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WO2012136111A1 - Phenylpropionic acid compound, preparation method therefor and medicinal use thereof - Google Patents

Phenylpropionic acid compound, preparation method therefor and medicinal use thereof Download PDF

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Publication number
WO2012136111A1
WO2012136111A1 PCT/CN2012/073192 CN2012073192W WO2012136111A1 WO 2012136111 A1 WO2012136111 A1 WO 2012136111A1 CN 2012073192 W CN2012073192 W CN 2012073192W WO 2012136111 A1 WO2012136111 A1 WO 2012136111A1
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WIPO (PCT)
Prior art keywords
phenyl
alkyl
group
thiazole
compound
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PCT/CN2012/073192
Other languages
French (fr)
Chinese (zh)
Inventor
李松
钟武
林忠宝
王晓奎
刘洪英
谢云德
赵国明
郑志兵
肖军海
李行舟
Original Assignee
中国人民解放军军事医学科学院毒物药物研究所
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Application filed by 中国人民解放军军事医学科学院毒物药物研究所 filed Critical 中国人民解放军军事医学科学院毒物药物研究所
Priority to CN201280002759.2A priority Critical patent/CN103097367B/en
Publication of WO2012136111A1 publication Critical patent/WO2012136111A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • 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
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D277/30—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/38—Nitrogen atoms
    • C07D277/42—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals

Definitions

  • Phenylpropionic acid compound preparation method thereof and medical use thereof
  • the present invention relates to the field of pharmaceutical and chemical engineering, and relates to a phenylpropionic acid compound or a pharmaceutically acceptable salt thereof, a pharmaceutical composition comprising the same, a process for the preparation thereof, and a pharmaceutical use thereof.
  • These compounds are S1P EDG1 receptor agonists, which regulate lymphocyte transport, regulate lymphocyte cell transport, accumulate lymphocytes in secondary lymphoid tissues, and enhance vascular integrity to exert immunosuppressive, anti-inflammatory and hemostatic effects.
  • Immunosuppressive and anti-inflammatory drugs have been shown to be useful in many autoimmune and chronic inflammatory diseases (including systemic lupus erythematosus, chronic rheumatoid arthritis, type I diabetes, inflammatory bowel disease, biliary cirrhosis, grapes) Membrane inflammation, multiple sclerosis, and other diseases such as Crohn's disease, ulcerative colitis, bullous pemphigoid, sarcoidosis, psoriasis, autoimmune myositis, Wegener's granulomatosis , ichthyosis, Graves' eye disease, atopic dermatitis and asthma, chronic lung disease, acute lung injury, acute respiratory distress syndrome and sepsis. They have also been shown to be useful in the treatment of cancer, lymphoma and leukemia chemotherapy regimens.
  • Anti-inflammatory drugs act primarily by blocking the action or secretion of the above mediators, but do not improve the immune basis of the disease.
  • cytotoxic drugs such as cyclophosphamide
  • cytotoxic drugs act in a non-specific manner such that both normal and autoimmune responses are blocked. In fact, with death Like autoimmune diseases, patients treated with such non-specific immunosuppressive drugs are likely to die from infection.
  • Cyclosporin A is a drug that prevents rejection of transplanted organs.
  • FK-506 is another drug approved for the prevention of rejection in transplanted organs, especially liver transplants.
  • the body's immune system mobilizes its vast pool of natural protective factors to reject transplanted foreign proteins, and cyclosporin A and FK-506 act by suppressing the immune system.
  • Cyclosporin A is approved for the treatment of severe psoriasis and has been approved by European regulatory agencies for the treatment of atopic dermatitis.
  • cyclosporin A and FK-506 are effective in delaying or inhibiting transplant rejection, they can cause a variety of adverse side effects including nephrotoxicity, neurotoxicity and gastrointestinal discomfort. Therefore, there is still a need to develop immunosuppressive agents which do not have the above-mentioned side effects, and such immunosuppressive agents are also highly desirable.
  • the immunosuppressant FTY720 is currently marketed for the treatment of multiple sclerosis.
  • FTY720 is metabolized in mammals to an effective agonist compound of the sphingosine-1-phosphate receptor.
  • the sphingosine 1-phosphate receptor regulates leukocyte trafficking, induces lymphocytes (T cells and B cells) to accumulate in lymph nodes without causing lymphocyte deficiency, and does not destroy the spleen structure, thereby interfering with T cell-dependent antibodies.
  • S1P receptor agonist traces have anti-inflammatory properties by enhancing endothelial integrity and inhibiting vascular damage caused by activation of the immune system.
  • Such immunosuppressive and anti-inflammatory effects are required to prevent rejection after organ transplantation, to treat autoimmune diseases, and to treat diseases whose major defects are vascular integrity, such as acute lung injury, acute respiratory distress syndrome, and sepsis.
  • Sphingosine 1-phosphate is a biologically active sphingolipid metabolite secreted by hematopoietic cells, stored in platelets and released from living platelets. It acts as an agonist on the G protein-coupled receptor family to regulate cell proliferation, differentiation, survival, and movement.
  • sphingosine 1-phosphate administered to the animal induces the accumulation of lymphocytes in the peripheral blood to the secondary lymphoid organs, thereby producing a useful therapeutic immunosuppressive effect.
  • sphingosine 1-phosphate also has cardiovascular and bronchoconstrictive effects, and such effects limit its use as a therapeutic drug.
  • Intravenous administration of sphingosine 1-phosphate will reduce heart rate, ventricular contraction, and blood pressure in rats.
  • sphingosine 1 -phosphate regulates bronchial growth Contraction, airway inflammation, and contraction of airway remodeling in asthma, cell growth, and cytokine production.
  • the adverse effects of sphingosine 1-phosphate are related to its non-selective potent agonist activity on all S1P receptors.
  • SlP Edgl receptor selective agonists have advantages over existing therapies, broadening the therapeutic window of lymphocyte aggregation drugs and vascular intact drugs, resulting in better tolerance at higher doses, thus increasing monotherapy efficacy.
  • immunosuppressants and anti-inflammatory agents are mainly used to treat bone marrow, organs and graft rejection
  • other uses of these compounds include the treatment of arthritis (especially rheumatoid arthritis), insulin-dependent diabetes, non-insulin dependence. Diabetes, multiple sclerosis, psoriasis, inflammatory bowel disease, Crohn's disease, lupus erythematosus, asthma, allergies, chronic lung disease, acute lung injury, acute respiratory disease, sepsis, etc.
  • the present inventors have unexpectedly discovered in the study that the following compound of formula I is a SlPi/EDG1 receptor agonist which regulates lymphocyte transport by regulating leukocyte trafficking, allowing lymphocytes to accumulate in secondary lymphoid tissues and improving vascular integrity. It exerts immunosuppressive effects, anti-inflammatory activity and hemostasis. Therefore, this issue:
  • K is independently selected from - C00H, -P0 3 H, -P0 2 H 2 , - S0 3 H, -0 (P0 3 ) H;
  • U, V, W and J are independently selected from -C(R 2 ) - and -N-, and constitute a substituted or unsubstituted six-membered aromatic ring;
  • R 2 is independently selected from the group consisting of -H, -F, -Cl, -Br, -1, -CN, -OH, d- 4 alkyl,
  • CH alkyl, CH alkenyl, CH alkynyl and CH alkoxy groups are each optionally substituted with a substituent independently selected from the group consisting of: - F, - C l, -Br, -1, -OH and d - 8 alkoxy;
  • the A ring and the B ring may be directly linked or connected via G;
  • d- 3 alkyl group, C 2 -4 alkenyl group, C 2 -4 alkynyl group are each optionally selected from -F, -Cl, -Br, -1, -OH, -CN, CH alkyl and CH alkane Oxygen substitution;
  • R 3 may be H, d- 3 alkyl, C 2 -4 alkenyl, C 2 -4 alkynyl, wherein the d- 3 alkyl, C 2 -4 alkenyl, C 2 -4 alkynyl are each Optionally substituted with -F, -C1, -Br, -1, -OH, -CN, CH alkyl and CH alkoxy;
  • the Q and T thus obtained constitute a heterocyclic ring;
  • R ⁇ R 5 and R 6 are each independently selected from - H, d- 6 alkyl, C 2 - 6 alkenyl, C 2 - 6 alkynyl, and d- 6 alkoxy, d- 6 alkyl group described above, C 2 -6 alkenyl, C 2 -6 alkynyl and d- 6 alkoxy are each optionally -F, -Cl, -Br, -1, -OH, -CN, d- 4 alkyl and d- 4 alkoxy substituted;
  • R 1 is selected from the group consisting of phenyl, pyrimidinyl, pyridyl, pyrazinyl, pyridazinyl, thienyl and thiazolyl, wherein each of the groups is optionally substituted with the following substituents: - F, - Cl, -Br, -1, -0H, - CN, - NR 7 R 8, - N0 2, phenyl, benzyl, benzyloxy, d- 6 alkyl, (3 - 6 cycloalkyl group, C 2 - 6 women group, .2-6 block group, Ci- burning 3 ⁇ 4 ⁇ , C3-6 cycloalkyl group burning, C2-6 women oxo group, C2-6 block ⁇ ⁇ , d- 6 alkylthio, C 3 - 6 cycloalkylthio And C 2 -6 acyloxy, the above phenyl, benzyl and benzyloxy may
  • R 7 and R 8 are independently selected from -H, d- 6 alkyl, C 2 -6 alkenyl and C 2 -6 alkynyl, wherein said d- 6 alkyl, C 2 - 6 alkenyl and C
  • the 2 - 6 alkynyl groups are each optionally substituted with a substituent independently selected from the group consisting of: - F, - Cl, - Br, -1, -OH, - CN and d- 6 alkoxy;
  • R 7 and R 8 may together with the nitrogen atom to which they are attached form a saturated monocyclic ring of from 3 to 8 atoms, optionally containing from 1 to 2 oxygen atoms, optionally substituted with a substituent selected from the group consisting of: - F, - Cl, -Br, -1, -OH, - CN and d- 6 alkoxy.
  • a compound of formula I wherein U, V, J and W are -CH-.
  • the compound of formula I is a compound of formula la or a pharmaceutically acceptable salt thereof:
  • J and W are independently selected from -C(R 4 )- and -N -, and constitute a substituted or unsubstituted six-membered aromatic ring;
  • R 4 is independently selected from the group consisting of -H, -F, -Cl, -Br, -1, -CN, -0 ⁇ , CH alkyl,
  • CH alkyl group, C 2 -4 alkenyl group, C 2 -4 alkynyl group and CH alkoxy group are each optionally substituted with a substituent independently selected from the group consisting of: - F, - Cl, -Br, -1. -OH and d- 8 alkoxy;
  • the A ring and the B ring can be directly connected or connected through G;
  • d- 3 alkyl group, C 2 -4 alkenyl group, C 2 -4 alkynyl group are each optionally selected from the group consisting of -F, -C1, -Br, -1, -OH, -CN, d- Substituted with a 4- alkyl and CH alkoxy group;
  • R 4 may be H, d- 3 alkyl, C 2 -4 alkenyl, C 2 -4 alkynyl, wherein said d- 3 alkyl, C 2 -4 alkenyl, C 2 -4 alkynyl are each optionally substituted by -F, -Cl, -Br, -1, -OH, -CN, CH alkyl and CH alkoxy;
  • R 5 , R 6 and R 7 are each independently selected from -H, d- 6 alkyl, C 2 -6 alkenyl, C 2 -6 alkynyl and ( ⁇ -6 alkoxy, above d- 6 alkyl , C 2 -6 alkenyl, C 2 -6 alkynyl and d- 6 alkoxy are each optionally -F, -Cl, -Br, -1, -OH, -CN, d- 4 alkyl and d - 4 alkoxy substituted;
  • Each of U and V is optionally independently selected from C and N;
  • Each of R 1 , R 2 and R 3 is optionally independently selected from the group consisting of: - F, - Cl, -Br, -1, -OH, - CN, -NR 8 R 9 , - N0 2 , phenyl , benzyl, benzyloxy, d- 6 alkyl, C 3 - 6 cycloalkyl group burning.
  • 2-6 women's base In 2-6 women's base,. 2-6 blocks, Cl-alkyl, C3-6 ring base. 2-6 women's base ⁇ ⁇ ,
  • R 8 and R 9 are independently selected from -H, d- 6 alkyl, C 2 -6 alkenyl and C 2 -6 alkynyl, wherein said d- 6 alkyl, C 2 - 6 alkenyl and C
  • the 2 - 6 alkynyl groups are each optionally substituted with a substituent independently selected from the group consisting of: - F, - Cl, -Br, -1, -OH, - CN and d- 6 alkoxy;
  • R 8 and R 9 may, together with the nitrogen atom to which they are attached, form a saturated monocyclic ring of 3-8 atoms, optionally containing 1-2 oxygen atoms, optionally substituted with a substituent selected from the group consisting of: - F, - Cl, -Br, -1, -OH, - CN and d- 6 alkoxy.
  • the above C ring may be a six-membered aromatic heterocyclic ring or a benzene ring, and the broken line represents 1-3 double bonds.
  • the compound of formula I is a compound of formula I b or is pharmaceutically acceptable
  • J and W are independently selected from -C(R 4 )- and -N -, and constitute a substituted or unsubstituted six-membered aromatic ring;
  • R 4 is independently selected from the group consisting of -H, -F, -Cl, -Br, -1, -CN, -0H, CH alkyl,
  • CH alkyl, CH alkenyl, C 2 -4 alkynyl and CH alkoxy groups are each optionally substituted with a substituent independently selected from the group consisting of: - F, - Cl, -Br, -1, -OH and D- 8 alkoxy;
  • a ring and B ring are linked by G;
  • R 4 may be H, d- 3 alkyl, C 2 -4 alkenyl, C 2 -4 alkynyl, wherein the d- 3 alkyl, C 2 -4 alkenyl, C 2 -4 alkynyl are each Optionally substituted with -F, -Cl, -Br, -1, -OH, -CN, CH alkyl and CH alkoxy;
  • R 5 may be selected from the group consisting of: - H, d- 6 alkyl, C 2 - 6 alkenyl, C 2 - 6 alkynyl and d- 6 alkoxy, the above-mentioned d- 6 alkyl, C 2 - 6 alkenyl, C 2 - 6 block and ( ⁇ 6 alkoxy are each optionally substituted by -F, -Cl, -Br, -1, -OH, -CN, CH alkyl and CH alkoxy ;
  • Each of R 1 , R 2 and R 3 is optionally independently selected from the group consisting of: - F, - Cl, -Br, -1, -OH, - CN, - NR 6 R 7 , - N0 2 , phenyl , benzyl, benzyloxy, d- 6 alkyl, C 3 - 6 cycloalkyl group burning.
  • C 2 -6 alkynyloxy, ( ⁇ 6 alkylthio, C 3 - 6 cycloalkylthio and C 2 - 6 acyloxy, the above phenyl, benzyl and benzyloxy may be 1 - 3 or less Substituent substitution: - F, - Cl, -Br, -1, -CN, -NR 7 R 8 , -N0 2 ;
  • R 6 and R 7 are independently selected from -H, d- 6 alkyl, C 2 -6 alkenyl and C 2 -6 alkynyl, wherein said d- 6 alkyl, C 2 - 6 alkenyl and C
  • the 2 - 6 alkynyl groups are each optionally substituted with a substituent independently selected from the group consisting of: - F, - Cl, -Br, -1, -OH, - CN and d- 6 alkoxy;
  • R 6 and R 7 may together with the nitrogen atom to which they are attached form a saturated monocyclic ring of 3-8 atoms, optionally containing 1-2 oxygen atoms, optionally substituted with a substituent selected from the group consisting of: - F, - Cl, -Br, -1, -OH, - CN and d- 6 alkoxy.
  • the compound of the formula I of the present invention or a pharmaceutically acceptable salt thereof is further preferably selected from the following specific compounds or pharmaceutically acceptable salts of these compounds, as shown in Table 1 below. Show:
  • the invention further relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof, or a compound of formula la or a pharmaceutically acceptable salt thereof, or a compound of formula lb, or a pharmaceutically acceptable salt thereof, or a specific compound thereof , and a pharmaceutically acceptable carrier or excipient.
  • the invention further relates to a compound of formula I, or a pharmaceutically acceptable salt thereof, or a compound of formula la, or a pharmaceutically acceptable salt thereof, or a compound of formula lb, or a pharmaceutically acceptable salt thereof, or a specific compound thereof, for use in the treatment of immunity Use in the regulation of abnormal drugs.
  • the invention further relates to a method of treating an immunomodulatory abnormality in a mammalian subject, the method comprising administering to the patient an immunosuppressively effective amount of a compound of formula I.
  • the immunomodulatory abnormality is selected from the group consisting of an autoimmune disease or a chronic inflammatory disease: systemic lupus erythematosus, chronic rheumatoid arthritis, type I diabetes, inflammatory bowel disease, biliary cirrhosis, Uveitis, multiple sclerosis, Crohn's disease, Ulcerative colitis, bullous pemphigoid, sarcoidosis, psoriasis, autoimmune myositis, Wegener's granulomatosis, ichthyosis, Graves' eye disease and asthma.
  • an autoimmune disease or a chronic inflammatory disease systemic lupus erythematosus, chronic rheumatoid arthritis, type I diabetes, inflammatory bowel disease, biliary cirrhosis, Uveitis, multiple sclerosis, Crohn's disease, Ulcerative colitis, bullous pemphigoid, sarcoidosis, psoria
  • the immunomodulatory abnormality is bone marrow or organ transplant rejection or graft versus host disease.
  • the immunomodulatory abnormality is selected from the group consisting of organ or tissue transplantation, graft-versus-host disease caused by transplantation, autoimmune syndrome, including rheumatoid arthritis, systemic lupus erythematosus, Hashimoto's thyroiditis, multiple Sclerotherapy, myasthenia gravis, type I diabetes, uveitis, posterior uveitis, allergic encephalomyelitis, glomerulonephritis, post-infectious autoimmune diseases (including rheumatic fever and post-infectious glomerulonephritis) , inflammatory and hyperproliferative skin diseases, psoriasis, atopic dermatitis, contact dermatitis, eczema dermatitis, seborrheic dermatitis, lichen planus, pemphigus, bullous pemphigoid, bullous Epidermolysis, urticaria, angioedema, vasculitis,
  • the immunomodulatory abnormality is selected from
  • the invention further relates to a compound of formula I or a pharmaceutically acceptable salt thereof for use in the treatment of immunomodulatory disorders, organ transplant rejection, respiratory diseases or disorders, inflammation, vascular related diseases or disorders in a mammalian patient.
  • the invention also encompasses a method of treating a respiratory disease or condition in a mammalian patient in need of such treatment, the method comprising administering to the patient an effective amount of a compound of formula I or a therapeutic agent for the respiratory disease or condition.
  • the respiratory disease or condition is selected from the group consisting of asthma, chronic bronchitis, chronic obstructive pulmonary disease, adult respiratory distress syndrome, infant respiratory distress syndrome, cough, eosinophilic granuloma, respiratory tract Syncytial bronchiolitis, bronchiectasis, idiopathic pulmonary fibrosis, acute lung injury, and obliterative bronchiolitis with organizing pneumonia.
  • the invention also includes a method of treating an vascular integrity-related disease or condition in a patient in need of such treatment, wherein the disease or condition is selected from the group consisting of angioedema, vasculitis, ischemic disease, and vascular injury caused by thrombosis , ischemic bowel disease, inflammatory bowel disease, necrotizing enterocolitis, thermal burn-related intestinal damage, arteriosclerosis, atherosclerosis, aortitis syndrome, preservation, transplantation or ischemic Organ ischemia after re-injection injury, endotoxin shock, pseudomembranous colitis, colitis caused by drugs or radiation, ischemic acute renal insufficiency, chronic renal insufficiency, pulmonary oxygen or drug-induced a disease caused by poisoning, sepsis, pancreatitis, histamine or leukotriene-C4 release, necrosis caused by toxins, viral hepatitis, shock or hypoxia, senile dementia and trauma, the method comprising administering the said
  • the invention also encompasses a method of treating a cerebral edema or pulmonary edema-associated disease or condition in a patient in need of such treatment, the method comprising administering to the patient an effective amount of a compound of the formula I or the disease.
  • a disease or condition selected from the group consisting of shock, sepsis, acute respiratory distress syndrome, and cerebral edema is included.
  • This embodiment is also included in the above method, wherein the patient also has a respiratory disease or condition.
  • compositions claimed in the present invention also include pharmaceutically acceptable salts and hydrates thereof.
  • Pharmaceutically acceptable salts include metal (inorganic) salts and organic salts, and it is well known to those skilled in the art to select suitable salt forms based on physicochemical stability, fluidity, hygroscopicity and solubility.
  • pharmaceutically acceptable salts include, but are not limited to, salts of inorganic acids such as hydrochlorides, sulfates, phosphates, diphosphates, hydrobromides and nitrates, or salts of organic acids.
  • pharmaceutically acceptable cations include, but are not limited to, sodium, potassium, calcium, aluminum, lithium, and ammonium (especially ammonium salts of secondary amines).
  • Preferred salts of the invention include potassium, sodium, calcium and ammonium salts for the reasons indicated above. Crystal forms, hydrates and solvates of the compounds of formula I are also included within the scope of the invention.
  • pharmaceutically acceptable hydrate refers to a hydrated form of the compound of the invention formed by crystallisation of one or more water molecules.
  • the compounds of the formula I according to the invention may comprise one or more asymmetric centers, thereby enabling racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and diastereomers Form exists.
  • the invention includes all of the above isomeric forms of the compounds of formula I.
  • Some of the compounds of the present invention contain olefinic double bonds, and unless otherwise stated, these double bonds include E and Z geometric isomers.
  • Some of the compounds of the invention may have different hydrogen attachment points, referred to as tautomers.
  • Such an example may be a ketone known as a keto-enol tautomer and its enol form.
  • the compounds of formula I include the individual tautomers and mixtures thereof.
  • the compound of formula I can be isolated as a diastereomeric pair of enantiomers, for example by fractional crystallization using a suitable solvent such as methanol, ethyl acetate or a mixture thereof.
  • a suitable solvent such as methanol, ethyl acetate or a mixture thereof.
  • the enantiomer pair thus obtained can be separated into individual stereoisomers by a conventional method (e.g., using an optically active acid as a resolving agent).
  • the enantiomers of the compounds of formula I can be obtained by stereospecific synthesis using neat optically active starting materials or reagents of known configuration.
  • the invention also includes substantially pure forms or mixtures of stereoisomers of one or more stereoisomers of formula I.
  • the invention includes all such isomers. Since the compound of the present invention has SIP Edgl agonist activity, it is an immunomodulator useful for treating or preventing autoimmune or chronic inflammatory diseases.
  • the compounds of the invention may be used to inhibit the immune system, for example, for bone marrow, organ or graft rejection, autoimmune or chronic inflammatory diseases, including systemic lupus erythematosus, chronic rheumatoid arthritis , type I diabetes, inflammatory bowel disease, biliary cirrhosis, uveitis, multiple sclerosis, Crohn's disease, ulcerative colitis, bullous pemphigoid, sarcoidosis, psoriasis, Autoimmune myositis, Wegener's granulomatosis, ichthyosis, Graves' eye disease, and asthma.
  • the compounds of the invention are also useful for enhancing vascular integrity.
  • the compounds of the invention are useful for the treatment or prevention of a disease or condition selected from the group consisting of organ or tissue transplantation, graft versus host disease caused by transplantation, autoimmune syndrome, including rheumatoid arthritis, systemic erythema Lupus, Hashimoto's thyroiditis, multiple sclerosis, myasthenia gravis, type I diabetes, uveitis, posterior uveitis, allergic encephalomyelitis, glomerulonephritis, autoimmune diseases after infection (including rheumatic fever) And post-infection glomerulonephritis, inflammatory and hyperproliferative skin diseases, rickets, atopic dermatitis, contact dermatitis, eczema dermatitis, seborrheic dermatitis, lichen planus, pemphigus, bullous Pemphigus, bullous epidermolysis, urticaria, angioedema, vasculitis, erythem
  • the compounds of the invention are also useful in the treatment or prevention of Alzheimer's sdi sease.
  • Embodiments of the invention also include a method of preventing or treating graft resistance or transplant rejection of an organ or tissue in a mammalian subject in need of such treatment, the method comprising administering a therapeutically effective amount of a compound of formula I.
  • Another embodiment of the invention is a method of inhibiting the immune system in a mammalian patient in need of such inhibition, the method comprising administering to the patient an effective amount of an immune system a compound of formula I.
  • the methods described herein include a method of treating or preventing bone marrow or organ transplant rejection comprising administering to a mammalian patient in need of such treatment or prevention an effective amount of a bone marrow or organ transplant rejection treatment Formula I or their pharmaceutically acceptable salts or hydrates.
  • the compounds of the invention are also useful in the treatment of respiratory diseases or conditions, such as asthma, chronic bronchitis, chronic obstructive pulmonary disease, adult respiratory distress syndrome, infant respiratory distress syndrome, cough, eosinophilic granuloma, respiratory syncytial virus bronchioles Inflammation, bronchiectasis, idiopathic pulmonary fibrosis, acute lung injury, and obliterative bronchiolitis with organizing pneumonia.
  • respiratory diseases or conditions such as asthma, chronic bronchitis, chronic obstructive pulmonary disease, adult respiratory distress syndrome, infant respiratory distress syndrome, cough, eosinophilic granuloma, respiratory syncytial virus bronchioles Inflammation, bronchiectasis, idiopathic pulmonary fibrosis, acute lung injury, and obliterative bronchiolitis with organizing pneumonia.
  • the compounds of the invention are selective agonists of the SIP Edgl receptor with selectivity superior to the SIP 3 /Edg3 receptor.
  • Edgl selective agonists are superior to existing therapies, broadening the therapeutic window of lymphocyte aggregating agents, resulting in better tolerance at higher doses, thus increasing the efficacy of monotherapy.
  • the pharmaceutical composition of the present invention can be used in various pharmaceutical preparation forms, and comprises a pharmaceutically acceptable carrier and Formula I or a pharmaceutically acceptable salt or hydrate thereof.
  • a second immunosuppressive agent can also be included in the formulation.
  • other immunosuppressive agents include, but are not limited to, azathioprine, buquina sodium, deoxyspermectin, mizar ibine, mycophenolate mofetil, cyclosporin, FK-506, rapamycin , FTY720 and ISAtx247 (Isotechnika), methods of administering a compound of formula I in combination with other immunosuppressive agents, including one or more immunosuppressive agents as described above, are also included in the present invention.
  • the compounds of the invention are useful in the treatment of autoimmune diseases, including prevention of bone marrow transplantation, rejection of foreign organ transplants, and/or related conditions and diseases.
  • the compound of the present invention can be administered by any means as long as the active ingredient compound is in effective contact with the site of action in the warm-blooded animal.
  • it can be administered orally, topically (including transdermal administration), ocular, buccal, intranasal, inhaled, intravaginal, rectal, intracisternal, and parenteral.
  • parenteral is intended to include the following Mode of drug: subcutaneous, intravenous, intramuscular, intra-articular injection or infusion, sternal flesh and intraperitoneal administration.
  • the compounds of the present invention can be administered in a separate preparation or a combined therapeutic agent by any conventional method for combination therapy.
  • These therapeutic agents may be administered alone, but are usually administered in combination with a pharmaceutically acceptable carrier which is selected according to the chosen route of administration and standard pharmaceutical practice.
  • the dosage will depend on the age, health and weight of the recipient, the severity of the disease, the type of combination therapy (if any), the frequency of treatment, and the nature of the desired effect.
  • the daily dose of the active ingredient compound is from about 0.1 to 2000 g/day. Usually, 1-100 grams per day or more can be effectively obtained to achieve the desired effect.
  • These doses are effective amounts for the treatment of autoimmune diseases, prevention of exogenous organ transplant rejection and/or related conditions and diseases.
  • the active ingredient can be administered orally in a solid dosage form (e.g., capsules, tablets, troches, lozenges, granules, and powders) or in liquid form (such as elixirs, syrups, emulsions, dispersions and suspensions).
  • a solid dosage form e.g., capsules, tablets, troches, lozenges, granules, and powders
  • liquid form such as elixirs, syrups, emulsions, dispersions and suspensions.
  • the active ingredient can also be administered parenterally in a sterile liquid form such as a dispersion, suspension or solution.
  • dosage forms may also be used for the administration of active ingredients, such as ointments, creams, drops, transdermal patches or powders for topical administration, ophthalmic solutions or suspensions for ophthalmic administration (ie drops) Eye drops), an aerosol or powder composition for inhaled or intranasal administration, or a cream, ointment, spray or suppository for rectal or vaginal administration.
  • active ingredients such as ointments, creams, drops, transdermal patches or powders for topical administration, ophthalmic solutions or suspensions for ophthalmic administration (ie drops) Eye drops), an aerosol or powder composition for inhaled or intranasal administration, or a cream, ointment, spray or suppository for rectal or vaginal administration.
  • Gelatin capsules contain the active ingredient and a powder carrier, such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, and the like. Similar diluents can be used to prepare compressed tablets. Both tablets and capsules can be prepared as sustained release products for continuous release of the drug over a period of hours. Compressed tablets are sugar coated or film coated to mask any unpleasant taste and to isolate the tablet from the air, or enteric coated for selective disintegration in the gastrointestinal tract.
  • a powder carrier such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, and the like. Similar diluents can be used to prepare compressed tablets. Both tablets and capsules can be prepared as sustained release products for continuous release of the drug over a period of hours. Compressed tablets are sugar coated or film coated to mask any unpleasant taste and to isolate the tablet from the air, or enteric coated for selective disintegration in the gastrointestinal tract.
  • Oral liquid dosage forms can contain coloring and flavoring to increase patient acceptance.
  • water, a suitable oil, saline, aqueous dextrose and related sugar solutions and glycols such as propylene glycol or polyethylene glycol are suitable carriers for parenteral solutions.
  • the solution for parenteral administration preferably comprises a water-soluble salt of the active ingredient, a suitable stabilizer, and if necessary, a buffer substance.
  • Antioxidant eg hydrogen bisulfite alone
  • Sodium, sodium sulfite, ascorbic acid or a combination thereof is a suitable stabilizer.
  • Citric acid and its salts and sodium edetate can also be used.
  • Parenteral solutions may also contain preservatives such as benzalkonium chloride, methyl paraben, propyl paraben and chlorobutanol.
  • the compounds of the invention may conveniently be administered by aerosol spray, which is produced by a pressure pack or nebulizer.
  • the compounds of the invention may also be administered in powder form, the powder may be formulated, and the powder composition may be inhaled by means of a powder inhaler.
  • a preferred delivery system for inhalation is a metered dose inhalation (MDI) aerosol which can be formulated as a suspension or solution of a compound of formula I in a suitable propellant such as a fluorocarbon or hydrocarbon.
  • MDI metered dose inhalation
  • the ophthalmic preparation can be formulated as a solution or suspension of the compound of formula I in a suitable ophthalmic vehicle in a suitable ophthalmic vehicle such that contact of the compound with the ocular surface is maintained for a sufficient period of time to allow for the compound Penetrate the cornea and inner area of the eye.
  • the present invention also includes any one of the following items (1) to (4):
  • a method for treating and/or preventing immunomodulatory abnormalities, respiratory diseases or symptoms, vascular phase integrity diseases or symptoms, cerebral edema or pulmonary edema-related diseases, or anti-inflammatory or hemostasis in a mammalian patient including administration An effective amount of a compound of the invention or a pharmaceutically acceptable salt thereof.
  • a method of modulating the activity of an S1P EDG1 receptor in vivo or in vitro comprising the step of using an effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof.
  • Methods of preparing the compounds of the invention are illustrated by the following description, and one skilled in the art can prepare the compounds of the invention in accordance with the teachings below.
  • a solvent such as N, N-dimethylformamide, dimethyl sulfoxide or dichloromethane, by using carbonic acid clock, sodium carbonate, sodium hydrogencarbonate.
  • the acid produced during the neutralization reaction of triethylamine, the compound ii is prepared by heating or at room temperature; the thio group is thiolated by sodium hydrosulfide to obtain the thioamide compound iii; the thioamide and the bromo ketone compound in methanol .
  • Compound v can be prepared in a suitable solvent using reagents such as thionyl chloride, oxalyl chloride, phosphorus oxychloride and phosphorus pentoxide.
  • Compound V can also be prepared using a condensing agent such as DCC, DIEA, DBU, EDCI or the like; Vi-Pd-C catalytic hydrogenation debenzylation method commonly used by workers in the chemical field to prepare vi, which can be prepared by using cyclohexene, hydrogen or ammonium formate as a hydrogen donor under suitable pressure conditions; a base reaction (the method is similar to the preparation of compound ii); the last use of the compound;
  • a condensing agent such as DCC, DIEA, DBU, EDCI or the like
  • Vi-Pd-C catalytic hydrogenation debenzylation method commonly used by workers in the chemical field to prepare vi, which can be prepared by using cyclohexene, hydrogen or ammonium formate as a hydrogen donor under suitable pressure conditions
  • a base reaction the method is similar to the preparation of compound ii); the last use of the compound;
  • Scheme 2 shows that G is a -NH-formula compound I b (corresponding to Scheme 2)
  • the preparation method of the compound of the formula X firstly, the compound 1 is obtained by using an amino-substituted arylpropionic acid with a thiocyanate clock or ammonium thiocyanate in methanol, ethanol or water; the compound viii and 2-bromo-4, The hydroxyacetophenone is refluxed with various short-chain low-boiling alcohols to obtain the compound ix; the compound ix is obtained by a similar method in the reaction scheme 1, to obtain the final product.
  • alkyl means a straight or branched alkyl group having 1 to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl. Base, etc. d- 6 alkyl can also be similarly understood.
  • alkoxy refers to a straight or branched alkoxy group having from 1 to 4 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy Alkyl, tert-butoxy, etc. Alkoxy or d- 6 alkoxy can also be similarly understood.
  • C 2 -4 alkenyl refers to a straight or branched alkenyl group having 2 to 4 carbon atoms, such as ethenyl, propenyl, butenyl and the like. - 6 alkenyl can also be similarly understood.
  • C 2 -4 alkynyl refers to a straight or branched alkynyl group having 2 to 4 carbon atoms, such as ethynyl, propynyl, butynyl and the like. A similar understanding can also be made for the C 2 -6 alkynyl group.
  • C 3 - 6 cycloalkyl group means a cyclic alkoxy group having 3-6 carbon atoms, for example, each having 3, 4, 5, or cycloalkyl group having 6 carbon atoms.
  • the C 2 -6 alkenyloxy group means an alkenyloxy group having 2 to 6 carbon atoms, for example, an alkenyloxy group having 2, 3, 4, 5, or 6 carbon atoms, respectively.
  • the C 2 -6 alkynyloxy group means an alkynyloxy group having 2 to 6 carbon atoms, for example, an alkynyloxy group having 2, 3, 4, 5, or 6 carbon atoms, respectively.
  • the d- 6 alkylthio group means a linear or branched alkylthio group having 1 to 6 carbon atoms, for example, an alkylthio group having 1, 2, 3, 4, 5, or 6 carbon atoms, respectively.
  • C 3 - 6 cycloalkylthio refers to a cycloalkylthio group having 3 to 6 carbon atoms, for example, a cycloalkylthio group having 3, 4, 5, or 6 carbon atoms, respectively.
  • the C 2 -6 acyloxy group means an acyloxy group having 2 to 6 carbon atoms, for example, an acyloxy group having 2, 3, 4, 5, or 6 carbon atoms, respectively.
  • the melting point was determined by YRT-3 melting point apparatus (temperature uncorrected); mass spectrometry was determined by American ABI API 3000 triple quadrupole tandem mass spectrometer; nuclear magnetic resonance spectrum was determined by JEOL-ECA-400 superconducting instrument 11 (operating frequency) : NMR 400 MHz ) • High resolution mass spectrometry by Buker Hybrid Quadrupole Fourier Transform Ion Cyclotron Resonance Mass Spectrometer (Q-FT-MS). The reagents used in the experiment are chemically pure or analytically pure, and the boiling point of the petroleum ether used. Both are 60 to 90.
  • Example 1 Preparation of 4-benzyloxybenzonitrile
  • the compound iv4. 16g was hydrolyzed with 2M aqueous NaOH solution and heated to 50 for 5 hours. Then, the reaction solution was directly added with concentrated hydrochloric acid to adjust the solution pH 2, and a white solid was precipitated. After filtering off the solid, the filter cake was washed with about 200 ml of water to wash. 0% ⁇ The yield of 95.0%, the yield of 95.0%.
