WO2018019222A1 - 作为jak抑制剂杂环化合物，该化合物的盐类及其治疗用途 - Google Patents

作为jak抑制剂杂环化合物，该化合物的盐类及其治疗用途 Download PDF

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WO2018019222A1
WO2018019222A1 PCT/CN2017/094253 CN2017094253W WO2018019222A1 WO 2018019222 A1 WO2018019222 A1 WO 2018019222A1 CN 2017094253 W CN2017094253 W CN 2017094253W WO 2018019222 A1 WO2018019222 A1 WO 2018019222A1
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pyrrolo
pyridin
pyrimidin
amino
pyrazol
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PCT/CN2017/094253
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English (en)
French (fr)
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张文燕
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张文燕
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Priority to EA201990385A priority Critical patent/EA039344B1/ru
Priority to EP17833525.3A priority patent/EP3492468B1/en
Priority to US16/320,178 priority patent/US11414413B2/en
Priority to KR1020197004634A priority patent/KR102598246B1/ko
Priority to CN201780044794.3A priority patent/CN109790158B/zh
Priority to JP2019504824A priority patent/JP6978097B2/ja
Publication of WO2018019222A1 publication Critical patent/WO2018019222A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • 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
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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

Definitions

  • the present invention relates to a class of heterocyclic compounds as JAK inhibitors, salts of the compounds and drugs which are active by the compounds or salts thereof, and preparation thereof for treating diseases of the immune system, rheumatoid arthritis, tumors, etc. Use in drugs for JAK-related target diseases.
  • JAK-STAT signaling pathway is a cytokine-stimulated signal transduction pathway discovered in recent years. JAK plays an important role in cytokine signaling.
  • the downstream substrates of the kinase JAK family include transcriptional protein signal transducers and Activator (STAT).
  • STAT transcriptional protein signal transducers and Activator
  • JAK protein is an important member of this pathway, and its abnormal increase in activity often leads to disease, many diseases are related to abnormal cellular responses of JAK-STAT signaling pathway, including autoimmune diseases, inflammatory diseases, bone diseases, metabolic diseases , neurological and neurodegenerative diseases, cancer, cardiovascular disease, allergy and asthma, Alzheimer's disease.
  • RA Rheumatoid arthritis
  • NSAIDs non-steroidal anti-inflammatory drugs
  • DMARDs improved anti-rheumatic drugs
  • antibody drugs for a long time, the first-line drugs for the treatment of RA were DMARDs.
  • MTX methotrexate
  • RA treatment has made great progress, and the patient's condition can be effectively controlled by existing treatment methods.
  • patients with RA are still suffering from recurrence of disease, unsatisfactory treatment effectiveness, poor long-term tolerance, and some adverse reactions.
  • the quality of life of patients with RA including organ functions such as joints, has not really improved in existing treatments. Therefore, it is aimed at restoring normal patients. There are still huge unmet clinical needs in this area.
  • RA synovial tissue and infiltrating mononuclear/macrophage, lymphocytes, etc. in the cell produce a large number of cytokines through autocrine, and these cytokines interact through different Pathway activation of JAK/STAT signaling pathway (Janus kinase/Signal transducer and activators of transcription signaling pathway) can block the cascading amplification of these cytokines by specifically inhibiting the JAK/STAT signaling pathway, thereby improving the damaged joints of RA patients. Symptoms, therefore, the JAK/STAT signaling pathway is a potential target for the treatment of RA.
  • the oral JAK inhibitor Tofacitinib was first approved by the FDA for the treatment of rheumatoid arthritis (RA), making it the first successful kinase inhibitor drug in the field.
  • JAK-STAT signaling pathway is a cytokine-stimulated signal transduction pathway discovered in recent years. JAK plays an important role in cytokine signaling.
  • JAK kinase JAK kinase (JANus kinase, referred to as JAKs, includes four known members JAK1). , JAK2, JAK3, TYK2) is a small family of cytoplasmic non-receptor tyrosine protein kinase superfamilies.
  • JAK3 is distributed in the bone marrow and lymphatic system, and JAK1, TYK2, and JAK2 are widely distributed in various tissue cells.
  • JAKs When JAKs bind to cytokine receptors on the cell surface, they activate receptor-coupled JAKs, which in turn phosphorylate receptors, which are cytoplasmic signaling and activators of STAT proteins (Signal Transducers and ActivatorsOf Transcription, STAT1-4).
  • STAT5a, STAT5b, STAT6 provide a recruitment site, and JAKs phosphorylate STAT protein, which is dimerized and transferred to the nucleus to regulate gene expression.
  • This pathway is JAK/STAT signaling pathway (0'Shea JJ, et Al., N. Engl. J. Med., 2013, 368:161-170).
  • the JAK/STAT signaling pathway is a signaling pathway stimulated by a variety of cytokines and growth factor receptors, including interleukins, interferons (IFN- ⁇ , IFN- ⁇ , IFN- ⁇ ), and erythropoietin. (EPO), granulocyte and giant cell colony stimulating factor (GM-CSF), somatotropin (GH), prolactin (PRL), thrombopoietin (TPO), etc., which are involved in the proliferation of immune cells and hematopoietic stem cells.
  • EPO interleukins, interferons
  • GM-CSF granulocyte and giant cell colony stimulating factor
  • GH somatotropin
  • PRL prolactin
  • TPO thrombopoietin
  • JAK1 can interact with IL-10, IL-19, IL-20, IL-22, IL-26, IL-28, IFN- réelle, IFN- ⁇ , IL-6 in the gp130 family, and other receptors containing ⁇ c. Binding (Rodig SJ, et al. Cell, 1998, 93: 373-383). JAK1 knockout experiments on mouse models indicate that this enzyme plays a key role in regulating the biological effects of various cytokine receptors described above (Kisseleva T., et al., Gene, 2002, 285: 1-24) . JAK1 is a novel target in the field of diseases such as immune-related diseases, inflammation and cancer.
  • JAK1 inhibitors can be used to treat/prevent inflammation of autoimmune diseases and (Hornakova T., et al., Blood, 2010, 115: 3287-3295), such as leukemia, lymphoma, melanoma, arthritis, psoriasis, Crohn's disease, lupus erythematosus, acquired immunodeficiency syndrome (Hou S., et al., Hum. Genet., 2013, 132: 1049-1058) and so on.
  • autoimmune diseases and such as leukemia, lymphoma, melanoma, arthritis, psoriasis, Crohn's disease, lupus erythematosus, acquired immunodeficiency syndrome (Hou S., et al., Hum. Genet., 2013, 132: 1049-1058) and so on.
  • JAK2 plays an important role in the regulation of various receptor signals including IL-3, IFN- ⁇ , EPO, GH (Levy DE, et al., Nat. Rev. Mol. Cell Biol., 2002, 3: 651 -662;). Knocking out JAK2 in a mouse model can lead to death in anemia animals (Schindler C., et al., J. Biol.
  • JAK3 regulates cell signaling by binding to the gamma co-chain ( ⁇ c) in cytokine receptor complexes such as IL-2, IL-4, IL-7, IL-9, IL-15, IL-21. Both JAK3 or ⁇ c mutations can lead to severe combined immunodeficiency (SCID) (Villa A., et al., Blood, 1996, 88: 817-823). Abnormal JAK3 activity is characterized by a large decrease in T cells and NK cells, loss of B cell function, and severely affecting the normal biological functions of the immune system. Based on its functional characteristics and special tissue distribution, JAK3 has become an attractive drug target for immune system-related diseases.
  • SCID severe combined immunodeficiency
  • RA rheumatoid arthritis
  • Crohn's disease systemic lupus erythematosus
  • multiple It has important clinical application value in the treatment/prevention of diseases such as sclerosis, type I diabetes, psoriasis, allergic diseases, asthma, chronic obstructive pulmonary disease, leukemia, lymphoma, organ transplantation and others (Papageorgiou AC, et Al., 2004, Trends Pharm. Sci., 2004, 25: 558-562).
  • TYK2 is the first member of the JAK family and is activated by a variety of receptors such as interferons (IFNs), IL-10, IL-12, IL-23, IL-27. In mice, loss of TYK2 function causes signals from multiple cytokine receptors
  • JAK kinase is involved in various important physiological processes in the body, extensive inhibition of different subtypes may have adverse reactions.
  • Tofacitinib is used in patients with moderate to severe RA with insufficient MTX response or intolerance. Clinical trials have been accompanied by certain adverse reactions. Including infection, tuberculosis, cancer, anemia, liver damage and increased cholesterol. Tofacitinib has significant inhibitory activity on JAK1, JAK2, and JAK3 subtypes. Since JAK2 activity is associated with red blood cell differentiation and lipid metabolism, some of the above adverse reactions are thought to be related to the non-selective inhibition characteristics of the drug. Therefore, the search for selective JAK1 and / or JAK3 inhibitors will become a new direction of RA drug research.
  • JAK inhibitors have been proven to be useful in the treatment of blood system diseases, tumors, rheumatoid arthritis and psoriasis. Since JAK inhibitors have significant medical uses, they can be used in a variety of related diseases. Therefore, the research and discovery of such compounds is extremely beneficial.
  • a first object of the invention is to provide a class of JAK inhibitor heterocyclic derivatives.
  • the invention provides a class of JAK inhibitor heterocyclic derivatives having the structure of formula (I):
  • R is selected from:
  • R 4 is hydrogen, C 1 -C 6 alkyl, or C 3 -C 6 cycloalkyl, and may be optionally substituted by a halogen atom;
  • R 1 , R 2 are independently selected from hydrogen, C 1 -C 6 alkyl, and may be substituted by C 1 -C 6 alkoxy, C 1 -C 6 alkanesulfonyl acyl, and R 1 , R 2 may also be The linked carbon atoms form a 4-10 heterocyclic ring which may be replaced by N, O, S, -SO 2 - which may be a C 6 alkane sulfonate group, a C 1 -C 6 alkyl group, a C 1 -C 6 alkanoyl substitution;
  • R 3 is hydrogen, C 1 -C 7 alkanoyl, or C 3 -C 7 cycloalkanoyl
  • n is selected from 0, 1, 2, 3, 4, 5;
  • X 1 is N, -CR 5
  • R 5 is H, -CN, or a halogen atom
  • R 1 and R 2 are hydrogen, C 1 -C 6 alkyl, and may be substituted by a C 1 -C 6 alkoxy group, a C 1 -C 6 alkanesulfonyl group, when R 1 , R 2 are bonded to a carbon atom.
  • Forming a 4-10 membered ring which may be substituted by a C 1 -C 6 alkyl group, a C 1 -C 6 alkylsulfonyl group, a C 1 -C 6 alkanoyl group, the C 1 -C 6 alkyl group, C 1 -C a 6 alkylsulfonyl group or a C 1 -C 6 alkanoyl group may be optionally substituted by a halogen atom;
  • R 1 and R 2 are selected from a carbon atom to which they are bonded to form a 5-8 membered ring, which may be replaced by N, O, S, or -SO 2 -, which may be C 1 -C 6 alkane. a C 1 -C 6 alkanesulfonyl group;
  • X 2 is N, CR 6 ;
  • X 3 is N, CR 7 ;
  • R 6 and R 7 are independently selected from the group consisting of hydrogen, -CN, and a halogen atom;
  • X 1 is N, or -CR 5
  • R 5 is H, -CN, or a halogen atom
  • R is selected from:
  • R 4 is hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, and may be optionally substituted by a halogen atom;
  • R 1 and R 2 are selected from a carbon atom to which they are attached to form a 4-10 membered ring which may be replaced by N, O, S, or -SO 2 -, which may be C 1 -C 6 alkyl, a C 1 -C 6 alkanesulfonyl group or a C 1 -C 6 alkanoyl group;
  • R 1, R 2 are independently selected from hydrogen, C 1 -C 6 alkyl, and C 1 -C 6 can alkoxy, C 1 -C 6 alkyl sulfonate group, aryl group, heteroaryl substituted with an aryl group, R 1 , R 2 may also form a 4-10 membered ring with a carbon atom to which it is attached, the ring carbon atom may be replaced by N, O, S, or -SO 2 -, the ring may be alkanesulfonate, C 1 -C a 6 alkyl group, a C 1 -C 6 alkanoyl group; one of R 1 , R 2 may also be bonded to R 8 to form a 4-6 membered ring;
  • R 8 is hydrogen or C 1 -C 6 alkyl
  • n is selected from 0, 1, 2, 3, 4, 5;
  • the compound of the present invention has the structure of formula (II):
  • R 4 is hydrogen, C 1 -C 6 alkyl, or C 3 -C 6 cycloalkyl, and may be optionally substituted by a halogen atom;
  • R 1 , R 2 are independently selected from hydrogen, C 1 -C 6 alkyl, and may be substituted by C 1 -C 6 alkoxy, C 1 -C 6 alkanesulfonyl acyl, and R 1 , R 2 may also be The linked carbon atoms form a 4-10 heterocyclic ring which may be replaced by N, O, S, or -SO 2 - which may be a C 6 alkane sulfonate group, a C 1 -C 6 alkyl group, or C 1 -C 6 alkanoyl substitution;
  • R 3 is hydrogen, C 1 -C 7 alkanoyl, or C 3 -C 7 cycloalkanoyl
  • n is selected from 0, 1, 2, 3, 4, 5;
  • X 1 is N, or -CR 5
  • R 5 is H, -CN, or a halogen atom
  • R 1, R 2 is hydrogen, C 1 -C 6 alkyl group, and may be substituted by C 1 -C 6 alkoxy, C 1 -C 6 alkyl or a sulfonic acid group, when R 1, R 2 carbon they are attached
  • the atom forms a 4-10 membered ring which may be substituted by a C 1 -C 6 alkyl group, a C 1 -C 6 alkylsulfonyl group, a C 1 -C 6 alkanoyl group, the C 1 -C 6 alkyl group, C 1 -
  • the C 6 alkylsulfonyl group and the C 1 -C 6 alkanoyl group may be optionally substituted by a halogen atom;
  • R 1 and R 2 are selected from a carbon atom to which they are bonded to form a 5-8 membered ring, which may be replaced by N, O, S, or -SO 2 -, which may be C 1 -C 6 alkane. a group or a C 1 -C 6 alkanesulfonyl group;
  • the compound of formula (II) according to the invention is selected from the group consisting of, but not limited to, the following structure:
  • the compound of the present invention has the structure of formula (III):
  • X 2 is N, or CR 6 ;
  • X 3 is N, or CR 7 ;
  • R 6 and R 7 are independently selected from the group consisting of H, -CN, and a halogen atom;
  • X 1 is N, -CR 5 ;
  • R 5 is H, -CN, a halogen atom
  • R 1 and R 2 are selected from a 4-10 membered ring with a covalently bonded carbon atom, and the ring carbon atom may be replaced by N, O, S, -SO 2 -, which may be C 1 -C 6 alkyl, C 1- C 6 alkylsulfonyl, C 1 -C 6 alkanoyl substituted;
  • R 4 is hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, and may be optionally substituted by a halogen atom;
  • R 1, R 2 are independently selected from hydrogen, C 1 -C 6 alkyl, and C 1 -C 6 can alkoxy, C 1 -C 6 alkyl sulfonate group, an aryl group, a substituted aryl or heteroaryl, R 1 , R 2 may also form a 4-10 membered ring with a carbon atom to which it is attached, and the ring carbon atom may be replaced by N, O, S, or -SO 2 -, which may be alkanoic acid group, C 1 - a C 6 alkyl group, a C 1 -C 6 alkanoyl group; one of R 1 , R 2 may also be bonded to R 8 to form a 4-6 membered ring;
  • R 8 is hydrogen or C 1 -C 6 alkyl
  • n is selected from 0, 1, 2, 3, 4, 5;
  • the compound of formula (III) according to the invention is selected from, but not limited to, the following structure:
  • alkyl refers to a straight or branched alkyl group having from 1 to 12 carbon atoms in the chain, and examples of the alkyl group include methyl (Me), ethyl (Et), n-propyl, isopropyl. , butyl, isobutyl, sec-butyl, tert-butyl (t-Bu), pentyl, isopentyl, tert-amyl, hexyl, isohexyl, and according to the teachings provided by one of ordinary skill in the art and the text It is considered to be equivalent to any one of the above examples.
