WO2016192563A1 - Janus激酶抑制剂 - Google Patents

Janus激酶抑制剂 Download PDF

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Publication number
WO2016192563A1
WO2016192563A1 PCT/CN2016/083426 CN2016083426W WO2016192563A1 WO 2016192563 A1 WO2016192563 A1 WO 2016192563A1 CN 2016083426 W CN2016083426 W CN 2016083426W WO 2016192563 A1 WO2016192563 A1 WO 2016192563A1
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group
alkyl
acid
pharmaceutically acceptable
compound
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PCT/CN2016/083426
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English (en)
French (fr)
Inventor
吴颢
毛魏魏
黄奕强
樊莉莉
陈曙辉
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南京明德新药研发股份有限公司
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Priority to KR1020177034636A priority Critical patent/KR102081272B1/ko
Priority to UAA201710092A priority patent/UA118822C2/uk
Priority to DK16802486.7T priority patent/DK3305788T3/da
Priority to ES16802486T priority patent/ES2822748T3/es
Priority to US15/577,674 priority patent/US10174056B2/en
Priority to EA201792116A priority patent/EA036063B1/ru
Priority to MX2017013797A priority patent/MX2017013797A/es
Priority to PL16802486T priority patent/PL3305788T3/pl
Priority to AU2016271904A priority patent/AU2016271904B2/en
Priority to EP16802486.7A priority patent/EP3305788B1/en
Priority to CA2983481A priority patent/CA2983481C/en
Priority to JP2017561893A priority patent/JP6564473B2/ja
Priority to CN201680022631.0A priority patent/CN107531711B/zh
Publication of WO2016192563A1 publication Critical patent/WO2016192563A1/zh

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    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • 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