  • 1-24-(4-Benzyloxyphenyl)-4-thiazole acid 1.24g was added to a 50ml eggplant-shaped bottle, and then 10 times the amount of thionyl chloride and 30 ml of anhydrous THF were added, and the reflux condenser was placed above. Dry the tube, heat and reflux for 4 h, then distill off the solvent under reduced pressure and excess thionyl chloride. The dried solid was dissolved in anhydrous THF.
  • the compound v 4.38 g was first added, and then 3.32 g of 10% Pd-C was added slowly, and finally 150 ml of anhydrous methanol was added, and then reacted at 3 atm in a hydrogenation apparatus at room temperature for 24 hours, TLC monitoring. It shows that there is no raw material, there is a new point with a larger polarity. After filtering 10% Pd-C, after concentrating the reaction solution to 50ml, after adding 100ml of water, a large amount of solid is precipitated. After filtering out the solid, use a small amount of water. The product is 3. 15g, yield 88. 2 ° /. .
  • 5 ⁇ PEG-400 ⁇ 40ml ⁇ Add 0. 37g ( 2. 52mmol) of compound vi to a 50m three-necked bottle, add acid-breaking clock 0. 7g (about 2 times the amount), then add a 'j, granules, 0. 5ml PEG-400 and 40ml DMF, After heating to 80 ° C, the reaction is carried out for 30 min, 2 times the amount of RX is added, the reaction time is 2-10 ml, 2 times the amount of water is added to the reaction solution, and then extracted with ethyl acetate (3 ⁇ 50 ml), and the acetic acid is combined. After the ester layer, the organic layer was washed with water and saturated brine, and the solvent was evaporated to dryness under reduced pressure.
  • the mixture was stirred with 2M of LiOH water and tetrahydrofuran solvent, and then reacted for 5 h, TLC monitoring, substantially no starting point, finally added 5% ⁇
  • the yield of the final product is 0. 15g, the yield is 40. 5%.
  • the final product is 0. 15g, the yield is 40. 5%.
  • This compound was prepared according to the preparation method of Example 6, to give 0.46 g of compound vi and bromoisobutane in a yield of 37.1%.
  • the product is obtained by the preparation of the compound 3-(4-((5-(4-isopropoxyphenyl)thiazol-2)amino)phenyl)propanoic acid and bromoisopropane. , yield 12.6%.
  • the temperature of the low temperature reaction tank is lowered to -78. 5.27g ( 21. 96mmo l ) of dried 5-bromo-2-isopropoxybenzonitrile and 50ml of anhydrous THF were added to a 100ml three-necked flask, cooled and protected by nitrogen for about 15 minutes. The needle was pipetted with 13. 2 ml of n-BuLi, and slowly injected into a three-necked bottle. It took about 1 hour to complete the addition, and -78: stirred for 2 hours. After adding 11. Olg (47.83mmo l) tributyl borate reaction 1.
  • Example 39 Preparation of ethyl 3-methyl-4-(5-bromothiazol-2-yl)benzenepropanoate 7.03 g (25.52 mmol) 3-methyl-4-(thiazol-2-yl)benzene Ethyl propionate was added to a 100 ml three-necked flask, and then 4.31 g (52.54 mmol) of sodium acetate, 50 ml of glacial acetic acid was added, and stirred. A 1.5 ml (about 29.29 mmol) bromine was pipetted into a 50 ml dropping funnel, diluted with 20 ml of glacial acetic acid, and bromine was slowly added dropwise.
  • Example 47 The reaction procedure is similar to that of Example 47, which is prepared from the compound 3-(4-(4-(3-bromo-4-hydroxyphenyl)thiazol-2-imino)phenyl)propanoic acid and bromopropane. Rate: 14.6%.
  • Example 47 The reaction procedure is similar to that of Example 47, which is prepared from the compound 3-(4-(4-(3-bromo-4-hydroxyphenyl)thiazole-2-imino)phenyl)propanoic acid and bromocyclopentane. Yield: 9. 12%.
  • Example 47 The reaction procedure is similar to that of Example 47, which is prepared from the compound 3-(4-(4-(3-bromo-4-hydroxyphenyl)thiazole-2-imino)phenyl)propanoic acid and bromoisobutane. Yield: 11.3%.
  • Example 47 The reaction procedure is similar to that of Example 47, which is prepared from the compound 3-(4-(4-(3-bromo-4-hydroxyphenyl)thiazole-2-imino)phenyl)propanoic acid and bromobutane. Rate: 19. 43°/. .
  • Example 53 Preparation of 2-bromo-1-(4-chloro-3-methoxyphenyl)ethanone The reaction procedure was similar to that of Example 42, using the compound 2-chloroanisole and bromoacetyl bromide. Yield: 98. 6°/o 0
  • Example 59 Preparation of 3-(4-(4-(3-chloro-4-isobutoxyphenyl)thiazole-2-imino)phenyl)propanoic acid
  • the reaction procedure was similar to that of Example 47, which was prepared from the compound 3-(4-(4-(3-chloro-4-hydroxyphenyl)thiazole-2-imino)phenyl)propanoic acid and bromoisobutane. , Yield: 11.9%.
  • Example 47 The reaction procedure was similar to that of Example 47, which was prepared from the compound 3-(4-(4-(3-chloro-4-hydroxyphenyl)thiazole-2-imino)phenyl)propanoic acid and bromocyclopentane. , Yield: 11. 2%.
  • Example 47 The reaction procedure was similar to that of Example 47, which was prepared from the compound 3-(4-(4-(3-chloro-4-hydroxyphenyl)thiazole-2-imino)phenyl)propanoic acid and bromoisopentane. , Yield: 20. 0%.
  • Example 47 The reaction procedure is similar to that of Example 47, which is prepared by using the compound 2-(4-(4-(3-chloro-4-hydroxyphenyl)thiazole-2-imide)phenyl)acetic acid and bromocyclopentane. Rate: 24.8%.
  • Cell culture medium DMEM high glucose medium containing 0.5 mg/ml G418 and 10%
  • FBS Analytical medium F12 medium containing lOmM HEPES, 0.1% defatting BSA
  • the analytical medium of DMS0 was used as a 4 Control control working solution at a final concentration of 1%.
  • the sieved compound was formulated into a 30 mM mother liquor by DMS0, and diluted to a continuous concentration gradient of 1000 X mother liquor by DMS0 ratio, and then analyzed to prepare a 4 X working solution.
  • the final concentration of ⁇ and 3 ⁇ was selected for the initial selection.
  • the final concentration of 30 ⁇ , ⁇ , 300 ⁇ , 1 ⁇ , 3nM, 10nM, 30nM, 100nM, 300nM, 1 ⁇ , 3 ⁇ , 10 ⁇ was selected according to the gradient of the compound activity.
  • a dose-effect relationship is made for six to eight consecutive concentrations.
  • U20S cells stably expressing the EGFP-SPiPi fusion protein, 5% CO 2 were cultured in DMEM high glucose medium containing 0.5 mg/ml G418 and 10% FBS.
  • the cells were seeded in a 96-well black-bottomed cell culture plate according to the cells at 0.8x10 4 ⁇ /well, and cultured in 5% CO 2 for 18-24 hours.
  • the cells were washed once with 200 ⁇ l/well assay medium, and 150 ⁇ l/well assay medium was added and incubated for 37 min at 37 5% CO 2 .
  • Compound agonistic intensity (the total area of particles per cell contained in the compound-treated group - the total area of particles per cell contained in the Control control treatment group) I Control The total area of particles per cell contained in the control treatment group.
  • the excitation intensity was calculated by taking the average of 15 fields (5 per well) in 3 wells measured in parallel for each test concentration point of the compound.
  • the first initial screening was carried out at two final concentrations of ⁇ and 3 ⁇ M.
  • the experimental results are shown in Table 2.
  • the preliminary screening results show that the embodiment 6, the embodiment 12, the embodiment 21, the embodiment 22, the embodiment 45, the embodiment 47, the embodiment 48, the embodiment 49, the embodiment 50, the embodiment 52, the embodiment 56, and the implementation In Example 59 and Example 70, respectively, the agonistic activity reached 3 or more standard deviations at 3 ⁇ , and further screening was possible.
  • the EGFP-S1P!_U20S cell is a commercial cell strain of a compound used by the American company to screen for the S1P1 receptor, and the SIP receptor is activated after endocytosis, which is represented by the aggregation of the green fluorescent protein reporter gene in the cytoplasmic granule. Therefore, a compound having an agonistic activity on the SI receptor can cause a change in the reporter molecule £0??-31? 1 .
  • the agonist S1P activates S1 and causes its endocytic formation of particle aggregation, which is about 2- to 3-fold at 10 nM and about 5-6 times at 250 nM.
  • the agonistic activity at 1 ⁇ is approximately 7-8 times its EC 5 .
  • the value is approximately 25 nM.

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Abstract

Disclosed is as represented by Formula I a compound or a pharmaceutically acceptable salt thereof. The compound or the pharmaceutically acceptable salt thereof of the present invention can be used as an immunosuppressant. By regulating the transport of leukocytes, and by regulating the cellular transport of lymphocytes, the lymphocytes are gathered in secondary lymphoid tissues, thus improving the integrity of blood vessels to allow for immunosuppression effect, anti-inflammatory activity, and hemostatic effect.

Description

苯丙酸化合物、 其制备方法及其医药用途 技术领域  Phenylpropionic acid compound, preparation method thereof and medical use thereof
本发明属于医药化工领域， 涉及苯丙酸化合物或其药学上可接受 的盐、 包含它们的药物组合物、 它们的制备方法、 以及它们的医药用 途。 这些化合物是 S1P EDG1 受体激动剂， 通过调节白细胞运输， 调 节淋巴细胞细胞转运， 使淋巴细胞聚集在次级淋巴组织， 提高血管的 完整性而发挥免疫抑制作用， 抗炎活性以及止血作用。 背景技术  The present invention relates to the field of pharmaceutical and chemical engineering, and relates to a phenylpropionic acid compound or a pharmaceutically acceptable salt thereof, a pharmaceutical composition comprising the same, a process for the preparation thereof, and a pharmaceutical use thereof. These compounds are S1P EDG1 receptor agonists, which regulate lymphocyte transport, regulate lymphocyte cell transport, accumulate lymphocytes in secondary lymphoid tissues, and enhance vascular integrity to exert immunosuppressive, anti-inflammatory and hemostatic effects. Background technique
已经证实免疫抑制药和抗炎药可用于许多自身免疫性疾病和慢性 炎性疾病（包括系统性红斑狼疮、 慢性类风湿性关节炎、 I型糖尿病、 炎性肠病、 胆汁性肝硬化、 葡萄膜炎、 多发性硬化以及其它疾病， 例 如节段性回肠炎、 溃疡性结肠炎、 大疱性类天疱疮、 结节病、 银屑病、 自身免疫性肌炎、 韦格纳肉芽肿病、 鱼鳞病、 格雷夫斯眼病、 特应性 皮炎和哮喘、慢性肺病、 急性肺损伤、 急性呼吸窘迫综合征和脓毒病。 还证实它们可用于治疗癌症、 淋巴瘤和白血病的化疗方案。  Immunosuppressive and anti-inflammatory drugs have been shown to be useful in many autoimmune and chronic inflammatory diseases (including systemic lupus erythematosus, chronic rheumatoid arthritis, type I diabetes, inflammatory bowel disease, biliary cirrhosis, grapes) Membrane inflammation, multiple sclerosis, and other diseases such as Crohn's disease, ulcerative colitis, bullous pemphigoid, sarcoidosis, psoriasis, autoimmune myositis, Wegener's granulomatosis , ichthyosis, Graves' eye disease, atopic dermatitis and asthma, chronic lung disease, acute lung injury, acute respiratory distress syndrome and sepsis. They have also been shown to be useful in the treatment of cancer, lymphoma and leukemia chemotherapy regimens.
尽管上述各种疾病的基础发病机理可能完全不同， 但是它们的共 同之处是激活免疫系统以及出现各种自身抗体、自反应性淋巴细胞和 I 或激活参与先天免疫的细胞。 这样的自反应性可能是部分因为丧失体 内平衡控制而造成，正常的免疫系统在体内平衡控制下运行。类似地， 在骨髓或器官移植之后， 宿主免疫细胞识别外来的组织抗原， 并开始 产生细胞应答和体液应答， 包括导致移植排斥反应的抗体、 细胞因子 和细胞毒性淋巴细胞。  Although the underlying pathogenesis of the various diseases mentioned above may be quite different, they share a commonality in the activation of the immune system as well as the appearance of various autoantibodies, autoreactive lymphocytes and I or activation of cells involved in innate immunity. Such self-reactivity may be due in part to loss of intra-body balance control, and the normal immune system operates under homeostatic control. Similarly, after bone marrow or organ transplantation, host immune cells recognize foreign tissue antigens and begin to produce cellular and humoral responses, including antibodies, cytokines, and cytotoxic lymphocytes that cause transplant rejection.
自身免疫作用或排斥作用的一种最终后果是增加血管通透性以及 由炎性细胞和它们释放的介质引起的组织破坏作用。 抗炎药（例如 NSAID)主要通过阻滞上述介质的作用或分泌而起作用， 但不能改善疾 病的免疫基础。 另一方面， 细胞毒性药 （例如环磷酰胺） 以非特异性 方式作用， 使得正常应答和自身免疫应答均被阻断。 事实上， 与死于 自身免疫性疾病一样， 用这样的非特异性免疫抑制药治疗的患者很可 能死于感染。 A final consequence of autoimmunity or rejection is increased vascular permeability and tissue destruction caused by inflammatory cells and the media they release. Anti-inflammatory drugs (such as NSAIDs) act primarily by blocking the action or secretion of the above mediators, but do not improve the immune basis of the disease. On the other hand, cytotoxic drugs (such as cyclophosphamide) act in a non-specific manner such that both normal and autoimmune responses are blocked. In fact, with death Like autoimmune diseases, patients treated with such non-specific immunosuppressive drugs are likely to die from infection.
环孢菌素 A是一种预防移植器官排斥反应的药物。 FK- 506是另一 种被批准用于预防移植器官 （尤其是肝脏移植）排斥反应的药物。 身 体免疫系统动员它的巨大天然保护因子库以排斥移植的外来蛋白， 环 孢菌素 A和 FK-506就是通过抑制免疫系统而起作用。环孢菌素 A被批 准用于治疗严重的银屑病， 并且已被欧洲管理机构批准用于治疗特应 性皮炎。  Cyclosporin A is a drug that prevents rejection of transplanted organs. FK-506 is another drug approved for the prevention of rejection in transplanted organs, especially liver transplants. The body's immune system mobilizes its vast pool of natural protective factors to reject transplanted foreign proteins, and cyclosporin A and FK-506 act by suppressing the immune system. Cyclosporin A is approved for the treatment of severe psoriasis and has been approved by European regulatory agencies for the treatment of atopic dermatitis.
尽管环孢菌素 A和 FK- 506有效延迟或抑制移植排斥反应，但是它 们可引起多种不良副作用， 包括肾毒性、神经毒性和胃肠不适。 因此， 仍然需要开发没有上述副作用的免疫抑制剂， 并且也非常需要这样的 免疫抑制剂。  Although cyclosporin A and FK-506 are effective in delaying or inhibiting transplant rejection, they can cause a variety of adverse side effects including nephrotoxicity, neurotoxicity and gastrointestinal discomfort. Therefore, there is still a need to develop immunosuppressive agents which do not have the above-mentioned side effects, and such immunosuppressive agents are also highly desirable.
免疫抑制剂 FTY720 是目前已经上市的用于治疗多发性硬化的药 物。 FTY720在哺乳动物体内代谢为鞘氨醇 1-磷酸受体的有效激动剂化 合物。 激动鞘氨醇 1-磷酸受体将调节白细胞运输， 诱导淋巴细胞（T 细胞和 B细胞）在淋巴结中聚集而不会造成淋巴细胞缺乏， 并且不破 坏脾构造， 由此干扰 T细胞依赖性抗体应答。 S1P受体激动剂迹通过 增强内皮完整性以及抑制激活免疫系统引发的血管损伤而具有抗炎特 性。 需要这样的免疫抑制和消炎作用来防止器官移植后的排斥反应， 治疗自身免疫性疾病以及治疗主要缺陷在于血管完整性的疾病， 例如 急性肺损伤、 急性呼吸窘迫综合征和脓毒病。  The immunosuppressant FTY720 is currently marketed for the treatment of multiple sclerosis. FTY720 is metabolized in mammals to an effective agonist compound of the sphingosine-1-phosphate receptor. The sphingosine 1-phosphate receptor regulates leukocyte trafficking, induces lymphocytes (T cells and B cells) to accumulate in lymph nodes without causing lymphocyte deficiency, and does not destroy the spleen structure, thereby interfering with T cell-dependent antibodies. Answer. S1P receptor agonist traces have anti-inflammatory properties by enhancing endothelial integrity and inhibiting vascular damage caused by activation of the immune system. Such immunosuppressive and anti-inflammatory effects are required to prevent rejection after organ transplantation, to treat autoimmune diseases, and to treat diseases whose major defects are vascular integrity, such as acute lung injury, acute respiratory distress syndrome, and sepsis.
鞘氨醇 1-磷酸是有生物活性的鞘脂类代谢物， 由造血细胞分泌， 贮存在血小板内并从活血小板幹放。 它作为激动剂作用于 G蛋白偶联 受体家族以调节细胞增殖、 分化、 存活以及运动。  Sphingosine 1-phosphate is a biologically active sphingolipid metabolite secreted by hematopoietic cells, stored in platelets and released from living platelets. It acts as an agonist on the G protein-coupled receptor family to regulate cell proliferation, differentiation, survival, and movement.
给予动物鞘氨醇 1-磷酸将诱导外周血中淋巴细胞聚集到次级淋 巴器官， 由此产生有用的治疗性免疫抑制作用。 然而， 鞘氨醇 1-磷酸 还具有心血管及支气管收缩作用， 这类作用限制了它作为治疗药物的 用途。 静脉给予鞘氨醇 1-磷酸将使大鼠的心率减少、 心室收缩减弱和 血压降低。 在人气道平滑肌细胞中， 鞘氨醇 1一磷酸调节促进支气管 收缩、 气道炎症以及哮喘中气道重塑的收缩、 细胞生长以及细胞因子 的产生。鞘氨醇 1-磷酸的不良作用与它对所有 S1P受体的非选择性有 效激动剂活性有关。 Administration of the sphingosine 1-phosphate to the animal induces the accumulation of lymphocytes in the peripheral blood to the secondary lymphoid organs, thereby producing a useful therapeutic immunosuppressive effect. However, sphingosine 1-phosphate also has cardiovascular and bronchoconstrictive effects, and such effects limit its use as a therapeutic drug. Intravenous administration of sphingosine 1-phosphate will reduce heart rate, ventricular contraction, and blood pressure in rats. In human airway smooth muscle cells, sphingosine 1 -phosphate regulates bronchial growth Contraction, airway inflammation, and contraction of airway remodeling in asthma, cell growth, and cytokine production. The adverse effects of sphingosine 1-phosphate are related to its non-selective potent agonist activity on all S1P receptors.
因此需要寻找 SlPl / Edgl 受体的激动剂， 它们相对 SlP3/Edg3 受体具有选择性。 SlP Edgl 受体选择性激动剂相对现有疗法具有优 势， 拓宽了淋巴细胞聚集药和血管完整药的治疗窗， 使得在较高给药 剂量下具有更好的耐受性， 因此提高单一疗法的功效。  Therefore, it is necessary to look for agonists of the SlPl / Edgl receptor, which are selective for the SlP3/Edg3 receptor. SlP Edgl receptor selective agonists have advantages over existing therapies, broadening the therapeutic window of lymphocyte aggregation drugs and vascular intact drugs, resulting in better tolerance at higher doses, thus increasing monotherapy efficacy.
虽然免疫抑制剂和抗炎剂主要用于治疗骨髓、 器官以及移植物的 排斥反应， 但是这些化合物的其它用途包括治疗关节炎（特别是类风 湿性关节炎） 、 胰岛素依赖性糖尿病、 非胰岛素依赖性糖尿病、 多发 性硬化、 银屑病、 炎性肠病、 节段性回肠炎、 红斑狼疮、 哮喘、 变态 反应、 慢性肺病、 急性肺损伤、 急性呼吸道疾病、 脓毒病等。 发明内容  Although immunosuppressants and anti-inflammatory agents are mainly used to treat bone marrow, organs and graft rejection, other uses of these compounds include the treatment of arthritis (especially rheumatoid arthritis), insulin-dependent diabetes, non-insulin dependence. Diabetes, multiple sclerosis, psoriasis, inflammatory bowel disease, Crohn's disease, lupus erythematosus, asthma, allergies, chronic lung disease, acute lung injury, acute respiratory disease, sepsis, etc. Summary of the invention
本发明者在研究中出人意料发现下面的通式 I 化合物是 SlPi/EDGl受体激动剂，其通过调节白细胞运输，调节淋巴细胞细胞转 运， 使淋巴细胞聚集在次级淋巴组织， 提高血管的完整性而发挥免疫 抑制作用， 抗炎活性以及止血作用。 因此， 本发 ：  The present inventors have unexpectedly discovered in the study that the following compound of formula I is a SlPi/EDG1 receptor agonist which regulates lymphocyte transport by regulating leukocyte trafficking, allowing lymphocytes to accumulate in secondary lymphoid tissues and improving vascular integrity. It exerts immunosuppressive effects, anti-inflammatory activity and hemostasis. Therefore, this issue:
R 1 R 1
Figure imgf000004_0001
Figure imgf000004_0001
I  I
其中：  among them:
K独立地选自 - C00H, -P03H, -P02H2, - S03H， -0 (P03) H; K is independently selected from - C00H, -P0 3 H, -P0 2 H 2 , - S0 3 H, -0 (P0 3 ) H;
U、 V、 W和 J独立地选自- C (R2) -和 - N-， 构成取代或者未被取代的 六元芳香环； U, V, W and J are independently selected from -C(R 2 ) - and -N-, and constitute a substituted or unsubstituted six-membered aromatic ring;
其中 R2独立地选自 -H、 - F、 - Cl、 -Br, -1、 - CN、 -OH, d-4烷基、Wherein R 2 is independently selected from the group consisting of -H, -F, -Cl, -Br, -1, -CN, -OH, d- 4 alkyl,
C2-4 ^ ¾- > C2-4 ^和 Cl-4 ^^α-¾- ) 上述的 CH烷基、 CH烯基、 CH炔基和 CH烷氧基各自任选被独立 地选自以下的取代基取代： - F、 - C l、 -Br , -1、 -OH和 d—8烷氧基；C2-4 ^ 3⁄4- > C2-4 ^ and Cl-4 ^^α-3⁄4- ) The above CH alkyl, CH alkenyl, CH alkynyl and CH alkoxy groups are each optionally substituted with a substituent independently selected from the group consisting of: - F, - C l, -Br, -1, -OH and d - 8 alkoxy;
A环和 B环（分别表示六元芳香杂环或者苯环和五元芳香杂环，虚 线表示 1-3个双键 )可以直接连接或者通过 G连接； The A ring and the B ring (respectively represent a six-membered aromatic heterocyclic ring or a benzene ring and a five-membered aromatic heterocyclic ring, and the dotted line represents 1-3 double bonds) may be directly linked or connected via G;
其中 A环和 B环可以直接连接时， J和 W同时为 -N=;  Where A and B rings can be directly connected, J and W are both -N=;
其中 G可以是 d-3烷基， C2-4烯基， C2-4炔基， - N- R3-、 - 0- R3-、 -S- R3 -、 - Se- R3-、 - C (=0) - R3-、 - C (=0) NH- R3-、 - C (=0) 0- R3-、 -C (=S) - R3 -、 - C (=S) NH- R3-、 -C (=Se) - R3-、 -C (=Se) NH- R3-; Wherein G may be d- 3 alkyl, C 2 -4 alkenyl, C 2 -4 alkynyl, -N-R 3 -, - 0- R 3 -, -S-R 3 -, - Se- R 3 -, - C (=0) - R 3 -, - C (=0) NH- R 3 -, - C (=0) 0- R 3 -, -C (=S) - R 3 -, - C (=S) NH- R 3 -, -C (=Se) - R 3 -, -C (=Se) NH- R 3 -;
其中所述 d-3烷基， C2-4烯基， C2-4炔基各自任选被 -F、 - Cl、 -Br、 - 1、 -OH , - CN、 CH烷基及 CH烷氧基取代； Wherein the d- 3 alkyl group, C 2 -4 alkenyl group, C 2 -4 alkynyl group are each optionally selected from -F, -Cl, -Br, -1, -OH, -CN, CH alkyl and CH alkane Oxygen substitution;
R3可以是 H、 d-3烷基， C2-4烯基， C2-4炔基， 其中所述的 d-3烷基， C2-4烯基， C2-4炔基各自任选被- F、 - C l、 -Br , -1、 -OH, - CN、 CH烷基 及 CH烷氧基取代； R 3 may be H, d- 3 alkyl, C 2 -4 alkenyl, C 2 -4 alkynyl, wherein the d- 3 alkyl, C 2 -4 alkenyl, C 2 -4 alkynyl are each Optionally substituted with -F, -C1, -Br, -1, -OH, -CN, CH alkyl and CH alkoxy;
X、 Y和 Z独立地选自- C (R4) =、 - C (=R5) -、 - 0-、 - N=、 - N (R6) -、 -S -和 -Se-， 这样所得 Q和 T构成杂环； X, Y and Z are independently selected from - C (R 4 ) =, - C (= R 5 ) -, - 0-, - N =, - N (R 6 ) -, -S - and -Se-, The Q and T thus obtained constitute a heterocyclic ring;
Q和 Τ独立地选自
Figure imgf000005_0001
； R\ R5和 R6各自独立地选自- H、 d-6烷基、 C2—6烯基、 C2—6炔基和 d—6 烷氧基， 上述 d-6烷基、 C2-6烯基、 C2-6炔基和 d-6烷氧基各自任选被- F、 - Cl、 -Br , -1、 -OH, - CN、 d— 4烷基及 d— 4烷氧基取代； Q and Τ are independently selected from
Figure imgf000005_0001
; R \ R 5 and R 6 are each independently selected from - H, d- 6 alkyl, C 2 - 6 alkenyl, C 2 - 6 alkynyl, and d- 6 alkoxy, d- 6 alkyl group described above, C 2 -6 alkenyl, C 2 -6 alkynyl and d- 6 alkoxy are each optionally -F, -Cl, -Br, -1, -OH, -CN, d- 4 alkyl and d- 4 alkoxy substituted;
R1选自苯基、 嘧啶基、 吡啶基、 吡嗪基、 哒嗪基、 噻吩基和噻唑 基， 其中所述各基团任选自以下取代基取代： - F、 - Cl、 -Br , -1、 -0H、 - CN、 - NR7R8、 - N02、 苯基、 苄基、 苄氧基、 d—6烷基、 （3—6环烷基、 C2—6 婦基、 。2—6块基、 Ci-燒 ¾^、 C3-6环燒 基、 C2-6婦氧基基、 C2-6块 ί^、 d-6烷硫基、 C3-6环烷硫基和 C2-6酰氧基， 上述苯基、 苄基和苄氧基可以 被 1 - 3个以下的取代基取代： - F、 - Cl、 -Br , -1、 - CN、 - NR7R8、 - N02; R 1 is selected from the group consisting of phenyl, pyrimidinyl, pyridyl, pyrazinyl, pyridazinyl, thienyl and thiazolyl, wherein each of the groups is optionally substituted with the following substituents: - F, - Cl, -Br, -1, -0H, - CN, - NR 7 R 8, - N0 2, phenyl, benzyl, benzyloxy, d- 6 alkyl, (3 - 6 cycloalkyl group, C 2 - 6 women group, .2-6 block group, Ci- burning ¾ ^, C3-6 cycloalkyl group burning, C2-6 women oxo group, C2-6 block ί ^, d- 6 alkylthio, C 3 - 6 cycloalkylthio And C 2 -6 acyloxy, the above phenyl, benzyl and benzyloxy may be substituted by 1 - 3 or less substituents: - F, - Cl, -Br, -1, - CN, - NR 7 R 8 , - N0 2 ;
R7和 R8独立地选自- H、 d-6烷基、 C2-6烯基和 C2-6炔基， 其中所述的 d-6烷基、 C2-6烯基和 C2-6炔基各自任选被独立地选自以下的取代基取 代： - F、 - Cl、 - Br、 -1、 -OH, - CN和 d—6烷氧基； R7和 R8可以与它们连接的氮原子一起构成 3- 8个原子的饱和单环， 其中任选包含 1-2个氧原子， 所述环任选独立地选自以下的取代基取 代： - F、 - Cl、 - Br、 -1、 -OH, - CN和 d—6烷氧基。 本发明的一个优选实施方案中， 包含这样式 I的化合物： 其中 U、 V、 J和 W为 -CH -。 本发明的一个优选实施方案中，通式 I化合物为式 la的化合物或 其可药用盐： R 7 and R 8 are independently selected from -H, d- 6 alkyl, C 2 -6 alkenyl and C 2 -6 alkynyl, wherein said d- 6 alkyl, C 2 - 6 alkenyl and C The 2 - 6 alkynyl groups are each optionally substituted with a substituent independently selected from the group consisting of: - F, - Cl, - Br, -1, -OH, - CN and d- 6 alkoxy; R 7 and R 8 may together with the nitrogen atom to which they are attached form a saturated monocyclic ring of from 3 to 8 atoms, optionally containing from 1 to 2 oxygen atoms, optionally substituted with a substituent selected from the group consisting of: - F, - Cl, -Br, -1, -OH, - CN and d- 6 alkoxy. In a preferred embodiment of the invention, there is included a compound of formula I: wherein U, V, J and W are -CH-. In a preferred embodiment of the invention, the compound of formula I is a compound of formula la or a pharmaceutically acceptable salt thereof:
Figure imgf000006_0001
Figure imgf000006_0001
( la) (la)
其中：  among them:
上述的 J和 W独立地选自- C(R4)-和- N -， 构成取代或者未被取代 的六元芳香环； The above J and W are independently selected from -C(R 4 )- and -N -, and constitute a substituted or unsubstituted six-membered aromatic ring;
其中 R4独立地选自 -H、 - F、 - Cl、 - Br、 - 1、 - CN、 - 0Η、 CH烷基、Wherein R 4 is independently selected from the group consisting of -H, -F, -Cl, -Br, -1, -CN, -0Η, CH alkyl,
。2一4^^>¾^、 。2— 4 ^和 Cl-4
Figure imgf000006_0002
. 2 a 4 ^ ^ > 3⁄4 ^, . 2-4 ^ and Cl-4
Figure imgf000006_0002
上述的 CH烷基、 C2-4烯基、 C2-4炔基和 CH烷氧基各自任选被独立 地选自以下的取代基取代： - F、 - Cl、 -Br, -1、 -OH和 d—8烷氧基；The above CH alkyl group, C 2 -4 alkenyl group, C 2 -4 alkynyl group and CH alkoxy group are each optionally substituted with a substituent independently selected from the group consisting of: - F, - Cl, -Br, -1. -OH and d- 8 alkoxy;
A环和 B环可以直接连接或者通过 G连接； The A ring and the B ring can be directly connected or connected through G;
其中 A环和 B环可以直接连接时， J和 W同时为 -N=;  Where A and B rings can be directly connected, J and W are both -N=;
其中 G可以是 d-3烷基， C2-4烯基， C2-4炔基， - N- R4-、 -0- R4 -、 -S- R4-、 -Se- R4-、 -C (=0) - R4-、 -C (=0) NH- R4-、 -C (=0) 0- R4 -、 -C (=S) - R4-、 -C (=S) NH- R4-、 -C (=Se) - R4-、 - C(=Se)NH- R4-; Wherein G may be d- 3 alkyl, C 2 -4 alkenyl, C 2 -4 alkynyl, -N-R 4 -, -0- R 4 -, -S- R 4 -, -Se- R 4 -, -C (=0) - R 4 -, -C (=0) NH- R 4 -, -C (=0) 0- R 4 -, -C (=S) - R 4 -, -C (=S) NH- R 4 -, -C (=Se) - R 4 -, - C(=Se)NH- R 4 -;
其中所述 d-3烷基， C2-4烯基， C2-4炔基各自任选被选自以下 - F、- C 1、 -Br, -1、 -OH, - CN、 d-4烷基及 CH烷氧基基团取代； Wherein the d- 3 alkyl group, C 2 -4 alkenyl group, C 2 -4 alkynyl group are each optionally selected from the group consisting of -F, -C1, -Br, -1, -OH, -CN, d- Substituted with a 4- alkyl and CH alkoxy group;
R4可以是 H、 d-3烷基， C2-4烯基， C2-4炔基， 其中所述的 d-3烷基， C2-4烯基， C2-4炔基各自任选被- F、 - Cl、 -Br, -1、 -OH, - CN、 CH烷基 及 CH烷氧基取代； R 4 may be H, d- 3 alkyl, C 2 -4 alkenyl, C 2 -4 alkynyl, wherein said d- 3 alkyl, C 2 -4 alkenyl, C 2 -4 alkynyl are each optionally substituted by -F, -Cl, -Br, -1, -OH, -CN, CH alkyl and CH alkoxy;
X、 Y和 Z独立地选自- C(R4)=、 - C(=R5)-、 - 0-、 - N=、 - N(R6)-、 - S -和- Se-X, Y and Z are independently selected from -C(R 4 )=, -C(=R 5 )-, - 0-, -N=, -N(R 6 )-, -S - and -Se-
R5、 R6和 R7各自独立地选自 -H、 d-6烷基、 C2-6烯基、 C2-6炔基和 (^-6烷氧基， 上述 d-6烷基、 C2-6烯基、 C2-6炔基和 d-6烷氧基各自任选 被- F、 - Cl、 -Br, -1、 -OH, - CN、 d-4烷基及 d-4烷氧基取代； R 5 , R 6 and R 7 are each independently selected from -H, d- 6 alkyl, C 2 -6 alkenyl, C 2 -6 alkynyl and (^ -6 alkoxy, above d- 6 alkyl , C 2 -6 alkenyl, C 2 -6 alkynyl and d- 6 alkoxy are each optionally -F, -Cl, -Br, -1, -OH, -CN, d- 4 alkyl and d - 4 alkoxy substituted;
U和 V各自任选独立地选自 C和 N;  Each of U and V is optionally independently selected from C and N;
R1 ， R2和 R3各自任选独立地选自以下取代基取代： - F、 - Cl、 -Br、 - 1、 -OH, - CN、 - NR8R9、 - N02、 苯基、 苄基、 苄氧基、 d—6烷基、 C3—6 环燒基、 。2—6婦基、 。2—6块基、 Cl-燒 基、 C3—6环燒 基、 。2—6婦 基Ϊ^、Each of R 1 , R 2 and R 3 is optionally independently selected from the group consisting of: - F, - Cl, -Br, -1, -OH, - CN, -NR 8 R 9 , - N0 2 , phenyl , benzyl, benzyloxy, d- 6 alkyl, C 3 - 6 cycloalkyl group burning. 2-6 women's base,. 2-6 blocks, Cl-alkyl, C3-6 ring base. 2-6 women's base Ϊ ^,
C2-6炔氧基、 （^6烷硫基、 C3-6环烷硫基和 C2-6酰氧基， 上述苯基、 苄基 和苄氧基可以被 1 -3个以下的取代基取代： - F、 - Cl、 -Br, -1、 -CN、 -NR7R8、 -N02; C 2 - 6 alkynyl group, (6 ^ alkylthio, C 3 - 6 cycloalkyl group and a C 2 - 6 acyloxy, where the phenyl, benzyl and benzyloxy may be 1-3 or less Substituent substitution: - F, - Cl, -Br, -1, -CN, -NR 7 R 8 , -N0 2 ;
R8和 R9独立地选自- H、 d-6烷基、 C2-6烯基和 C2-6炔基， 其中所述 的 d-6烷基、 C2-6烯基和 C2-6炔基各自任选被独立地选自以下的取代基 取代： - F、 - Cl、 -Br, -1、 -OH, - CN和 d—6烷氧基； R 8 and R 9 are independently selected from -H, d- 6 alkyl, C 2 -6 alkenyl and C 2 -6 alkynyl, wherein said d- 6 alkyl, C 2 - 6 alkenyl and C The 2 - 6 alkynyl groups are each optionally substituted with a substituent independently selected from the group consisting of: - F, - Cl, -Br, -1, -OH, - CN and d- 6 alkoxy;
R8和 R9可以与它们连接的氮原子一起构成 3-8 个原子的饱和单 环， 其中任选包含 1-2个氧原子， 所述环任选独立地选自以下的取代 基取代： - F、 - Cl、 -Br, -1、 -OH, - CN和 d—6烷氧基。 R 8 and R 9 may, together with the nitrogen atom to which they are attached, form a saturated monocyclic ring of 3-8 atoms, optionally containing 1-2 oxygen atoms, optionally substituted with a substituent selected from the group consisting of: - F, - Cl, -Br, -1, -OH, - CN and d- 6 alkoxy.
