WO2021219100A1 - 一类含有稠合三环结构的化合物 - Google Patents

一类含有稠合三环结构的化合物 Download PDF

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WO2021219100A1
WO2021219100A1 PCT/CN2021/091148 CN2021091148W WO2021219100A1 WO 2021219100 A1 WO2021219100 A1 WO 2021219100A1 CN 2021091148 W CN2021091148 W CN 2021091148W WO 2021219100 A1 WO2021219100 A1 WO 2021219100A1
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alkyl
group
compound
aryl
substituted
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French (fr)
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张汉承
叶向阳
程鑫
王建设
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杭州英创医药科技有限公司
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    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5383—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with heterocyclic ring systems
    • 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
    • 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
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems

Definitions

  • the present invention relates to the field of medicinal chemistry; specifically, the present invention relates to a new type of derivatives containing fused tricyclic rings, its synthesis method and its use as one or more protein kinase inhibitors in the preparation of drugs for the treatment of tumors, etc. Application in disease.
  • Cancer also known as malignant tumor, is one of the diseases with the highest morbidity and mortality in the world. It is characterized by abnormal cell proliferation and metastasis, which spreads and metastasizes in a short or relatively short time after the onset of disease.
  • Traditional treatment options include resection (if the conditions for resection are met), radiotherapy, and chemotherapy.
  • Targeted therapy developed in recent years has the advantages of reducing toxicity and negative effects on patients, as well as improving survival rates. But after using targeted drugs for a period of time, drug resistance will develop, after which the growth and spread of cancer cells will be extremely rapid.
  • Common cancers are: blood cancer, lung cancer, liver cancer, bladder cancer, rectal cancer, stomach cancer, and so on.
  • Autoimmune diseases refer to diseases caused by the body's immune response to self-antigens, resulting in damage to its own tissues. Many diseases have been classified as autoimmune diseases one after another. It is worth mentioning that the existence of autoantibodies and autoimmune diseases are not two equivalent concepts. Autoantibodies can exist in normal people without autoimmune diseases, especially the elderly. Such as anti-thyroglobulin antibody, thyroid epithelial cell antibody, gastric parietal cell antibody, nuclear DNA antibody and so on. Sometimes, damaged or antigenic changed tissues can stimulate the production of autoantibodies. For example, when myocardial ischemia, necrotic myocardium can lead to the formation of anti-myocardial autoantibodies, but this antibody has no pathogenic effect and is secondary immune response.
  • Organ-specific autoimmune diseases such as chronic lymphocytic thyroiditis, hyperthyroidism, insulin-dependent diabetes, myasthenia gravis, ulcerative colitis, pernicious anemia with chronic atrophic gastritis, Pulmonary hemorrhage nephritis syndrome, pemphigus vulgaris, pemphigoid, primary biliary cirrhosis, multiple cerebrospinal sclerosis, acute idiopathic polyneuritis, etc.
  • Organ-specific autoimmune diseases such as chronic lymphocytic thyroiditis, hyperthyroidism, insulin-dependent diabetes, myasthenia gravis, ulcerative colitis, pernicious anemia with chronic atrophic gastritis, Pulmonary hemorrhage nephritis syndrome, pemphigus vulgaris, pemphigoid, primary biliary cirrhosis, multiple cerebrospinal sclerosis, acute idiopathic polyneuritis, etc.
  • Systemic autoimmune diseases such as lupus erythematosus, rheumatoid arthritis, scleroderma, systemic vascular inflammation, pemphigus, dermatomyositis, ulcerative colitis, etc.
  • the spleen tyrosine kinase (SYK) gene was cloned from pig spleen cDNA for the first time in 1991, and it encodes a non-receptor protein tyrosine kinase.
  • the human SYK gene is located in the q22 region of chromosome 9.
  • the SYK protein contains 635 amino acids and plays an important role in autoimmune diseases and hematological malignancies.
  • SYK gene can inhibit the proliferation and proliferation of breast cancer, melanoma, liver cancer and other malignant tumor cells. Migrating.
  • SYK inhibitors have been used in clinical phase II/III trials of rheumatoid arthritis and chronic lymphocytic leukemia. Recent studies have shown that the use of SYK inhibitors or interference with SYK gene expression can effectively slow down the process of liver fibrosis/sclerosis, and has a good therapeutic effect (see CN 105664178A).
  • Janus kinase is a cytoplasmic tyrosine kinase that transduces cytokine signals from membrane receptors to STAT transcription factors, also known as Janus-activated kinase-signal transducers and activators of transcriprion). This is a newly discovered intracellular signal transduction pathway closely related to cytokines in recent years, and it participates in many important biological processes such as cell proliferation, differentiation, apoptosis, and immune regulation. Janus kinase is a non-receptor type tyrosine protein kinase. There are 4 family members, namely JAK1, JAK2, TYK2 and JAK3.
  • JAK3 The first three are widely present in various tissues and cells, while JAK3 only exists in the bone marrow and lymphatic system.
  • JAK family members have 7 homology domains (JAK homology domain, JH) from the C-terminal to the N-terminal: JH1 is the kinase domain, whose function is to encode kinase protein; JH2 is the kinase-like domain or "pseudo" kinase domain.
  • JH1 is the kinase domain, whose function is to encode kinase protein; JH2 is the kinase-like domain or "pseudo" kinase domain.
  • JH1 is the kinase domain, whose function is to encode kinase protein; JH2 is the kinase-like domain or "pseudo" kinase domain.
  • JH1 is the kinase domain, whose function is to encode
  • Cerdulatinib developed by Portola Pharmaceuticals, is an under-research, oral inhibitor that targets both spleen tyrosine kinase (Syk) and Janus kinase (JAK) for the treatment of peripheral T-cell lymphoma (PTCL).
  • Ser spleen tyrosine kinase
  • JAK Janus kinase
  • PTCL peripheral T-cell lymphoma
  • ASCO American Society of Clinical Oncology
  • EHA European Association of Hematology 23rd Congress reported the new data of this study. Cerdulatinib shows a wide range of clinical activities, with an objective response rate of 47% for all patients, and it is well tolerated.
  • ASN002 is a SYK-JAK dual pathway inhibitor developed by Asana BioSciences. At the end of 2018, it was granted Fast Track qualification for the treatment of moderate to severe atopic dermatitis by the FDA.
  • SYK-JAK dual pathway inhibitor is expected to be applied in the treatment of lymphoma, solid tumor, atopic dermatitis, arthritis, alopecia, lupus erythematosus and other diseases.
  • the purpose of the present invention is to provide a new type of protein kinase inhibitor.
  • the first aspect of the present invention provides a compound of the following formula (I), or its optical isomers (including racemates, single enantiomers, and possible diastereomers) ), pharmaceutically acceptable salts, prodrugs, deuterated forms, hydrates, solvates:
  • R 1 is selected from the following group: 3- to 8-membered cycloalkyl, 3- to 12-membered heterocyclic group (including monocyclic, spiro and fused ring), aryl, heteroaryl, OR b , or NR b R c ;
  • each cycloalkyl, heterocyclic, aryl and heteroaryl is optionally substituted by 1-3 substituents each independently selected from the group: deuterium, halogen , CN, OR h , NR h R h , C(O)R e , C(O)OR h , C(O)NR h R h , NR h C(O)R e , S(O) 2 R e , S(O) 2 NR h R h , C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy substituted C 1-4 alkyl, hydroxy substituted C 1-4 alkyl , cyano
  • R b and R c are each independently hydrogen, C 1-4 alkyl, 3- to 8-membered cycloalkyl, 3- to 8-membered heterocyclyl, aryl, heteroaryl;
  • Each R 2 is independently deuterium, halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl, OR h , SR h , NR h R h , CN , C(O)R e , C(O)OR h , C(O)NR h R h , OC(O)R e , NR h C(O)R e , or S(O) 2 R e ;
  • J and G are each independently NR f , O, S, S(O), S(O) 2 or CR g R g ;
  • n 0, 1, 2, or 3;
  • q 0, 1, 2, or 3;
  • R f is hydrogen, C 1-8 alkyl, C 1-8 haloalkyl, C 2-8 alkenyl, C 2-8 alkynyl, 3- to 8-membered cycloalkyl, 3- to 12-membered hetero Cyclic, aryl, heteroaryl, C(O)R e , C(O)OR h , C(O)NR h R h , S(O) 2 R e , or S(O) 2 NR h R h ; wherein each alkyl group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group are optionally and each independently by 1-3 substituents each independently selected from the following group Substitution: halogen, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, 3- to 8-membered cycloalkyl, 3- to 8-membered heterocyclic group, aryl, heteroaryl
  • Each R e is independently a group selected from the group consisting of hydrogen, C 1-4 alkyl, C 1-4 haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl, 3- to 8- Membered cycloalkyl, 3- to 8-membered heterocyclyl, aryl, or heteroaryl;
  • Each R h is independently hydrogen or C 1-4 alkyl; or two R h and the nitrogen atom to which they are attached together form a 3- to 8-membered heterocyclic group, which contains 1 or 2 N atoms and 0 or 1 heteroatom selected from O and S;
  • each of the above-mentioned alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups is optionally and independently selected from 1-3 each independently Substituent substitution of the group: deuterium, halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl, 3- to 8-membered cycloalkyl, 3- To 8-membered heterocyclic group, aryl, heteroaryl, CN, NO 2 , OR h , SR h , NR h R h , C(O)R e , C(O)OR h , C(O)NR h R h , NR h C(O)R e , or S(O) 2 R e , provided that the chemical structure formed is stable and meaningful; wherein the definitions of R e and R h are
  • aryl groups are aromatic groups containing 6-12 carbon atoms; heteroaryl groups are 5- to 15-membered heteroaromatic groups; cyclic structures are saturated or unsaturated, containing heteroatoms Or cyclic groups without heteroatoms.
  • the R 1 is selected from the following group: 3- to 12-membered heterocyclic group, aryl group, or heteroaryl group; wherein, each of the heterocyclic group, aryl group and heteroaryl group is optional Ground is substituted by 1-2 substituents each independently selected from the group: deuterium, halogen, CN, OR h , NR h R h , C(O)R e , C(O)OR h , C(O) NR h R h , NR h C(O)R e , S(O) 2 R e , S(O) 2 NR h R h , C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 Alkoxy substituted C 1-4 alkyl, hydroxy substituted C 1-4 alkyl, cyano substituted C 1-4 alkyl, di(C 1-4 alkyl)amino substituted C 1-4 Alkyl, 3- to 6-membered heterocyclyl
  • Each R 2 is independently hydrogen, deuterium, halogen, C 1-4 alkyl, NR h R h , or NR h C(O)R e ;
  • n 0, 1, or 2;
  • q 0, 1, or 2;
  • R e and R h are as described in the first aspect of the present invention.
  • formula (I) is:
  • each R 2 is independently hydrogen, deuterium, halogen, C 1-2 alkyl, NR h R h , or NR h C(O)R e ;
  • R f is hydrogen, C 1-4 alkyl, C 1-4 haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl, 3- to 8-membered cycloalkyl, 3- to 9-membered hetero Cyclic, aryl, heteroaryl, C(O)R e , C(O)OR h , C(O)NR h R h , S(O) 2 R e , or S(O) 2 NR h R h ; wherein each alkyl group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group is optionally and each independently substituted by 1-3 substituents each independently selected from the following group : Deuterium, halogen, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, 3- to 8-membered cycloalkyl, 3- to 8-membered heterocyclic group,
  • R e and R h are as described in the first aspect of the present invention.
  • formula (I) is:
  • R 2 is hydrogen, deuterium, halogen, C 1-2 alkyl, NR h R h , or NR h C(O)R e ;
  • R f is hydrogen, C 1-4 alkyl, C 1-4 haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl, 3- to 8-membered cycloalkyl, 3- to 9-membered hetero Cyclic, aryl, heteroaryl, C(O)R e , C(O)OR h , C(O)NR h R h , S(O) 2 R e , or S(O) 2 NR h R h ; wherein each alkyl group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group is optionally and each independently substituted by 1-3 substituents each independently selected from the following group : Deuterium, halogen, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, 3- to 8-membered cycloalkyl, 3- to 8-membered heterocyclic group,
  • R 1 is as described in the first aspect of the present invention
  • R e and R h is as described in the first aspect of the present invention.
  • formula (I) is:
  • R 2 is hydrogen, deuterium, halogen, C 1-2 alkyl, NR h R h , or NR h C(O)R e ;
  • R f is hydrogen, C 1-4 alkyl, C 1-4 haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl, 3- to 8-membered cycloalkyl, 3- to 9-membered hetero Cyclic, aryl, heteroaryl, C(O)R e , C(O)OR h , C(O)NR h R h , S(O) 2 R e , or S(O) 2 NR h R h ; wherein each alkyl group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group is optionally and each independently substituted by 1-3 substituents each independently selected from the following group : Deuterium, halogen, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, 3- to 8-membered cycloalkyl, 3- to 8-membered heterocyclic group,
  • R 1 is as described in the first aspect of the present invention
  • R e and R h is as described in the first aspect of the present invention.
  • said R 2 is hydrogen, halogen, C 1-2 alkyl
  • R f is selected from the group consisting of hydrogen, C 1-4 alkyl, C 1-4 haloalkyl, 3- to 8-membered cycloalkyl, 3- to 9-membered heterocyclyl, aryl, heteroaryl, C(O)R e , or S(O) 2 R e ; wherein each alkyl group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group is optionally and each independently by 1-3 each independently Substituent substitution selected from the group: deuterium, halogen, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, 3- to 8-membered cycloalkyl, 3- to 8-membered Heterocyclyl, aryl, heteroaryl, CN, NO 2 , OR e , SR e , NR e R e , C(O)R e , C(O)OR e , C(O)NR
  • R e and R h are as described in the first aspect of the present invention.
  • formula (I) is:
  • R 2 is hydrogen, halogen, C 1-2 alkyl
  • s and t are each independently 1, 2, or 3;
  • A is NR k , O, or CR g R g ; wherein R k is hydrogen, C 1-4 alkyl, C 1-4 haloalkyl, hydroxy substituted C 1-4 alkyl, C 1-4 alkoxy Substituted C 1-4 alkyl, di(C 1-4 alkyl) amino substituted C 1-4 alkyl, 3- to 8-membered cycloalkyl, 3- to 9-membered heterocyclic group, aryl Group, heteroaryl, C(O)R e , C(O)OR h , C(O)NR h R h , S(O) 2 R e , or S(O) 2 NR h R h ;
  • R 1 is defined as in the first aspect of the present invention
  • R g, R e, and R h is defined as the first aspect of the present invention.
  • R 1 is a 3- to 12-membered heterocyclic group; wherein, the heterocyclic group refers to a saturated or partially unsaturated monocyclic or polycyclic heterocyclic group; a polycyclic heterocyclic group refers to Heterocyclic groups including spiro rings, fused rings and bridged rings; heterocyclic groups are optionally substituted with 1-2 substituents each independently selected from the group consisting of deuterium, halogen, CN, OR h , NR h R h , C(O)R e , C(O)OR h , C(O)NR h R h , NR h C(O)R e , S(O) 2 R e , S(O) 2 NR h R h , C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy substituted C 1-4 alkyl, hydroxy substituted C 1-4 alkyl, cyano substituted C 1-4 alkane
  • R 1 is selected from the following group:
  • Each R t is independently hydrogen, C 1-4 alkyl, C 1-4 haloalkyl, hydroxy substituted C 1-4 alkyl, C 1-4 alkoxy substituted C 1-4 alkyl, cyano Group substituted C 1-4 alkyl group, di(C 1-4 alkyl) amino group substituted C 1-4 alkyl group, 3- to 8-membered cycloalkyl group, 3- to 8-membered heterocyclic group, Aryl, heteroaryl, C(O)R e , or S(O) 2 R e ;
  • p 0, 1, or 2;
  • u and v are each independently 0, 1, or 2;
  • R 1 is selected from the following group:
  • the compound is selected from the following group:
  • the second aspect of the present invention provides a compound of formula (I) as described in the first aspect of the present invention, or optical isomers, pharmaceutically acceptable salts, prodrugs, deuterated derivatives, hydrates thereof ,
  • solvates which are used for:
  • the protein kinase is selected from the following group: SYK, JAK1, JAK2, JAK3, TYK2, etc., or a combination thereof.
  • the third aspect of the present invention provides a pharmaceutical composition, the pharmaceutical composition comprising: (i) an effective amount of the compound of formula I as described in the first aspect of the present invention, or an optical isomer thereof, pharmacy The above acceptable salts, prodrugs, deuterated derivatives, hydrates, solvates; and (ii) pharmaceutically acceptable carriers.
  • the fourth aspect of the present invention provides a method for preparing the compound according to the first aspect of the present invention, which includes the steps:
  • the inventors unexpectedly discovered a class of compounds with novel structures containing fused tricyclic structures as SYK and JAK kinase inhibitors, as well as their preparation methods and applications.
  • the compound of the present invention can be applied to the treatment of various diseases related to the activity of SYK, JAK1, JAK2, JAK3, and TYK2. Based on the above findings, the inventor completed the present invention.
  • each chiral carbon atom may optionally be in the R configuration or the S configuration, or a mixture of the R configuration and the S configuration.
  • alkyl refers to a linear (ie, unbranched) or branched saturated hydrocarbon group containing only carbon atoms, or a combination of linear and branched groups .
  • the number of carbon atoms in front of the alkyl group is limited (such as C 1-10 ), it means that the alkyl group contains 1-10 carbon atoms.
  • C 1-8 alkyl refers to an alkyl group containing 1-8 carbon atoms, including methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, or Similar groups.
  • alkenyl refers to a straight or branched chain carbon chain group with at least one carbon-carbon double bond. Alkenyl groups can be substituted or unsubstituted. When the alkenyl group has a limited number of carbon atoms (such as C 2-8 ), it means that the alkenyl group contains 2-8 carbon atoms.