Definitions

  • the present invention relates to a series of Janus kinase inhibitors, in particular to a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • JAK belongs to the family of tyrosine kinases involved in inflammation, autoimmune diseases, proliferative diseases, transplant rejection, diseases involving cartilage turnover, congenital cartilage malformations, and/or diseases associated with excessive secretion of IL6.
  • the present invention also provides a method for producing the compound, a pharmaceutical composition containing the same, and a disease for preventing and/or treating inflammation, autoimmune diseases, proliferative diseases, transplant rejection, and diseases involving cartilage turnover by administering the compound of the present invention.
  • Janus kinase is a cytoplasmic tyrosine kinase that transduces cytokine signaling from membrane receptors to STAT transcription factors.
  • JAK family members have been described in the prior art: JAK1, JAK2, JAK3, and TYK2. When a cytokine binds to its receptor, members of the JAK family autophosphorylate and/or transphosphorylate to each other, followed by phosphorylation of STATs and then migration into the nucleus to regulate transcription.
  • JAK-STAT intracellular signal transduction is suitable for interferon, most interleukins, and various cytokines and endocrine factors such as EPO, TPO, GH, OSM, LIF, CNTF, GM-CSF, and PRL (Vainchenker W. People (2008)).
  • JAK3 was confirmed to be an immunosuppressive target by mouse and human genetics (O'Shea J. et al. (2004)). JAK3 inhibitors have been successfully used in clinical development, initially for organ transplant rejection, but later also for other immunoinflammatory indications such as rheumatoid arthritis (RA), psoriasis and Crohn's disease (http://clinicaltrials .gov/).
  • TYK2 is a potential target for immunoinflammatory diseases and has been confirmed by human genetics and mouse knockout studies (Levy D. and Loomis C. (2007)). JAK1 is a new target in the field of immunoinflammatory diseases.
  • JAK1 is dimerized with other JAKs to transduce cytokine-driven pro-inflammatory signaling.
  • inhibition of JAK1 and/or other JAKs is expected to have therapeutic benefit for a range of inflammatory conditions and other diseases driven by JAK-mediated signaling.
  • the present invention provides a compound of the formula (I) or a pharmaceutically acceptable salt thereof,
  • R is selected from C(R) or N;
  • R 1 is selected from H, CN, OH, NH 2 , halogen, or selected from the group consisting of 1, 2 , 3 or 4 R substituted: C 1-6 alkyl, C 1-6 heteroalkyl, C 3 -6 membered cycloalkyl, 3-6 membered heterocycloalkyl;
  • R is independently selected from H, CN, OH, NH 2 , halogen, or respectively selected from C 2 1-6 alkyl, C 1-6 heteroalkyl optionally substituted by 1, 2 , 3 or 4 R'. base;
  • R' is selected from the group consisting of halogen, OH, NH 2 , CN, Me, Et, CF 3 , CH 2 CF 3 , NHCH 3 , N(CH 3 ) 2 ;
  • the number of "hetero” in any of the above cases is independently selected from 1, 2 or 3.
  • the above R is selected from the group consisting of H, CN, OH, NH 2 , halogen, or selected from the group consisting of 1, 2 or 3 R' substitutions: Me, Et, NHCH 3 , N (CH 3 2 , NHCH 3 , N(CH 3 ) 2 ,
  • R 1 is selected from the group consisting of CN or selected from the group consisting of 1, 2, 3 or 4 R: Me, Et,
  • R 1 is selected from the group consisting of CN, Me,
  • the invention also provides a preparation method of the compound of formula (I), comprising the following steps:
  • PG is an amino protecting group selected from the group consisting of benzyloxycarbonyl (Cbz), tert-butoxycarbonyl (Boc), fluorenyloxycarbonyl (Fmoc), allyloxycarbonyl (Alloc), trimethylsilyloxycarbonyl (Teco) , methoxycarbonyl, ethoxycarbonyl, phthaloyl (Pht), p-toluenesulfonyl (Tos), trifluoroacetyl (Tfa), benzyl (Bn), p-methoxybenzyl (PMB).
  • the invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound as described above, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • the present invention also provides the use of the above compound or a pharmaceutically acceptable salt thereof or the above pharmaceutical composition for the preparation of a medicament for the treatment of a disease associated with Janus kinase.
  • the disease is arthritis.
  • the disease is rheumatoid arthritis.
  • pharmaceutically acceptable salt refers to a salt of a compound of the invention prepared from a compound having a particular substituent found in the present invention and a relatively non-toxic acid or base.
  • a base addition salt can be obtained by contacting a neutral amount of such a compound with a sufficient amount of a base in a neat solution or a suitable inert solvent.
  • Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic ammonia or magnesium salts or similar salts.
  • an acid addition salt can be obtained by contacting a neutral form of such a compound with a sufficient amount of an acid in a neat solution or a suitable inert solvent.
  • pharmaceutically acceptable acid addition salts include inorganic acid salts including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, hydrogencarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, Hydrogen sulfate, hydroiodic acid, phosphorous acid, etc.; and an organic acid salt, such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, Similar acids such as fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, and me
  • the salt is contacted with a base or acid in a conventional manner, and the parent compound is separated, thereby regenerating the neutral form of the compound.
  • the parent form of the compound differs from the form of its various salts by certain physical properties, such as differences in solubility in polar solvents.
  • a "pharmaceutically acceptable salt” is a derivative of a compound of the invention wherein the parent compound is modified by salt formation with an acid or with a base.
  • pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of bases such as amines, alkali metal or organic salts of acid groups such as carboxylic acids, and the like.
  • Pharmaceutically acceptable salts include the conventional non-toxic salts or quaternary ammonium salts of the parent compound, for example salts formed from non-toxic inorganic or organic acids.
  • non-toxic salts include, but are not limited to, those derived from inorganic acids and organic acids selected from the group consisting of 2-acetoxybenzoic acid, 2-hydroxyethanesulfonic acid, acetic acid, ascorbic acid, Benzenesulfonic acid, benzoic acid, hydrogencarbonate, carbonic acid, citric acid, edetic acid, ethane disulfonic acid, ethanesulfonic acid, fumaric acid, glucoheptose, gluconic acid, glutamic acid, glycolic acid, Hydrobromic acid, hydrochloric acid, hydroiodide, hydroxyl, hydroxynaphthalene, isethionethane, lactic acid, lactose, dodecylsulfonic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, nitric acid, oxalic acid, Pamoic acid, pantothenic acid, phenylacetic acid, phen
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound containing an acid group or a base by conventional chemical methods.
  • such salts are prepared by reacting these compounds in water or an organic solvent or a mixture of the two via a free acid or base form with a stoichiometric amount of a suitable base or acid.
  • a nonaqueous medium such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile is preferred.
  • the compounds provided herein also exist in the form of prodrugs.
  • Prodrugs of the compounds described herein are readily chemically altered under physiological conditions to convert to the compounds of the invention.
  • prodrugs can be converted to the compounds of the invention by chemical or biochemical methods in an in vivo setting.
  • Certain compounds of the invention may exist in unsolvated or solvated forms, including hydrated forms.
  • the solvated forms are equivalent to the unsolvated forms and are included within the scope of the invention.
  • Certain compounds of the invention may have asymmetric carbon atoms (optical centers) or double bonds. Racemates, diastereomers, geometric isomers and individual isomers are included within the scope of the invention.
  • the compounds of the invention may exist in specific geometric or stereoisomeric forms.
  • the present invention contemplates all such compounds, including the cis and trans isomers, the (-)- and (+)-p-enantiomers, the (R)- and (S)-enantiomers, and the diastereomeric a conformation, a (D)-isomer, a (L)-isomer, and a racemic mixture thereof, and other mixtures, such as enantiomerically or diastereomeric enriched mixtures, all of which belong to It is within the scope of the invention.
  • Additional asymmetric carbon atoms may be present in the substituents such as alkyl groups. All of these isomers and mixtures thereof, It is included in the scope of the invention.
  • optically active (R)- and (S)-isomers as well as the D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If an enantiomer of a compound of the invention is desired, it can be prepared by asymmetric synthesis or by derivatization with a chiral auxiliary wherein the resulting mixture of diastereomers is separated and the auxiliary group cleaved to provide pure The desired enantiomer.
  • a diastereomeric salt is formed with a suitable optically active acid or base, followed by conventional methods well known in the art.
  • the diastereomers are resolved and the pure enantiomer is recovered.
  • the separation of enantiomers and diastereomers is generally accomplished by the use of chromatography using a chiral stationary phase, optionally in combination with chemical derivatization (eg, formation of an amino group from an amine). Formate).
  • the compounds of the present invention may contain unnatural proportions of atomic isotopes on one or more of the atoms that make up the compound.
  • radiolabeled compounds can be used, such as tritium (3 H), iodine -125 (125 I) or C-14 (14 C). Alterations of all isotopic compositions of the compounds of the invention, whether radioactive or not, are included within the scope of the invention.
  • pharmaceutically acceptable carrier refers to any formulation or carrier medium that is capable of delivering an effective amount of an active substance of the present invention, does not interfere with the biological activity of the active substance, and has no toxic side effects to the host or patient, including water, oil, Vegetables and minerals, cream bases, lotion bases, ointment bases, etc. These bases include suspending agents, tackifiers, transdermal enhancers and the like. Their formulations are well known to those skilled in the cosmetic or topical pharmaceutical arts. For additional information on vectors, reference is made to Remington: The Science and Practice of Pharmacy, 21st Ed., Lippincott, Williams & Wilkins (2005), the contents of which are hereby incorporated by reference.
  • excipient generally refers to the carrier, diluent and/or vehicle required to formulate an effective pharmaceutical composition.
  • an "effective amount” or “therapeutically effective amount” with respect to a pharmaceutical or pharmacologically active agent refers to a sufficient amount of a drug or agent that is non-toxic but that achieves the desired effect.
  • an "effective amount” of an active substance in a composition refers to the amount required to achieve the desired effect when used in combination with another active substance in the composition. The determination of the effective amount will vary from person to person, depending on the age and general condition of the recipient, and also on the particular active substance, and a suitable effective amount in a case can be determined by one skilled in the art based on routine experimentation.
  • active ingredient refers to a chemical entity that is effective in treating a target disorder, disease or condition.
  • substituted means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, and may include variants of heavy hydrogen and hydrogen, as long as the valence of the particular atom is normal and the substituted compound is stable. of.
  • Ketone substitution does not occur on the aryl group.
  • optionally substituted means that it may or may not be substituted, and unless otherwise specified, the kind and number of substituents may be arbitrary on the basis of chemically achievable.
  • any variable eg, R
  • its definition in each case is independent.
  • the group may optionally be substituted with at most two R, and each case has an independent option.
  • combinations of substituents and/or variants thereof are permissible only if such combinations result in stable compounds.
  • linking group When the number of one linking group is 0, such as -(CRR) 0 -, it indicates that the linking group is a single bond.
  • one of the variables When one of the variables is selected from a single bond, it means that the two groups to which it is attached are directly linked. For example, when L represents a single bond in A-L-Z, the structure is actually A-Z.
  • substituent When a substituent is vacant, it means that the substituent is absent. For example, when X is vacant in AX, the structure is actually A. When a bond of a substituent can be cross-linked to two atoms on a ring, the substituent can be bonded to any atom on the ring. When the recited substituents do not indicate which atom is attached to a compound included in the chemical structural formula including but not specifically mentioned, such a substituent may be bonded through any atomic phase thereof. Combinations of substituents and/or variants thereof are permissible only if such combinations result in stable compounds. For example, a structural unit It is indicated that it can be substituted at any position on the cyclohexyl or cyclohexadiene.
  • hetero denotes a hetero atom or a hetero atomic group (ie, a radical containing a hetero atom), including atoms other than carbon (C) and hydrogen (H), and radicals containing such heteroatoms, including, for example, oxygen (O).
  • ring means substituted or unsubstituted cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, cycloalkynyl, heterocycloalkynyl, aryl or heteroaryl. So-called rings include single rings, interlocking rings, spiral rings, parallel rings or bridge rings. The number of atoms on the ring is usually defined as the number of elements of the ring. For example, "5 to 7-membered ring” means 5 to 7 atoms arranged in a circle. Unless otherwise specified, the ring optionally contains from 1 to 3 heteroatoms.
  • 5- to 7-membered ring includes, for example, phenyl, pyridine, and piperidinyl; on the other hand, the term “5- to 7-membered heterocycloalkyl ring” includes pyridyl and piperidinyl, but does not include phenyl.
  • ring also includes ring systems containing at least one ring, each of which "ring” independently conforms to the above definition.
  • heterocycle or “heterocyclyl” means a stable monocyclic, bicyclic or tricyclic ring containing a hetero atom or a heteroatom group which may be saturated, partially unsaturated or unsaturated ( Aromatic) which comprise a carbon atom and 1, 2, 3 or 4 ring heteroatoms independently selected from N, O and S, wherein any of the above heterocycles may be fused to a phenyl ring to form a bicyclic ring.
  • the nitrogen and sulfur heteroatoms can be optionally oxidized (i.e., NO and S(O)p, p is 1 or 2).
  • the nitrogen atom can be substituted or unsubstituted (i.e., N or NR, wherein R is H or other substituents as already defined herein).
  • the heterocyclic ring can be attached to the side groups of any hetero atom or carbon atom to form a stable structure. If the resulting compound is stable, the heterocycles described herein can undergo substitutions at the carbon or nitrogen sites.
  • the nitrogen atom in the heterocycle is optionally quaternized.
  • a preferred embodiment is that when the total number of S and O atoms in the heterocycle exceeds 1, these heteroatoms are not adjacent to each other. Another preferred embodiment is that the total number of S and O atoms in the heterocycle does not exceed one.
  • aromatic heterocyclic group or "heteroaryl” as used herein means a stable 5, 6, or 7 membered monocyclic or bicyclic or aromatic ring of a 7, 8, 9 or 10 membered bicyclic heterocyclic group, It contains carbon atoms and 1, 2, 3 or 4 ring heteroatoms independently selected from N, O and S.
  • the nitrogen atom can be substituted or unsubstituted (i.e., N or NR, wherein R is H or other substituents as already defined herein).
  • the nitrogen and sulfur heteroatoms can be optionally oxidized (i.e., NO and S(O)p, p is 1 or 2).
  • bridged rings are also included in the definition of heterocycles.
  • a bridged ring is formed when one or more atoms (ie, C, O, N, or S) join two non-adjacent carbon or nitrogen atoms.
  • Preferred bridged rings include, but are not limited to, one carbon atom, two carbon atoms, one nitrogen atom, two nitrogen atoms, and one carbon-nitrogen group. It is worth noting that a bridge always converts a single ring into a three ring. In the bridged ring, a substituent on the ring can also be present on the bridge.
  • heterocyclic compounds include, but are not limited to, acridinyl, octanoyl, benzimidazolyl, benzofuranyl, benzofuranylfuranyl, benzindenylphenyl, benzoxazolyl, benzimidin Oxazolinyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolyl, oxazolyl, 4aH-carbazolyl, Porphyrin, chroman, chromene, porphyrin-decahydroquinolinyl, 2H, 6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b] Tetrahydrofuranyl, furyl, furfuryl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-carbazolyl, nonenyl,
  • hydrocarbyl or its subordinate concept (such as alkyl, alkenyl, alkynyl, aryl, etc.), by itself or as part of another substituent, is meant to be straight-chain, branched or cyclic.
  • the hydrocarbon atom group or a combination thereof may be fully saturated (such as an alkyl group), a unit or a polyunsaturated (such as an alkenyl group, an alkynyl group, an aryl group), may be monosubstituted or polysubstituted, and may be monovalent (such as Methyl), divalent (such as methylene) or polyvalent (such as methine), may include divalent or polyvalent radicals with a specified number of carbon atoms (eg, C 1 -C 12 represents 1 to 12 carbons) , C 1-12 is selected from C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 , C 11 and C 12 ; C 3-12 is selected from C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 , C 11 and C 12 .).
  • C 1-12 is selected from C 1
  • Hydrocarbyl includes, but is not limited to, aliphatic hydrocarbyl groups including chain and cyclic, including but not limited to alkyl, alkenyl, alkynyl groups including, but not limited to, 6-12 members.
  • An aromatic hydrocarbon group such as benzene, naphthalene or the like.
  • hydrocarbyl means a straight or branched chain radical or a combination thereof, which may be fully saturated, unitary or polyunsaturated, and may include divalent and multivalent radicals.
  • saturated hydrocarbon radicals include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, isobutyl, cyclohexyl, (cyclohexyl).
  • a homolog or isomer of a methyl group, a cyclopropylmethyl group, and an atomic group such as n-pentyl, n-hexyl, n-heptyl, n-octyl.
  • the unsaturated hydrocarbon group has one or more double or triple bonds, and examples thereof include, but are not limited to, a vinyl group, a 2-propenyl group, a butenyl group, a crotyl group, a 2-isopentenyl group, and a 2-(butadienyl group). , 2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and higher homologs and isomers body.
  • heterohydrocarbyl or its subordinate concept (such as heteroalkyl, heteroalkenyl, heteroalkynyl, heteroaryl, etc.), by itself or in combination with another term, means a stable straight chain, branched chain. Or a cyclic hydrocarbon radical or a combination thereof having a number of carbon atoms and at least one heteroatom.
  • heteroalkyl by itself or in conjunction with another term refers to a stable straight chain, branched hydrocarbon radical or combination thereof, having a number of carbon atoms and at least one heteroatom.
  • the heteroatoms are selected from the group consisting of B, O, N, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen heteroatoms are optionally quaternized.
  • the hetero atom or heteroatom group may be located at any internal position of the heterohydrocarbyl group, including where the hydrocarbyl group is attached to the rest of the molecule, but the terms "alkoxy”, “alkylamino” and “alkylthio” (or thioalkoxy). By customary expression, those alkyl groups which are attached to the remainder of the molecule through an oxygen atom, an amino group or a sulfur atom, respectively.
  • Up to two heteroatoms may be consecutive, for example, -CH 2 -NH-OCH 3.
  • cycloalkyl refers to any heterocyclic alkynyl group, etc., by itself or in combination with other terms, denotes a cyclized “hydrocarbyl group” or “heterohydrocarbyl group”, respectively.
  • a hetero atom may occupy a position at which the hetero ring is attached to the rest of the molecule.
  • cycloalkyl groups include, but are not limited to, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like.
  • heterocyclic groups include 1-(1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothiophen-2-yl, tetrahydrothiophen-3-yl, 1-piperazinyl and 2-piperazinyl.
  • alkyl is used to denote a straight or branched saturated hydrocarbon group, which may be monosubstituted (eg, -CH 2 F) or polysubstituted (eg, -CF 3 ), and may be monovalent (eg, Methyl), divalent (such as methylene) or polyvalent (such as methine).
  • alkyl group include methyl (Me), ethyl (Et), propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, s-butyl). , t-butyl), pentyl (eg, n-pentyl, isopentyl, neopentyl) and the like.
  • alkenyl refers to an alkyl group having one or more carbon-carbon double bonds at any position of the chain, which may be mono- or poly-substituted, and may be monovalent, divalent or multivalent.
  • alkenyl group include a vinyl group, a propenyl group, a butenyl group, a pentenyl group, a hexenyl group, a butadienyl group, a pentadienyl group, a hexadienyl group and the like.
  • alkynyl refers to an alkyl group having one or more carbon-carbon triple bonds at any position of the chain, which may be mono- or poly-substituted, and may be monovalent, divalent or multivalent.
  • alkynyl groups include ethynyl, propynyl, butynyl, pentynyl and the like.
  • a cycloalkyl group includes any stable cyclic or polycyclic hydrocarbon group, any carbon atom which is saturated, may be monosubstituted or polysubstituted, and may be monovalent, divalent or multivalent.
  • Examples of such cycloalkyl groups include, but are not limited to, cyclopropyl, norbornyl, [2.2.2]bicyclooctane, [4.4.0]bicyclononane, and the like.
  • a cycloalkenyl group includes any stable cyclic or polycyclic hydrocarbon group which contains one or more unsaturated carbon-carbon double bonds at any position of the ring, and may be monosubstituted or polysubstituted, It can be one price, two price or multiple price.
  • Examples of such cycloalkenyl groups include However, it is not limited to cyclopentenyl, cyclohexenyl and the like.
  • a cycloalkynyl group includes any stable cyclic or polycyclic hydrocarbon group which contains one or more carbon-carbon triple bonds at any position of the ring, which may be monosubstituted or polysubstituted, and may be one Price, price or price.
  • halo or “halogen”, by itself or as part of another substituent, denotes a fluorine, chlorine, bromine or iodine atom.
  • haloalkyl is intended to include both monohaloalkyl and polyhaloalkyl.
  • halo(C 1 -C 4 )alkyl is intended to include, but is not limited to, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like. Wait.
  • examples of haloalkyl include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, and pentachloroethyl.
  • alkoxy represents attached through an oxygen bridge
  • C 1-6 alkoxy groups include C 1, C 2, C 3 , C 4, C 5 , and C 6 alkoxy groups.
  • alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentyloxy and S- Pentyloxy.
  • aryl denotes a polyunsaturated, aromatic hydrocarbon substituent which may be monosubstituted or polysubstituted, which may be monovalent, divalent or polyvalent, which may be monocyclic or polycyclic ( For example, 1 to 3 rings; at least one of which is aromatic), they are fused together or covalently linked.
  • heteroaryl refers to an aryl (or ring) containing one to four heteroatoms. In an illustrative example, the heteroatoms are selected from the group consisting of B, N, O, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom is optionally quaternized.
  • a heteroaryl group can be attached to the remainder of the molecule through a heteroatom.
  • aryl or heteroaryl groups include phenyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyridyl Azyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxan Azyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thiophene , 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-benzothiazolyl, 5-
  • aryl groups when used in conjunction with other terms (e.g., aryloxy, arylthio, aralkyl), include aryl and heteroaryl rings as defined above.
  • aralkyl is intended to include those radicals to which an aryl group is attached to an alkyl group (eg, benzyl, phenethyl, pyridylmethyl, and the like), including wherein the carbon atom (eg, methylene) has been, for example, oxygen.
  • alkyl groups substituted by an atom such as phenoxymethyl, 2-pyridyloxymethyl 3-(1-naphthyloxy)propyl and the like.
  • leaving group refers to a functional group or atom which may be substituted by another functional group or atom by a substitution reaction (for example, an affinity substitution reaction).
  • substituent groups include triflate; chlorine, bromine, iodine; sulfonate groups such as mesylate, tosylate, p-bromobenzenesulfonate, p-toluenesulfonic acid Esters and the like; acyloxy groups such as acetoxy, trifluoroacetoxy and the like.
  • protecting group includes, but is not limited to, "amino protecting group", “hydroxy protecting group” or “thiol protecting group”.
  • amino protecting group refers to a protecting group suitable for preventing side reactions at the amino nitrogen position.
  • Representative amino protecting groups include, but are not limited to, formyl; acyl, such as alkanoyl (e.g., acetyl, trichloroacetyl or trifluoroacetyl); alkoxycarbonyl, e.g., tert-butoxycarbonyl (Boc) Arylmethoxycarbonyl, such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethoxycarbonyl (Fmoc); arylmethyl, such as benzyl (Bn), trityl (Tr), 1, 1-di -(4'-methoxy Phenyl)methyl; silyl groups such as trimethylsilyl (TMS) and tert
  • hydroxy protecting group refers to a protecting group suitable for use in preventing hydroxy side reactions.
  • Representative hydroxy protecting groups include, but are not limited to, alkyl groups such as methyl, ethyl and t-butyl groups; acyl groups such as alkanoyl groups (e.g., acetyl); arylmethyl groups such as benzyl (Bn), Oxybenzyl (PMB), 9-fluorenylmethyl (Fm) and diphenylmethyl (diphenylmethyl, DPM); silyl groups such as trimethylsilyl (TMS) and tert-butyl Dimethylsilyl (TBS) and the like.
  • alkyl groups such as methyl, ethyl and t-butyl groups
  • acyl groups such as alkanoyl groups (e.g., acetyl)
  • arylmethyl groups such as benzyl (Bn), Oxybenzyl (PMB), 9-fluoreny
  • the compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments set forth below, combinations thereof with other chemical synthetic methods, and those well known to those skilled in the art. Equivalent alternatives, preferred embodiments include, but are not limited to, embodiments of the invention.
  • the solvent used in the present invention is commercially available.
  • the present invention employs the following abbreviations: aq for water; HATU for O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate ; EDC stands for N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride; m-CPBA stands for 3-chloroperoxybenzoic acid; eq stands for equivalent, equivalent; CDI stands for Carbonyldiimidazole; DCM stands for dichloromethane; PE stands for petroleum ether; DIAD stands for diisopropyl azodicarboxylate; DMF stands for N,N-dimethylformamide; DMSO stands for dimethyl sulfoxide; EtOAc stands for acetic acid Esters; EtOH for ethanol; MeOH for methanol; Cbz for benzyl
  • Step 4 To a solution of 4-nitropyridin-2-amine (200 mg, 1.4 mmol) in DME (5 mL), ethyl 3-bromo-2-oxo-propanoate (280 mg, 1.4 mmol). After the mixture was stirred at 25 ° C for 1 hour, the solvent was evaporated, evaporated, evaporated, evaporated. TLC showed the reaction was complete. The reaction solution was cooled to room temperature, and the solvent was concentrated under reduced pressure. The residue was basified with aq. EtOAc (EtOAc)EtOAc.
  • Step 6 7-Amino-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxylic acid ethyl ester hydrochloride (100 mg, 0.4 mmol) and 4-chloro-7 -(p-Toluenesulfonyl)pyrrolo[2,3-d]pyrimidine (137 mg, 0.4 mmol) was dissolved in n-BuOH (5 mL), and DIEA (158 mg, 1.2 mmol) was added, and the mixture was stirred and refluxed for 16 hours. . LC-MS showed the reaction was complete.
  • Step 7 7-[[7-(p-toluenesulfonyl)pyrrolo[2,3-d]pyrimidin-4-yl]amino]-5,6,7, in a N 2 atmosphere at 0 ° C.
  • a solution of ethyl 4-tetrahydroimidazo[1,2-a]pyridine-2-carboxylate (3.0 g, 6.2 mmol) in THF (150 mL) The mixture was further stirred at this temperature for 1 hour, and then MeI (7.1 g, 50.2 mmol) was added dropwise, and after the addition was completed, the mixture was stirred at room temperature for further 1 hour. TLC showed the reaction was complete.
  • Step 8 7-[Methyl-[7-(p-toluenesulfonyl)pyrrolo[2,3-d]pyrimidin-4-yl]amino]-5,6,7,8- at 25 °C
  • EtOAc EtOAc
  • EtOAc EtOAc
  • Step 10 7-[Methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-5,6,7,8-tetrahydroimidazo[1,2- at room temperature
  • dichloromethane 300 mg, 2.5 mmol was added and the mixture was stirred at 70 ° C for 1 hour.
  • Step 11 To N-[2-(chloromethyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-7-yl]-N-methyl-7H-pyrrole To a solution of [2,3-d]pyrimidin-4-amine (150 mg, 0.42 mmol) in EtOAc (5 mL). LC-MS indicated complete consumption of the starting material and product formation. It was quenched by the addition of water (10 mL)EtOAc. The organic phase was combined and washed with EtOAc EtOAc (EtOAc m.
  • Step 12 Oscillating 2-[7-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-5,6,7,8-tetrahydroimidazo[1] , 2-a]pyridin-2-yl]acetonitrile (WX552) (30 mg) was isolated on a chiral column to give (S or R)2-[7-[methyl(7H-pyrrolo[2,3-d] Pyrimidin-4-yl)amino]-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-2-yl]acetonitrile (WX612, 10 mg) and (R or S) 2-[7 -[Methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-2-yl] Acetonitrile (WX613, 11 mg).
  • Nozzle temperature 60 ° C
  • Step 1 7-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-5,6,7,8-tetrahydroimidazo[1,2- at room temperature
  • Pyridin-2-yl]methanol (Intermediate 2) (200 mg, 0.44 mmol) in EtOAc (EtOAc)
  • EtOAc EtOAc
  • LC-MS showed the reaction was consumed completely.
  • Step 2 In a nitrogen atmosphere at 0 ° C, to contain 7-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-5,6,7,8-tetrahydro Diethylaminosulfur trifluoride (DAST) (228 mg, 1.41 mmol) was added to a solution of the imidazo[1,2-a]pyridine-2-carboxaldehyde (159 mg, 0.35 mmol) in DCM (8 mL). The mixture was transferred to 25 ° C and the reaction was stirred for 14 hours. LC-MS showed the reaction was complete. The reaction mixture was poured into aq.
  • DAST Diethylaminosulfur trifluoride
  • Step 2 At 0 ° C, N-[2-(aminomethyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-7-yl]-N-A was dissolved. Methanesulfonyl chloride was added to a solution of benzyl-7-(p-methylbenzenesulfonyl)pyrrolo[2,3-d]pyrimidin-4-amine (150 mg, 0.33 mmol) and TEA (100 mg, 1 mmol) in DCM (5 mL) (46 mg, 0.4 mmol), the resulting mixture was transferred to 25 ° C and stirred for 16 hours. LC-MS showed the reaction was complete. The mixture was concentrated under reduced pressure to remove the solvent.
  • Step 3 To N-((7-(methyl-(7-(p-tolyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amine)-5,6,7 at room temperature , 8-tetrahydro-imidazo [1,2-a] pyridin-2-yl) methyl) methanesulfonamide (50mg, 0.94mmol) in H 2 O (5mL) / THF (5 mL) was added NaOH solution ( 6 mg, 0.14 mmol). The obtained mixture was stirred and refluxed for 4 hours at 90 ° C. TLC showed that the starting material was consumed completely, and a new point was formed; LCMS showed the target molecular weight. The reaction mixture was concentrated under reduced pressure to remove solvent.
  • Step 1 in ethyl 7-[methyl-[7-(p-toluenesulfonyl)pyrrole[2,3-d]pyrimidin-4-yl]amino]-5,6,7,8-tetrahydroimidazole [ 1,2-a] pyridine-2-carboxylate (4.0g, 8.1mmol) in THF (40mL) and H 2 O (8mL) was added LiOH.H 2 O (509mg, 12.1mmol) , the The mixture was stirred at 20 ° C for 10 hours. TLC indicated that the reactants were completely consumed.
  • Step 2 7-[Methyl-[7-(p-toluenesulfonyl)pyrrole[2,3-d]pyrimidin-4-yl]amino]-5,6,7,8-four at 0 °C
  • a solution of hydrogen imidazole [1,2-a]pyridine-2-carboxylic acid (1.8 g, 3.9 mmol) in DMF (20 mL).
  • solid ammonium chloride 2.1 g, 38.6 mmol
  • Step 3 7-[Methyl-[7-(p-toluenesulfonyl)pyrrole[2,3-d]pyrimidin-4-yl]amino]-5,6,7,8-tetrahydroimidazole [1, 2-a]pyridine-2-carboxamide (2.5 g, 5.4 mmol) was dissolved in THF (20 mL), MeOH (10 mL) and H2O (6 mL). The mixture was heated to 60 ° C and stirred for 30 minutes. LC-MS showed the reaction was consumed completely.
  • Step 4 7-[Methyl-[7-hydropyrrole[2,3-d]pyrimidin-4-yl]amino]-5,6,7,8-tetrahydroimidazole [1,2] at 0 °C -a] a solution of pyridine-2-carboxamide (2.0 g, 6.4 mmol) and triethylamine (3.9 g, 38.5 mmol) in THF (20 mL), THF (4.1 g, 19.3 mmol). The reaction solution was stirred at room temperature for 30 minutes. LC-MS showed the starting material was completely consumed. The reaction mixture was poured into ice water (20 mL)EtOAc. The combined organic layers were washed with EtOAc EtOAc m.
  • Step 5 Cyclotron 7-[methyl-[7-hydropyrrole[2,3-d]pyrimidin-4-yl]amino]-5,6,7,8-tetrahydroimidazole [1,2-a Pyridine-2-carbonitrile (30 mg, 102.3 umol) was isolated by chiral column to give (S or R)-7-[methyl-[7-hydropyrrole[2,3-d]pyrimidin-4-yl]amino]- 5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carbonitrile (P1, WX614, 10 mg, yield 32.8%) and (R or S)-7-[methyl-[ 7-hydropyrrole[2,3-d]pyrimidin-4-yl]amino]-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carbonitrile (WX615, 10 mg, yield 31.9%).
  • Nozzle temperature 60 ° C
  • Step 1 7-[Methyl(7H-pyrrole[2,3-d]pyrimidin-4-yl)amino]-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-
  • Preparation and purification of carboxylic acid with 7-[methyl-[7-hydropyrrole[2,3-d]pyrimidin-4-yl]amino]-5,6,7,8-tetrahydroimidazole [1,2-a The preparation and purification of pyridine-2-carboxamide are the same.
  • MS (ESI) calcd C 2 312, the measured value 15 H 16 N 6 O 313 [ M + H] +.
  • Step 2 7-[Methyl(7H-pyrrole[2,3-d]pyrimidin-4-yl)amino]-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2 -
  • Carboxylic acid 120 mg, 384.2 umol
  • EDCI 184 mg, 960.5 umol
  • pyridine 5 mL
  • 3,3-difluorocyclobutylamine 49 mg, 461.1
  • Recombinant human JAK1, JAK2, and JAK3 proteases were purchased from Life technology.
  • LANCE Ultra ULight TM -JAK-1 ( Tyr1023) peptide and LANCE Eu-W1024 Anti-phosphotyrosine ( PT66) were purchased from PerkinElmer. The plates were read using a multi-plate reader Envision (PerkinElmer).
  • test compounds were subjected to a 3-fold concentration gradient dilution at a final concentration of 10 uM to 0.17 nM 11 concentrations of two replicate wells per concentration; DMSO was 1% in the assay reaction.
  • test plate was a White Proxiplate 384-Plus plate (PerkinElmer), and reacted at room temperature for 90 minutes, and the reaction system was 10 ul.
  • test plate was a White Proxiplate 384-Plus plate (PerkinElmer), and reacted at room temperature for 60 minutes, and the reaction system was 10 ul.
  • test plate was a White Proxiplate 384-Plus plate (PerkinElmer), and reacted at room temperature for 90 minutes, and the reaction system was 10 ul.
  • the clear solution obtained by dissolving the test compound was administered to male DBA/1 mice by tail vein injection and intragastric administration (overnight fast, 7-8 weeks old).
  • the intravenous group was at 0.083, 0.25, 0.5, 1, 2, 4, 8 and 24 hours
  • the gavage group was at 0.25, 0.5, 1, 2, 4, 8 and 24 hours, respectively, from the mandibular vein.
  • Plasma was obtained after blood collection and centrifugation. Determination of plasma concentration, using WinNonlin TM Version 6.3 pharmacokinetics software to noncompartmental pharmacokinetic parameters linear correlation calculation of the log trapezoidal method using LC-MS / MS method.
  • the compounds of the invention WX552, WX591, WX614 have good oral bioavailability in mice, and the high exposure is beneficial to the in vivo efficacy.
  • test compounds Female, 160-180 g of Lewis rats were anesthetized with isoflurane and subcutaneously injected with 0.1 ml of M. tuberculosis suspension in the left hind foot. After 13 days of modeling, the corresponding test compounds were grouped, for example, 1 mpk, 3 mpk, 10 mpk of test compound WX614, 10 mpk of test compound WX552, and 10 mpk of test compound WX591 were dissolved in DMSO/ Female Lewis rats were orally administered in a PEG400/H2O mixed vehicle (the number of test animals per dose group was 10). The rats were observed for two weeks, and the state of the rats was observed, and the swelling of the foot volume was recorded and scored. Tests have shown that the compounds of the invention WX614, WX552 and WX591 all exhibit good arthritis inhibitory activity.
  • mice DBA/l male mice were selected, and collagens of collagen and Freund's complete adjuvant were injected subcutaneously on the roots of the tails on days 0 and 21, and grouping was started on the 29th day, and the inventive compound WX6144 (3mpk, 10mpk, 30mpk) was dissolved.
  • DMSO/PEG400/H2O [5/20/75 (v/v/v)] CIA mice were orally administered (Shanghai Slack Laboratory Animal Co., Ltd., the number of test animals per dose group was 10). After 2 weeks of continuous administration, the body weight of the mice was recorded, and the joint inflammation of the mice was clinically scored. The results showed that the compound of the present invention WX614 was rheumatoid to mice. Arthritis has a significant therapeutic effect.