上述 C环可以是六元芳香杂环或者苯环，虚线表示 1-3个双键。 本发明的另一个实施方案中， 通式 I化合物为式 I b的化合物或 者其药学上可  The above C ring may be a six-membered aromatic heterocyclic ring or a benzene ring, and the broken line represents 1-3 double bonds. In another embodiment of the invention, the compound of formula I is a compound of formula I b or is pharmaceutically acceptable
Figure imgf000007_0001
Figure imgf000007_0001
( l b ) 上述的 J和 W独立地选自- C(R4)-和- N -， 构成取代或者未被取代 的六元芳香环； ( lb ) The above J and W are independently selected from -C(R 4 )- and -N -, and constitute a substituted or unsubstituted six-membered aromatic ring;
其中 R4独立地选自 -H、 - F、 - Cl、 -Br, -1、 -CN、 -0H、 CH烷基、Wherein R 4 is independently selected from the group consisting of -H, -F, -Cl, -Br, -1, -CN, -0H, CH alkyl,
C2-4 ^¾-> C2-4 ^和 Cl-4 ^^α-¾-) C2-4 ^3⁄4-> C2-4 ^ and Cl-4 ^^α-3⁄4-)
上述的 CH烷基、 CH烯基、 C2-4炔基和 CH烷氧基各自任选被独立 地选自以下的取代基取代： - F、 - Cl、 -Br, -1、 -OH和 d—8烷氧基； A环和 B环通过 G连接； The above CH alkyl, CH alkenyl, C 2 -4 alkynyl and CH alkoxy groups are each optionally substituted with a substituent independently selected from the group consisting of: - F, - Cl, -Br, -1, -OH and D- 8 alkoxy; A ring and B ring are linked by G;
其中 G有选自以下基团： d—3烷基， C2-4烯基， C2-4块基， - N- R4 -、 -O-R4-、 - S- R4-、 - Se- R4-、 - C(=0)- R4-、 - C (=0) NH- R4-、 -C (=0) 0- R4 -、 -C (=S) - R4-、 -C (=S) NH- R4-、 - C(=Se)- R4-、 -C (=Se) NH- R4 其中所述 d-3烷基， C2-4烯基， C2-4炔基各自任选被 -F、 - Cl、 -Br、 - 1、 -OH, - CN、 CH烷基及 CH烷氧基取代； Wherein G is selected from the group consisting of: d- 3 alkyl, C 2 -4 alkenyl, C 2 - 4 block, -N-R 4 -, -OR 4 -, -S-R 4 -, - Se - R 4 -, - C(=0)- R 4 -, - C (=0) NH- R 4 -, -C (=0) 0- R 4 -, -C (=S) - R 4 - -C (=S) NH- R 4 -, -C(=Se)- R 4 -, -C (=Se) NH- R 4 wherein the d- 3 alkyl group, C 2 -4 alkenyl group, Each of C 2 -4 alkynyl is optionally substituted by -F, -Cl, -Br, -1, -OH, -CN, CH alkyl and CH alkoxy;
R4可以是 H、 d-3烷基， C2-4烯基， C2-4炔基， 其中所述的 d-3烷基， C2-4烯基， C2-4炔基各自任选被- F、 - Cl、 -Br, -1、 -OH, - CN、 CH烷基 及 CH烷氧基取代； R 4 may be H, d- 3 alkyl, C 2 -4 alkenyl, C 2 -4 alkynyl, wherein the d- 3 alkyl, C 2 -4 alkenyl, C 2 -4 alkynyl are each Optionally substituted with -F, -Cl, -Br, -1, -OH, -CN, CH alkyl and CH alkoxy;
Y和 Z独立地选自 - C (R5) =和一 N=; Y and Z are independently selected from - C (R 5 ) = and one N =;
R5可以选自以下基团作为取代基： - H、 d-6烷基、 C2-6烯基、 C2—6 炔基和 d-6烷氧基， 上述 d-6烷基、 C2-6烯基、 C2-6块基和（^6烷氧基各 自任选被- F、 - Cl、 -Br, -1、 -OH, - CN、 CH烷基及 CH烷氧基取代；R 5 may be selected from the group consisting of: - H, d- 6 alkyl, C 2 - 6 alkenyl, C 2 - 6 alkynyl and d- 6 alkoxy, the above-mentioned d- 6 alkyl, C 2 - 6 alkenyl, C 2 - 6 block and (^ 6 alkoxy are each optionally substituted by -F, -Cl, -Br, -1, -OH, -CN, CH alkyl and CH alkoxy ;
R1 ， R2和 R3各自任选独立地选自以下取代基取代： - F、 - Cl、 -Br、 - 1、 -OH, - CN、 - NR6R7、 - N02、 苯基、 苄基、 苄氧基、 d—6烷基、 C3—6 环燒基、 。2—6婦基、 。2—6块基、 Cl-燒 基、 。3—6环燒 基、 。2—6婦 基Ϊ^、Each of R 1 , R 2 and R 3 is optionally independently selected from the group consisting of: - F, - Cl, -Br, -1, -OH, - CN, - NR 6 R 7 , - N0 2 , phenyl , benzyl, benzyloxy, d- 6 alkyl, C 3 - 6 cycloalkyl group burning. 2-6 women's base,. 2-6 blocks, Cl-alkyl,. 3-6 ring-burning base,. 2-6 women's base Ϊ ^,
C2-6炔氧基、 （^6烷硫基、 C3-6环烷硫基和 C2-6酰氧基， 上述苯基、 苄基 和苄氧基可以被 1 - 3个以下的取代基取代： - F、 - Cl、 -Br, -1、 -CN、 -NR7R8、 -N02; C 2 -6 alkynyloxy, (^ 6 alkylthio, C 3 - 6 cycloalkylthio and C 2 - 6 acyloxy, the above phenyl, benzyl and benzyloxy may be 1 - 3 or less Substituent substitution: - F, - Cl, -Br, -1, -CN, -NR 7 R 8 , -N0 2 ;
R6和 R7独立地选自- H、 d-6烷基、 C2-6烯基和 C2-6炔基， 其中所述 的 d-6烷基、 C2-6烯基和 C2-6炔基各自任选被独立地选自以下的取代基 取代： - F、 - Cl、 -Br, -1、 -OH, - CN和 d—6烷氧基； R6和 R7可以与它们连接的氮原子一起构成 3-8 个原子的饱和单 环， 其中任选包含 1-2个氧原子， 所述环任选独立地选自以下的取代 基取代： - F、 - Cl、 -Br, -1、 -OH, - CN和 d—6烷氧基。 本发 R 6 and R 7 are independently selected from -H, d- 6 alkyl, C 2 -6 alkenyl and C 2 -6 alkynyl, wherein said d- 6 alkyl, C 2 - 6 alkenyl and C The 2 - 6 alkynyl groups are each optionally substituted with a substituent independently selected from the group consisting of: - F, - Cl, -Br, -1, -OH, - CN and d- 6 alkoxy; R 6 and R 7 may together with the nitrogen atom to which they are attached form a saturated monocyclic ring of 3-8 atoms, optionally containing 1-2 oxygen atoms, optionally substituted with a substituent selected from the group consisting of: - F, - Cl, -Br, -1, -OH, - CN and d- 6 alkoxy. This hair
Figure imgf000009_0001
Figure imgf000009_0001
II 其中该方法进一步说明见下面反应路线 3 根据本发明， 本发明通式 I化合物或其可药用盐进一步优选自下 面具体化合物或者这些化合物的药学上可接受的盐， 如下面的表 1所 示：  Further, the method is further illustrated by the following Scheme 3. According to the present invention, the compound of the formula I of the present invention or a pharmaceutically acceptable salt thereof is further preferably selected from the following specific compounds or pharmaceutically acceptable salts of these compounds, as shown in Table 1 below. Show:
Figure imgf000009_0002
Figure imgf000010_0001
Figure imgf000009_0002
Figure imgf000010_0001
Figure imgf000011_0001
3- (4- (4- (3-氯 -4- CI H 丙氧基苯基）噻唑
Figure imgf000011_0001
3- (4- (4-(3-chloro-4- CI H propoxyphenyl)thiazole)
- 2 -亚胺基)苯基）丙 - 2 -imino)phenyl)propyl
酸 Acid
3- (4- (4- (3-氯 -4- CI H 正丁氧基苯基)塞唑  3-(4- (4-(3-chloro-4- CI H-n-butoxyphenyl)-pyrazole
- 2 -亚胺基)苯基）丙 - 2 -imino)phenyl)propyl
酸 Acid
3- (4- (4- (3-氯 -4- 异丁氧基苯基)噻唑  3- (4- (4-chloro-4-isobutoxyphenyl)thiazole
- 2 -亚胺基)苯基）丙 - 2 -imino)phenyl)propyl
酸 Acid
3- (4- (4- (3-氯 -4- 环戊氧基苯基)噻唑  3- (4- (4-chloro-4-cyclopentyloxyphenyl)thiazole
- 2 -亚胺基)苯基）丙 - 2 -imino)phenyl)propyl
酸 Acid
3- (4- (4- (3-氯 -4- 异戊氧基苯基)噻唑  3- (4- (4-chloro-4-isopentyloxyphenyl)thiazole
- 2 -亚胺基)苯基）丙 - 2 -imino)phenyl)propyl
酸 Acid
3- (4- (4- (3-氯 -4- 苄氧基苯基）噻唑  3- (4- (4-chloro-4-benzyloxyphenyl)thiazole
- 2 -亚胺基)苯基）丙
Figure imgf000012_0001
- 2 -imino)phenyl)propyl
Figure imgf000012_0001
酸 Acid
2- (4- (4- (3-氯 -4- CI H 曱氧基苯基）噻唑  2-(4- (4-(3-chloro-4- CI H decyloxyphenyl)thiazole
-2-亚胺)苯基）乙酸 -2-imine)phenyl)acetic acid
2- (4- (4- (3-氯 -4- 环戊氧基苯基)噻唑  2-(4- (4-(3-chloro-4-cyclopentyloxyphenyl)thiazole
-2-亚胺)苯基）乙酸 -2-imine)phenyl)acetic acid
3- (4- (4- (4-环丁氧 3- (4- (4- (4-cyclobutoxy)
基苯基）噻唑- 2 -亚 Phenyl)thiazole-2A
胺)苯基）丙烷- 1 -醇 Amine)phenyl)propane-1-ol
3- (4- (4- (4-丙氧基  3- (4- (4- (4-propoxy)
苯基) 唑- 2-亚胺） Phenyl) azole-2-imine)
苯基）丙烷- 1 -醇 Phenyl)propane-1-ol
Figure imgf000013_0001
本发明还涉及药物组合物， 其包括通式 I化合物或其可药用盐， 或通式 la化合物或其可药用盐，或通式 lb化合物或其可药用盐，或它 们的具体化合物， 及药用载体或赋形剂。 本发明还涉及通式 I化合物或其可药用盐，或通式 la化合物或其 可药用盐，或通式 lb化合物或其可药用盐， 或它们的具体化合物在制 备用于治疗免疫调节异常的药物中用途。 本发明还涉及治疗哺乳动物患者中免疫调节异常的方法， 该方法 包括给予所述患者治疗所述免疫调节异常有效量的式 I化合物。
Figure imgf000013_0001
The invention further relates to a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof, or a compound of formula la or a pharmaceutically acceptable salt thereof, or a compound of formula lb, or a pharmaceutically acceptable salt thereof, or a specific compound thereof , and a pharmaceutically acceptable carrier or excipient. The invention further relates to a compound of formula I, or a pharmaceutically acceptable salt thereof, or a compound of formula la, or a pharmaceutically acceptable salt thereof, or a compound of formula lb, or a pharmaceutically acceptable salt thereof, or a specific compound thereof, for use in the treatment of immunity Use in the regulation of abnormal drugs. The invention further relates to a method of treating an immunomodulatory abnormality in a mammalian subject, the method comprising administering to the patient an immunosuppressively effective amount of a compound of formula I.
在本发明中， 所述免疫调节异常选自以下的自身免疫性疾病或慢 性炎性疾病： 系统性红斑狼疮、 慢性类风湿性关节炎、 I 型糖尿病、 炎性肠病、 胆汁性肝硬化、 葡萄膜炎、 多发性硬化、 节段性回肠炎、 溃疡性结肠炎、 大疱性类天疱疮、 结节病、 银屑病、 自身免疫性肌炎、 韦格纳肉芽肿病、 鱼鳞病、 格雷夫斯眼病和哮喘。 In the present invention, the immunomodulatory abnormality is selected from the group consisting of an autoimmune disease or a chronic inflammatory disease: systemic lupus erythematosus, chronic rheumatoid arthritis, type I diabetes, inflammatory bowel disease, biliary cirrhosis, Uveitis, multiple sclerosis, Crohn's disease, Ulcerative colitis, bullous pemphigoid, sarcoidosis, psoriasis, autoimmune myositis, Wegener's granulomatosis, ichthyosis, Graves' eye disease and asthma.
进一步讲， 所述免疫调节异常是骨髓或器官移植排斥反应或移植 物抗宿主病。  Further, the immunomodulatory abnormality is bone marrow or organ transplant rejection or graft versus host disease.
进一步说明的是， 其中所述免疫调节异常选自器官或组织移植、 移植引起的移植物抗宿主病、 自身免疫综合征， 包括类风湿性关节炎、 系统性红斑狼疮、 桥本甲状腺炎、 多发性硬化、 重症肌无力、 I 型糖 尿病、 葡萄膜炎、 后葡萄膜炎、 变应性脑脊髓炎、 肾小球肾炎、 感染 后自身免疫性疾病 （包括风湿热和感染后肾小球肾炎） 、 炎性和高增 生性皮肤病、 银屑病、 特应性皮炎、 接触性皮炎、 湿疹性皮炎、 脂溢 性皮炎、 扁平苔藓、 天疱疮、 大疱性类天疱疮、 大疱性表皮松解症、 荨麻疹、 血管性水肿、 血管炎、 红斑、 皮肤嗜酸粒细胞增多、 红斑狼 疮、 痤疮、 斑秃、 角膜结膜炎、 春季结膜炎、 贝切特氏病相关性葡萄 膜炎、 角膜炎、 疱疹性角膜炎、 圆锥形角膜、 角膜上皮营养不良、 角 膜白斑、 眼天疱疮、 莫伦溃疡、 巩膜炎、 格雷夫斯眼病、 伏格特 -小柳 -原田综合征、 结节病、 花粉变态反应、 可逆阻塞性气道疾病、 支气管 哮喘、 变应性哮喘、 内源性哮喘、 外源性哮喘、 尘埃性哮喘、 慢性或 顽固性哮喘、 晚期哮喘和气道高反应性、 支气管炎、 胃溃疡、 局部缺 血疾病和血栓形成引起的血管损伤、 缺血性肠病、 炎性肠病、 坏死性 小肠结肠炎、 热灼伤相关性肠损伤、 乳糜泻、 直肠炎、 嗜酸细胞性胃 肠炎、 肥大细胞病、 节段性回肠炎、 溃疡性结肠炎、 偏头痛、 鼻炎、 湿疹、 间质性腎炎、 古德帕斯彻综合征、 溶血性尿毒症综合征、 糖尿 病性肾病、多发性肌炎、格-巴二氏综合征、梅尼埃尔氏病、多神经炎、 多发性神经炎、 单神经炎、 神经根病、 甲状腺机能亢进、 突眼性甲状 腺肿、 纯红细胞再生障碍、 再生障碍性贫血、 再生不良性贫血、 特发 性血小板减少性紫癜、 自身免疫性溶血性贫血、 粒细胞缺乏症、 恶性 贫血、 巨红细胞性贫血、 红细胞发生不能、 骨质疏松症、 结节病、 肺 纤维症、 特发性间质性肺炎、 皮肌炎、 寻常白斑病、 寻常鱼鳞病、 光 过敏、 皮肤 T细胞淋巴瘤、 动脉硬化、 动脉粥样硬化、 主动脉炎综合 征、 结节性多动脉炎、 非炎性心肌病、 硬皮病、 韦格纳肉芽肿病、 斯 耶格伦综合征、 肥胖症、 嗜酸性筋膜炎、 齿龈损伤、 牙周组织损伤、 牙槽骨损伤、牙骨质损伤、 腎小球肾炎、男性型脱发或老年性脱发（通 过预防脱发或者使头发萌生和 /或促进头发产生及头发生长进行治 疗） 、 肌肉萎缩症、 脓皮病和赛塞利综合征、 阿狄森氏病、 在进行保 存、移植或患上缺血性疾病时发生的器官缺血 -再 ¾注损伤、 内毒素休 克、 假膜性结肠炎、 药物或辐射引起的结肠炎、 缺血性急性腎功能不 全、 慢性肾功功能不全、 肺氧或药物引起的中毒症、 肺癌、 肺气肿、 白内障、 铁质沉着病、 色素性视网膜炎、 老年性黄斑变性、 玻璃体瘢 痕形成、 角膜碱烧伤、 皮炎多形性红斑、 线状 IgA大疱性皮炎和水泥 性皮炎、 龈炎、 牙周炎、 脓毒病、 胰腺炎、 由环境污染、 衰老、 致癌 作用、 癌转移和低气压病引起的疾病、 组胺或白三烯 -C4 释放引起的 疾病、 贝切特氏病、 自身免疫性肝炎、 原发性胆汁性肝硬化、 硬化性 胆管炎、 部分肝切除、 急性肝坏死、 由毒素、 病毒性肝炎、 休克或缺 氧引起的坏死、 乙型肝炎、 非甲 /非乙型肝炎、 肝硬化、 酒精性肝硬 化、 肝衰竭、 暴发性肝衰竭、 迟发性肝衰竭、 急性肝衰竭、 化疗作用 的扩大、 巨细胞病毒感染、 HCMV感染、 爱滋病（AIDS)、 癌症、 老年性 痴呆、 创伤和慢性细菌感染。 Further, wherein the immunomodulatory abnormality is selected from the group consisting of organ or tissue transplantation, graft-versus-host disease caused by transplantation, autoimmune syndrome, including rheumatoid arthritis, systemic lupus erythematosus, Hashimoto's thyroiditis, multiple Sclerotherapy, myasthenia gravis, type I diabetes, uveitis, posterior uveitis, allergic encephalomyelitis, glomerulonephritis, post-infectious autoimmune diseases (including rheumatic fever and post-infectious glomerulonephritis) , inflammatory and hyperproliferative skin diseases, psoriasis, atopic dermatitis, contact dermatitis, eczema dermatitis, seborrheic dermatitis, lichen planus, pemphigus, bullous pemphigoid, bullous Epidermolysis, urticaria, angioedema, vasculitis, erythema, skin eosinophilia, lupus erythematosus, acne, alopecia areata, keratoconjunctivitis, spring conjunctivitis, Becht's disease-associated uveitis, Keratitis, herpetic keratitis, keratoconus, corneal epithelial dystrophy, corneal leukoplakia, pemphigus, malon ulcer, scleritis, granule Eye disease, Vogt-Koyanagi-Harada syndrome, sarcoidosis, pollen allergy, reversible obstructive airway disease, bronchial asthma, allergic asthma, endogenous asthma, exogenous asthma, dusty asthma , chronic or refractory asthma, advanced asthma and airway hyperresponsiveness, bronchitis, gastric ulcer, ischemic disease and vascular injury caused by thrombosis, ischemic bowel disease, inflammatory bowel disease, necrotizing enterocolitis, Thermal burn-related intestinal damage, celiac disease, proctitis, eosinophilic gastroenteritis, mastocytosis, Crohn's disease, ulcerative colitis, migraine, rhinitis, eczema, interstitial nephritis, Gude Pascher syndrome, hemolytic uremic syndrome, diabetic nephropathy, polymyositis, Ge-Barth's syndrome, Meniere's disease, polyneuritis, polyneuritis, mononeuritis, Radiculopathy, hyperthyroidism, exophthalmia, pure red cell aplasia, aplastic anemia, aplastic anemia, idiopathic thrombocytopenia癜, autoimmune hemolytic anemia, agranulocytosis, pernicious anemia, macrocytic anemia, erythrocytosis, osteoporosis, sarcoidosis, pulmonary fibrosis, idiopathic interstitial pneumonia, dermatomyositis , leukoplakia, ichthyosis, photoallergic, cutaneous T-cell lymphoma, arteriosclerosis, atherosclerosis, aortitis Signs, nodular polyarteritis, non-inflammatory cardiomyopathy, scleroderma, Wegener's granulomatosis, Sjogren's syndrome, obesity, eosinophilic fasciitis, gingival injury, periodontal tissue damage, Alveolar bone injury, cementum damage, glomerulonephritis, male pattern hair loss or senile alopecia (treatment by preventing hair loss or hair growth and/or promoting hair production and hair growth), muscular dystrophy, pyoderma And Seychelles syndrome, Addison's disease, organ ischemia during ischemia, transplantation, or ischemic disease - re-injection injury, endotoxin shock, pseudomembranous colitis, drug or radiation Caused by colitis, ischemic acute renal insufficiency, chronic renal insufficiency, pulmonary oxygen or drug-induced poisoning, lung cancer, emphysema, cataract, ironosis, retinitis pigmentosa, age-related macular degeneration , vitreous scar formation, corneal alkali burn, dermatitis erythema multiforme, linear IgA bullous dermatitis and cement dermatitis, tendinitis, periodontitis, sepsis, pancreatitis, by environment Diseases caused by infection, aging, carcinogenesis, cancer metastasis and hypobaric disease, diseases caused by histamine or leukotriene-C4 release, Becht's disease, autoimmune hepatitis, primary biliary cirrhosis, sclerosis Cholangitis, partial hepatectomy, acute hepatic necrosis, necrosis caused by toxins, viral hepatitis, shock or hypoxia, hepatitis B, non-A/non-B hepatitis, cirrhosis, alcoholic cirrhosis, liver failure, Fulminant liver failure, delayed liver failure, acute liver failure, expansion of chemotherapy, cytomegalovirus infection, HCMV infection, AIDS, cancer, senile dementia, trauma and chronic bacterial infections.
根具体讲， 其中所述免疫调节异常选自  Specifically, wherein the immunomodulatory abnormality is selected from
1)多发性硬化，  1) Multiple sclerosis,
2)类风湿性关节炎，  2) Rheumatoid arthritis,
3)系统性红斑狼疮，  3) Systemic lupus erythematosus,
4)银屑病，  4) Psoriasis,
5)移植器官或组织的排斥反应，  5) rejection of transplanted organs or tissues,
6)炎性肠病，  6) Inflammatory bowel disease,
7)源自淋巴的恶性肿瘤，  7) malignant tumors derived from lymph,
8)急性和慢性淋巴细胞白血病和淋巴瘤  8) Acute and chronic lymphocytic leukemia and lymphoma
9)胰岛素和非胰岛素依赖性糖尿病。 本发明还涉及用于治疗哺乳动物患者中免疫调节异常， 器官移植 排斥， 呼吸道疾病或病症， 炎症， 血管相关疾病或病症的式 I化合物 或其可药用盐。 本发明还包括一种治疗需要这种治疗的哺乳动物患者的呼吸道疾 病或病症的方法， 该方法包括给予所述患者治疗所述呼吸道疾病或病 症有效量的式 I化合物或。 本实施方案包括在以上方法中， 其中所述 呼吸道疾病或病症选自哮喘、 慢性支气管炎、 慢性阻塞性肺疾病、 成 人呼吸窘迫综合征、 婴儿呼吸窘迫综合征、 咳嗽、 嗜酸性肉芽肿、 呼 吸道合胞病毒细支气管炎、 支气管扩张、 特发性肺纤维化、 急性肺损 伤和闭塞性细支气管炎伴机化性肺炎。 9) Insulin and non-insulin dependent diabetes. The invention further relates to a compound of formula I or a pharmaceutically acceptable salt thereof for use in the treatment of immunomodulatory disorders, organ transplant rejection, respiratory diseases or disorders, inflammation, vascular related diseases or disorders in a mammalian patient. The invention also encompasses a method of treating a respiratory disease or condition in a mammalian patient in need of such treatment, the method comprising administering to the patient an effective amount of a compound of formula I or a therapeutic agent for the respiratory disease or condition. The present embodiment is included in the above method, wherein the respiratory disease or condition is selected from the group consisting of asthma, chronic bronchitis, chronic obstructive pulmonary disease, adult respiratory distress syndrome, infant respiratory distress syndrome, cough, eosinophilic granuloma, respiratory tract Syncytial bronchiolitis, bronchiectasis, idiopathic pulmonary fibrosis, acute lung injury, and obliterative bronchiolitis with organizing pneumonia.
本发明还包括一种治疗需要这种治疗的患者的血管完整相关性疾 病或病症的方法， 其中所述疾病或病症选自血管性水肿、 血管炎、 局 部缺血疾病和血栓形成引起的血管损伤、 缺血性肠病、 炎性肠病、 坏 死性小肠结肠炎、 热灼伤相关性肠损伤、 动脉硬化、 动脉粥样硬化、 主动脉炎综合征、 在进行保存、 移植或患上缺血性疾病时发生的器官 缺血-再濯注损伤、 内毒素休克、假膜性结肠炎、 药物或辐射引起的结 肠炎、 缺血性急性腎功能不全、 慢性肾功能不全、 肺氧或药物引起的 中毒症、 脓毒病、 胰腺炎、 组胺或白三烯 -C4 释放引起的疾病、 由毒 素、 病毒性肝炎、 休克或缺氧引起的坏死、 老年性痴呆和创伤， 该方 法包括给予所述患者治疗所述疾病或病症有效量的式 I。  The invention also includes a method of treating an vascular integrity-related disease or condition in a patient in need of such treatment, wherein the disease or condition is selected from the group consisting of angioedema, vasculitis, ischemic disease, and vascular injury caused by thrombosis , ischemic bowel disease, inflammatory bowel disease, necrotizing enterocolitis, thermal burn-related intestinal damage, arteriosclerosis, atherosclerosis, aortitis syndrome, preservation, transplantation or ischemic Organ ischemia after re-injection injury, endotoxin shock, pseudomembranous colitis, colitis caused by drugs or radiation, ischemic acute renal insufficiency, chronic renal insufficiency, pulmonary oxygen or drug-induced a disease caused by poisoning, sepsis, pancreatitis, histamine or leukotriene-C4 release, necrosis caused by toxins, viral hepatitis, shock or hypoxia, senile dementia and trauma, the method comprising administering the said The patient treats the disease or condition in an amount effective to formula I.
本发明还包括一种治疗需要这种治疗的患者的脑水肿或肺水肿相 关性疾病或病症的方法， 该方法包括给予所述患者治疗所述疾病或病 症有效量的式 I他合物。在本实施方案中包括选自以下的疾病或病症： 休克、 脓毒病、 急性呼吸窘迫综合征和脑水肿。  The invention also encompasses a method of treating a cerebral edema or pulmonary edema-associated disease or condition in a patient in need of such treatment, the method comprising administering to the patient an effective amount of a compound of the formula I or the disease. In the present embodiment, a disease or condition selected from the group consisting of shock, sepsis, acute respiratory distress syndrome, and cerebral edema is included.
本实施方案也包括在以上方法中， 其中所述患者也患有呼吸道疾 病或病症。  This embodiment is also included in the above method, wherein the patient also has a respiratory disease or condition.
本实施方案也包括在以上方法中， 其中所述患者也患有心血管疾 病或病症。 本发明要求的化合物也包括其药学上可接受的盐和水合物。 药学 上可接受的盐包括金属（无机）盐和有机盐， 本领域技术人员众所周知 的是根据物理化学稳定性、 流动性、 吸湿性和溶解性选择合适的盐形 式。 本领域技术人员能够理解的是药学上可接受的盐包括但不限于无 机酸的盐例如盐酸盐、 硫酸盐、 磷酸盐、 二磷酸盐、 氢溴酸盐和硝酸 盐， 或者有机酸的盐， 例加苹果酸盐、 马来酸盐、 延胡索酸盐、 酒石 酸盐、 琥珀酸盐、 柠檬酸盐、 乙酸盐、 乳酸盐、 甲磺酸盐、 对甲苯磺 酸盐或双羟萘酸盐、 水杨酸盐和硬脂酸盐。 类似地， 药物可接受的阳 离子包括但不限于钠、 钾、 钙、 铝、 锂和铵（尤其是仲胺的铵盐） 。 因为上文指出的原因， 本发明的优选盐包括钾盐、钠盐、钙盐和铵盐。 式 I化合物的晶型、 水合物和溶剂合物也包括在本发明范围内。 This embodiment is also included in the above method, wherein the patient also has a cardiovascular disease or condition. The compounds claimed in the present invention also include pharmaceutically acceptable salts and hydrates thereof. Pharmaceutically acceptable salts include metal (inorganic) salts and organic salts, and it is well known to those skilled in the art to select suitable salt forms based on physicochemical stability, fluidity, hygroscopicity and solubility. Those skilled in the art will appreciate that pharmaceutically acceptable salts include, but are not limited to, salts of inorganic acids such as hydrochlorides, sulfates, phosphates, diphosphates, hydrobromides and nitrates, or salts of organic acids. , adding malate, maleate, fumarate, tartrate, succinate, citrate, acetate, lactate, methanesulfonate, p-toluenesulfonate or pamoate , salicylates and stearates. Similarly, pharmaceutically acceptable cations include, but are not limited to, sodium, potassium, calcium, aluminum, lithium, and ammonium (especially ammonium salts of secondary amines). Preferred salts of the invention include potassium, sodium, calcium and ammonium salts for the reasons indicated above. Crystal forms, hydrates and solvates of the compounds of formula I are also included within the scope of the invention.
对于本说明书来讲， "药物可接受的水合物" 是指本发明化合物 与一个或多个水分子结晶形成的水合物形式。 本发明式 I化合物可包 含一个或多个不对称中心， 由此能够以外消旋物和外消旋混合物、 单 一对映异构体、 非对映异构体混合物以及各非对映异构体形式存在。 本发明包括所有以上异构体形式的式 I化合物。  For the purposes of this specification, "pharmaceutically acceptable hydrate" refers to a hydrated form of the compound of the invention formed by crystallisation of one or more water molecules. The compounds of the formula I according to the invention may comprise one or more asymmetric centers, thereby enabling racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and diastereomers Form exists. The invention includes all of the above isomeric forms of the compounds of formula I.
本发明部分化合物包含烯属双键， 除非另有说明， 否则这些双键 包括 E型和 Z型几何异构体。  Some of the compounds of the present invention contain olefinic double bonds, and unless otherwise stated, these double bonds include E and Z geometric isomers.
本发明部分化合物可能存在不同的氢连接点， 称为互变异构体。 这样的例子可以是称为酮一烯醇互变异构体的酮及其烯醇形式。 式 I 化合物包括各互变异构体以及它们的混合物。  Some of the compounds of the invention may have different hydrogen attachment points, referred to as tautomers. Such an example may be a ketone known as a keto-enol tautomer and its enol form. The compounds of formula I include the individual tautomers and mixtures thereof.
式 I化合物可以被分离为对映异构体的非对映异构体对， 例如用 合适的溶剂 （例如甲醇、 乙酸乙酯或它们的混合物）通过分步结晶分 离。 由此获得的对映异构体对可以通过常规方法 （例如采用旋光酸作 为拆分剂）分离为各立体异构体。 或者， 采用已知构型的纯净的旋光 原料或试剂， 通过立体有择合成法可以得到通式 I化合物的对映异构 体。  The compound of formula I can be isolated as a diastereomeric pair of enantiomers, for example by fractional crystallization using a suitable solvent such as methanol, ethyl acetate or a mixture thereof. The enantiomer pair thus obtained can be separated into individual stereoisomers by a conventional method (e.g., using an optically active acid as a resolving agent). Alternatively, the enantiomers of the compounds of formula I can be obtained by stereospecific synthesis using neat optically active starting materials or reagents of known configuration.
本发明还包括一种或多种立体异构体形武的式 I化舍物的基本纯 净形式或者立体异构体混合物形式。 本发明包括所有这样的异构体。 由于本发明化合物具有 SIP Edgl 激动剂活性， 所以是可用于治 疗或预防自身免疫性或慢性炎性疾病的免疫调节剂。 在适宜免疫抑制 的情况下， 本发明化合物可用于抑制免疫系统， 例如可用于骨髓、 器 官或移植物排斥反应、 自身免疫性或慢性炎性疾病， 包括系统性红斑 狼疮、 慢性类风湿性关节炎、 I型糖尿病、 炎性肠病、 胆汁性肝硬化、 葡萄膜炎、 多发性硬化、 节段性回肠炎、 溃疡性结肠炎、 大疱性类天 疱疮、 结节病、 银屑病、 自身免疫性肌炎、 韦格纳肉芽肿病、 鱼鳞病、 格雷夫斯眼病和哮喘。 本发明化合物还可用于提高血管完整性。 The invention also includes substantially pure forms or mixtures of stereoisomers of one or more stereoisomers of formula I. The invention includes all such isomers. Since the compound of the present invention has SIP Edgl agonist activity, it is an immunomodulator useful for treating or preventing autoimmune or chronic inflammatory diseases. In the case of suitable immunosuppression, the compounds of the invention may be used to inhibit the immune system, for example, for bone marrow, organ or graft rejection, autoimmune or chronic inflammatory diseases, including systemic lupus erythematosus, chronic rheumatoid arthritis , type I diabetes, inflammatory bowel disease, biliary cirrhosis, uveitis, multiple sclerosis, Crohn's disease, ulcerative colitis, bullous pemphigoid, sarcoidosis, psoriasis, Autoimmune myositis, Wegener's granulomatosis, ichthyosis, Graves' eye disease, and asthma. The compounds of the invention are also useful for enhancing vascular integrity.