  • alkoxy refers to an alkyl group as defined above which is bonded to an oxygen atom.
  • the alkoxy group is attached to the parent structure via an oxygen atom.
  • amino refers to an -NH 2 group or mono or dialkylamino.
  • cycloalkyl refers to saturated and partially saturated, monocyclic, fused polycyclic, bridged polycyclic, or polycyclic carbocyclic rings having from 3 to 12 ring atoms per carbon atom.
  • cycloalkyl groups include the following entities in the form of suitable bonding moieties:
  • aryl refers to a 5-6 membered carbon aromatic ring, such as benzene
  • Bicyclic rings wherein at least one of the rings is a carbon aromatic ring such as naphthalene, anthracene and 1,2,3,4-tetrahydroquinoline; and a tricyclic ring wherein at least one of the rings is a carbon aromatic ring, such as hydrazine.
  • an aryl group includes a 5-6 membered carbon aromatic ring and a 5-7 membered heterocyclic ring including one or more heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, provided that the point of attachment is in the carbon aromatic ring
  • a divalent radical by a substituted benzene derivative and having a free valence state on the ring, it is named as a substituted phenylene radical.
  • a naphthyl group having two points of attachment is referred to as a naphthylene group.
  • the aryl group does not contain, nor does it overlap in any way with the heterocyclic aryl groups respectively defined below.
  • the resulting ring system is an aromatic heterocyclic group rather than an aryl group.
  • arylhetero refers to:
  • An atom is a carbon atom
  • N, O and S such as from 1 to 4 heteroatoms, and in some embodiments, from 1 to 3 heteroatoms, other atoms on the ring.
  • heterocycloalkyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent comprising from 3 to 20 ring atoms wherein one or more ring atoms are selected from nitrogen, oxygen or S (O) a hetero atom of m (where m is an integer from 0 to 2), and the remaining ring atoms are carbon. It preferably comprises from 3 to 12 ring atoms, wherein from 1 to 4 heteroatoms, more preferably a heterocycloalkyl ring contains from 3 to 10 ring atoms, more preferably a heterocycloalkyl ring contains from 5 to 6 ring atoms.
  • Non-limiting examples of monocyclic heterocycloalkyl groups include pyrrolidinyl, piperidinyl, morpholinyltetrahydrofuranyl and the like.
  • Polycyclic heterocycloalkyl groups include spiro, fused, and bridged heterocycloalkyl groups.
  • the heterocyclic ring may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, haloalkyl, alkoxy, alkylamino, halo, hydroxy Amino, oxo, alkylamino, cycloalkyl, heterocycloalkyl, heterocycloalkoxy, hydroxyalkyl, carboxy or carboxylate.
  • halogen means chloro, fluoro, bromo or iodo.
  • halo denotes chloro, fluoro, bromo or iodo.
  • haloalkyl refers to an alkyl group as defined above which is substituted by one or more halogen atoms.
  • haloalkoxy refers to an alkoxy group as defined above which is substituted by one or more halogen atoms.
  • acyl refers to a radical RC(0)- of a straight, branched, or cyclic configuration of 1 to 10 carbon atoms, or a combination thereof, which is attached to the parent structure through a hydroxy function, such a group It is saturated or unsaturated, and ester or aromatic.
  • the compound of the present invention if it contains a basic group, can be salted with an acid, and a salt of a pyrimidine derivative can be produced by a method well known to those skilled in the art.
  • Common acid salts include organic acid salts, inorganic acid salts, and the like.
  • organic acid salts are citrate, fumarate, oxalate, malate, lactate, sulfonate (eg camphor sulfonate, p-toluenesulfonate, methanesulfonic acid) Salts, etc.
  • inorganic acid salts include hydrohalides, sulfates, phosphates, nitrates, and the like.
  • a lower alkylsulfonic acid such as methanesulfonic acid, trifluoromethanesulfonic acid or the like may form a mesylate salt, a triflate salt; and an arylsulfonic acid such as benzenesulfonic acid or p-toluenesulfonic acid.
  • p-toluenesulfonate besylate; forming an appropriate salt with an organic carboxylic acid such as acetic acid, fumaric acid, tartaric acid, oxalic acid, maleic acid, malic acid, succinic acid or citric acid;
  • glutamic acid or aspartic acid can form glutamate or aspartate.
  • Corresponding salts may also be formed with inorganic acids such as hydrohalic acids (e.g., hydrofluoric acid, hydrobromic acid, hydroiodic acid, hydrochloric acid), nitric acid, carbonic acid, sulfuric acid or phosphoric acid.
  • hydrohalic acids e.g., hydrofluoric acid, hydrobromic acid, hydroiodic acid, hydrochloric acid
  • nitric acid e.g., carbonic acid, sulfuric acid or phosphoric acid.
  • the compound of the present invention if it contains an acidic group, can be salted with a base, and a salt of the compound of the present invention can be prepared by a method well known to those skilled in the art, for example, with an alkali metal.
  • a salt such as sodium, potassium or lithium
  • a salt formed with an alkaline earth metal such as calcium or barium
  • other metals such as magnesium and aluminum.
  • the present invention provides a medicament using the JAK inhibitor compound of the formula (I), an isomer or a pharmaceutically acceptable salt or solvent compound thereof as an active ingredient.
  • the above medicament may further comprise one or more pharmaceutically acceptable carriers, including conventional diluents, excipients, fillers, binders, humectants, disintegrants, absorption promotion in the pharmaceutical field.
  • a surfactant, a surfactant, an adsorption carrier, a lubricant, etc., if necessary, a flavoring agent, a sweetener or the like may be added.
  • the medicament of the present invention can be prepared into various forms such as tablets, powders, granules, capsules, oral liquids and injectable preparations, and the medicaments of the above respective dosage forms can be prepared according to a conventional method in the pharmaceutical field.
  • the present invention provides a compound (I) JAK inhibitor heterocyclic compound, isomer and pharmaceutically acceptable salt thereof for use in the treatment of human or animal autoimmune diseases, rheumatoid arthritis, skin disorders, multiple Use in hardening, psoriatic arthritis, inflammatory bowel disease, myasthenia gravis, psoriasis, especially in drugs related to JAK kinase-related diseases.
  • the inventors of the present invention have confirmed by experiments that some of the compounds disclosed in the present invention have a good inhibitory effect on JAK kinase, particularly JAK1, and have low inhibitory activity on JAK2 and JAK3, suggesting that the product is a selective JAK inhibitor.
  • step 3 Take 0.5 g of the product of step 3, add 5 ml of trifluoroacetic acid, react at room temperature for 3 h, and perform thin layer chromatography (B Ethyl acetate/petroleum ether 1:2), until the reaction was completed, concentrated to dryness, and then reacted with 1 ml of ethylenediamine for 2 h, concentrated to dryness, filtered, and concentrated.
  • step 1 Take 5g of the product of step 1, add 30ml of trifluoroacetic acid, react at room temperature for 3h, thin layer chromatography (ethyl acetate / petroleum ether 1:2), complete the reaction, concentrate to dryness, add 1ml of ethylenediamine for 2h, concentrate to Dry, filter, concentrate, and column chromatography to give the object 2.6 g.
  • Example (1) 0.3 g of the product of Example (1), 10 ml of methanol, 2 ml of 1 M sodium hydroxide, 2 hours of reaction at 50 ° C, pH adjusted to 7 with hydrochloric acid, methanol, and filtered.
  • Example (1) 0.6 g of the product of Example (1) was added, 4 ml of 1 M sodium hydroxide and 20 ml of methanol were added thereto, and the mixture was refluxed for 10 hours, and the mixture was adjusted to pH 6 with hydrochloric acid, and extracted with methanol, dichloromethane, dried, concentrated, and filtered to give the object.
  • step 1 0.4 g of the product of step 1 was dissolved in 5 ml of dry DMF, and 0.18 g of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDC.HCl) was added and stirred for 1 hour. After adding 0.1 g of trifluoroethylamine, after 2 hours of reaction, it was diluted with water, extracted with dichloromethane, dried, concentrated, and then purified by column chromatography.
  • EDC.HCl N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride
  • step 1 product 2g dissolved in 10ml, add 2M potassium hydroxide 4ml, stir at room temperature After 2 hours, remove the solvent, add hydrochloric acid to adjust the pH to 6, filter, and dry the target 1.6g.
  • step 3 0.8 g of the product of step 3 was added with 2 ml of 2M potassium hydroxide, 10 ml of methanol, and refluxed for 2 hours. The solvent was removed, hydrochloric acid was added to adjust the pH to 6 and filtered to obtain 0.5 g of the target.
  • step 4 0.3 g of the product of step 4 was dissolved in 5 ml of dry DMF, and 0.16 g of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDC.HCl) was added and stirred for 2 hours. Then, 0.098 g of 2,2,2-trifluoroethylamine was added, and after completion of the reaction for 1 hour, it was diluted with water, extracted with dichloromethane, dried, concentrated, and then subjected to column chromatography to obtain 0.2 g of the object.
  • EDC.HCl N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride
  • the effect of the study compound on the activity of purified recombinant JAK was to study the inhibitory activity of the compound against JAK at the enzymatic level.
  • the experimental principle is to use a luminescent kinase assay to detect the ADP content produced by the reaction of JAK with the substrate Poly (4:1Glu, Tyr) peptide: ADP can be used as Ultra-Glo fluorescein after ADP is converted to ATP. The enzyme catalyzes the substrate of the reaction, producing an optical signal. The luminescent signal is positively correlated with the amount of ADP and kinase activity. Therefore, the inhibitory effect on the recombinant JAK was determined by observing the luminescence signal produced by the reaction of the compound with JAK and the substrate, and it was expressed by IC 50 .
  • Example 3 had high inhibitory activity against JAK1 and low inhibitory activity against JAK2, suggesting that the selectivity of the compound for JAK1 is higher than that of Baricitinib and Ruxolitinib (the compound disclosed in CN101448826A), and the latter two positive drugs against JAK1, JAK2 No selectivity.
  • Example 64 Effect of repeated administration of the compound of the present invention on hematological parameters in rats
  • the compound of Example 3 was administered in a dose of 1.5 mg ⁇ kg -1 ⁇ d -1 and 4.5 mg ⁇ kg -1 ⁇ d -1 , and the blood score of the animal was compared with the control group (Veh). There was no significant decrease in the group (P ⁇ 0.05); in the dose group of 4.5 mg ⁇ kg -1 ⁇ d -1 of Ruxolitinib (the compound disclosed in CN101448826A), the WBC value of the hematological index of the animal was significantly lower than that of the control group (Veh). ⁇ 0.05), suggesting that the compounds of the present invention have less side effects when treating rheumatoid arthritis.
  • Example 3 had high inhibitory activity against JAK1 and low inhibitory activity against JAK2, suggesting that the selectivity of the compound for JAK1 is higher than that of Baricitinib and Ruxolitinib (the compound disclosed in CN101448826A), and the latter two positive drugs against JAK1, JAK2 No selectivity.