  • C 2-8 alkenyl refers to an alkenyl group containing 2-8 carbon atoms, including vinyl, propenyl, 1,2-butenyl, 2,3-butenyl, butadienyl, or the like group.
  • alkynyl refers to an aliphatic hydrocarbon group having at least one carbon-carbon triple bond.
  • the alkynyl group can be linear or branched, or a combination thereof.
  • the alkynyl group has a limited number of carbon atoms (such as C 2-8 alkynyl), it means that the alkynyl group contains 2-8 carbon atoms.
  • C 2-8 alkynyl refers to a straight-chain or branched alkynyl group having 2-8 carbon atoms, including ethynyl, propynyl, isopropynyl, butynyl, isobutynyl, S-butynyl, tert-butynyl, or similar groups.
  • cycloalkyl refers to a saturated or partially saturated unitary ring, bicyclic or polycyclic (fused, bridged, or spiro) ring system group .
  • a certain cycloalkyl group has a limit on the number of carbon atoms (such as C 3-10 ), it means that the cycloalkyl group contains 3-10 carbon atoms.
  • the term "3- to 8-membered cycloalkyl” refers to a saturated or partially saturated monocyclic or bicyclic alkyl group with 3-8 carbon atoms, including cyclopropyl, cyclobutyl, Cyclopentyl, cycloheptyl, or similar groups.
  • “Spirocycloalkyl” refers to a bicyclic or polycyclic group that shares one carbon atom (called a spiro atom) between single rings. These can contain one or more double bonds, but none of the rings have fully conjugated ⁇ electrons. system.
  • “Fused cycloalkyl” refers to a full-carbon bicyclic or polycyclic group in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more rings may contain one or more bicyclic rings. Bond, but none of the rings have a fully conjugated ⁇ -electron system.
  • “Bridged cycloalkyl” refers to all-carbon polycyclic groups in which any two rings share two carbon atoms that are not directly connected. These can contain one or more double bonds, but none of the rings have a fully conjugated ⁇ -electron system .
  • the atoms contained in the cycloalkyl group are all carbon atoms.
  • the following are some examples of cycloalkyl groups, and the present invention is not limited to the following cycloalkyl groups.
  • Aryl refers to an all-carbon monocyclic or fused polycyclic (i.e., rings sharing adjacent pairs of carbon atoms) groups having a conjugated ⁇ -electron system, such as phenyl and naphthyl.
  • the aryl ring can be fused to other cyclic groups (including saturated and unsaturated rings), but cannot contain heteroatoms such as nitrogen, oxygen, or sulfur, and the point of connection to the parent must be in a conjugated ⁇ -electron system On the carbon atom on the ring.
  • Aryl groups can be substituted or unsubstituted.
  • Heteroaryl refers to an aromatic monocyclic or polycyclic group containing one to more heteroatoms (optionally from nitrogen, oxygen, and sulfur), or a heterocyclic group (containing one to more heteroatoms).
  • Heteroaryl groups can be optionally substituted or unsubstituted. The following are some examples of heteroaryl groups, and the present invention is not limited to the following heteroaryl groups.
  • Heterocyclyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent in which one or more ring atoms are selected from nitrogen, oxygen or sulfur, and the remaining ring atoms are carbon.
  • monocyclic heterocyclic groups include pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, and homopiperazinyl.
  • the polycyclic heterocyclic group refers to a heterocyclic group including a spiro ring, a condensed ring, and a bridged ring.
  • “Spirocyclic heterocyclic group” refers to a polycyclic heterocyclic group that shares one atom (called a spiro atom) between each ring in the system and other rings in the system, wherein one or more ring atoms are selected from nitrogen and oxygen. Or sulfur, and the remaining ring atoms are carbon.
  • “Fused ring heterocyclic group” refers to a polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with other rings in the system. One or more rings may contain one or more double bonds, but no A ring has a fully conjugated ⁇ -electron system, and one or more of the ring atoms are selected from nitrogen, oxygen, or sulfur, and the remaining ring atoms are carbon.
  • “Bridged heterocyclic group” refers to a polycyclic heterocyclic group in which any two rings share two atoms that are not directly connected. These may contain one or more double bonds, but none of the rings have a fully conjugated ⁇ -electron system , And one or more of the ring atoms are selected from nitrogen, oxygen or sulfur, and the remaining ring atoms are carbon. If there are both saturated and aromatic rings in the heterocyclic group (for example, the saturated ring and the aromatic ring are fused together), the point of connection to the parent must be on the saturated ring. Note: When the point of attachment to the parent is on the aromatic ring, it is called a heteroaryl group, not a heterocyclic group. The following are some examples of heterocyclic groups, and the present invention is not limited to the following heterocyclic groups.
  • halogen refers to F, Cl, Br, and I when alone or as part of other substituents.
  • substituted refers to the replacement of one or more hydrogen atoms on a specific group with a specific substituent.
  • the specific substituents are the substituents correspondingly described in the foregoing, or the substituents appearing in each embodiment.
  • an arbitrarily substituted group may have a substituent selected from a specific group at any substitutable position of the group, and the substituent may be the same or different in each position.
  • a cyclic substituent, such as a heterocyclic group can be connected to another ring, such as a cycloalkyl group, to form a spirobicyclic ring system, that is, two rings have a common carbon atom.
  • substituents contemplated by the present invention are those that are stable or chemically achievable.
  • the substituents are for example (but not limited to): C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, 3- to 8-membered cycloalkyl, 3- to 12-membered hetero Cyclic groups, aryl, heteroaryl, halogen, hydroxyl, carboxy (-COOH), C 1-8 aldehyde, C 2-10 acyl, C 2-10 ester, amino.
  • the term "pharmaceutically acceptable salt” refers to a salt suitable for contact with the tissue of a subject (e.g., a human) without causing unpleasant side effects.
  • the pharmaceutically acceptable salt of a certain compound of the present invention includes a salt of the compound of the present invention having an acidic group (e.g., potassium salt, sodium salt, magnesium salt, calcium salt) or a salt with basic The group is a salt of the compound of the present invention (e.g., sulfate, hydrochloride, phosphate, nitrate, carbonate).
  • the present invention provides a class of compounds of formula (I), or their deuterated derivatives, their salts, isomers (enantiomers or diastereomers, if they exist), prodrugs , Hydrates, solvates, pharmaceutically acceptable carriers or excipients for inhibiting protein kinase.
  • the protein kinases referred to here include SYK, JAK1, JAK2, JAK3, TYK2, etc., but are not limited to the above kinases.
  • the compounds of the present invention can be used as one or more kinase inhibitors.
  • certain types of compounds in the present invention can be used as SYK, JAK1, JAK2, JAK3, and TYK2 kinase inhibitors.
  • the expression or activity of the various protein kinases mentioned above are significantly increased. These overexpression and/or abnormal protein kinase activity levels are directly related to the occurrence and development of tumors.
  • the compounds of the invention are single and/or dual inhibitors of these protein kinases. By regulating the activity of these protein kinases, diseases can be prevented, alleviated or cured.
  • the diseases referred to include liver cancer, rectal cancer, bladder cancer, throat cancer, non-small cell lung cancer, small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, breast cancer, prostate cancer, glioma, ovarian cancer, head and neck cancer Squamous cell carcinoma, cervical cancer, esophageal cancer, kidney cancer, pancreatic cancer, colon cancer, skin cancer, lymphoma, stomach cancer, multiple bone marrow cancer and solid tumors, etc.
  • dual protein kinase inhibitors interfere with two different kinases at the same time, and the anti-tumor effects produced by them are often additive, so they have the potential to treat various cancers more effectively.
  • the compounds of the present invention can be combined with biological agents such as PD-1 inhibitors with As a combination medicine to treat various cancers and related diseases.
  • the compound of the present invention and its deuterated derivatives, as well as pharmaceutically acceptable salts or isomers thereof (if present) or hydrates and/or compositions thereof can be combined with pharmaceutically acceptable excipients or
  • the carrier is formulated together, and the resulting composition can be administered in vivo to mammals, such as men, women and animals, for the treatment of disorders, symptoms and diseases.
  • the composition can be: tablets, pills, suspensions, solutions, emulsions, capsules, aerosols, sterile injections. Sterile powder, etc.
  • pharmaceutically acceptable excipients include microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, dibasic calcium phosphate, mannitol, hydroxypropyl- ⁇ -cyclodextrin, ⁇ -cyclodextrin (Increase), glycine, disintegrating agents (such as starch, croscarmellose sodium, composite silicate and macromolecular polyethylene glycol), granulation binders (such as polyvinylpyrrolidone, sucrose, gelatin and Gum arabic) and lubricants (such as magnesium stearate, glycerin and talc).
  • disintegrating agents such as starch, croscarmellose sodium, composite silicate and macromolecular polyethylene glycol
  • granulation binders such as polyvinylpyrrolidone, sucrose, gelatin and Gum arabic
  • lubricants such as magnesium stearate, glycerin and talc.
  • the pharmaceutical composition is a dosage form suitable for oral administration, including but not limited to tablets, solutions, suspensions, capsules, granules, and powders.
  • the amount of the compound or the pharmaceutical composition administered to the patient is not fixed, and is usually administered in a pharmaceutically effective amount.
  • the amount of the compound actually administered can be determined by the physician according to the actual situation, including the disease to be treated, the route of administration selected, the actual compound administered, the individual condition of the patient, and so on.
  • the dosage of the compound of the present invention depends on the specific use of the treatment, the mode of administration, the state of the patient, and the judgment of the physician.
  • the ratio or concentration of the compound of the present invention in the pharmaceutical composition depends on a variety of factors, including dosage, physical and chemical properties, route of administration, and the like.
  • the compound of formula (I) of the present invention can be prepared by the following methods, the reagents and conditions of each step can be selected from the conventional reagents or conditions in the art for such preparation methods, reactants, solvents, bases, amounts of compounds used, and reaction temperature The time required for the reaction, etc. are not limited to the following explanations.
  • the compounds of the present invention can also be conveniently prepared by combining various synthetic methods described in this specification or known in the art, and such combinations can be easily performed by those skilled in the art to which the present invention belongs.
  • each reaction is usually carried out in an inert solvent, and the reaction temperature is usually -20 to 150°C (preferably 0 to 120°C.
  • the reaction time of each step is usually 0.5 to 48 hours, preferably 2 to 2 hours. 12h.
  • Reaction formula 1 describes the general synthesis method of intermediates 1-A-5-1 and 1-A5-2:
  • Reaction formula 2 describes the general synthesis method of intermediates 2-B3-1 and 2-B3-2:
  • Reaction formula 5 describes another general synthetic method of compound IIa:
  • the pharmaceutical composition of the main active ingredient can be used to treat, prevent and alleviate diseases related to the activity or expression of protein kinases such as EGFR, EGFR (C797S), ALK, and HPK1.
  • the pharmaceutical composition of the present invention contains a safe and effective amount of the compound of the present invention or a pharmacologically acceptable salt thereof and a pharmacologically acceptable excipient or carrier.
  • the "safe and effective amount” refers to: the amount of the compound is sufficient to significantly improve the condition without causing serious side effects.
  • the pharmaceutical composition contains 1-2000 mg of the compound of the present invention/agent, more preferably, 5-200 mg of the compound of the present invention/agent.
  • the "one dose" is a capsule or tablet.
  • “Pharmaceutically acceptable carrier” refers to: one or more compatible solid or liquid fillers or gel substances, which are suitable for human use, and must have sufficient purity and sufficiently low toxicity. "Compatibility” here means that the components in the composition can be blended with the compound of the present invention and between them without significantly reducing the efficacy of the compound.
  • pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, and solid lubricants (such as stearic acid).
  • Magnesium stearate calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as Tween) ), wetting agents (such as sodium lauryl sulfate), coloring agents, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.
  • vegetable oils such as soybean oil, sesame oil, peanut oil, olive oil, etc.
  • polyols such as propylene glycol, glycerin, mannitol, sorbitol, etc.
  • emulsifiers such as Tween
  • wetting agents such as sodium lauryl sulfate
  • coloring agents such as sodium lauryl sulfate
  • flavoring agents such as pepperminophen, sorbitol, etc.
  • antioxidants
  • the method of administration of the compound or pharmaceutical composition of the present invention is not particularly limited.
  • Representative administration methods include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular, or subcutaneous), and topical administration .
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules.
  • the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or mixed with the following ingredients: (a) fillers or compatibilizers, for example, Starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders such as hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and gum arabic; (c) humectants, For example, glycerin; (d) disintegrants, such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slow solvents, such as paraffin; (f) Absorption accelerators, such as quaternary amine compounds; (g) wetting agents, such as cetyl alcohol and glycty
  • Solid dosage forms such as tablets, sugar pills, capsules, pills and granules can be prepared with coatings and shell materials, such as enteric coatings and other materials known in the art. They may contain opacifying agents, and the active compound or the release of the compound in such a composition may be released in a certain part of the digestive tract in a delayed manner. Examples of embedding components that can be used are polymeric substances and waxes. If necessary, the active compound can also be formed into microcapsules with one or more of the above-mentioned excipients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures.
  • the liquid dosage form may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-Butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances.
  • composition may also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents and perfumes.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents and perfumes.
  • the suspension may contain suspending agents, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances, and the like.
  • suspending agents for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances, and the like.
  • composition for parenteral injection may contain physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions.
  • Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.
  • the dosage form of the compound of the present invention for topical administration includes ointment, powder, patch, propellant and inhalant.
  • the active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be required if necessary.
  • the compounds of the present invention can be administered alone or in combination with other pharmaceutically acceptable compounds.
  • a safe and effective amount of the compound of the present invention is applied to a mammal (such as a human) in need of treatment.
  • the dosage is usually 1 to 2000 mg, preferably 5 to 500 mg.
  • the specific dosage should also consider factors such as the route of administration and the patient's health status, which are all within the skill range of a skilled physician.
  • novel structurally novel inhibitor of protein kinases such as SYK, JAK1, JAK2, JAK3, and TYK2, and its preparation and application.
  • the inhibitor can inhibit the activity of the aforementioned protein kinases at a very low concentration.
  • compositions for treating diseases related to protein kinase activity such as SYK, JAK1, JAK2, JAK3, TYK2, etc.
  • Compound 1R-a was prepared according to the experimental procedure in patent WO2018108084.
  • Compound 1R-a 200 mg, 0.85 mmol
  • a palladium-carbon catalyst (10%, 50 mg) were added to methanol (10 mL) at room temperature, and the reaction mixture was reacted overnight under a hydrogen atmosphere at room temperature and 1 atm. TLC monitors the completion of the reaction.
  • the reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure.
  • the crude compound 1R-g (67 mg, 0.13 mmol) was dissolved in methanol (5 mL), and sodium periodate (134 mg, 0.63 mmol) was added in batches under ice bath. The reaction mixture was raised to room temperature and stirred for 3 hours. TLC monitors the completion of the reaction. The reaction solution was filtered, and the obtained filtrate was concentrated under reduced pressure to obtain the crude compound 1R-h (used directly in the next step without purification).
  • the crude compound 1R-h (62 mg, 0.13 mmol) was dissolved in ethanol (5 mL), and then hydrazine hydrate (16 mg, 0.26 mmol) was added. The reaction mixture was stirred at 80°C for 3 hours. TLC monitors the completion of the reaction. The reaction solution was filtered to obtain a filter cake, and the filter cake was separated and purified by preparative thin-plate chromatography to obtain yellow solid compound 1R (2.2 mg, yield 3.7%).
  • Compound 2R-i was synthesized from 2R-d according to the preparation procedure of compound 1R-h.
  • Compound 3R-b was synthesized from 2R-b according to the preparation procedure of compound 2R-d.
  • Compound 3R-g was synthesized from 3R-b according to the preparation procedure of compound 1R-h.
  • Compound 4R-b was synthesized from 2R-b according to the preparation procedure of compound 2R-d.
  • Compound 4R-g was synthesized from 4R-b according to the preparation procedure of compound 1R-h.
  • Compound 5R-g was synthesized from 5R-b according to the preparation procedure of compound 1R-h.
  • Compound 6R-f is synthesized from 6R-a according to the preparation procedure of compound 1R-h.
  • Compound 6S-b was synthesized from 6S-a according to the preparation procedure of compound 2R-b.
  • Compound 6S-c was synthesized from 6S-b according to the preparation procedure of compound 6R-a.
  • Compound 7R-g was synthesized from 7R-b according to the preparation procedure of compound 1R-h.
  • Compound 8R-g was synthesized from 8R-b according to the preparation procedure of compound 1R-h.
  • the crude compound 18R-d (329 mg, 0.54 mmol) was dissolved in methanol (5 mL), and sodium periodate (347 mg, 1.62 mmol) was added in batches under ice bath. The reaction mixture was raised to room temperature and stirred for 3 hours. TLC monitors the completion of the reaction. The reaction solution was filtered, and the obtained filtrate was concentrated under reduced pressure to obtain the crude compound 18R-e (used directly in the next step without purification).
  • the crude compound 18R-e (306 mg, 0.54 mmol) was dissolved in ethanol (5 mL), and then hydrazine hydrate (68 mg, 1.08 mmol) was added. The reaction mixture was stirred at 80°C for 3 hours. TLC monitors the completion of the reaction. The reaction solution was distilled under reduced pressure, and the obtained crude product was separated and purified by preparative thin-plate chromatography to obtain yellow solid compound 18R-f (56 mg, yield 19%).
  • the crude compound 20R-g (174 mg, 0.27 mmol) was dissolved in methanol (5 mL), and sodium periodate (172 mg, 0.82 mmol) was added in batches under ice bath. The reaction mixture was raised to room temperature and stirred for 3 hours. TLC monitors the completion of the reaction. The reaction solution was filtered, and the obtained filtrate was concentrated under reduced pressure to obtain the crude compound 20R-h (used directly in the next step without purification).