更具体地讲， 本发明化合物可用于治疗或预防选自以下的疾病或 病症： 器官或组织移植、 移植引起的移植物抗宿主病、 自身免疫综合 征， 包括类风湿性关节炎、 系统性红斑狼疮、 桥本甲状腺炎、 多发性 硬化、 重症肌无力、 I型糖尿病、 葡萄膜炎、 后葡萄膜炎、 变应性脑 脊髓炎、 肾小球肾炎、 感染后自身免疫性疾病 （包括风湿热和感染后 肾小球肾炎、 炎性和高增生性皮肤病、 银埽病、 特应性皮炎、 接触性 皮炎、 湿疹性皮炎、 脂溢性皮炎、 扁平苔藓、 天疱疮、 大疱性类天疱 疮、 大疱性表皮松解症、 荨麻疹、 血管性水肿、 血管炎、 红斑、 皮肤 嗜酸粒细胞增多、 红斑狼疮、 痤疮、 斑秃、 角膜结膜炎、 春季结膜炎、 贝切特氏病相关性葡萄膜炎、 角膜炎、 疱疹性角膜炎、 圆雉形角膜、 角膜上皮营养不良、 角膜白斑、 眼天疱疮、 莫伦溃疡、 巩膜炎、 格雷 夫斯眼病、 伏格特-小柳-原田综合征、 结节病、 花粉变态反应、 可逆 阻塞性气道疾病、 支气管哮喘、 变应性哮喘、 内源性哮喘、 外源性哮 喘、 尘埃性哮喘、 慢性或顽固性哮喘、 晚期哮喘和气道高反应性、 吏 气管炎、 胃溃疡、 局部缺血疾病和血栓形成引起的血管损伤、 缺血性 肠病、 炎性肠病、 坏死性小肠结肠炎、 热灼伤相关性肠损伤、 乳糜泻、 直肠炎、 嗜酸细胞性胃肠炎、 肥大细胞病、 节段性回肠炎、 溃疡性结 肠炎、 偏头痛、 鼻炎、 湿疹、 间质性肾炎、 古德帕斯彻综合征、 溶血 性尿毒症综合征、 糖尿病性肾病、 多发性肌炎、 格一巴二氏综合征、 梅尼埃尔氏病、 多神经炎、 多发性神经炎、 单神经炎、 神经根病、 甲 状腺机能亢进、 突眼性甲状腺肿、 纯红细胞再生障碍、 再生障碍性贫 血、 再生不良性贫血、 特发性血小板减少性紫癜、 自身免疫性溶血性 贫血、 粒细胞缺乏症、 恶性贫血、 巨红细胞性贫血、 红细胞发生不能、 骨质疏松症、 结节病、 肺纤维症、 特发性间质性肺炎、 皮肌炎、 寻常 白斑病、 寻常鱼鳞病、 光过敏、 皮肤 T细胞淋巴瘤、 动脉硬化、 动脉 粥样硬化、 主动脉炎综合征、 结节性多动脉炎、 非炎性心肌病、 硬皮 病、 韦格纳肉芽肿病、 斯耶格伦综合征、 肥胖症、 嗜酸性筋膜炎、 齿 龈损伤、 牙周组织损伤、 牙槽骨损伤、 牙骨质损伤、 腎小球腎炎、 男 性型脱发或老年性脱发（通过预防脱发或者使头发萌生和 /或促进头 发产生及头发生长进行治疗）、肌肉萎缩症、脓皮病和赛塞利综合征、 阿狄森氏病、 在进行保存、 移植或患上缺血性疾病时发生的器官缺血 一再濯注损伤、 内毒素休克、 假膜性结肠炎、 药物或辐射引起的结肠 炎、 缺血性急性肾功能不全、 慢性肾功能不全、 肺氧或药物引起的中 毒症、 肺癌、 肺气肿、 白内障、 铁质沉着病、 色素性视网膜炎、 老年 性黄斑变性、 玻璃体瘢痕形成、 角膜碱烧伤、 皮炎多形性红斑、 线状 IgA 大疱性皮炎和水泥性皮炎、 龈炎、 牙周炎、 脓毒病、 胰腺炎、 由 环境污染、 衰老、 致癌作用、 癌转移和低气压病引起的疾病、 组胺或 白三烯 -C4释放引起的疾病、 贝切特氏病、 自身免疫性肝炎、 原发性胆 汁性肝硬化、 硬化性胆管炎、 部分肝切除、 急性肝坏死、 由毒素、 病 毒性肝炎、 休克或缺氧引起的坏死、 乙型肝炎、 非甲 /非乙型肝炎、 肝硬化、 酒精性肝硬化、 肝衷竭、 暴发性肝衰竭、 迟发性肝衰竭、 慢 性加急性肝衰竭、 化疗作用的扩大、 巨细胞病毒感染、 HCMV感染、 爱 滋病、 癌症、 老年性痴呆、 创伤和慢性细菌感染。 More specifically, the compounds of the invention are useful for the treatment or prevention of a disease or condition selected from the group consisting of organ or tissue transplantation, graft versus host disease caused by transplantation, autoimmune syndrome, including rheumatoid arthritis, systemic erythema Lupus, Hashimoto's thyroiditis, multiple sclerosis, myasthenia gravis, type I diabetes, uveitis, posterior uveitis, allergic encephalomyelitis, glomerulonephritis, autoimmune diseases after infection (including rheumatic fever) And post-infection glomerulonephritis, inflammatory and hyperproliferative skin diseases, rickets, atopic dermatitis, contact dermatitis, eczema dermatitis, seborrheic dermatitis, lichen planus, pemphigus, bullous Pemphigus, bullous epidermolysis, urticaria, angioedema, vasculitis, erythema, skin eosinophilia, lupus erythematosus, acne, alopecia areata, keratoconjunctivitis, spring conjunctivitis, Bechter's Disease-related uveitis, keratitis, herpetic keratitis, round sacral cornea, corneal epithelial dystrophy, corneal leukoplakia, pemphigus, Mo Ulcer, scleritis, Graves' eye disease, Vogt-Koyanagi-Harada syndrome, sarcoidosis, pollen allergy, reversible obstructive airway disease, bronchial asthma, allergic asthma, endogenous asthma, exogenous Asthma, dusty asthma, chronic or refractory asthma, advanced asthma and airway hyperresponsiveness, sputum bronchitis, gastric ulcer, ischemic disease and vascular injury caused by thrombosis, ischemic bowel disease, inflammatory bowel disease , necrotizing enterocolitis, thermal burn-related intestinal damage, celiac disease, proctitis, eosinophilic gastroenteritis, mast cell disease, Crohn's disease, ulcerative colitis, migraine, rhinitis, eczema, Interstitial nephritis, Goodpasture syndrome, hemolytic uremic syndrome, diabetic nephropathy, polymyositis, Gebba's syndrome, Meniere's disease, polyneuritis, multiple Neuritis, mononeuritis, radiculopathy, hyperthyroidism, ocular goiter, pure red cell aplasia, aplastic deprivation Blood, aplastic anemia, idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia, agranulocytosis, pernicious anemia, macrocytic anemia, erythrocytosis, osteoporosis, sarcoidosis, lung fiber Symptoms, idiopathic interstitial pneumonia, dermatomyositis, leukoplakia, ichthyosis, photoallergic, cutaneous T-cell lymphoma, arteriosclerosis, atherosclerosis, aortitis syndrome, nodular arteries Inflammatory, non-inflammatory cardiomyopathy, scleroderma, Wegener's granulomatosis, Sjogren's syndrome, obesity, eosinophilic fasciitis, gingival injury, periodontal tissue damage, alveolar bone damage, cement Quality damage, glomerulonephritis, male pattern hair loss or senile alopecia (treatment by preventing hair loss or hair growth and/or promoting hair production and hair growth), muscular dystrophy, pyoderma and Seychelles syndrome, Addison's disease, repeated ischemia, organ damage, endotoxin shock, pseudomembranous colitis, preservation, transplantation, or ischemic disease Drug or radiation-induced colitis, ischemic acute renal insufficiency, chronic renal insufficiency, pulmonary oxygen or drug-induced toxicosis, lung cancer, emphysema, cataract, ironosis, retinitis pigmentosa, senile Macular degeneration, vitreous scar formation, corneal alkali burn, dermatitis erythema multiforme, linear IgA bullous dermatitis and cement dermatitis, tendinitis, periodontitis, sepsis, pancreatitis, environmental pollution, aging, carcinogenesis Effects, cancer metastasis and diseases caused by hypotonic diseases, diseases caused by histamine or leukotriene-C 4 release, Becht's disease, autoimmune hepatitis, primary biliary cirrhosis, sclerosing cholangitis, Partial hepatectomy, acute hepatic necrosis, necrosis caused by toxins, viral hepatitis, shock or hypoxia, hepatitis B, non-A/non-B hepatitis, cirrhosis, alcoholic cirrhosis, liver exhaustion, fulminant liver Failure, delayed liver failure, chronic plus acute liver failure, expansion of chemotherapy, cytomegalovirus infection, HCMV infection, AIDS, cancer, senile Stay, trauma, and chronic bacterial infections.
本发明化合物还可用 于治 疗 或预防阿 尔 茨海默病 (Alzheimer' sdi sease)。  The compounds of the invention are also useful in the treatment or prevention of Alzheimer's sdi sease.
本发明实施方案还包括一种对需要这种治疗的哺乳动物患者预防 或治疗移植抵抗或者器官或组织的移植排斥反应的方法， 该方法包括 给予治疗有效量的式 I化合物。  Embodiments of the invention also include a method of preventing or treating graft resistance or transplant rejection of an organ or tissue in a mammalian subject in need of such treatment, the method comprising administering a therapeutically effective amount of a compound of formula I.
本发明另一种实施方案是一种对需要这种抑制的哺乳动物患者抑 制免疫系统的方法， 该方法包括给予所述患者抑制免疫系统有效量的 式 I化合物。 Another embodiment of the invention is a method of inhibiting the immune system in a mammalian patient in need of such inhibition, the method comprising administering to the patient an effective amount of an immune system a compound of formula I.
更具体地讲， 本文介绍的方法包括一种治疗或预防骨髓或器官移 植排斥反应的方法， 该方法包括给予需要这种治疗或预防的哺乳动物 患者治疗或预防骨髓或器官移植排斥反应有效量的式 I化舍物或者它 们的药学上可接受的盐或水合物。  More specifically, the methods described herein include a method of treating or preventing bone marrow or organ transplant rejection comprising administering to a mammalian patient in need of such treatment or prevention an effective amount of a bone marrow or organ transplant rejection treatment Formula I or their pharmaceutically acceptable salts or hydrates.
本发明化合物还可用于治疗呼吸道疾病或病症， 例如哮喘、 慢性 支气管炎、 慢性阻塞性肺疾病、 成人呼吸窘迫综合征、 婴儿呼吸窘迫 综合征、 咳嗽、 嗜酸性肉芽肿、 呼吸道合胞病毒细支气管炎、 支气管 扩张、 特发性肺纤维化、 急性肺损伤和闭塞性细支气管炎伴机化性肺 炎。  The compounds of the invention are also useful in the treatment of respiratory diseases or conditions, such as asthma, chronic bronchitis, chronic obstructive pulmonary disease, adult respiratory distress syndrome, infant respiratory distress syndrome, cough, eosinophilic granuloma, respiratory syncytial virus bronchioles Inflammation, bronchiectasis, idiopathic pulmonary fibrosis, acute lung injury, and obliterative bronchiolitis with organizing pneumonia.
此外本发明化合物是 SIP Edgl 受体的选择性激动剂， 其选择性 优于 SIP3/Edg3受体。 Edgl选择性激动剂优于现有的疗法， 拓宽了淋 巴细胞聚集剂的治疗窗， 使得在较高给药剂量下有更好的耐受性， 因 此提高了单一疗法的功效。 Furthermore, the compounds of the invention are selective agonists of the SIP Edgl receptor with selectivity superior to the SIP 3 /Edg3 receptor. Edgl selective agonists are superior to existing therapies, broadening the therapeutic window of lymphocyte aggregating agents, resulting in better tolerance at higher doses, thus increasing the efficacy of monotherapy.
本发明的药物组合物可以各种药物制剂形式使用， 其包含药物可 接受的载体以及式 I或者它们的药学上可接受的盐或水合物。 作为所 述制剂的一种优选实施方案是在制剂中还可包括第二种免疫抑制剂。 其它免疫抑制剂的例子包括但不限于硫唑嘌呤、 布喹那钠、 脱氧精胍 菌素、 mizar ibine、 霉考酚酸吗啉代酯、 环孢菌素、 FK- 506、 雷帕霉 素、 FTY720 和 ISAtx247 (Isotechnika) , 将式 I化合物与其它免疫 抑制剂 （包括上述的一种或多种免疫抑制剂）联合给药的方法也包括 在本发明中。  The pharmaceutical composition of the present invention can be used in various pharmaceutical preparation forms, and comprises a pharmaceutically acceptable carrier and Formula I or a pharmaceutically acceptable salt or hydrate thereof. As a preferred embodiment of the formulation, a second immunosuppressive agent can also be included in the formulation. Examples of other immunosuppressive agents include, but are not limited to, azathioprine, buquina sodium, deoxyspermectin, mizar ibine, mycophenolate mofetil, cyclosporin, FK-506, rapamycin , FTY720 and ISAtx247 (Isotechnika), methods of administering a compound of formula I in combination with other immunosuppressive agents, including one or more immunosuppressive agents as described above, are also included in the present invention.
本发明化合物 （包括它们的盐和水合物）可用于治疗自身免疫性 疾病， 包括预防骨髓移植、 外来器官移植物的排斥反应和 /或相关的 疾患和疾病。  The compounds of the invention, including their salts and hydrates, are useful in the treatment of autoimmune diseases, including prevention of bone marrow transplantation, rejection of foreign organ transplants, and/or related conditions and diseases.
本发明化合物可以通过任何方式给药， 只要这种方式可使活性成 分化合物与温血动物体内的作用部位有效接触。例如，可以通过口服、 局部 （包括透皮给药） 、 眼、 口腔、 鼻内、 吸入、 阴道内、 直肠、 脑 池内和胃肠外给药。 此处使用的术语 "胃肠外， ， 是指包括以下的给 药模式： 皮下、 静脉内、 肌内、 关节内注射或输注、 胸骨肉和腹膜内 给药。 The compound of the present invention can be administered by any means as long as the active ingredient compound is in effective contact with the site of action in the warm-blooded animal. For example, it can be administered orally, topically (including transdermal administration), ocular, buccal, intranasal, inhaled, intravaginal, rectal, intracisternal, and parenteral. The term "parenteral," as used herein, is intended to include the following Mode of drug: subcutaneous, intravenous, intramuscular, intra-articular injection or infusion, sternal flesh and intraperitoneal administration.
本发明化合物可以通过用于联合药物的任何常规方法以单独的制 剂或组合的治疗剂给予。 可以仅仅给予这些治疗剂本身， 但是通常结 合药用载体给药，药用载体根据所选给药途径和标准药学实践来选择。  The compounds of the present invention can be administered in a separate preparation or a combined therapeutic agent by any conventional method for combination therapy. These therapeutic agents may be administered alone, but are usually administered in combination with a pharmaceutically acceptable carrier which is selected according to the chosen route of administration and standard pharmaceutical practice.
药剂量将取决于接受者的年龄、 健康和体重、 疾病的严重程度、 联合疗法的类型（如果有的话）、 治疗频率和所需效果的性质。 通常， 活性成分化合物的日剂量为约 0. 1— 2000亳克 /天。 通常， 每天分 1 次或多次给予 1-100亳克可有效获得所需疗效。 这些剂量是治疗自身 免疫性疾病、 预防外来器官移植物排斥反应和 /或相关疾患和疾病的 有效量。  The dosage will depend on the age, health and weight of the recipient, the severity of the disease, the type of combination therapy (if any), the frequency of treatment, and the nature of the desired effect. Usually, the daily dose of the active ingredient compound is from about 0.1 to 2000 g/day. Usually, 1-100 grams per day or more can be effectively obtained to achieve the desired effect. These doses are effective amounts for the treatment of autoimmune diseases, prevention of exogenous organ transplant rejection and/or related conditions and diseases.
活性成分可以固体剂型 （例如胶嚢剂、 片剂、 锭剂、 糖锭剂、 颗 粒剂和散剂）或液体剂型 （酏剂、 糖浆剂、 乳剂、 分散体和混悬剂） 口服给予。 活性成分还可以无菌液体剂型 （例如分散体、 混悬剂或溶 液剂） 胃肠外给药。 其它剂型也可用于给予活性成分， 例如用于局部 给药的软膏剂、 乳膏剂、 滴剂、 透皮贴剂或散剂， 用于眼部给药的眼 用溶液剂或混悬剂 （即滴眼剂） ， 用于吸入或鼻内给药的气雾剂或粉 末组合物， 或者用于直肠或阴道给药的乳膏剂、 软膏剂、 喷雾剂或栓 剂。  The active ingredient can be administered orally in a solid dosage form (e.g., capsules, tablets, troches, lozenges, granules, and powders) or in liquid form (such as elixirs, syrups, emulsions, dispersions and suspensions). The active ingredient can also be administered parenterally in a sterile liquid form such as a dispersion, suspension or solution. Other dosage forms may also be used for the administration of active ingredients, such as ointments, creams, drops, transdermal patches or powders for topical administration, ophthalmic solutions or suspensions for ophthalmic administration (ie drops) Eye drops), an aerosol or powder composition for inhaled or intranasal administration, or a cream, ointment, spray or suppository for rectal or vaginal administration.
明胶胶嚢剂包含活性成分和粉末载体， 例加乳糖、 淀粉、 纤维素 衍生物、 硬脂酸镁、 硬脂酸等。 类似的稀释剂可用于制备压制片剂。 片剂和胶嚢剂均可制备为緩释产品， 用于在数小时内连续释放药物。 压制片剂是包糖衣或薄膜包衣的， 以便遮蔽任何不良味道并且使片剂 与空气隔绝， 或者是肠溶包衣的， 用于在胃肠道中选择性崩解。  Gelatin capsules contain the active ingredient and a powder carrier, such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, and the like. Similar diluents can be used to prepare compressed tablets. Both tablets and capsules can be prepared as sustained release products for continuous release of the drug over a period of hours. Compressed tablets are sugar coated or film coated to mask any unpleasant taste and to isolate the tablet from the air, or enteric coated for selective disintegration in the gastrointestinal tract.
口服液体剂型可以包含着色剂和矫味剂，从而增加患者的接受度。 一般而言， 水、 合适的油、 盐水、 葡萄糖水溶液以及相关的糖溶 液和二元醇（例如丙二醇或聚乙二醇）是用于胃肠外溶液剂的合适载 体。 胃肠外给药的溶液剂优选包含活性成分的水溶性盐、 合适的稳定 剂， 如果需要， 还可包含緩冲物质。 抗氧化剂 （例如单独的亚硫酸氢 钠、 亚硫酸钠、 抗坏血酸或它们的组合）是合适的稳定剂。 还可使用 柠檬酸及其盐和乙二胺四乙酸钠。 胃肠外溶液剂还可包含防腐剂， 例 如苯扎氯铵、 对羟基苯甲酸甲酯、 对羟基苯甲酸丙酯和三氯叔丁醇。 Oral liquid dosage forms can contain coloring and flavoring to increase patient acceptance. In general, water, a suitable oil, saline, aqueous dextrose and related sugar solutions and glycols such as propylene glycol or polyethylene glycol are suitable carriers for parenteral solutions. The solution for parenteral administration preferably comprises a water-soluble salt of the active ingredient, a suitable stabilizer, and if necessary, a buffer substance. Antioxidant (eg hydrogen bisulfite alone) Sodium, sodium sulfite, ascorbic acid or a combination thereof is a suitable stabilizer. Citric acid and its salts and sodium edetate can also be used. Parenteral solutions may also contain preservatives such as benzalkonium chloride, methyl paraben, propyl paraben and chlorobutanol.
对于吸入给药， 本发明化合物可以方便地以气溶胶喷雾给药， 气 溶胶喷雾由压力包装或喷雾器产生。 本发明化合物还可以粉末形式给 予， 粉末可用于配制， 可以借助于吹入粉末吸入器吸入粉末组合物。 吸入法的优选给药系统是定量吸入 (MDI)气雾剂，它可配制为式 I化合 物在合适抛射剂 （例如碳氟化合物或碳氢化合物） 中的混悬剂或溶液 剂。  For administration by inhalation, the compounds of the invention may conveniently be administered by aerosol spray, which is produced by a pressure pack or nebulizer. The compounds of the invention may also be administered in powder form, the powder may be formulated, and the powder composition may be inhaled by means of a powder inhaler. A preferred delivery system for inhalation is a metered dose inhalation (MDI) aerosol which can be formulated as a suspension or solution of a compound of formula I in a suitable propellant such as a fluorocarbon or hydrocarbon.
对于眼部给药， 眼用制剂可以配制为在适当眼用溶媒中具有合适 重量百分数的式 I化合物化合物的溶液或混悬液， 这样化合物与眼表 面的接触维持足够长的时间， 从而允许化合物渗过眼的角膜和内区。  For ophthalmic administration, the ophthalmic preparation can be formulated as a solution or suspension of the compound of formula I in a suitable ophthalmic vehicle in a suitable ophthalmic vehicle such that contact of the compound with the ocular surface is maintained for a sufficient period of time to allow for the compound Penetrate the cornea and inner area of the eye.
本发明还包括如下的 （1 ) - ( 4 ) 项中的任一项：  The present invention also includes any one of the following items (1) to (4):
( 1 )本发明的化合物或其可药用盐在制备用于治疗和 /或预防哺 乳动物患者的免疫调节异常、 呼吸道疾病或症状、 血管相完整关性疾 病或症状、 脑水肿或肺水肿相关疾病、 抗炎或止血的药物中的用途。  (1) A compound of the present invention or a pharmaceutically acceptable salt thereof for use in the preparation of a medicament for the treatment and/or prevention of immunomodulatory abnormalities, respiratory diseases or symptoms, vascular intact diseases or symptoms, cerebral edema or pulmonary edema in a mammalian patient Use in medicines for disease, anti-inflammatory or hemostasis.
( 2 )本发明的化合物或其可药用盐在制备或作为 S1P EDG1受体 激动剂的药物中的用途。  (2) Use of a compound of the present invention or a pharmaceutically acceptable salt thereof for the preparation or use as a medicament for an S1P EDG1 receptor agonist.
( 3 )一种治疗和 /或预防哺乳动物患者的免疫调节异常、 呼吸道 疾病或症状、血管相完整关性疾病或症状、脑水肿或肺水肿相关疾病、 或者抗炎或止血的方法， 包括给予有效量的本发明的化合物或其可药 用盐的步骤。  (3) A method for treating and/or preventing immunomodulatory abnormalities, respiratory diseases or symptoms, vascular phase integrity diseases or symptoms, cerebral edema or pulmonary edema-related diseases, or anti-inflammatory or hemostasis in a mammalian patient, including administration An effective amount of a compound of the invention or a pharmaceutically acceptable salt thereof.
( 4 )一种在体内或体外调节 S1P EDG1受体活性的方法， 包括使 用有效量的本发明的化合物或其可药用盐的步骤。 本发明化合物的制备方法通过下面说明举例说明， 本领域技术人 员可根据下面的教导制备本发明的化合物。 例如， 作为举例但不限于 此的 G为- NH-或- C (=0) NH-通式化合物 I b的制备方法分别用反应路线 1和反应路线 2表示： 反应路线 1 (4) A method of modulating the activity of an S1P EDG1 receptor in vivo or in vitro, comprising the step of using an effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof. Methods of preparing the compounds of the invention are illustrated by the following description, and one skilled in the art can prepare the compounds of the invention in accordance with the teachings below. For example, the preparation of G, which is by way of example but not limited to, is -NH- or -C(=0) NH-formula Ib is represented by Scheme 1 and Scheme 2, respectively: Reaction route 1
如下的反应路线表述了一种 G为- C (=0) NH-通式化合物 I b的制备 方法。首先用溴苄将对羟基苯甲腈的羟基保护，在 N， N-二甲基甲酰胺， 二甲基亚砜， 二氯甲垸等溶剂中， 通过使用碳酸钟、 碳酸钠、 碳酸氢 钠、三乙胺中和反应过程中产生的酸，加热或者常温下制得化合物 ii ; 通过硫氢化钠将氰基硫解得到硫代酰胺类化合物 iii; 硫代酰胺与溴代 酮类化合物在甲醇。 乙醇或者异丙醇等极性较大的溶剂中环合得到噻 峻环 （化合物 iv ) ； 再通过经典的酰氯与氨缩合制备酰胺方法将两个 芳香环连接制得化合物 V， 其中酰氯的制备方法可以使用二氯亚砜， 草酰氯，三氯氧磷和五氯氧磷等试剂，在合适的溶剂中制备化合物 v， 化合物 V也可以使用 DCC， DIEA, DBU, EDCI等缩合剂制备； 然后通过化 学领域工作人员通用的 Pd- C催化氢化脱苄基方法制得 vi，其中可以使 用环己烯、 氢气或甲酸铵等作为供氢体， 在合适的压力条件下制备； 通过经典的酚羟基烷基化反应 （其方法与制备化合物 ii类似） ； 最后 使用 化合物;  The following reaction scheme describes a process for preparing G as a -C(=0)NH-formula compound Ib. First, the hydroxy group of p-hydroxybenzonitrile is protected with benzyl bromide in a solvent such as N, N-dimethylformamide, dimethyl sulfoxide or dichloromethane, by using carbonic acid clock, sodium carbonate, sodium hydrogencarbonate. , the acid produced during the neutralization reaction of triethylamine, the compound ii is prepared by heating or at room temperature; the thio group is thiolated by sodium hydrosulfide to obtain the thioamide compound iii; the thioamide and the bromo ketone compound in methanol . Cyclic ring to obtain a thicyclic ring (compound iv) in a solvent such as ethanol or isopropanol; and amide method to prepare an amide by condensation of a classic acid chloride with ammonia to prepare a compound V, wherein the method for preparing an acid chloride Compound v can be prepared in a suitable solvent using reagents such as thionyl chloride, oxalyl chloride, phosphorus oxychloride and phosphorus pentoxide. Compound V can also be prepared using a condensing agent such as DCC, DIEA, DBU, EDCI or the like; Vi-Pd-C catalytic hydrogenation debenzylation method commonly used by workers in the chemical field to prepare vi, which can be prepared by using cyclohexene, hydrogen or ammonium formate as a hydrogen donor under suitable pressure conditions; a base reaction (the method is similar to the preparation of compound ii); the last use of the compound;
Figure imgf000023_0001
Figure imgf000023_0001
1  1
反应路线 2  Reaction route 2
反应路线 2展示了 G为- NH-通式化合物 I b (对应反应路线 2中化 合物通式 X ) 的制备方法， 首先对氨基取代芳基丙酸与硫氰酸钟或者 硫氰酸铵在甲醇、 乙醇或水作为溶剂得到化合物 l; 化合物 viii与 2 -溴 - 4， -羟基苯乙酮以各种短链低沸点醇为溶剂， 回流既得到化合物 ix; 化合物 ix采用反应路线 1中类似的方法后， 即得到终产物 。Scheme 2 shows that G is a -NH-formula compound I b (corresponding to Scheme 2) The preparation method of the compound of the formula X), firstly, the compound 1 is obtained by using an amino-substituted arylpropionic acid with a thiocyanate clock or ammonium thiocyanate in methanol, ethanol or water; the compound viii and 2-bromo-4, The hydroxyacetophenone is refluxed with various short-chain low-boiling alcohols to obtain the compound ix; the compound ix is obtained by a similar method in the reaction scheme 1, to obtain the final product.
Figure imgf000024_0001
Figure imgf000024_0001
反应路线 3 Reaction route 3
Figure imgf000025_0001
Figure imgf000025_0001
Figure imgf000025_0002
Figure imgf000025_0002
本发明中， 术语 烷基"是指具有 1-4个碳原子的直链或支链 烷基， 例如甲基、 乙基、 丙基、 异丙基、 正丁基、 仲丁基、 叔丁基等。 d-6烷基也可做类似理解。 In the present invention, the term "alkyl" means a straight or branched alkyl group having 1 to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl. Base, etc. d- 6 alkyl can also be similarly understood.
术语 烷氧基" 是指具有 1-4个碳原子的直链或支链烷氧基， 例如甲氧基、 乙氧基、 丙氧基、 异丙氧基、 正丁氧基、 仲丁氧基、 叔 丁氧基等。 烷氧基或 d-6烷氧基也可做类似理解。 术语 "C2-4烯基"是指具有 2-4个碳原子的直链或支链烯基， 例如 乙烯基、 丙烯基、 丁烯基等。 -6烯基也可做类似理解。 The term "alkoxy" refers to a straight or branched alkoxy group having from 1 to 4 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy Alkyl, tert-butoxy, etc. Alkoxy or d- 6 alkoxy can also be similarly understood. The term "C 2 -4 alkenyl" refers to a straight or branched alkenyl group having 2 to 4 carbon atoms, such as ethenyl, propenyl, butenyl and the like. - 6 alkenyl can also be similarly understood.
术语 "C2-4炔基"是指具有 2-4个碳原子的直链或支链炔基， 例如 乙炔基、 丙炔基、 丁炔基等。 C2-6炔基也可做类似理解。 The term "C 2 -4 alkynyl" refers to a straight or branched alkynyl group having 2 to 4 carbon atoms, such as ethynyl, propynyl, butynyl and the like. A similar understanding can also be made for the C 2 -6 alkynyl group.
C3-6环烷氧基是指具有 3-6个碳原子的环烷氧基，例如分别具有 3、 4、 5、 或 6个碳原子的环烷氧基。 C 3 - 6 cycloalkyl group means a cyclic alkoxy group having 3-6 carbon atoms, for example, each having 3, 4, 5, or cycloalkyl group having 6 carbon atoms.
C2-6烯氧基是指具有 2-6个碳原子的烯氧基， 例如分别具有 2、 3、 4、 5、 或 6个碳原子的烯氧基。 The C 2 -6 alkenyloxy group means an alkenyloxy group having 2 to 6 carbon atoms, for example, an alkenyloxy group having 2, 3, 4, 5, or 6 carbon atoms, respectively.
C2-6炔氧基是指具有 2-6个碳原子的炔氧基， 例如分别具有 2、 3、 4、 5、 或 6个碳原子的炔氧基。 The C 2 -6 alkynyloxy group means an alkynyloxy group having 2 to 6 carbon atoms, for example, an alkynyloxy group having 2, 3, 4, 5, or 6 carbon atoms, respectively.
d-6烷硫基是指具有 1-6个碳原子的直链或支链烷硫基，例如分别 具有 1、 2、 3、 4、 5、 或 6个碳原子的烷硫基。 The d- 6 alkylthio group means a linear or branched alkylthio group having 1 to 6 carbon atoms, for example, an alkylthio group having 1, 2, 3, 4, 5, or 6 carbon atoms, respectively.
C3-6环烷硫基是指具有 3-6个碳原子的环烷硫基，例如分别具有 3、 4、 5、 或 6个碳原子的环烷硫基. C 3 - 6 cycloalkylthio refers to a cycloalkylthio group having 3 to 6 carbon atoms, for example, a cycloalkylthio group having 3, 4, 5, or 6 carbon atoms, respectively.
C2-6酰氧基是指具有 2-6个碳原子的酰氧基， 例如分别具有 2、 3、 4、 5、 或 6个碳原子的酰氧基。 具体实施方式 The C 2 -6 acyloxy group means an acyloxy group having 2 to 6 carbon atoms, for example, an acyloxy group having 2, 3, 4, 5, or 6 carbon atoms, respectively. detailed description
下面将结合实施例对本发明的实施方案进行详细描述， 但是本领 域技术人员将会理解， 下面的实施例仅用于说明本发明， 而不应视为 限定本发明的范围。 实施例中未注明具体条件者， 按照常规条件或制 造商建议的条件进行。 所用试剂或仪器未注明生产厂商者， 均为可以 通过市购获得的常规产品。 熔点由 YRT- 3熔点仪测定（温度未经校正） ； 质谱由美国 ABI公 司 API 3000 三重四级杆串联质谱仪测定； 核磁共振谱由日本电子 JNM- ECA- 400超导 11仪测定（工作频率： NMR 400 MHz ) ·高分辨 质谱由 Buker 混合型四极杆傅里叶变换离子回旋共振质谱仪 ( Q-FT- MS )。 实验所用试剂为化学纯或者分析纯， 所用石油醚的沸点 均为 60 ~ 90 实施例 1 : 4-苄氧基苯甲腈的制备 The embodiments of the present invention will be described in detail below with reference to the accompanying drawings. If no specific conditions are specified in the examples, they are carried out according to the general conditions or the conditions recommended by the manufacturer. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products that can be obtained commercially. The melting point was determined by YRT-3 melting point apparatus (temperature uncorrected); mass spectrometry was determined by American ABI API 3000 triple quadrupole tandem mass spectrometer; nuclear magnetic resonance spectrum was determined by JEOL-ECA-400 superconducting instrument 11 (operating frequency) : NMR 400 MHz ) • High resolution mass spectrometry by Buker Hybrid Quadrupole Fourier Transform Ion Cyclotron Resonance Mass Spectrometer (Q-FT-MS). The reagents used in the experiment are chemically pure or analytically pure, and the boiling point of the petroleum ether used. Both are 60 to 90. Example 1: Preparation of 4-benzyloxybenzonitrile
依据反应路线 1方法， 红外干燥后得到终产物， 收率 98. 4%。  4%。 According to the method of the reaction of the first step, the infrared yield of the final product, yield 98. 4%.
'H-NMR (400MHz, DMS0-d6) δ (ppm)： · 7. 78 (d, J=6. 8， 2H)， 7. 31- 7. 48 (m， 5H)， 7. 19 (d, J=8. 8， 2H)， 5. 21 (S， 2H)， ESI -MS (M+H+)， 232. 2。 实施例 2: 4-苄氧基硫代苯甲酰胺的制备  'H-NMR (400MHz, DMS0-d6) δ (ppm): · 7.78 (d, J=6. 8, 2H), 7. 31- 7. 48 (m, 5H), 7. 19 (d , J=8. 8, 2H), 5. 21 (S, 2H), ESI-MS (M+H+), 232. 2. Example 2: Preparation of 4-benzyloxythiobenzamide
依据反应路线 1方法， 干燥后得到产品， 收率 95. 6%。  6%。 According to the method of the reaction, the product was obtained after drying, the yield was 95.6%.
'H-NMR (400MHz, DMS0-d6) δ (ppm)： 9. 64, (s, 1H)， 9. 32，（s， 1H)， 'H-NMR (400MHz, DMS0-d6) δ (ppm): 9. 64, (s, 1H), 9. 32, (s, 1H),
7. 94 (d, J=8. 8, 2H) , 7. 31-7. 47 (brs, 5H)， 7. 17 (d, J=9. 2， 2H)， 5. 18 (S，7. 94 (d, J=8. 8, 2H), 7. 31-7. 47 (brs, 5H), 7. 17 (d, J=9. 2, 2H), 5. 18 (S,
1H)。 实施例 3: 2- ( 4-苄氧基苯基） -4-噻唑酸乙酯的制备 1H). Example 3: Preparation of ethyl 2-(4-benzyloxyphenyl)-4-thiazole
依据反应路线 1方法， 得到中间体 2- ( 4-苄氧基苯基） -4-噻唑 酸乙酯， 收率是 77. 3%。  3%。 The yield of the intermediate 2-(4-benzyloxyphenyl)-4-thiazole ethyl ester, the yield was 77.3%.
'H-NMR (400MHz, DMS0-d6) δ (ppm)： 8. 50 (s， 1H)， 7. 93 'H-NMR (400MHz, DMS0-d6) δ (ppm): 8. 50 (s, 1H), 7. 93
(d, J=8. 8, 2H)， 7. 31-7. 47 (brs, 5H) , 7. 17 (d, J=8. 8， 2H) , 5. 20 (S, 1H)，(d, J=8. 8, 2H), 7. 31-7. 47 (brs, 5H) , 7. 17 (d, J=8. 8, 2H) , 5. 20 (S, 1H),
4. 33 (q, J=6. 8, 2H)， 1. 33 (t, J=7. 2， 3H)。 实施例 4: 3- ( 4- ( 2- ( 4-苄氧基苯基 ) -4-噻唑甲酰胺基）苯基 ) 丙酸乙酯的制备 4. 33 (q, J=6. 8, 2H), 1. 33 (t, J=7.2, 3H). Example 4: Preparation of ethyl 3-(4-(2-(4-benzyloxyphenyl)-4-thiazolecarboxamido)phenyl)propionate
将化合物 iv4. 16g用 2M NaOH水溶液水解， 加热至 50 反应 5h 后， 反应液直接加入浓盐酸调节溶液 PH 2， 有白色的固体析出， 滤出 固体后， 用约 200ml水洗涤滤饼， 以洗去无机盐杂志， 红外干燥后， 得到 2- ( 4 -苄氧基苯基 ) -4-噻唑酸 3. 95g， 收率 95. 0%。  The compound iv4. 16g was hydrolyzed with 2M aqueous NaOH solution and heated to 50 for 5 hours. Then, the reaction solution was directly added with concentrated hydrochloric acid to adjust the solution pH 2, and a white solid was precipitated. After filtering off the solid, the filter cake was washed with about 200 ml of water to wash. 0%。 The yield of 95.0%, the yield of 95.0%.
将 2- ( 4-苄氧基苯基 ) -4-噻唑酸 1. 24g加入 50ml茄形瓶， 然后 加入 10倍量的氯化亚砜和 30ml的无水 THF后， 上方放置回流冷凝管 和干燥管， 加热回流 4h后， 减压蒸除溶剂以及过量的氯化亚砜后， 用 无水 THF溶解蒸干后的固体。这时向 100ml三口瓶例加入 0. 77g (约 1 倍量）对氨基苯甲酸乙酯溶于 20mlTHF和 0. 6g (约 1. 5倍量）的三乙 胺， 把上述的酰氯溶液用恒压滴液漏洞緩慢滴至三口瓶中， 2. 5h小时 后， TLC 监测， 两种原料已基本消失， 有一个荧光颜色较深的点。 反 应液中有大量三乙胺盐酸盐析出， 滤除三乙胺盐酸盐后， 减压蒸除二 氯甲烷后， 加入 20ml 乙酸乙酯重结晶， 析出固体红外灯下干燥， 得到 化合物 v l. 36g， 收率 70. 1°/。。 1-24-(4-Benzyloxyphenyl)-4-thiazole acid 1.24g was added to a 50ml eggplant-shaped bottle, and then 10 times the amount of thionyl chloride and 30 ml of anhydrous THF were added, and the reflux condenser was placed above. Dry the tube, heat and reflux for 4 h, then distill off the solvent under reduced pressure and excess thionyl chloride. The dried solid was dissolved in anhydrous THF. At this time, a solution of 0.75 g (about 1 times the amount) of ethyl p-aminobenzoate in 20 ml of THF and 0.6 g (about 1.5 times the amount) of triethylamine is added to the 100 ml three-necked bottle. The drip leak was slowly dripped into the three-necked bottle. 2. After 5 hours, TLC monitoring, the two raw materials have basically disappeared, and there is a point with a darker fluorescent color. A large amount of triethylamine hydrochloride was precipitated in the reaction mixture. After the triethylamine hydrochloride was filtered off, dichloromethane was evaporated under reduced pressure, and then 20 ml of ethyl acetate was added to crystallize. l. 36g, yield 70. 1 ° /. .