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Abstract

公开了一类作为JAK抑制剂杂环衍生物，及该化合物的盐类，（II）、（III）、R的定义详见说明书。此外，还公开了以该化合物、及其盐类为活性成分的药物，及其在制备治疗免疫系统疾病、类风湿关节炎、肿瘤等与JAK相关靶点疾病的药物中的用途。

Description

作为JAK抑制剂杂环化合物，该化合物的盐类及其治疗用途 技术领域
本发明涉及一类作为JAK抑制剂杂环化合物，该化合物的盐类和以该化合物或其盐类为活性成涉分的药物，及其在制备治疗免疫系统疾病、类风湿关节炎、肿瘤等JAK相关靶点疾病的药物中的用途。
背景技术
JAK-STAT信号通路是近年来发现的一条由细胞因子刺激的信号转导通路，JAK在细胞因子信号传导中起着重要的作用，激酶JAK家族的下游底物包括转录蛋白的信号转导剂和激活剂(STAT)。JAK蛋白是该通路中重要成员，而其活性的异常提高往往导致疾病的发生，很多疾病都与JAK-STAT信号通路异常细胞反应有关，这些疾病包括自身免疫病、炎性病、骨病、代谢病、神经和神经变性病、癌症、心血管病、变态反应和哮喘、阿尔兹海默氏病。
类风湿性关节炎(rheumatoid arthritis,RA)是一种临床常见的慢性自身免疫性疾病，主要表现为关节肿胀、疼痛、僵硬、畸形和功能严重受损等，人群发病率为0.5％-1.0％。由于RA的发病机制尚未明确，因此其病理过程难以控制，致残率高，严重损害患者身心健康，降低患者生存质量。目前用于治疗RA的药物主要有非甾体抗炎药(NSAID)、改善病情抗风湿药(DMARD)、以及抗体类药物。长期以来，治疗RA的一线药物为DMARDs，1988年，第1个DMARD药物甲氨蝶呤(MTX)获FDA批准治疗RA，MTX是RA治疗史上的一个重要里程碑。该药物因其有效性、耐受性、安全性等优势而被广泛应用，但其具有包括恶心、呕吐、胃部不适、肝毒性等不良反应。相比之下，新近发展的抗体类药物对于中重度RA具有较好的疗效性和安全性指标，但是因其靶向特定的细胞因子，获益人群受到明显限制，同时治疗费用和注射方式给药也限制了这类药物的推广。
在过去20年的发展历程中，RA治疗已经取得长足进步，患者病情经现有治疗方法已经可以有效控制。尽管如此，RA患者仍经受疾病复发、治疗有效性不理想、长期耐受性差及一些不良反应等问题。更为重要的是，RA患者的生活质量包括关节等器官功能在现有治疗手段并没有得到真正的改善，因此，着眼于恢复患者的正常 机能在这一领域仍存在巨大的未满足的临床需求。
研究表明，在RA中起核心治病作用的是RA滑膜组织及细胞中浸润的单核/巨噬细胞、淋巴细胞等通过自分泌的方式产生大量细胞因子，这些细胞因子相互作用，通过不同途径激活JAK/STAT信号通路(Janus kinase/Signal transducer and activators of transcription signaling pathway)，通过特异性抑制JAK/STAT信号通路，可阻断上述细胞因子的级联放大作用，从而改善RA患者受损关节症状，因此，JAK/STAT信号通路成为治疗RA的潜在靶点。2012年11月，口服JAK抑制剂Tofacitinib首获FDA批准用于治疗类风湿性关节炎(rheumatoid arthritis，RA)，成为该领域第1个成功的激酶抑制剂药物。
JAK-STAT信号通路是近年来发现的一条由细胞因子刺激的信号转导通路，JAK在细胞因子信号传导中起着重要的作用，JAK激酶(Janus kinase，简称JAKs，包括四个已知成员JAK1、JAK2、JAK3、TYK2)是胞浆内非受体酪氨酸蛋白激酶超家族中的一个小家族。JAK3分布于骨髓和淋巴系统中，JAK1、TYK2、JAK2则广泛分布于多种组织细胞中。当JAKs结合到细胞表面的细胞因子受体后，激活受体偶联的JAKs，进而使受体磷酸化，这为胞浆信号传导和转录激活因子STAT蛋白(Signal Transducers and ActivatorsOf Transcription，STAT1-4、STAT5a、STAT5b、STAT6)提供了募集反应位点，JAKs磷酸化STAT蛋白，后者二聚化后转移到细胞核内调控基因表达，这条途径即JAK/STAT信号通路(0’Shea J.J.,et al.,N.Engl.J.Med.,2013,368:161-170)。
JAK/STAT信号通路是一条由多种细胞因子和生长因子受体刺激的信号传导通路，这些因子包括白介素类、干扰素类(IFN-а、IFN-β、IFN-γ)、促红细胞生成素(EPO)、粒细胞和巨细胞集落刺激因子(GM-CSF)、促生长素(GH)、催乳素(PRL)、促血小板生成素(TPO)等，其在参与免疫细胞和造血干细胞的增殖、免疫调节的生物学过程中起关键作用(Ghoreschi K.,et al.Immunol.Rev.,2009,228:273-287)。
JAK1可与IL-10、IL-19、IL-20、IL-22、IL-26、IL-28、IFN-а、IFN-γ、gp130家族中的IL-6以及含γc的其它受体等结合(Rodig S.J.,et al.Cell,1998,93:373-383)。小鼠模型上的JAK1基因敲除实验表明该酶在调节上述多种细胞因子受体的生物学效应中起着关键作用(Kisseleva T.,et al.,Gene,2002,285:1-24)。JAK1是免疫相关疾病、炎症和癌症等疾病领域的新型靶点。JAK1抑制剂可用于治疗/预防自身免疫性疾病炎症和(Hornakova T.,et al.,Blood,2010,115:3287-3295)，如白血病、淋巴瘤、黑色素瘤、关节炎、银屑病、克罗恩病、红斑狼疮、获得性免疫缺陷综合症(Hou S.,et al., Hum.Genet.,2013,132:1049-1058)等。
JAK2在包括IL-3、IFN-γ、EPO、GH等多种受体信号的调节过程中发挥重要作用(Levy D.E.,et al.,Nat.Rev.Mol.Cell Biol.,2002,3:651-662；)。在小鼠模型中敲除JAK2可导致贫血动物死亡(Schindler C.,et al.,J.Biol.Chem.,2007,282:20059-20063)；人体中的JAK2基因上的一个碱基突变JAK2V617F，其与骨髓增生性疾病中的真性红细胞增多症(PV)、特发性血小板增多症(ET)等的发生密切相关(Ghoreschi K.,et al.,Immunol.Rev.,2009,228:273-287)。
JAK3通过与IL-2、IL-4、IL-7、IL-9、IL-15、IL-21等细胞因子受体复合物中的γ共链(γc)相结合，调节细胞信号传导。JAK3或γc突变都可导致重症联合免疫缺陷(SCID)(Villa A.,et al.,Blood,1996,88:817-823)。JAK3活性异常表现为T细胞和NK细胞大量减少，B细胞功能丧失，严重影响免疫系统等的正常生物学功能。基于其功能特点和特殊的组织分布，JAK3成为针对免疫系统相关疾病极具吸引力的药物靶点，其抑制剂在类风湿性关节炎(RA)、克罗恩病、系统性红斑狼疮、多发性硬化症、I型糖尿病、银屑病、过敏性疾病、哮喘、慢性阻塞性肺病、白血病、淋巴瘤、器官移植和其它等疾病的治疗/预防方面具有重要的临床应用价值(Papageorgiou A.C.,et al.,2004,Trends Pharm.Sci.,2004,25:558-562)。
TYK2是JAK家族中的第一个成员，其可被干扰素(IFNs)、IL-10、IL-12、IL-23、IL-27等多种受体激活。在小鼠中，TYK2功能缺失会引起多种细胞因子受体的信号
通路发生缺陷，进而导致病毒感染、抗菌免疫功能下降并增加了肺部感染的可能性等(Kisseleva T.,et al.，2002,Gene,285:1-24)。另外，LarnerA.C小组的研究表明TYK2可有助于抑制乳腺癌的生长和转移(Zhang Q.,et al.,2011,J.Interferon Cytokine Res.,31:671-677)。
由于JAK激酶参与体内各种重要的生理过程，对不同亚型的广泛抑制有可能产生不良反应，Tofacitinib用于MTX反应不足或不耐受的中重度RA患者，临床试验观察其伴随一定的不良反应，包括感染、结核、肿瘤、贫血、肝损伤及胆固醇增加等。Tofacitinib对JAK1，JAK2，JAK3亚型均有显著的抑制活性，由于JAK2活性与红细胞分化以及脂代谢过程相关，上述部分不良反应被认为与该药物的非选择性抑制特点相关。因此，寻找选择性JAK1和/或JAK3抑制剂将成为RA药物研究的新方向。
目前JAK抑制剂已经被证实可以用于血液系统疾病、肿瘤、类风湿性关节炎及银屑病等治疗药物。由于JAK抑制剂有显著的医疗用途可以用于各种相关疾病药物， 所以对该类化合物的研究及发现是极其有益的。
发明内容
本发明的第一个目的是提供一类JAK抑制剂杂环衍生物。
具体地说，本发明提供了一类JAK抑制剂杂环衍生物，其具有式(I)结构：
Figure PCTCN2017094253-appb-000001
及其异构体、溶剂合物、或其药学上可接受的盐。
当
Figure PCTCN2017094253-appb-000002
选自:
Figure PCTCN2017094253-appb-000003
R选自：
Figure PCTCN2017094253-appb-000004
当X为-CONH-R4时，R4为氢、C1-C6烷基、或C3-C6环烷基，并可被卤原子任意取代；
Figure PCTCN2017094253-appb-000005
选自:
Figure PCTCN2017094253-appb-000006
R1，R2独立地选自氢、C1-C6烷基，并可被C1-C6烷氧基、C1-C6烷磺酸酰基取代，R1，R2还可与其相连的碳原子形成4-10杂环，该环碳原子可被N、O、S、-SO2-替代，该环可被C-C6烷磺酸基、C1-C6烷基、C1-C6烷酰基取代；
R3为氢、C1-C7烷酰基、或C3-C7环烷酰基；
n选自0、1、2、3、4、5；
X1为N、-CR5
R5为H、-CN、或卤原子；
当X为-CN时，
Figure PCTCN2017094253-appb-000007
选自：
Figure PCTCN2017094253-appb-000008
其中：
R1、R2为氢、C1-C6烷基，并可被C1-C6烷氧基、C1-C6烷磺酸酰基取代，当R1、R2与其相连的碳原子形成4-10元环，该环可被C1-C6烷基、C1-C6烷磺酰基、C1-C6烷酰基取代，该C1-C6烷基、C1-C6烷磺酰基、或C1-C6烷酰基可被卤原子任意取代；
Figure PCTCN2017094253-appb-000009
选自:
Figure PCTCN2017094253-appb-000010
这时R1、R2选自与其相连的碳原子形成5-8元环，该环碳原子可被N、O、S、或-SO2-替代，该环可被C1-C6烷基、C1-C6烷磺酰基取代；
当
Figure PCTCN2017094253-appb-000011
选自：
Figure PCTCN2017094253-appb-000012
时，
X2为N、CR6；
X3为N、CR7；
R6、R7独立地选自氢、-CN、卤原子；
Figure PCTCN2017094253-appb-000013
选自:
Figure PCTCN2017094253-appb-000014
X1为N、或-CR5
R5为H、-CN、或卤原子；
R选自：
Figure PCTCN2017094253-appb-000015
当X选自-CONH-R4时，R4为氢、C1-C6烷基、C3-C6环烷基，并可被卤原子任意取代；
R1、R2选自与其相连的碳原子形成4-10元环，该环碳原子可被N、O、S、或-SO2-替代，该环可被C1-C6烷基、C1-C6烷磺酰基、或C1-C6烷酰基取代；
当X为-CN时，
R1，R2独立地选自氢、C1-C6烷基，并可使C1-C6烷氧基、C1-C6烷磺酸基、芳 基、杂芳基取代，R1，R2还可与其相连的碳原子形成4-10元环，该环碳原子可被N、O、S、或-SO2-替代，该环可被烷磺酸基、C1-C6烷基、C1-C6烷酰基取代；R1，R2之一还可以与R8连接成4-6元环；
R8为氢、或C1-C6烷基；
m选自0、1、2、3、4、5；
具体地，本发明所述的化合物具有式(II)结构：
Figure PCTCN2017094253-appb-000016
及其异构体、溶剂合物、或其药学上可接受的盐。
其中：
当X为-CONH-R4时，R4为氢、C1-C6烷基、或C3-C6环烷基，并可被卤原子任意取代；
Figure PCTCN2017094253-appb-000017
选自:
Figure PCTCN2017094253-appb-000018
R1，R2独立地选自氢、C1-C6烷基，并可被C1-C6烷氧基、C1-C6烷磺酸酰基取代，R1，R2还可与其相连的碳原子形成4-10杂环，该环碳原子可被N、O、S、或-SO2-替代，该环可被C-C6烷磺酸基、C1-C6烷基、或C1-C6烷酰基取代；
R3为氢、C1-C7烷酰基、或C3-C7环烷酰基；
n选自0、1、2、3、4、5；
X1为N、或-CR5
R5为H、-CN、或卤原子；
当X为-CN时，
Figure PCTCN2017094253-appb-000019
选自：
Figure PCTCN2017094253-appb-000020
其中：
R1、R2为氢、C1-C6烷基，并可被C1-C6烷氧基、或C1-C6烷磺酸酰基取代，当R1、R2与其相连的碳原子形成4-10元环，该环可被C1-C6烷基、C1-C6烷磺酰基、C1-C6烷酰基取代，该C1-C6烷基、C1-C6烷磺酰基、C1-C6烷酰基可被卤原子任意取 代；
当
Figure PCTCN2017094253-appb-000021
选自:
Figure PCTCN2017094253-appb-000022
这时R1、R2选自与其相连的碳原子形成5-8元环，该环碳原子可被N、O、S、或-SO2-替代，该环可被C1-C6烷基、或C1-C6烷磺酰基取代；
优选地，本发明所述的式(Ⅱ)化合物选自但不限于以下结构：