Abstract

本发明公开了一系列Janus激酶抑制剂，具体公开了式(Ⅰ)化合物或其药学上可接受的盐及其在制备治疗与JAK相关疾病的药物中的应用。

Description

Janus激酶抑制剂 技术领域
本发明涉及一系列Janus激酶抑制剂，具体涉及式(Ⅰ)化合物或其药学上可接受的盐。
背景技术
JAK属于参与炎症、自身免疫疾病、增殖性疾病、移植排斥、涉及软骨更新(turnover)受损的疾病、先天软骨畸形和/或与IL6分泌过多相关的疾病的酪氨酸激酶家族。本发明还提供所述化合物、含有所述化合物的药物组合物的生产方法和通过施用本发明化合物预防和/或治疗炎症、自身免疫疾病、增殖性疾病、移植排斥、涉及软骨更新受损的疾病、先天软骨畸形和/或与IL6分泌过多相关的疾病的方法。
Janus激酶(JAK)是转导细胞因子信号从膜受体到STAT转录因子的细胞质酪氨酸激酶。现有技术已经描述了四种JAK家族成员：JAK1、JAK2、JAK3和TYK2。当细胞因子与其受体结合时，JAK家族成员自磷酸化和/或彼此转磷酸化，随后STATs磷酸化，然后迁移至细胞核内以调节转录。JAK-STAT细胞内信号转导适用于干扰素、大多数白细胞介素以及多种细胞因子和内分泌因子，例如EPO、TPO、GH、OSM、LIF、CNTF、GM-CSF和PRL(Vainchenker W.等人(2008))。
遗传学模型和小分子JAK抑制剂的组合研究揭示了几种JAKs的治疗潜能。通过小鼠和人遗传学确证JAK3是免疫抑制靶点(O’Shea J.等人(2004))。JAK3抑制剂成功用于临床开发，最初用于器官移植排斥，但后来也用于其它免疫炎性适应证，例如类风湿性关节炎(RA)、银屑病和克隆病(http：//clinicaltrials.gov/)。TYK2是免疫炎性疾病的潜在靶点，已经通过人遗传学和小鼠剔除研究确证(Levy D.和Loomis C.(2007))。JAK1是免疫炎性疾病领域的新靶点。将JAK1与其它JAKs杂二聚化以转导细胞因子驱动的促炎信号传导。因此，预期抑制JAK1和/或其它JAK对于一系列炎性病症和其它由JAK介导的信号转导驱动的疾病是具有治疗益处的。
发明内容
本发明提供了式(Ⅰ)所示化合物或其药学上可接受的盐，
Figure PCTCN2016083426-appb-000001
其中，
R选自C(R)或N；
L1选自单键、-C(＝O)O-、-C(＝O)-、-S(＝O)-、-S(＝O)2-、-C(＝O)N(R)-、-N(R)C(＝O)N(R)-、-N(R)-、-S(＝O)N(R)-、-S(＝O)2N(R)C(R)2-、-S(＝O)N(R)C(R)2-；
R1选自H、CN、OH、NH2、卤素，或选自任选被1、2、3或4个R取代的：C1-6烷基、C1-6杂烷基、C3-6元环烷基、3～6元杂环烷基；
R分别独立地选自H、CN、OH、NH2、卤素，或分别选自任选被1、2、3或4个R’取代的：C1-6烷基、C1-6杂烷基；
R’选自卤素、OH、NH2、CN、Me、Et、CF3、CH2CF3、NHCH3、N(CH3)2；
所述“杂”选自杂原子或杂原子团，选自N、O、S、-C(＝O)O-、-C(＝O)-、-S(＝O)-、-S(＝O)2-，上述任意一种情况下所述“杂”的数目分别独立地选自1、2或3。
本发明的一些方案中，上述R选自H、CN、OH、NH2、卤素，或选自任选被1、2或3个R’取代的：Me、Et、NHCH3、N(CH3)2、NHCH3、N(CH3)2、
Figure PCTCN2016083426-appb-000002
本发明的一些方案中，上述L1选自单键、-C(＝O)O-、-C(＝O)-、-S(＝O)-、-S(＝O)2-、-C(＝O)NH-、-NHC(＝O)NH-、-NH-、-S(＝O)NH-、-S(＝O)2NHCH2-、-S(＝O)NHCH2-。
本发明的一些方案中，上述R1选自CN、OH、NH2，或选自任选被1、2、3或4个R取代的：C1-3烷基、C1-2烷基-N(C1-2烷基)2、C1-2烷基-NH-C1-2烷基、C1-3烷基-S(＝O)2-C1-3烷基、C1-3烷基-S(＝O)-C1-3烷基、C4-5环烷基、4～5元杂环烷基。
本发明的一些方案中，上述R1选自CN，或选自任选被1、2、3或4个R取代的：Me、Et、
Figure PCTCN2016083426-appb-000003
Figure PCTCN2016083426-appb-000004
本发明的一些方案中，上述R1选自CN、Me、
Figure PCTCN2016083426-appb-000005
Figure PCTCN2016083426-appb-000006
本发明的化合物，其选自：
Figure PCTCN2016083426-appb-000007
本发明还提供式(Ⅰ)化合物的制备方法，包括如下步骤：
Figure PCTCN2016083426-appb-000008
其中，PG为氨基保护基，选自苄氧羰基(Cbz)、叔丁氧羰基(Boc)、笏氧羰基(Fmoc)、烯丙氧羰基(Alloc)、三甲基硅乙氧羰基(Teco)、甲氧羰基、乙氧羰基、邻苯二甲酰基(Pht)、对甲苯磺酰基(Tos)、三氟乙酰基(Tfa)、苄基(Bn)、对甲氧基苄基(PMB)。
本发明还提供一种药物组合物，包括治疗有效量的上述化合物或其药学上可接受的盐以及药学上可接受的载体。
本发明还提供了上述化合物或其药学上可接受的盐或上述药物组合物在制备治疗治疗与Janus激酶相关疾病的药物中的应用。
本发明的一些方案中，上述疾病为关节炎。
本发明的一些方案中，上述疾病为类风湿性关节炎。
相关定义
除非另有说明，本文所用的下列术语和短语旨在具有下列含义。一个特定的术语或短语在没有特别定义的情况下不应该被认为是不确定的或不清楚的，而应该按照普通的含义去理解。当本文中出现商品名时，意在指代其对应的商品或其活性成分。这里所采用的术语“药学上可接受的”，是针对那些化合物、材料、组合物和/或剂型而言，它们在可靠的医学判断的范围之内，适用于与人类和动物的组织接触使用，而没有过多的毒性、刺激性、过敏性反应或其它问题或并发症，与合理的利益/风险比相称。
术语“药学上可接受的盐”是指本发明化合物的盐，由本发明发现的具有特定取代基的化合物与相对无毒的酸或碱制备。当本发明的化合物中含有相对酸性的功能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的碱与这类化合物的中性形式接触的方式获得碱加成盐。药学上可接受的碱加成盐包括钠、钾、钙、铵、有机氨或镁盐或类似的盐。当本发明的化合物中含有相对碱性的官能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的酸与这类化合物的中性形式接触的方式获得酸加成盐。药学上可接受的酸加成盐的实例包括无机酸盐，所述无机酸包括例如盐酸、氢溴酸、硝酸、碳酸，碳酸氢根，磷酸、磷酸一氢根、磷酸二氢根、硫酸、硫酸氢根、氢碘酸、亚磷酸等；以及有机酸盐，所述有机酸包括如乙酸、丙酸、异丁酸、马来酸、丙二酸、苯甲酸、琥珀酸、辛二酸、反丁烯二酸、乳酸、扁桃酸、邻苯二甲酸、苯磺酸、对甲苯磺酸、柠檬酸、酒石酸和甲磺酸等类似的酸；还包括氨基酸(如精氨酸等)的盐，以及如葡糖醛酸等有机酸的盐(参见Berge et al.,"Pharmaceutical Salts",Journal of Pharmaceutical  Science 66:1-19(1977))。本发明的某些特定的化合物含有碱性和酸性的官能团，从而可以被转换成任一碱或酸加成盐。
优选地，以常规方式使盐与碱或酸接触，再分离母体化合物，由此再生化合物的中性形式。化合物的母体形式与其各种盐的形式的不同之处在于某些物理性质，例如在极性溶剂中的溶解度不同。
本文所用的“药学上可接受的盐”属于本发明化合物的衍生物，其中，通过与酸成盐或与碱成盐的方式修饰所述母体化合物。药学上可接受的盐的实例包括但不限于：碱基比如胺的无机酸或有机酸盐、酸根比如羧酸的碱金属或有机盐等等。药学上可接受的盐包括常规的无毒性的盐或母体化合物的季铵盐，例如无毒的无机酸或有机酸所形成的盐。常规的无毒性的盐包括但不限于那些衍生自无机酸和有机酸的盐，所述的无机酸或有机酸选自2-乙酰氧基苯甲酸、2-羟基乙磺酸、乙酸、抗坏血酸、苯磺酸、苯甲酸、碳酸氢根、碳酸、柠檬酸、依地酸、乙烷二磺酸、乙烷磺酸、富马酸、葡庚糖、葡糖酸、谷氨酸、乙醇酸、氢溴酸、盐酸、氢碘酸盐、羟基、羟萘、羟乙磺酸、乳酸、乳糖、十二烷基磺酸、马来酸、苹果酸、扁桃酸、甲烷磺酸、硝酸、草酸、双羟萘酸、泛酸、苯乙酸、磷酸、多聚半乳糖醛、丙酸、水杨酸、硬脂酸、亚乙酸、琥珀酸、氨基磺酸、对氨基苯磺酸、硫酸、单宁、酒石酸和对甲苯磺酸。
本发明的药学上可接受的盐可由含有酸根或碱基的母体化合物通过常规化学方法合成。一般情况下，这样的盐的制备方法是：在水或有机溶剂或两者的混合物中，经由游离酸或碱形式的这些化合物与化学计量的适当的碱或酸反应来制备。一般地，优选醚、乙酸乙酯、乙醇、异丙醇或乙腈等非水介质。
除了盐的形式，本发明所提供的化合物还存在前药形式。本文所描述的化合物的前药容易地在生理条件下发生化学变化从而转化成本发明的化合物。此外，前体药物可以在体内环境中通过化学或生化方法被转换到本发明的化合物。
本发明的某些化合物可以以非溶剂化形式或者溶剂化形式存在，包括水合物形式。一般而言，溶剂化形式与非溶剂化的形式相当，都包含在本发明的范围之内。
本发明的某些化合物可以具有不对称碳原子(光学中心)或双键。外消旋体、非对映异构体、几何异构体和单个的异构体都包括在本发明的范围之内。
本文中消旋体、ambiscalemic and scalemic或者对映体纯的化合物的图示法来自Maehr,J.Chem.Ed.1985,62:114-120。1985年，62：114-120。除非另有说明，用楔形键和虚线键表示一个立体中心的绝对构型。当本文所述化合物含有烯属双键或其它几何不对称中心，除非另有规定，它们包括E、Z几何异构体。同样地，所有的互变异构形式均包括在本发明的范围之内。
本发明的化合物可以存在特定的几何或立体异构体形式。本发明设想所有的这类化合物，包括顺式和反式异构体、(-)-和(+)-对对映体、(R)-和(S)-对映体、非对映异构体、(D)-异构体、(L)-异构体，及其外消旋混合物和其他混合物，例如对映异构体或非对映体富集的混合物，所有这些混合物都属于本发明的范围之内。烷基等取代基中可存在另外的不对称碳原子。所有这些异构体以及它们的混合物，均 包括在本发明的范围之内。
可以通过的手性合成或手性试剂或者其他常规技术制备光学活性的(R)-和(S)-异构体以及D和L异构体。如果想得到本发明某化合物的一种对映体，可以通过不对称合成或者具有手性助剂的衍生作用来制备，其中将所得非对映体混合物分离，并且辅助基团裂开以提供纯的所需对映异构体。或者，当分子中含有碱性官能团(如氨基)或酸性官能团(如羧基)时，与适当的光学活性的酸或碱形成非对映异构体的盐，然后通过本领域所公知的常规方法进行非对映异构体拆分，然后回收得到纯的对映体。此外，对映异构体和非对映异构体的分离通常是通过使用色谱法完成的，所述色谱法采用手性固定相，并任选地与化学衍生法相结合(例如由胺生成氨基甲酸盐)。
本发明的化合物可以在一个或多个构成该化合物的原子上包含非天然比例的原子同位素。例如，可用放射性同位素标记化合物，比如氚(3H)，碘-125(125I)或C-14(14C)。本发明的化合物的所有同位素组成的变换，无论放射性与否，都包括在本发明的范围之内。
术语“药学上可接受的载体”是指能够递送本发明有效量活性物质、不干扰活性物质的生物活性并且对宿主或者患者无毒副作用的任何制剂或载体介质代表性的载体包括水、油、蔬菜和矿物质、膏基、洗剂基质、软膏基质等。这些基质包括悬浮剂、增粘剂、透皮促进剂等。它们的制剂为化妆品领域或局部药物领域的技术人员所周知。关于载体的其他信息，可以参考Remington:The Science and Practice of Pharmacy,21st Ed.,Lippincott,Williams&Wilkins(2005)，该文献的内容通过引用的方式并入本文。
术语“赋形剂”通常是指配制有效的药物组合物所需要载体、稀释剂和/或介质。
针对药物或药理学活性剂而言，术语“有效量”或“治疗有效量”是指无毒的但能达到预期效果的药物或药剂的足够用量。对于本发明中的口服剂型，组合物中一种活性物质的“有效量”是指与该组合物中另一种活性物质联用时为了达到预期效果所需要的用量。有效量的确定因人而异，取决于受体的年龄和一般情况，也取决于具体的活性物质，个案中合适的有效量可以由本领域技术人员根据常规试验确定。
术语“活性成分”、“治疗剂”，“活性物质”或“活性剂”是指一种化学实体，它可以有效地治疗目标紊乱、疾病或病症。
术语“被取代的”是指特定原子上的任意一个或多个氢原子被取代基取代，可以包括重氢和氢的变体，只要特定原子的价态是正常的并且取代后的化合物是稳定的。当取代基为酮基(即＝O)时，意味着两个氢原子被取代。酮取代不会发生在芳香基上。术语“任选被取代的”是指可以被取代，也可以不被取代，除非另有规定，取代基的种类和数目在化学上可以实现的基础上可以是任意的。
当任何变量(例如R)在化合物的组成或结构中出现一次以上时，其在每一种情况下的定义都是独立的。因此，例如，如果一个基团被0-2个R所取代，则所述基团可以任选地至多被两个R所取代，并且每种情况下的R都有独立的选项。此外，取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。
当一个连接基团的数量为0时，比如-(CRR)0-，表示该连接基团为单键。
当其中一个变量选自单键时，表示其连接的两个基团直接相连，比如A-L-Z中L代表单键时表示该结构实际上是A-Z。
当一个取代基为空缺时，表示该取代基是不存在的，比如A-X中X为空缺时表示该结构实际上是A。当一个取代基的键可以交叉连接到一个环上的两个原子时，这种取代基可以与这个环上的任意原子相键合。当所列举的取代基中没有指明其通过哪一个原子连接到化学结构通式中包括但未具体提及的化合物时，这种取代基可以通过其任何原子相键合。取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。例如，结构单元
Figure PCTCN2016083426-appb-000009
表示其可在环己基或者环己二烯上的任意一个位置发生取代。
除非另有规定，术语“杂”表示杂原子或杂原子团(即含有杂原子的原子团)，包括碳(C)和氢(H)以外的原子以及含有这些杂原子的原子团，例如包括氧(O)、氮(N)、硫(S)、硅(Si)、锗(Ge)、铝(Al)、硼(B)、-O-、-S-、＝O、＝S、-C(＝O)O-、-C(＝O)-、-C(＝S)-、-S(＝O)、-S(＝O)2-，以及任选被取代的-C(＝O)N(H)-、-N(H)-、-C(＝NH)-、-S(＝O)2N(H)-或-S(＝O)N(H)-。
除非另有规定，“环”表示被取代或未被取代的环烷基、杂环烷基、环烯基、杂环烯基、环炔基、杂环炔基、芳基或杂芳基。所谓的环包括单环、联环、螺环、并环或桥环。环上原子的数目通常被定义为环的元数，例如，“5～7元环”是指环绕排列5～7个原子。除非另有规定，该环任选地包含1～3个杂原子。因此，“5～7元环”包括例如苯基、吡啶和哌啶基；另一方面，术语“5～7元杂环烷基环”包括吡啶基和哌啶基，但不包括苯基。术语“环”还包括含有至少一个环的环系，其中的每一个“环”均独立地符合上述定义。
除非另有规定，术语“杂环”或“杂环基”意指稳定的含杂原子或杂原子团的单环、双环或三环，它们可以是饱和的、部分不饱和的或不饱和的(芳族的)，它们包含碳原子和1、2、3或4个独立地选自N、O和S的环杂原子，其中上述任意杂环可以稠合到一个苯环上形成双环。氮和硫杂原子可任选被氧化(即NO和S(O)p，p是1或2)。氮原子可以是被取代的或未取代的(即N或NR，其中R是H或本文已经定义过的其他取代基)。该杂环可以附着到任何杂原子或碳原子的侧基上从而形成稳定的结构。如果产生的化合物是稳定的，本文所述的杂环可以发生碳位或氮位上的取代。杂环中的氮原子任选地被季铵化。一个优选方案是，当杂环中S及O原子的总数超过1时，这些杂原子彼此不相邻。另一个优选方案是，杂环中S及O原子的总数不超过1。如本文所用，术语“芳族杂环基团”或“杂芳基”意指稳定的5、6、7元单环或双环或7、8、9或10元双环杂环基的芳香环，它包含碳原子和1、2、3或4个独立地选自N、O和S的环杂原子。氮原子可以是被取代的或未取代的(即N或NR，其中R是H或本文已经定义过的其他取代基)。氮和硫杂原子可任选被氧化(即NO和S(O)p，p是1或2)。值得注意的是， 芳香杂环上S和O原子的总数不超过1。桥环也包含在杂环的定义中。当一个或多个原子(即C、O、N或S)连接两个不相邻的碳原子或氮原子时形成桥环。优选的桥环包括但不限于：一个碳原子、两个碳原子、一个氮原子、两个氮原子和一个碳-氮基。值得注意的是，一个桥总是将单环转换成三环。桥环中，环上的取代基也可以出现在桥上。