'H-NMR (400MHz, DMS0-d6) δ (ppm)： 10. 13 (s， 1H)， 8. 36 'H-NMR (400MHz, DMS0-d6) δ (ppm): 10. 13 (s, 1H), 8. 36
( s, lH ) , 8. 09 (d, J=9. 2， 2H)， 7. 75 (d, J=8. 4， 2H)， 7. 31-7. 50 (brs, 5H) ; ( s, lH ) , 8. 09 (d, J=9. 2, 2H), 7. 75 (d, J=8.4, 2H), 7. 31-7. 50 (brs, 5H) ;
7. 23 (d, J=8. 4， 2H)， 7. 19 (d, J=9. 2， 2H)， 5. 22 (S， 1H)， 4. 05 (q, J=6. 8， 2 H)， 2. 84 (t， J=7. 6， 2H)， 2. 62 (t, J=7. 6， 2H)， 1. 16 (t, J=7. 2， 3H)。 实施例 5: 3- ( 4- ( 2- ( 4-羟基苯基 ) -4噻唑甲酰胺）苯基 ) 丙 酸乙酯的制备 7. 23 (d, J=8. 4, 2H), 7. 19 (d, J=9. 2, 2H), 5. 22 (S, 1H), 4. 05 (q, J=6. 8 , 2 H), 2. 84 (t, J=7. 6, 2H), 2. 62 (t, J=7. 6, 2H), 1. 16 (t, J=7.2, 3H). Example 5: Preparation of ethyl 3-(4-(2-(4-hydroxyphenyl)-4-ylthiazolecarboxamide) phenyl) propionate
向 250ml 三口瓶中首先加入加入化合物 v 4. 38g， 再緩慢加入 3. 32g的 10% Pd- C,最后加入 150ml的无水甲醇后，在氢化装置中 3atm， 室温条件下反应 24h， TLC监测显示已无原料点， 有一个极性较大的 新点， 滤除 10%Pd- C后， 浓缩反应液至 50ml后， 加入 100ml水后， 有 大量固体析出， 滤出固体后， 用少量水洗涤滤饼， 红外灯下干燥， 即 得到化合物 vi， 产品质量 3. 15g， 收率 88. 2°/。。  To the 250 ml three-necked bottle, the compound v 4.38 g was first added, and then 3.32 g of 10% Pd-C was added slowly, and finally 150 ml of anhydrous methanol was added, and then reacted at 3 atm in a hydrogenation apparatus at room temperature for 24 hours, TLC monitoring. It shows that there is no raw material, there is a new point with a larger polarity. After filtering 10% Pd-C, after concentrating the reaction solution to 50ml, after adding 100ml of water, a large amount of solid is precipitated. After filtering out the solid, use a small amount of water. The product is 3. 15g, yield 88. 2 ° /. .
'H-NMR (400MHz, DMS0-d6) δ (ppm) : 10. 11 (s, 1H) , 10. 09 (s, 1H) , 'H-NMR (400MHz, DMS0-d6) δ (ppm): 10. 11 (s, 1H) , 10. 09 (s, 1H) ,
8. 31 (s， 1H) 7. 98 (d, J=6. 8， 2H)， 7. 75 (d, J=8. 8， 2H)， 7. 22 (d, J=8. 4， 2H) ， 6. 91 (d, J=6. 8, 2H)， 5. 22 (S, 1H)， 4. 05 (q, J=7. 2， 2H)， 2. 84 (t， J=7. 2， 2H )， 2. 61 (t, J=7. 2， 2H)，1. 16 (t， J=6. 8， 3H)。 实施例 6: 3- ( 4- ( 2- ( 4-异丙氧基苯基）-4-噻唑甲酰胺）苯基） 丙酸的制备 8. 31 (s, 1H) 7. 98 (d, J=6. 8, 2H), 7. 75 (d, J=8. 8, 2H), 7. 22 (d, J=8.44, 2H) , 6. 91 (d, J=6. 8, 2H), 5. 22 (S, 1H), 4. 05 (q, J=7. 2, 2H), 2. 84 (t, J= 7. 2, 2H ), 2. 61 (t, J=7. 2, 2H), 1. 16 (t, J=6. 8, 3H). Example 6: Preparation of 3-(4-(2-(4-isopropoxyphenyl)-4-thiazolecarboxamide)phenyl)propionic acid
将约 0. 37g ( 2. 52mmol ) 的化合物 vi加入 50m三口瓶中， 加入破 酸钟 0. 7g(约 2倍量），再加入一' j、粒 Π， 0. 5ml PEG- 400和 40ml DMF, 加热至 80 "C后， 反应 30min， 加入 2倍量的 RX，反应时间 2- 10ml， 向 反应液中加入溶剂 2倍量的水后， 用乙酸乙酯（3 χ 50ml )萃取， 合并 乙酸乙酯层后， 用水和饱和食盐水洗涤有机层， 减压蒸干溶剂后， 用 2M的 LiOH水和四氢呋喃混合溶剂组成的溶液，加热至 ，反应 5h， TLC监测， 已基本无原料点， 最后加入浓盐酸调节反应液 PH 1， 析出 白色固体， 最后滤出固体并用水洗涤滤饼， 红外灯下干燥后， 再用乙 酸乙酯重结晶得到终产物 0. 15g， 收率 40. 5%。 5克的PEG-400和40ml。 Add 0. 37g ( 2. 52mmol) of compound vi to a 50m three-necked bottle, add acid-breaking clock 0. 7g (about 2 times the amount), then add a 'j, granules, 0. 5ml PEG-400 and 40ml DMF, After heating to 80 ° C, the reaction is carried out for 30 min, 2 times the amount of RX is added, the reaction time is 2-10 ml, 2 times the amount of water is added to the reaction solution, and then extracted with ethyl acetate (3 χ 50 ml), and the acetic acid is combined. After the ester layer, the organic layer was washed with water and saturated brine, and the solvent was evaporated to dryness under reduced pressure. The mixture was stirred with 2M of LiOH water and tetrahydrofuran solvent, and then reacted for 5 h, TLC monitoring, substantially no starting point, finally added 5%。 The yield of the final product is 0. 15g, the yield is 40. 5%. The final product is 0. 15g, the yield is 40. 5%.
'H-NMR (400MHz, DMS0-d6) δ (ppm) : 12. 11 (s, 1H) , 10. 12 (s， 1H) , 8. 35 (s， 1H) 8. 06 (d, J=8. 8， 2H)， 7. 75 (d, J=8. 4， 2H)， 7. 23 (d, J=8. 4， 2H ) , 7. 19 (d, J=8. 8, 2H)， 5. 22 (S， 1H)， 2. 81 (t, J=7. 2， 2H)， 2. 61 (t， J=7. 2 ， 2H) , 1. 31 (d, J=5. 6， 6H) TOF-MS (M+H+) 259. 14， C22H24N204S。 实施例 7: 3- ( 4- ( 2- ( 4-苄氧基苯基） -4噻唑甲酰胺）苯基） 丙酸的制备 'H-NMR (400MHz, DMS0-d6) δ (ppm) : 12. 11 (s, 1H) , 10. 12 (s, 1H) , 8. 35 (s, 1H) 8. 06 (d, J= 8. 8, 2H), 7. 75 (d, J=8. 4, 2H), 7. 23 (d, J=8. 4, 2H ) , 7. 19 (d, J=8. 8, 2H ), 5. 22 (S, 1H), 2. 81 (t, J=7. 2, 2H), 2. 61 (t, J=7. 2 , 2H) , 1. 31 (d, J=5 6, 6H) TOF-MS (M+H+) 259. 14, C 22 H 24 N 2 0 4 S. Example 7: Preparation of 3-(4-(2-(4-benzyloxyphenyl)-4-thiazolecarboxamide)phenyl)propionic acid
该化合物参考实施例 4 的制备方法， 以化合物 vi和溴苄制得 0. 23g， 收率 60. 7%。  7%。 The compound was obtained by the method of the preparation of the compound vi and benzyl bromide.
'H-NMR (400MHz, DMS0-d6) δ (ppm)： 10. 15 (s, 1H) , 8. 31 (s， 1H) 8. 10 (d， J=6. 8, 2H) , 7. 75 (d, J=8. 8， 2H)， 7. 31-7. 50 (m， 5H)， 7. 23 (d, J= 8. 4， 2H)， 7. 07 (d, J=8. 8, 2H)， 4. 75 (hept, J=6. 4， 1H)， 3. 64 (br， 1H)， 2. 81 (t, J=7. 2， 2H)， 2. 61 (t， J=7. 2， 2H)， TOF-MS (M+H+) 411. 14, C26H23N204S。 实施例 8: 3- ( 4- ( 2- ( 4-环戊氧基苯基） -4噻唑甲酰胺）苯基） 丙酸的制备 'H-NMR (400MHz, DMS0-d6) δ (ppm): 10. 15 (s, 1H) , 8. 31 (s, 1H) 8. 10 (d, J=6. 8, 2H), 7. 75 (d, J=8. 8, 2H), 7. 31-7. 50 (m, 5H), 7. 23 (d, J= 8. 4, 2H), 7. 07 (d, J=8 . 8, 2H), 4. 75 (hept, J=6. 4, 1H), 3. 64 (br, 1H), 2. 81 (t, J=7. 2, 2H), 2. 61 (t , J=7. 2, 2H), TOF-MS (M+H + ) 411. 14, C 26 H 23 N 2 0 4 S. Example 8: Preparation of 3-(4-(2-(4-cyclopentyloxyphenyl)-4-thiazolecarboxamide)phenyl)propionic acid
该化合物参考实施例 6制备方法， 以化合物 vi和溴代环戊烷制得 0. 65g， 收率 50. 8%。  8%。 The compound was obtained by the method of the preparation of the compound vi and bromocyclopentane.
'H-NMR (400MHz, DMS0-d6) δ (ppm) : 12. 12 (s, 1H) , 10. 12 (s， 1H) , 8. 35 (s， 1H) 8. 06 (d, J=8. 8， 2H)， 7. 75 (d, J=8. 8， 2H)， 7. 23 (d, J=8. 4， 2H ) , 7. 06 (d, J=8. 8, 2H)， 4. 94 (pent, J=5. 6， 1H)， 2. 81 (t， J=7. 2， 2H)， 2. 5 4 (t， J=7. 2， 2H)， 1. 61-2. 00 (m， 8H) TOF-MS (M+H+) 259. 14， C22H24N204S。 实施例 9: 3- (4- (2- (4-异丁氧基苯基） -4噻唑甲酰胺）苯基） 丙酸的制备 'H-NMR (400MHz, DMS0-d6) δ (ppm): 12. 12 (s, 1H) , 10. 12 (s, 1H) , 8. 35 (s, 1H) 8. 06 (d, J= 8. 8, 2H), 7. 75 (d, J=8. 8, 2H), 7. 23 (d, J=8. 4, 2H ) , 7. 06 (d, J=8. 8, 2H ), 4. 94 (pent, J=5. 6, 1H), 2. 81 (t, J=7. 2, 2H), 2. 5 4 (t, J=7.2, 2H), 1. 61-2. 00 (m, 8H) TOF-MS (M+H+) 259. 14, C 22 H 24 N 2 0 4 S. Example 9: Preparation of 3-(4-(2-(4-isobutoxyphenyl)-4-thiazolecarboxamide)phenyl)propionic acid
该化合物参考实施例 6制备方法， 以化合物 vi和溴代异丁烷制得 0.46g, 收率 37.1%。  This compound was prepared according to the preparation method of Example 6, to give 0.46 g of compound vi and bromoisobutane in a yield of 37.1%.
'H-NMR (400MHz, DMS0-d6) δ (ppm): 12.04 (s, IH), 10.12 (s， IH), 8.35 (s， IH) 8.06 (d, J=8.8， 2H)， 7.75 (d, J=8.8， 2H)， 7.23 (d, J=8.4， 2H ),7.08 (d, J=9.2， 2H) ,4.53 (hex, J=6.0， IH)， 2.81 (t, J=7.6， 2H)， 2.61 (t， J=7.2, 2H) , 1.56-2.74 (m， 2H)， 1.27 (d, J=6.4， 3H)， 0.95 (d, J=7.2， 3H)， TOF-MS (M+H+) 425.15， C23H25N204S。 实施例 10: 3- (4- (2- (4-环丁氧基苯基）-4噻唑甲酰胺）苯基） 丙酸的制备 'H-NMR (400MHz, DMS0-d6) δ (ppm): 12.04 (s, IH), 10.12 (s, IH), 8.35 (s, IH) 8.06 (d, J=8.8, 2H), 7.75 (d , J=8.8, 2H), 7.23 (d, J=8.4, 2H ), 7.08 (d, J=9.2, 2H) , 4.53 (hex, J=6.0, IH), 2.81 (t, J=7.6, 2H ), 2.61 (t, J=7.2, 2H) , 1.56-2.74 (m, 2H), 1.27 (d, J=6.4, 3H), 0.95 (d, J=7.2, 3H), TOF-MS (M+ H + ) 425.15, C 23 H 25 N 2 0 4 S. Example 10: Preparation of 3-(4-(2-(4-cyclobutoxyphenyl)-4thiazolecarboxamide)phenyl)propionic acid
该化合物参考实施例 6的制备方法， 以化合物 vi和溴代环丁烷制 得 0.23g， 收率 60.7°/。。  This compound was subjected to the production method of Example 6 to give 0.23 g of compound vi and bromocyclobutane in a yield of 60.7 °. .
'H-NMR (400MHz, DMS0-d6) δ (ppm): 12.10 (s, IH), 10.12 (s， IH), 8.36 (s， IH) 8.06 (d, J=8.8， 2H)， 7.75 (d, J=8.4， 2H)， 7.23 (d, J=8.8， 2H ),7.00 (d, J=8.8, 2H) ,4.80 (pent, J=7.2， IH)， 2.81 (t， J=7.6， 2H)， 2.6 0 (t， J=12, 2H) , 1.62-2.12 (m， 6H)， TOF-MS (M+H+) 423.14， C23H23N204S。 实施例 11: 3- (4- (2- (4-丁氧基苯基） -4噻唑甲酰胺）苯基） 丙酸的制备 'H-NMR (400MHz, DMS0-d6) δ (ppm): 12.10 (s, IH), 10.12 (s, IH), 8.36 (s, IH) 8.06 (d, J=8.8, 2H), 7.75 (d , J=8.4, 2H), 7.23 (d, J=8.8, 2H), 7.00 (d, J=8.8, 2H), 4.80 (pent, J=7.2, IH), 2.81 (t, J=7.6, 2H ), 2.6 0 (t, J=12, 2H) , 1.62-2.12 (m, 6H), TOF-MS (M+H+) 423.14, C 23 H 23 N 2 0 4 S. Example 11: Preparation of 3-(4-(2-(4-butoxyphenyl)-4-thiazolecarboxamide)phenyl)propionic acid
该化合物参考实施例 6的制备方法， 以化合物 vi和溴代丁烷制得 0.77g， 收率 60.6%。  This compound was subjected to the production method of Example 6 to give 0.77 g of compound vi and bromobutane in a yield of 60.6%.
'H-NMR (400MHz, DMS0-d6) δ (ppm): 12.08 (s, IH), 10.12 (s， IH), 8.36 (s， IH) 8.07 (d, J=9.2， 2H)， 7.75 (d, J=8.4， 2H)， 7.23 (d, J=8.4， 2H ),7.09 (d, J=6.4， 2H)， 4.07 (t， J=7.2， IH)， 2.81 (t， J=7.6， 2H)， 2.60 (t ， J=12， 2H)， 1.74 (pent, 2H)， 1.46 (hex, J=7.2， 2H)， 0.95 (t， J=7.2， 3H)， TOF-MS (M+H+) 425.15， C23H25N204S。 实施例 12: 3- ( 4- ( 2- ( 4-丙氧基苯基） -4噻唑甲酰胺）苯基） 丙酸的制备 'H-NMR (400MHz, DMS0-d6) δ (ppm): 12.08 (s, IH), 10.12 (s, IH), 8.36 (s, IH) 8.07 (d, J=9.2, 2H), 7.75 (d , J=8.4, 2H), 7.23 (d, J=8.4, 2H ), 7.09 (d, J=6.4, 2H), 4.07 (t, J=7.2, IH), 2.81 (t, J=7.6, 2H ), 2.60 (t , J=12, 2H), 1.74 (pent, 2H), 1.46 (hex, J=7.2, 2H), 0.95 (t, J=7.2, 3H), TOF-MS (M+H + ) 425.15, C 23 H 25 N 2 0 4 S. Example 12: Preparation of 3-(4-(2-(4-propoxyphenyl)-4-thiazolylcarboxamide)phenyl)propionic acid
该化合物参考实施例 6的制备方法， 以化合物 vi和溴代丙烷制得 0. 45g , 收率 50. 6%。  6%。 The compound was obtained by the method of the preparation of the compound vi and bromopropane.
'H-NMR (400MHz, DMS0-d6) δ (ppm) : 12. 08 (s, 1H) , 10. 12 (s， 1H) , 8. 36 (s， 1H) 8. 07 (d, J=9. 2， 2H)， 7. 75 (d, J=8. 4， 2H)， 7. 23 (d, J=8. 4， 2H ) , 7. 09 (d, J=6. 4， 2H)， 4. 07 (t， J=7. 2， 1H)， 2. 81 (t， J=7. 6， 2H)， 2. 60 (t ， J=12， 2H)， 1. 74 (pent, 2H)， 1. 46 (hex, J=7. 2， 2H)， 0. 95 (t， J=7. 2， 3H)， TOF-MS (M+H+) 425. 15， C23H25N204S。 实施例 13: 3- ( 4-硫脲基苯基） 丙酸的制备 'H-NMR (400MHz, DMS0-d6) δ (ppm): 12. 08 (s, 1H) , 10. 12 (s, 1H) , 8. 36 (s, 1H) 8. 07 (d, J= 9. 2, 2H), 7. 75 (d, J=8. 4, 2H), 7. 23 (d, J=8. 4, 2H), 7. 09 (d, J=6. 4, 2H ), 4. 07 (t, J=7. 2, 1H), 2. 81 (t, J=7. 6, 2H), 2. 60 (t , J=12, 2H), 1. 74 (pent , 2H), 1. 46 (hex, J=7. 2, 2H), 0. 95 (t, J=7. 2, 3H), TOF-MS (M+H + ) 425. 15, C 23 H 25 N 2 0 4 S. Example 13: Preparation of 3-(4-thioureidophenyl)propionic acid
依据反应路线 2的制备方法， 以化合物 3- ( 4-氨基苯基） 丙酸和 硫氰酸氨制得， 收率 85. 1%。  1%。 According to the preparation method of the reaction scheme 2, using the compound 3- (4-aminophenyl) propionic acid and ammonia thiocyanate, the yield of 85.1%.
'H-NMR (400MHz, DMS0-d6) δ (ppm)： 12. 12 (s， 1H)， 9. 62 (s， 1H)， 7. 27 (d, J=8. 4, 2H) , 7. 17 (d, J=8. 4， 2H)， 2. 78 (t, J=7. 2， 2H)，  'H-NMR (400MHz, DMS0-d6) δ (ppm): 12. 12 (s, 1H), 9. 62 (s, 1H), 7. 27 (d, J=8. 4, 2H) , 7 . 17 (d, J=8. 4, 2H), 2. 78 (t, J=7. 2, 2H),
2. 51 (t， J=7. 2, 2H) , ESI— MS ( (M+H+) 225. 1。 实施例 14: 3- ( 4- ( ( 5- ( 4-羟基苯基 )噻唑- 2 )氨基）苯基） 丙酸乙酯的制备 2. 51 (t, J=7.2, 2H), ESI-MS ((M+H + ) 225. 1. Example 14: 3-(4-((5-(4-hydroxyphenyl)thiazole) - 2) Preparation of ethylamino)phenyl)propionate
向 50ml三口瓶中加入 4-羟基- 2， -溴代苯乙酮 2. 13g (约 1. 1倍 量）和上步反应产物 2. Olg ( 1倍量） ， 加热回流 4h， 静止过夜， 反 应液中析出大量黄色固体，用少量水和乙醇洗涤后，真空干燥箱干燥， 得到产品 3- ( 4- ( ( 5- ( 4-羟基苯基 )噻唑- 2 )氨基）苯基） 丙酸乙 酯 2. 05g， 收率 73. 4°/0。 To a 50 ml three-necked flask, 4-hydroxy-2-bromoacetophenone 2.13 g (about 1.1 times the amount) and the above reaction product 2. Olg (1 times the amount), heated under reflux for 4 h, and allowed to stand overnight. A large amount of yellow solid precipitated in the reaction mixture, washed with a small amount of water and ethanol, and dried in a vacuum oven to give the product 3-( 4 -((5-( 4 -hydroxyphenyl)thiazole- 2 )amino)phenyl)propanoic acid. Ethyl acetate 2. 05g, yield 73. 4 ° / 0 .
'H-NMR (400MHz, DMS0-d6) δ (ppm)： 10. 18 (s, 1H) , 7. 71 (d, J=8. 4, 2H)， 7. 65 (d, J=8. 4, 2H)， 7. 19 (d, J=8. 4， 2H)， 7. 03 (s， 1H)， 6. 81 (d, J=8 . 8， 2H)， 4. 05 (quad, J=7. 2， 2H)， 2. 81 (t， J=7. 2， 2H)， 2. 59 (t， J=7. 2， 2H ) , 1. 16 (t, J=7. 2, 3H)„ 实施例 15: 3- ( 4- ( ( 5- ( 4-异丙氧基苯基）噻唑- 2 )氨基）苯 基） 丙酸的制备 'H-NMR (400MHz, DMS0-d6) δ (ppm): 10. 18 (s, 1H) , 7. 71 (d, J=8. 4, 2H), 7. 65 (d, J=8. 4, 2H), 7. 19 (d, J=8. 4, 2H), 7. 03 (s, 1H), 6. 81 (d, J=8 . 8, 2H), 4. 05 (quad, J=7. 2, 2H), 2. 81 (t, J=7. 2, 2H), 2. 59 (t, J=7. 2, 2H), 1. 16 (t, J=7. 2 , 3H)„ Example 15: Preparation of 3-(4-((5-(4-isopropoxyphenyl)thiazole-2)amino)phenyl)propanoic acid
参考实施例 6制备方法， 以化合物 3- ( 4- ( ( 5- ( 4-异丙氧基苯 基）噻唑 -2 )氨基）苯基） 丙酸和溴代异丙烷制得产物 0. 13g， 收率 12. 6%。  The product is obtained by the preparation of the compound 3-(4-((5-(4-isopropoxyphenyl)thiazol-2)amino)phenyl)propanoic acid and bromoisopropane. , yield 12.6%.
'H-NMR (400MHz, DMS0-d6) δ (ppm) : 12. 13 (s, 1H) , 10. 16 (s， 1H) , 7. 81 (d, J=8. 8, 2H) , 7. 61 (d, J=8. 4， 2H)， 7. 19 (d, J=8. 4， 2H)， 7. 12 (s， 1 H)， 6. 96 (d, J=8. 8， 2H)， 4. 66 (hept, J=5. 6， 2H)， 2. 81 (t， J=7. 2， 2H)， 2. 59 (t， J=7. 2, 2H) , 1. 27 (t, J=6. 0， 6H)， ESI-MS (M+H+) 383. 1， TOF-MS ( ( M+H+) 383. 14，C21H23N203S。 实施例 16: 3- ( 4- ( ( 5- ( 4-异丁氧基苯基 )噻唑- 2 )氨基）苯 基） 丙酸的制备 'H-NMR (400MHz, DMS0-d6) δ (ppm): 12. 13 (s, 1H) , 10. 16 (s, 1H) , 7. 81 (d, J=8. 8, 2H) , 7 . 61 (d, J=8. 4, 2H), 7. 19 (d, J=8. 4, 2H), 7. 12 (s, 1 H), 6. 96 (d, J=8. 8 , 2H), 4. 66 (hept, J=5. 6, 2H), 2. 81 (t, J=7. 2, 2H), 2. 59 (t, J=7. 2, 2H) , 1 27 (t, J=6. 0, 6H), ESI-MS (M+H+) 383. 1, TOF-MS ((M+H + ) 383. 14, C 21 H 23 N 2 0 3 S. Example 16: Preparation of 3-(4-((5-(4-isobutoxyphenyl)thiazole-2)amino)phenyl)propanoic acid
参考实施例 6得到产品 0. 33g , 以化合物 3- ( 4- ( ( 5- ( 4-异丙 氧基苯基）噻唑 -2 )氨基）苯基）丙酸和溴代异丁烷制得，收率 30. 8%。 Reference Example 6 to give the product 0. 33g, the compound 3- (4- ((5- (4 - isopropoxyphenyl) thiazol-2) amino) phenyl) propionic acid and isobutane bromo prepared , yield 30. 8%.
'H-NMR (400MHz, DMS0-d6) δ (ppm) : 12. 12 (s, 1H) , 10. 17 (s， 1H) , 'H-NMR (400MHz, DMS0-d6) δ (ppm): 12. 12 (s, 1H) , 10. 17 (s, 1H) ,
7. 81 (d, J=8. 8, 2H) , 7. 61 (d, J=8. 8， 2H)， 7. 19 (d, J=8. 4， 2H)， 7. 12 (s， 1 H)， 6. 97 (d, J=9. 2， 2H)， 4. 43 (hex, J=6. 0， 1H)， 2. 78 (t， J=7. 6， 2H)， 2. 5 9 (t， 2H)， 1. 5-1. 7 (m， 2H)， 1. 26 (d, J=6. 0， 3H)， 0. 94 (t， J=7. 6， 3H)， ESI -MS (M+H+) 397. 2， TOF-MS ( (M+H+) 397. 16， C22H25N203S。 实施例 17: 3- ( 4- ( ( 5- ( 4-丙氧基苯基 )噻唑- 2 )氨基）苯基） 丙酸的制备 7. 81 (d, J=8. 8, 2H) , 7. 61 (d, J=8. 8, 2H), 7. 19 (d, J=8. 4, 2H), 7. 12 (s , 1 H), 6. 97 (d, J=9. 2, 2H), 4. 43 (hex, J=6. 0, 1H), 2. 78 (t, J=7. 6, 2H), 2. 5 9 (t, 2H), 1. 5-1. 7 (m, 2H), 1. 26 (d, J=6. 0, 3H), 0. 94 (t, J=7. 6, 3H), ESI-MS (M+H+) 397. 2, TOF-MS ((M+H+) 397. 16, C 22 H 25 N 2 0 3 S. Example 17: 3- ( 4- ( ( 5 - Preparation of (4-propoxyphenyl)thiazole-2(amino)phenyl)propionic acid
参考实施例 6得到产品 0. 20g , 以化合物 3- ( 4- ( ( 5- ( 4-异丙 氧基苯基）噻唑 -2 )氨基）苯基） 丙酸和溴代丙烷制得， 收率 12. 7%。 Reference Example 6 to give the product 0. 20g, starting from 3- (4 - ((5- (4 - isopropoxyphenyl) thiazol-2) amino) phenyl) propionic acid The compound was prepared bromopropane and close The rate is 12.7%.
'H-NMR (400MHz, DMS0-d6) δ (ppm)： 10. 15 (s, 1H)， 7. 82 (d, J= 'H-NMR (400MHz, DMS0-d6) δ (ppm): 10. 15 (s, 1H), 7. 82 (d, J=
8. 8， 2H)， 7. 61 (d, J=8. 8， 2H) , 7. 19 (d, J=8. 8， 2H) , 7. 12 (s， 1H)， 6. 98 (d ， J=8. 8, 2H)， 5. 10 (br， 2H)， 3. 96 (t， J=6. 4， 2H)， 2. 78 (t, J=7. 6， 2H)， 2. 51 (t, 7. 6, 2H) , 1. 71 (pent, J=8. 0， 2H)， 1. 45 (hex, J=7. 6， 2H)， 0. 95 (t, J=7. 6， 3H)， ESI-MS (M+H+) 383. 2， TOF-MS ( (M+H+) 383. 14, C21H23N203S。 实施例 18: 3- ( 4- ( ( 5- ( 4-丁氧基苯基 )噻唑- 2 )氨基）苯基） 丙酸的制备 8. 8, 2H), 7. 61 (d, J=8. 8, 2H) , 7. 19 (d, J=8. 8, 2H) , 7. 12 (s, 1H), 6. 98 ( d , J=8. 8, 2H), 5. 10 (br, 2H), 3. 96 (t, J=6. 4, 2H), 2. 78 (t, J=7. 6, 2H), 2. 51 (t, 7. 6, 2H) , 1. 71 (pent, J=8. 0, 2H), 1. 45 (hex, J=7. 6, 2H), 0. 95 (t, J=7 6, 3H), ESI-MS (M+H+) 383. 2, TOF-MS ((M+H + ) 383. 14, C 21 H 23 N 2 0 3 S. Example 18: 3- ( 4 - Preparation of ((5-(4-butoxyphenyl)thiazole-2)amino)phenyl)propionic acid
参考实施例 6得到产品 0. 14g , 以化合物 3- ( 4- ( ( 5- ( 4-异丙 氧基苯基）噻唑 -2 )氨基）苯基） 丙酸和溴代丁烷制得， 收率 8. 6%。 Reference Example 6 gave the product 0. 14 g, which was obtained from the compound 3-(4-((5-( 4 -isopropoxyphenyl)thiazole-2)amino)phenyl)propanoic acid and bromobutane. The yield was 8.6%.
'H-NMR (400MHz, DMS0-d6) δ (ppm)： 10. 15 (s, 1H)， 7. 82 'H-NMR (400MHz, DMS0-d6) δ (ppm): 10. 15 (s, 1H), 7. 82
(d, J=8. 8, 2H) , 7. 61 (d, J=8. 8， 2H)， 7. 19 (d, J=8. 8， 2H)， 7. 12 (s， 1H)， 6 . 98 (d, J=9. 2， 2H)， 4. 00 (t， J=6. 4， 2H)， 2. 78 (t, J=7. 6， 2H)， 2. 59 (t, 2H )，1. 75 (hex, 2H)， 1. 06 (t， J=6. 8， 3H)， ESI-MS (M+H+) 397. 3, TOF-MS ( (M+ H+) 397. 16，C22H25N203S。 实施例 19: 3- ( 4- ( ( 5- ( 4-环戊氧基苯基 )噻唑- 2 )氨基 )苯 基） 丙酸的制备 (d, J=8. 8, 2H) , 7. 61 (d, J=8. 8, 2H), 7. 19 (d, J=8. 8, 2H), 7. 12 (s, 1H) , 6. 98 (d, J=9. 2, 2H), 4. 00 (t, J=6. 4, 2H), 2. 78 (t, J=7. 6, 2H), 2. 59 ( t, 2H ), 1. 75 (hex, 2H), 1. 06 (t, J=6. 8, 3H), ESI-MS (M+H + ) 397. 3, TOF-MS ( (M+ H + 397. 16, C 22 H 25 N 2 0 3 S. Example 19: 3-(4-((5-(4-cyclopentyloxyphenyl)thiazole-2)amino)phenyl)propanoic acid preparation
参考实施例 6， 得到产品 0. 10g, 以化合物 3- ( 4- ( ( 5- ( 4 -异 丙氧基苯基）噻唑- 2 )氨基）苯基）丙酸和溴代环戊烷制得，收率 6. 0%。 Reference Example 6, the product obtained 0. 10g, the compound 3- (4 - ((5- (4 - isopropoxyphenyl) thiazol - 2) amino) phenyl) propanoic acid and bromo cyclopentane 0%。 Yield, 6. 0%.
'H-NMR (400MHz, DMS0-d6) δ (ppm)： 10. 16 (s, 1H) , 7. 81 (d, J=9. 2, 2H)， 7. 61 (d, J=8. 4, 2H)， 7. 19 (d, J=8. 4， 2H) , 7. 11 (s， 1H)， 6. 95 (d, J=8 . 8， 2H)， 4. 86 (pent, J=6. 0， 1H)， 2. 78 (t， J=7. 6， 2H)， 2. 51 (t， 2H)， 1. 59 -2. 0 (br， 8H)， ESI-MS (M+H+) 409. 2， TOF-MS ( (M+H+) 409. 16， C23H25N203S。 实施例 20: 3- ( 4- ( ( 5- ( 4-苄氧基苯基 )噻唑- 2 )氨基）苯基） 丙酸的制备 'H-NMR (400MHz, DMS0-d6) δ (ppm): 10. 16 (s, 1H) , 7. 81 (d, J=9. 2, 2H), 7. 61 (d, J=8. 4, 2H), 7. 19 (d, J=8. 4, 2H), 7. 11 (s, 1H), 6. 95 (d, J=8. 8, 2H), 4. 86 (pent, J=6. 0, 1H), 2. 78 (t, J=7. 6, 2H), 2. 51 (t, 2H), 1. 59 -2. 0 (br, 8H), ESI-MS ( M+H + ) 409. 2, TOF-MS ((M+H+) 409. 16, C 23 H 25 N 2 0 3 S. Example 20: 3-(4-((5- 4-benzyloxy) Preparation of phenyl)thiazol-2(amino)phenyl)propionic acid
参考实施例 6， 得到产品 0. 05g, 以化合物 3- ( 4- ( ( 5- ( 4 -异 丙氧基苯基）噻唑 -2 )氨基）苯基） 丙酸和溴苄制得， 收率 10. 2%。 Reference Example 6, the product obtained 0. 05g, starting from 3- (4 - ((5- (4 - isopropoxyphenyl) thiazol-2) amino) phenyl) propionic acid The compound was prepared and benzyl bromide, yield Rate 10.2%.
'H-NMR (400MHz, DMS0-d6) δ (ppm)： 10. 15 (s, 1H)， 7. 84 (d, J= 9. 2， 2H)， 7. 61 (d, J=8. 8， 2H)， 7. 31-7. 50 (br， 5H) , 7. 19 (d, J=8. 8, 2H)， 7. 13 (s， 1H)， 7. 07 (d, J=8. 8, 2H) , 5. 15 (s， 2H)， 4. 48 (br， 4H) , 2. 78 (t， J =7. 6, 2H) , 2. 51 (t, 2H)， TOF-MS (M+H+)， 431. 14， C25H23N203S。 实施例 21 : 3- ( 4- ( ( 5- ( 2， 4-二氟苯基 )噻唑 -2 )氨基）苯基） 丙酸的制备 'H-NMR (400MHz, DMS0-d6) δ (ppm): 10. 15 (s, 1H), 7. 84 (d, J= 9. 2, 2H), 7. 61 (d, J=8. 8, 2H), 7. 31-7. 50 (br, 5H) , 7. 19 (d, J=8. 8, 2H), 7. 13 (s, 1H), 7. 07 (d, J= 8. 8, 2H) , 5. 15 (s, 2H), 4. 48 (br, 4H) , 2. 78 (t, J =7. 6, 2H), 2. 51 (t, 2H), TOF-MS (M+H + ), 431. 14, C 25 H 23 N 2 0 3 S. Example 21: Preparation of 3-(4-((5-(4-,4-difluorophenyl)thiazol-2)amino)phenyl)propanoic acid
参考实施例 14， 以化合物 3- ( 4-硫脲基苯基）丙酸和 2,4-二氟- 2， -溴代苯乙酮制得产品 0. 40g， 收率 38. 5%。  5%。 The product was obtained by the compound 3-(4-thioureidophenyl)propanoic acid and 2,4-difluoro-2-bromoacetophenone.