2-(3-(4-(1H-吡咯并[2,3-b]吡啶-3-基)-1H-吡唑-1-基)-1-(乙磺酰基)氮杂环丁-3-基)乙腈；
2-(4-(4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基)-1,1-二氧代四氢-2H-硫代吡喃-4-基)乙腈
2-(4-(4-(1H-吡咯并[2,3-b]吡啶-4-基)-1H-吡唑-1-基)-1,1-二氧代四氢-2H-硫代吡喃-4-基)乙腈
2-(4-(4-(1H-吡咯并[2,3-b]吡啶-3-基)-1H-吡唑-1-基)-1,1-二氧代四氢-2H-硫代吡喃-4-基)乙腈；
2-(4-(4-(1H-吡咯并[2,3-b]吡啶-3-基)-1H-吡唑-1-基)-1-(甲磺酰基)哌啶-4-基)-N-(2,2,2-三氟乙基)乙腈；
2-(3-(4-(1H-吡咯并[2,3-b]吡啶-3-基)-1H-吡唑-1-基)-1-(乙磺酰基)氮杂环丁-3-基)乙酰胺；
2-(3-(4-(1H-吡咯并[2,3-b]吡啶-3-基)-1H-吡唑-1-基)-1-(乙磺酰基)氮杂环丁-3-基)-N-(2,2,2-三氟乙基)乙酰胺；
2-(3-(4-(1H-吡咯[并2,3-d]嘧啶-4-基)-1H-吡唑-1-基)-1-(乙磺酰基)氮杂环丁-3-基)-N-(2,2,2-三氟乙基)乙酰胺；
2-(3-(4-(1H-吡咯[并2,3-b]吡啶-4-基)-1H-吡唑-1-基)-1-(乙磺酰基)氮杂环丁-3-基)-N-(2,2,2-三氟乙基)乙酰胺；
2-(3-(4-(1H-吡咯并[2,3-b]吡啶-4-基)-1H-吡唑-1-基)-1-(乙磺酰基)氮杂环丁-3-基)–N-甲基乙酰胺；
2-(3-(4-(1H-吡咯并[2,3-b]吡啶-4-基)-1H-吡唑-1-基)-1-(乙磺酰基)氮杂环丁-3-基)乙酰胺；
2-(3-(4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基)-1--(甲磺酰基) 氮杂环丁-3-基)-N-(2,2,2-三氟乙基)乙酰胺；
2-(3-(4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基)-1--(甲磺酰基)氮杂环丁-3-基)-N-甲基乙酰胺；
2-(3-(4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基)-1--(甲磺酰基)氮杂环丁-3-基)乙酰胺；
2-(3-(4-(1H-吡咯并[2,3-b]吡啶-4-基)-1H-吡唑-1-基)-1-(甲磺酰基)氮杂环丁-3-基)-N-(2,2,2-三氟乙基)乙酰胺；
2-(3-(4-(1H-吡咯并[2,3-b]吡啶-4-基)-1H-吡唑-1-基)-1-(甲磺酰基)氮杂环丁-3-基)–N-甲基乙酰胺；
2-(3-(4-(1H-吡咯并[2,3-b]吡啶-4-基)-1H-吡唑-1-基)-1-(甲磺酰基)氮杂环丁-3-基)乙酰胺；
2-(4-(4-(1H-吡咯并[2,3-b]吡啶-3-基)-1H-吡唑-1-基)-1,1-二氧代四氢-2H-硫代吡喃-4-基)乙酰胺
2-(4-(4-(1H-吡咯并[2,3-b]吡啶-3-基)-1H-吡唑-1-基)-1,1-二氧代四氢-2H-硫代吡喃-4-基)-N-(2,2,2-三氟乙基)乙酰胺；
2-(4-(4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基)-1,1-二氧代四氢-2H-硫代吡喃-4-基)-N-(2,2,2-三氟乙基)乙酰胺；
2-(4-(4-(7H-吡咯并[2,3-b]吡啶-4-基)-1H-吡唑-1-基)-1,1-二氧代四氢-2H-硫代吡喃-4-基)-N-(2,2,2-三氟乙基)乙酰胺；
2-(4-(4-(7H-吡咯并[2,3-b]吡啶-3-基)-1H-吡唑-1-基)-1-(甲磺酰基)哌啶-4-基)-N-(2,2,2-三氟乙基)乙酰胺；
2-(4-(4-(7H-吡咯并[2,3-b]嘧啶-4-基)-1H-吡唑-1-基)-1-(甲磺酰基)哌啶-4-基)-N-(2,2,2-三氟乙基)乙酰胺；
2-(4-(4-(7H-吡咯并[2,3-b]吡啶-4-基)-1H-吡唑-1-基)-1-(甲磺酰基)哌啶-4-基)-N-(2,2,2-三氟乙基)乙酰胺；
2-(1-(4-(1H-吡咯并[2,3-b]吡啶-3-基)-1H-吡唑-1-基)环戊基)-N-(2,2,2-三氟乙基)乙酰胺；
2-(1-(4-(1H-吡咯并[2,3-b]嘧啶-4-基)-1H-吡唑-1-基)环戊基)-N-(2,2,2-三氟乙基)乙酰胺；
2-(1-(4-(1H-吡咯并[2,3-b]吡啶-4-基)-1H-吡唑-1-基)环戊基)-N-(2,2,2-三氟乙基)乙酰胺；
3-(4-(1H-吡咯并[2,3-b]吡啶-3-基)-1H-吡唑-1-基)-3-甲基-N-(2,2,2-三氟乙基)丁酰胺；
3-(4-(7H-吡咯并[2,3-b]嘧啶-4-基)-1H-吡唑-1-基)-3-甲基-N-(2,2,2-三氟乙基)丁酰胺；
3-(4-(7H-吡咯并[2,3-b]吡啶-4-基)-1H-吡唑-1-基)-3-甲基-N-(2,2,2-三氟乙基)丁酰胺；
及其异构体、溶剂合物、或其药学上可接受的盐。
具体地、本发明所述的化合物具有式(Ⅲ)结构:
Figure PCTCN2017094253-appb-000023
其中:
X2为N、或CR6；
X3为N、或CR7；
R6、R7独立地选自H、-CN、卤原子；
Figure PCTCN2017094253-appb-000024
选自:
Figure PCTCN2017094253-appb-000025
X1为N、-CR5；
R5为H、-CN、卤原子；
当X选自-CONH-R4时，
R1、R2选自与共相连的碳原子形成4-10元环，该环碳原子可被N、O、S、-SO2-替代，该环可被C1-C6烷基、C1-C6烷磺酰基、C1-C6烷酰基取代；
R4为氢、C1-C6烷基、C3-C6环烷基，并可被卤原子任意取代；
当X为-CN时，
R1，R2独立地选自氢、C1-C6烷基，并可使C1-C6烷氧基、C1-C6烷磺酸基、芳基、或杂芳基取代，R1，R2还可与其相连的碳原子形成4-10元环，该环碳原子可被N、O、S、或-SO2-替代，该环可被烷磺酸基、C1-C6烷基、C1-C6烷酰基取代；R1，R2之一还可以与R8连接成4-6元环；
R8为氢、或C1-C6烷基；
m选自0、1、2、3、4、5；
优选地，本发明所述的式(Ⅲ)化合物选自但不限于以下结构：
3-((2-(1H-吡咯并[2,3-b]吡啶-3-基)嘧啶-4-基)氨基)-1--(甲磺酰基)-N-(2,2,2-三氟乙基)氮杂环丁烷-3-甲酰胺；
3-((2-(1H-吡咯并[2,3-b]吡啶-3-基)嘧啶-4-基)氨基)-1-(乙磺酰基)-N-(2,2,2-三氟乙基)氮杂环丁烷-3-甲酰胺；
3-((2-(1H-吡咯并[2,3-b]吡啶-3-基)嘧啶-4-基)氨基)-1-(环丙磺酰基)-N-(2,2,2-三氟乙基)氮杂环丁烷-3-甲酰胺；
3-(5-氟-2-(1H-吡咯并[2,3-b]吡啶-3-基)嘧啶-4-基)氨基)-1-(甲磺酰基)-N-(2,2,2-三氟乙基)氮杂环丁烷-3-甲酰胺；
3-(5-氟-2-(1H-吡咯并[2,3-b]吡啶-3-基)嘧啶-4-基)氨基)-1-(乙磺酰基)-N-(2,2,2-三氟乙基)氮杂环丁烷-3-甲酰胺；
3-(5-氟-2-(1H-吡咯并[2,3-b]吡啶-3-基)嘧啶-4-基)氨基)-1-(环丙磺酰基)-N-(2,2,2-三氟乙基)氮杂环丁烷-3-甲酰胺；
4-((2-(1H-吡咯并[2,3-b]吡啶-3-基)嘧啶-4-基)氨基)-1-(甲磺酰基)-N-(2,2,2-三氟乙基)哌啶-4-甲酰胺；
4-((2-(1H-吡咯并[2,3-b]吡啶-3-基)嘧啶-4-基)氨基)-1-(乙磺酰基)-N-(2,2,2-三氟乙基)哌啶-4-甲酰胺；
4-((2-(1H-吡咯并[2,3-b]吡啶-3-基)嘧啶-4-基)氨基)-1-(环丙磺酰基)-N-(2,2,2-三氟乙基)哌啶-4-甲酰胺；
4-((5-氟-2-(1H-吡咯并[2,3-b]吡啶-3-基)嘧啶-4-基)氨基)-1-(甲磺酰基)-N-(2,2,2-三氟乙基)哌啶-4-甲酰胺；
4-((5-氟-2-(1H-吡咯并[2,3-b]吡啶-3-基)嘧啶-4-基)氨基)-1-(乙磺酰基)-N-(2,2,2-三氟乙基)哌啶-4-甲酰胺；
4-((5-氟-2-(1H-吡咯并[2,3-b]吡啶-3-基)嘧啶-4-基)氨基)-1-(环丙磺酰基)-N-(2,2,2-三氟乙基)哌啶-4-甲酰胺；
4-((2-(1H-吡咯并[2,3-b]吡啶-3-基)嘧啶-4-基)氨基)-N-(2,2,2-三氟乙基)四氢-2H硫代吡喃-4-甲酰胺1,1-二氧化物；
4-((5-氟-2-(1H-吡咯并[2,3-b]吡啶-3-基)嘧啶-4-基)氨基)-N-(2,2,2-三氟乙基)四氢-2H硫代吡喃-4-甲酰胺1,1-二氧化物；
3-((2-(1H-吡咯并[2,3-b]吡啶-3-基)嘧啶-4-基)氨基)-1-(乙磺酰基)氮杂环丁烷-3-腈；
3-((2-(7H-吡咯并[2,3-d]嘧啶-4-基)嘧啶-4-基)氨基)-1-(乙磺酰基)氮杂环丁烷-3-腈；
3-((2-(1H-吡咯并[2,3-b]吡啶-4-基)嘧啶-4-基)氨基)-1-(乙磺酰基)氮杂环丁烷-3-腈；
3-((2-(1H-吡咯并[2,3-b]吡啶-3-基)嘧啶-4-基)氨基)-1-(甲磺酰基)氮杂环丁烷-3-腈；
3-((2-(7H-吡咯并[2,3-d]嘧啶-4-基)嘧啶-4-基)氨基)-1-(甲磺酰基)氮杂环丁烷-3-腈；
3-((2-(1H-吡咯并[2,3-b]吡啶-4-基)嘧啶-4-基)氨基)-1-(甲磺酰基)氮杂环丁烷-3-腈；
4-((2-(1H-吡咯并[2,3-b]吡啶-3-基)嘧啶-4-基)氨基)四氢-2H-硫代吡喃-4-腈1,1-二氧化物；
4-((2-(7H-吡咯并[2,3-d]嘧啶-4-基)嘧啶-4-基)氨基)四氢-2H-硫代吡喃-4-腈1,1-二氧化物；
4-((2-(1H-吡咯并[2,3-b]吡啶-4-基)嘧啶-4-基)氨基)四氢-2H-硫代吡喃-4-腈1,1-二氧化物；
1-((2-(1H-吡咯并[2,3-b]吡啶-3-基)嘧啶-4-基)氨基)环丁烷-3-腈；
1-((2-(7H-吡咯并[2,3-d]嘧啶-4-基)嘧啶-4-基)氨基)环丁烷-3-腈；
1-((2-(1H-吡咯并[2,3-b]吡啶-4-基)嘧啶-4-基)氨基)环丁烷腈；
1-((2-(1H-吡咯并[2,3-b]吡啶-3-基)嘧啶-4-基)氨基)环戊腈；
1-((2-(7H-吡咯并[2,3-d]嘧啶-4-基)嘧啶-4-基)氨基)环戊烷腈；
1-((2-(1H-吡咯并[2,3-b]吡啶-4-基)嘧啶-4-基)氨基)环戊烷腈；
(R)-2-((2-(1H-吡咯并[2,3-b]吡啶-3-基)嘧啶-4-基)氨基2-甲基丁腈；
(R)-2-((2-(7H-吡咯并[2,3-d]嘧啶-4-基)嘧啶-4-基)氨基-2-甲基丁腈；
(R)-2-((2-(1H-吡咯并[2,3-b]吡啶-4-基)嘧啶-4-基)氨基-2-甲基丁腈；及其异构体、溶剂合物、或其药学上可接受的盐。
专业术语
术语“烷基”是指链中具有1至12个碳原子的直链或支链的烷基，烷基的实例包括甲基(Me)、乙基(Et)、正丙基、异丙基、丁基、异丁基、仲丁基、叔丁基(t-Bu)、戊基，异戊基、叔戊基、己基，异己基、以及根据本领域普通技术人员和文本所提供的教导认为是相当于上述实例中的任何一种基团。
术语“烷氧基”是指键接氧原子的如上定义的烷基。烷氧基经由氧原子连接到母体结构。
术语“氨基”是指-NH2基团或单或二烷基氨基。
术语环烷基是指饱和和部分饱和的，单环的、稠合多环的、桥连多环的、或爆多环的碳环，每个碳原子具有3至12个环原子数。环烷基的说明性实例包括以下的适当键合部分形式的实体：
Figure PCTCN2017094253-appb-000026
术语“芳基”是指5-6元的碳芳香环，如，苯；
双环，其中至少有一个环是碳芳香环，如，萘，茚和1，2，3，4-四氢喹啉；以及三环，其中至少有一个环是碳芳香环，如，芴。
例如，芳基包括含5-6元的碳芳香环并一个5-7元杂环，这个杂环包括一个或多个选自氮﹑氧和硫的杂原子，条件是连接点在碳芳香环上.通过取代的苯的衍生物且环上原子有自由价态的形成二价自由基，其命名为取代的亚苯基自由基。由命名以“基”结尾的单价多环烃自由基通过减少一个自由价态的氢原子衍生而来的二价自由基，其命名就是在相应的单价自由基的后面加上“亚基”，例如，有两个连接点的萘基被称为亚萘基。但是，芳基不包含﹑也不通过任何方式与下面分别定义的杂环芳基重叠。因此，在此定义，如果一个或多个碳芳香环与一个杂芳香环并列，由此产生的环系统是芳杂环基，而不是芳基。
术语“芳杂基”指的是：
5-8元的单环芳烃，含一个或多个选自N，O和S的杂原子，如1-4个杂原子，在一些实施方案中，为1-3个杂原子，环上其它原子是碳原子；
8-12元的双环芳烃，含一个或多个选自N，O和S的杂原子，如1-4个杂原子，在一些实施方案中，为1-3个杂原子，环上其它原子是碳原子；其中至少有一个环是芳香环；以及
Figure PCTCN2017094253-appb-000027
Figure PCTCN2017094253-appb-000028
术语“杂环烷基”是指饱和或部分不饱和单环或多环环状烃取代基，其包括3至20个环原子，其中一个或多个环原子选自氮、氧或S(O)m(其中m是0-2的整数)的杂原子，其余环原子为碳。优选包括3至12个环原子，其中1～4个杂原子，更优选的杂环烷基环包含3至10个环原子，更优选的杂环烷基环包含5至6个环原子。单环杂环烷基的非限制性实例包含吡咯烷基、哌啶基、吗啉基四氢呋喃基等。多环杂环烷基包括螺环、稠环和桥环的杂环烷基。杂环可以是取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、卤代烷基、烷氧基、烷基氨基、卤素、羟基、氨基、氧代基、烷氨基、环烷基、杂环烷基、杂环烷氧基、羟烷基、羧基或羧酸酯基。
术语”卤素”表示氯、氟、溴或碘。术语“卤代”代表氯代，氟代，溴代或碘代。术语“卤代烷基”是指如上所定义的烷基，其被一个或多个卤原子取代。