杂环化合物的实例包括但不限于：吖啶基、吖辛因基、苯并咪唑基、苯并呋喃基、苯并巯基呋喃基、苯并巯基苯基、苯并恶唑基、苯并恶唑啉基、苯并噻唑基、苯并三唑基、苯并四唑基、苯并异恶唑基、苯并异噻唑基、苯并咪唑啉基、咔唑基、4aH-咔唑基、咔啉基、苯并二氢吡喃基、色烯、噌啉基十氢喹啉基、2H,6H-1,5,2-二噻嗪基、二氢呋喃并[2,3-b]四氢呋喃基、呋喃基、呋咱基、咪唑烷基、咪唑啉基、咪唑基、1H-吲唑基、吲哚烯基、二氢吲哚基、中氮茚基、吲哚基、3H-吲哚基、异苯并呋喃基、异吲哚基、异二氢吲哚基、异喹啉基、异噻唑基、异恶唑基、亚甲二氧基苯基、吗啉基、萘啶基，八氢异喹啉基、恶二唑基、1,2,3-恶二唑基、1,2,4-恶二唑基、1,2,5-恶二唑基、1,3,4-恶二唑基、恶唑烷基、恶唑基、羟吲哚基、嘧啶基、菲啶基、菲咯啉基、吩嗪、吩噻嗪、苯并黄嘌呤基、酚恶嗪基、酞嗪基、哌嗪基、哌啶基、哌啶酮基、4-哌啶酮基、胡椒基、蝶啶基、嘌呤基、吡喃基、吡嗪基、吡唑烷基、吡唑啉基、吡唑基、哒嗪基、吡啶并恶唑、吡啶并咪唑、吡啶并噻唑、吡啶基、吡咯烷基、吡咯啉基、2H-吡咯基、吡咯基、喹唑啉基、喹啉基、4H-喹嗪基、喹喔啉基、奎宁环基、四氢呋喃基、四氢异喹啉基、四氢喹啉基、四唑基，6H-1,2,5-噻二嗪基、1,2,3-噻二唑基、1,2,4-噻二唑基、1,2,5-噻二唑基、1,3,4-噻二唑基、噻蒽基、噻唑基、异噻唑基噻吩基、噻吩并恶唑基、噻吩并噻唑基、噻吩并咪唑基、噻吩基、三嗪基、1,2,3-三唑基、1,2,4-三唑基、1,2,5-三唑基、1,3,4-三唑基和呫吨基。还包括稠环和螺环化合物。
除非另有规定，术语“烃基”或者其下位概念(比如烷基、烯基、炔基、芳基等等)本身或者作为另一取代基的一部分表示直链的、支链的或环状的烃原子团或其组合，可以是完全饱和的(如烷基)、单元或多元不饱和的(如烯基、炔基、芳基)，可以是单取代或多取代的，可以是一价(如甲基)、二价(如亚甲基)或者多价(如次甲基)，可以包括二价或多价原子团，具有指定数量的碳原子(如C1-C12表示1至12个碳，C1-12选自C1、C2、C3、C4、C5、C6、C7、C8、C9、C10、C11和C12；C3-12选自C3、C4、C5、C6、C7、C8、C9、C10、C11和C12。)。“烃基”包括但不限于脂肪烃基和芳香烃基，所述脂肪烃基包括链状和环状，具体包括但不限于烷基、烯基、炔基，所述芳香烃基包括但不限于6-12元的芳香烃基，例如苯、萘等。在一些实施例中，术语“烃基”表示直链的或支链的原子团或它们的组合，可以是完全饱和的、单元或多元不饱和的，可以包括二价和多价原子团。饱和烃原子团的实例包括但不限于甲基、乙基、正丙基、异丙基、正丁基、叔丁基、异丁基、仲丁基、异丁基、环己基、(环己基)甲基、环丙基甲基，以及正戊基、正己基、正庚基、正辛基等原子团的同系物或异构体。不饱和烃基具有一个或多个双键或三键，其实例包括但不限于乙烯基、2-丙烯基、丁烯基、巴豆基、2-异戊烯基、2-(丁二烯基)、2，4-戊二烯基、3-(1，4-戊二烯基)、乙炔基、1-和3-丙炔基，3-丁炔基，以及更高级的同系物和异构 体。
除非另有规定，术语“杂烃基”或者其下位概念(比如杂烷基、杂烯基、杂炔基、杂芳基等等)本身或者与另一术语联合表示稳定的直链的、支链的或环状的烃原子团或其组合，有一定数目的碳原子和至少一个杂原子组成。在一些实施例中，术语“杂烷基”本身或者与另一术语联合表示稳定的直链的、支链的烃原子团或其组合物，有一定数目的碳原子和至少一个杂原子组成。在一个典型实施例中，杂原子选自B、O、N和S，其中氮和硫原子任选地被氧化，氮杂原子任选地被季铵化。杂原子或杂原子团可以位于杂烃基的任何内部位置，包括该烃基附着于分子其余部分的位置，但术语“烷氧基”、“烷氨基”和“烷硫基”(或硫代烷氧基)属于惯用表达，是指分别通过一个氧原子、氨基或硫原子连接到分子的其余部分的那些烷基基团。实例包括但不限于-CH2-CH2-O-CH3、-CH2-CH2-NH-CH3、-CH2-CH2-N(CH3)-CH3、-CH2-S-CH2-CH3、-CH2-CH2、-S(O)-CH3、-CH2-CH2-S(O)2-CH3、-CH＝CH-O-CH3、-CH2-CH＝N-OCH3和–CH＝CH-N(CH3)-CH3。至多两个杂原子可以是连续的，例如-CH2-NH-OCH3。
除非另有规定，术语“环烃基”、“杂环烃基”或者其下位概念(比如芳基、杂芳基、环烷基、杂环烷基、环烯基、杂环烯基、环炔基、杂环炔基等等)本身或与其他术语联合分别表示环化的“烃基”、“杂烃基”。此外，就杂烃基或杂环烃基(比如杂烷基、杂环烷基)而言，杂原子可以占据该杂环附着于分子其余部分的位置。环烃基的实例包括但不限于环戊基、环己基、1-环己烯基、3-环己烯基、环庚基等。杂环基的非限制性实例包括1-(1,2,5,6-四氢吡啶基)、1-哌啶基、2-哌啶基，3-哌啶基、4-吗啉基、3-吗啉基、四氢呋喃-2-基、四氢呋喃吲哚-3-基、四氢噻吩-2-基、四氢噻吩-3-基，1-哌嗪基和2-哌嗪基。
除非另有规定，术语“烷基”用于表示直链或支链的饱和烃基,可以是单取代(如-CH2F)或多取代的(如-CF3)，可以是一价(如甲基)、二价(如亚甲基)或者多价(如次甲基)。烷基的例子包括甲基(Me)，乙基(Et)，丙基(如，n-丙基和异丙基)，丁基(如，n-丁基，异丁基，s-丁基，t-丁基)，戊基(如，n-戊基，异戊基，新戊基)等。
除非另有规定，“烯基”指在链的任何位点上具有一个或多个碳碳双键的烷基,可以是单取代或多取代的，可以是一价、二价或者多价。烯基的例子包括乙烯基，丙烯基，丁烯基，戊烯基，己烯基，丁间二烯基，戊间二烯基，己间二烯基等。
除非另有规定，“炔基”指在链的任何位点上具有一个或多个碳碳三键的烷基，可以是单取代或多取代的，可以是一价、二价或者多价。炔基的例子包括乙炔基，丙炔基，丁炔基，戊炔基等。
除非另有规定，环烷基包括任何稳定的环状或多环烃基，任何碳原子都是饱和的，可以是单取代或多取代的，可以是一价、二价或者多价。这些环烷基的实例包括，但不限于，环丙基、降冰片烷基、[2.2.2]二环辛烷、[4.4.0]二环癸烷等。
除非另有规定，环烯基包括任何稳定的环状或多环烃基，该烃基在环的任何位点含有一个或多个不饱和的碳-碳双键，可以是单取代或多取代的，可以是一价、二价或者多价。这些环烯基的实例包括， 但不限于，环戊烯基、环己烯基等。
除非另有规定，环炔基包括任何稳定的环状或多环烃基，该烃基在环的任何位点含有一个或多个碳-碳三键，可以是单取代或多取代的，可以是一价、二价或者多价。
除非另有规定，术语“卤代素”或“卤素”本身或作为另一取代基的一部分表示氟、氯、溴或碘原子。此外，术语“卤代烷基”意在包括单卤代烷基和多卤代烷基。例如，术语“卤代(C1-C4)烷基”意在包括但不仅限于三氟甲基、2，2，2-三氟乙基、4-氯丁基和3-溴丙基等等。除非另有规定，卤代烷基的实例包括但不仅限于：三氟甲基、三氯甲基、五氟乙基，和五氯乙基。
“烷氧基”代表通过氧桥连接的具有特定数目碳原子的上述烷基，除非另有规定，C1-6烷氧基包括C1、C2、C3、C4、C5和C6的烷氧基。烷氧基的例子包括但不限于：甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、仲丁氧基、叔丁氧基、正戊氧基和S-戊氧基。除非另有规定，术语“芳基”表示多不饱和的芳族烃取代基，可以是单取代或多取代的，可以是一价、二价或者多价，它可以是单环或多环(比如1至3个环；其中至少一个环是芳族的)，它们稠合在一起或共价连接。术语“杂芳基”是指含有一至四个杂原子的芳基(或环)。在一个示范性实例中，杂原子选自B、N、O和S，其中氮和硫原子任选地被氧化，氮原子任选地被季铵化。杂芳基可通过杂原子连接到分子的其余部分。芳基或杂芳基的非限制性实施例包括苯基、1-萘基、2-萘基、4-联苯基、1-吡咯基、2-吡咯基、3-吡咯基、3-吡唑基、2-咪唑基、4-咪唑基、吡嗪基、2-恶唑基、4-恶唑基、2-苯基-4-恶唑基、5-恶唑基、3-异恶唑基、4-异恶唑基、5-异恶唑基、2-噻唑基、4-噻唑基、5-噻唑基、2-呋喃基、3-呋喃基、2-噻吩基、3-噻吩基、2-吡啶基、3-吡啶基、4-吡啶基、2-嘧啶基、4-嘧啶基、5-苯并噻唑基、嘌呤基、2-苯并咪唑基、5-吲哚基、1-异喹啉基、5-异喹啉基、2-喹喔啉基、5-喹喔啉基、3-喹啉基和6-喹啉基。上述任意一个芳基和杂芳基环系的取代基选自下文所述的可接受的取代基。
除非另有规定，芳基在与其他术语联合使用时(例如芳氧基、芳硫基、芳烷基)包括如上定义的芳基和杂芳基环。因此，术语“芳烷基”意在包括芳基附着于烷基的那些原子团(例如苄基、苯乙基、吡啶基甲基等)，包括其中碳原子(如亚甲基)已经被例如氧原子代替的那些烷基，例如苯氧基甲基、2-吡啶氧甲基3-(1-萘氧基)丙基等。
术语“离去基团”是指可以被另一种官能团或原子通过取代反应(例如亲和取代反应)所取代的官能团或原子。例如，代表性的离去基团包括三氟甲磺酸酯；氯、溴、碘；磺酸酯基，如甲磺酸酯、甲苯磺酸酯、对溴苯磺酸酯、对甲苯磺酸酯等；酰氧基，如乙酰氧基、三氟乙酰氧基等等。
术语“保护基”包括但不限于“氨基保护基”、“羟基保护基”或“巯基保护基”。术语“氨基保护基”是指适合用于阻止氨基氮位上副反应的保护基团。代表性的氨基保护基包括但不限于：甲酰基；酰基，例如链烷酰基(如乙酰基、三氯乙酰基或三氟乙酰基)；烷氧基羰基，如叔丁氧基羰基(Boc)；芳基甲氧羰基，如苄氧羰基(Cbz)和9-芴甲氧羰基(Fmoc)；芳基甲基，如苄基(Bn)、三苯甲基(Tr)、1,1-二-(4'-甲氧基 苯基)甲基；甲硅烷基，如三甲基甲硅烷基(TMS)和叔丁基二甲基甲硅烷基(TBS)等等。术语“羟基保护基”是指适合用于阻止羟基副反应的保护基。代表性羟基保护基包括但不限于：烷基，如甲基、乙基和叔丁基；酰基，例如链烷酰基(如乙酰基)；芳基甲基，如苄基(Bn)，对甲氧基苄基(PMB)、9-芴基甲基(Fm)和二苯基甲基(二苯甲基，DPM)；甲硅烷基，如三甲基甲硅烷基(TMS)和叔丁基二甲基甲硅烷基(TBS)等等。
本发明的化合物可以通过本领域技术人员所熟知的多种合成方法来制备，包括下面列举的具体实施方式、其与其他化学合成方法的结合所形成的实施方式以及本领域技术上人员所熟知的等同替换方式，优选的实施方式包括但不限于本发明的实施例。
本发明所使用的溶剂可经市售获得。本发明采用下述缩略词：aq代表水；HATU代表O-(7-氮杂苯并三唑-1-基)-N，N，N'，N'-四甲基脲六氟磷酸盐；EDC代表N-(3-二甲基氨基丙基)-N'-乙基碳二亚胺盐酸盐；m-CPBA代表3-氯过氧苯甲酸；eq代表当量、等量；CDI代表羰基二咪唑；DCM代表二氯甲烷；PE代表石油醚；DIAD代表偶氮二羧酸二异丙酯；DMF代表N，N-二甲基甲酰胺；DMSO代表二甲亚砜；EtOAc代表乙酸乙酯；EtOH代表乙醇；MeOH代表甲醇；Cbz代表苄氧羰基，是一种胺保护基团；BOC代表叔丁基羰基是一种胺保护基团；HOAc代表乙酸；NaCNBH3代表氰基硼氢化钠；r.t.代表室温；O/N代表过夜；THF代表四氢呋喃；Boc2O代表二-叔丁基二碳酸酯；TFA代表三氟乙酸；DIPEA代表二异丙基乙基胺；SOCl2代表氯化亚砜；CS2代表二硫化碳；TsOH代表对甲苯磺酸；NFSI代表N-氟-N-(苯磺酰基)苯磺酰胺；NCS代表1-氯吡咯烷-2,5-二酮；n-Bu4NF代表氟化四丁基铵；iPrOH代表2-丙醇；mp代表熔点；LDA代表二异丙基胺基锂；Fmoc代表笏氧羰基；Alloc代表烯丙氧羰基、Teco代表三甲基硅乙氧羰基；Pht代表邻苯二甲酰基；Tos代表对甲苯磺酰基；Tfa代表三氟乙酰基；Bn代表苄基；PMB代表对甲氧基苄基。
化合物经手工或者
Figure PCTCN2016083426-appb-000010
软件命名，市售化合物采用供应商目录名称。
具体实施方式
实施例1:
Figure PCTCN2016083426-appb-000011
步骤1：将2-氯-4-硝基-1-氧-吡啶-1-鎓(40.0g，229.2mmol)和(4-甲氧基苯基)甲胺(63g,458.4mmol)溶于EtOH(400mL)中，所得溶液搅拌回流反应5小时。TLC(PE：EA＝2:1)显示反应完全。将EtOH体积浓缩一半，并在冰浴中冷却2～3小时，将所得冷的混合物过滤，分离出的固体分别用PE(60mL*3)和冰水(60mL*3)洗涤。真空干燥得橙色固体N-[(4-甲氧基苯基)甲基]-4-硝基-1-氧-吡啶-1-鎓-2-胺(38.6g，140.2mmol，产率61.2％)。MS(ESI)计算值C13H13N3O4 275,测定值276[M+H]+。
步骤2：在0℃下，向N-[(4-甲氧基苯基)甲基]-4-硝基-1-氧-吡啶-1-鎓-2-胺(5.0g，18.16mmol)的CHCl3(50mL)逐滴加入的PCl3(8.4g，60.8mmol)，加完后将反应混合物升至25℃并剧烈搅拌反应16小时。TLC(PE：EA＝1：1)显示反应完全。将反应混合物过滤，所得固体用PE(30mL*3)洗涤，得到黄色固体化合物N-[(4-甲氧基苯基)甲基]-4-硝基-吡啶-2-胺(4.2克，粗品)未经进一步纯化，直接用于下一步反应。MS(ESI)计算值C15H18N6 259,测定值260[M+H]+。
步骤3：常温下，向N-[(4-甲氧基苯基)甲基]-4-硝基-吡啶-2-胺(4.2g，16.2mmol)的甲苯溶液中(10mL)逐滴加入TFA(5.0mL)。然后，将混合物在80℃下搅拌反应2小时。TLC(PE：EA＝1：1)显示反应完全。将混合物在减压下浓缩除去溶剂。将残余物用H2O(50mL)稀释，用固体NaHCO3调节pH至中性，水相用EA(50mL*3)萃取。合并的有机相用无水硫酸钠干燥、过滤、并减压浓缩，所 得残留物用柱色谱法纯化(二氧化硅，石油醚/乙酸乙酯＝1/0～1：1)，得到橙色固体化合物4-硝基吡啶-2-胺(700mg，5.0mmol，产率31.1％)。MS(ESI)计算值C5H5N3O2 139,测定值140[M+H]+。
步骤4：常温下，向4-硝基吡啶-2-胺(200mg，1.4mmol)的DME(5mL)中加入3-溴-2-氧代-丙酸乙酯(280mg，1.4mmol)。所得混合物在25℃下搅拌反应1小时后，减压浓缩除去溶剂，残余物用EtOH(10mL)溶解，并回流反应3小时。TLC显示反应完全。反应液冷却至常温，减压浓缩溶剂。残余物用饱和NaHCO3水溶液(25mL)碱化，水相用DCM(15mL*3)萃取，合并的有机相用无水硫酸钠干燥、过滤、并减压浓缩，所得到残余物用快速柱色谱法(EA:PE＝10-60％)纯化，得到浅黄色固体化合物7-硝基咪唑并[1,2-]吡啶-2-羧酸乙酯(302mg，产率88.9％)。MS(ESI)计算值C10H9N3O4235,测定值236[M+H]+。
步骤5:常温下，向7-硝基咪唑并[1,2-a]吡啶-2-羧酸乙酯(150mg，637.8mmol)的乙醇(20mL)溶液中，分别加入HCl(7mg，0.2mmol)和PtO2(15mg，0.6mmol)，反应体系重复抽真空充N2三次后，充入H2(50psi)并在50℃搅拌反应16小时。TLC(PE：EA＝1：1)显示反应完全。将反应混合物体积浓缩过半，过滤，得到白色固体化合物7-氨基-5,6,7,8-四氢咪唑并[1,2-α]吡啶-2-羧酸乙酯盐酸盐(120mg，粗品)。MS(ESI)计算值C10H15N3O2 209,测定值210[M+H]+。
步骤6:将7-氨基-5,6,7,8-四氢咪唑并[1,2-a]吡啶-2-羧酸乙酯盐酸盐(100mg，0.4mmol)和4-氯-7-(对甲苯磺酰基)吡咯并[2,3-d]嘧啶(137mg，0.4mmol)溶解于n-BuOH(5mL)中，并加入DIEA(158mg，1.2mmol)，所得混合物搅拌回流反应16小时。LC-MS显示反应完全。反应混合液减压浓缩，所得残余物用H2O(10mL)稀释，水相用EA萃取(20mL*3)。合并的有机相用无水硫酸钠干燥、过滤、减压浓缩，得到的残余物通过制备型TLC(PE：EA＝0:1)纯化得到浅黄色固体化合物7-[[7-(对甲苯磺酰基)吡咯并[2,3-d]嘧啶-4-基]氨基]-5,6,7,8-四氢咪唑并[1,2-a]吡啶-2-羧酸乙酯(55mg，0.11mmol，产率28.1％)。