  • the crude compound 20R-h (163 mg, 0.27 mmol) was dissolved in ethanol (5 mL), and then hydrazine hydrate (33 mg, 0.53 mmol) was added. The reaction mixture was stirred at 80°C for 5 hours. TLC monitors the completion of the reaction. The reaction solution was filtered to obtain a filter cake, and the filter cake was separated and purified by preparative thin-plate chromatography to obtain a yellow solid compound 20R-i (67 mg, yield 42%).
  • the crude compound 21S-g (102 mg, 0.18 mmol) was dissolved in methanol (5 mL), and sodium periodate (195 mg, 0.91 mmol) was added in batches under ice bath. The reaction mixture was raised to room temperature and stirred for 3 hours. TLC monitors the completion of the reaction. The reaction solution was filtered, and the obtained filtrate was concentrated under reduced pressure to obtain the crude compound 21S-h (used directly in the next step without purification).
  • Method 1 Caliper mobility shift assay was used to measure Syk protein kinase activity.
  • the compound was dissolved in DMSO and diluted with kinase buffer (20mM HEPES, 0.01% Triton X-100, 5mM MgCl 2 , 1mM MnCl 2 , 2mM DTT), and 5 ⁇ L of the compound ( 10% DMSO).
  • kinase buffer 20mM HEPES, 0.01% Triton X-100, 5mM MgCl 2 , 1mM MnCl 2 , 2mM DTT
  • Method 2 Use the Caliper Mobility Shift Assay method to detect the inhibitory effect of the compound on the kinase Syk.
  • the final concentration of the compound tested is 1000 nM starting, 3 times dilution, 7 or 8 concentrations.
  • Use a dispenser Echo 550 to transfer 250 nL of 100-fold final concentration compound to a 384-well reaction plate, add 10 ⁇ L of kinase solution with a final concentration of 1 nM Syk, and pre-incubate at room temperature for 10 minutes (the negative control well contains 10 ⁇ L of kinase buffer and 250 nL of 100% DMSO ; The positive control well contains 10 ⁇ L of kinase solution and 250 nL of 100% DMSO).
  • Conversion inhibition rate% (average positive control conversion rate%-sample conversion rate%/(average positive control conversion rate%-negative control conversion rate%). Among them: negative control wells represent the conversion rate readings without enzyme active wells; Positive control wells represent the conversion rate readings of wells without compound inhibition.
  • Method 1 Kinase Jak2 enzyme activity inhibition IC 50 evaluation experiment:
  • the buffer is made up of the following components: 50 mM HEPES, pH 7.5, 0.00015% Brij-35.
  • the compound was configured into a concentration gradient in 100% DMSO, diluted with a buffer solution to 10% DMSO, and added to a 384-well plate. For example, if the initial concentration of the compound is 250nM, use 100% DMSO to prepare 12.5 ⁇ M, and dilute it to 5 or 6 concentrations, and then dilute 10 times with buffer to prepare an intermediate dilution of the compound containing 10% DMSO, and transfer 5 ⁇ L to 384-well plate.
  • Jak2 enzyme is diluted to the optimal concentration with the following buffer: 50mM HEPES, pH7.5, 0.00015% Brij-35, 2mM DTT. Transfer 10 ⁇ L to a 384-well plate and incubate with the compound for 10-15 minutes. The substrate was diluted to the optimal concentration with the following buffer: 50mM HEPES, pH 7.5, 0.00015% Brij-35, 10mM MgCl 2 , adenosine triphosphate at Km. Add 10 ⁇ L to the 384-well plate to start the reaction, and react at 28°C for 1 hour. Then use Caliper Reader to read the conversion rate and calculate the inhibition rate.
  • Method 2 Use the Caliper Mobility Shift Assay method to detect the inhibitory effect of the compound on the kinase Jak2.
  • the final concentration of the compound tested is 200 nM starting, 3 times dilution, 7 or 8 concentrations.
  • Conversion inhibition rate% (average positive control conversion rate%-sample conversion rate%/(average positive control conversion rate%-negative control conversion rate%). Among them: negative control wells represent the conversion rate readings without enzyme active wells; Positive control wells represent the conversion rate readings of wells without compound inhibition.

Abstract

提供式(I)所示结构的化合物，或其光学异构体，药学上可接受的盐，前药，氘代形式，水合物，溶剂合物，式(I)化合物的制备方法，以及含有式(I)化合物的药物组合物。式(I)化合物能够有效抑制SYK和/或JAK等蛋白激酶，从而起到治疗各种自身免疫性疾病和肿瘤的作用。

Description

一类含有稠合三环结构的化合物 技术领域
本发明涉及药物化学领域；具体地说，本发明涉及一类新型含有稠合三环的衍生物，其合成方法及其作为一种或多种蛋白激酶抑制剂在制备药物用于治疗肿瘤等相关疾病中的应用。
背景技术
癌症亦称恶性肿瘤，是世界上发病率最高和死亡率最高的一种疾病之一，其特点是以细胞异常增殖及转移，在发病后短时间内或相对短时间内扩散，转移。传统的治疗方案包括切除(如果符合切除条件)，放疗，化疗。近年来发展起来的靶向治疗法，有降低毒性和对病人的负作用，及提高生存率等优点。但在使用靶向药物一段时间内又会产生抗药性，之后癌细胞的生长扩散就会异常迅猛。常见的癌症有：血癌，肺癌，肝癌，膀胱癌，直肠癌，胃癌，等等。
自身免疫性疾病是指机体对自身抗原发生免疫反应而导致自身组织损害所引起的疾病。许多疾病相继被列为自身免疫性疾病，值得提出的是，自身抗体的存在与自身免疫性疾病并非两个等同的概念，自身抗体可存在于无自身免疫性疾病的正常人特别是老年人，如抗甲状腺球蛋白抗体、甲状腺上皮细胞抗体、胃壁细胞抗体、细胞核DNA抗体等。有时，受损或抗原性发生变化的组织可激发自身抗体的产生，如心肌缺血时，坏死的心肌可导致抗心肌自身抗体形成，但此抗体并无致病作用，是一种继发性免疫反应。临床上的表现有：(1)器官特异性自身免疫病，如慢性淋巴细胞性甲状腺炎、甲状腺功能亢进、胰岛素依赖型糖尿病、重症肌无力、溃疡性结肠炎、恶性贫血伴慢性萎缩性胃炎、肺出血肾炎综合征、寻常天疱疮、类天疱疮、原发性胆汁性肝硬化、多发性脑脊髓硬化症、急性特发性多神经炎等。(2)系统性自身免疫病，如红斑狼疮、类风湿性关节炎、硬皮病、系统性血管炎症、天疱疮、皮肌炎、溃疡性结肠炎等。
脾酪氨酸激酶(spleen tyrosine kinase,SYK)基因是1991年首次从猪脾cDNA克隆出来，编码一种非受体型蛋白酪氨酸激酶。人类SYK基因定位于9号染色体q22区，SYK蛋白含635个氨基酸，在自身免疫性疾病和血液恶性肿瘤中作用重要，如SYK基因可抑制乳腺癌、黑色素瘤和肝癌等恶性肿瘤细胞的增殖与迀移。目前，SYK抑制剂已用于类风湿性关节炎、慢性淋巴细胞白血病等的临床II/III期实验。最近研究表明，使用SYK抑制剂或者干扰SYK基因的表达，可以有效地减缓肝纤维化/硬化的进程，具有很好地治疗作用(参见CN 105664178A)。
Janus激酶(Janus kinase，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，又称为Janus激酶-信号传导及转录激活因子(Janus-activated kinase Singal transducers and activators of transcriprion)。这是近年来新发现的一条与细胞因子密切相关的细胞内信号传导通路，参与细胞的增殖、分化、凋亡以及免疫调节等许多重要的生物学过程。Janus激酶是一种非受体型酪氨酸蛋白激酶。有4个家族成员，分别是JAK1、JAK2、TYK2和JAK3。前3者广泛存在于各种组织和细胞中，而JAK3 仅存在于骨髓和淋巴系统。这些JAK家族成员从C末端到N端依次都拥有7个同源结构域(JAK homologydomain，JH)：JH1为激酶区，功能是编码激酶蛋白；JH2为激酶样区或“假”激酶区，对JH1的活性起调节作用；JH3～JH7组成一个四合一结构域，调节JAK与受体的结合。科学研究表明，抑制JAK可以成为有前途的抗癌药的靶点。
SYK和JAK属于不同的信号通路。用一个小分子同时靶向这两个靶点，具有优越性。Portola Pharmaceuticals公司开发的Cerdulatinib是一款在研的，口服的，同时靶向脾酪氨酸激酶(Syk)和Janus激酶(JAK)的抑制剂，用于治疗外周T细胞淋巴瘤(PTCL)。2018年美国临床肿瘤学会(ASCO)年会和欧洲血液学协会(EHA)第23届大会上报告了该项研究的新数据。Cerdulatinib表现出广泛的临床活性，所有患者的客观反应率为47％，并且耐受良好。ASN002是由Asana BioSciences开发的SYK-JAK双通路抑制剂，2018年底被FDA授予治疗中度至重度特应性皮炎的快速通道资格。
SYK-JAK双通路抑制剂有望在治疗淋巴瘤、固体瘤、特应性皮炎、关节炎、脱发症、红斑狼疮等疾病领域得到应用。
综上所述，开发新型的SYK-JAK双通路抑制剂具有重要的意义。
发明内容
本发明的目的是提供一类新型的蛋白激酶抑制剂。
本发明的第一方面，提供了一种如下式(I)所示结构的化合物，或其光学异构体(包括消旋体、单一的对映异构体、可能的非对映异构体)，药学上可接受的盐，前药，氘代形式，水合物，溶剂合物：
Figure PCTCN2021091148-appb-000001
其中“*”表示手性中心；在没有标明是R或S的情况下，带“*”的化合物表示消旋体，或R构型或S构型的光学异构体；
R 1选自下组：3-至8-元环烷基、3-至12-元杂环基(包括单环、螺环和并环)、芳基、杂芳基、OR b、或NR bR c；在所述的R 1中，各个环烷基、杂环基、芳基和杂芳基任选地被1-3个各自独立地选自下组的取代基取代：氘、卤素、CN、OR h、NR hR h、C(O)R e、C(O)OR h、C(O)NR hR h、NR hC(O)R e、S(O) 2R e、S(O) 2NR hR h、C 1-4烷基、C 1-4卤代烷基、C 1-4烷氧基取代的C 1-4烷基、羟基取代的C 1-4烷基、氰基取代的C 1-4烷基、二(C 1-4烷基)胺基取代的C 1-4烷基、3-至6-元杂环基取代的C 1-4烷基、芳基取代的C 1-4烷基、杂芳基取代的C 1-4烷基、C 2-4烯基、C 2-4炔基、3-至8-元环烷基、3-至8-元杂环基、芳基、或杂芳基，前提条件是所形成的化学结构是稳定的和有意义的；
其中，R b和R c各自独立为氢、C 1-4烷基、3-至8-元环烷基、3-至8-元杂环基、芳基、杂 芳基；
各个R 2各自独立为氘、卤素、C 1-4烷基、C 1-4卤代烷基、C 2-4烯基、C 2-4炔基、OR h、SR h、NR hR h、CN、C(O)R e、C(O)OR h，C(O)NR hR h、OC(O)R e、NR hC(O)R e、或S(O) 2R e；
各个R 3各自独立为氘、或C 1-4烷基；或当两个R 3同时连接到同一个碳原子上时，两个R 3与其相连的碳原子共同形成羰基(C＝O)；所述的R 3位于环上除N原子和G上的任意位点；
J和G各自独立地为NR f、O、S、S(O)、S(O) 2或CR gR g；
n为0、1、2、或3；
q为0、1、2、或3；
R f为氢、C 1-8烷基、C 1-8卤代烷基、C 2-8烯基、C 2-8炔基、3-至8-元环烷基、3-至12-元杂环基、芳基、杂芳基、C(O)R e、C(O)OR h、C(O)NR hR h、S(O) 2R e、或S(O) 2NR hR h；其中，各个烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基任选地且各自独立地被1-3个各自独立地选自下组的取代基取代：卤素、C 1-4烷基、C 2-4烯基、C 2-4炔基、3-至8-元环烷基、3-至8-元杂环基、芳基、杂芳基、CN、NO 2、OR h、SR h、NR hR h、C(O)R e、C(O)OR h、C(O)NR hR h、NR hC(O)R e、S(O) 2R e、或S(O) 2NR hR h；
各个R e各自独立地为选自下组的基团：氢、C 1-4烷基、C 1-4卤代烷基、C 2-4烯基、C 2-4炔基、3-至8-元环烷基、3-至8-元杂环基、芳基、或杂芳基；
各个R g各自独立地选自下组：氢、氘、卤素、或C 1-4烷基；或两个R g与其相连的碳原子共同形成羰基(C＝O)；或两个R g与其连接的同一个碳原子一起形成3-至8-元环状结构，此环状结构任选地含有0、1或2个选自N、O、S的杂原子；
各个R h各自独立为氢、或C 1-4烷基；或两个R h与其连接的氮原子一起形成3-至-8元杂环基，此杂环基含有1或2个N原子以及0或1个选自O、S的杂原子；
其中，除非特别说明，各个上述的烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基任选地且各自独立地被1-3个各自独立地选自下组的取代基取代：氘、卤素、C 1-4烷基、C 1-4卤代烷基、C 2-4烯基、C 2-4炔基、3-至8-元环烷基、3-至8-元杂环基、芳基、杂芳基、CN、NO 2、OR h、SR h、NR hR h、C(O)R e、C(O)OR h、C(O)NR hR h、NR hC(O)R e、或S(O) 2R e，前提条件是所形成的化学结构是稳定的和有意义的；其中R e和R h的定义如上所述；
除非特别说明，上述的芳基为含有6-12个碳原子的芳香基团；杂芳基为5-至15-元杂芳香基团；环状结构为饱和的或不饱和的、含杂原子或不含杂原子的环状基团。
在另一优选例中，所述的R 1选自下组：3-至12-元杂环基、芳基、或杂芳基；其中，各个杂环基、芳基和杂芳基任选地被1-2个各自独立地选自下组的取代基取代：氘、卤素、CN、OR h、NR hR h、C(O)R e、C(O)OR h、C(O)NR hR h、NR hC(O)R e、S(O) 2R e、S(O) 2NR hR h、C 1-4烷基、C 1-4卤代烷基、C 1-4烷氧基取代的C 1-4烷基、羟基取代的C 1-4烷基、氰基取代的C 1-4烷基、二(C 1-4烷基)胺基取代的C 1-4烷基、3-至6-元杂环基取代的C 1-4烷基、芳基取代的C 1-4烷基、杂芳基取代的C 1-4烷基、3-至8-元环烷基、3-至8-元杂环基、芳基、或杂芳基，前提条件是所形成的化学结构是稳定的和有意义的；