术语“卤代烷氧基”是指如上所定义的烷氧基，其被一个或多个卤原子取代。
术语“酰基”是指1至10个碳原子的直链、支链、或环状构型或其组合的基团R-C(0)-，其通过羟基官能团连接到母体结构，这样的基团可以是饱和的或不饱和的，和酯族或芳族的。
在本发明所提供的实施方案中，本发明的化合物如含有碱性基团，则可与酸成盐，采用本领域技术人员所熟知的方法可以制备嘧啶类衍生物的盐。
常见酸盐有有机酸盐、无机酸盐等。通常，比较常用的有机酸盐有枸橼酸盐、富马酸盐、草酸盐、苹果酸盐、乳酸盐、磺酸盐(例如樟脑磺酸盐、对甲苯磺酸盐、甲磺酸盐等)等；无机酸盐有氢卤酸盐、硫酸盐、磷酸盐、硝酸盐等。
例如，与低级烷基磺酸，如甲磺酸，三氟甲磺酸等可形成甲磺酸盐、三氟甲磺酸盐；与芳基磺酸，如苯磺酸或对甲苯磺酸等可形成对甲苯磺酸盐、苯磺酸盐；与有机羧酸，如乙酸，富马酸，酒石酸，草酸，马来酸，苹果酸，琥珀酸或柠檬酸等可形成相应的盐；与氨基酸，如谷氨酸或天冬氨酸可形成谷氨酸盐或天冬氨酸盐。与无机酸，如氢卤酸(如氢氟酸、氢溴酸、氢碘酸、氢氯酸)，硝酸，碳酸，硫酸或磷酸等也可形成相应的盐。
在本发明所提供的实施方案中，本发明的化合物如含有酸性基团，则可与碱成盐，采用本领域技术人员所熟知的方法可以制备本发明化合物的盐，例如，与碱金属，如钠、钾或锂形成的盐；与碱土金属如钙或钡形成的盐；与其它金属如镁、铝 形成的盐；也可与有机碱形成的盐，也可与有机碱形成盐，如二环己基胺、胍或三乙胺形成盐。
第二方面，本发明提供利用本发明式(I)JAK抑制剂化合物、异构体或其药学上可接受的盐或溶剂化合物为活性成分的药物。在上述药物中还可以含有一种或多种药学上可接受的载体，所述载体包括药学领域的常规稀释剂，赋形剂，填充剂，粘合剂，湿润剂，崩解剂，吸收促进剂，表面活性剂，吸附载体，润滑剂等，必要时还可以加入香味剂，甜味剂等。本发明药物可以制成片剂，粉剂，粒剂，胶囊，口服液及注射用药等多种形式，上述各剂型的药物均可以按照药学领域的常规方法制备。
第三方面，本发明提供式(I)JAK抑制剂杂环化合物、异构体及其药学上可接受的盐可应用治疗人或动物自身免疫疾病、类风湿性关节炎、皮肤病症、多发性硬化，银屑性关节炎、炎性肠病、重症肌无力、牛皮藓中的药物中，特别是JAK激酶相关疾病的药物中的应用。
本发明发明人通过实验证实，本发明所公开的一些化合物对JAK激酶特别是JAK1具有较好的抑制作用，对JAK2、JAK3抑制活性较低，提示本品为选择性JAK抑制剂，对采用式(I)化合物、或其药学上可接的盐治疗自身免疫疾病、类风湿性关节炎、皮肤病症、多发性硬化，类风湿关节炎、银屑性关节炎、炎性肠病、重症肌无力、牛皮藓的药物中，具有更低的毒性。
具体实施方式
下面通过实施例来说明本发明的可实施性，本领域的技术人员应当理解，根据现有技术的教导，对相应的技术特征进行修改或替换，仍然属于本发明要求保护的范围
实施例1、2-(3-(4-(1H-吡咯并[2,3-b]吡啶-3-基)-1H-吡唑-1-基)-1-(乙磺酰基)氮杂环丁-3-基)乙腈
Figure PCTCN2017094253-appb-000029
步骤1、3-(1-(1-乙氧乙基)-1H-吡唑-4-基)-1-((2-三甲硅基)乙氧基)甲基)-1H-吡咯并[2,3-b]吡啶
Figure PCTCN2017094253-appb-000030
将2.7g 3-溴-1-((2-(三甲基硅基)乙氧基)甲基)-1H-吡咯并[2,3-b]吡啶，3.2g 1-(1-乙氧乙基)-4-(4,4,5,5-四甲基-1,3,2-二氧硼戊烷-2-基)-1H-吡唑，3g碳酸钾，90mg Pd(dppf)Cl2溶于21ml正丁醇和7ml水，加热到100℃反应20小时，反应完全，将反应也浓缩至干，乙酸乙酯萃取，有机层用无水硫酸钠干燥，过滤，浓缩，硅胶柱层析，得1.2g油状物。
步骤2、3-(1H-吡唑-4-基)-1-((2-三甲硅基)乙氧基)甲基)-1H-吡咯并[2,3-b]吡啶
Figure PCTCN2017094253-appb-000031
将步骤1产物1.2g加入四氢呋喃9ml，H2O 22.5ml，然后加入10％稀盐酸3ml，室温搅拌反应，1小时后反应完全，然后加入30％氢氧化钠调PH至7，二氯甲烷萃取，干燥(Na2SO4)，浓缩得1.0g油状物。
步骤3、2-(1-(乙磺酰基)-3-(4-(1-((2-三甲硅基)乙氧基)甲基)-1H-吡咯并[2,3-b]吡啶-3-基)-1H-吡唑-1-基)-氮杂环丁-3-基)乙腈
Figure PCTCN2017094253-appb-000032
将步骤2产物0.5g，2-(1-(乙磺酰基)氮杂环丁-3-亚基)乙腈0.2g加入20ml乙腈中，在室温下加入DBU 10mg，反应5小时，待反应完全，加乙酸乙酯萃取，水洗，有机层干燥，过滤，浓缩，柱层析得目标物0.6g。
步骤4、2-(3-(4-(1H-吡咯并[2,3-b]吡啶-3-基)-1H-吡唑-1-基)-1-(乙磺酰基)氮杂环丁-3-基)乙腈
取步骤3产物0.5g，加入5ml三氟乙酸，室温反应3h，薄层层析(乙 酸乙酯/石油醚1：2)，待反应完全，浓缩至干，加入1ml乙二胺反应2h，浓缩至干，过滤，浓缩，柱层析得目标物0.3g。
1HNMR(400MHz,DMSO-D6)δ11.74(s,1H),8.51(s,1H),8.33(d,J＝7.9Hz,1H),8.26(d,J＝4.6Hz,1H),8.09(s,1H),7.80(d,J＝1.8Hz,1H),7.15(dd,J＝7.9,4.7Hz,1H),4.55(d,J＝8.8Hz,2H),4.22(d,J＝8.8Hz,2H),3.64(s,2H),3.25(q,J＝7.3Hz,2H),1.25(t,J＝7.3Hz,3H).
MS(ESI):367.14(M+1)
实施例2、2-(4-(4-(1H-吡咯并[2,3-b]吡啶-3-基)-1H-吡唑-1-基)-1,1-二氧代四氢-2H-硫代吡喃-4-基)乙腈
Figure PCTCN2017094253-appb-000033
参考实施例1方法合成。
1HNMR(400MHz,DMSO-D6)δ11.72(s,1H),8.50(s,1H),8.36-8.31(m,1H),8.26(dd,1H),8.06(s,1H),7.79(d,1H),7.14(dd,1H),3.29(d,4H),3.13-2.96(m,4H),2.55(d,2H).
MS(ESI):356.11(M+1)
实施例3、2-(4-(4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基)-1,1-二氧代四氢-2H-硫代吡喃-4-基)乙腈
Figure PCTCN2017094253-appb-000034
参考实施例1方法合成；
或按下列步骤合成：
步骤1、2-(1,1-二氧代-4-(4-(7-((2-(三甲硅基)乙氧基)甲基)-7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基)-四氢-2H-硫代吡喃-4-基)乙腈
Figure PCTCN2017094253-appb-000035
在250ml圆底烧瓶中，室温加入15g 4-(1H-吡唑-4-基)-7-((2-(三甲硅基)乙氧基)甲基)-7H-吡咯并[2,3-d]嘧啶、100ml乙腈，氮气保护，冰浴冷却至0℃，然后加入0.72g DBU，9.0g 2-(1,1-二氧代二氢-2H-硫代吡喃-4(3H)-亚基)乙腈，继续在0℃反应5小时，然后室温20℃反应一晚上，至原料基本反应完毕，薄层层析监测反应，过滤固体，乙酸乙酯洗涤，滤液浓缩至干，加乙酸乙酯析出固体，乙酸乙酯/正己烷洗涤，得固体，合并固体，干燥后得产物8g。
步骤2、2-(4-(4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基)-1,1-二氧代四氢-2H-硫代吡喃-4-基)乙腈
取5g步骤1产物，加入30ml三氟乙酸，室温反应3h，薄层层析(乙酸乙酯/石油醚1：2)，待反应完全，浓缩至干，加入1ml乙二胺反应2h，浓缩至干，过滤，浓缩，柱层析得目标物2.6g。
1HNMR(400MHz,DMSO-D6)δ12.15(s,1H),8.91(s,1H),8.71(s,1H),8.47(s,1H),7.62(m,1H),7.10(m,1H),3.41(s,2H),3.29(m,2H),3.00-3.17(m,4H),2.54-2.60(m,2H).
MS(ESI):356.11(M+1)
实施例4、2-(4-(4-(1H-吡咯并[2,3-b]吡啶-4-基)-1H-吡唑-1-基)-1,1-二氧代四氢-2H-硫代吡喃-4-基)乙腈
Figure PCTCN2017094253-appb-000036
参考实施例1方法合成。
1HNMR(400MHz,DMSO-D6)δ11.72(s,1H),8.78(s,1H),8.33(s, 1H),8.20(d,1H),7.53(d,1H),7.36(d,1H),6.90(d,1H),3.38(s,2H),3.28-3.33(m,2H),3.12(m,2H),3.02(m,2H),2.56(m,2H).
MS(ESI):356.11(M+1)
施例5、2-(4-(4-(1H-吡咯并[2,3-b]吡啶-3-基)-1H-吡唑-1-基)-1-(甲磺酰基)哌啶-4-基)-N-(2,2,2-三氟乙基)乙腈
Figure PCTCN2017094253-appb-000037
参考实施例1方法合成。
MS(ESI):385.14(M+1)
实施例6、2-(3-(4-(1H-吡咯并[2,3-b]吡啶-3-基)-1H-吡唑-1-基)-1-(乙磺酰基)氮杂环丁-3-基)乙酰胺
Figure PCTCN2017094253-appb-000038
取实施例(1)产物0.3g，甲醇10ml，加1M氢氧化钠2ml，50℃反应2小时，盐酸调PH至7，除甲醇，过滤的目的物。
1HNMR(400MHz,DMSO-D6)δ11.70(s,1H),8.33–8.23(m,3H),7.99(s,1H),7.74(d,J＝2.5Hz,1H),7.47(s,1H),7.12(dd,J＝7.9,4.7Hz,1H),6.97(s,1H),4.46(d,J＝8.9Hz,2H),4.35(d,J＝8.9Hz,2H),3.20(q,J＝7.1Hz,2H),3.08(s,2H),1.24(t,J＝7.3Hz,3H).
MS(ESI):389.14(M+1)
实施例7、2-(3-(4-(1H-吡咯并[2,3-b]吡啶-3-基)-1H-吡唑-1-基)-1-(乙磺酰基)氮杂环丁-3-基)-N-(2,2,2-三氟乙基)乙酰胺
Figure PCTCN2017094253-appb-000039
步骤1、2-(3-(4-(1H-吡咯并[2,3-b]吡啶-3-基)-1H-吡唑-1-基)-1-(乙磺酰基)氮杂环丁-3-基)乙酸
Figure PCTCN2017094253-appb-000040
取0.6g实施例(1)产物，加1M氢氧化钠4ml，20ml甲醇，回流反应10小时，盐酸调PH至6，除甲醇，二氯甲烷萃取，干燥，浓缩，过滤得目的物0.4g。
步骤2、2-(3-(4-(1H-吡咯并[2,3-b]吡啶-3-基)-1H-吡唑-1-基)-1-(乙磺酰基)氮杂环丁-3-基)-N-(2,2,2-三氟乙基)乙酰胺
取0.4g步骤1产物溶于5ml干燥DMF中，加入0.18g N-(3-二甲氨基丙基)-N'-乙基碳二亚胺盐酸盐(EDC.HCl)，搅拌1小时后，加入0.1g三氟乙胺，2小时反应完毕后，加水稀释，二氯甲烷萃取，干燥，浓缩，柱层析得目的物0.3g。
1H NMR(400MHz,DMSO-D6)δ11.68(s,1H),8.76(m,1H),8.24-8.28(m,3H),7.98(s,1H),7.12(m,1H),4.47(d,2H),4.35(d,2H),3.83(m,2H),3.20(m,4H),1.24(t,3H).
MS(ESI):471.14(M+1)
实施例8、2-(3-(4-(1H-吡咯[并2,3-d]嘧啶-4-基)-1H-吡唑-1-基)-1-(乙磺酰基)氮杂环丁-3-基)-N-(2,2,2-三氟乙基)乙酰胺
Figure PCTCN2017094253-appb-000041
参考实施例7步骤2方法制备
1H NMR(400MHz,DMSO-D6)δ11.12(s,1H),8.73(m,1H),8.71(m,1H),8.68(m,1H),8.39(s,1H),7.59(d,1H),7.02(d,1H),4.53(d,2H),4.36(d,2H),3.81(m,2H),3.27(s,2H),3.18-3.23(m,2H),1.23(t,3H).
MS(ESI):472.13(M+1)
实施例9、2-(3-(4-(1H-吡咯[并2,3-b]吡啶-4-基)-1H-吡唑-1-基)-1-(乙磺酰基)氮杂环丁-3-基)-N-(2,2,2-三氟乙基)乙酰胺
Figure PCTCN2017094253-appb-000042
参考实施例7步骤2方法制备
MS(ESI):471.14(M+1)
实施例10、2-(3-(4-(1H-吡咯并[2,3-b]吡啶-4-基)-1H-吡唑-1-基)-1-(乙磺酰基)氮杂环丁-3-基)–N-甲基乙酰胺
Figure PCTCN2017094253-appb-000043
参考实施例7步骤2方法制备
MS(ESI):403.15(M+1)
实施例11、2-(3-(4-(1H-吡咯并[2,3-b]吡啶-4-基)-1H-吡唑-1-基)-1-(乙磺酰基)氮杂环丁-3-基)乙酰胺
Figure PCTCN2017094253-appb-000044
参考实施例6方法制备。
1HNMR(400MHz,DMSO-D6)δ11.72(s,1H),8.52(s,1H),8.21(s,1H),8.14(d,J＝5.0Hz,1H),7.46(dd,J＝8.5,5.4Hz,2H),7.27(d,J＝5.0Hz,1H),6.94(s,1H),7.79(dd,J＝3.5,1.8Hz,1H),3.64(s,2H),4.47(d,J＝9.0Hz,2H),4.32(d,J＝9.0Hz,2H),3.17(q,J＝7.3Hz,2H),3.08(s,2H),1.20(t,J＝7.3Hz,3H).