MS(ESI)计算值C23H24N6O4S 480,测定值481[M+H]+。
步骤7:在0℃下，N2氛围中，向7-[[7-(对甲苯磺酰基)吡咯并[2,3-d]嘧啶-4-基]氨基]-5,6,7,8-四氢咪唑并[1,2-a]吡啶-2-羧酸乙酯(3.0g，6.2mmol)的THF(150mL)溶液中,分批加入NaH(499mg，12.5mmol)。该混合物在此温度下继续搅拌1小时，然后逐滴加入MeI(7.1g，50.2mmol)，加完后，移到常温继续搅拌1小时。TLC显示反应完成。加入饱和NH4Cl(10mL)淬灭，稍后加入冰水(50mL)冲释，水相用DCM/MeOH(3：1,50mL*3)混合溶剂萃取。将合并的有机相用硫酸钠干燥、过滤、减 压浓缩，得到粗产物用快速柱色谱法(DCM：MeOH＝10：1)纯化得到淡黄色固体7-[甲基-[7-(对甲苯磺酰基)吡咯并[2,3-d]嘧啶-4-基]氨基]-5,6,7,8-四氢咪唑并[1,2-a]吡啶-2-羧酸乙酯(中间体1)(1.5g，产率45％)。MS(ESI)计算值C24H26N6O4S 494,测定值495[M+H]+。
步骤8:在25℃下，向7-[甲基-[7-(对甲苯磺酰基)吡咯并[2,3-d]嘧啶-4-基]氨基]-5,6,7,8-四氢咪唑并[1,2-a]吡啶-2-羧酸乙酯(1.5g，3.0mmol)的EtOH(20mL)溶液中，加入NaOEt(1.0g，15mmol)并在此温度下搅拌16小时。TLC(DCM：MeOH＝10：1)显示反应完全。反应混合物在减压下浓缩，将残余物用水(50mL)稀释，水相用DCM/MeOH(10：1,50mL*3)萃取。合并的有机相用无水硫酸钠干燥、过滤、减压浓缩，得到残留物通过柱色谱法纯化(二氧化硅，DCM/MeOH＝1/0～10：1)，得到白色固体化合物7-[甲基(7H-吡咯并[2,3-d]嘧啶-4-基)氨基]-5,6,7,8-四氢咪唑并[1,2-a]吡啶-2-羧酸乙酯(WX550,中间体2)(600mg，1.76mmol，产率58.2％)。MS(ESI)计算值C17H20N6O2 340,测定值341[M+H]+。
步骤9:在0℃下，向7-[甲基(7H-吡咯并[2,3-d]嘧啶-4-基)氨基]-5,6,7,8-四氢咪唑并[1,2-a]吡啶-2-羧酸乙酯(500mg，1.5mmol)的THF(10.00mL)溶液中，分批加入LiAlH4(111mg，2.9mmol)，所得混合物移到常温搅拌2小时。TLC(DCM:MeOH＝10:1)显示反应完成。在0℃下，加入H2O/THF＝1/1(20mL)淬灭，过滤，水相用DCM\MeOH(10：1,50mL*3)萃取。合并的有机相用无水硫酸钠干燥、过滤、减压浓缩，得到浅黄色固体化合物7-[甲基(7H-吡咯并[2,3-d]嘧啶-4-基)氨基]-5,6,7,8-四氢咪唑并[1,2-a]吡啶-2-基]甲醇(中间体3)(320mg，粗品)，未经进一步纯化，直接用于下一步反应。MS(ESI)计算值C15H18N6O 298,测定值299[M+H]+。
步骤10:常温下，向7-[甲基(7H-吡咯并[2,3-d]嘧啶-4-基)氨基]-5,6,7,8-四氢咪唑并[1,2-a]吡啶-2-基]甲醇(150mg，0.5mmol)的DCM(5mL)溶液中，加入二氯亚砜(300mg，2.5mmol)，所得混合物在70℃下搅拌1小时。TLC(DCM：MeOH＝10：1)显示反应完成。减压下浓缩，得到粗产物N-〔2-(氯甲基)-5,6,7,8-四氢咪唑并[1,2-a]吡啶-7-基]-N-甲基-7H-吡咯并[2,3-d]嘧啶-4-胺(150mg，盐酸盐粗品)(中间体4)，未经进一步纯化，直接用于下一步反应。MS(ESI)计算值C15H17ClN6 316,测定值317[M+H]+。
步骤11:向N-[2-(氯甲基)-5,6,7,8-四氢咪唑并[1,2-a]吡啶-7-基]-N-甲基-7H-吡咯并[2,3-d]嘧啶-4-胺(150mg，0.42mmol)的DMSO(5mL)溶液中，加入氰化钠(41mg，0.85mmol)，然后将混合物在40℃下搅拌反应10小时。LC-MS表明原料消耗完全，产物生成。加入水(10mL)淬灭，水相用DCM/MeOH (3：1,20mL*3)萃取。合并有机相并用饱和盐水(20mL*2)洗涤，无水硫酸钠干燥、过滤、减压浓缩，得到的残余物用制备型HPLC(碱性条件)分离得到白色固体化化合物2-[7-[甲基(7H-吡咯并[2,3-d]嘧啶-4-基)氨基]-5,6,7,8-四氢咪唑并[1,2-a]吡啶-2-基]乙腈(WX552)(60mg，产率46％)。MS(ESI)计算值C16H17N7 307,测定值308[M+H]+.1H NMR(400MHz,DMSO-d6)8.12(s，1H)，7.16(d，J＝3.01Hz,1H),7.02(s,1H),6.61(d,J＝3.01Hz,1H),4.11-4.22(m,1H),3.95-4.08(m,1H),3.79(s,2H),3.28(s,3H),2.88-3.08(m,2H),2.26-2.41(m,1H),2.05(d,J＝11.80Hz,1H).
步骤12:将消旋的2-[7-[甲基(7H-吡咯并[2,3-d]嘧啶-4-基)氨基]-5,6,7,8-四氢咪唑并[1,2-a]吡啶-2-基]乙腈(WX552)(30mg)通过手性柱分离，得到(S或R)2-[7-[甲基(7H-吡咯并[2,3-d]嘧啶-4-基)氨基]-5,6,7,8-四氢咪唑并[1,2-a]吡啶-2-基]乙腈(WX612，10mg)和(R或S)2-[7-[甲基(7H-吡咯并[2,3-d]嘧啶-4-基)氨基]-5,6,7,8-四氢咪唑并[1,2-a]吡啶-2-基]乙腈(WX613，11mg)。
SFC分离条件:
柱:AD(250mm*30mm,10um)手性柱
流动相:A:超临界CO2,B:B:异丙醇(含0.1％氨水),A:B＝60:40
流速:80mL/min
柱温:38℃
波长:220nm
喷射压力:100Bar
喷嘴温度:60℃
蒸发温度:20℃
修整温度:25℃
WX612:保留时间4.870min；MS(ESI)计算值C16H17N7 307,测定值308[M+H]+.1H NMR(400MHz,METHANOL-d4)8.15(s，1H)，7.14(d，J＝3.51Hz,1H),7.05(s,1H),6.71(d,J＝3.51Hz,1H),5.41-5.51(m,1H),4.23-4.30(m,1H),4.14(dt,J＝4.27,12.17Hz,1H),3.77(s,2H),3.40(s,3H),3.04-3.19(m,2H),2.46(dq,J＝5.77,12.38Hz,1H),2.21(d,J＝13.05Hz,1H)
WX613:保留时间5.709min；MS(ESI)计算值C16H17N7 307,测定值308[M+H]+.1H NMR(400MHz,METHANOL-d4)8.15(s，1H)，7.14(d，J＝3.51Hz,1H),7.04(s,1H),6.70(d,J＝3.51Hz,1H),5.37-5.51(m,1H),4.22-4.31(m,1H),4.14(dt,J＝4.52,12.30Hz,1H),3.77(s,2H),3.40(s,3H),3.03-3.20(m,2H),2.46(dq,J＝5.90,12.34Hz,1H),2.21(d,J＝11.80Hz,1H)
实施例2:
Figure PCTCN2016083426-appb-000012
步骤1：常温下，向7-[甲基(7H-吡咯并[2,3-d]嘧啶-4-基)氨基]-5,6,7,8-四氢咪唑并[1,2-a]吡啶-2-基]甲醇(中间体2)(200mg，0.44mmol)的DCM(20mL)溶液中，加入活化的二氧化锰(384mg，4.4mmol)。所得悬浊液在50℃搅拌反应4小时。LC-MS显示反应物被完全消耗。将反应混合物冷却至室温，过滤、浓缩、得到白色固体7-[甲基(7H-吡咯并[2,3-d]嘧啶-4-基)氨基]-5,6,7,8-四氢咪唑并[1,2-a]吡啶-2-甲醛(160mg，粗品)，无需进一步纯化，直接用于下一步反应。MS(ESI)计算值C15H16N6O 296,测定值297[M+H]+.
步骤2：在0℃下，氮气氛围中，向含有7-[甲基(7H-吡咯并[2,3-d]嘧啶-4-基)氨基]-5,6,7,8-四氢咪唑并[1,2-a]吡啶-2-甲醛(159mg，0.35mmol)的DCM(8mL)溶液中加入二乙氨基三氟化硫(DAST)(228mg，1.41mmol)，加完后将该混合物移到25℃搅拌反应14小时。LC-MS显示反应完全。将反应混合物倒入冷却的饱和碳酸氢钠溶液(10mL)中，水相用DCM/MeOH(10：1，15mL*3)萃取。合并的有机相用饱和盐水洗涤、无水硫酸钠干燥、过滤、减压浓缩。将残余物通过制备型HPLC(碱性方法)纯化，得到N-(2-(二氟甲基)-5,6,7,8-四氢咪唑并[1,2-a]吡啶-7-基)-N-甲基-7H-吡咯并[2,3-d]嘧啶-4-氨基(WX611)(156mg，产率93.6％)。MS(ESI)计算值C16H18F2N6 332,测定值333[M+H]+.1H NMR(400MHz,METHANOL-d4)8.44(br.s.，1H)，8.01(br.s.，1H)，7.40(br.s.，1H)，7.03(br.s.，1H)，5.84-6.22(m,1H),5.64(br.s.,1H),4.55(d,J＝9.79Hz,1H),4.40(d,J＝10.29Hz,1H),3.78(t,J＝14.43Hz,2H),3.56(br.s.,3H),3.48(br.s.,2H),3.37(s,1H),2.68(d,J＝7.53Hz,1H),2.42(d,J＝12.30Hz,1H)
实施例3
Figure PCTCN2016083426-appb-000013
步骤1：常温下，向N-[2-(氯甲基)-5,6,7,8-四氢咪唑并[1,2-a]吡啶-7-基]-N-甲基-7-(对甲基苯磺酰基)吡咯并[2,3-d]嘧啶-4-胺(中间体5)(130mg，0.28mmol)的吡啶(5mL)溶液中加入NH3的MeOH溶液(10mL,10M)，所得的该混合物在25℃搅拌10小时。TLC(DCM：MeOH＝10：1)显示反应完全。加入H2O(20mL)淬灭。水相用DCM/MeOH(5：1，15mL*3)萃取。合并的有机相用饱和盐水洗涤、无水硫酸钠干燥、过滤、减压浓缩。得到黄色固体化合物N-[2-(胺甲基)-5,6,7,8-四氢咪唑并[1,2-a]吡啶-7-基]-N-甲基-7-(对甲基苯磺酰基)吡咯并[2,3-d]嘧啶-4-胺(60mg，粗品)，无需进一步纯化，直接用于下一步反应。MS(ESI)计算值C22H25N7O2S 451,测定值452[M+H]+。
步骤2：0℃下，向溶解有N-[2-(胺甲基)-5,6,7,8-四氢咪唑并[1,2-a]吡啶-7-基]-N-甲基-7-(对甲基苯磺酰基)吡咯并[2,3-d]嘧啶-4-胺(150mg，0.33mmol)和TEA(100mg，1mmol)的DCM(5mL)溶液中加入甲磺酰氯(46mg，0.4mmol)，所得混合物移到25℃下搅拌反应16小时。LC-MS显示反应完全。将该混合物在减压下浓缩以除去溶剂。所得残余物用H2O(15mL)溶解，并用DCM/MeOH(5：1，30mL*3)萃取。将合并的有机层用无水硫酸钠干燥，过滤、减压浓缩得到浅黄色固体化合物N-((7-(甲基-(7-(对甲苯酰基-7H-吡咯并[2,3-d]嘧啶-4-基)胺)-5,6,7,8-四氢咪唑并[1,2-a]吡啶-2-基)甲基)甲烷磺酰胺(60mg，粗品)，无需进一步纯化，直接用于下一步反应。MS(ESI)计算值C23H27N7O4S2 529,测定值530[M+H]+。
步骤3：常温下，向N-((7-(甲基-(7-(对甲苯酰基-7H-吡咯并[2,3-d]嘧啶-4-基)胺)-5,6,7,8-四氢咪唑并[1,2-a]吡啶-2-基)甲基)甲烷磺酰胺(50mg，0.94mmol)的H2O(5mL)/THF(5毫升)溶液中加入NaOH(6mg，0.14mmol)。所得的该混合物在90℃搅拌回流4小时。TLC显示原料消耗完全，新点生成；LCMS显示目标分子量。将反应混合物在减压下浓缩以除去溶剂。将残余物用H2O(15mL)溶解，并用二 氯甲烷/异丙醇(3:1，20mL*3)萃取。将合并的有机层用无水硫酸钠干燥、过滤、减压浓缩。得到残余物通过制备型HPLC(碱性条件)纯化得到N-((7-(甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)胺)-5,6,7,8-四氢咪唑并[1,2-a]吡啶-2-基)甲基)甲烷磺酰胺(WX606，22mg，产率62.1％)。MS(ESI)计算值C16H21N7O2S375,测定值376[M+H]+。1H NMR(400MHz,METHANOL-d4)8.15(s，1H)，7.13(d，J＝3.51Hz,1H),7.01(s,1H),6.70(d,J＝3.76Hz,1H),5.39-5.48(m,1H),4.22-4.29(m,1H),4.17(s,3H),3.40(s,3H),3.04-3.14(m,2H),2.91(s,3H),2.45(dq,J＝5.90,12.34Hz,1H),2.21(d,J＝11.29Hz,1H)
实施例4
Figure PCTCN2016083426-appb-000014
N-甲基-N-[2-(甲氨甲基)-5,6,7,8-四氢咪唑并[1,2-a]吡啶-7-基]-7H-7H-吡咯并[2,3-d]嘧啶-4-胺(WX605)的制备和纯化方法与WX606的制备和纯化方法相类似。向N-[2-(氯甲基)-5,6,7,8-四氢咪唑并[1,2-a]吡啶-7-基]-N-甲基-7-(对甲基苯磺酰基)吡咯并[2,3-d]嘧啶-4-胺(中间体5)(130mg，0.28mmol)的吡啶(5mL)溶液中加入甲胺的MeOH溶液,得到甲胺化合物,然后用NaOH在H2O(5mL)/THF(5毫升)溶液中水解,反应完全后用同样的后处理和HPLC分离,得到N-甲基-N-[2-(甲氨甲基)-5,6,7,8-四氢咪唑并[1,2-a]吡啶-7-基]-7H-7H-吡咯并[2,3-d]嘧啶-4-胺(WX605)(25mg,产率68％)。MS(ESI)计算值C16H21N7 311,测定值312[M+H]+。1H NMR(400MHz,CHLOROFORM-d)8.15(s，1H)，7.02(d，J＝3.51Hz,1H),6.83(s,1H),6.54(d,J＝3.51Hz,1H),5.46(br.s.,1H),4.00-4.18(m,2H),3.67(s,2H),3.37(d,J＝16.31Hz,2H),3.32(s,3H),3.08-3.19(m,1H),2.96(dd,J＝11.80,16.06Hz,1H),2.44(s,3H)
实施例5:
Figure PCTCN2016083426-appb-000015
步骤1：在乙基7-[甲基-[7-(对甲苯磺酰基)吡咯[2,3-d]嘧啶-4-基]氨基]-5,6,7,8-四氢咪唑[1,2-a]吡啶-2-羧酸甲酯(4.0g,8.1mmol)的THF(40mL)和H2O(8mL)溶液中，加入LiOH.H2O(509mg,12.1mmol)，将混合物在20℃下搅拌10小时。TLC表明反应物完全被消耗。将反应混合物在减压下除去THF，残余物用2M HCl(4mL)调至pH＝2-3，生成白色固体，将固体滤出并在减压下浓缩得到7-[甲基-[7-(对甲苯磺酰基)吡咯[2,3-d]嘧啶-4-基]氨基]-5,6,7,8-四氢咪唑[1,2-a]吡啶-2-羧酸(3.6g,产率95.4％)为白色固体。MS(ESI)计算值C22H22N6O4S 466,测定值467[M+H]+.
步骤2:在0℃下，向7-[甲基-[7-(对甲苯磺酰基)吡咯[2,3-d]嘧啶-4-基]氨基]-5,6,7,8-四氢咪唑[1,2-a]吡啶-2-羧酸(1.8g,3.9mmol)的DMF(20mL)溶液中，加入CDI(751mg,4.6mmol)，反应液温度升至25℃搅拌2小时后,加入固体氯化铵(2.1g,38.6mmol)后，反应常温过夜。LC-MS显示反应物完全被消耗。将反应混合物倒入冰水(50mL)中，白色固体析出，将固体滤出，用水(20mL)洗涤，减压旋干得到7-[甲基-[7-(对甲苯磺酰基)吡咯[2,3-d]嘧啶-4-基]氨基]-5,6,7,8-四氢咪唑[1,2-a]吡啶-2-甲酰胺(2.5g粗品)为白色固体,产品直接用于下一步。MS(ESI)计算值C22H23N7O3S 465,测定值466[M+H]+。