各个R 2各自独立为氢、氘、卤素、C 1-4烷基、NR hR h、或NR hC(O)R e；
各个R 3各自独立为氢或C 1-4烷基；或当两个R 3同时连接到同一个碳原子上时，这两个R 3与其相连的碳原子共同形成羰基(C＝O)；
n为0、1、或2；
q为0、1、或2；
其中R e和R h的定义如本发明第一方面中所述。
在另一优选例中，式(I)为：
Figure PCTCN2021091148-appb-000002
其中各个基团的定义如本发明第一方面中所述。
在另一优选例中，式(IIa)中的结构片段
Figure PCTCN2021091148-appb-000003
选自：
Figure PCTCN2021091148-appb-000004
Figure PCTCN2021091148-appb-000005
表示上述结构片段与式(IIa)中其它结构的连接位点；
其中，各个R 2各自独立为氢、氘、卤素、C 1-2烷基、NR hR h、或NR hC(O)R e；
各个R 3各自独立为氢或C 1-4烷基；当两个R 3连接在同一个碳原子上时，两个R 3和连接它们的碳原子可以一起组成C＝O；
n为0、1、或2；q为0或1；
R f为氢、C 1-4烷基、C 1-4卤代烷基、C 2-4烯基、C 2-4炔基、3-至8-元环烷基、3-至9-元杂环基、芳基、杂芳基、C(O)R e、C(O)OR h、C(O)NR hR h、S(O) 2R e、或S(O) 2NR hR h；其中各个烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基任选地且各自独立地被1-3个各自独立地选自下组的取代基取代：氘、卤素、C 1-4烷基、C 2-4烯基、C 2-4炔基、3-至8-元环烷基、3-至8-元杂环基、芳基、杂芳基、CN、NO 2、OR h、SR h、NR hR h、C(O)R e、C(O)OR h、C(O)NR hR h、NR hC(O)R e、S(O) 2R e、或S(O) 2NR hR h；
R e和R h的定义如本发明第一方面中所述。
在另一优选例中，式(I)为：
Figure PCTCN2021091148-appb-000006
其中，R 2为氢、氘、卤素、C 1-2烷基、NR hR h、或NR hC(O)R e；
R f为氢、C 1-4烷基、C 1-4卤代烷基、C 2-4烯基、C 2-4炔基、3-至8-元环烷基、3-至9-元杂环基、芳基、杂芳基、C(O)R e、C(O)OR h、C(O)NR hR h、S(O) 2R e、或S(O) 2NR hR h；其中各个烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基任选地且各自独立地被1-3个各自独立地选自下组的取代基取代：氘、卤素、C 1-4烷基、C 2-4烯基、C 2-4炔基、3-至8-元环烷基、3-至8-元杂环基、芳基、杂芳基、CN、NO 2、OR h、SR h、NR hR h、C(O)R e、C(O)OR h、C(O)NR hR h、NR hC(O)R e、S(O) 2R e、或S(O) 2NR hR h；
R 1的定义如本发明第一方面中所述；R e和R h的定义如本发明第一方面中所述。
在另一优选例中，式(I)为：
Figure PCTCN2021091148-appb-000007
其中，R 2为氢、氘、卤素、C 1-2烷基、NR hR h、或NR hC(O)R e；
R f为氢、C 1-4烷基、C 1-4卤代烷基、C 2-4烯基、C 2-4炔基、3-至8-元环烷基、3-至9-元杂环基、芳基、杂芳基、C(O)R e、C(O)OR h、C(O)NR hR h、S(O) 2R e、或S(O) 2NR hR h；其中各个烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基任选地且各自独立地被1-3个各自独立地选自下组的取代基取代：氘、卤素、C 1-4烷基、C 2-4烯基、C 2-4炔基、3-至8-元环烷基、3-至8-元杂环基、芳基、杂芳基、CN、NO 2、OR h、SR h、NR hR h、C(O)R e、C(O)OR h、C(O)NR hR h、NR hC(O)R e、S(O) 2R e、或S(O) 2NR hR h；
R 1的定义如本发明第一方面中所述；R e和R h的定义如本发明第一方面中所述。
在另一优选例中，所述的R 2为氢、卤素、C 1-2烷基；
R f选自下组：氢、C 1-4烷基、C 1-4卤代烷基、3-至8-元环烷基、3-至9-元杂环基、芳基、杂芳基、C(O)R e、或S(O) 2R e；其中各个烷基、环烷基、杂环基、芳基和杂芳基任选地且各自独立地被1-3个各自独立地选自下组的取代基取代：氘、卤素、C 1-4烷基、C 2-4烯基、C 2-4炔基、3-至8-元环烷基、3-至8-元杂环基、芳基、杂芳基、CN、NO 2、OR e、SR e、NR eR e、 C(O)R e、C(O)OR e、C(O)NR eR e、NR eC(O)R e、S(O) 2R e、或S(O) 2NR hR h；
R e和R h的定义如本发明第一方面中所述。
在另一优选例中，式(I)为：
Figure PCTCN2021091148-appb-000008
其中，R 2为氢、卤素、C 1-2烷基；
s和t各自独立为1、2、或3；
A为NR k、O、或CR gR g；其中R k为氢、C 1-4烷基、C 1-4卤代烷基、羟基取代的C 1-4烷基、C 1-4烷氧基取代的C 1-4烷基、二(C 1-4烷基)胺基取代的C 1-4烷基、3-至8-元环烷基、3-至9-元杂环基、芳基、杂芳基、C(O)R e、C(O)OR h、C(O)NR hR h、S(O) 2R e、或S(O) 2NR hR h；
R 1的定义如本发明第一方面中所述；R g、R e、和R h的定义如本发明第一方面中所述。
在另一优选例中，R 1为3-至12-元杂环基；其中，所述的杂环基指饱和或部分不饱和的单环或多环杂环基；多环杂环基指包括螺环、稠环和桥环的杂环基；杂环基任选地被1-2个各自独立地选自下组的取代基取代：氘、卤素、CN、OR h、NR hR h、C(O)R e、C(O)OR h、C(O)NR hR h、NR hC(O)R e、S(O) 2R e、S(O) 2NR hR h、C 1-4烷基、C 1-4卤代烷基、C 1-4烷氧基取代的C 1-4烷基、羟基取代的C 1-4烷基、氰基取代的C 1-4烷基、二(C 1-4烷基)胺基取代的C 1-4烷基、3-至6-元杂环基取代的C 1-4烷基、芳基取代的C 1-4烷基、杂芳基取代的C 1-4烷基、3-至8-元环烷基、3-至8-元杂环基、芳基、或杂芳基，前提条件是所形成的化学结构是稳定的和有意义的。
在另一优选例中，R 1选自下组：
Figure PCTCN2021091148-appb-000009
Figure PCTCN2021091148-appb-000010
表示上述结构片段与式(I)中其它结构的连接位点；
其中，各个R s各自独立为氢、氘、卤素、C 1-4烷基、CN、OR h、NR hR h；或当两个R s同时连接到同一个碳原子上时，这两个R s与其相连的碳原子可以任选地共同形成羰基(C＝O)或形成3-至6-元环烷基；
或位于不同碳原子上的两个R s共同构成选自下组的结构：化学键、C 1-2的亚烷基；
B为NR t、O、或CR wR w；各个R w各自独立地选自下组：氢、氘、卤素、CN、OR h、NR hR h、C(O)R e、C(O)OR h、C(O)NR hR h、NR hC(O)R e、S(O) 2R e、S(O) 2NR hR h、C 1-4烷基、C 1- 4卤代烷基、C 1-4烷氧基取代的C 1-4烷基、羟基取代的C 1-4烷基、氰基取代的C 1-4烷基、二 (C 1-4烷基)胺基取代的C 1-4烷基、3-至8-元环烷基、3-至8-元杂环基、芳基、或杂芳基；或两个R w与其连接的同一个碳原子一起形成3-至8-元环状结构，此环状结构任选地含有0、1或2个选自NR t、O、S的环成员；
各个R t各自独立地为氢、C 1-4烷基、C 1-4卤代烷基、羟基取代的C 1-4烷基、C 1-4烷氧基取代的C 1-4烷基、氰基取代的C 1-4烷基、二(C 1-4烷基)胺基取代的C 1-4烷基、3-至8-元环烷基、3-至8-元杂环基、芳基、杂芳基、C(O)R e、或S(O) 2R e；
p为0、1、或2；
u和v各自独立为0、1、或2；
各个R e和R h的定义如本发明第一方面中所述。
在另一优选例中，R 1选自下组：
Figure PCTCN2021091148-appb-000011
Figure PCTCN2021091148-appb-000012
表示上述结构片段与式(I)中其它结构的连接位点。
在另一优选例中，所述化合物选自下组：
Figure PCTCN2021091148-appb-000013
Figure PCTCN2021091148-appb-000014
Figure PCTCN2021091148-appb-000015
本发明的第二方面，提供了一种如本发明第一方面所述的式(I)化合物，或其光学异构体，药学上可接受的盐，前药，氘代衍生物，水合物，溶剂合物的用途，其用于：
(a)制备治疗与蛋白激酶活性或表达量相关的疾病的药物；
(b)制备蛋白激酶靶向抑制剂；和/或
(c)体外非治疗性地抑制蛋白激酶的活性；
其中，所述的蛋白激酶选自下组：SYK、JAK1、JAK2、JAK3、TYK2等，或其组合。
本发明的第三方面，提供了一种药物组合物，所述的药物组合物包括：(i)有效量的如本发明第一方面所述的式I化合物，或其光学异构体，药学上可接受的盐，前药，氘代衍生物，水合物，溶剂合物；和(ii)药学上可接受的载体。
本发明的第四方面，提供了一种如本发明第一方面所述的化合物的制备方法，包括步骤：
Figure PCTCN2021091148-appb-000016
(1)用式C2化合物与DMF-DMA反应，得到式C3化合物；
Figure PCTCN2021091148-appb-000017
(2)用式C3化合物与NaIO 4反应，得到式C4化合物；
Figure PCTCN2021091148-appb-000018
(3)用式C4化合物与NH 2NH 2反应，得到式I化合物。
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。限于篇幅，在此不再一一累述。
具体实施方式
本发明人经过长期而深入的研究，意外地发现了一类结构新颖的含有稠合三环结构的化合物作为SYK和JAK激酶抑制剂，以及它们的制备方法和应用。本发明化合物可以应用于与SYK、JAK1、JAK2、JAK3、TYK2的活性相关的各种疾病的治疗。基于上述发现，发明人完成了本发明。
术语
除特别说明之处，本文中提到的“或”具有与“和/或”相同的意义(指“或”以及“和”)。
除特别说明之处，本发明的所有化合物之中，各手性碳原子(手性中心)可以任选地为R构型或S构型，或R构型和S构型的混合物。
如本文所用，在单独或作为其他取代基一部分时，术语“烷基”指只含碳原子的直链(即，无支链)或支链饱和烃基，或直链和支链组合的基团。当烷基前具有碳原子数限定(如C 1-10)时，指所述的烷基含有1-10个碳原子。例如，C 1-8烷基指含有1-8个碳原子的烷基，包括甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、或类似基团。
如本文所用，在单独或作为其他取代基一部分时，术语“烯基”是指直链或支链，具有至少一个碳-碳双键的碳链基团。烯基可以是取代的或未取代的。当烯基前具有碳原子数限定(如C 2-8)时，指所述的烯基含有2-8个碳原子。例如，C 2-8烯基指含有2-8个碳原子烯基，包括乙烯基、丙烯基、1,2-丁烯基、2,3-丁烯基、丁二烯基、或类似基团。
如本文所用，在单独或作为其他取代基一部分时，术语“炔基”是指具有至少一个碳-碳三键的脂肪族碳氢基团。所述的炔基可以是直链或支链的，或其组合。当炔基前具有碳原子数限定(如C 2-8炔基)时，指所述的炔基含有2-8个碳原子。例如，术语“C 2-8炔基”指具有2-8个碳原子的直链或支链炔基，包括乙炔基、丙炔基、异丙炔基、丁炔基、异丁炔基、仲丁炔基、叔丁炔基、或类似基团。
如本文所用，在单独或作为其他取代基一部分时，术语“环烷基”指具有饱和的或部分饱和的单元环，二环或多环(稠环、桥环或螺环)环系基团。当某个环烷基前具有碳原子数限定(如C 3-10)时，指所述的环烷基含有3-10个碳原子。在一些优选实施例中，术语“3-至8-元环烷基”指具有3-8个碳原子的饱和或部分饱和的单环或二环烷基，包括环丙基、环丁基、环戊基、环庚基、或类似基团。“螺环烷基”指单环之间共用一个碳原子(称螺原子)的二环或多环基团，这些可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。“稠环烷基”指系统中的每个环与体系中的其他环共享毗邻的一对碳原子的全碳二环或多环基团，其中一个或多个环可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。“桥环烷基”指任意两个环共用两个不直接连接的碳原子的全碳多环基团，这些可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。所述环烷基所含原子全部为碳原子。如下是环烷基的一些例子，本发明并不仅局限下述的环烷基。
Figure PCTCN2021091148-appb-000019
除非有相反陈述，否则下列用在说明书和权利要求书中的术语具有下述含义。“芳基”指具有共轭的π电子体系的全碳单环或稠合多环(也就是共享毗邻碳原子对的环)基 团，例如苯基和萘基。所述芳基环可以稠合于其它环状基团(包括饱和和不饱和环)，但不能含有杂原子如氮，氧，或硫，同时连接母体的点必须在具有共轭的π电子体系的环上的碳原子上。芳基可以是取代的或未取代的。如下是芳基的一些例子，本发明并不仅局限下述的芳基。
Figure PCTCN2021091148-appb-000020
“杂芳基”指包含一个到多个杂原子(任选自氮、氧和硫)的具有芳香性的单环或多环基团，或者包含杂环基(含一个到多个杂原子任选自氮、氧和硫)与芳基稠合形成的多环基团，且连接位点位于芳基上。杂芳基可以是任选取代的或未取代的。如下是杂芳基的一些例子，本发明并不仅局限下述的杂芳基。
Figure PCTCN2021091148-appb-000021
“杂环基”指饱和或部分不饱和单环或多环环状烃取代基，其中一个或多个环原子选自氮、氧或硫，其余环原子为碳。单环杂环基的非限制性实施例包含吡咯烷基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、高哌嗪基。多环杂环基指包括螺环、稠环和桥环的杂环基。“螺环杂环基”指系统中的每个环与体系中的其他环之间共用一个原子(称螺原子)的多环杂环基团，其中一个或多个环原子选自氮、氧或硫，其余环原子为碳。“稠环杂环基”指系统中的每个环与体系中的其他环共享毗邻的一对原子的多环杂环基团，一个或多个环可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统，而且其中一个或多个环原子选自氮、氧或硫，其余环原子为碳。“桥环杂环基”指任意两个环共用两个不直接连接的原子的多环杂环基团，这些可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统，而且其中一个或多个环原子选自氮、氧或硫，其余环原子为碳。如果杂环基里同时有饱和环和芳环存在(比如说饱和环和芳环稠合在一起)，连接到母体的点一定是在饱和的环上。注：当连接到母体的点在芳环上时，称为杂芳基，不称为杂环基。如下是杂环基的一些例子，本发明并不仅局限下述的杂环基。
Figure PCTCN2021091148-appb-000022
如本文所用，在单独或作为其他取代基一部分时，术语“卤素”指F、Cl、Br和I。
如本文所用，术语“取代”(在有或无“任意地”修饰时)指特定的基团上的一个或多个氢原子被特定的取代基所取代。特定的取代基为在前文中相应描述的取代基，或各实施例中所出现的取代基。除非特别说明，某个任意取代的基团可以在该基团的任何可取代的位点上具有一个选自特定组的取代基，所述的取代基在各个位置上可以是相同或不同的。环状取代基，例如杂环基，可以与另一个环相连，例如环烷基，从而形成螺二环系，即两个环具有一个共用碳原子。本领域技术人员应理解，本发明所预期的取代基的组合是那些稳定的或化学上可实现的组合。所述取代基例如(但并不限于)：C 1-8烷基、C 2-8烯基、C 2-8炔基、3-至8-元环烷基、3-至12-元杂环基，芳基、杂芳基、卤素、羟基、羧基(-COOH)、C 1-8醛基、C 2-10酰基、C 2-10酯基、氨基。
为了方便以及符合常规理解，术语“任意取代”或“任选取代”只适用于能够被取代基所取代的位点，而不包括那些化学上不能实现的取代。
如本文所用，除非特别说明，术语“药学上可接受的盐”指适合与对象(例如，人)的组织接触，而不会产生不适度的副作用的盐。在一些实施例中，本发明的某一化合物的药学上可接受的盐包括具有酸性基团的本发明的化合物的盐(例如，钾盐，钠盐，镁盐，钙盐)或具有碱性基团的本发明的化合物的盐(例如，硫酸盐，盐酸盐，磷酸盐，硝酸盐，碳酸盐)。
用途：
本发明提供了一类式(I)化合物，或它们的氘代衍生物、它们的盐、异构体(对映异构体或非对映异构体，如果存在的情况下)、前药、水合物、溶剂合物、可药用载体或赋形剂用于抑制蛋白激酶的用途。这里所指的蛋白激酶包括SYK、JAK1、JAK2、JAK3、TYK2等，在内，但并不仅限于以上几种激酶。
本发明化合物可用作一种或多种激酶抑制剂，例如一些实施例中，本发明中的某类化合物可用作SYK、JAK1、JAK2、JAK3、TYK2激酶抑制剂。
在癌症病人体内，上述所提到的各种蛋白激酶的表达或活性都明显增高。这些过度表达和/或异常的蛋白激酶活性水平与肿瘤的发生发展直接关联。本发明化合物是这些蛋白激酶的单一和/或双重抑制剂。通过调节这些蛋白激酶活性得到预防、缓解或治愈疾病。所指疾病包括肝癌、直肠癌、膀胱癌、咽喉癌、非小细胞肺癌、小细胞肺癌、肺腺癌、肺鳞癌、乳腺癌、前列腺癌、神经胶质细胞瘤、卵巢癌、头颈部鳞癌、宫颈癌、食管癌、肾癌、胰腺癌、结肠癌、皮肤癌、淋巴瘤、胃癌、多发性骨髓癌和实体瘤等等。
从某种角度上说，双重蛋白激酶抑制剂同时干扰两种不同的激酶，所产生的抗肿瘤效果往往具有叠加性，因此具有更有效治疗各种癌症的潜力。
本发明化合物可与生物制剂如PD-1抑制剂
Figure PCTCN2021091148-appb-000023
和
Figure PCTCN2021091148-appb-000024