'H-NMR (400MHz, DMS0-d6) δ (ppm)： 12. 13 (s, IH) , 10. 26 (s， IH)， 7. 84 (d, J=9. 2, 2H) , 7. 61 (d, J=8. 8， 2H)， 7. 31-7. 50 (br， 5H)， 7. 19 (d, J =8. 8, 2H) , 7. 13 (s， IH)， 7. 07 (d, J=8. 8, 2H)， 5. 15 (s， 2H)， 4. 48 (br， 4H) ， 2. 78 (t， J=7. 6， 2H)， 2. 51 (t, 2H)， ESI-MS (M+H+)， 361. 3， TOF-MS (M+H+) ， 361. 08，C18H15F2N202S。 实施例 22: 3- ( 4- ( ( 5- ( 4-溴苯基 )噻唑- 2 )氨基）苯基） 丙 酸的制备 'H-NMR (400MHz, DMS0-d6) δ (ppm): 12. 13 (s, IH) , 10. 26 (s, IH), 7. 84 (d, J=9. 2, 2H) , 7 . 61 (d, J=8. 8, 2H), 7. 31-7. 50 (br, 5H), 7. 19 (d, J = 8. 8 2), 7. 13 (s, IH) , 7. 07 (d, J=8. 8, 2H), 5. 15 (s, 2H), 4. 48 (br, 4H) , 2. 78 (t, J=7. 6, 2H), 2 51 (t, 2H), ESI-MS (M+H+), 361. 3, TOF-MS (M+H+), 361. 08, C 18 H 15 F 2 N 2 0 2 S. Example 22: Preparation of 3-(4-((5-(4-bromophenyl)thiazole-2)amino)phenyl)propanoic acid
参考实施例 14， 3- ( 4-硫脲基苯基） 丙酸和 4-溴- 2， -溴代苯乙 酮制得到产品 0. 04g， ， 收率 4. 5%0 5% 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
'H-NMR (400MHz, DMS0-d6) δ (ppm)： 10. 27 (s, IH)， 7. 87 'H-NMR (400MHz, DMS0-d6) δ (ppm): 10. 27 (s, IH), 7. 87
(d, J=8. 8, 2H) , 7. 63 (d, J=6. 4， 2H)， 7. 61 (d, J=6. 4， 2H)， 7. 40 (s， IH)， 7 . 20 (d, J=8. 8， 2H)， 2. 78 (t， J=7. 6， 2H) , 2. 51 (2H)， ESI-MS (M+H+) 403. 1， TOF-MS ( (M+H+) 403. 01, C18H16BrN202S。 实施例 23: 3- ( 4- ( ( 5- ( 4-甲氧基苯基 )噻唑- 2 )氨基）苯基） 丙酸的制备 (d, J=8. 8, 2H), 7. 63 (d, J=6. 4, 2H), 7. 61 (d, J=6. 4, 2H), 7. 40 (s, IH) , 7. 20 (d, J=8. 8, 2H), 2. 78 (t, J=7. 6, 2H), 2. 51 (2H), ESI-MS (M+H+) 403. 1, TOF-MS ((M+H+) 403. 01, C 18 H 16 BrN 2 0 2 S. Example 23: 3-(4-((5-(4-methoxyphenyl)thiazole-2)amino) Preparation of phenyl) propionic acid
参考实施例 I4， 以化合物 3- ( 4- ( ( 5- ( 4-异丙氧基苯基）噻唑 -2 )氨基）苯基） 丙酸和溴代甲烷制得产品 0. 32g, 收率 15. 5%。 Reference Example I 4, the compound 3- (4 - ((5- (4 - isopropoxyphenyl) thiazol-2) amino) phenyl) propionic acid methyl bromide and the product were 0. 32g, yield Rate 15.5%.
'H-NMR (400MHz, DMS0-d6) δ (ppm) : 10. 09 (s, IH) , 10. 14 (s, IH) , 7. 84 (d, J=8. 4, 2H) , 7. 61 (d, J=8. 4， 2H)， 7. 19 (d, J=8. 4， 2H)， 7. 12 (s， 1 H)， 6. 99 (d, J=8. 8， 2H)， 3. 79 (s， IH)， 2. 78 (t， J=7. 6， 2H)， 2. 54 (t， J=7. 6， 2H)， TOF-MS ( (M+H+) 383. 11， C2。H19N204S。 实施例 24: 3- ( 4- ( ( 5- ( 4-氯苯基 )噻唑 -2 )氨基）苯基） 丙 酸的制备 'H-NMR (400MHz, DMS0-d6) δ (ppm) : 10. 09 (s, IH) , 10. 14 (s, IH) , 7. 84 (d, J=8. 4, 2H) , 7 . 61 (d, J=8. 4, 2H), 7. 19 (d, J=8. 4, 2H), 7. 12 (s, 1 H), 6. 99 (d, J=8. 8 , 2H), 3. 79 (s, IH), 2. 78 (t, J=7. 6, 2H), 2. 54 (t, J=7. 6, 2H), TOF-MS ( (M+ H+) 383. 11, C 2 .H 19 N 2 04S. Example 24: Preparation of 3-(4-((5-(4-chlorophenyl)thiazol-2)amino)phenyl)propanoic acid
参考实施例 14， 3- ( 4-硫脲基苯基） 丙酸和 4-溴- 2， -氯代苯乙 酮制得， 得到产品 0. 05g， 收率 10. 2%。  Reference Example 14, 3-(4-thioureidophenyl)propanoic acid and 4-bromo-2-chloroacetophenone were obtained to give the product 0. 05 g, yield 10.2%.
'H-NMR (400MHz, DMS0-d6) δ (ppm)： 10. 27 (s, 1H)， 7. 93 'H-NMR (400MHz, DMS0-d6) δ (ppm): 10. 27 (s, 1H), 7. 93
(d, J=8. 4, 2H) , 7. 61 (d, J=8. 4， 2H)， 7. 50 (d, J=8. 8， 2H)， 7. 40 (s， 1H)， 7 . 20 (d, J=8. 4， 2H)， 2. 78 (t， J=7. 6， 2H)， 2. 5 (2H)， ESI-MS (M+H+) 359. 2， T OF-MS ( (M+H+) 359. 06， C18H16C1N202S。 实施例 25: 3- ( 4- ( ( 5- ( 4-正己氧苯基）噻唑- 2 )氨基）苯基） 丙酸的制备 (d, J=8. 4, 2H), 7. 61 (d, J=8. 4, 2H), 7. 50 (d, J=8. 8, 2H), 7. 40 (s, 1H) , 7 . 20 (d, J=8. 4, 2H), 2. 78 (t, J=7. 6, 2H), 2. 5 (2H), ESI-MS (M+H+) 359. 2, T OF-MS ((M+H + ) 359. 06, C 18 H 16 C1N 2 0 2 S. Example 25: 3-(4-((5-(4-n-hexyloxyphenyl)thiazole-2) Preparation of amino)phenyl)propionic acid
参照 3- ( 4- ( ( 5- ( 4-异丙氧基苯基 )噻唑- 2 )氨基）苯基） 丙 酸的合成方法， 得到产品 0. 05g , 收率 10. 2%。  A method of synthesizing 3-(4-((5-(4-isopropoxyphenyl)thiazole-2)amino)phenyl)propanoic acid was used to give the product 0. 05 g, yield 10.2%.
'H-NMR (400MHz, DMS0-d6) δ (ppm) : 12. 13 (s, 1H) , 10. 16 (s， 1H) , 7. 82 (d, J=8. 8, 2H) , 7. 61 (d, J=8. 8， 2H)， 7. 19 (d, J=8. 8， 2H)， 7. 13 (s， 1 H)， 6. 98 (d, J=8. 4， 2H)， 6. 99 (t， J=6. 8, 2H)， 2. 78 (t, J=7. 6， 2H)， 2. 51 ( 2H)， ESI-MS (M+H+) 425. 4, TOF-MS ( (M+H+) 425. 19， C24H29N203S。 实施例 26: 5-溴水杨醛肟的制备 'H-NMR (400MHz, DMS0-d6) δ (ppm): 12. 13 (s, 1H) , 10. 16 (s, 1H) , 7. 82 (d, J=8. 8, 2H) , 7 . 61 (d, J=8. 8, 2H), 7. 19 (d, J=8. 8, 2H), 7. 13 (s, 1 H), 6. 98 (d, J=8. 4 , 2H), 6. 99 (t, J=6. 8, 2H), 2. 78 (t, J=7. 6, 2H), 2. 51 ( 2H), ESI-MS (M+H + ) 425. 4, TOF-MS ((M+H + ) 425. 19, C 24 H 29 N 2 0 3 S. Example 26: Preparation of 5-bromo salicylaldoxime
向 100ml三口瓶中加入 2. 53g ( 36. 41mmol )的盐酸羟胺。 然后加 入 20ml水溶解， 分批加入碳酸氢钠 2. 41g ( 28. 68mmol ) ， 使溶液呈 弱酸性， 待无气泡后， 一次性加入 5-溴水杨醛， 最后加入 70ml无水 乙醇， 加热回流， 原料全部溶解， 回流 5h。 将反应液冷却， 减压蒸馏， 蒸出大部分乙醇， 有固体析出。 抽滤， 水洗（2 x 10ml )滤饼， 干燥即 得到白色粉末状固体， 得到 5. 84g化合物 （2 ) ， 收率 91. 1%。  To a 100 ml three-necked flask was added 2.53 g (36.41 mmol) of hydroxylamine hydrochloride. Then, it was dissolved in 20 ml of water, and 2.41 g (28.68 mmol) of sodium hydrogencarbonate was added in portions to make the solution weakly acidic. After the bubbles were not added, 5-bromo salicylaldehyde was added in one portion, and finally 70 ml of absolute ethanol was added and heated. After refluxing, all the raw materials were dissolved and refluxed for 5 hours. The reaction solution was cooled, distilled under reduced pressure, and most of ethanol was evaporated to give a solid. The mixture was filtered, washed with water (2×10 ml), and dried to give a white powdery solid.
'H-NMR (400MHz, DMS0-d6) δ ： 10. 98 (s, 1H) , 10. 21 (s， 1H) , 7. 72 (d, J=2. 8Hz, 1H) , 7. 66 (dd, J=9. 2Hz, 1H) , 6. 99 (d, J=9. 2Hz, 1H)。 实施例 27: 5-溴- 2-羟基苯甲腈的制备 'H-NMR (400MHz, DMS0-d6) δ : 10. 98 (s, 1H) , 10. 21 (s, 1H) , 7. 72 (d, J=2. 8Hz, 1H) , 7. 66 ( Dd, J=9. 2Hz, 1H), 6. 99 (d, J=9. 2Hz, 1H). Example 27: Preparation of 5-bromo-2-hydroxybenzonitrile
将 5. 84g ( 26. 92mmo l ) 5-溴水杨醛溶于 50ml醋酐中， 然后加热 回流 4. 5h， 室温搅拌约 16h。 将混合物加入冰水中， 再加入 100ml水 后， 用乙酸乙酯 （5 x 100ml )萃取水层， 合并有机层后， 将乙酸乙酯 蒸干，得到油状物，加入 NaOH( 2M )的甲醇溶液 120ml，室温下搅拌 6h。 将反应液中加入 100ml水后， 蒸出甲醇后， 用乙酸乙酯萃取产物后， 加入约 3倍量粗硅胶拌样， 硅胶柱色谱分离 （二氯甲烷： AcOH体积比 200: 1 ) 。 分离得到 3. 15g ( 15. 91mmol ) ， 收率 58. 8%化合物 （ 3 ) 。  5. 84 g ( 26. 92 mmol) of 5-bromo salicylaldehyde was dissolved in 50 ml of acetic anhydride, and then heated to reflux for 4. 5 h, and stirred at room temperature for about 16 h. After the mixture was added to ice water, water (100 ml) was added, and the aqueous layer was extracted with ethyl acetate (5×100 ml). The organic layer was combined and evaporated to ethyl ether. Stir at room temperature for 6 h. After 100 ml of water was added to the reaction mixture, methanol was distilled off, and the product was extracted with ethyl acetate. Then, the mixture was mixed with about 3 times of crude silica gel and separated by silica gel column chromatography (dichloromethane: AcOH volume ratio: 200:1). Isolated 3.15 g ( 15.91 mmol), yield 58.8% compound (3).
'H-NMR (400MHz, DMS0-d6) δ ： 11. 47 (s, 1H)， 7. 889d, J=2. 4, 1H)， 7. 66 (dd, J=8. 8， 1H)， 6. 96 (d, J=8. 8， 1H)。 实施例 28: 5-溴- 2-异丙氧基苯甲腈的制备  'H-NMR (400MHz, DMS0-d6) δ : 11. 47 (s, 1H), 7. 889d, J=2. 4, 1H), 7. 66 (dd, J=8. 8, 1H), 6. 96 (d, J=8. 8, 1H). Example 28: Preparation of 5-bromo-2-isopropoxybenzonitrile
将 2. 74g ( 13. 84mmol ) 5 -溴 -2-羟基苯甲腈， 加入 K2C03 3. 89g ( 28. 19mmo l ) 。 KI一小粒， 加入 30mlDMF后加热至 90"€反应 30min 后， 再加入约 2ml PEG- 400和 2. 25g ( 31. 71mmo l ) 2-溴丙烷反应 lh。 向反应液中加入 100ml水后， 用乙酸乙酯（ 5 50ml )萃取后， 合并有 机层， 用 lM NaOH ( 3 χ 30ml ) 水溶液洗有机层， 再用适量水和饱和氯 化钠水溶液洗有机层， 加入无水 MgS04干燥过夜。 第二天过滤， 蒸除 溶剂， 干燥得到 2. 75g ( 11. 41腿 ol )化合物 ( 4 ) , 收率： 82. 4%„2.74 g ( 13.84 mmol) of 5-bromo-2-hydroxybenzonitrile was added to K 2 C0 3 3. 89 g ( 28.19 mmo l ). KI a small pellet, add 30ml DMF and heat to 90" for 30min, then add about 2ml PEG-400 and 2. 25g (31.71mmo l) 2-bromopropane for 1h. Add 100ml water to the reaction solution, then use After extracting ethyl acetate (5 50 ml), the organic layer was combined, and then organic layer was washed with 1M NaOH (3 χ 30 ml) aqueous solution, and the organic layer was washed with an appropriate amount of water and a saturated aqueous solution of sodium chloride, and dried overnight. Filtration, evaporation of the solvent, drying to give 2.75 g ( 11. 41 leg ol) of compound ( 4 ), yield: 82. 4% „
'H-NMR (400MHz, DMS0-d6) δ： 7. 98 (d, J=2. 4, 1H) , 7. 80 (dd, J=9. 2， 1H)， 7. 25 (d, J=9. 2, 1H)， 4. 79 (hept, J=6. 0， 1H)， 1. 3 (d, J =6. 0， 6H)。 实施例 29: 3-氰基- 4-异丙氧基苯硼酸的制备 'H-NMR (400MHz, DMS0-d6) δ: 7. 98 (d, J=2. 4, 1H) , 7. 80 (dd, J=9. 2, 1H), 7. 25 (d, J =9. 2, 1H), 4. 79 (hept, J=6. 0, 1H), 1. 3 (d, J = 6. 0, 6H). Example 29: Preparation of 3-cyano-4-isopropoxybenzeneboronic acid
首先将低温反应槽的温度降至- 78 。 把 5. 27g ( 21. 96mmo l )干 燥的 5-溴- 2-异丙氧基苯甲腈和 50ml无水 THF加入 100ml三口瓶中， 冷却并通入氮气保护约 15 分钟后， 用一次性针头吸取 13. 2ml 的 n-BuLi , 緩慢注射进入三口瓶中， 约需 lh滴加完毕， - 78 :搅拌 2h。 再加入 11. Olg ( 47. 83mmo l )硼酸三丁酯反应 1. 5h， 緩慢升至室温后 再搅摔 2h， 最后加入 15ml饱和氯化氨溶液猝灭反应， 再加入浓盐酸 酸化至 PH<2， 在室温下搅拌 lh。 向反应液中加入 100ml水， 用乙酸 乙酯（ 5 X 50ml )萃取反应液，合并有机层后，再用 3M NaOH ( 5 30ml ) 水溶液洗涤有机层， 合并水层， 弃掉有机层， 用浓盐酸酸化水层至 PH <2, 再用乙酸乙酯 （3 χ 50ml) 洗涤水层， 合并乙酸乙酯后， 弃掉水 层， 用适量水和饱和氯化钠洗涤乙酸乙酯， 用无水硫酸镁干燥过夜。 得到 2.25g (10.98mmol) 中间体 1， 收率： 50.0%。 First, the temperature of the low temperature reaction tank is lowered to -78. 5.27g ( 21. 96mmo l ) of dried 5-bromo-2-isopropoxybenzonitrile and 50ml of anhydrous THF were added to a 100ml three-necked flask, cooled and protected by nitrogen for about 15 minutes. The needle was pipetted with 13. 2 ml of n-BuLi, and slowly injected into a three-necked bottle. It took about 1 hour to complete the addition, and -78: stirred for 2 hours. After adding 11. Olg (47.83mmo l) tributyl borate reaction 1. 5h, slowly rise to room temperature and then stir for 2h, finally add 15ml saturated ammonium chloride solution to quench the reaction, then add concentrated hydrochloric acid Acidified to pH < 2 and stirred at room temperature for 1 h. 100 ml of water was added to the reaction mixture, and the reaction mixture was extracted with ethyl acetate (5×50 ml). The organic layer was combined, and then the organic layer was washed with aqueous 3M NaOH (5 30 ml), the aqueous layer was combined, and the organic layer was discarded. The aqueous layer was acidified to pH <2, then the aqueous layer was washed with ethyl acetate (3 χ 50ml). After ethyl acetate was combined, the aqueous layer was discarded, and ethyl acetate was washed with an appropriate amount of water and saturated sodium chloride. Dry over magnesium sulfate overnight. 2.25 g (10.98 mmol) of Intermediate 1 was obtained in a yield: 50.0%.
'H-NMR (400MHz, DMS0-D6) δ ： 8.17 (s, 2H) , 8.03 (d, J=2.4Hz, 1H) , 8.01 (dd,， J=8.8， 1H)， 7.24 (d, J=8.8， 1H)， 4.83 (hept, J=6.0， 1H), 1.32 (d, J=6.0, 6H),MS[M+H]+ , m/z: 206.0o 实施例 30: 3-甲基 4-溴-苯甲酸乙酯的制备 'H-NMR (400MHz, DMS0-D6) δ : 8.17 (s, 2H) , 8.03 (d, J=2.4Hz, 1H) , 8.01 (dd,, J=8.8, 1H), 7.24 (d, J= 8.8, 1H), 4.83 (hept, J=6.0, 1H), 1.32 (d, J=6.0, 6H), MS[M+H] + , m/z: 206.0 o Example 30: 3-methyl 4 -Preparation of bromo-benzoic acid ethyl ester
将 3-甲基 4-溴-苯甲酸 3.29g( 15.30mmol )和501111乙醇加入 lOOnl 三口瓶， 再沿瓶壁緩慢加入 4 g浓硫酸， 回流 3h。 反应液加入适量碳 酸氢钠溶液， 调节 PH值至中性， 用乙酸乙酯（5 χ 100ml)萃取， 合并 乙酸乙酯成， 用适量水和饱和氯化钠溶液洗涤后， 无水硫酸镁干燥， 得到产品 3 -甲基 4 -溴-苯甲酸乙酯 3.6g ( 14.81mmol ) 。 收率 96.8%。 实施例 31: 3-甲基- 4-氰基苯甲酸乙酯的制备  3-29 4-bromo-benzoic acid 3.29 g (15.30 mmol) and 501111 ethanol were added to a lOOnl three-necked flask, and then 4 g of concentrated sulfuric acid was slowly added along the wall of the bottle and refluxed for 3 hours. The reaction solution was added with an appropriate amount of sodium hydrogencarbonate solution, and the pH was adjusted to neutral. The mixture was extracted with ethyl acetate (5 χ 100 ml), and ethyl acetate was combined, washed with water and saturated sodium chloride solution, dried over anhydrous magnesium sulfate. The product 3-ethyl 4-bromo-benzoic acid ethyl ester 3.6 g (14.81 mmol) was obtained. The yield was 96.8%. Example 31: Preparation of ethyl 3-methyl-4-cyanobenzoate
将 3-甲基 4-溴-苯甲酸乙酯 5.16g( 21.23mmol )和 60ml加入 100ml 三口瓶中， 然后通入氮气保护 10min， 称量 2.97g ( 33.16腿 ol)氰化 亚铜， 緩慢加入反应也中， 反应瓶密闭， 加热至 140 后通入氮气保 护 10min， 反应过夜。 向反应液中加入 150水后放置 3h， 有固体析出， 抽滤得到固体， 但是溶液中仍然有部分产物， 所以用乙酸乙酯 （5 χ 100ml)萃取， 合并乙酸乙酯层， 用适量水和饱和氯化钠溶液洗涤后， 无水硫酸镁干燥，得到 2.96g(15.64mmol)化合物（8)，收率： 73.7%。  5.16 g (21.23 mmol) of 3-methyl 4-bromo-benzoate and 60 ml were added to a 100 ml three-necked flask, then protected with nitrogen for 10 min, and 2.97 g (33.16 leg ol) of cuprous cyanide was weighed and slowly added. In the reaction, the reaction flask was sealed, heated to 140, and then purged with nitrogen for 10 min, and allowed to react overnight. After adding 150 water to the reaction solution, the mixture was allowed to stand for 3 hours, and a solid precipitated. After suction filtration, a solid was obtained, but there was still some product in the solution, so it was extracted with ethyl acetate (5 χ 100 ml), and the ethyl acetate layer was combined with an appropriate amount of water and After washing with a saturated sodium chloride solution and dried over anhydrous magnesium sulfate, 2.96 g (15.64 mmol) of Compound (8), yield: 73.7%.
^-NMR (400MHz, CDC13) δ ： 7.99 (s, 1H) , 7.93 (d, J=8.8, 1H) , 7.68 (d, J=8.8, 1H)， 4.41 (q, J=7.2， 2H)， 2.61 (s， 3H)， 1.41 (t, J=6.8， 3H)。 实施例 32: 2-甲基- 4-异丙氧叛基硫代苯甲酰胺的制备 称取 3-甲基- 4-氰基苯甲酸乙酯 2. 28g ( 12. 05腿 ol ) ， 加入六水 和氯化镁 1. 97g ( 9. 7mmol ) ， DMF 50ml后， 一次性加入硫氢化钠（纯 化后） 1. 50g ( 26. 77腿 ol ) ， 溶液变成深绿色， 室温下搅拌过夜。 第 二天， 取样点板， 展开剂： 乙酸乙酯： 石油醚 =1 : 2， Rf=0. 55， 原料 点已消失，只有一个产物点。向反应液中加入 100ml水和 20ml浓盐酸 后， 溶液变为无色， 用乙酸乙酯（5 x 50ml )萃取后， 用水与饱和氯化 钠溶液洗涤， 无水硫酸镁干燥。 产品 2-甲基 -4-异丙氧羰基硫代苯甲 酰胺质量 2. 25g ( 10. 08mmol ) ， 收率： 83. 65%。 ^-NMR (400MHz, CDC1 3 ) δ : 7.99 (s, 1H) , 7.93 (d, J=8.8, 1H) , 7.68 (d, J=8.8, 1H), 4.41 (q, J=7.2, 2H) , 2.61 (s, 3H), 1.41 (t, J=6.8, 3H). Example 32: Preparation of 2-methyl-4-isopropoxythiobenzamide Weigh 2-ethyl 4-cyanobenzoic acid ethyl ester 2. 28g ( 12. 05 leg ol ), add 1.97g ( 9. 7mmol ) of hexahydrate and magnesium chloride, 50ml of DMF, add sodium hydrosulfide in one step. (After purification) 1. 50 g ( 26.77 leg ol), the solution turned dark green and stirred at room temperature overnight. The next day, sampling plate, developing agent: ethyl acetate: petroleum ether = 1: 2, Rf = 0.55, the raw material point has disappeared, only one product point. After adding 100 ml of water and 20 ml of concentrated hydrochloric acid to the reaction mixture, the solution was obtained as a colorless mixture, ethyl acetate (5 x 50 ml), and washed with water and saturated sodium chloride. 5%。 The yield of 2-methyl-4-isopropoxycarbonyl thiobenzamide 2.25g ( 10. 08mmol), yield: 83. 65%.
^NMR (400MHz, CDC13) δ ： 7. 86 (d (br, 2H) , 7. 79 (s, 1H) 7. 41 (d, J= 8. 0， 1H)， 6. 97 (s， 1H)， 4. 38 (q, J=7. 2， 2H) 2. 50 (s， 3H)， 1. 40 (t， J=6. 8, 3H)。 实施例 33: 3-甲基- 4- (噻唑 -2-基）苯甲酸乙酯的制备 ^NMR (400MHz, CDC1 3 ) δ : 7. 86 (d (br, 2H) , 7. 79 (s, 1H) 7. 41 (d, J= 8. 0, 1H), 6. 97 (s, 1H), 4. 38 (q, J=7.2, 2H) 2. 50 (s, 3H), 1. 40 (t, J=6. 8, 3H). Example 33: 3-methyl- Preparation of ethyl 4-(thiazol-2-yl)benzoate
将 2. 54g ( 11. 37腿 ol ) 2-甲基 -4-异丙氧羰基硫代苯甲酰胺， 溴 乙缩醛 4. 63g ( 23. 49mmol )和 50ml 乙醇加入 100ml茄形瓶中， 通入 氮气保护 10min， 回流 4h。 向反应液中加入 150ml水后， 用乙酸乙酯 ( 4 50ml ) ， 萃取， 减压蒸除溶剂， 硅胶柱色谱（乙酸乙酯： 石油醚 2.54g ( 11.37 leg ol) of 2-methyl-4-isopropyloxycarbonylthiobenzamide, bromoacetal 4.63g ( 23.49mmol ) and 50ml of ethanol were added to a 100ml eggplant bottle. It was purged with nitrogen for 10 min and refluxed for 4 h. After adding 150 ml of water to the reaction mixture, ethyl acetate (4 50 ml) was added, and the solvent was evaporated.
=1 : 40 )分离。 得到 1. 36g ( 5. 50mmol )化合物 （ 10 ) ， 收率 48. 4%。 =1 : 40 ) Separation. 6%。 The yield of 1. 36g ( 5. 50mmol) of compound ( 10 ), yield 48.4%.
'H-NMR (400MHz, CDC13) δ ： 8. 40 (d, J=3. 6， 1H) , 8. 17 (d, J=8. 4， 1H)'H-NMR (400MHz, CDC1 3 ) δ : 8. 40 (d, J=3. 6, 1H) , 8. 17 (d, J=8. 4, 1H)
8. 11 (d (br)， J=7. 2， 2H)， 7. 99 (d, J=3. 6， 1H)， 4. 43 (q, J=7. 2, 2H) , 2. 758. 11 (d (br), J=7. 2, 2H), 7. 99 (d, J=3. 6, 1H), 4. 43 (q, J=7. 2, 2H), 2. 75
(s，3H)，1. 43 (t， J=7. 2，3H)。 实施例 34: 3-甲基- 4- (噻唑 -2-基）苄酵的制备 (s, 3H), 1.43 (t, J=7.2, 3H). Example 34: Preparation of 3-methyl-4-(thiazol-2-yl)benzylidene
将四氢铝锂 2. 06g ( 54. 38mmol )和 15mlTHF加入 100ml三口瓶中 后， 放置在低温反应槽中冷却至 -5 TC， 把 3-甲基- 4- (噻唑 -2-基）苯 甲酸乙酯 2. 07g ( 9. 44mmol )溶于 20mlTHF中， 放置在 50ml滴液漏斗 中， 緩慢滴加 THF溶液， 控制反应液温度不高于 0 ，约 30min， 滴加 完毕，然后转至室温下搅拌 lh，取样点板，只有一个极性较大的点生 成。将反应液转移至烧杯中，逐滴緩慢加入水，以防止喷溅.直到破坏所 有的四氢铝锂，生成氢氧化铝胶状物， 用大量乙酸乙酯洗涤这些胶状 物。用无水硫酸镁直接干燥滤液，得到 1. 61g (7. 84腿 ol)化合物（11 )， 收率， 83. 05%。 实施例 35: 3-甲基- 4- (噻唑 -2-基）苯甲醛的制备 After adding 0.66 g (54.38 mmol) of lithium tetrahydrogenate and 15 ml of THF to a 100 ml three-necked flask, it was placed in a low temperature reaction tank and cooled to -5 TC to give 3-methyl-4-(thiazol-2-yl)benzene. Ethyl formate 2. 07g ( 9. 44mmol ) was dissolved in 20ml of THF, placed in a 50ml dropping funnel, slowly added THF solution, control the temperature of the reaction solution is not higher than 0, about 30min, the addition is completed, then transferred to room temperature Stir lh, sample the plate, only one point with a larger polarity is generated. Transfer the reaction solution to a beaker and slowly add water dropwise to prevent splashing. Some lithium aluminum hydride was formed into an aluminum hydroxide gum, which was washed with a large amount of ethyl acetate. The yield of the compound (11) was obtained in a yield of 83. 05%. Example 35: Preparation of 3-methyl-4-(thiazol-2-yl)benzaldehyde
将 1. 61g ( 7. 84画 1 ) 3-甲基- 4- (噻唑- 2-基 ) 苄醇， 10. 74g ( 123. 53mmol )活性二氧化锰和 70ml丙酮加入 250ml茄形瓶中， 室温 下搅摔 30h。 将反应液抽滤， 要求布氏漏斗密闭性要好， 防止二氧化 锰漏入抽滤瓶中， 用约 150ml 乙酸乙酯洗涤二氧化锰， 直至二氧化锰 层点板无荧光为止。溶液加入无水硫酸镁干燥。得到 1. 41g (6. 94mmol) 化合物 ( 12 ) ，收率， 88. 52%. 实施例 36: 3-甲基- 4- (噻唑 -2-基）苯丙烯酸的制备  1.61g ( 7. 84 of 1) 3-methyl-4-(thiazol-2-yl)benzyl alcohol, 10. 74g (123.53mmol) of active manganese dioxide and 70ml of acetone were added to a 250ml eggplant bottle. Stir at room temperature for 30 h. The reaction solution was suction filtered, and the Buchner funnel was required to have good airtightness. The manganese dioxide was prevented from leaking into the filter flask, and the manganese dioxide was washed with about 150 ml of ethyl acetate until the manganese dioxide layer plate had no fluorescence. The solution was dried over anhydrous magnesium sulfate. 1. 41 g (6. 94 mmol) of compound (12), yield, 88. 52%. Example 36: Preparation of 3-methyl-4-(thiazol-2-yl)phenylacrylic acid
将 1. 41g (6. 94mmol) _ 3-甲基 -4- (噻唑 - 2-基） 苯甲醛， 2. 15g ( 20. 66mmol ) 丙二酸， 吡 30ml， 加入 100ml三口瓶中， 最后滴入 10滴哌啶， 加热至 反应 5h。 将吡啶蒸出后， 为黄色固体， 用 少量水洗涤滤饼， 即得到产物。 若产品不存， 有较多杂质， 则需要硅 胶柱分离。 得到 1. 26g ( 5. 14mmol )化合物 （ 13 ) ， 收率， 74. 1%。  1. 41g (6. 94mmol) _ 3-methyl-4-(thiazol-2-yl)benzaldehyde, 2. 15g (20.66mmol) malonic acid, 30ml of pyridin, added to a 100ml three-necked bottle, the last drop 10 drops of piperidine were added and heated to reaction for 5 h. After the pyridine was distilled off, it was a yellow solid, and the cake was washed with a small amount of water to give a product. If the product does not exist and there are more impurities, the silica gel column needs to be separated. 6%。 The compound (13), yield, 74.1%.
'H-NMR (400MHz, DMS0-d6) δ： 12. 52 (s， 1H)， 8. 02 (d, J=3. 2Hz, 1H)， 7. 90 (d, J=3. 2, 1H) , 7. 83 (d, J=8. 0， 1H) , 7. 73 (s， 1H)， 7. 66 (dd, J=8. 0， 1H) , 7. 60 (d, J=16. 0Hz, 1H) , 6. 62 (d, J=16. 0, 1H) , 2. 59 (s, 1H) 。 实施例 37: 3-甲基- 4- (噻唑 -2-基）苯丙酸的制备  'H-NMR (400MHz, DMS0-d6) δ: 12. 52 (s, 1H), 8. 02 (d, J=3. 2Hz, 1H), 7. 90 (d, J=3. 2, 1H ) , 7. 83 (d, J=8. 0, 1H) , 7. 73 (s, 1H), 7. 66 (dd, J=8. 0, 1H) , 7. 60 (d, J=16 . 0Hz, 1H) , 6. 62 (d, J=16. 0, 1H) , 2. 59 (s, 1H). Example 37: Preparation of 3-methyl-4-(thiazol-2-yl)benzenepropionic acid
将原料 6. 38g ( 26. Olmmol ) 3-甲基- 4- (噻唑- 2-基 )苯丙烯酸和 120ml 乙酸乙酯加入氢化装置的反应瓶中， 向反应瓶中通入氮气后， 加入 10%Pd- C 1. 5g， 将放应瓶放在氢化装置中， 保持氢气压力 2atm， 室温下反应 3h。反应液抽滤，滤除 Pd- C，再用少量乙酸乙酯洗涤 Pd-C。 滤液干燥， 减压蒸干溶剂后， 得到 6. 29g ( 25. 43腿 ol )化合物（ 14 ) ， 收率， 97. 8%。 'HNMR (400MHz, DMS0-D6) δ ： 12.515 (s, 1H) , 7.95 (d, J=3.2， 1H)， 7.81 (d, J=3.2, 1H) , 7.65 (d, J=7.6， 1H)， 7.24 (s， 1H)， 7.19 (dd, J=7.6H z， 1H) 2.84 (t, J=7.6Hz, 2H)， 2.65 (t， J=7.6， 2H)， 2.52 (s， 1H)。 实施例 38: 3-甲基- 4- (噻唑 -2-基）苯丙酸乙酯的制备 6.38 g ( 26. Olmmol) of 3-methyl- 4- (thiazol- 2 -yl)benzeneacrylic acid and 120 ml of ethyl acetate were added to a reaction flask of a hydrogenation apparatus, and nitrogen gas was introduced into the reaction flask, followed by adding 10 %Pd- C 1. 5g, place the vial in a hydrogenation unit, maintain a hydrogen pressure of 2 atm, and react at room temperature for 3 h. The reaction solution was suction filtered, and then filtered, and then filtered, and then washed with Pd-C. 8%。 The filtrate was dried, and the solvent was evaporated to dryness. 'HNMR (400MHz, DMS0-D6) δ : 12.515 (s, 1H) , 7.95 (d, J=3.2, 1H), 7.81 (d, J=3.2, 1H) , 7.65 (d, J=7.6, 1H) , 7.24 (s, 1H), 7.19 (dd, J=7.6H z, 1H) 2.84 (t, J=7.6Hz, 2H), 2.65 (t, J=7.6, 2H), 2.52 (s, 1H). Example 38: Preparation of ethyl 3-methyl-4-(thiazol-2-yl)benzenepropanoate
将原料 7.09g( 28.67mmol )3-甲基- 4~(噻唑- 2-基）苯丙酸和 100ml 乙醇加入 250ml三口瓶， 再沿瓶壁緩' I 加入 15ml浓硫酸， 回流 3h。 反应液加入适量水， 用乙酸乙酯（ 5 100ml )萃取， 合并乙酸乙酯层， 用适量水和饱和氯化钠溶液洗涤后，无水硫酸镁干燥，减压蒸干溶剂， 得到 7.03g ( 25.52mmol )化合物 （ 15 ) 。 收率 88.7%。 实施例 39: 3-甲基- 4- ( 5-溴噻唑 -2-基）苯丙酸乙酯的制备 将 7.03g ( 25.52mmol ) 3-甲基- 4- (噻唑 -2-基）苯丙酸乙酯加入 100ml三口瓶， 再加入 4.31g ( 52.54mmol )醋酸钠， 50ml冰醋酸， 搅 拌。 用一次性吸管吸 1.5ml (约 29.29mmol ) 的溴， 加入 50ml滴液漏 斗中， 再加入 20ml冰醋酸稀释， 緩慢滴加溴。 发现溴滴入溶液中， 颜 色就消失， 约 40min全部滴加完毕， 溶液呈红色。 反应 lh。 向反应液 中加入 150ml水后， 乙酸乙酯（5 x 60ml )萃取， 合并乙酸乙酯层， 用 适量水和饱和氯化钠溶液洗涤后， 加入粗硅胶拌样， 硅胶柱色谱（乙 酸乙酯 -石油醚体积比是 1: 50)分离， 得到 4.36g ( 12.31mmol ) 中间 体 2， 收率 48. Vk。  7.09 g (28.67 mmol) of 3-methyl-4~(thiazol-2-yl)benzenepropionic acid and 100 ml of ethanol were added to a 250 ml three-necked flask, and then 15 ml of concentrated sulfuric acid was added along the wall of the bottle to reflux for 3 hours. The reaction mixture was added with aq. EtOAc (EtOAc) (EtOAc) 25.52 mmol) of compound (15). The yield was 88.7%. Example 39: Preparation of ethyl 3-methyl-4-(5-bromothiazol-2-yl)benzenepropanoate 7.03 g (25.52 mmol) 3-methyl-4-(thiazol-2-yl)benzene Ethyl propionate was added to a 100 ml three-necked flask, and then 4.31 g (52.54 mmol) of sodium acetate, 50 ml of glacial acetic acid was added, and stirred. A 1.5 ml (about 29.29 mmol) bromine was pipetted into a 50 ml dropping funnel, diluted with 20 ml of glacial acetic acid, and bromine was slowly added dropwise. It was found that the bromine was dropped into the solution, and the color disappeared. After about 40 minutes, the solution was completely added, and the solution was red. Reaction lh. After adding 150 ml of water to the reaction mixture, ethyl acetate (5 x 60 ml) was extracted, and the ethyl acetate layer was combined, washed with water and saturated sodium chloride solution, and then the mixture was applied to silica gel. Separation of the petroleum ether in a volume ratio of 1:50) gave 4.36 g (1,31 mmol) of Intermediate 2, yield 48. Vk.