步骤3:将7-[甲基-[7-(对甲苯磺酰基)吡咯[2,3-d]嘧啶-4-基]氨基]-5,6,7,8-四氢咪唑[1,2-a]吡啶-2-甲酰胺(2.5g,5.4mmol)溶解在THF(20mL),MeOH(10mL)和H2O(6mL)中，加入NaOH(429.6mg,10.7mmol)。将混合物加热至60℃搅拌30分钟。LC-MS显示反应物被完全消耗。将反应混合物在减压下浓缩得到7-[甲基-[7氢吡咯[2,3-d]嘧啶-4-基]氨基]-5,6,7,8-四氢咪唑[1,2-a]吡啶-2-甲酰胺(2.0g粗品)为白色固体，产品直接用于下一步。MS(ESI)计算值C15H17N7O 311,测定值312[M+H]+。
步骤4：在0℃下，向7-[甲基-[7氢吡咯[2,3-d]嘧啶-4-基]氨基]-5,6,7,8-四氢咪唑[1,2-a]吡啶-2-甲酰胺(2.0g,6.4mmol)和三乙胺(3.9g,38.5mmol)的THF(20mL)溶液中逐滴加入TFAA(4.1g,19.3 mmol)，加完后，将反应液常温搅拌30分钟。LC-MS显示原料被完全消耗。将反应混合物倒入冰水(20mL)中，用DCM/MeOH(5:1,100mL*2)萃取。将合并的有机层用饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤并在减压下浓缩得到残余物。将残余物通过柱色谱法纯化(DCM/MeOH＝40/1to20:1)得到7-[甲基-[7氢吡咯[2,3-d]嘧啶-4-基]氨基]-5,6,7,8-四氢咪唑[1,2-a]吡啶-2-腈(WX591,378mg,产率为19.8％)。MS(ESI)计算值C15H15N7 293,测定值294[M+H]+.1H NMR(400MHz,DMSO-d6)11.44-11.71(m,1H),7.99-8.17(m,2H),7.11-7.20(m,1H),6.63(dd,J＝1.76,3.26Hz,1H),5.33(br.s.,1H),4.21-4.31(m,1H),4.13(dt,J＝4.14,12.49Hz,1H),3.27(s,3H),2.91-3.11(m,2H),2.31-2.44(m,1H),2.07(d,J＝11.54Hz,1H).
步骤5:将消旋的7-[甲基-[7氢吡咯[2,3-d]嘧啶-4-基]氨基]-5,6,7,8-四氢咪唑[1,2-a]吡啶-2-腈(30mg,102.3umol)通过手性柱分离得到(S或R)-7-[甲基-[7氢吡咯[2,3-d]嘧啶-4-基]氨基]-5,6,7,8-四氢咪唑[1,2-a]吡啶-2-腈(P1,WX614,10mg,产率为32.8％)和(R或S)-7-[甲基-[7氢吡咯[2,3-d]嘧啶-4-基]氨基]-5,6,7,8-四氢咪唑[1,2-a]吡啶-2-腈(WX615，10mg,产率为31.9％)。
SFC分离条件:
柱:AD(250mm*30mm,10um)手性柱
流动相:A:超临界CO2,B:B:乙醇(含0.1％异丙醇),A:B＝55:45
流速:80mL/min
柱温:38℃
波长:220nm
喷射压力:100Bar
喷嘴温度:60℃
蒸发温度:20℃
修整温度:25℃
WX614:保留时间5.507min；MS(ESI)计算值C15H15N7 293,测定值294[M+H]+.1H NMR(400MHz,DMSO-d6)11.44-11.71(m,1H),7.99-8.17(m,2H),7.11-7.20(m,1H),6.63(dd,J＝1.76,3.26Hz,1H),5.33(br.s.,1H),4.21-4.31(m,1H),4.13(dt,J＝4.14,12.49Hz,1H),3.27(s,3H),2.91-3.11(m,2H),2.31-2.44(m,1H),2.07(d,J＝11.54Hz,1H).
WX615:保留时间6.407min；MS(ESI)计算值C15H15N7 293,测定值294[M+H]+.1H NMR(400MHz,DMSO-d6)11.44-11.71(m,1H),7.99-8.17(m,2H),7.11-7.20(m,1H),6.63(dd,J＝1.76,3.26Hz,1H),5.33(br.s.,1H),4.21-4.31(m,1H),4.13(dt,J＝4.14,12.49Hz,1H),3.27(s,3H),2.91-3.11(m,2H),2.31-2.44(m,1H),2.07(d,J＝11.54Hz,1H).
实施例6:
Figure PCTCN2016083426-appb-000016
步骤1：7-[甲基(7H-吡咯[2,3-d]嘧啶-4-基)氨基]-5,6,7,8-四氢咪唑[1,2-a]吡啶-2-羧酸的制备和纯化与7-[甲基-[7氢吡咯[2,3-d]嘧啶-4-基]氨基]-5,6,7,8-四氢咪唑[1,2-a]吡啶-2-甲酰胺的制备和纯化相同。MS(ESI)计算值C15H16N6O2 312,测定值313[M+H]+。
步骤2：将7-[甲基(7H-吡咯[2,3-d]嘧啶-4-基)氨基]-5,6,7,8-四氢咪唑[1,2-a]吡啶-2-羧酸(120mg,384.2umol)，EDCI(184mg,960.5umol)溶解在吡啶(5mL)中，反应液在25℃下搅拌15分钟后，加入3,3-二氟环丁胺(49mg,461.1umol)，混合物在25℃下搅拌1小时。LC-MS显示原料消耗完全。反应液加水(20mL)稀释，用DCM:i-PrOH＝3:1(20mL*3)萃取，合并的有机层用无水硫酸钠干燥，过滤和减压浓缩得到残余物。将残余物通过制备型HPLC纯化(碱性条件)得到氮-(3,3-二氟环丁基)-7-[甲基(7H-吡咯[2,3-d]嘧啶-4-基)氨基]-5,6,7,8-四氢咪唑并[1,2-a]吡啶-2-甲酰胺(WX593)(30mg,产率15.9％)。MS(ESI)计算值C19H21F2N7O 401,测定值402[M+H]+。1H NMR(400MHz,METHANOL-d4)8.15(s，1H)，7.61(s，1H)7.14(d，J＝3.76Hz,1H),6.71(d,J＝3.51Hz,1H),5.42-5.53(m,1H),4.30-4.39(m,2H),4.14-4.27(m,1H),3.41(s,3H),3.08-3.23(m,2H),2.91-3.05(m,2H),2.62-2.78(m,2H),2.48(dq,J＝5.65,12.34Hz,1H),2.23(d,J＝11.29Hz,1H)
类似于化合物WX593的制备和纯化方法得到化合物WX579，WX580，WX581，WX592和WX604。WX579(15mg,产率9.6％)。MS(ESI)计算值C17H18F3N7O 393,测定值394[M+H]+。1H NMR(400MHz,METHANOL-d4)8.15(s，1H)，7.66(s，1H)7.14(d，J＝3.51Hz,1H),6.71(d,J＝3.51Hz,1H),5.41-5.54(m,1H),4.28-4.39(m,1H),4.20(dt,J＝4.39,12.36Hz,1H),4.03-4.13(m,2H),3.40(s,3H),3.08-3.23(m,2H),2.47(dq,J＝5.77,12.38Hz,1H),2.23(d,J＝11.54Hz,1H)
WX580(25mg,产率29.7％)。MS(ESI)计算值C17H19F2N7O 375,测定值376[M+H]+。1H NMR(400MHz,METHANOL-d4)8.44(br.s.，1H)8.01(br.s.，1H)，7.40(br.s.，1H)，7.03(br.s.，1H)，5.84-6.22(m, 1H),5.64(br.s.,1H),4.55(d,J＝9.79Hz,1H),4.40(d,J＝10.29Hz,1H),3.78(t,J＝14.43Hz,2H),3.56(br.s.,3H),3.48(br.s.,2H),3.37(s,1H),2.68(d,J＝7.53Hz,1H),2.42(d,J＝12.30Hz,1H)
WX581(35mg,产率44.6％)。MS(ESI)计算值C17H18N8O 350,测定值351[M+H]+。1H NMR(400MHz,METHANOL-d4)8.15(s，1H)，7.67(s，1H)7.14(d，J＝3.76Hz,1H),6.71(d,J＝3.51Hz,1H),5.42-5.55(m,1H),4.30-4.40(m,3H),4.21(dt,J＝4.52,12.42Hz,1H),3.41(s,3H),3.08-3.23(m,2H),2.48(tt,J＝6.24,12.45Hz,1H),2.23(d,J＝10.29Hz,1H)
WX592(25mg,产率15.6％)。MS(ESI)计算值C18H23N7O3S 417,测定值418[M+H]+。1H NMR(400MHz,METHANOL-d4)8.44(s，1H)，7.95(s，1H)7.41(d，J＝3.51Hz,1H),7.04(d,J＝3.76Hz,1H),5.64(d,J＝8.53Hz,1H),4.55(dd,J＝4.02,13.30Hz,1H),4.37(dt,J＝4.27,12.55Hz,1H),3.88(t,J＝6.65Hz,2H),3.56(s,3H),3.42-3.49(m,4H),3.05(s,3H),2.59-2.74(m,1H),2.42(d,J＝13.05Hz,1H)
WX604(65mg,产率41.6％)。MS(ESI)计算值C16H19N7O 325,测定值326[M+H]+。1H NMR(400MHz,CHLOROFORM-d)8.13(s，1H)，7.45(s，1H)7.02(d，J＝3.51Hz,1H),6.52(d,J＝3.51Hz,1H),5.45(br.s.,1H),4.06-4.25(m,2H),4.02(br.s.,2H),3.26-3.36(m,4H),3.07-3.19(m,1H),2.96(dd,J＝11.80,16.06Hz,1H),2.09-2.37(m,2H)
Jak1,2,Jak3激酶体外活性测试
实验材料
重组人源JAK1、JAK2、JAK3蛋白酶均购自Life technology。LANCE Ultra ULightTM-JAK-1(Tyr1023)peptide和LANCE Eu-W1024 Anti-phosphotyrosine(PT66)均购自PerkinElmer。使用多联酶标仪Envision(PerkinElmer)读板。
实验方法
将测试化合物进行3倍浓度梯度稀释，终浓度为10uM到0.17nM 11个浓度，每个浓度两个复孔；DMSO在检测反应中的含量为1％。
JAK1酶反应：
2nM JAK1蛋白激酶,50nM LANCE Ultra ULightTM-JAK-1(Tyr1023)peptide,38uM ATP，50mM HEPES(pH 7.5),10mM MgCl2,1mM EGTA,2mM DTT，0.01％BRIJ-35。检测板为White Proxiplate 384-Plus plate(PerkinElmer)，室温反应90分钟，反应体系为10ul。
JAK2酶反应：
0.02nM JAK2蛋白激酶,50nM LANCE Ultra ULightTM-JAK-1(Tyr1023)peptide,12uM ATP，50mM HEPES(pH 7.5),10mM MgCl2,1mM EGTA,2mM DTT，0.01％BRIJ-35。检测板为White Proxiplate 384-Plus plate(PerkinElmer)，室温反应60分钟，反应体系为10ul。
JAK3酶反应：
0.05nM JAK2蛋白激酶,50nM LANCE Ultra ULightTM-JAK-1(Tyr1023)peptide,4uM ATP，50mM HEPES(pH 7.5),10mM MgCl2,1mM EGTA,2mM DTT，0.01％BRIJ-35。检测板为White Proxiplate 384-Plus plate(PerkinElmer)，室温反应90分钟，反应体系为10ul。
反应检测：
加10ul检测试剂至反应板中，其中LANCE Eu-W1024Anti-phosphotyrosine(PT66)终浓度为2nM，EDTA终浓度为10mM，室温孵育60分钟，Envision仪器读板。
数据分析
通过下列公式将读数转化成抑制率(％)＝(Min-Ratio)/(Max-Min)×100％。4参数曲线拟合(Model 205 in XLFIT5,iDBS)测得IC50数据，具体见表1。
表1
化合物 JAK1 JAK2
WX550 C D
WX551 C D
WX552 B C
WX579 C D
WX580 C D
WX581 C D
WX593 D D
WX592 D D
WX604 C D
WX605 D D
WX606 C D
WX591 B C
WX612 D D
WX613 B C
WX614 A B
WX615 D D
WX611 B C
WX550 C D
WX551 C D
WX552 B C
WX579 C D
WX580 C D
WX581 C D
WX593 D D
WX592 D D
WX604 C D
WX605 D D
WX606 C D
WX591 B C
WX612 D D
WX613 B C
WX614 A B
WX615 D D
WX611 B C
A≤10nM；10＜B≤100nM；100＜C≤1000nM；D>1000nM
药代动力学(PK)试验
将试验化合物溶解后得到的澄清溶液分别经尾静脉注射和灌胃给予雄性DBA/1小鼠体内(过夜禁食，7～8周龄)。给予受试化合物后，静脉注射组在0.083,0.25,0.5,1,2,4,8和24小时，灌胃组在0.25,0.5,1,2,4,8和24小时，分别从下颌静脉采血并离心后获得血浆。采用LC-MS/MS法测定血药浓度，使用WinNonlinTMVersion 6.3药动学软件，以非房室模型线性对数梯形法计算相关药代动力学参数。
表2-1 WX552在小鼠中的PK测试结果
PK Parameters Mean
T1/2(hr) 1.18
Cmax(nM) 3723
AUC0-inf(nM.hr) 11448
Bioavailability(％)a 74.39
表2-2 WX591在小鼠中的PK测试结果
PK Parameters Mean
T1/2(hr) 2.26
Cmax(nM) 3017
AUC0-inf(nM.hr) 10467
Bioavailability(％)a 87.0
表2-3 WX614在小鼠中的PK测试结果
PK Parameters Mean
T1/2(h) 1.76
Cmax(nM) 3087
AUC0-inf(nM.h) 10200
Bioavailability(％)a 73.9
本发明的化合物WX552,WX591,WX614在小鼠中都有良好的口服生物利用度,较高的暴露量,有利于产生体内药效.
大鼠佐剂诱导的关节炎模型药效试验：
用大鼠佐剂关节炎模型验证本发明化合物的治疗关节炎的作用。
雌性,体重160-180克Lewis大鼠用异氟烷麻醉后，在左后脚皮下注射0.1ml结核分枝杆菌悬浮液。在造模13天后分组并给予相应的受试化合物，如对大鼠分别给予1mpk,、3mpk、10mpk的受试化合物WX614,10mpk的受试化合物WX552,和10mpk的受试化合物WX591溶解在DMSO/PEG400/H2O混合溶媒中，并口服给予雌性Lewis大鼠(每个剂量组的受试动物数为10)。连续给药两周，期间观察大鼠状态，记录足体积肿胀情况并评分。试验表明本发明化合物WX614,WX552和WX591均展示出良好的关节炎抑制活性。
表3-1
Figure PCTCN2016083426-appb-000017
小鼠胶原诱导的关节炎模型药效试验：：
用小鼠胶原诱导的关节炎模型验证本发明化合物的治疗关节炎的作用。
选择DBA/l雄性小鼠，于第0天和第21天尾根部皮下注射胶原与弗氏完全佐剂的乳剂，第29天左右开始分组,将发明化合物WX6144(3mpk,10mpk,30mpk)、溶解在DMSO/PEG400/H2O[5/20/75(v/v/v)]中，并口服给予CIA小鼠(上海斯莱克实验动物有限公司，每个剂量组的受试动物数为10)，连续给药2周,期间记录小鼠体重，并对小鼠的关节炎症进行临床评分，结果显示本发明化合物WX614对小鼠类风湿性 关节炎有明显的治疗作用。
表3-2
Figure PCTCN2016083426-appb-000018