作为组合药物治疗各种癌症及相关疾病。
可将本发明化合物及其氘代衍生物，以及药学上可接受的盐或其异构体(如果存在的情况下)或其水合物和/或组合物与药学上可接受的赋形剂或载体配制在一起，得到的组合物可在体内给予哺乳动物，例如男人、妇女和动物，用于治疗病症、症状和疾病。组合物可以是：片剂、丸剂、混悬剂、溶液剂、乳剂、胶囊、气雾剂、无菌注射液。无菌粉末等。一些实施例中，药学上可接受的赋形剂包括微晶纤维素、乳糖、柠檬酸钠、碳酸钙、磷酸氢钙、甘露醇、羟丙基-β-环糊精、β-环糊精(增加)、甘氨酸、崩解剂(如淀粉、交联羧甲基纤维素钠、复合硅酸盐和高分子聚乙二醇)，造粒粘合剂(如聚乙烯吡咯烷酮、蔗糖、明胶和阿拉伯胶)和润滑剂(如硬脂酸镁、甘油和滑石粉)。在优选的实施方式中，所述药物组合物是适于口服的剂型，包括但不限于片剂、溶液剂、混悬液、胶囊剂、颗粒剂、粉剂。向患者施用本发明化合物或药物组合物的量不固定，通常按药用有效量给药。同时，实际给予的化合物的量可由医师根据实际情况决定，包括治疗的病症、选择的给药途径、给予的实际化合物、患者的个体情况等。
本发明化合物的剂量取决于治疗的具体用途、给药方式、患者状态、医师判断。本发明化合物在药物组合物中的比例或浓度取决于多种因素，包括剂量、理化性质、给药途径等。
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。
化合物的通用合成方法
本发明的式(I)化合物可以通过以下方法制备得到，各步骤的试剂和条件可以选用本领域进行该类制备方法常规的试剂或条件，反应物、溶剂、碱、所用化合物的量、反应温度、反应所需时间等不限于下面的解释。本发明化合物还可以任选将在本说明书中描述的或本领域已知的各种合成方法组合起来而方便的制得，这样的组合可由本发明所属领域的技术人员容易地进行。
在本发明的制备方法中，各反应通常在惰性溶剂中，反应温度通常为-20～150℃(优选0～120℃下进行。各步反应时间通常为0.5～48h，较佳地为2～12h。
反应式1描述了中间体1-A-5-1和1-A5-2的通用合成方法：
反应式1:
Figure PCTCN2021091148-appb-000025
反应式2描述了中间体2-B3-1和2-B3-2的通用合成方法：
反应式2:
Figure PCTCN2021091148-appb-000026
化合物IIa是化合物I的一部分。反应式3描述了化合物IIa的通用合成方法：
反应式3:
Figure PCTCN2021091148-appb-000027
化合物IIb是化合物I的一部分。反应式4描述了化合物IIb的通用合成方法：
反应式4:
Figure PCTCN2021091148-appb-000028
反应式5描述了化合物IIa的另一种通用合成方法：
反应式5:
Figure PCTCN2021091148-appb-000029
上述反应式1-5中R 2、R f、和q的定义同上文中所述。
药物组合物和施用方法
由于本发明化合物具有优异的对一系列蛋白激酶的抑制活性，因此本发明化合物及其各种晶型，药学上可接受的无机或有机盐，水合物或溶剂合物，以及含有本发明化合物为主要活性成分的药物组合物可用于治疗、预防以及缓解与EGFR、EGFR(C797S)、ALK、和 HPK1等蛋白激酶活性或表达量相关的疾病。
本发明的药物组合物包含安全有效量范围内的本发明化合物或其药理上可接受的盐及药理上可以接受的赋形剂或载体。其中“安全有效量”指的是：化合物的量足以明显改善病情，而不至于产生严重的副作用。通常，药物组合物含有1-2000mg本发明化合物/剂，更佳地，含有5-200mg本发明化合物/剂。较佳地，所述的“一剂”为一个胶囊或药片。
“药学上可以接受的载体”指的是：一种或多种相容性固体或液体填料或凝胶物质，它们适合于人使用，而且必须有足够的纯度和足够低的毒性。“相容性”在此指的是组合物中各组份能和本发明的化合物以及它们之间相互掺和，而不明显降低化合物的药效。药学上可以接受的载体部分例子有纤维素及其衍生物(如羧甲基纤维素钠、乙基纤维素钠、纤维素乙酸酯等)、明胶、滑石、固体润滑剂(如硬脂酸、硬脂酸镁)、硫酸钙、植物油(如豆油、芝麻油、花生油、橄榄油等)、多元醇(如丙二醇、甘油、甘露醇、山梨醇等)、乳化剂(如吐温
Figure PCTCN2021091148-appb-000030
)、润湿剂(如十二烷基硫酸钠)、着色剂、调味剂、稳定剂、抗氧化剂、防腐剂、无热原水等。
本发明化合物或药物组合物的施用方式没有特别限制，代表性的施用方式包括(但并不限于)：口服、瘤内、直肠、肠胃外(静脉内、肌肉内或皮下)、和局部给药。
用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。在这些固体剂型中，活性化合物与至少一种常规惰性赋形剂(或载体)混合，如柠檬酸钠或磷酸二钙，或与下述成分混合：(a)填料或增容剂，例如，淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸；(b)粘合剂，例如，羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和阿拉伯胶；(c)保湿剂，例如，甘油；(d)崩解剂，例如，琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐、和碳酸钠；(e)缓溶剂，例如石蜡；(f)吸收加速剂，例如，季胺化合物；(g)润湿剂，例如鲸蜡醇和单硬脂酸甘油酯；(h)吸附剂，例如，高岭土；和(i)润滑剂，例如，滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠，或其混合物。胶囊剂、片剂和丸剂中，剂型也可包含缓冲剂。
固体剂型如片剂、糖丸、胶囊剂、丸剂和颗粒剂可采用包衣和壳材制备，如肠衣和其它本领域公知的材料。它们可包含不透明剂，并且，这种组合物中活性化合物或化合物的释放可以延迟的方式在消化道内的某一部分中释放。可采用的包埋组分的实例是聚合物质和蜡类物质。必要时，活性化合物也可与上述赋形剂中的一种或多种形成微胶囊形式。
用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂。除了活性化合物外，液体剂型可包含本领域中常规采用的惰性稀释剂，如水或其它溶剂，增溶剂和乳化剂，例知，乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇、二甲基甲酰胺以及油，特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油或这些物质的混合物等。
除了这些惰性稀释剂外，组合物也可包含助剂，如润湿剂、乳化剂和悬浮剂、甜味剂、矫味剂和香料。
除了活性化合物外，悬浮液可包含悬浮剂，例如，乙氧基化异十八烷醇、聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、甲醇铝和琼脂或这些物质的混合物等。
用于肠胃外注射的组合物可包含生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液，和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的含水和非水载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合物。
用于局部给药的本发明化合物的剂型包括软膏剂、散剂、贴剂、喷射剂和吸入剂。活性成分在无菌条件下与生理上可接受的载体及任何防腐剂、缓冲剂，或必要时可能需要的推进剂一起混合。
本发明化合物可以单独给药，或者与其他药学上可接受的化合物联合给药。
使用药物组合物时，是将安全有效量的本发明化合物适用于需要治疗的哺乳动物(如人)，其中施用时剂量为药学上认为的有效给药剂量，对于60kg体重的人而言，日给药剂量通常为1～2000mg，优选5～500mg。当然，具体剂量还应考虑给药途径、病人健康状况等因素，这些都是熟练医师技能范围之内的。
本发明的主要优点包括：
1.提供了一种如式(I)所示的化合物。
2.提供了一种结构新颖的SYK、JAK1、JAK2、JAK3、TYK2等蛋白激酶的抑制剂，及其制备和应用，所述的抑制剂在极低浓度下即可抑制上述蛋白激酶的活性。
3.提供了一类治疗与SYK、JAK1、JAK2、JAK3、TYK2等，等蛋白激酶活性相关疾病的药物组合物。
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件，或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数按重量计算。
实施例1:化合物1R的制备
Figure PCTCN2021091148-appb-000031
化合物1R-a是根据专利WO2018108084里的实验步骤制备的。室温下向甲醇(10mL)中加入化合物1R-a(200mg,0.85mmol)和钯碳催化剂(10％,50mg)，该反应 混合物在室温和1大气压的氢气氛围下反应过夜。TLC监测反应完成。反应混合物经过硅藻土过滤，滤液经减压浓缩。所得粗品经硅胶柱层析(DCM:MeOH＝60:1)分离纯化得棕色固体化合物1R-b(150mg,收率86％)。
将化合物1R-b(100mg,0.48mmol)溶于乙腈(10mL)中，然后在冰浴下依次加入2,4-二氯-6-甲基嘧啶-5-羧酸甲酯(1R-c,118mg,0.54mmol)和二异丙基乙基胺(125mg,0.97mmol)。反应混合物缓慢升至室温反应3小时。TLC监测反应完毕。反应液减压浓缩。所得粗品经硅胶柱层析(二氯甲烷:乙酸乙酯＝50:1)分离纯化得淡黄色固体化合物1R-d(145mg,收率76％)。
将化合物1R-d(145mg,0.37mmol)溶于乙腈(10mL)中，然后依次加入2-(哌啶-4-基)乙腈盐酸盐(1R-e,72mg,0.45mmol)和二异丙基乙基胺(144mg,1.11mmol)。反应混合物在60℃下搅拌3小时。TLC监测反应完毕。反应混合物减压浓缩。所得粗品经硅胶柱层析(二氯甲烷:乙酸乙酯＝30:1)分离纯化得淡黄色固体化合物1R-f(136mg,收率77％)。
将化合物1R-f(60mg,0.13mmol)溶于DMF(5mL)中，然后加入DMF-DMA(0.2mL)。反应混合物在130℃下搅拌过夜。TLC监测反应完毕。将反应液倒入适量的饱和氯化钠溶液中，再用乙酸乙酯萃取(3 x 30mL)。合并的有机相用无水硫酸钠干燥。过滤除去干燥剂，所得滤液经减压浓缩后得粗品化合物1R-g(不经纯化直接用于下步反应)。
将粗品化合物1R-g(67mg,0.13mmol)溶于甲醇(5mL)中，冰浴下分批加入高碘酸钠(134mg,0.63mmol)。反应混合物升至室温搅拌3小时。TLC监测反应完毕。将反应液过滤，所得到的滤液减压浓缩得粗品化合物1R-h(不经纯化直接用于下步反应)。
将粗品化合物1R-h(62mg，0.13mmol)溶于乙醇(5mL)中，然后加入水合肼(16mg，0.26mmol)。反应混合物在80℃下搅拌3小时。TLC监测反应完毕。将反应液过滤得滤饼，滤饼再经制备型薄板层析分离纯化得黄色固体化合物1R(2.2mg,收率3.7％)。 1H NMR(500MHz,DMSO-d 6)δ12.76(s,1H),11.15(s,1H),7.88(s,1H),7.28(d,J＝2.3Hz,1H),7.06(dd,J＝8.7,2.4Hz,1H),6.89(d,J＝8.9Hz,1H),4.85-4.62(br.,2H),4.24(dd,J＝10.6,2.6Hz,1H),3.97(dd,J＝11.0,3.2Hz,1H),3.90-3.84(m,2H),3.68-3.55(m,2H),3.18(t,J＝10.7Hz,1H),3.14-3.07(m,1H),3.03-2.98(m,2H),2.71-2.65(m,1H),2.55(d,J＝6.7Hz,2H),2.01-1.93(m,1H),1.82(d,J＝11.4Hz,2H),1.28-1.20(m,2H).
实施例2:化合物2R的制备
Figure PCTCN2021091148-appb-000032
化合物2R-a是根据专利WO2018108084里的实验步骤制备的。将化合物2R-a(2.0g,5.96mmol)溶于二氯甲烷(15mL)中，冰浴下加入盐酸二氧六环溶液(4M,2mL)。反应混合物升至室温搅拌过夜。TLC监测反应完毕。将反应液减压浓缩得黄色固体化合物2R-b(1.32g,收率81％)。
将化合物2R-b(80mg,0.34mmol)溶于二氯甲烷(10mL)中，冰浴下依次加入甲基磺酰氯(2R-c,58mg,0.51mmol)和三乙胺(103mg,1.02mmol)。反应混合物升至室温搅拌2小时。TLC监测反应完毕。向反应液中加入水(30mL)，再用二氯甲烷萃取(3 x 30mL)。合并的有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤后滤液减压浓缩。所得粗品经硅胶柱层析(二氯甲烷：乙酸乙酯＝10:1)分离纯化得黄色固体化合物2R-d(75mg,收率70％)。
化合物2R-i是从2R-d出发根据化合物1R-h的制备步骤合成得到的。
将化合物2R-i(60mg,0.11mmol)溶于乙醇(5mL)中，然后加入水合肼(20mg,0.32mmol)。反应混合物在80℃下搅拌3小时。TLC监测反应完毕。将反应液过滤得滤饼，滤饼再经制备型薄板层析分离纯化得黄色固体化合物2R(3.0mg,收率5.2％)。MS m/z 552.4[M+H] +。
实施例3:化合物3R的制备
Figure PCTCN2021091148-appb-000033
化合物3R-b是从2R-b出发根据化合物2R-d的制备步骤合成得到的。
化合物3R-g是从3R-b出发根据化合物1R-h的制备步骤合成得到的。
将化合物3R-g(50mg,0.09mmol)溶于乙醇(5mL)中，然后加入水合肼(16mg，0.26mmol)。反应混合物在80℃下搅拌3小时。TLC监测反应完毕。将反应液过滤得滤饼，滤饼再经制备型薄板层析分离纯化得黄色固体化合物3R(5.0mg,收率10％)。MS m/z 566.7[M+H] +。
实施例4:化合物4R的制备
Figure PCTCN2021091148-appb-000034
化合物4R-b是从2R-b出发根据化合物2R-d的制备步骤合成得到的。
化合物4R-g是从4R-b出发根据化合物1R-h的制备步骤合成得到的。
将化合物4R-g(52mg,0.09mmol)溶于乙醇(5mL)中，然后加入水合肼(16mg，0.26mmol)。反应混合物在80℃下搅拌3小时。TLC监测反应完毕。将反应液过滤得 滤饼，滤饼再经制备型薄板层析分离纯化得黄色固体化合物4R(5.1mg,收率10％)。MS m/z 578.7[M+H] +。
实施例5:化合物5R的制备
Figure PCTCN2021091148-appb-000035
将化合物2R-b(100mg,0.43mmol)溶于二氯甲烷(10mL)中，冰浴下加入醋酸酐(5R-a,87mg,0.85mmol)。反应混合物升至室温搅拌过夜。TLC监测反应完毕。向反应液中加入适量饱和碳酸氢钠水溶液，用二氯甲烷萃取(3 x 30mL)。合并的有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤后滤液减压浓缩。所得粗品经硅胶柱层析(二氯甲烷：乙酸乙酯＝20:1)分离纯化得黄色固体化合物5R-b(73mg,收率73％)。
化合物5R-g是从5R-b出发根据化合物1R-h的制备步骤合成得到的。
将化合物5R-g(50mg,0.09mmol)溶于乙醇(5mL)中，然后加入水合肼(18mg，0.28mmol)。反应混合物在80℃下搅拌3小时。TLC监测反应完毕。将反应液过滤得滤饼，滤饼再经制备型薄板层析分离纯化得黄色固体化合物5R(2.1mg,收率4.3％)。MS m/z 516.4[M+H] +。
实施例6:化合物6R的制备
Figure PCTCN2021091148-appb-000036
将化合物2R-b(100mg,0.37mmol)溶于二氯乙烷(10mL)中，加入37％甲醛水溶液(1mL)，再加入2滴醋酸，室温下搅拌30分钟。然后加入氰基硼氢化钠(58mg,0.92mmol)，室温下搅拌3小时。TLC监测反应完毕。反应混合物在减压条件下浓缩。所得粗品经硅胶柱层析(二氯甲烷:甲醇＝60:1)分离纯化得黄色固体6R-a(82mg,收率89％)。
化合物6R-f是从6R-a出发根据化合物1R-h的制备步骤合成得到的。
将化合物6h(50mg，0.01mmol)溶于乙醇(5mL)中，然后加入水合肼(19mg，0.30mmol)。反应混合物在80℃下搅拌3小时。TLC监测反应完毕。将反应液过滤得滤饼，滤饼用乙腈打浆，过滤得黄色固体化合物6R(11.0mg,收率23％)。 1H NMR(500MHz,DMSO-d 6)δ12.75(s,1H),11.13(s,1H),7.87(s,1H),7.26(s,1H),7.04(dd,J＝8.6,1.9Hz,1H),6.88(d,J＝8.8Hz,1H),4.85-4.62(br.,2H),4.25(dd,J＝10.6,2.2Hz,1H),3.95-3.88(m,1H),3.69(d,J＝11.4Hz,1H),3.08-2.94(m,3H),2.86(d,J＝10.8Hz,1H),2.79(d,J＝10.2Hz,1H),2.68-2.58(m,1H),2.54(d,J＝6.7Hz,2H),2.22(s,3H),2.13-2.03(m,1H),2.02-1.94(m,1H),1.82(d,J＝11.8Hz,2H),1.69(t,J＝10.6Hz,1H),1.28-1.20(m,2H)。MS m/z 488.6[M+H] +。
实施例7:化合物6S的制备
Figure PCTCN2021091148-appb-000037
化合物6S-b是从6S-a出发根据化合物2R-b的制备步骤合成得到的。
化合物6S-c是从6S-b出发根据化合物6R-a的制备步骤合成得到的。
化合物6S-h是从6S-c出发根据化合物1R-h的制备步骤合成得到的。
将化合物6S-h(55mg，0.11mmol)溶于乙醇(5mL)中，然后加入水合肼(21mg，0.33mmol)。反应混合物在80℃下搅拌3小时。TLC监测反应完毕。将反应液过滤得滤饼，滤饼用乙腈打浆，过滤得黄色固体化合物6S(13.0mg,收率24％)。 1H NMR(500MHz,DMSO-d 6)δ12.75(br.s,1H),11.13(s,1H),7.87(s,1H),7.26(d,J＝2.3Hz,1H),7.04(dd,J＝8.7,2.4Hz,1H),6.88(d,J＝8.9Hz,1H),4.85-4.62(br.,2H),4.25(dd,J＝10.6,2.7Hz,1H),3.95-3.88(m,1H),3.69(d,J＝11.5Hz,1H),3.07-2.94(m,3H),2.86(d,J＝10.2Hz,1H),2.79(d,J＝10.2Hz,1H),2.68-2.58(m,1H),2.54(d,J＝6.7Hz,2H),2.22(s,3H),2.12-2.04(m,1H),2.03-1.94(m,1H),1.82(d,J＝10.7Hz,2H),1.69(t,J＝10.6Hz,1H),1.28-1.20(m,2H)。MS m/z 488.6[M+H] +。
