BaF3-EpoR-JAK2细胞和BaF3-EpoR-JAK2/V617F细胞具有更强效或相当的活性。代表性实施例化合物对癌细胞的体外增殖的抑制作用的结果归纳于如下表2中。
表2
Figure PCTCN2018109043-appb-000021
(3)代谢稳定性评价
微粒体实验：人肝微粒体：0.5mg/mL，Xenotech；大鼠肝微粒体：0.5mg/mL，Xenotech；小鼠肝微粒体：0.5mg/mL，Xenotech；辅酶(NADPH/NADH)：1mM，Sigma Life Science；氯化镁：5mM，100mM磷酸盐缓冲剂(pH为7.4)。
储备液的配制：精密称取一定量的实施例化合物的粉末，并用DMSO分别溶解至5mM。
磷酸盐缓冲液(100mM，pH7.4)的配制：取预先配好的150mL的0.5M磷酸二氢钾和700mL的0.5M磷酸氢二钾溶液混合，再用0.5M磷酸氢二钾溶液调节混合液pH值至7.4，使用前用超纯 水稀释5倍，加入氯化镁，得到磷酸盐缓冲液(100mM)，其中含100mM磷酸钾，3.3mM氯化镁，pH为7.4。
配制NADPH再生***溶液(含有6.5mM NADP，16.5mM G-6-P，3U/mL G-6-P D，3.3mM氯化镁)，使用前置于湿冰上。
配制终止液：含有50ng/mL盐酸***和200ng/mL甲苯磺丁脲(内标)的乙腈溶液。取25057.5μL磷酸盐缓冲液(pH7.4)至50mL离心管中，分别加入812.5μL人肝微粒体、大鼠肝微粒体和小鼠肝微粒体，混匀，得到蛋白浓度为0.625mg/mL的肝微粒体稀释液。样品的孵育：用含70％乙腈的水溶液将相应化合物的储备液分别稀释至0.25mM，作为工作液，备用。分别取398μL的人肝微粒体或者大鼠肝微粒体或者小鼠肝微粒体稀释液加入96孔孵育板中(N＝2)，分别加入2μL0.25mM的的工作液中，混匀。
代谢稳定性的测定：在96孔深孔板的每孔中加入300μL预冷的终止液，并置于冰上，作为终止板。将96孔孵育板和NADPH再生***置于37℃水浴箱中，100转/分钟震荡，预孵5min。从孵育板每孔取出80μL孵育液加入终止板，混匀，补充20μL NADPH再生***溶液，作为0min样品。再向孵育板每孔加入80μL的NADPH再生***溶液，启动反应，开始计时。相应化合物的反应浓度为1μM，蛋白浓度为0.5mg/mL。分别于反应10、30、90min时，各取100μL反应液，加入终止板中，涡旋3min终止反应。将终止板于5000×g，4℃条件下离心10min。取100μL上清液至预先加入100μL蒸馏水的96孔板中，混匀，采用LC-MS/MS进行样品分析。
数据分析：通过LC-MS/MS***检测相应化合物及内标的峰面积，计算化合物与内标峰面积比值。通过化合物剩余量的百分率的自然对数与时间作图测得斜率，并根据以下公式计算t 1/2和CL int，其中V/M即等于1/蛋白浓度。
Figure PCTCN2018109043-appb-000022
在上述代谢稳定性评价实验中测试了本发明化合物和未经氘代的化合物Fedratinib，发现本发明化合物具有更长的半衰期和更短的清除率，具有更优异的代谢稳定性。代表性实施例化合物代谢稳定性结果归纳于表3中。
表3
Figure PCTCN2018109043-appb-000023
Figure PCTCN2018109043-appb-000024
(4)大鼠药代动力学实验
6只雄性Sprague-Dawley大鼠，7-8周龄，体重约210g，分成2组，每组3只，经静脉或口服单个剂量的化合物(静脉3mg/kg；口服10mg/kg)，比较其药代动力学差异。
大鼠采用标准饲料饲养，给予水。试验前16小时开始禁食。药物用PEG400和二甲亚砜溶解。眼眶采血，采血的时间点为给药后0.083小时，0.25小时、0.5小时、1小时、2小时、4小时、6小时、8小时、12小时和24小时。
大鼠吸入***后短暂麻醉，眼眶采集300μL血样于试管。试管内有30μL 1％肝素盐溶液。使用前，试管于60℃烘干过夜。在最后一个时间点血样采集完成之后，大鼠***麻醉后处死。
血样采集后，立即温和地颠倒试管至少5次，保证混合充分后放置于冰上。血样在4℃ 5000rpm离心5分钟，将血浆与红细胞分离。用移液器吸出100μL血浆到干净的塑料离心管中，标明化合物的名称和时间点。血浆在进行分析前保存在-80℃。用LC-MS/MS测定血浆中本发明化合物的浓度。药代动力学参数基于每只动物在不同时间点的血药浓度进计算。
在上述大鼠药代动力学实验中测试了本发明化合物和未经氘代的化合物Fedratinib，发现本发明化合物具有更好的口服利用度。代表性实施例化合物的口服利用度结果归纳于表4中。