'H-NMR (400MHz, DMS0-D6) δ ： 8.02 (s, 1H) , 7.62 (d, J=8.0, 1H)， 7.24 (s， 1H) , 7.19 (dd, J=8.0， 1H)， 4.05 (q, J=6.8Hz, 2H)， 2.87 (t， J=7. 6Hz, 2H),2.65(t, J=7.6Hz, 2H), 2.50 (s, 1H), 1.16 (t, J=7.2Hz, 3H)。 实施例 40: 3-甲基- 4- ( 5- ( 3-氰基- 4-异丙氧基- 1-苯基）噻唑 - 2 -基）苯丙酸乙酯的制备  'H-NMR (400MHz, DMS0-D6) δ : 8.02 (s, 1H) , 7.62 (d, J=8.0, 1H), 7.24 (s, 1H) , 7.19 (dd, J=8.0, 1H), 4.05 (q, J=6.8Hz, 2H), 2.87 (t, J=7. 6Hz, 2H), 2.65(t, J=7.6Hz, 2H), 2.50 (s, 1H), 1.16 (t, J=7.2 Hz, 3H). Example 40: Preparation of ethyl 3-methyl-4-(3-(3-cyano-4-isopropoxy-1-phenyl)thiazole-2-yl)benzenepropanoate
将 2.05g ( 10. Ommol ) 3-氰基 -4-异丙氧基苯硼酸和 2.54g ( 7.17mmol ) 3-甲基- 4- ( 5-溴噻唑 -2-基）苯丙酸乙酯加入 100ml三 口瓶中， 通入氮气保护， 加入 2.5M的碳酸氢钠溶液 15ml， 约 15min 后， 加入少量催化剂。 lOmin后加热至 保持恒定的氮气流反应 4h。 反应液中加入适量水以后， 用二氯甲烷（5x 100ml)萃取， 合并 有机层后， 用适量水和饱和氯化钠溶液洗涤后， 加入粗硅胶拌样， 硅 胶柱色谱（乙酸乙酯：石油醚 =1: 10)分离。 得到 0.87g (2.00mmol) 的化合物 （17) ， 收率 27.9%。 2.05 g (10 Ommol) of 3-cyano-4-isopropoxybenzeneboronic acid and 2.54 g (7.17 mmol) of ethyl 3-methyl-4-(5-bromothiazol-2-yl)benzenepropanoate Add 100ml three The vial was purged with nitrogen and 15 ml of a 2.5 M sodium bicarbonate solution was added. After about 15 min, a small amount of catalyst was added. After lOmin, it was heated to a constant nitrogen flow for 4 h. After adding an appropriate amount of water to the reaction mixture, the mixture was extracted with methylene chloride (5×100 ml), and the organic layer was combined, washed with water and saturated sodium chloride solution, and then the mixture was applied to silica gel column chromatography (ethyl acetate: petroleum Ether = 1: 10) Separation. 0.87 g (2.00 mmol) of the compound (17) was obtained in a yield of 27.9%.
'HNMR (400MHz, DMS0-D6) δ ： 8.35 (s, 1H) ,8.16 (d, J=2.4, 1H)， 7.94 (dd, J=9.2， 1H)， 7.70 (d，， J=7.6， 1H)， 7.38 (d, J=9.2， 1H)， 7.26 (s ， 1H) , 7.2 (dd, J=7.6， 1H)， 4.87 (hept, J=6.4， 1H)， 4.05 (q, J=6.8， 2H)， 2.88(t, J=7.6, 2H),2.57(t， J=7.6， 2H) , 2.67 (s, 1H), 1.35 (d, J=5.6, 6H),1.17(t， J=7.2，3H)。 实施例 41: 3-甲基- 4- (5- (3-氰基- 4-异丙氧基- 1-苯基）噻唑 -2 -基）苯丙酸的制备  'HNMR (400MHz, DMS0-D6) δ : 8.35 (s, 1H) , 8.16 (d, J=2.4, 1H), 7.94 (dd, J=9.2, 1H), 7.70 (d,, J=7.6, 1H ), 7.38 (d, J=9.2, 1H), 7.26 (s , 1H) , 7.2 (dd, J=7.6, 1H), 4.87 (hept, J=6.4, 1H), 4.05 (q, J=6.8, 2H), 2.88(t, J=7.6, 2H), 2.57(t, J=7.6, 2H), 2.67 (s, 1H), 1.35 (d, J=5.6, 6H), 1.17(t, J=7.2 , 3H). Example 41: Preparation of 3-methyl-4-(5-(3-cyano-4-isopropoxy- 1-phenyl)thiazole-2-yl)benzenepropionic acid
将 0.87g ( 2. OOmmol ) 3-甲基 -4- ( 5- ( 3-氰基- 4-异丙氧基 -1 -苯 基） 噻唑- 2-基） 苯丙酸乙酯加入 100ml 茄形瓶中， 加入 1.5g ( 62.63mmol )氢氧化锂和 15ml水及 15ml THF, 加热回流约 3h。 将反 应液用盐酸调至 PH<1，终产物析出呈絮状， 黄绿色。 再用硅胶柱色谱 (乙酸乙酯-石油醚体积比 1: 2 )分离，用 THF作为溶剂拌样。得到 0.78g ( 1.92mmol )终产物， 熔点 164.9-165. 收率 96.0°/。。  Add 0.87 g (2.0 mmol) of 3-methyl-4-(5-(3-cyano-4-isopropoxy-1-phenyl)thiazol-2-yl)propanate to 100 ml of eggplant Into a vial, 1.5 g (62.63 mmol) of lithium hydroxide and 15 ml of water and 15 ml of THF were added and heated to reflux for about 3 h. The reaction solution was adjusted to pH <1 with hydrochloric acid, and the final product precipitated as a flocculent, yellow-green. It was separated by silica gel column chromatography (ethyl acetate-petroleum ether: 1: 2), and the mixture was mixed with THF. 0.78 g ( 1.92 mmol) of the final product are obtained, m.p. .
'HNMR (400MHz, DMS0-D6) δ ： 12.16 (s, 1H) , 8.34s, 1H)， 8.14 (d, J =2.4, 1H) , 7.94 (dd, J=8.8, 1H) , 7.70 (d, J=7.6， 1H)， 7.37 (d, J=7.6Hz, 1H)， 7.26 (s， 1H)， 7.21 (dd, J=8.4， 1H)， 4.87 (hept, J=6.4， 1H)， 2.85 (t ， J=7.6， 2H)， 2.57 (s， 1H)， 2.50 (t, J=2.0Hz, 2H)， 1.35 (d, J=6.4， 6H)， E SI -MS (M+H+) 407.1， TOF-MS ( (M+H+) 407.14， C21H23N203S, ESI— MS (M+H+) 407.4。 实施例 42: 2-溴- 1- (4-溴- 3-甲氧基苯基） 乙酮的制备 'HNMR (400MHz, DMS0-D6) δ : 12.16 (s, 1H) , 8.34s, 1H), 8.14 (d, J =2.4, 1H) , 7.94 (dd, J=8.8, 1H) , 7.70 (d, J=7.6, 1H), 7.37 (d, J=7.6Hz, 1H), 7.26 (s, 1H), 7.21 (dd, J=8.4, 1H), 4.87 (hept, J=6.4, 1H), 2.85 ( t , J=7.6, 2H), 2.57 (s, 1H), 2.50 (t, J=2.0Hz, 2H), 1.35 (d, J=6.4, 6H), E SI -MS (M+H+) 407.1, TOF-MS ((M+H + ) 407.14, C 21 H 23 N 2 0 3 S, ESI-MS (M+H+) 407.4. Example 42: 2-bromo-1-(4-bromo-3- Preparation of oxyphenyl) ethyl ketone
将 20ml邻溴苯甲醚（密度 =1.5g/ml ) ， 32gAlC13， 100mlCH2C12 加入 250ml俩口瓶中， 水盐浴冷却至零度以下。 将 22ml 溴乙酰溴， 100mlCH2C12加入 250ml真空滴液漏斗， 混勾后緩慢滴加至冷却好的 反应瓶中， 大约一小时滴毕， 滴完后继续搅拌 2小时。 反应完毕緩慢 将反应液倒入盛有碎冰的大烧杯中，摇勾，分出有机层，水层用 CH2C12 萃取， 合并有机层， 水洗 4次， 饱和 NaCl洗一遍， 无水硫酸钠干燥， 过夜， 过滤， 旋干溶剂， 干燥得白色固体 37. 93g。 收率： 76. 9%。 20 ml o-bromoanisole (density = 1.5 g / ml), 32 g AlC13, 100 ml CH2C12 Add 250ml two-necked bottle and cool the water to below zero. 22 ml of bromoacetyl bromide and 100 ml of CH2C12 were placed in a 250 ml vacuum dropping funnel, and the mixture was slowly added dropwise to the cooled reaction flask, and the mixture was dropped for about one hour. After the completion of the dropwise addition, stirring was continued for 2 hours. After the reaction was completed, the reaction liquid was poured into a large beaker containing crushed ice. The organic layer was separated by shaking the hook. The aqueous layer was extracted with CH2C12. The organic layer was combined, washed with water four times, washed with saturated NaCl and dried over anhydrous sodium sulfate. The mixture was dried over EtOAc (EtOAc). Yield: 76.9%.
'H-NMR (400MHz, DMS0-d6) δ (ppm)： 8. 21 (d, J=2. 2, 1H ) ， 7. 97 (dd, J=dl-d2=2. 4; dl-d3=8. 8, 1H) , 6. 98 (d, J=8. 8， 1H) , 4. 38 (s， 2 H)，3. 99 (s，3H)。 实施例 43: 3- ( 4-氨基苯基） 丙酸的制备  'H-NMR (400MHz, DMS0-d6) δ (ppm): 8. 21 (d, J=2. 2, 1H ) , 7. 97 (dd, J=dl-d2=2.4; dl-d3 =8. 8, 1H), 6. 98 (d, J=8. 8, 1H), 4. 38 (s, 2 H), 3.99 (s, 3H). Example 43: Preparation of 3-(4-aminophenyl)propionic acid
将 12g对硝基苯丙酸， 0. 8gl O%Pa-C, 200ml 乙酸乙酯加入 500ml 的氢气反应瓶中， 固定好装置， 充气 -放气 3次， 将压力稳定在 4个大 气压， 反应 5h。  12 g of p-nitrophenylpropionic acid, 0.8 g of O%Pa-C, 200 ml of ethyl acetate was added to a 500 ml hydrogen reaction flask, the device was fixed, and the device was inflated and deflated three times, and the pressure was stabilized at 4 atm. 5h.
反应完过滤除去 Pa— C， 旋干溶剂， 干燥得白色片状固体 9. 75g。 收率： 96. 1%。  After the reaction was filtered, the Pa-C was removed, and the solvent was evaporated to dryness. Yield: 96. 1%.
'H-NMR (400MHz, DMS0-d6) δ (ppm) : 11. 96 (brs, 1H)， 6. 86 (d, J= 'H-NMR (400MHz, DMS0-d6) δ (ppm): 11. 96 (brs, 1H), 6. 86 (d, J=
1. 2， 2H)， 6. 47 (q, J=8. 4， 2H)， 2. 63 (t, J=8. 0， 2H)， 2. 43 (t, J=8. 0， 2H)。 实施例 44: 3- ( 4-硫脲基苯基） 丙酸的制备 1. 2, 2H), 6. 47 (q, J=8. 4, 2H), 2. 63 (t, J=8. 0, 2H), 2. 43 (t, J=8. 0, 2H ). Example 44: Preparation of 3-(4-thioureidophenyl)propionic acid
将 15g对氨基笨丙酸， 8. 33ml l2N的浓盐酸， 30ml水加入 100ml 茄形瓶中， 80 C加热搅拌至完全溶解， 再加入 7. 27g硫氰酸氨， 继续 加热搅拌 20小时。  15 g of p-aminopropionic acid, 8.33 ml of 1 2 concentrated hydrochloric acid, and 30 ml of water were placed in a 100 ml eggplant-shaped flask, stirred at 80 C until completely dissolved, and then 7.27 g of ammonium thiocyanate was added thereto, and heating and stirring were continued for 20 hours.
反应毕， 有大量固体析出， 冷却， 过滤， 水洗 3次， 干燥的白色 粉末状固体 12. 5g.  After the reaction, a large amount of solid precipitated, cooled, filtered, washed 3 times, dried white powdery solid 12. 5g.
收率： 61. 4°/。。  Yield: 61. 4°/. .
'H-NMR (400MHz, DMS0-d6) δ (ppm) : 12. 16 (s, 1H) , 9. 62 (s, 1H) , 7. 27 (d, J=8. 4, 2H)， 7. 17 (d, J=8. 4, 2H) , 2. 78 (t， J=7. 2， 2H) , 'H-NMR (400MHz, DMS0-d6) δ (ppm): 12. 16 (s, 1H) , 9. 62 (s, 1H) , 7. 27 (d, J=8. 4, 2H), 7 . 17 (d, J=8. 4, 2H) , 2. 78 (t, J=7. 2, 2H),
2. 52 (t, J=7. 2， 2H) ; ESI -MS m/z (M+H+) 225. 1。 实施例 45: 3- (4- (4- (3-溴- 4-甲氧基苯基)噻唑- 2-亚胺基)苯基） 丙酸的制备 2. 52 (t, J=7. 2, 2H); ESI-MS m/z (M+H+) 225. 1. Example 45: Preparation of 3-(4-(4-(3-bromo-4-methoxyphenyl)thiazole-2-imino)phenyl)propanoic acid
将 27. 5g3- ( 4-硫脲基苯基） 丙酸， 20g2-溴- 1- ( 4-溴- 3-甲氧基 苯基） 乙酮以摩尔比 1: 1加入茄形瓶中， 加入 200ml无水乙醇， 加热 搅摔， 回流。 溶液逐渐澄清， 一小时后有大量沉淀生成， 停止反应， 冷却， 过滤， 无水乙醇洗涤， 干燥， 滤液旋去大部分乙醇， 冷却， 有 白色固体析出， 过滤， 干燥， 共得白色块状固体 35. 7g。 收率： 92. 2%。  27.5 g of 3-(4-thioureidophenyl)propionic acid, 20 g of 2-bromo-1-(4-bromo-3-methoxyphenyl)ethanone were added to the eggplant bottle at a molar ratio of 1:1. Add 200 ml of absolute ethanol, heat and stir, and reflux. The solution gradually clarified, and a large amount of precipitate formed after one hour, the reaction was stopped, cooled, filtered, washed with absolute ethanol, dried, and the filtrate was rotated to remove most of the ethanol, cooled, precipitated as a white solid, filtered, and dried to give a white solid. 35. 7g. Yield: 92. 2%.
'H-NMR (400MHz, DMS0-d6) δ (ppm)： 12. 11 (brs, 1H) , 10. 20 (s, 1H) , 8. 10 (d， J=2. 0, 1H) , 7. 91 (dd, Jdl-d2=l. 7， Jdl-d3=8. 4， 1H)， 7. 59 (d, J =8. 4, 2H) , 7. 29 (s， 1H)， 7. 21 (q, J=14. 6， 3H)， 3. 89 (s， 3H)， 2. 80 (t, J=8 . 0, 2H) , 2. 54 (t, J=7. 3, 2H) ; ESI-MS m/z (M+H+) 435. 3。 实施例 46: 3- (4- (4- (3-溴- 4-羟基苯基)噻唑- 2-亚胺基)苯基）丙 酸的制备 'H-NMR (400MHz, DMS0-d6) δ (ppm): 12. 11 (brs, 1H) , 10. 20 (s, 1H) , 8. 10 (d, J=2. 0, 1H) , 7 91 (dd, Jdl-d2=l. 7, Jdl-d3=8. 4, 1H), 7. 59 (d, J = 8. 4, 2H) , 7. 29 (s, 1H), 7. 21 (q, J=14. 6, 3H), 3. 89 (s, 3H), 2. 80 (t, J=8 . 0, 2H) , 2. 54 (t, J=7. 3, 2H ESI-MS m/z (M+H + ) 435. 3. Example 46: Preparation of 3-(4-(4-(3-bromo-4-hydroxyphenyl)thiazole-2-imino)phenyl)propanoic acid
将 lg3- (4- (4- (3-溴- 4-甲氧基苯基)噻唑- 2-亚胺基)苯基）丙酸， 15ml无水二氯甲烷加入 100ml三口瓶中， 搅拌使之成为混浊液， 置入 - 78 :低温反应槽降温， 同时通入氮气保护。 将 0. 66mlBBr3 (密度 =2. 65g/ml)及 20ml无水二氯甲烷加到干燥恒压漏斗中混勾，緩慢滴加 到已冷却的反应液中。 滴加完毕后自然升温至 -20 C左右， 滴加 50ml 水。 过滤， 水洗， 干燥得白色固体 0. 78g。 收率： 96. 76%。 Add lg3-(4-(4-(3-bromo-4-methoxyphenyl)thiazole-2-imino)phenyl)propanoic acid, 15 ml of anhydrous dichloromethane to a 100 ml three-necked flask, stir It becomes a turbid liquid, and is placed in - 78: the low temperature reaction tank is cooled, and nitrogen gas is supplied at the same time. 0.66 ml of BBr 3 (density = 2.65 g/ml) and 20 ml of anhydrous dichloromethane were added to a dry constant pressure funnel, and the mixture was slowly added dropwise to the cooled reaction solution. After the addition is completed, the temperature is naturally raised to about -20 C, and 50 ml of water is added dropwise. The filter was washed with water and dried to give a white solid. Yield: 96. 76%.
'H-NMR (400MHz, DMS0-d6) δ (ppm) : 10. 46 (brs, 1H) , 10. 21 (s, 1H) , 8. 01 (d, J=2, 1H)， 7. 75 (dd, Jdl-d2=2, Jdl-d3=8. 4， 1H)， 7. 59 (d, J=8. 8 ， 2H) , 7. 21 (s， 1H) , 7. 19 (d, J=8， 2H)， 7. 02 (d, J=8. 4， 1H)， 2. 80 (t, J=7. 6, 2H) , 2. 51 (t, J=7. 6, 2H) ; ESI-MS m/z (M+H+) 421. 2。 实施例 47: 3- (4- (4- (3-溴- 4-异丙氧基苯基)噻唑- 2-亚胺基）苯 基）丙酸的制备  'H-NMR (400MHz, DMS0-d6) δ (ppm) : 10. 46 (brs, 1H) , 10. 21 (s, 1H) , 8. 01 (d, J=2, 1H), 7. 75 (dd, Jdl-d2=2, Jdl-d3=8. 4, 1H), 7. 59 (d, J=8. 8 , 2H) , 7. 21 (s, 1H) , 7. 19 (d, J=8, 2H), 7. 02 (d, J=8. 4, 1H), 2. 80 (t, J=7. 6, 2H) , 2. 51 (t, J=7. 6, 2H ESI-MS m/z (M+H+) 421. 2. Example 47: Preparation of 3-(4-(4-(3-bromo-4-isopropoxyphenyl)thiazole-2-imino)phenyl)propionic acid
将 0. 87g3- (4- (4- (3-溴- 4-羟基苯基）噻唑- 2-亚胺基）苯基）丙 酸， 15mlDMF加到 50ml茄型瓶中， 再加入 0. 58mlSM2， 緩慢搅拌升温 至 80Χ， 反应 4小时， 停止反应。 将反应液倒入 100ml水里， 乙酸乙 酯萃取， 水洗， 旋干， 柱分， 得油状物。 将油状物在 3mol /L的 NaOH 水溶液里， 80Ό下反应 2小时， 稀盐酸中和， 有黄色固体析出， 过滤， 水洗， 柱分纯化， 得白色固体 0. l lg。 收率： 4. 85°/。。 0. 87g 3-(4-(4-(3-bromo-4-hydroxyphenyl)thiazole-2-imino)phenyl)propane The acid, 15 ml of DMF was added to a 50 ml eggplant type bottle, and then 0.58 ml of SM2 was added, and the temperature was slowly stirred to 80 Torr, and the reaction was continued for 4 hours to stop the reaction. The reaction solution was poured into 100 ml of water, extracted with ethyl acetate, washed with water, dried, and then evaporated. The lg is obtained as a white solid. lg. Yield: 4. 85 ° /. .
'H-NMR (400MHz, DMS0-d6) δ (ppm)： 10. 27 (s， 1H)， 8. 09 (d, J=2. 0， 1H)， 7. 88 (dd, Jdl-d2=2. 0， Jdl-d3=8. 4， 1H)， 7. 60 (d, J=8. 4， 2H ) , 7. 29 (s， 1H)， 7. 21 (d, J=7. 2， 3H) , 4. 73 (m， 1H) , 2. 80 (t, J=7. 6， 2H)， 2 . 54 (t, J=7. 6, 2H) , 1. 33 (d, J=6. 4, 6H)； ESI -MS m/z (M+H+) 463. 2。 实施例 48: 3- (4- (4- (3-溴- 4-丙氧基苯基)噻唑- 2-亚胺基)苯基） 丙酸的制备  'H-NMR (400MHz, DMS0-d6) δ (ppm): 10. 27 (s, 1H), 8. 09 (d, J=2. 0, 1H), 7. 88 (dd, Jdl-d2= 2. 0, Jdl-d3=8. 4, 1H), 7. 60 (d, J=8. 4, 2H), 7. 29 (s, 1H), 7. 21 (d, J=7. 2 , 3H) , 4. 73 (m, 1H) , 2. 80 (t, J=7. 6, 2H), 2 . 54 (t, J=7. 6, 2H) , 1. 33 (d, J =6. 4, 6H); ESI - MS m/z (M+H+) 463. 2. Example 48: Preparation of 3-(4-(4-(3-bromo-4-propoxyphenyl)thiazole-2-imino)phenyl)propanoic acid
反应步骤类似于实施例 47，以化合物 3- (4- (4- (3-溴- 4-羟基苯基) 噻唑- 2-亚胺基）苯基）丙酸和溴代丙烷制得， 收率： 14. 6%。  The reaction procedure is similar to that of Example 47, which is prepared from the compound 3-(4-(4-(3-bromo-4-hydroxyphenyl)thiazol-2-imino)phenyl)propanoic acid and bromopropane. Rate: 14.6%.
'H-NMR (400MHz, DMS0-d6) δ (ppm)： 10. 24 (s， 1H)， 8. 09 (d, J= 2. 4， 1H)， 7. 89 (dd, Jdl-d2=2. 0， Jdl-d3=8. 4， 1H)， 7. 60 (d, J=8. 4, 2H)， 7. 29 (s， 1H)， 7. 21 (d, J=8. 4， 2H) , 7. 18 (d, J=8. 4， 1H)， 4. 07 (t， J=6. 4， 2 H)， 2. 78 (t， J=7. 6， 2H)， 2. 52 (t, J=7. 6， 2H)， 1. 78 (m， 2H)， 1. 04 (t, J=7. 'H-NMR (400MHz, DMS0-d6) δ (ppm): 10. 24 (s, 1H), 8. 09 (d, J= 2. 4, 1H), 7. 89 (dd, Jdl-d2= 2. 0, Jdl-d3=8. 4, 1H), 7. 60 (d, J=8. 4, 2H), 7. 29 (s, 1H), 7. 21 (d, J=8. 4 , 2H) , 7. 18 (d, J=8. 4, 1H), 4. 07 (t, J=6. 4, 2 H), 2. 78 (t, J=7. 6, 2H), 2. 52 (t, J=7. 6, 2H), 1. 78 (m, 2H), 1. 04 (t, J=7.
6, 3H)； ESI -MS m/z (M+H+) 463. 2。 实施例 49: 3- (4- (4- (3-溴- 4-环戊氧基苯基）噻唑- 2-亚胺基）苯 基）丙酸的制备 6, 3H); ESI-MS m/z (M+H+) 463. 2. Example 49: Preparation of 3-(4-(4-(3-bromo-4-cyclopentyloxyphenyl)thiazole-2-imino)phenyl)propionic acid
反应步骤类似于实施例 47，以化合物 3- (4- (4- (3-溴- 4-羟基苯基) 噻唑- 2-亚胺基）苯基）丙酸和溴环戊烷制得， 收率： 9. 12%。  The reaction procedure is similar to that of Example 47, which is prepared from the compound 3-(4-(4-(3-bromo-4-hydroxyphenyl)thiazole-2-imino)phenyl)propanoic acid and bromocyclopentane. Yield: 9. 12%.
'H-NMR (400MHz, DMS0-d6) δ (ppm)： 10. 22 (s， 1H)， 8. 07 (d, J= 2. 0, 1H)， 7. 88 (dd, Jdl-d2=2. 0, Jdl-d3=8. 4, 1H) , 7. 60 (d, J=8. 4, 2H)， 'H-NMR (400MHz, DMS0-d6) δ (ppm): 10. 22 (s, 1H), 8. 07 (d, J= 2. 0, 1H), 7. 88 (dd, Jdl-d2= 2. 0, Jdl-d3=8. 4, 1H) , 7. 60 (d, J=8. 4, 2H),
7. 28 (s， 1H)， 7. 21 (s， 1H)， 7. 19 (d, J=8. 8， 2H)， 4. 96 (brs, 1H)， 2. 79 (t, J=5. 6, 2H) , 1. 77 (m, 4H) , 1. 61 (m, 2H)； ESI— MS m/z (M+H+) 487. 5。 实施例 50: 3- (4- (4- (3-溴- 4-异丁氧基笨基)噻唑- 2-亚胺基）苯 基）丙酸的制备 7. 28 (s, 1H), 7. 21 (s, 1H), 7. 19 (d, J=8. 8, 2H), 4. 96 (brs, 1H), 2. 79 (t, J= 5. 6, 2H), 1. 77 (m, 4H), 1. 61 (m, 2H); ESI-MS m/z (M+H+) 487. Example 50: Preparation of 3-(4-(4-(3-bromo-4-isobutoxyphenyl)thiazole-2-imino)phenyl)propionic acid
反应步骤类似于实施例 47，以化合物 3- (4- (4- (3-溴- 4-羟基苯基) 噻唑- 2-亚胺基)苯基）丙酸和溴异丁烷制得， 收率： 11. 3%。  The reaction procedure is similar to that of Example 47, which is prepared from the compound 3-(4-(4-(3-bromo-4-hydroxyphenyl)thiazole-2-imino)phenyl)propanoic acid and bromoisobutane. Yield: 11.3%.
'H-NMR (400MHz, DMS0-d6) δ (ppm) : 10. 34 (brs, IH) , 10. 26 (s, IH) , 8. 08 (d, J=2. 4, IH) , 7. 87 (dd, Jdl-d2=2. 0， Jdl-d3=8. 8, IH) , 7. 60 (d, J =8. 4, 2H) , 7. 28 (s， IH)， 7. 21 (q, J=3. 2， 3H)， 4. 52 (brs, IH)， 2. 79 (t, J= 7. 2， 2H)， 2. 51 (t， J=7. 2， 2H)， 1. 70 (brs, 2H)， 1. 29 (d, J=6. 0， 3H)， 0. 98 (t， J=7. 2, 3H)； ESI-MS m/z (M+H+) 477. 3。 实施例 51: 3- (4- (4- (3-溴- 4-正丁氧基苯基）噻唑- 2-亚胺基）苯 基）丙酸的制备 'H-NMR (400MHz, DMS0-d6) δ (ppm): 10. 34 (brs, IH) , 10. 26 (s, IH) , 8. 08 (d, J=2. 4, IH) , 7 87 (dd, Jdl-d2=2.0, Jdl-d3=8. 8, IH), 7. 60 (d, J = 8. 4, 2H), 7. 28 (s, IH), 7. 21 (q, J=3. 2, 3H), 4. 52 (brs, IH), 2. 79 (t, J= 7. 2, 2H), 2. 51 (t, J=7. 2, 2H ), 1. 70 (brs, 2H), 1. 29 (d, J=6. 0, 3H), 0. 98 (t, J=7. 2, 3H); ESI-MS m/z (M+ H + ) 477. 3. Example 51: Preparation of 3-(4-(4-(3-bromo-4-n-butoxyphenyl)thiazole-2-imino)phenyl)propanoic acid
反应步骤类似于实施例 47，以化合物 3- (4- (4- (3-溴- 4-羟基苯基) 噻唑- 2-亚胺基)苯基）丙酸和溴丁烷制得， 收率： 19. 43°/。。  The reaction procedure is similar to that of Example 47, which is prepared from the compound 3-(4-(4-(3-bromo-4-hydroxyphenyl)thiazole-2-imino)phenyl)propanoic acid and bromobutane. Rate: 19. 43°/. .
'H-NMR (400MHz, DMS0-d6) δ (ppm)： 10. 25 (s， IH)， 8. 09 (d, J= 2. 4， IH)， · 87 (dd, Jdl-d2=2. 0, Jdl-d3=8. 4， IH)， 7. 60 (d, J=8. 4， 2H)， 'H-NMR (400MHz, DMS0-d6) δ (ppm): 10. 25 (s, IH), 8. 09 (d, J= 2. 4, IH), · 87 (dd, Jdl-d2=2 0, Jdl-d3=8. 4, IH), 7. 60 (d, J=8. 4, 2H),
7. 29 (s， IH)， 7. 21 (q, J=8. 8, 3H) , 4. 11 (q, J=6. 4， 2H)， 2. 80 (t， J=7. 6， 2 H)， . 51 (t， J=7. 6， 2H)， 1. 76 (m，2H)， 1. 52 (m，2H)， 0. 98 (m，3H) ; ESI-MS m/z (M+H+) 477. 3。 实施例 52: 3- (4- (4- (3-溴- 4-卞氧基苯基)噻唑- 2-亚胺基)苯基） 丙酸的制备 7. 29 (s, IH), 7. 21 (q, J=8. 8, 3H) , 4. 11 (q, J=6. 4, 2H), 2. 80 (t, J=7. 6 , 2 H), . 51 (t, J=7. 6, 2H), 1. 76 (m, 2H), 1. 52 (m, 2H), 0. 98 (m, 3H) ; ESI-MS m /z (M+H+) 477. 3. Example 52: Preparation of 3-(4-(4-(3-bromo-4-yloxyphenyl)thiazole-2-imino)phenyl)propanoic acid
反应步骤类似于实施例 47，以化合物 3- (4- (4- (3-溴- 4-羟基苯基) 噻唑- 2-亚胺基)苯基）丙酸和溴苄制得， 收率： 12. 5°/。。  The reaction procedure is similar to that of Example 47, using the compound 3-(4-(4-(3-bromo-4-hydroxyphenyl)thiazole-2-imino)phenyl)propanoic acid and benzyl bromide, yield. : 12. 5°/. .
'H-NMR (400MHz, DMS0-d6) δ (ppm) : 10. 14 (s, IH) , 10. 22 (s, IH) , 'H-NMR (400MHz, DMS0-d6) δ (ppm) : 10. 14 (s, IH) , 10. 22 (s, IH) ,
8. 12 (d, J=2. 4, IH) , 7. 90 (dd, Jdl-d2=2. 4， Jdl-d3=8. 8, IH) , 7. 60 (d, J =8. 8, 2H) , 7. 52 (m， 2H)， 7. 45 (m， 3H)， 7. 31 (m， 3H)， 7. 29 (d, J=8. 8， 2H)， 5. 26 (s， 2H) , 2. 80 (t， J=7. 6， 2H)， 2. 51 (t， J=7. 6， 2H)； ESI-MS m/z (M+H+) 511. 3。 实施例 53: 2-溴- 1- ( 4-氯- 3-甲氧基苯基） 乙酮的制备 反应步骤类似于实施例 42， 以化合物 2-氯苯甲醚和溴乙酰溴制 得， 收率： 98. 6°/o 0 8. 12 (d, J=2. 4, IH), 7. 90 (dd, Jdl-d2=2.4, Jdl-d3=8. 8, IH), 7. 60 (d, J = 8. 8, 2H) , 7. 52 (m, 2H), 7. 45 (m, 3H), 7. 31 (m, 3H), 7. 29 (d, J=8. 8, 2H), 5. 26 (s, 2H) , 2. 80 (t, J=7. 6, 2H), 2. 51 (t, J=7. 6, 2H); ESI-MS m/z (M+H + ) 511. 3. Example 53: Preparation of 2-bromo-1-(4-chloro-3-methoxyphenyl)ethanone The reaction procedure was similar to that of Example 42, using the compound 2-chloroanisole and bromoacetyl bromide. Yield: 98. 6°/o 0
'H-NMR (400MHz, DMS0-d6) δ (ppm) : 8. 03 (d, J=2. 4, IH ) ，7. 93 'H-NMR (400MHz, DMS0-d6) δ (ppm) : 8. 03 (d, J=2. 4, IH ) , 7. 93
(dd, J=dl-d2=2. 4; dl-d3=8. 8， IH)， 6. 98 (d, J=8. 8， IH)， 4. 38 (s， 2H)， 4(dd, J=dl-d2=2. 4; dl-d3=8. 8, IH), 6. 98 (d, J=8. 8, IH), 4. 38 (s, 2H), 4
. 01 (s， 3H)。 实施例 54: 3- (4- (4- (3-氯- 4-甲氧基苯基)噻唑- 2-亚胺基)苯基） 丙酸的制备 . 01 (s, 3H). Example 54: Preparation of 3-(4-(4-(3-chloro-4-methoxyphenyl)thiazole-2-imino)phenyl)propanoic acid
反应步骤类似于实施例 45， 以化合物 2-溴- 1- ( 4-氯- 3-甲氧基苯 基） 乙酮和 3- ( 4-硫脲基）苯丙酸制得， 收率： 83. 1%。  The reaction procedure was similar to that of Example 45, using the compound 2-bromo-1-(4-chloro-3-methoxyphenyl)ethanone and 3-(4-thioureido)benzenepropanoic acid, yield: 83. 1%.
'H-NMR (400MHz, DMS0-d6) δ (ppm)： 10. 23 (s， IH)， 7. 95 (d, J= 2， IH)， 7. 88 (dd, Jdl-d2=2. 4， Jdl-d3=8. 8, IH)， 7. 60 (d, J=8. 4， 2H)， 7. 30 (s, IH)， 7. 23 (s， IH)， 7. 21 (d, J=8. 4， 2H) , 3. 90 (s， 3H)， 2. 78 (t, J=7. 6, 2H) , 2. 54 (t, J=7. 6, 2H) ; ESI— MS m/z (M+H+) 389. 10 实施例 55: 3- (4- (4- (3-氯- 4-羟基苯基)噻唑- 2-亚胺基)苯基）丙 酸的制备 'H-NMR (400MHz, DMS0-d6) δ (ppm): 10. 23 (s, IH), 7. 95 (d, J= 2, IH), 7. 88 (dd, Jdl-d2=2. 4, Jdl-d3=8. 8, IH), 7. 60 (d, J=8. 4, 2H), 7. 30 (s, IH), 7. 23 (s, IH), 7. 21 ( d, J=8. 4, 2H), 3. 90 (s, 3H), 2. 78 (t, J=7. 6, 2H), 2. 54 (t, J=7. 6, 2H); ESI-MS m/z (M+H + ) 389. 1 0. Example 55: 3- (4- (4-(3-chloro-4-hydroxyphenyl)thiazole-2-imino)phenyl) Preparation of propionic acid
反应步骤类似于实施例 46， 以 3- (4- (4- (3-氯- 4-甲氧基苯基）噻 唑- 2-亚胺基）苯基）丙酸和 BBr3制得， 收率： 79. 6%。 The reaction procedure is similar to Example 46, starting from 3- (4- (4- (3-Chloro --4- methoxyphenyl) thiazol --2- imino) phenyl) propanoic acid and BBr 3 was obtained, yield Rate: 79.6%.