实施例8:化合物7R的制备
Figure PCTCN2021091148-appb-000038
向化合物2R-b(150mg,0.55mmol)的二氯乙烷(10mL)溶液中依次加入7R-a(111mg,1.10mmol)和2滴醋酸。反应混合物在室温下搅拌30分钟。然后加入氰基硼氢化钠(87mg,1.38mmol)。反应混合物在室温下搅拌3小时。TLC监测反应完毕。反应液在减压条件下浓缩。所得粗品经硅胶柱层析(二氯甲烷:甲醇＝60:1)分离纯化得黄色固体7R-b(130mg,收率74％)。 1H NMR(500MHz,CDCl 3)δ6.61(d,J＝8.5Hz,1H),6.28-6.18(m,2H),4.14(dd,J＝10.5,2.6Hz,1H),4.10-3.91(m,3H),3.60(d,J＝11.6Hz,1H),3.45-3.32(m,2H),3.11-3.00(m,2H),2.89(d,J＝10.5Hz,1H),2.79-2.70(m,1H),2.57-2.42(m,2H),2.04(t,J＝10.5Hz,1H),1.79(d,J＝12.3Hz,2H),1.66-1.54(m,2H)。
化合物7R-g是从7R-b出发根据化合物1R-h的制备步骤合成得到的。
将化合物7R-g(126mg，0.22mmol)溶于乙醇(8mL)中，然后加水合肼(41mg，0.66mmol)。反应混合物在80℃下搅拌3小时。TLC监测反应完毕。将反应液过滤得滤饼，滤饼用乙腈打浆，过滤得黄色固体化合物7R(57.5mg,收率47％)。 1H NMR(500MHz,DMSO-d 6)δ12.74(bs,1H),11.14(s,1H),7.87(s,1H),7.25(d,J＝1.9Hz,1H),7.04(dd,J＝8.7,2.1Hz,1H),6.87(d,J＝8.9Hz,1H),4.85-4.62(br.,2H),4.27(dd,J＝10.5,2.1Hz,1H),4.33-4.21(m,3H),3.72(d,J＝11.3Hz,1H),3.27(d,J＝11.5Hz,2H),3.05-2.90(m,5H),2.66-2.53(m,3H),2.43(t,J＝11.3Hz,1H),2.34-2.24(m,1H),2.02-1.94(m,1H),1.91-1.79(m,3H),1.73(d,J＝12.1Hz,2H),1.49-1.37(m,2H),1.28-1.20(m,2H)。MS m/z 558.8[M+H] +。
实施例9:化合物8R的制备
Figure PCTCN2021091148-appb-000039
将化合物2R-b(150mg，0.55mmol)溶于DMF(6mL)中，然后依次加入碘化钠(17mg,0.11mmol)，碳酸钾(229mg，1.66mmol)和2-溴乙醇(8R-a,103mg,0.83mmol)。反应混合物在50℃下搅拌过夜。TLC监测反应完毕。向反应混合物中加水(30mL)，用乙酸乙酯萃取(3 x 30mL)。合并的有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤后滤液在减压条件下浓缩。所得粗品经硅胶柱层析(二氯甲烷：乙酸乙酯＝3:1)分离纯化得黄色固体化合物8R-b(130mg,收率84％)。
化合物8R-g是从8R-b出发根据化合物1R-h的制备步骤合成得到的。
将化合物8R-g(110mg，0.21mmol)溶于乙醇(8mL)中，然后加水合肼(39mg，0.62mmol)。反应混合物在80℃下搅拌3小时。TLC监测反应完毕。将反应液过滤得滤饼，滤饼用乙腈打浆，过滤得黄色固体化合物8R(38.0mg,收率36％)。 1H NMR(500MHz,DMSO-d 6)δ12.75(s,1H),11.14(s,1H),7.87(s,1H),7.26(s,1H),7.04(d,J＝8.0Hz,1H),6.88(d,J＝8.7Hz,1H),4.85-4.62(br.,2H),4.46(s,1H),4.25(d,J＝9.5Hz,1H),3.91(t,J＝9.7Hz,1H),3.68(d,J＝11.1Hz,1H),3.60-3.50(m,2H),3.06-2.95(m,4H),2.92(d,J＝10.3Hz,1H),2.66-2.58(m,1H),2.55(d,J＝6.4Hz,2H),2.48-2.40(m,2H),2.18(t,J＝10.6Hz,1H),2.02-1.94(m,1H),1.85-1.78(m,3H),1.28-1.20(m,2H)。MS m/z 518.7[M+H] +。
实施例10:化合物9R的制备
Figure PCTCN2021091148-appb-000040
将化合物9R-a(1.04g，1.81mmol，采用化合物5R的制备步骤合成得到)溶于二氯甲烷/甲醇(v/v＝20/20mL)中，冰浴下滴加HCl的1,4-二氧六环溶液(4.0M，2mL)。反应混合物于室温下搅拌过夜。TLC监测反应完毕。反应液减压除去溶剂，加入二氯甲烷(20mL)和饱和碳酸氢钠水溶液(20mL)，室温搅拌0.5h，再用二氯甲烷萃取(3 x 20mL)。合并的有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤后减压浓缩。所得粗品经硅胶柱层析(二氯甲烷：甲醇＝10:1)分离纯化得到黄色固体化合物9R(825mg，收率96％)。 1H NMR(500MHz,DMSO-d 6)δ12.75(bs,1H),11.12(s,1H),7.86(s,1H),7.23(d,J＝2.5Hz,1H),7.03(dd,J＝8.7,2.5Hz,1H),6.84(d,J＝8.9Hz,1H),4.85-4.62(br.,2H),4.22(dd,J＝10.6,2.6Hz,1H),3.92-3.84(m,1H),3.63-3.57(m,1H),3.05-2.88(m,5H),2.77-2.70(m,1H),2.54(d,J＝6.6Hz,2H),2.53-2.51(m,1H),2.30(t,J＝11.7Hz,1H),2.03-1.92(m,1H),1.85-1.78(m,2H),1.25-1.19(m,2H)。MS m/z474.7[M+H] +。
实施例11:化合物10R的制备
Figure PCTCN2021091148-appb-000041
室温下向甲醇(2mL)中加入化合物9R(60mg，0.13mmol)，N-甲基-4-哌啶酮(10R-a,43mg，0.38mmol)和钯碳催化剂(10％，10mg)。该反应混合物在室温和1大气压的氢气氛围下搅拌过夜。TLC监测反应完成。反应混合物经过硅藻土过滤，滤液经减压浓缩除去溶剂。所得粗品经制备型薄板层析(二氯甲烷：甲醇＝10:1)分离纯化得黄色固体化合物10R(14mg，收率19％)。 1H NMR(500MHz,DMSO-d 6)δ12.75(s,1H),11.14(s,1H),7.87(s,1H),7.25(d,J＝2.4Hz,1H),7.03(dd,J＝8.9,2.4Hz,1H),6.87(d,J＝9.0Hz,1H),4.85-4.62(br.,2H),4.26(dd,J＝10.5,2.6Hz,1H),3.95-3.88(m,1H),3.75-3.65(m,1H),3.07-2.79(m,7H),2.61-2.56(m,1H),2.54(d,J＝6.6Hz,2H),2.53-2.51(m,1H),2.32-2.26(m,1H),2.25-2.15(m,4H),2.02-1.94(m,2H),1.88(t,J＝10.4Hz,1H),1.85-1.79(m,2H),1.79-1.73(m,2H),1.52-1.40(m,2H),1.28-1.22(m,2H)。MS m/z 571.8[M+H] +。
实施例12:化合物11R的制备
Figure PCTCN2021091148-appb-000042
将化合物9R(60mg，0.13mmol)溶于DMF(1mL)中，加入二异丙基乙基胺(33mg，0.25mmol)，再在0℃下滴加丙烯酰氯(11R-a,14mg，0.16mmol)。滴加完毕后，反应液在0℃下搅拌1小时。TLC监测反应完毕。向反应液中加入水(5mL)，以二氯甲烷萃取(3 x 10mL)。合并的有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤后减压浓缩。所得粗品经制备型薄板层析(二氯甲烷：甲醇＝10:1)分离纯化得到黄色固体化合物11R(33mg，收率49％)。 1H NMR(500MHz,DMSO-d 6)δ12.75(s,1H),11.14(s,1H),7.86(s,1H),7.28(d,J＝11.2Hz,1H),7.06(t,J＝9.2Hz,1H),6.93(d,J＝8.9Hz,1H),6.91-6.84(m,1H),6.16(dd,J＝16.7,2.3Hz,1H),5.73(dd,J＝10.4,2.3Hz,1H),4.85-4.62(br.,2H),4.55-4.45(m,1H),4.37(t,J＝13.1Hz,1H),4.25-4.14(m,1H),4.00-3.92(m,1H),3.88-3.79(m,1H),3.31-3.22(m,1H),3.06-2.93(m,3H),2.92-2.82(m,1H),2.65-2.57(m,1H),2.55(d,J＝6.6Hz,2H),2.01-1.92(m,1H),1.82(d,J＝12.7Hz,2H),1.27-1.20(m,2H)。MS m/z 528.5[M+H] +。
实施例13:化合物12R的制备
Figure PCTCN2021091148-appb-000043
将化合物9R(60mg，0.13mmol)，2-丁炔酸(12R-a,11mg，0.13mmol)，N-甲基咪唑(36mg，0.44mmol)溶于乙腈(1mL)中，再加入四甲基氯代脲六氟磷酸酯(43mg，0.15mmol)。反应混合物于室温下搅拌3小时。TLC监测反应完毕。向反应混合物中加入水(5mL)，用二氯甲烷萃取(3 x 10mL)。合并的有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤后减压浓缩。所得粗品经制备型薄板层析(二氯甲烷：甲醇＝10:1)分离纯化得到黄色固体化合物12R(28mg，收率41％)。 1H NMR(500MHz,DMSO-d 6)δ12.75(s,1H),11.14(s,1H),7.87(s,1H),7.29(dd,J＝10.0,2.5Hz,1H),7.10-7.03(m,1H),6.94(d,J＝8.5Hz,1H),4.85-4.62(br.,2H),4.43-4.26(m,3H),4.00-3.92(m,1H),3.92-3.83(m,1H),3.30-2.93(m,4H),2.91-2.59(m,1H),2.58-2.52(m,3H),2.06(d,J＝2.3Hz,3H),2.02-1.94(m,1H),1.85-1.79(m,2H),1.26-1.22(m,2H)。MS m/z 540.5[M+H] +。
实施例14:化合物13R的制备
Figure PCTCN2021091148-appb-000044
将化合物9R(60mg，0.13mmol)，碘乙烷(13R-a,20mg，0.13mmol)溶于DMF(2mL)中，再加入无水碳酸钾(36mg，0.26mmol)。反应混合物在90℃下搅拌过夜。TLC监测反应完毕。向反应混合物中加入水(5mL)，用二氯甲烷萃取(3 x 10mL)。合并的有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤后减压浓缩。所得粗品经制备型薄板层析(二氯甲烷：甲醇＝10:1)分离纯化得到黄色固体化合物13R(25mg，收率39％)。 1H NMR(500MHz,DMSO-d 6)δ12.75(s,1H),11.14(s,1H),7.87(s,1H),7.26(d,J＝2.4Hz,1H),7.04(dd,J＝8.8,2.5Hz,1H),6.87(d,J＝9.0Hz,1H),4.85-4.60(br.,2H),4.27(dd,J＝10.7,2.7Hz,1H),3.95-3.86(m,1H),3.73-3.66(m,1H),3.05-2.94(m,4H),2.90(d,J＝10.1Hz,1H),2.64-2.59(m,1H),2.54(d,J＝6.6Hz,2H),2.42-2.33(m,2H),2.11-2.04(m,1H),2.02-1.92(m,1H),1.85-1.79(m,2H),1.67(t,J＝10.8Hz,1H),1.29-1.20(m,2H),1.03(t,J＝7.2Hz,3H)。MS m/z 502.5[M+H] +。
实施例15:化合物14R的制备
Figure PCTCN2021091148-appb-000045
将化合物9R(60mg，0.13mmol)，溴乙腈(14R-a,15mg，0.13mmol)溶于DMF(1mL)中，再加入碳酸钾(35mg，0.25mmol)。反应混合物在室温下搅拌4小时。TLC监测反应完毕。向反应混合物中加入水(5mL)，再用二氯甲烷萃取(3 x 10mL)。合并的有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤后减压浓缩。所得粗品经制备型薄板层析(二氯甲烷：甲醇＝10:1)分离纯化得到黄色固体化合物14R(26mg，收率39％)。 1H NMR(500MHz,CDCl 3)δ10.81(s,1H),9.73(s,1H),7.82(s,1H),7.35(d,J＝2.5Hz,1H),7.09(dd,J＝8.8,2.5Hz,1H),6.77(d,J＝8.8Hz,1H),5.00-4.93(br.,2H),4.21(dd,J＝10.6,2.7Hz,1H),4.09-4.01(m,1H),3.76-3.71(m,1H),3.60(s,2H),3.26-3.19(m,1H),2.99-2.88(m,3H),2.88-2.81(m,1H),2.80-2.76(m,1H),2.70-2.65(m,1H),2.35(d,J＝6.7Hz,2H),2.27(t,J＝10.5Hz,1H),2.05-1.92(m,3H),1.37-1.32(m,2H)。MS  m/z 513.5[M+H] +。
实施例16:化合物15R的制备
Figure PCTCN2021091148-appb-000046
将化合物9R(60mg，0.13mmol)，2-氯乙基甲基醚(15R-a,15mg，0.13mmol)溶于DMF(2mL)中，再加入二异丙基乙基胺(50mg，0.39mmol)。反应混合物在90℃下搅拌过夜。TLC监测反应完毕。向反应混合物中加入水(5mL)，再用二氯甲烷萃取(3 x10mL)。合并的有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤后减压浓缩。所得粗品经制备型薄板层析(二氯甲烷：甲醇＝10:1)纯化得到黄色固体化合物15R(13mg，收率19％)。 1H NMR(500MHz,DMSO-d 6)δ12.75(s,1H),11.14(s,1H),7.87(s,1H),7.26(d,J＝2.6Hz,1H),7.04(dd,J＝8.9,2.4Hz,1H),6.87(d,J＝9.2Hz,1H),4.85-4.60(br.,2H),4.25(dd,J＝10.5,2.7Hz,1H),3.96-3.88(m,1H),3.71-3.66(m,1H),3.47(t,J＝5.8Hz,2H),3.25(s,3H),3.05-2.95(m,4H),2.94-2.88(m,1H),2.65-2.58(m,1H),2.57-2.52(m,4H),2.23-2.17(m,1H),2.03-1.93(m,1H),1.86-1.77(m,3H),1.28-1.22(m,2H)。MS m/z 532.6[M+H] +。
实施例17:化合物16R的制备
Figure PCTCN2021091148-appb-000047
将化合物9R(100mg，0.21mmol)，2,2,2-三氟乙基三氟甲烷磺酸酯(16R-a,49mg，0.21mmol)溶于DMF(3mL)中，再加入二异丙基乙基胺(81mg,0.63mmol)。反应混合物在60℃下搅拌2小时。TLC监测反应完毕。向反应混合物中加入水(5mL)，再用二氯甲烷萃取(3 x 10mL)。合并的有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤后减压浓缩。所得粗品经制备型薄板层析(二氯甲烷：甲醇＝20:1)分离纯化得到黄色固体化合物16R(42mg，收率36％)。 1H NMR(500MHz,DMSO-d 6)δ12.75(s,1H),11.14(s,1H),7.87(s,1H),7.27(s,1H),7.04(d,J＝8.7Hz,1H),6.89(d,J＝8.8Hz,1H),4.85-4.60(br.,2H),4.30-4.23(m,1H),3.95-3.87(m,1H),3.75-3.68(m,1H),3.27(q,J＝10.3Hz,2H),3.10-2.93(m,5H),2.69-2.61(m,1H),2.61-2.56(m,1H),2.54(d,J＝6.7Hz, 2H),2.18(t,J＝11.0Hz,1H),2.03-1.93(m,1H),1.86-1.78(m,2H),1.29-1.17(m,2H)。MS m/z 556.5[M+H] +。
实施例18:化合物17R的制备
Figure PCTCN2021091148-appb-000048
将化合物9R(60mg，0.13mmol)，3-溴吡啶(17R-a,23mg，0.14mmol)，叔丁醇钠(24mg，0.23mmol)，Pd 2(dba) 3(12mg，0.013mmol)和BINAP(16mg，0.026mmol)溶于甲苯(2mL)中。反应混合物在110℃和氮气氛围下搅拌过夜。TLC监测反应完毕。待反应混合物冷却至室温，加入水(5mL)，用乙酸乙酯萃取(3 x 10mL)。合并的有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤后减压浓缩。所得粗品经制备型薄板层析(二氯甲烷：甲醇＝10:1)分离纯化得到黄色固体化合物17R(16mg，收率23％)。 1H NMR(500MHz,CDCl 3)δ10.85(s,1H),10.35(s,1H),8.38(s,1H),8.17(d,J＝3.5Hz,1H),7.83(s,1H),7.38(d,J＝2.5Hz,1H),7.29-7.25(m,1H),7.24-7.19(m,1H),7.12(dd,J＝8.7,2.5Hz,1H),6.83(d,J＝8.8Hz,1H),5.05-4.85(br.,2H),4.31(dd,J＝10.6,2.7Hz,1H),4.15-4.09(m,1H),3.88-3.80(m,1H),3.78-3.72(m,1H),3.63-3.56(m,1H),3.38-3.30(m,1H),3.09-2.88(m,4H),2.66(t,J＝11.1Hz,1H),2.35(d,J＝6.7Hz,2H),2.06-1.90(m,3H),1.41-1.30(m,2H)。MS m/z 551.6[M+H] +。