表4
实施例化合物 Fedratinib T-5
口服利用度F(％) 7.24 7.48
以上内容是结合具体的优选实施方式对本发明所作的进一步详细说明，不能认定本发明的具体实施只局限于这些说明。对于本发明所属技术领域的普通技术人员来说，在不脱离本发明构思的前提下，还可以做出若干简单推演或替换，都应当视为属于本发明的保护范围。

Claims (17)

  1. 式(I)的化合物：
    Figure PCTCN2018109043-appb-100001
    其中，
    R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8、R 9、R 10、R 11、R 12、Y 1、Y 2、Y 3、Y 4、Y 5、Y 6、Y 7、Y 8和Y 9各自独立地选自自氢或氘；
    X 1、X 2、X 3和X 4各自独立地选自CH 3、CD 3、CHD 2和CH 2D；
    条件是如果X 1、X 2、X 3和X 4每个都是CH 3，那么R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8、R 9、R 10、R 11、R 12、Y 1、Y 2、Y 3、Y 4、Y 5、Y 6、Y 7、Y 8和Y 9中至少一个是氘；
    或其药学上可接受的盐、前药、水合物或溶剂化合物、晶型、N-氧化物和各种非对映体。
  2. 根据权利要求1所述的化合物，其为式(II)的化合物：
    Figure PCTCN2018109043-appb-100002
    其中，
    R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8、R 9、R 10、R 11、R 12、Y 5、X 1、X 2、X 3和X 4如权利要求1所定义；
    或其药学上可接受的盐、前药、水合物或溶剂化合物、晶型、N-氧化物和各种非对映体。
  3. 根据权利要求2所述的化合物，其中，R 5、R 6、R 7、R 8、R 9、R 10、R 11、R 12为氢。
  4. 根据权利要求2或3所述的化合物，其中，X 2为CH 3。
  5. 根据权利要求2-4中任一项所述的化合物，其中，Y 5为氢且X 4为CH 3。
  6. 根据权利要求2-5中任一项所述的化合物，其中，X 1和X 3是CH 3。
  7. 根据权利要求1-6中任一项所述的化合物，其中，R 1、R 2、R 3和R 4是氘。
  8. 根据权利要求1所述的化合物，其中所述化合物选自下述化合物：
    Figure PCTCN2018109043-appb-100003
    Figure PCTCN2018109043-appb-100004
    Figure PCTCN2018109043-appb-100005
    Figure PCTCN2018109043-appb-100006
    或其药学上可接受的盐、前药、水合物或溶剂化合物、晶型、N-氧化物和各种非对映体。
  9. 一种药物组合物，其含有药学上可接受的赋形剂和权利要求1-8中任一项所述的化合物，或其药学上可接受的盐、前药、水合物或溶剂化合物、晶型、N-氧化物和各种非对映体。
  10. 制备权利要求1-8中任一项所述的化合物，或其药学上可接受的盐、前药、水合物或溶剂化合物、晶型、N-氧化物和各种非对映体，或权利要求9所述的药物组合物用于治疗至少部分由JAK2介导的疾病的药物的方法。
  11. 制备权利要求1-8中任一项所述的化合物，或其药学上可接受的盐、前药、水合物或溶剂化合物、晶型、N-氧化物和各种非对映体，或权利要求9所述的药物组合物用于治疗至少部分由JAK2/V617F介导的疾病的药物的方法。
  12. 权利要求10或11所述的方法，其中所述疾病为骨髓组织增殖病症，真性红细胞增多症，特发性血小板增多，骨髓纤维化，任何其它与骨髓相关的病症，增生型糖尿病视网膜病变，癌症，眼病，炎症，银屑病，与血管发生相关的任何疾病或病毒感染。
  13. 权利要求12所述的方法，其中所述的疾病为真性红细胞增多症。
  14. 权利要求12所述的方法，其中所述的疾病为特发性血小板增多。
  15. 权利要求12所述的方法，其中所述的疾病为具有髓样化生的骨髓纤维化。
  16. 权利要求12所述的方法，其中所述的疾病为任何与骨髓相关的病症。
  17. 权利要求12所述的方法，其中所述疾病选自心血管疾病，血液病，慢性髓性白血病，骨髓增殖性疾病。
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