Claims (12)

  1. 式(Ⅰ)所示化合物或其药学上可接受的盐，
    Figure PCTCN2016083426-appb-100001
    其中，
    A选自C(R)或N；
    L1选自单键、-C(＝O)O-、-C(＝O)-、-S(＝O)-、-S(＝O)2-、-C(＝O)N(R)-、-N(R)C(＝O)N(R)-、-N(R)-、-S(＝O)N(R)-、-S(＝O)2N(R)C(R)2-、-S(＝O)N(R)C(R)2-；
    R1选自H、CN、OH、NH2、卤素，或选自任选被1、2、3或4个R取代的：C1-6烷基、C1-6杂烷基、C3-6元环烷基、3～6元杂环烷基；
    R分别独立地选自H、CN、OH、NH2、卤素，或分别选自任选被1、2、3或4个R’取代的：C1-6烷基、C1-6杂烷基；
    R’选自卤素、OH、NH2、CN、Me、Et、CF3、CH2CF3、NHCH3、N(CH3)2；
    所述“杂”选自杂原子或杂原子团，选自N、O、S、-C(＝O)O-、-C(＝O)-、-S(＝O)-、-S(＝O)2-，上述任意一种情况下所述“杂”的数目分别独立地选自1、2或3。
  2. 根据权利要求1所述化合物或其药学上可接受的盐，其中，R选自H、CN、OH、NH2、卤素，或选自任选被1、2或3个R’取代的：Me、Et、NHCH3、N(CH3)2、NHCH3、N(CH3)2、
    Figure PCTCN2016083426-appb-100002
  3. 根据权利要求1或2任意一项所述化合物或其药学上可接受的盐，其中，L1选自单键、-C(＝O)O-、-C(＝O)-、-S(＝O)-、-S(＝O)2-、-C(＝O)NH-、-NH C(＝O)NH-、-NH-、-S(＝O)NH-、-S(＝O)2NHCH2-、-S(＝O)NHCH2-。
  4. 根据权利要求1或2任意一项所述化合物或其药学上可接受的盐，其中，R1选自H、CN、OH、NH2，或选自任选被1、2、3或4个R取代的：C1-3烷基、C1-2烷基-N(C1-2烷基)2、C1-2烷基-NH-C1-2烷基、C1-3烷基-S(＝O)2-C1-3烷基、C1-3烷基-S(＝O)-C1-3烷基、C4-5环烷基、4～5元杂环烷基。
  5. 根据权利要求4所述化合物或其药学上可接受的盐，R1选自CN，或选自任选被1、2、3或4个R取代的：Me、Et、
    Figure PCTCN2016083426-appb-100003
  6. 根据权利要求5所述化合物或其药学上可接受的盐，上述R1选自CN、Me、
    Figure PCTCN2016083426-appb-100004
    Figure PCTCN2016083426-appb-100005
  7. 根据权利要求1所述化合物，其选自：
    Figure PCTCN2016083426-appb-100006
    Figure PCTCN2016083426-appb-100007
  8. 根据权利要求1所述式(Ⅰ)化合物的制备方法，包括如下步骤：
    Figure PCTCN2016083426-appb-100008
    其中，PG为氨基保护基，优选自Cbz、Boc、Fmoc、Alloc、Teco、甲氧羰基、乙氧羰基、Pht、Tos、Tfa、Bn、PMB；
    R1如权利要求1所定义。
  9. 一种药物组合物，包括治疗有效量的根据权利要求1～8任意一项所述的化合物或其药学上可接受的盐，以及药学上可接受的载体。
  10. 根据权利要求1～8任意一项所述的化合物或其药学上可接受的盐或根据权利要求9所述的药物组合物在制备治疗与Janus激酶相关疾病的药物中的应用。
  11. 根据权利要求10所述的应用，其中所述疾病为关节炎。
  12. 根据权利要求10所述的应用，其中所述疾病为类风湿性关节炎。
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Cited By (21)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107573364A (zh) * 2017-10-31 2018-01-12 无锡福祈制药有限公司 一种jak激酶抑制剂
CN107602590A (zh) * 2017-10-31 2018-01-19 无锡福祈制药有限公司 具有Janus激酶抑制活性的桥环化合物
CN107602591A (zh) * 2017-10-31 2018-01-19 无锡福祈制药有限公司 一种Janus激酶3抑制剂
CN107652308A (zh) * 2017-10-31 2018-02-02 无锡福祈制药有限公司 一种Janus激酶3抑制剂
CN107778321A (zh) * 2017-10-31 2018-03-09 无锡福祈制药有限公司 一种托法替尼类似物
CN107805259A (zh) * 2017-10-31 2018-03-16 无锡福祈制药有限公司 一种吡咯并嘧啶类化合物
CN109563097A (zh) * 2016-11-23 2019-04-02 无锡福祈制药有限公司 一种7H-吡咯并[2,3-d]嘧啶类化合物的晶型、盐型及其制备方法
WO2019061299A1 (en) * 2017-09-29 2019-04-04 Rhodia Operations PROCESS FOR THE PREPARATION OF AMINOMETHYL-SUBSTITUTED HETEROCYCLOCCANE
CN110923288A (zh) * 2019-12-19 2020-03-27 卓和药业集团有限公司 一种wxfl10203614中间体的生物学拆分方法
CN111004236A (zh) * 2019-12-19 2020-04-14 卓和药业集团有限公司 一种wxfl10203614中间体的动态动力学拆分方法
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WO2020188015A1 (en) 2019-03-21 2020-09-24 Onxeo A dbait molecule in combination with kinase inhibitor for the treatment of cancer
WO2020244614A1 (zh) * 2019-06-05 2020-12-10 南京明德新药研发有限公司 吡咯并嘧啶类化合物及其应用
CN112168827A (zh) * 2020-11-03 2021-01-05 卓和药业集团有限公司 一种用于治疗银屑病的药物组合物及其制备方法
WO2021089791A1 (en) 2019-11-08 2021-05-14 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods for the treatment of cancers that have acquired resistance to kinase inhibitors
WO2021148581A1 (en) 2020-01-22 2021-07-29 Onxeo Novel dbait molecule and its use
CN113372366A (zh) * 2020-12-04 2021-09-10 广州嘉越医药科技有限公司 一种吡咯并嘧啶类化合物的盐、其晶型及其应用
CN113372343A (zh) * 2020-12-04 2021-09-10 广州嘉越医药科技有限公司 一种吡咯并嘧啶类化合物中间体及其制备方法
CN114591333A (zh) * 2020-12-04 2022-06-07 广州嘉越医药科技有限公司 一种吡咯并嘧啶类化合物的制备方法