实施例19:化合物18R的制备
Figure PCTCN2021091148-appb-000049
将化合物18R-a(400mg,0.82mmol)溶于乙腈(5mL)中，然后依次加入六亚甲基亚胺(18R-b,81mg,0.82mmol)和二异丙基乙基胺(317mg,2.46mmol)。反应混合物在60℃下搅拌3小时。TLC监测反应完毕。反应混合物减压浓缩。所得粗品经硅胶柱层析(二氯甲烷:甲醇＝30:1)分离纯化得淡黄色固体化合物18R-c(326mg,收率72％)。
将化合物18R-c(300mg,0.54mmol)溶于DMF(10mL)中，然后加入DMF-DMA(2mL)。反应混合物在130℃下搅拌过夜。TLC监测反应完毕。将反应液减压浓缩后得粗品化合物18R-d(不经纯化直接用于下步反应)。
将粗品化合物18R-d(329mg,0.54mmol)溶于甲醇(5mL)中，冰浴下分批加入高碘酸钠(347mg,1.62mmol)。反应混合物升至室温搅拌3小时。TLC监测反应完毕。将反应液过滤，所得到的滤液减压浓缩得粗品化合物18R-e(不经纯化直接用于下步反应)。
将粗品化合物18R-e(306mg，0.54mmol)溶于乙醇(5mL)中，然后加入水合肼(68mg，1.08mmol)。反应混合物在80℃下搅拌3小时。TLC监测反应完毕。将反应液减压蒸馏，所得粗品经制备型薄板层析分离纯化得黄色固体化合物18R-f(56mg,收率19％)。
将化合物18R-f(56mg,0.10mmol)溶于甲醇(5mL)中，再加入HCl的二氧六环溶液(4.0M,1mL)。反应混合物在40℃下搅拌3小时。TLC监测反应完毕。反应混合物冷却至室温后减压浓缩。将所得混合物溶于少量甲醇中，用氨水将pH值调至7～8，再减压浓缩。所得粗品经制备型薄板层析(二氯甲烷：甲醇＝20:1,2％氨水)分离纯化得到淡黄色固体化合物18R-g(44mg,收率98％)。MS m/z 449.2[M+H] +。
将化合物18R-g(20mg,0.04mmol)，多聚甲醛(3mg,0.09mmol)，无水氯化锌(19mg,0.14mmol)溶于甲醇(3mL)中，再加入氰基硼氢化钠(9mg,0.14mmol)。将反应混合物加热至60℃搅拌1小时。TLC监测反应完毕。反应混合物冷却至室温后减压浓缩。所得粗品经制备型薄板层析(二氯甲烷:甲醇＝20:1,2％氨水)分离纯化得到黄色固体化合物18R(14mg,收率68％)。 1H NMR(500MHz,CDCl 3)δ10.81(s,1H),9.66(s,1H),7.81(s,1H),7.47(d,J＝1.8Hz,1H),7.14(dd,J＝8.7,2.0Hz,1H),6.75(d,J＝8.8Hz,1H),4.23-4.16(m,1H),4.05-3.99(m,1H),3.89-3.77(m,4H),3.69-3.63(m,1H),3.25-3.16(m,1H),2.99-2.92(m,1H),2.89-2.77(m,2H),2.36(s,3H),2.43-2.19(m,1H),1.89-1.79(m,5H),1.62-1.55(m,4H)。MS m/z 463.5[M+H] +。
实施例20:化合物19R的制备
Figure PCTCN2021091148-appb-000050
化合物18R-g(23mg,0.05mmol)和2-溴乙醇(8R-a,6mg,0.05mmol)溶于DMF(2mL)中，再加入碳酸钾(21mg,0.15mmol)。反应混合液在60℃下加热搅拌过夜。TLC监测反应完毕。将反应混合物过滤，滤液减压浓缩，所得粗品经制备型薄板层析(二氯甲烷:甲醇＝20:1,2％氨水)分离纯化得到黄色固体化合物19R(10mg,收率40％)。 1H NMR(500MHz,CDCl 3)δ11.04(s,1H),7.86(s,1H),7.47(d,J＝2.3Hz,1H),7.13(dd,J＝8.8,2.2Hz,1H),6.74(d,J＝8.8Hz,1H),4.34(t,2H),4.17(dd,J＝10.5,2.5Hz,1H),4.05-3.96(m,3H),3.88-3.76(m,4H),3.66-3.61(m,1H),3.19-3.13(m,1H),3.09-2.94(m,3H),2.71-2.64(m,1H),2.53(t,J＝11.1Hz,1H),1.90-1.77(m,4H),1.59-1.54(m,4H)。MS m/z 493.4[M+H] +。
实施例21:化合物20R的制备
Figure PCTCN2021091148-appb-000051
将化合物20R-a(200mg,1.13mmol)溶于DMSO(5mL)中，然后依次加入化合物(R)-1-Boc-3-羟甲基哌嗪(20R-b,244mg,1.13mmol)和氢氧化钾(190mg,3.39mmol)。反应混合物室温搅拌1小时，再加热至60℃搅拌2小时。TLC监测反应完毕。将反应液倒入适量的饱和氯化钠溶液中，再用乙酸乙酯萃取(3 x 30mL)。合并的有机相用无水硫酸钠干燥，过滤后减压浓缩。所得粗品经硅胶柱层析(二氯甲烷)分离纯化得淡黄色固体化合物20R-c(316mg,收率79％)。
室温下向甲醇(10mL)中加入化合物20R-c(300mg,0.42mmol)和钯碳催化剂(10％,40mg)，该反应混合物在40℃和1大气压的氢气氛围下搅拌0.5小时。TLC监测反应完毕。反应混合物经过硅藻土过滤，所得滤液经减压浓缩得到粗品。该粗品 经硅胶柱层析(二氯甲烷:甲醇＝30:1)分离纯化得淡黄色固体化合物20R-d(180mg,收率62％)。
将化合物20R-d(180mg,0.56mmol)溶于乙腈(5mL)中，然后依次加入2,4-二氯-6-甲基嘧啶-5-羧酸甲酯(1R-c,123mg,0.56mmol)和二异丙基乙基胺(217mg,1.68mmol)。反应混合物在60℃下搅拌过夜。TLC监测反应完毕。反应液减压浓缩。所得粗品经硅胶柱层析(二氯甲烷:甲醇＝50:1)分离纯化得淡黄色固体化合物20R-e(164mg,收率58％)。
将化合物20R-e(164mg,0.32mmol)溶于乙腈(5mL)中，然后依次加入2-(哌啶-4-基)乙腈盐酸盐(1R-e,51mg,0.32mmol)和二异丙基乙基胺(124mg,0.96mmol)。反应混合物在60℃下搅拌1小时。TLC监测反应完毕。反应混合物减压浓缩。所得粗品经硅胶柱层析(二氯甲烷:甲醇＝30:1)分离纯化得淡黄色固体化合物20R-f(160mg,收率83％)。
将化合物20R-f(160mg,0.27mmol)溶于DMF(3mL)中，然后加入DMF-DMA(1mL)。反应混合物在130℃下搅拌过夜。TLC监测反应完毕。将反应液经减压浓缩后得粗品化合物20R-g(不经纯化直接用于下步反应)。
将粗品化合物20R-g(174mg,0.27mmol)溶于甲醇(5mL)中，冰浴下分批加入高碘酸钠(172mg,0.82mmol)。反应混合物升至室温搅拌3小时。TLC监测反应完毕。将反应液过滤，所得到的滤液减压浓缩得粗品化合物20R-h(不经纯化直接用于下步反应)。
将粗品化合物20R-h(163mg，0.27mmol)溶于乙醇(5mL)中，然后加入水合肼(33mg，0.53mmol)。反应混合物在80℃下搅拌5小时。TLC监测反应完毕。将反应液过滤得滤饼，滤饼再经制备型薄板层析分离纯化得黄色固体化合物20R-i(67mg,收率42％)。
将化合物20R-i(67mg,0.11mmol)溶于甲醇(5mL)中，再加入HCl的二氧六环溶液(4.0M,1mL)。反应混合物在40℃下搅拌3小时。TLC监测反应完毕。反应混合物冷却至室温后减压浓缩。将所得混合物溶于少量甲醇中，用氨水将pH值调至7～8，再减压浓缩。所得粗品经制备型薄板层析(二氯甲烷:甲醇＝20:1,2％氨水)分离纯化得到淡黄色固体化合物20R-j(47mg,收率84％)。MS m/z 449.2[M+H] +。
将化合物20R-j(47mg,0.10mmol)，多聚甲醛(6mg,0.19mmol)，无水氯化锌(39mg,0.29mmol)溶于甲醇(3mL)中，再加入氰基硼氢化钠(18mg,0.29mmol)。将反应混合物加热至60℃搅拌1小时。TLC监测反应完毕。反应混合物冷却至室温后减压浓缩。所得粗品经制备型薄板层析(二氯甲烷:甲醇＝20:1,2％氨水)分离纯化得到黄色固体化合物20R(31mg,收率64％)。 1H NMR(500MHz,DMSO-d 6)δ12.79(s,1H),11.21(s,1H),7.89(s,1H),7.16(dd,J＝15.0,2.4Hz,1H),7.05(s,1H),4.99-4.48(br.,2H),4.20(dd,J＝10.8,2.6Hz,1H),4.10-4.04(m,1H),3.60-3.52(m,1H),3.18-3.11(m,1H),3.09-2.96(m,3H),2.70-2.61(m,2H),2.55(d,J＝6.6Hz,2H),2.40-2.33(m,1H),2.30-2.23(m,1H),2.20(s,3H),2.03-1.95(m,1H),1.83(d,J＝12.2Hz,2H),1.29-1.19(m,2H)。MS m/z 506.3[M+H] +。
实施例22:化合物21S的制备
Figure PCTCN2021091148-appb-000052
将化合物21S-a(300mg,0.86mmol)溶于甲醇(5mL)中，再加入HCl的二氧六环溶液(4.0M,5mL)。反应混合物在室温下搅拌3小时。TLC监测反应完毕。反应液减压除去溶剂，加入二氯甲烷(10mL)和饱和碳酸氢钠水溶液(10mL)，室温搅拌0.5h，再用二氯甲烷萃取(3 x 10mL)。合并的有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤后减压浓缩。所得到的黄色固体化合物21S-b直接用于下一步反应。MS m/z 250.2[M+H] +。
将化合物21S-b(214mg,0.86mmol)，多聚甲醛(52mg,1.72mmol)，无水氯化锌(351mg,2.58mmol)溶于甲醇(10mL)中，再加入氰基硼氢化钠(162mg,2.58mmol)。将反应混合物加热至60℃搅拌1小时。TLC监测反应完毕。反应混合物冷却至室温后减压浓缩。所得粗品经制备型薄板层析(二氯甲烷:甲醇＝30:1,2％氨水)分离纯化得到黄色固体化合物21S-c(226mg,收率100％)。MS m/z 264.4[M+H] +。
室温下向甲醇(5mL)中加入化合物21S-c(226mg,0.86mmol)和钯碳催化剂(10％,100mg)。该反应混合物在室温氢气氛围下搅拌3小时。TLC监测反应完毕。反应混合物经过硅藻土过滤，滤液减压浓缩得到粗品。该粗品经硅胶柱层析(二氯甲烷：甲醇＝20:1)分离纯化得到化合物21S-d(130mg,三步收率65％)。MS m/z 234.3[M+H] +。
将化合物21S-d(130mg,0.56mmol)和化合物1R-c(123mg,0.56mmol)溶于乙腈(5mL)中，冰盐浴下逐滴加入二异丙基乙基胺(0.28mL,1.68mmol)。搅拌半小时后升至室温，室温下搅拌3小时。TLC监测反应完毕。将反应混合物减压浓缩(低温)。所得粗品经制备型薄板层析(二氯甲烷:甲醇＝20:1)分离纯化得黄色化合物21S-e(100mg,收率43％)。MS m/z 418.4[M+H] +。
将化合物21S-e(100mg,0.24mmol)和化合物1R-e(59mg,0.48mmol)溶于乙腈(5mL)中，再滴加入二异丙基乙基胺(0.28mL,1.68mmol)。反应混合物在60℃下搅拌3小时。TLC监测反应完毕。将反应混合物减压浓缩。所得粗品经制备型薄板层析(二氯甲烷:甲醇＝30:1)分离纯化得黄色固体化合物21S-f(92mg,收率 76％)。MS m/z 506.7[M+H] +。
将化合物21S-f(92mg,0.18mmol)溶于DMF(2mL)中，然后加入DMF-DMA(393mg,3.30mmol)。反应混合物在130℃下搅拌过夜。TLC监测反应完毕。将反应液减压浓缩后得粗品化合物21S-g(不经纯化直接用于下步反应)。
将粗品化合物21S-g(102mg,0.18mmol)溶于甲醇(5mL)中，冰浴下分批加入高碘酸钠(195mg,0.91mmol)。反应混合物升至室温搅拌3小时。TLC监测反应完毕。将反应液过滤，所得到的滤液减压浓缩得粗品化合物21S-h(不经纯化直接用于下步反应)。
将粗品化合物21S-h(94mg，0.18mmol)溶于乙醇(5mL)中，然后加入水合肼(113mg，1.80mmol)。反应混合物在80℃下搅拌3小时。TLC监测反应完毕。将反应液减压浓缩，所得粗品经制备型薄板层析(二氯甲烷:甲醇＝15:1)分离纯化得淡黄色固体化合物21S(6mg,收率6％)。MS m/z 502.4[M+H] +。
实施例23:激酶活性抑制实验
1.Syk激酶活性抑制实验
方法1：采用Caliper迁移率变动检测技术(Caliper mobility shift assay)测定Syk蛋白激酶活性。将化合物用DMSO溶解后用激酶缓冲液(20mM HEPES,0.01％Triton X-100，5mM MgCl 2，1mM MnCl 2，2mM DTT)稀释，在384孔板中加入5μL的5倍反应终浓度的化合物(10％DMSO)。加入10μL的2.5倍酶(用Syk)溶液后在室温下孵育10分钟，再加入10μL的2.5倍底物(Peptide FAM-P22和ATP)溶液。28℃下孵育30分钟，后加25μL终止液(pH7.5的100mM HEPES,0.015％Brij-35，0.2％Coating Reagent#3，50mM EDTA)终止反应。Caliper EZ Reader II(Caliper Life Sciences)上读取转化率数据。把转化率转化成抑制率数据(％抑制率＝(max-转化率)/(max-min)*100)。其中max是指DMSO对照的转化率，min是指无酶活对照的转化率。以化合物浓度和抑制率为横纵坐标，绘制曲线，使用XLFit excel add-in version4.3.1软件拟合曲线并计算IC 50。
方法2：利用Caliper Mobility Shift Assay方法检测化合物对激酶Syk的抑制效果，化合物测试终浓度为1000nM起始，3倍稀释，7个或8个浓度。使用分液器Echo 550向384孔反应板中转移250nL的100倍终浓度化合物，加入10μL终浓度为1nM Syk的激酶溶液，室温预孵育10分钟(阴性对照孔含10μL激酶缓冲液和250nL100％DMSO；阳性对照孔含10μL的激酶溶液和250nL 100％DMSO)。在Syk上加入15μL终浓度为4μM的ATP和3μM底物22号肽混合溶液起始反应，室温反应30分钟，加入30μL含EDTA的终止检测液停止激酶反应。用Caliper EZ Reader读取转化率。换算抑制率％＝(阳性对照转化率均值％-样品转化率％/(阳性对照转化率均值％-阴性对照转化率均值％)。其中：阴性对照孔，代表没有酶活孔的转化率读数；阳性对照孔，代表没有化合物抑制孔的转化率读数。以浓度的log值作为X轴，百分比抑制率为Y轴，采用分析软件GraphPad Prism 5的log(inhibitor)vs.response-Variable slope拟合量效曲线，从而得出各个化合物对酶活性的IC 50值。计算公式：Y＝Bottom+(Top-Bottom)/(1+10^((LogIC 50-X)*HillSlope))。
部分代表性化合物的活性如表1所示。IC 50值通过以下方式表示：
A:IC 50值≤20nM；B:20nM<IC 50值≤50nM；C:50nM<IC 50值≤100nM；D:IC 50值>100nM。
表1.Syk激酶活性抑制(IC 50，nM)
Figure PCTCN2021091148-appb-000053
2.Jak2激酶活性抑制实验
方法1：激酶Jak2酶活抑制IC 50评价实验：缓冲液是由如下成分配置的：50mM HEPES,pH 7.5，0.00015％Brij-35。将化合物在100％DMSO中配置成浓度梯度，并用缓冲液稀释成10％DMSO,加入384孔板。例如化合物起始浓度为250nM，则用100％DMSO配制成12.5μM，并梯度稀释5或6个浓度，再用缓冲液稀释10倍，配成含10％DMSO的化合物中间稀释体，转移5μL到384孔板。Jak2酶用以下缓冲液稀释成最佳浓度：50mM HEPES,pH7.5，0.00015％Brij-35，2mM DTT。转移10μL到384孔板中，与化合物孵育10-15分钟。底物用以下缓冲液稀释成最佳浓度：50mM HEPES,pH 7.5，0.00015％Brij-35，10mM MgCl 2，Km下的三磷酸腺苷。加入10μL到384孔板起始反应，并于28℃反应1小时。然后用Caliper Reader读取转化率，计算抑制率。公式如下：Percent inhibition＝(max-conversion)/(max-min)*100。其中max是指DMSO对照的转化率，min是指无酶活对照的转化率。用XLFit excel add-in version 5.4.0.8拟合IC 50值。拟合公式:Y＝Bottom+(Top-Bottom)/(1+(IC 50/X)^HillSlope)。
方法2：利用Caliper Mobility Shift Assay方法检测化合物对激酶Jak2的抑制效果，化合物测试终浓度为200nM起始，3倍稀释，7个或8个浓度。使用分液器Echo550向384孔反应板中转移250nL的100倍终浓度化合物，加入10μL终浓度为0.25 nM Jak2的激酶溶液，室温预孵育10分钟(阴性对照孔含10μL激酶缓冲液和250nL100％DMSO；阳性对照孔含10μL的激酶溶液和250nL 100％DMSO)。在Jak2上加入15μL终浓度为11.4μM的ATP和3μM底物22号肽混合溶液起始反应，室温反应15分钟，加入30μL含EDTA的终止检测液停止激酶反应。用Caliper EZ Reader读取转化率。换算抑制率％＝(阳性对照转化率均值％-样品转化率％/(阳性对照转化率均值％-阴性对照转化率均值％)。其中：阴性对照孔，代表没有酶活孔的转化率读数；阳性对照孔，代表没有化合物抑制孔的转化率读数。以浓度的log值作为X轴，百分比抑制率为Y轴，采用分析软件GraphPad Prism 5的log(inhibitor)vs.response-Variable slope拟合量效曲线，从而得出各个化合物对酶活性的IC 50值。计算公式：Y＝Bottom+(Top-Bottom)/(1+10^((LogIC 50-X)*HillSlope))。