MS(ESI):389.14(M+1)
实施例12、2-(3-(4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基)-1--(甲磺酰基)氮杂环丁-3-基)-N-(2,2,2-三氟乙基)乙酰胺
Figure PCTCN2017094253-appb-000045
参考实施例7步骤2方法制备
MS(ESI):458.12(M+1)
实施例13、2-(3-(4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基)-1--(甲磺酰基)氮杂环丁-3-基)-N-甲基乙酰胺
Figure PCTCN2017094253-appb-000046
参考实施例7步骤2方法制备
MS(ESI):390.13(M+1)
实施例14、2-(3-(4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基)-1--(甲磺 酰基)氮杂环丁-3-基)乙酰胺
Figure PCTCN2017094253-appb-000047
参考实施例6方法制备。
MS(ESI):376.11(M+1)
实施例15、2-(3-(4-(1H-吡咯并[2,3-b]吡啶-4-基)-1H-吡唑-1-基)-1-(甲磺酰基)氮杂环丁-3-基)-N-(2,2,2-三氟乙基)乙酰胺
Figure PCTCN2017094253-appb-000048
参考实施例7步骤2方法制备
MS(ESI):457.12(M+1)
实施例16、2-(3-(4-(1H-吡咯并[2,3-b]吡啶-4-基)-1H-吡唑-1-基)-1-(甲磺酰基)氮杂环丁-3-基)–N-甲基乙酰胺
Figure PCTCN2017094253-appb-000049
参考实施例7步骤2方法制备
MS(ESI):389.14(M+1)
实施例17、2-(3-(4-(1H-吡咯并[2,3-b]吡啶-4-基)-1H-吡唑-1-基)-1-(甲磺酰基)氮杂环丁-3-基)乙酰胺
Figure PCTCN2017094253-appb-000050
参考实施例6方法制备。
MS(ESI):375.12(M+1)
实施例18、2-(4-(4-(1H-吡咯并[2,3-b]吡啶-3-基)-1H-吡唑-1-基)-1,1-二氧代四氢-2H-硫代吡喃-4-基)乙酰胺
Figure PCTCN2017094253-appb-000051
参考实施例6方法制备
1HNMR(400MHz,DMSO-D6)δ11.67(s,1H),8.37-8.27(m,2H),8.25(dd,J＝4.6Hz,1.4Hz,1H),7.98(s,1H),7.75(d,J＝2.5Hz,1H),7.31(s,1H),7.12(dd,J＝7.9,4.7Hz,1H),6.91(s,1H),3.21(d,J＝13.2Hz,2H),2.55(d,J＝11.9Hz,2H).3.08(d,J＝14.7Hz,2H),3.08(t,J＝13.4Hz,2H),2.95(t,J＝13.4Hz,2H),2.69(t,J＝12.5Hz,2H),2.61(s,2H).
MS(ESI):374.12(M+1)
实施例19、2-(4-(4-(1H-吡咯并[2,3-b]吡啶-3-基)-1H-吡唑-1-基)-1,1-二氧代四氢-2H-硫代吡喃-4-基)-N-(2,2,2-三氟乙基)乙酰胺
Figure PCTCN2017094253-appb-000052
参考实施例7步骤2方法制备
1HNMR(400MHz,DMSO-D6)δ11.68(s,1H),8.61(m,1H),8.28-8.32(m,2H),8.24-8.25(m,1H),7.98(s,1H),7.74(d,1H),7.12(m,1H),3.82 (m,2H),2.65-3.34(m,8H),2.50(m,2H).
MS(ESI):456.13(M+1)
实施例20、2-(4-(4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基)-1,1-二氧代四氢-2H-硫代吡喃-4-基)-N-(2,2,2-三氟乙基)乙酰胺
Figure PCTCN2017094253-appb-000053
参考实施例7步骤2方法制备
1HNMR(400MHz,DMSO-D6)δ12.11(s,1H),8.72(s,1H),8.67(s,1H),8.59(m,1H),8.39(s,1H),7.59(d,1H),7.05(d,1H),3.81(m,2H),3.24(m,2H),3.12(m,2H),2.97(m,2H),2.83(s,2H),2.67(m,2H).
MS(ESI):457.12(M+1)
实施例21、2-(4-(4-(7H-吡咯并[2,3-b]吡啶-4-基)-1H-吡唑-1-基)-1,1-二氧代四氢-2H-硫代吡喃-4-基)-N-(2,2,2-三氟乙基)乙酰胺
Figure PCTCN2017094253-appb-000054
参考实施例7步骤2方法制备
MS(ESI):456.12(M+1)
实施例22、2-(4-(4-(7H-吡咯并[2,3-b]吡啶-3-基)-1H-吡唑-1-基)-1-(甲磺酰基)哌啶-4-基)-N-(2,2,2-三氟乙基)乙酰胺
Figure PCTCN2017094253-appb-000055
参考实施例7步骤2方法制备
MS(ESI):485.15(M+1)
实施例23、2-(4-(4-(7H-吡咯并[2,3-b]嘧啶-4-基)-1H-吡唑-1-基)-1-(甲磺酰基)哌啶-4-基)-N-(2,2,2-三氟乙基)乙酰胺
Figure PCTCN2017094253-appb-000056
参考实施例7步骤2方法制备
MS(ESI):486.15(M+1)
实施例24、2-(4-(4-(7H-吡咯并[2,3-b]吡啶-4-基)-1H-吡唑-1-基)-1-(甲磺酰基)哌啶-4-基)-N-(2,2,2-三氟乙基)乙酰胺
Figure PCTCN2017094253-appb-000057
参考实施例7步骤2方法制备
MS(ESI):485.15(M+1)
实施例25、2-(1-(4-(1H-吡咯并[2,3-b]吡啶-3-基)-1H-吡唑-1-基)环戊基)-N-(2,2,2-三氟乙基)乙酰胺
Figure PCTCN2017094253-appb-000058
参考实施例7步骤2方法制备
1HNMR(400MHz,DMSO-D6)δ11.60(s,1H),8.42(m,1H),8.22(m,2H),8.10(s,1H),7.84(s,1H),7.66(d,1H),7.10(m,1H),3.79(m,2H),2.86(s,2H),2.50(m,2H),2.07(m,2H),1.71(m,2H),1.58(m,2H).
MS(ESI):485.15(M+1)
实施例26、2-(1-(4-(1H-吡咯并[2,3-b]嘧啶-4-基)-1H-吡唑-1-基)环戊基) -N-(2,2,2-三氟乙基)乙酰胺
Figure PCTCN2017094253-appb-000059
参考实施例7步骤2方法制备
MS(ESI):485.15(M+1)
实施例27、2-(1-(4-(1H-吡咯并[2,3-b]吡啶-4-基)-1H-吡唑-1-基)环戊基)-N-(2,2,2-三氟乙基)乙酰胺
Figure PCTCN2017094253-appb-000060
参考实施例7步骤2方法制备
MS(ESI):392.17(M+1)
实施例28、3-(4-(1H-吡咯并[2,3-b]吡啶-3-基)-1H-吡唑-1-基)-3-甲基-N-(2,2,2-三氟乙基)丁酰胺
Figure PCTCN2017094253-appb-000061
参考实施例7步骤2方法制备。
MS(ESI):366.15(M+1)
实施例29、3-(4-(7H-吡咯并[2,3-b]嘧啶-4-基)-1H-吡唑-1-基)-3-甲基-N-(2,2,2-三氟乙基)丁酰胺
Figure PCTCN2017094253-appb-000062
参考实施例7步骤2方法制备
MS(ESI):367.14(M+1)
实施例30、3-(4-(7H-吡咯并[2,3-b]吡啶-4-基)-1H-吡唑-1-基)-3-甲基-N-(2,2,2-三氟乙基)丁酰胺
Figure PCTCN2017094253-appb-000063
参考实施例7步骤2方法制备
MS(ESI):367.14(M+1)
实施例31、3-((2-(1H-吡咯并[2,3-b]吡啶-3-基)嘧啶-4-基)氨基)-1--(甲磺酰基)-N-(2,2,2-三氟乙基)氮杂环丁烷-3-甲酰胺
Figure PCTCN2017094253-appb-000064
步骤1、3-((2-氯嘧啶-4-基)氨基)-1-(甲磺酰基)氮杂环丁烷-3-甲酸甲酯
Figure PCTCN2017094253-appb-000065
3.3g 2,4-二氯嘧啶、5g 3-氨基-1-(甲磺酰基)氮杂环丁烷-3-甲酸甲酯溶于50ml四氢呋喃中，加入5ml DIPEA，40℃反应3小时，加水稀释，二氯甲烷萃取，干燥，过滤，浓缩，柱层析得目标物6g。
步骤2、3-((2-氯嘧啶-4-基)氨基)-1-(甲磺酰基)氮杂环丁烷-3-甲酸
Figure PCTCN2017094253-appb-000066
取步骤1产物2g溶于10ml，加2M氢氧化钾4ml，室温搅拌反 应2小时，除溶剂，加盐酸调PH值至6，过滤，晾干的目的物1.6g。
步骤3、1-(甲磺酰基)-3-((2-(1-对甲苯磺酰基-1H-吡咯并[2,3-b]吡啶-3-基)嘧啶-4-基)氨基)氮杂环丁烷-3-甲酸
Figure PCTCN2017094253-appb-000067
在二氧元环/水(5:1)24ml中，加入2g步骤2产物，1.26g 3-(4,4,5,5-四甲基-1,3,2-二氧杂环戊烷-2-基)-1-对甲苯磺酰基-1H-吡咯并[2,3-b]吡啶，1.0g碳酸钾，0.1g Pd(dppf)Cl2，加热至90℃反应3h，加盐酸调PH值至6，过滤，滤液，减压除二氧六环加水稀释，乙酸乙酯萃取，干燥，浓缩，柱层析析得目标物1.8g。
步骤4、3-((2-(1H-吡咯并[2,3-b]吡啶-3-基)嘧啶-4-基)氨基)-1-(甲磺酰基)氮杂环丁烷-3-甲酸
Figure PCTCN2017094253-appb-000068
取0.8g步骤3产物加2M氢氧化钾3ml，10ml甲醇，回流2小时，除溶剂，加盐酸调PH值至6，过滤，得目标物0.5g。
步骤5、3-((2-(1H-吡咯并[2,3-b]吡啶-3-基)嘧啶-4-基)氨基)-1--(甲磺酰基)-N-(2,2,2-三氟乙基)氮杂环丁烷-3-甲酰胺
取0.3g步骤4产物溶于5ml干燥DMF中，加入0.16g N-(3-二甲氨基丙基)-N'-乙基碳二亚胺盐酸盐(EDC.HCl)，搅拌2小时后，加入0.098g2,2,2-三氟乙胺，1小时反应完毕后，加水稀释，二氯甲烷萃取，干燥，浓缩，柱层析得目的物0.2g。
MS(ESI):470.12(M+1)
实施例32、3-((2-(1H-吡咯并[2,3-b]吡啶-3-基)嘧啶-4-基)氨基)-1-(乙磺酰基)-N-(2,2,2-三氟乙基)氮杂环丁烷-3-甲酰胺
Figure PCTCN2017094253-appb-000069
参考实施例31方法制备。
MS(ESI):484.13(M+1)
实施例33、3-((2-(1H-吡咯并[2,3-b]吡啶-3-基)嘧啶-4-基)氨基)-1-(环丙磺酰基)-N-(2,2,2-三氟乙基)氮杂环丁烷-3-甲酰胺
Figure PCTCN2017094253-appb-000070
参考实施例31方法制备。
MS(ESI):496.13(M+1)
实施例34、3-(5-氟-2-(1H-吡咯并[2,3-b]吡啶-3-基)嘧啶-4-基)氨基)-1-(甲磺酰基)-N-(2,2,2-三氟乙基)氮杂环丁烷-3-甲酰胺
Figure PCTCN2017094253-appb-000071
参考实施例31方法制备。
MS(ESI):488.10(M+1)
实施例35、3-(5-氟-2-(1H-吡咯并[2,3-b]吡啶-3-基)嘧啶-4-基)氨基)-1-(乙磺酰基)-N-(2,2,2-三氟乙基)氮杂环丁烷-3-甲酰胺
Figure PCTCN2017094253-appb-000072
参考实施例31方法制备。
MS(ESI):502.12(M+1)
实施例36、3-(5-氟-2-(1H-吡咯并[2,3-b]吡啶-3-基)嘧啶-4-基)氨基)-1-(环丙磺酰基)-N-(2,2,2-三氟乙基)氮杂环丁烷-3-甲酰胺
Figure PCTCN2017094253-appb-000073
参考实施例31方法制备。
MS(ESI):514.12(M+1)
实施例37、4-((2-(1H-吡咯并[2,3-b]吡啶-3-基)嘧啶-4-基)氨基)-1-(甲磺酰基)-N-(2,2,2-三氟乙基)哌啶-4-甲酰胺
Figure PCTCN2017094253-appb-000074
参考实施例31方法制备。
MS(ESI):498.15(M+1)
实施例38、4-((2-(1H-吡咯并[2,3-b]吡啶-3-基)嘧啶-4-基)氨基)-1-(乙磺酰基)-N-(2,2,2-三氟乙基)哌啶-4-甲酰胺
Figure PCTCN2017094253-appb-000075
参考实施例31方法制备。
MS(ESI):412.16(M+1)
实施例39、4-((2-(1H-吡咯并[2,3-b]吡啶-3-基)嘧啶-4-基)氨基)-1-(环丙磺酰基)-N-(2,2,2-三氟乙基)哌啶-4-甲酰胺
Figure PCTCN2017094253-appb-000076
参考实施例31方法制备。
MS(ESI):524.16(M+1)
实施例40、4-((5-氟-2-(1H-吡咯并[2,3-b]吡啶-3-基)嘧啶-4-基)氨基)-1-(甲磺酰基)-N-(2,2,2-三氟乙基)哌啶-4-甲酰胺
Figure PCTCN2017094253-appb-000077
参考实施例31方法制备。
MS(ESI):516.16(M+1)
实施例41、4-((5-氟-2-(1H-吡咯并[2,3-b]吡啶-3-基)嘧啶-4-基)氨基)-1-(乙磺酰基)-N-(2,2,2-三氟乙基)哌啶-4-甲酰胺