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1305480A (zh) * 1998-06-19 2001-07-25 辉瑞产品公司 吡咯并[2,3－d]嘧啶化合物
CN1409712A (zh) * 1999-12-10 2003-04-09 辉瑞产品公司 吡咯并[2,3－d]嘧啶化合物
CN102574863A (zh) * 2009-08-27 2012-07-11 拜奥克里斯特制药公司 作为janus激酶抑制剂的杂环化合物
CN103415520A (zh) * 2011-12-21 2013-11-27 江苏恒瑞医药股份有限公司 吡咯并六元杂芳环类衍生物、其制备方法及其在医药上的应用
WO2014128591A1 (en) * 2013-02-22 2014-08-28 Pfizer Inc. Pyrrolo [2, 3 -d]pyrimidine derivatives as inhibitors of janus- related kinases (jak)

Family Cites Families (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7160890B2 (en) 1999-12-02 2007-01-09 Osi Pharmaceuticals, Inc. Compounds specific to adenosine A3 receptor and uses thereof
MEP35308A (en) 2000-12-01 2011-02-10 Osi Pharm Inc COMPOUNDS SPECIFIC TO ADENOSINE A1, A2a, AND A3 RECEPTOR AND USES THEREOF
US7301023B2 (en) 2001-05-31 2007-11-27 Pfizer Inc. Chiral salt resolution
GB0719803D0 (en) 2007-10-10 2007-11-21 Cancer Rec Tech Ltd Therapeutic compounds and their use
SI2384326T1 (sl) 2008-08-20 2014-06-30 Zoetis Llc Pirolo(2,3-d)pirimidinske spojine
BRPI1007737A2 (pt) * 2009-04-20 2015-09-01 Auspex Pharmaceuticals Llc "composto da fórmula estrutural i, composição farmacêutica, método de tratamento de um distúbio mediano por janus quinase 3, método de preparação de um composto da fórmula estrutural ii, e método de preparação de um composto da fórmula estrutural xii"
UA109131C2 (ru) 2010-04-14 2015-07-27 Еррей Біофарма Інк. 5,7-ЗАМЕЩЕННЫЕ ИМИДАЗО[1,2-c]ПИРИМИДИНЫ КАК ИНГИБИТОРЫ JAK-КИНАЗ
CA2851623A1 (en) 2011-10-12 2013-04-18 Array Biopharma Inc. 5,7-substituted-imidazo[1,2-c]pyrimidines
EA025352B1 (ru) * 2011-12-12 2016-12-30 Др. Редди'С Лабораториз Лтд. ЗАМЕЩЕННЫЕ СОЕДИНЕНИЯ ПИРАЗОЛО[1,5-a]ПИРИДИНА В КАЧЕСТВЕ ИНГИБИТОРОВ ТРОПОМИОЗИН-РЕЦЕПТОРНОЙ КИНАЗЫ (Trk)
US8551542B1 (en) 2012-09-20 2013-10-08 Basic Research L.L.C. Methods and compositions for increasing growth hormones
AU2014221799B2 (en) * 2013-02-27 2017-09-28 Mochida Pharmaceutical Co., Ltd. Novel pyrazole derivative
SI3077395T1 (en) * 2013-12-05 2018-03-30 Pfizer Inc. Pyrrolo (2,3-d) pyrimidinyl, pyrrolo (2,3-b) pyrazinyl and pyrrolo (2,3-d) pyridinyl acrylamides
PT2994454T (pt) 2013-12-09 2019-04-02 Unichem Lab Ltd Um processo melhorado para a preparacao de (3r,4r)-(1-benzil-4- metilpiperidin-3-il)-metilamina
WO2015188369A1 (en) * 2014-06-13 2015-12-17 Merck Sharp & Dohme Corp. Purine inhibitors of human phosphatidylinositol 3-kinase delta

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1305480A (zh) * 1998-06-19 2001-07-25 辉瑞产品公司 吡咯并[2,3－d]嘧啶化合物
CN1409712A (zh) * 1999-12-10 2003-04-09 辉瑞产品公司 吡咯并[2,3－d]嘧啶化合物
CN102574863A (zh) * 2009-08-27 2012-07-11 拜奥克里斯特制药公司 作为janus激酶抑制剂的杂环化合物
CN103415520A (zh) * 2011-12-21 2013-11-27 江苏恒瑞医药股份有限公司 吡咯并六元杂芳环类衍生物、其制备方法及其在医药上的应用
WO2014128591A1 (en) * 2013-02-22 2014-08-28 Pfizer Inc. Pyrrolo [2, 3 -d]pyrimidine derivatives as inhibitors of janus- related kinases (jak)

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of EP3305788A4 *

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109563097A (zh) * 2016-11-23 2019-04-02 无锡福祈制药有限公司 一种7H-吡咯并[2,3-d]嘧啶类化合物的晶型、盐型及其制备方法
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CN107602590A (zh) * 2017-10-31 2018-01-19 无锡福祈制药有限公司 具有Janus激酶抑制活性的桥环化合物
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CN107778321A (zh) * 2017-10-31 2018-03-09 无锡福祈制药有限公司 一种托法替尼类似物
CN107805259A (zh) * 2017-10-31 2018-03-16 无锡福祈制药有限公司 一种吡咯并嘧啶类化合物
CN111499641A (zh) * 2019-01-30 2020-08-07 格格巫（珠海）生物科技有限公司 一种jak抑制剂及其制备方法
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AU2020288567B2 (en) * 2019-06-05 2023-06-15 Guangzhou Joyo Pharmatech Co., Ltd Pyrrolopyrimidine compound and use thereof
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