部分代表性化合物的活性如表2所示。IC 50值通过以下方式表示：
A:IC 50值≤5nM；B:5nM<IC 50值≤20nM；C:20nM<IC 50值≤100nM；D:IC 50值>100nM。
表2.Jak2激酶活性抑制(IC 50，nM)
Figure PCTCN2021091148-appb-000054
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。

Claims (15)

  1. 一种如下式(I)所示结构的化合物，或其光学异构体(包括消旋体、单一的对映异构体、可能的非对映异构体)，药学上可接受的盐，前药，氘代形式，水合物，溶剂合物：
    Figure PCTCN2021091148-appb-100001
    其中“*”表示手性中心；在没有标明是R或S的情况下，带“*”的化合物表示消旋体，或R构型或S构型的光学异构体；
    R 1选自下组：3-至8-元环烷基、3-至12-元杂环基(包括单环、螺环和并环)、芳基、杂芳基、OR b、或NR bR c；在所述的R 1中，各个环烷基、杂环基、芳基和杂芳基任选地被1-3个各自独立地选自下组的取代基取代：氘、卤素、CN、OR h、NR hR h、C(O)R e、C(O)OR h、C(O)NR hR h、NR hC(O)R e、S(O) 2R e、S(O) 2NR hR h、C 1-4烷基、C 1-4卤代烷基、C 1-4烷氧基取代的C 1-4烷基、羟基取代的C 1-4烷基、氰基取代的C 1-4烷基、二(C 1-4烷基)胺基取代的C 1-4烷基、3-至6-元杂环基取代的C 1-4烷基、芳基取代的C 1-4烷基、杂芳基取代的C 1-4烷基、C 2-4烯基、C 2-4炔基、3-至8-元环烷基、3-至8-元杂环基、芳基、或杂芳基，前提条件是所形成的化学结构是稳定的和有意义的；
    其中，R b和R c各自独立为氢、C 1-4烷基、3-至8-元环烷基、3-至8-元杂环基、芳基、杂芳基；
    各个R 2各自独立为氘、卤素、C 1-4烷基、C 1-4卤代烷基、C 2-4烯基、C 2-4炔基、OR h、SR h、NR hR h、CN、C(O)R e、C(O)OR h，C(O)NR hR h、OC(O)R e、NR hC(O)R e、或S(O) 2R e；
    各个R 3各自独立为氘、或C 1-4烷基；或当两个R 3同时连接到同一个碳原子上时，两个R 3与其相连的碳原子共同形成羰基(C＝O)；所述的R 3位于环上除N原子和G上的任意位点；
    J和G各自独立地为NR f、O、S、S(O)、S(O) 2或CR gR g；
    n为0、1、2、或3；
    q为0、1、2、或3；
    R f为氢、C 1-8烷基、C 1-8卤代烷基、C 2-8烯基、C 2-8炔基、3-至8-元环烷基、3-至12-元杂环基、芳基、杂芳基、C(O)R e、C(O)OR h、C(O)NR hR h、S(O) 2R e、或S(O) 2NR hR h；其中，各个烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基任选地且各自独立地被1-3个各自独立地选自下组的取代基取代：卤素、C 1-4烷基、C 2-4烯基、C 2-4炔基、3-至8-元环烷基、3-至8-元杂环基、芳基、杂芳基、CN、NO 2、OR h、SR h、NR hR h、C(O)R e、C(O)OR h、C(O)NR hR h、NR hC(O)R e、S(O) 2R e、或S(O) 2NR hR h；
    各个R e各自独立地为选自下组的基团：氢、C 1-4烷基、C 1-4卤代烷基、C 2-4烯基、C 2-4炔基、3-至8-元环烷基、3-至8-元杂环基、芳基、或杂芳基；
    各个R g各自独立地选自下组：氢、氘、卤素、或C 1-4烷基；或两个R g与其相连的碳原子共同形成羰基(C＝O)；或两个R g与其连接的同一个碳原子一起形成3-至8-元环状结构，此环状结构任选地含有0、1或2个选自N、O、S的杂原子；
    各个R h各自独立为氢、或C 1-4烷基；或两个R h与其连接的氮原子一起形成3-至-8元杂环基，此杂环基含有1或2个N原子以及0或1个选自O、S的杂原子；
    其中，除非特别说明，各个上述的烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基任选地且各自独立地被1-3个各自独立地选自下组的取代基取代：氘、卤素、C 1-4烷基、C 1-4卤代烷基、C 2-4烯基、C 2-4炔基、3-至8-元环烷基、3-至8-元杂环基、芳基、杂芳基、CN、NO 2、OR h、SR h、NR hR h、C(O)R e、C(O)OR h、C(O)NR hR h、NR hC(O)R e、或S(O) 2R e，前提条件是所形成的化学结构是稳定的和有意义的；其中R e和R h的定义如上所述；
    除非特别说明，上述的芳基为含有6-12个碳原子的芳香基团；杂芳基为5-至15-元杂芳香基团；环状结构为饱和的或不饱和的、含杂原子或不含杂原子的环状基团。
  2. 如权利要求2所述的化合物，其特征在于，所述的R 1选自下组：3-至12-元杂环基、芳基、或杂芳基；其中，各个杂环基、芳基和杂芳基任选地被1-2个各自独立地选自下组的取代基取代：氘、卤素、CN、OR h、NR hR h、C(O)R e、C(O)OR h、C(O)NR hR h、NR hC(O)R e、S(O) 2R e、S(O) 2NR hR h、C 1-4烷基、C 1-4卤代烷基、C 1-4烷氧基取代的C 1-4烷基、羟基取代的C 1-4烷基、氰基取代的C 1-4烷基、二(C 1-4烷基)胺基取代的C 1-4烷基、3-至6-元杂环基取代的C 1-4烷基、芳基取代的C 1-4烷基、杂芳基取代的C 1-4烷基、3-至8-元环烷基、3-至8-元杂环基、芳基、或杂芳基，前提条件是所形成的化学结构是稳定的和有意义的；
    各个R 2各自独立为氢、氘、卤素、C 1-4烷基、NR hR h、或NR hC(O)R e；
    各个R 3各自独立为氢或C 1-4烷基；或当两个R 3同时连接到同一个碳原子上时，这两个R 3与其相连的碳原子共同形成羰基(C＝O)；
    n为0、1、或2；
    q为0、1、或2；
    其中R e和R h的定义如权利要求1中所述。
  3. 如权利要求2所述的化合物，其特征在于，式(I)为：
    Figure PCTCN2021091148-appb-100002
    其中各个基团的定义如权利要求2中所述。
  4. 如权利要求3所述的化合物，其特征在于，式(IIa)中的结构片段
    Figure PCTCN2021091148-appb-100003
    选自：
    Figure PCTCN2021091148-appb-100004
    Figure PCTCN2021091148-appb-100005
    表示上述结构片段与式(IIa)中其它结构的连接位点；
    其中，各个R 2各自独立为氢、氘、卤素、C 1-2烷基、NR hR h、或NR hC(O)R e；
    各个R 3各自独立为氢或C 1-4烷基；当两个R 3连接在同一个碳原子上时，两个R 3和连接它们的碳原子可以一起组成C＝O；
    n为0、1、或2；q为0或1；
    R f为氢、C 1-4烷基、C 1-4卤代烷基、C 2-4烯基、C 2-4炔基、3-至8-元环烷基、3-至9-元杂环基、芳基、杂芳基、C(O)R e、C(O)OR h、C(O)NR hR h、S(O) 2R e、或S(O) 2NR hR h；其中各个烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基任选地且各自独立地被1-3个各自独立地选自下组的取代基取代：氘、卤素、C 1-4烷基、C 2-4烯基、C 2-4炔基、3-至8-元环烷基、3-至8-元杂环基、芳基、杂芳基、CN、NO 2、OR h、SR h、NR hR h、C(O)R e、C(O)OR h、C(O)NR hR h、NR hC(O)R e、S(O) 2R e、或S(O) 2NR hR h；
    R e和R h的定义如权利要求1中所述。
  5. 如权利要求3-4任一所述的化合物，其特征在于，式(I)为：
    Figure PCTCN2021091148-appb-100006
    其中，R 2为氢、氘、卤素、C 1-2烷基、NR hR h、或NR hC(O)R e；
    R f为氢、C 1-4烷基、C 1-4卤代烷基、C 2-4烯基、C 2-4炔基、3-至8-元环烷基、3-至9-元杂环基、芳基、杂芳基、C(O)R e、C(O)OR h、C(O)NR hR h、S(O) 2R e、或S(O) 2NR hR h；其中各个烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基任选地且各自独立地被1-3个各自独立地选自下组的取代基取代：氘、卤素、C 1-4烷基、C 2-4烯基、C 2-4炔基、3-至8-元环烷基、3- 至8-元杂环基、芳基、杂芳基、CN、NO 2、OR h、SR h、NR hR h、C(O)R e、C(O)OR h、C(O)NR hR h、NR hC(O)R e、S(O) 2R e、或S(O) 2NR hR h；
    R 1的定义如权利要求2中所述；R e和R h的定义如权利要求1中所述。
  6. 如权利要求3所述的化合物，其特征在于，式(I)为：
    Figure PCTCN2021091148-appb-100007
    其中，R 2为氢、氘、卤素、C 1-2烷基、NR hR h、或NR hC(O)R e；
    R f为氢、C 1-4烷基、C 1-4卤代烷基、C 2-4烯基、C 2-4炔基、3-至8-元环烷基、3-至9-元杂环基、芳基、杂芳基、C(O)R e、C(O)OR h、C(O)NR hR h、S(O) 2R e、或S(O) 2NR hR h；其中各个烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基任选地且各自独立地被1-3个各自独立地选自下组的取代基取代：氘、卤素、C 1-4烷基、C 2-4烯基、C 2-4炔基、3-至8-元环烷基、3-至8-元杂环基、芳基、杂芳基、CN、NO 2、OR h、SR h、NR hR h、C(O)R e、C(O)OR h、C(O)NR hR h、NR hC(O)R e、S(O) 2R e、或S(O) 2NR hR h；
    R 1的定义如权利要求2中所述；R e和R h的定义如权利要求1中所述。
  7. 如权利要求5-6任一所述的化合物，其特征在于，所述的R 2为氢、卤素、C 1-2烷基；
    R f选自下组：氢、C 1-4烷基、C 1-4卤代烷基、3-至8-元环烷基、3-至9-元杂环基、芳基、杂芳基、C(O)R e、或S(O) 2R e；其中各个烷基、环烷基、杂环基、芳基和杂芳基任选地且各自独立地被1-3个各自独立地选自下组的取代基取代：氘、卤素、C 1-4烷基、C 2-4烯基、C 2-4炔基、3-至8-元环烷基、3-至8-元杂环基、芳基、杂芳基、CN、NO 2、OR e、SR e、NR eR e、C(O)R e、C(O)OR e、C(O)NR eR e、NR eC(O)R e、S(O) 2R e、或S(O) 2NR hR h；
    R e和R h的定义如权利要求1中所述。
  8. 如权利要求7所述的化合物，其特征在于，式(I)为：
    Figure PCTCN2021091148-appb-100008
    Figure PCTCN2021091148-appb-100009
    其中，R 2为氢、卤素、C 1-2烷基；
    s和t各自独立为1、2、或3；
    A为NR k、O、或CR gR g；其中R k为氢、C 1-4烷基、C 1-4卤代烷基、羟基取代的C 1-4烷基、C 1-4烷氧基取代的C 1-4烷基、二(C 1-4烷基)胺基取代的C 1-4烷基、3-至8-元环烷基、3-至9-元杂环基、芳基、杂芳基、C(O)R e、C(O)OR h、C(O)NR hR h、S(O) 2R e、或S(O) 2NR hR h；
    R 1的定义如权利要求2中所述；R g、R e、和R h的定义如权利要求1中所述。
  9. 如权利要求1-8任一所述的化合物，其特征在于，R 1为3-至12-元杂环基；其中，所述的杂环基指饱和或部分不饱和的单环或多环杂环基；多环杂环基指包括螺环、稠环和桥环的杂环基；杂环基任选地被1-2个各自独立地选自下组的取代基取代：氘、卤素、CN、OR h、NR hR h、C(O)R e、C(O)OR h、C(O)NR hR h、NR hC(O)R e、S(O) 2R e、S(O) 2NR hR h、C 1-4烷基、C 1-4卤代烷基、C 1-4烷氧基取代的C 1-4烷基、羟基取代的C 1-4烷基、氰基取代的C 1-4烷基、二(C 1-4烷基)胺基取代的C 1-4烷基、3-至6-元杂环基取代的C 1-4烷基、芳基取代的C 1-4烷基、杂芳基取代的C 1-4烷基、3-至8-元环烷基、3-至8-元杂环基、芳基、或杂芳基，前提条件是所形成的化学结构是稳定的和有意义的。
  10. 如权利要求9所述的化合物，其特征在于，R 1选自下组：
    Figure PCTCN2021091148-appb-100010
    Figure PCTCN2021091148-appb-100011
    表示上述结构片段与式(I)中其它结构的连接位点；
    其中，各个R s各自独立为氢、氘、卤素、C 1-4烷基、CN、OR h、NR hR h；或当两个R s同时连接到同一个碳原子上时，这两个R s与其相连的碳原子可以任选地共同形成羰基(C＝O)或形成3-至6-元环烷基；
    或位于不同碳原子上的两个R s共同构成选自下组的结构：化学键、C 1-2的亚烷基；
    B为NR t、O、或CR wR w；各个R w各自独立地选自下组：氢、氘、卤素、CN、OR h、NR hR h、C(O)R e、C(O)OR h、C(O)NR hR h、NR hC(O)R e、S(O) 2R e、S(O) 2NR hR h、C 1-4烷基、C 1- 4卤代烷基、C 1-4烷氧基取代的C 1-4烷基、羟基取代的C 1-4烷基、氰基取代的C 1-4烷基、二(C 1-4烷基)胺基取代的C 1-4烷基、3-至8-元环烷基、3-至8-元杂环基、芳基、或杂芳基；或两个R w与其连接的同一个碳原子一起形成3-至8-元环状结构，此环状结构任选地含有0、1或2个选自NR t、O、S的环成员；
    上述各个R t各自独立地为氢、C 1-4烷基、C 1-4卤代烷基、羟基取代的C 1-4烷基、C 1-4烷氧基取代的C 1-4烷基、氰基取代的C 1-4烷基、二(C 1-4烷基)胺基取代的C 1-4烷基、3-至8-元环烷基、3-至8-元杂环基、芳基、杂芳基、C(O)R e、或S(O) 2R e；
    p为0、1、或2；
    u和v各自独立为0、1、或2；
    各个R e和R h的定义如权利要求1中所述。
  11. 如权利要求1-10任一所述的化合物，其特征在于，R 1选自下组：
    Figure PCTCN2021091148-appb-100012
    Figure PCTCN2021091148-appb-100013
    表示上述结构片段与式(I)中其它结构的连接位点。
  12. 如权利要求1所述的化合物，其特征在于，所述化合物选自下组：
    Figure PCTCN2021091148-appb-100014
    Figure PCTCN2021091148-appb-100015
    Figure PCTCN2021091148-appb-100016
  13. 如权利要求1所述的式(I)化合物，或其光学异构体，药学上可接受的盐，前药，氘代衍生物，水合物，溶剂合物的用途，其特征在于，用于：
    (a)制备治疗与蛋白激酶活性或表达量相关的疾病的药物；
    (b)制备蛋白激酶靶向抑制剂；和/或
    (c)体外非治疗性地抑制蛋白激酶的活性；
    其中，所述的蛋白激酶选自下组：SYK、JAK1、JAK2、JAK3、TYK2等，或其组合。
  14. 一种药物组合物，其特征在于，所述的药物组合物包括：(i)有效量的如权利要求1所述的式I化合物，或其光学异构体，药学上可接受的盐，前药，氘代衍生物，水合物，溶剂合物；和(ii)药学上可接受的载体。
  15. 如权利要求1所述的化合物的制备方法，其特征在于，包括步骤：
    Figure PCTCN2021091148-appb-100017
    (1)用式C2化合物与DMF-DMA反应，得到式C3化合物；
    Figure PCTCN2021091148-appb-100018
    (2)用式C3化合物与NaIO 4反应，得到式C4化合物；
    Figure PCTCN2021091148-appb-100019
    (3)用式C4化合物与NH 2NH 2反应，得到式I化合物。
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Publication number Priority date Publication date Assignee Title
CN103974955A (zh) * 2011-08-23 2014-08-06 远藤制药公司 嘧啶并-哒嗪酮化合物及其用途
WO2016197987A1 (zh) * 2015-06-12 2016-12-15 杭州英创医药科技有限公司 作为Syk抑制剂和/或Syk-HDAC双重抑制剂的杂环化合物
WO2017118438A1 (zh) * 2016-01-08 2017-07-13 杭州英创医药科技有限公司 作为fgfr抑制剂的杂环化合物
WO2018108084A1 (zh) * 2016-12-12 2018-06-21 杭州英创医药科技有限公司 一类含有三环杂芳基的化合物
CN108699055A (zh) * 2015-12-13 2018-10-23 杭州英创医药科技有限公司 用作抗癌药物的杂环化合物

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103974955A (zh) * 2011-08-23 2014-08-06 远藤制药公司 嘧啶并-哒嗪酮化合物及其用途
WO2016197987A1 (zh) * 2015-06-12 2016-12-15 杭州英创医药科技有限公司 作为Syk抑制剂和/或Syk-HDAC双重抑制剂的杂环化合物
CN108699055A (zh) * 2015-12-13 2018-10-23 杭州英创医药科技有限公司 用作抗癌药物的杂环化合物
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