Figure PCTCN2017094253-appb-000078
参考实施例31方法制备。
MS(ESI):530.16(M+1)
实施例42、4-((5-氟-2-(1H-吡咯并[2,3-b]吡啶-3-基)嘧啶-4-基)氨基)-1-(环丙磺酰基)-N-(2,2,2-三氟乙基)哌啶-4-甲酰胺
Figure PCTCN2017094253-appb-000079
参考实施例31方法制备。
MS(ESI):542.16(M+1)
实施例43、4-((2-(1H-吡咯并[2,3-b]吡啶-3-基)嘧啶-4-基)氨基)-N-(2,2,2-三氟乙基)四氢-2H硫代吡喃-4-甲酰胺1,1-二氧化物
Figure PCTCN2017094253-appb-000080
参考实施例31方法制备。
MS(ESI):469.12(M+1)
实施例44、4-((5-氟-2-(1H-吡咯并[2,3-b]吡啶-3-基)嘧啶-4-基)氨基)-N-(2,2,2-三氟乙基)四氢-2H硫代吡喃-4-甲酰胺1,1-二氧化物
Figure PCTCN2017094253-appb-000081
参考实施例31方法制备。
MS(ESI):487.11(M+1)
实施例45、3-((2-(1H-吡咯并[2,3-b]吡啶-3-基)嘧啶-4-基)氨基)-1-(乙磺酰基)氮杂环丁烷-3-腈
Figure PCTCN2017094253-appb-000082
参考实施例31方法制备。
MS(ESI):384.12(M+1)
实施例46、3-((2-(7H-吡咯并[2,3-d]嘧啶-4-基)嘧啶-4-基)氨基)-1-(乙磺酰基)氮杂环丁烷-3-腈
Figure PCTCN2017094253-appb-000083
参考实施例31方法制备。
MS(ESI):385.12(M+1)
实施例47、3-((2-(1H-吡咯并[2,3-b]吡啶-4-基)嘧啶-4-基)氨基)-1-(乙磺酰基)氮杂环丁烷-3-腈
Figure PCTCN2017094253-appb-000084
参考实施例31方法制备。
MS(ESI):385.12(M+1)
实施例48、3-((2-(1H-吡咯并[2,3-b]吡啶-3-基)嘧啶-4-基)氨基)-1-(甲磺酰基)氮杂环丁烷-3-腈
Figure PCTCN2017094253-appb-000085
参考实施例31方法制备。
MS(ESI):370.1(M+1)
实施例49、3-((2-(7H-吡咯并[2,3-d]嘧啶-4-基)嘧啶-4-基)氨基)-1-(甲磺酰基)氮杂环丁烷-3-腈
Figure PCTCN2017094253-appb-000086
参考实施例32方法制备。
MS(ESI):371.1(M+1)
实施例50、3-((2-(1H-吡咯并[2,3-b]吡啶-4-基)嘧啶-4-基)氨基)-1-(甲磺酰基)氮杂环丁烷-3-腈
Figure PCTCN2017094253-appb-000087
参考实施例31方法制备。
MS(ESI):370.1(M+1)
实施例51、4-((2-(1H-吡咯并[2,3-b]吡啶-3-基)嘧啶-4-基)氨基)四氢-2H-硫代吡喃-4-腈1,1-二氧化物
Figure PCTCN2017094253-appb-000088
参考实施例31方法制备。
MS(ESI):369.1(M+1)
实施例52、4-((2-(7H-吡咯并[2,3-d]嘧啶-4-基)嘧啶-4-基)氨基)四氢-2H-硫代吡喃-4-腈1,1-二氧化物
Figure PCTCN2017094253-appb-000089
参考实施例31方法制备。
MS(ESI):370.1(M+1)
实施例53、4-((2-(1H-吡咯并[2,3-b]吡啶-4-基)嘧啶-4-基)氨基)四氢-2H-硫代吡喃-4-腈1,1-二氧化物
Figure PCTCN2017094253-appb-000090
参考实施例31方法制备。
MS(ESI):369.1(M+1)
实施例54、1-((2-(1H-吡咯并[2,3-b]吡啶-3-基)嘧啶-4-基)氨基)环丁烷-3-腈
Figure PCTCN2017094253-appb-000091
参考实施例31方法制备。
MS(ESI):291.13(M+1)
实施例55、1-((2-(7H-吡咯并[2,3-d]嘧啶-4-基)嘧啶-4-基)氨基)环丁烷-3-腈
Figure PCTCN2017094253-appb-000092
参考实施例31方法制备。
MS(ESI):292.13(M+1)
实施例56、1-((2-(1H-吡咯并[2,3-b]吡啶-4-基)嘧啶-4-基)氨基)环丁烷腈
Figure PCTCN2017094253-appb-000093
参考实施例31方法制备。
MS(ESI):291.13(M+1)
实施例57、1-((2-(1H-吡咯并[2,3-b]吡啶-3-基)嘧啶-4-基)氨基)环戊腈
Figure PCTCN2017094253-appb-000094
参考实施例31方法制备。
MS(ESI):305.15(M+1)
实施例58、1-((2-(7H-吡咯并[2,3-d]嘧啶-4-基)嘧啶-4-基)氨基)环戊烷腈
Figure PCTCN2017094253-appb-000095
参考实施例31方法制备。
MS(ESI):306.14(M+1)
实施例59、1-((2-(1H-吡咯并[2,3-b]吡啶-4-基)嘧啶-4-基)氨基)环戊烷腈
Figure PCTCN2017094253-appb-000096
参考实施例31方法制备。
MS(ESI):305.14(M+1)
实施例60、(R)-2-((2-(1H-吡咯并[2,3-b]吡啶-3-基)嘧啶-4-基)氨基2-甲基丁腈
Figure PCTCN2017094253-appb-000097
参考实施例31方法制备。
MS(ESI):293.14(M+1)
实施例61、(R)-2-((2-(7H-吡咯并[2,3-d]嘧啶-4-基)嘧啶-4-基)氨基-2-甲基丁腈
Figure PCTCN2017094253-appb-000098
参考实施例31方法制备。
MS(ESI):294.15(M+1)
实施例62、(R)-2-((2-(1H-吡咯并[2,3-b]吡啶-4-基)嘧啶-4-基)氨基-2-甲基丁腈
Figure PCTCN2017094253-appb-000099
参考实施例31方法制备。
MS(ESI):293.15(M+1)
实施例63、对JAK的抑制作用
研究化合物对纯化的重组JAK活性的影响,是从酶学水平研究化合物对JAK的抑制活性。其实验原理为采用一种发光法激酶检测方法，用于检测JAK与底物Poly(4:1Glu,Tyr)肽反应产生的ADP含量：ADP转化为ATP后，ATP即可作为Ultra-Glo荧光素酶催化反应的底物，产生光信号。发光信号与ADP的量和激酶活性正相关。因此，通过观察化合物对JAK与底物反应产生的发光信号来确定其对重组的JAK的抑制效果，用IC50表示。
实验方法：10个不同浓度的化合物分别在37℃与JAK1、JAK2和JAK3孵育60分钟，然后加入底物及ATP混合，37℃反应50分钟后加入25μlADP-GloTM混合2分钟，室温反应50分钟。再加入50μl检测试剂混合2分钟，室温孵育50分钟，用化学发光仪检测。结果见表1。
表1本发明化合物对JAK的抑制作用实验结果
Figure PCTCN2017094253-appb-000100
Figure PCTCN2017094253-appb-000101
Figure PCTCN2017094253-appb-000102
注：1.(a)20nM以下；
2.(b)>20nM至50nM；
3.(c)>50nM
其中，以实施例3为例，与同等实验条件下的现有JAK抑制剂的实验结果进行比较，结果见表2。
表2本发明化合物与现有JAK抑制剂对JAK的抑制作用对比
Figure PCTCN2017094253-appb-000103
Figure PCTCN2017094253-appb-000104
注：Ruxolitinib*、Baricitinib*的试验结果来自FDA的新药申报资料。
结果表明：实施例3化合物对JAK1的抑制活性高，对JAK2的抑制活性低，提示化合物对JAK1的选择性较Baricitinib和Ruxolitinib(CN101448826A公开的化合物)更高，后两个阳性药对JAK1、JAK2没有选择性。
实施例64、本发明化合物重复给药对大鼠血液学指标的影响
取健康Wistar大鼠48只，♀♂各半。按体重随机分为对照组(Veh)，罐胃给药实施例3化合物，为剂量1.5mg·kg-1·d-1和4.5mg·kg-1·d-1，罐胃给药Ruxolitinib剂量4.5mg·kg-1·d-1，每组12只，♀♂各半。每天灌胃给药1次，连续给药4周，末次给药1d、2d后进行血液学指标检查。结果给药结束，罐胃给药实施例3化合物1.5mg·kg-1·d-1剂量组、4.5mg·kg-1·d-1剂量组，动物血液学指标WBC值与对照组(Veh)组比较无明显降低(P<0.05)；Ruxolitinib(CN101448826A公开的化合物)4.5mg·kg-1·d-1剂量组，动物血液学指标WBC值与对照组(Veh)组比较明显降低(P<0.05)，提示本发明化合物治疗内风湿关节炎时副作用较小。
结果表明：实施例3化合物对JAK1的抑制活性高，对JAK2的抑制活性低，提示化合物对JAK1的选择性较Baricitinib和Ruxolitinib(CN101448826A公开的化合物)更高，后两个阳性药对JAK1、JAK2没有选择性。

Claims (8)

  1. 式(Ⅰ)化合物：
    Figure PCTCN2017094253-appb-100001
    及其异构体、溶剂合物、以及其药学上可接受的盐。
    当
    Figure PCTCN2017094253-appb-100002
    选自：
    Figure PCTCN2017094253-appb-100003
    R选自：
    Figure PCTCN2017094253-appb-100004
    当X为-CONH-R4时，R4为氢、C1-C6烷基、或C3-C6环烷基，并可被卤原子任意取代；
    Figure PCTCN2017094253-appb-100005
    选自:
    Figure PCTCN2017094253-appb-100006
    R1，R2独立地选自氢、C1-C6烷基，并可被C1-C6烷氧基、C1-C6烷磺酸酰基取代，R1，R2还可与其相连的碳原子形成4-10杂环，该环碳原子可被N、O、S、-SO2-替代，该环可被C-C6烷磺酸基、C1-C6烷基、C1-C6烷酰基取代；
    R3为氢、C1-C7烷基酰基、或C3-C7环烷基酰基；
    n选自0、1、2、3、4、5；
    X1为N、-CR5；
    R5为H、-CN、或卤原子；
    当X为-CN时，
    Figure PCTCN2017094253-appb-100007
    选自：
    Figure PCTCN2017094253-appb-100008
    其中：
    R1、R2为氢、C1-C6烷基，并可被C1-C6烷氧基、C1-C6烷磺酸酰基取代，当R1、R2与其相连的碳原子形成4-10元环，该环可被C1-C6烷基、C1-C6烷磺酰基、或C1-C6 烷酰基取代，该C1-C6烷基、C1-C6烷磺酰基、或C1-C6烷酰基可被卤原子任意取代；
    Figure PCTCN2017094253-appb-100009
    选自:
    Figure PCTCN2017094253-appb-100010
    这时R1、R2选自与其相连的碳原子形成5-8元环，该环碳原子可被N、O、S、或-SO2-替代，该环可被C1-C6烷基、或C1-C6烷磺酰基进一步取代；
    当
    Figure PCTCN2017094253-appb-100011
    选自：
    Figure PCTCN2017094253-appb-100012
    时，
    X2为N、或CR6；
    X3为N、或CR7；
    R6、R7独立地选自H、-CN、卤原子；
    Figure PCTCN2017094253-appb-100013
    选自:
    Figure PCTCN2017094253-appb-100014
    X1为N、或-CR5
    R5为H、-CN、或卤原子；
    R选自：
    Figure PCTCN2017094253-appb-100015
    当X选自-CONH-R4时，
    R1、R2选自与其相连的碳原子形成4-10元环，该环碳原子可被N、O、S、或-SO2-替代，该环可被C1-C6烷基、C1-C6烷磺酰基、或C1-C6烷酰基取代；
    当X为-CN时，
    R1、R2独立地选自氢、C1-C6烷基，并可使C1-C6烷氧基、C1-C6烷磺酸基、芳基、杂芳基取代，R1，R2还可与其相连的碳原子形成4-10元环，该环碳原子可被N、O、S、或-SO2-替代，该环可被烷磺酸基、C1-C6烷基、或C1-C6烷酰基取代；R1，R2之一还可以与R8连接成4-6元环；
    R8为氢、或C1-C6烷基；
    m选自0、1、2、3、4、5；
  2. 根据权利要求书1所述的化合物，其特征在于所述的化合物共有式(Ⅱ)结构：
    Figure PCTCN2017094253-appb-100016
    及其异构体、溶剂合物、及其药学上可接受的盐。
    其中：
    当X为-CONH-R4时，R4为氢、C1-C6烷基、或C3-C6环烷基，并可被卤原子任意取代；
    Figure PCTCN2017094253-appb-100017
    选自:
    Figure PCTCN2017094253-appb-100018
    R1，R2独立地选自氢、C1-C6烷基，并可被C1-C6烷氧基、C1-C6烷磺酸酰基取代，R1，R2还可与其相连的碳原子形成4-10杂环，该环碳原子可被N、O、S、或-SO2-替代，该环可被C-C6烷磺酸基、C1-C6烷基、或C1-C6烷酰基取代；
    R3为氢、C1-C7烷酰基、或C3-C7环烷酰基；
    n选自0、1、2、3、4、5；
    X1为N、或-CR5
    R5为H、-CN、或卤原子；
    当X为-CN时，
    Figure PCTCN2017094253-appb-100019
    选自：
    Figure PCTCN2017094253-appb-100020
    其中：
    R1、R2为氢、C1-C6烷基，并可被C1-C6烷氧基、或C1-C6烷磺酸酰基取代，当R1、R2与其相连的碳原子形成4-10元环，该环可被C1-C6烷基、C1-C6烷磺酰基、或C1-C6烷酰基取代，该C1-C6烷基、C1-C6烷磺酰基、C1-C6烷酰基可被卤原子任意取代；
    当
    Figure PCTCN2017094253-appb-100021
    选自:
    Figure PCTCN2017094253-appb-100022
    这时R1、R2选自与其相连的碳原子形成5-8元环，该环碳原子可被N、O、S、或-SO2-替代，该环可被C1-C6烷基、或C1-C6烷磺酰基进一步取代；
  3. 根据权利要求书1所述的化合物、其特征在于所述的化合物选自以下结构：
    2-(3-(4-(1H-吡咯并[2,3-b]吡啶-3-基)-1H-吡唑-1-基)-1-(乙磺酰基)氮杂环丁-3-基)乙腈；
    2-(4-(4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基)-1,1-二氧代四氢-2H-硫代吡喃-4-基)乙腈；
    2-(4-(4-(1H-吡咯并[2,3-b]吡啶-4-基)-1H-吡唑-1-基)-1,1-二氧代四氢-2H-硫代吡喃-4-基)乙腈；
    2-(4-(4-(1H-吡咯并[2,3-b]吡啶-3-基)-1H-吡唑-1-基)-1,1-二氧代四氢-2H-硫代吡喃-4-基)乙腈；
    2-(4-(4-(1H-吡咯并[2,3-b]吡啶-3-基)-1H-吡唑-1-基)-1-(甲磺酰基)哌啶-4-基)-N-(2,2,2-三氟乙基)乙腈；
    2-(3-(4-(1H-吡咯并[2,3-b]吡啶-3-基)-1H-吡唑-1-基)-1-(乙磺酰基)氮杂环丁-3-基)乙酰胺；
    2-(3-(4-(1H-吡咯并[2,3-b]吡啶-3-基)-1H-吡唑-1-基)-1-(乙磺酰基)氮杂环丁-3-基)-N-(2,2,2-三氟乙基)乙酰胺；
    2-(3-(4-(1H-吡咯[并2,3-d]嘧啶-4-基)-1H-吡唑-1-基)-1-(乙磺酰基)氮杂环丁-3-基)-N-(2,2,2-三氟乙基)乙酰胺；
    2-(3-(4-(1H-吡咯[并2,3-b]吡啶-4-基)-1H-吡唑-1-基)-1-(乙磺酰基)氮杂环丁-3-基)-N-(2,2,2-三氟乙基)乙酰胺；
    2-(3-(4-(1H-吡咯并[2,3-b]吡啶-4-基)-1H-吡唑-1-基)-1-(乙磺酰基)氮杂环丁-3-基)–N-甲基乙酰胺；
    2-(3-(4-(1H-吡咯并[2,3-b]吡啶-4-基)-1H-吡唑-1-基)-1-(乙磺酰基)氮杂环丁-3-基)乙酰胺；
    2-(3-(4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基)-1--(甲磺酰基)氮杂环丁-3-基)-N-(2,2,2-三氟乙基)乙酰胺；
    2-(3-(4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基)-1--(甲磺酰基) 氮杂环丁-3-基)-N-甲基乙酰胺；
    2-(3-(4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基)-1--(甲磺酰基)氮杂环丁-3-基)乙酰胺；
    2-(3-(4-(1H-吡咯并[2,3-b]吡啶-4-基)-1H-吡唑-1-基)-1-(甲磺酰基)氮杂环丁-3-基)-N-(2,2,2-三氟乙基)乙酰胺；
    2-(3-(4-(1H-吡咯并[2,3-b]吡啶-4-基)-1H-吡唑-1-基)-1-(甲磺酰基)氮杂环丁-3-基)–N-甲基乙酰胺；
    2-(3-(4-(1H-吡咯并[2,3-b]吡啶-4-基)-1H-吡唑-1-基)-1-(甲磺酰基)氮杂环丁-3-基)乙酰胺；
    2-(4-(4-(1H-吡咯并[2,3-b]吡啶-3-基)-1H-吡唑-1-基)-1,1-二氧代四氢-2H-硫代吡喃-4-基)乙酰胺
    2-(4-(4-(1H-吡咯并[2,3-b]吡啶-3-基)-1H-吡唑-1-基)-1,1-二氧代四氢-2H-硫代吡喃-4-基)-N-(2,2,2-三氟乙基)乙酰胺；
    2-(4-(4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基)-1,1-二氧代四氢-2H-硫代吡喃-4-基)-N-(2,2,2-三氟乙基)乙酰胺；
    2-(4-(4-(7H-吡咯并[2,3-b]吡啶-4-基)-1H-吡唑-1-基)-1,1-二氧代四氢-2H-硫代吡喃-4-基)-N-(2,2,2-三氟乙基)乙酰胺；
    2-(4-(4-(7H-吡咯并[2,3-b]吡啶-3-基)-1H-吡唑-1-基)-1-(甲磺酰基)哌啶-4-基)-N-(2,2,2-三氟乙基)乙酰胺；
    2-(4-(4-(7H-吡咯并[2,3-b]嘧啶-4-基)-1H-吡唑-1-基)-1-(甲磺酰基)哌啶-4-基)-N-(2,2,2-三氟乙基)乙酰胺；
    2-(4-(4-(7H-吡咯并[2,3-b]吡啶-4-基)-1H-吡唑-1-基)-1-(甲磺酰基)哌啶-4-基)-N-(2,2,2-三氟乙基)乙酰胺；
    2-(1-(4-(1H-吡咯并[2,3-b]吡啶-3-基)-1H-吡唑-1-基)环戊基)-N-(2,2,2-三氟乙基)乙酰胺；
    2-(1-(4-(1H-吡咯并[2,3-b]嘧啶-4-基)-1H-吡唑-1-基)环戊基)-N-(2,2,2-三氟乙基)乙酰胺；
    2-(1-(4-(1H-吡咯并[2,3-b]吡啶-4-基)-1H-吡唑-1-基)环戊基)-N-(2,2,2-三氟乙基)乙酰胺；
    3-(4-(1H-吡咯并[2,3-b]吡啶-3-基)-1H-吡唑-1-基)-3-甲基-N-(2,2,2-三氟乙基)丁酰胺；
    3-(4-(7H-吡咯并[2,3-b]嘧啶-4-基)-1H-吡唑-1-基)-3-甲基-N-(2,2,2-三氟乙基)丁酰胺；
    3-(4-(7H-吡咯并[2,3-b]吡啶-4-基)-1H-吡唑-1-基)-3-甲基-N-(2,2,2-三氟乙基)丁酰胺；
    及其异构体、溶剂合物、或其药学上可接受的盐。
  4. 根据权利要求1所述的化合物，其特征在于所述的化合物共有式(Ⅲ)结构:
    Figure PCTCN2017094253-appb-100023
    及其异构体、溶剂合物、或其药学上可接受的盐。
    其中:
    X2为N、或CR6
    X3为N、或CR7
    R6、R7独立地选自H、-CN、卤原子；
    Figure PCTCN2017094253-appb-100024
    选自:
    Figure PCTCN2017094253-appb-100025
    X1为N、或-CR5
    R5为H、-CN、或卤原子；
    当X选自-CONH-R4时，R4为氢、C1-C6烷基、或C3-C6环烷基，并可被卤原子任意取代；
    R1、R2选自与共相连的碳原子形成4-10元环，该环碳原子可被N、O、S、或-SO2-替代，该环可被C1-C6烷基、C1-C6烷磺酰基、或C1-C6烷酰基取代；
    当X为-CN时，
    R1，R2独立地选自氢、C1-C6烷基，并可被C1-C6烷氧基、C1-C6烷磺酸基、芳基、或杂芳基取代，R1，R2还可与其相连的碳原子形成4-10元环，该环碳原子可被N、O、S、或-SO2-替代，该环可被烷磺酸基、C1-C6烷基、C1-C6烷酰基取代；R1，R2之一还可以与R8连接成4-6元环；
    R8为氢、或C1-C6烷基；
    m选自0、1、2、3、4、5；
  5. 根据权利要求书4所述化合物，其特征在于所述的化合物选自以下结构：
    3-((2-(1H-吡咯并[2,3-b]吡啶-3-基)嘧啶-4-基)氨基)-1--(甲磺酰基)-N-(2,2,2-三氟乙基)氮杂环丁烷-3-甲酰胺；
    3-((2-(1H-吡咯并[2,3-b]吡啶-3-基)嘧啶-4-基)氨基)-1-(乙磺酰基)-N-(2,2,2-三氟乙基)氮杂环丁烷-3-甲酰胺；
    3-((2-(1H-吡咯并[2,3-b]吡啶-3-基)嘧啶-4-基)氨基)-1-(环丙磺酰基)-N-(2,2,2-三氟乙基)氮杂环丁烷-3-甲酰胺；
    3-(5-氟-2-(1H-吡咯并[2,3-b]吡啶-3-基)嘧啶-4-基)氨基)-1-(甲磺酰基)-N-(2,2,2-三氟乙基)氮杂环丁烷-3-甲酰胺；
    3-(5-氟-2-(1H-吡咯并[2,3-b]吡啶-3-基)嘧啶-4-基)氨基)-1-(乙磺酰基)-N-(2,2,2-三氟乙基)氮杂环丁烷-3-甲酰胺；
    3-(5-氟-2-(1H-吡咯并[2,3-b]吡啶-3-基)嘧啶-4-基)氨基)-1-(环丙磺酰基)-N-(2,2,2-三氟乙基)氮杂环丁烷-3-甲酰胺；
    4-((2-(1H-吡咯并[2,3-b]吡啶-3-基)嘧啶-4-基)氨基)-1-(甲磺酰基)-N-(2,2,2-三氟乙基)哌啶-4-甲酰胺；
    4-((2-(1H-吡咯并[2,3-b]吡啶-3-基)嘧啶-4-基)氨基)-1-(乙磺酰基)-N-(2,2,2-三氟乙基)哌啶-4-甲酰胺；
    4-((2-(1H-吡咯并[2,3-b]吡啶-3-基)嘧啶-4-基)氨基)-1-(环丙磺酰基)-N-(2,2,2-三氟乙基)哌啶-4-甲酰胺；
    4-((5-氟-2-(1H-吡咯并[2,3-b]吡啶-3-基)嘧啶-4-基)氨基)-1-(甲磺酰基)-N-(2,2,2-三氟乙基)哌啶-4-甲酰胺；
    4-((5-氟-2-(1H-吡咯并[2,3-b]吡啶-3-基)嘧啶-4-基)氨基)-1-(乙磺酰基)-N-(2,2,2-三氟乙基)哌啶-4-甲酰胺；
    4-((5-氟-2-(1H-吡咯并[2,3-b]吡啶-3-基)嘧啶-4-基)氨基)-1-(环丙磺酰基)-N-(2,2,2-三氟乙基)哌啶-4-甲酰胺；
    4-((2-(1H-吡咯并[2,3-b]吡啶-3-基)嘧啶-4-基)氨基)-N-(2,2,2-三氟乙基)四氢-2H硫代吡喃-4-甲酰胺1,1-二氧化物；
    4-((5-氟-2-(1H-吡咯并[2,3-b]吡啶-3-基)嘧啶-4-基)氨基)-N-(2,2,2-三氟乙基)四氢-2H硫代吡喃-4-甲酰胺1,1-二氧化物；
    3-((2-(1H-吡咯并[2,3-b]吡啶-3-基)嘧啶-4-基)氨基)-1-(乙磺酰基)氮杂环丁烷-3-腈；
    3-((2-(7H-吡咯并[2,3-d]嘧啶-4-基)嘧啶-4-基)氨基)-1-(乙磺酰基)氮杂环丁烷-3-腈；
    3-((2-(1H-吡咯并[2,3-b]吡啶-4-基)嘧啶-4-基)氨基)-1-(乙磺酰基)氮杂环丁烷-3-腈；
    3-((2-(1H-吡咯并[2,3-b]吡啶-3-基)嘧啶-4-基)氨基)-1-(甲磺酰基)氮杂环丁烷-3-腈；
    3-((2-(7H-吡咯并[2,3-d]嘧啶-4-基)嘧啶-4-基)氨基)-1-(甲磺酰基)氮杂环丁烷-3-腈；
    3-((2-(1H-吡咯并[2,3-b]吡啶-4-基)嘧啶-4-基)氨基)-1-(甲磺酰基)氮杂环丁烷-3-腈；
    4-((2-(1H-吡咯并[2,3-b]吡啶-3-基)嘧啶-4-基)氨基)四氢-2H-硫代吡喃-4-腈1,1-二氧化物；
    4-((2-(7H-吡咯并[2,3-d]嘧啶-4-基)嘧啶-4-基)氨基)四氢-2H-硫代吡喃-4-腈1,1-二氧化物；
    4-((2-(1H-吡咯并[2,3-b]吡啶-4-基)嘧啶-4-基)氨基)四氢-2H-硫代吡喃-4-腈1,1-二氧化物；
    1-((2-(1H-吡咯并[2,3-b]吡啶-3-基)嘧啶-4-基)氨基)环丁烷-3-腈；
    1-((2-(7H-吡咯并[2,3-d]嘧啶-4-基)嘧啶-4-基)氨基)环丁烷-3-腈；
    1-((2-(1H-吡咯并[2,3-b]吡啶-4-基)嘧啶-4-基)氨基)环丁烷腈；
    1-((2-(1H-吡咯并[2,3-b]吡啶-3-基)嘧啶-4-基)氨基)环戊腈；
    1-((2-(7H-吡咯并[2,3-d]嘧啶-4-基)嘧啶-4-基)氨基)环戊烷腈；
    1-((2-(1H-吡咯并[2,3-b]吡啶-4-基)嘧啶-4-基)氨基)环戊烷腈；
    (R)-2-((2-(1H-吡咯并[2,3-b]吡啶-3-基)嘧啶-4-基)氨基2-甲基丁腈；
    (R)-2-((2-(7H-吡咯并[2,3-d]嘧啶-4-基)嘧啶-4-基)氨基-2-甲基丁腈；
    (R)-2-((2-(1H-吡咯并[2,3-b]吡啶-4-基)嘧啶-4-基)氨基-2-甲基丁腈；
    及其异构体、溶剂合物、或其药学上可接受的盐。
  6. 一种药物组合物，其包括根据权利要求所述的化合物、异构体或其药学上可接受的盐，以及药学上可接受的载体。
  7. 根据权利要求1-6中任意所述的化合物，在制备治疗JAK激酶相关疾病的药物中的应用。
  8. 根据权利要求7所述的应用，其特征在于是在制备治疗自身免疫疾病、类风湿性 关节炎、皮肤病症、多发性硬化、银屑性关节炎、炎性肠病、重症肌无力、牛皮藓中的应用。
PCT/CN2017/094253 2016-07-26 2017-07-25 作为jak抑制剂杂环化合物，该化合物的盐类及其治疗用途 WO2018019222A1 (zh)

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