'H-NMR (400MHz, DMS0-d6) δ (ppm)： 10. 21 (s， IH)， 7. 86 (d, J= 1. 6， IH)， 7. 71 (dd, Jdl-d2=2, Jdl-d3=8. 4， IH)， 7. 60 (d, J=8. 4， 2H)， 7. 21 (d, J=7. 2， 3H)， 7. 03 (d, J=8. 4, IH)， 2. 78 (t, J=7. 6， 2H)， 2. 51 (t， J=7 • 6， 2H)； ESI- MS m/z (M+H+) 375. 2。 实施例 56: 3- (4- (4- (3-氯- 4-异丙氧基苯基）噻唑- 2-亚胺基）苯 基）丙酸的制备  'H-NMR (400MHz, DMS0-d6) δ (ppm): 10. 21 (s, IH), 7. 86 (d, J = 1. 6, IH), 7. 71 (dd, Jdl-d2= 2, Jdl-d3=8. 4, IH), 7. 60 (d, J=8. 4, 2H), 7. 21 (d, J=7. 2, 3H), 7. 03 (d, J =8. 4, IH), 2. 78 (t, J=7. 6, 2H), 2. 51 (t, J=7 • 6, 2H); ESI- MS m/z (M+H+) 375 . 2. Example 56: Preparation of 3-(4-(4-(3-chloro-4-isopropoxyphenyl)thiazole-2-imino)phenyl)propionic acid
反应步骤类似于实施例 47，以化合物 3- (4- (4- (3-氯- 4-羟基苯基) 噻唑- 2-亚胺基)苯基）丙酸和溴代异丙烷制得， 收率： 7. 6%。 The reaction procedure is similar to that in Example 47, using the compound 3-(4-(4-(3-chloro-4-hydroxyphenyl)) Manufactured by thiazole-2-imino)phenyl)propanoic acid and bromoisopropane, yield: 7.6%.
'H-NMR (400MHz, DMS0-d6) δ (ppm) : 12. 14 (brs, IH) , 10. 23 (s, IH) , 7. 93 (d, J=2. 0, IH) , 7. 84 (dd, Jdl-d2=l. 6， Jdl-d3=8. 4， IH)， 7. 60 (d, J =8. 4, 2H) , 7. 29 (s， IH)， 7. 24 (d, J=8. 8, IH)， 7. 21 (d, J=8. 8， 2H)， 4. 73 ( m， IH)， 2. 78 (t, J=7. 6， 2H)， 2. 54 (t， J=7. 6， 2H)， 1. 33 (d, J=6. 0， 6H)；  'H-NMR (400MHz, DMS0-d6) δ (ppm): 12. 14 (brs, IH) , 10. 23 (s, IH) , 7. 93 (d, J=2. 0, IH) , 7 84 (dd, Jdl-d2=l. 6, Jdl-d3=8. 4, IH), 7. 60 (d, J =8.4, 2H), 7. 29 (s, IH), 7. 24 (d, J=8. 8, IH), 7. 21 (d, J=8. 8, 2H), 4. 73 ( m, IH), 2. 78 (t, J=7. 6, 2H ), 2. 54 (t, J=7. 6, 2H), 1. 33 (d, J=6. 0, 6H);
ESI-MS m/z (M+H+) 17. 3。 实施例 57: 3- (4- (4- (3-氯- 4-丙氧基苯基)噻唑- 2-亚胺基)苯基） 丙酸的制备 ESI-MS m/z (M+H + ) 17. 3. Example 57: Preparation of 3-(4-(4-(3-chloro-4-propoxyphenyl)thiazole-2-imino)phenyl)propanoic acid
反应步骤类似于实施例 47，以化合物 3- (4- (4- (3-氯- 4-羟基苯基) 噻唑- 2-亚胺基）苯基）丙酸和溴丙烷制得， 收率： 4. 67%。  The reaction procedure is similar to that of Example 47, using the compound 3-(4-(4-(3-chloro-4-hydroxyphenyl)thiazole-2-imino)phenyl)propanoic acid and bromopropane. : 4. 67%.
'H-NMR (400MHz, DMS0-d6) δ (ppm)： 10. 23 (s, IH)， 7. 94 'H-NMR (400MHz, DMS0-d6) δ (ppm): 10. 23 (s, IH), 7. 94
(d, J=2. 0, IH) , 7. 89 (dd, Jdl-d2=2. 4， Jdl-d3=8. 8， IH)， 7. 60 (d, J=8. 4 ， 2H) , 7. 29 (s， IH)， 7. 21 (d, J=2. 0， 2H)， 7. 19 (d, J=l. 2， IH)， 4. 08 (t, J=(d, J=2.0, IH), 7. 89 (dd, Jdl-d2=2.4, Jdl-d3=8. 8, IH), 7. 60 (d, J=8. 4 , 2H ), 7. 29 (s, IH), 7. 21 (d, J=2. 0, 2H), 7. 19 (d, J=l. 2, IH), 4. 08 (t, J=
6. 4， 2H)， 2. 80 (t， J=7. 6， 2H) , 2. 51 (t, J=7. 6， 2H)，1. 80 (m， 2H)， 1. 04 (t , J=7. 2, 3H) ; ESI-MS m/z (M+H+) 417. 2。 实施例 58: 3- (4- (4- (3-氯- 4-正丁氧基苯基）噻唑- 2-亚胺基）苯 基）丙酸的制备 6. 4, 2H), 2. 80 (t, J=7. 6, 2H), 2. 51 (t, J=7. 6, 2H), 1. 80 (m, 2H), 1. 04 ( t, J=7. 2, 3H); ESI-MS m/z (M+H+) 417. 2. Example 58: Preparation of 3-(4-(4-(3-chloro-4-n-butoxyphenyl)thiazole-2-imino)phenyl)propionic acid
反应步骤类似于实施例 47，以化合物 3- (4- (4- (3-氯- 4-羟基苯基) 噻唑- 2-亚胺基）苯基）丙酸和溴代正丁丙烷制得， 收率： 30. 3°/。。  The reaction procedure was similar to that of Example 47, using the compound 3-(4-(4-(3-chloro-4-hydroxyphenyl)thiazole-2-imino)phenyl)propanoic acid and bromo-n-butylpropane. , Yield: 30. 3 ° /. .
'H-NMR (400MHz, DMS0-d6) δ (ppm)： 10. 24 (s， IH)， 7. 94 (d, J= 2. 0, IH)， 7. 85 (dd, Jdl-d2=2. 0, Jdl-d3=8. 4, IH) , 7. 60 (d, J=8. 8, 2H)， 'H-NMR (400MHz, DMS0-d6) δ (ppm): 10. 24 (s, IH), 7. 94 (d, J= 2. 0, IH), 7. 85 (dd, Jdl-d2= 2. 0, Jdl-d3=8. 4, IH), 7. 60 (d, J=8. 8, 2H),
7. 29 (s， IH)， 7. 22 (m， 3H) , 4. 12 (t， J=6. 0， 2H)， 2. 80 (t, J=7. 6， 2H)， 2. 5 4 (t， J=7. 6， 2H)， 1. 76 (m， 2H)，1. 51 (m， 2H)， 0. 98 (t, J=7. 2， 3H)； ESI-MS m/z (M+H+) 431. 4。 实施例 59: 3- (4- (4- (3-氯- 4-异丁氧基苯基）噻唑- 2-亚胺基）苯 基）丙酸的制备 反应步骤类似于实施例 47，以化合物 3- (4- (4- (3-氯- 4-羟基苯基) 噻唑- 2-亚胺基)苯基）丙酸和溴代异丁烷制得， 收率： 11. 9%。 7. 29 (s, IH), 7. 22 (m, 3H) , 4. 12 (t, J=6. 0, 2H), 2. 80 (t, J=7. 6, 2H), 2. 5 4 (t, J=7. 6, 2H), 1. 76 (m, 2H), 1. 51 (m, 2H), 0. 98 (t, J=7.2, 3H); ESI-MS m/z (M+H+) 431. 4. Example 59: Preparation of 3-(4-(4-(3-chloro-4-isobutoxyphenyl)thiazole-2-imino)phenyl)propanoic acid The reaction procedure was similar to that of Example 47, which was prepared from the compound 3-(4-(4-(3-chloro-4-hydroxyphenyl)thiazole-2-imino)phenyl)propanoic acid and bromoisobutane. , Yield: 11.9%.
'H-NMR (400MHz, DMS0-d6) δ (ppm)： 10. 26 (s， IH) , 7. 93 (d, J= 2. 4， IH)， 7. 83 (dd, Jdl-d2=2. 0， Jdl-d3=8. 8， IH)， 7. 61 (d, J=8. 4, 2H)， 7. 28 (s， IH)， 7. 24 (s， IH)， 7. 22 (d, J=2. 8， IH)， 7. 19 (s， IH)， 4. 52 (m， IH )， 4. 12 (t， J=6. 0， 2H) , 2. 80 (t， J=7. 6， 2H)， 2. 54 (t, J=7. 6， 2H)， 1. 70 (m ， 2H) , 1. 28 (d, J=6. 4， 3H)， 0. 98 (t， J=7. 6， 3H)； ESI- MS m/z 'H-NMR (400MHz, DMS0-d6) δ (ppm): 10. 26 (s, IH) , 7. 93 (d, J= 2. 4, IH), 7. 83 (dd, Jdl-d2= 2. 0, Jdl-d3=8. 8, IH), 7. 61 (d, J=8. 4, 2H), 7. 28 (s, IH), 7. 24 (s, IH), 7. 22 (d, J=2. 8, IH), 7. 19 (s, IH), 4. 52 (m, IH), 4. 12 (t, J=6. 0, 2H), 2. 80 ( t, J=7. 6, 2H), 2. 54 (t, J=7. 6, 2H), 1. 70 (m , 2H) , 1. 28 (d, J=6. 4, 3H), 0. 98 (t, J=7. 6, 3H); ESI- MS m/z
(M+H+) 431. 3。 实施例 60: 3- (4- (4- (3-氯- 4-环戊氧基苯基）噻唑- 2-亚胺基）苯 基）丙酸的制备 (M+H + ) 431. 3. Example 60: Preparation of 3-(4-(4-(3-chloro-4-cyclopentyloxyphenyl)thiazole-2-imino)phenyl)propanoic acid
反应步骤类似于实施例 47，以化合物 3- (4- (4- (3-氯- 4-羟基苯基) 噻唑- 2-亚胺基）苯基）丙酸和溴代环戊烷制得， 收率： 11. 2%。  The reaction procedure was similar to that of Example 47, which was prepared from the compound 3-(4-(4-(3-chloro-4-hydroxyphenyl)thiazole-2-imino)phenyl)propanoic acid and bromocyclopentane. , Yield: 11. 2%.
'H-NMR (400MHz, DMS0-d6) δ (ppm)： 10. 24 (s， IH)， 7. 92 (d, J= 2. 0， IH)， 7. 84 (dd, Jdl-d2=2. 0， Jdl-d3=8. 4， IH)， 7. 61 (d, J=8. 4, 2H)， 7. 28 (q, 3H)， 7. 22 (d, J=2. 8, IH) , 4. 97 (m， IH)， 2. 80 (t, J=7. 2， 2H)， 2. 5 1 (t， J=7. 2， 2H)， 1. 95 (m， 2H)， 1. 77 (m， 4H)， 1. 61 (m， 2H)； ESI-MS m/z (M+H+) 443. 30 实施例 61: 3- (4- (4- (3-氯- 4-异戊氧基苯基）噻唑- 2-亚胺基）苯 基）丙酸的制备 'H-NMR (400MHz, DMS0-d6) δ (ppm): 10. 24 (s, IH), 7. 92 (d, J= 2. 0, IH), 7. 84 (dd, Jdl-d2= 2. 0, Jdl-d3=8. 4, IH), 7. 61 (d, J=8. 4, 2H), 7. 28 (q, 3H), 7. 22 (d, J=2. 8 , IH) , 4. 97 (m, IH), 2. 80 (t, J=7. 2, 2H), 2. 5 1 (t, J=7. 2, 2H), 1. 95 (m, 2H), 1. 77 (m, 4H), 1. 61 (m, 2H); ESI-MS m/z (M+H + ) 443. 3 0 Example 61: 3- (4- (4- Preparation of 3-chloro-4-isopentyloxyphenyl)thiazole-2-imino)phenyl)propionic acid
反应步骤类似于实施例 47，以化合物 3- (4- (4- (3-氯- 4-羟基苯基) 噻唑- 2-亚胺基）苯基）丙酸和溴代异戊烷制得， 收率： 20. 0%。  The reaction procedure was similar to that of Example 47, which was prepared from the compound 3-(4-(4-(3-chloro-4-hydroxyphenyl)thiazole-2-imino)phenyl)propanoic acid and bromoisopentane. , Yield: 20. 0%.
'H-NMR (400MHz, DMS0-d6) δ (ppm)： 10. 25 (s， IH)， 7. 94 (d, J= 2. 0, IH)， 7. 83 (dd, Jdl-d2=2. 0, Jdl-d3=8. 4, IH) , 7. 61 (d, J=8. 8, 2H)， 7. 29 (s， IH)， 7. 24 (s， IH)， 7. 22 (d, J=2. 8， IH)， 7. 19 (s， IH)， 4. 14 (t， J= 6. 8， 2H)， 2. 80 (t， J=7. 6， 2H)， 2. 54 (t, J=7. 6， 2H)， 1. 86 (m， IH)， 1. 69 (m , 2H) , 0. 96 (d, J=6. 8, 6H) ; ESI-MS m/z (M+H+) 445. 40 。o *s/,e(+H+w) z/ra SW-IS3 - (H3 's) ZS '£ ' (H 's) 06 * ' (He '« Π Ί ' (HI 's) Ί ' (Hi ^ *8=r 'P) t^9 Ί ' (HI ^ *8=eP-IPr '0 'Z=ZV-IV£ 'ΡΡ) 68 Ί ' (HI '0 Ί =Γ 'Ρ) 96 Ί ' (HI 's) 6Z *0t： ( ) Q (9P-0SWa 'zHWOOt N-HT 'H-NMR (400MHz, DMS0-d6) δ (ppm): 10. 25 (s, IH), 7. 94 (d, J= 2. 0, IH), 7. 83 (dd, Jdl-d2= 2. 0, Jdl-d3=8. 4, IH), 7. 61 (d, J=8. 8, 2H), 7. 29 (s, IH), 7. 24 (s, IH), 7. 22 (d, J=2. 8, IH), 7. 19 (s, IH), 4. 14 (t, J= 6. 8, 2H), 2. 80 (t, J=7. 6, 2H ), 2. 54 (t, J=7. 6, 2H), 1. 86 (m, IH), 1. 69 (m , 2H), 0. 96 (d, J=6. 8, 6H); ESI-MS m/z (M+H + ) 445. 4 0 . o *s/,e( + H+w) z/ra SW-IS3 - (H3 's) ZS '£ ' (H 's) 06 * ' (He '« Π Ί ' (HI 's) Ί ' (Hi ^ *8=r 'P) t^9 Ί ' (HI ^ *8=eP-IPr '0 'Z=ZV-IV£ 'ΡΡ) 68 Ί ' (HI '0 Ί =Γ 'Ρ) 96 Ί ' (HI 's) 6Z *0t: ( ) Q (9P-0SWa 'zHWOOt NH T
°%8 'iL ：古^ ' ^ z ( -ψ^ -^ ) -z °%8 'iL :古^ ' ^ z ( -ψ^ -^ ) -z
Figure imgf000049_0001
Figure imgf000049_0002
Figure imgf000049_0001
Figure imgf000049_0002
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' (HI 4s) L9 *6 ' (HI 's iq) t^ 'Zl '· (^d) g (9P-0SW0 'zHWOOt^) N-HT ' (HI 4 s) L9 *6 ' (HI 's iq) t^ 'Zl '· (^d) g (9P-0SW0 'zHWOOt^) NH T
°%s -is ：古^ ' ^w °%s -is :古^ ' ^w
-rn^mn ( -f ^-f 1-^ ) -i Ρ Λ ' [^ ^^
Figure imgf000049_0003
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Figure imgf000049_0003
( + H+W) z/ra SW-IS3 ί (H3 'L=i ^9 Ί ' (Hi 'L=[ 08 · ' (Hi 91 *S ' (H t ^ *8=Γ 'P) ' L ' (He '« 8C Ί ' (Hi '9 'L=i 'Ρ) ^ Ί ' (H3 Z 'L=i 'Ρ) IS 'L ' (Hi ^ *8=Γ 'P) 19 'L ' (HI '8 *8=eP-IPr '0 'l=ZV-\Vi 'ΡΡ) S8 Ί ' (HI '0 Ί
=Γ 'Ρ) L6 'L ' (HI 's) 9Z *0t： ( ) Q (9P-0SWa 'zHWOOt N-HT =Γ 'Ρ' L6 'L ' (HI 's) 9Z *0t: ( ) Q (9P-0SWa 'zHWOOt NH T
。％Π·9Ι ：古^ (f^ Cf¾i¾r-2-. %Π·9Ι :古^(f^ Cf3⁄4i3⁄4r-2-
Cf ^-f ^-t^-f -e) -e Ι^ Λ Cf ^-f ^-t^-f -e) -e Ι^ Λ
ΐΐΐ9εΐ Z OAV 基）噻唑- 2-亚胺）苯基）乙酸和 BBr3制得， 收率： 80. 0%。 Ϊ́ΐΐ9εΐ Z OAV 0%。 The thiophene-2-imine) phenyl) acetic acid and BBr 3 , yield: 80. 0%.
'H-NMR (400MHz, DMS0-d6) δ (ppm)： 10. 26 (s， 1H)， 7. 86 (d, J= 2. 0， 1H)， 7. 72 (dd, Jdl-d2=2. 0， Jdl-d3=8. 4， 1H)， 7. 63 (d, J=8. 4, 2H)， 7. 24 (s， 1H)， 7. 22 (m， J=2. 8, 2H) , 7. 03 (d, J=8. 4， 1H)， 3. 51 (s， 2H)；  'H-NMR (400MHz, DMS0-d6) δ (ppm): 10. 26 (s, 1H), 7. 86 (d, J= 2. 0, 1H), 7. 72 (dd, Jdl-d2= 2. 0, Jdl-d3=8. 4, 1H), 7. 63 (d, J=8. 4, 2H), 7. 24 (s, 1H), 7. 22 (m, J=2. 8 , 2H) , 7. 03 (d, J=8. 4, 1H), 3. 51 (s, 2H);
ESI -MS m/z (M+H+) 361. 9» 实施例 66: 2- (4- (4- (3-氯- 4-环戊氧基苯基）噻唑- 2-亚胺）苯基） 乙酸的制备 ESI - MS m/z (M+H + ) 361. 9» Example 66: 2-(4-(4-(3-chloro-4-cyclopentyloxyphenyl)thiazole-2-imine)benzene Preparation of acetic acid
反应步骤类似于实施例 47，以化合物 2- (4- (4- (3-氯- 4-羟基苯基) 噻唑- 2-亚胺）苯基）乙酸和溴代环戊烷制得， 收率： 24. 8%。  The reaction procedure is similar to that of Example 47, which is prepared by using the compound 2-(4-(4-(3-chloro-4-hydroxyphenyl)thiazole-2-imide)phenyl)acetic acid and bromocyclopentane. Rate: 24.8%.
'H-NMR (400MHz, DMS0-d6) δ (ppm) : 10. 29 (s， 1H) , 7. 93 (s， 1H)， 'H-NMR (400MHz, DMS0-d6) δ (ppm) : 10. 29 (s, 1H) , 7. 93 (s, 1H),
7. 84 (d, J=8. 8, 1H) , 7. 64 (d, J=8. 0， 2H)， 7. 30 (s， 1H)， 7. 24 (m， 3H)， 4. 9 5 (m， 1H)， 3. 51 (s， 2H)； 1. 96—1. 61 (m， 8H)， ESI— MS m/z (M+H+) 429. 2。 实施例 67: 3- (4- (4- (4-环丁氧基苯基）噻唑- 2-亚胺）苯基）丙烷 -1 -酵的制备 7. 84 (d, J=8. 8, 1H) , 7. 64 (d, J=8. 0, 2H), 7. 30 (s, 1H), 7. 24 (m, 3H), 4. 9 5 (m, 1H), 3. 51 (s, 2H); 1. 96-1. 61 (m, 8H), ESI-MS m/z (M+H+) 429. Example 67: Preparation of 3-(4-(4-(4-cyclobutoxyphenyl)thiazole-2-imine)phenyl)propane -1 - leaven
将 0. 15gLiAlH4, 15ml无水 THF加到 50ml三口瓶中在冰盐浴下冷 却， 滴加 0. 33g3- (4- (4- (4-环丁氧基苯基）噻唑- 2-亚胺）苯基）丙酸乙 酯的 THF溶液， 滴加完毕后， 反应 30分钟， 用水淬灭， 过滤， 乙酸乙 酯洗涤滤饼数次，旋干滤液，柱分，得淡黄色粉末 0. 06go收率： 17. 6%oThe 0. 15gLiAlH 4, 15ml of dry THF was added 50ml 3-necked flask was cooled in an ice-salt bath, was added dropwise 0. 33g3- (4- (4- (4- cyclobutoxy phenyl) thiazol --2- alkylene A solution of ethyl phenyl)propionate in THF, after completion of the dropwise addition, the reaction was carried out for 30 minutes, quenched with water, filtered, and the filtrate was washed with ethyl acetate several times, and the filtrate was evaporated to give a pale yellow powder. 06g o yield: 17. 6%o
'H-NMR (400MHz, DMS0-d6) δ (ppm)： 10. 14 (s， 1H)， 7. 82 (d, J='H-NMR (400MHz, DMS0-d6) δ (ppm): 10. 14 (s, 1H), 7. 82 (d, J=
8. 4， 2H)， 7. 62 (d, J=8. 4， 2H)， 7. 17 (d, J=8. 4， 2H) , 7. 11 (s， 1H)， 6. 90 (d ， J=8. 8, 2H)， 4. 74 (m， 1H)， 4. 49 (t， J=4. 8， 1H)， 3. 43 (q, J=6. 4， 2H)， 2. 5 8 (t， J=7. 6， 2H)， 2. 46 (m， 2H)， 2. 08 (m， 2H)， 1. 81 (m， 4H)； ESI-MS m/z (M+H+) 381. 4。 实施例 68: 3- (4- (4- (4-丙氧基苯基)噻唑- 2-亚胺）苯基）丙烷- 1- 酵的制备 8. 4, 2H), 7. 62 (d, J=8. 4, 2H), 7. 17 (d, J=8. 4, 2H), 7. 11 (s, 1H), 6. 90 ( d , J=8. 8, 2H), 4. 74 (m, 1H), 4. 49 (t, J=4. 8, 1H), 3. 43 (q, J=6. 4, 2H), 2. 5 8 (t, J=7. 6, 2H), 2. 46 (m, 2H), 2. 08 (m, 2H), 1. 81 (m, 4H); ESI-MS m/z ( M+H+) 381. 4. Example 68: Preparation of 3-(4-(4-(4-propoxyphenyl)thiazole-2-imine)phenyl)propane-1 - leaven
反应步骤类似于实施例 67， 以化合物 3- (4- (4- (4-丙氧基苯基） 噻唑- 2-亚胺）苯基）丙酸乙酯和 LiAlH4制得， 收率： 26. 0%。 The reaction procedure is similar to that in Example 67, using the compound 3-(4-(4-(4-propoxyphenyl)) Ethyl thiazole 2-imino)phenyl)propionate and LiAlH 4 were obtained in a yield: 26. 0%.
'H-NMR (400MHz, DMS0-d6) δ (ppm)： 10. 14 (s， IH)， 7. 84 (d, J= 8. 8， 2H)， 7. 61 (d, J=8. 4， 2H) , 7. 17 (d, J=8. 4， 2H) , 7. 12 (s， IH)， 6. 99 (d ， J=8. 8, 2H)， 4. 74 (s， IH)， 3. 98 (t， J=6. 4， IH)， 3. 42 (q, J=5. 2， 2H)， 2. 5 8 (t， J=7. 6， 2H)， 2. 46 (m， 2H)， 2. 08 (m， 2H)， 1. 81 (m， 4H)； ESI-MS m/z (M+H+) 368. 2。 实施例 69: 3- (4- (4- (4-溴苯基)噻唑- 2-亚胺）苯基）丙烷- 1-酵的 制备  'H-NMR (400MHz, DMS0-d6) δ (ppm): 10. 14 (s, IH), 7. 84 (d, J= 8. 8, 2H), 7. 61 (d, J=8. 4, 2H) , 7. 17 (d, J=8. 4, 2H) , 7. 12 (s, IH), 6. 99 (d , J=8. 8, 2H), 4. 74 (s, IH), 3. 98 (t, J=6. 4, IH), 3. 42 (q, J=5. 2, 2H), 2. 5 8 (t, J=7. 6, 2H), 2 46 (m, 2H), 2. 08 (m, 2H), 1. 81 (m, 4H); ESI-MS m/z (M+H+) 368. 2. Example 69: Preparation of 3-(4-(4-(4-bromophenyl)thiazole-2-imine)phenyl)propane 1-
反应步骤类似于实施例 67，以 3- (4- (4- (4-溴苯基）噻唑- 2-亚胺） 苯基）丙酸乙酯和 LiAlH4制得， 收率： 6. 1%。 The reaction procedure is similar to Example 67, starting from 3- (4- (4- (4-bromophenyl) thiazol --2- imine) phenyl) propionate and LiAlH 4 was prepared, yield: 6.1 %.
'H-NMR (400MHz, DMS0-d6) δ (ppm)： 10. 22 (s， IH)， 7. 88 (d, J= 8. 4， 2H)， 7. 64 (t， J=8. 8， 4H) , 7. 40 (s， IH)， 7. 18 (d, J=8. 4， 2H)， 4. 49 (t ， J=5. 2， 2H)， 3. 42 (q, J=6. 4， 2H) , 2. 58 (t, J=7. 2， 2H)， 1. 72 (m， 2H)； ESI-MS m/z (M+H+) 391. 3。 实施例 70: 3- (4- (4- (3-氯- 4-异丙氧基苯基)噻唑- 2-亚胺）苯基) 丙烷 -1-醇的制备 'H-NMR (400MHz, DMS0-d6) δ (ppm): 10. 22 (s, IH), 7. 88 (d, J= 8. 4, 2H), 7. 64 (t, J=8. 8, 4H) , 7. 40 (s, IH), 7. 18 (d, J=8. 4, 2H), 4. 49 (t , J=5. 2, 2H), 3. 42 (q, J=6. 4, 2H), 2. 58 (t, J=7.2, 2H), 1. 72 (m, 2H); ESI-MS m/z (M+H + ) 391. Example 70: Preparation of 3-(4-(4-(3-chloro-4-isopropoxyphenyl)thiazole-2-imine)phenyl)propan-1-ol
反应步骤类似于实施例 67， 以 3- (4- (4- (3-氯- 4-异丙氧基苯基） 噻唑- 2-亚胺）苯基）丙酸乙酯和 LiAlH4制得， 收率： 18. 7%。 The reaction procedure is similar to Example 67, starting from 3- (4- (4- (3-chloro --4- isopropoxyphenyl) thiazol --2- imine) phenyl) propionate and LiAlH 4 was prepared , Yield: 18.7%.
'H-NMR (400MHz, DMS0-d6) δ (ppm)： 10. 19 (s， IH)， 7. 94 (d, J= 2， IH)， 7. 85 (dd, Jdl-d2=2. 0， Jdl-d3=8. 8, IH)， 7. 60 (d, J=8. 4， 2H)， 7. 28 (s, IH)， 7. 24 (d, J=8. 8， IH)， 7. 18 (d, J=8. 4， 2H)， 4. 74 (t， J=6. 4， 2H) ， 4. 49 (t, J=5. 2， IH)， 3. 44 (q, J=6. 4， 2H)， 2. 57 (t， J=7. 6， 2H)， 1. 74 (m， IH) , 1. 33 (d, J=6. 4, 6H) ; ESI-MS m/z (M+H+) 403. 2。 实施例 71 : 3- (4- (4- (3-氯- 4-异戊氧基苯基)噻唑- 2-亚胺）苯基) 丙烷 -1-醇的制备  'H-NMR (400MHz, DMS0-d6) δ (ppm): 10. 19 (s, IH), 7. 94 (d, J= 2, IH), 7. 85 (dd, Jdl-d2=2. 0, Jdl-d3=8. 8, IH), 7. 60 (d, J=8. 4, 2H), 7. 28 (s, IH), 7. 24 (d, J=8. 8, IH ), 7. 18 (d, J=8. 4, 2H), 4. 74 (t, J=6. 4, 2H) , 4. 49 (t, J=5. 2, IH), 3. 44 (q, J=6. 4, 2H), 2. 57 (t, J=7. 6, 2H), 1. 74 (m, IH), 1. 33 (d, J=6. 4, 6H) ; ESI-MS m/z (M+H+) 403. 2. Example 71: Preparation of 3-(4-(4-(3-chloro-4-isopentyloxyphenyl)thiazole-2-imine)phenyl)propane-1-ol
反应步骤类似于实施例 67， 以 3- (4- (4- (3-氯- 4-异戊氧基苯基) 噻唑- 2-亚胺）苯基）丙酸乙酯和 LiAlH4制得， 收率： 32. 9%。 The reaction procedure was similar to Example 67, using 3-(4-(4-(3-chloro-4-isopentyloxyphenyl)) 9%。 The yield of thiazole 2-imine) phenyl) propionate and LiAlH 4 , yield: 32. 9%.
'H-NMR (400MHz, DMS0-d6) δ (ppm)： 10. 19 (s， IH)， 7. 94 (d, J= 2， IH)， 7. 85 (dd, Jdl-d2=2. 0， Jdl-d3=8. 8, IH)， 7. 60 (d, J=8. 4， 2H)， 7. 28 (s, IH)， 7. 23 (d, J=8. 4， IH)， 7. 18 (d, J=8. 8， 2H)， 4. 49 (s， IH) , 4. 14 ( t, J=6. 8， 2H)， 3. 44 (q, J=6. 8， 2H)， 2. 57 (t, J=7. 6， 2H)， 1. 84 (m， IH)， 1. 72 (m, 4H) ; ESI-MS m/z (M+H+) 431. 3。 实施例 72: 3- (4- (4- (4-异丙基苯基）噻唑- 2-亚胺）苯基） 丙烷 -1 -酵的制备  'H-NMR (400MHz, DMS0-d6) δ (ppm): 10. 19 (s, IH), 7. 94 (d, J= 2, IH), 7. 85 (dd, Jdl-d2=2. 0, Jdl-d3=8. 8, IH), 7. 60 (d, J=8. 4, 2H), 7. 28 (s, IH), 7. 23 (d, J=8. 4, IH ), 7. 18 (d, J=8. 8, 2H), 4. 49 (s, IH) , 4. 14 ( t, J=6. 8, 2H), 3. 44 (q, J=6 . 8, 2H), 2. 57 (t, J=7. 6, 2H), 1. 84 (m, IH), 1. 72 (m, 4H) ; ESI-MS m/z (M+H+) 431. 3. Example 72: Preparation of 3-(4-(4-(4-isopropylphenyl)thiazole-2-imine)phenyl)propane -1 - leaven
反应步骤类似于实施例 67， 以 3- (4- (4- (4-异丙基苯基）噻唑- 2- 亚胺）苯基） 丙酸乙酯和 LiAlH4制得， 收率： 19. 3%。 The reaction procedure is similar to Example 67, starting from 3- (4- (4- (4-isopropylphenyl) thiazole --2- imine) phenyl) propionate and LiAlH 4 was prepared, yield: 19 .3%.
'H-NMR (400MHz, DMS0-d6) δ (ppm)： 10. 14 (s， IH)， 7. 82 (d, J= 8. 4， IH)， 7. 62 (d, J=8. 4， 2H) , 7. 17 (d, J=8. 4， 2H) , 7. 12 (s， IH)， 6. 97 (d ， J=8. 8, 2H)， 4. 67 (m， IH)， 4. 48 (t， J=5. 2， IH)， 3. 43 (q, J=6. 4， 2H)， 2. 5 8 (t， J=7. 6， 2H)， 1. 72 (m， IH)， 1. 29 (d, J=6. 0， 6H)； ESI-MS m/z (M+H+) 369. 2。 实施例 73: 1- (4- (2-羟乙基）苯基)硫脲的制备 'H-NMR (400MHz, DMS0-d6) δ (ppm): 10. 14 (s, IH), 7. 82 (d, J= 8. 4, IH), 7. 62 (d, J=8. 4, 2H) , 7. 17 (d, J=8. 4, 2H) , 7. 12 (s, IH), 6. 97 (d , J=8. 8, 2H), 4. 67 (m, IH), 4. 48 (t, J=5. 2, IH), 3. 43 (q, J=6. 4, 2H), 2. 5 8 (t, J=7. 6, 2H), 1 72 (m, IH), 1. 29 (d, J = 6. 0, 6H); ESI-MS m/z (M+H + ) 369. 2. Example 73: Preparation of 1-(4-(2-hydroxyethyl)phenyl)thiourea
反应步骤类似于实施例 44， 以对氨基苯乙醇和硫氰酸氨制得， 收 率： 19. 7%。  The reaction procedure was similar to that of Example 44, using p-aminophenylethanol and ammonia thiocyanate, yield: 19.7%.
'H-NMR (400MHz, DMS0-d6) δ (ppm)： 9. 61 (s， IH)， 7. 27 (d, J= 8. 4， 2H)， 7. 17 (d, J=8. 4， 2H)， 3. 60 (q, J=7. 2， 2H)， 2. 70 (d, J=7. 6， 2H)； ESI-MS m/z (M+H+) 197. 3。 实施例 74: 2- (4- (4- (3-氯- 4-甲氧基苯基)噻唑- 2-亚胺）苯基）乙 酵的制备 'H-NMR (400MHz, DMS0-d6) δ (ppm): 9. 61 (s, IH), 7. 27 (d, J= 8. 4, 2H), 7. 17 (d, J=8. 4, 2H), 3. 60 (q, J=7. 2, 2H), 2. 70 (d, J=7. 6, 2H); ESI-MS m/z (M+H + ) 197. 3 . Example 74: Preparation of 2-(4-(4-(3-chloro-4-methoxyphenyl)thiazole-2-imine)phenyl)
反应步骤类似于实施例 45， 以化合物 2-溴- 1- ( 4-氯- 3-甲氧基苯 基） 乙酮和 1- (4- (2-羟乙基）苯基)硫脲制得， 收率： 53. 7°/。。  The reaction procedure was similar to that of Example 45, using the compound 2-bromo-1-(4-chloro-3-methoxyphenyl)ethanone and 1-(4-(2-hydroxyethyl)phenyl)thiourea. Yield: 53. 7°/. .
'H-NMR (400MHz, DMS0-d6) δ (ppm)： 10. 22 (s， IH)， 7. 95 (q, J= 2. 0, IH) , 7. 88 (dd, Jdl-d2=2. 0, Jdl-d3=8. 4， IH)， 7. 59 (d, J=8. 4, 2H) 7. 30 (s， IH)， 7. 21 (m， 3H) , 3. 90 (s， 3H)， 3. 60 (t, J=7. 2， IH)， 2. 70 (t， J 6. 8 2H) ; ESI— MS m/z (M+H+) 361. 1。 实施例 75: 2- (4- (4- (3-溴- 4-甲氧基苯基)噻唑- 2-亚胺）苯基）乙 酵的制备 'H-NMR (400MHz, DMS0-d6) δ (ppm): 10. 22 (s, IH), 7. 95 (q, J= 2. 0, IH), 7. 88 (dd, Jdl-d2=2.0, Jdl-d3=8. 4, IH), 7. 59 (d, J=8. 4, 2H) 7. 30 ( s, IH), 7. 21 (m, 3H) , 3. 90 (s, 3H), 3. 60 (t, J=7. 2, IH), 2. 70 (t, J 6. 8 2H) ; ESI - MS m/z (M+H+) 361. 1. Example 75: Preparation of 2-(4-(4-(3-bromo-4-methoxyphenyl)thiazole-2-iminamine)phenyl)glycine
反应步骤类似于实施例 45， 以化合物 2-溴- 1- ( 4-溴- 3-甲氧基苯 基） 乙酮和 1- (4- (2-羟乙基）苯基)硫脲制得， 收率： 58. 0°/。。  The reaction procedure was similar to that of Example 45, using the compound 2-bromo-1-(4-bromo-3-methoxyphenyl)ethanone and 1-(4-(2-hydroxyethyl)phenyl)thiourea. Yield: Yield: 58. 0°/. .
'H-NMR (400MHz, DMS0-d6) δ (ppm)： 10. 34 (s， IH)， 8. 10 (q， J= 2. 0， IH)， 7. 94 (m， 2H)， 7. 59 (d, J=8. 4， IH) , 7. 50 (d, J=8. 4， IH)， 7. 30 (s ， IH) , 7. 26 (d, J=8. 8)， 7. 20 (m， 2H)， 3. 89 (s， 3H)， 3. 59 (m， IH)， 2. 69 (m， 2H) ; ESI- MS m/z (M+H+) 405. 1。 实施例 76: 生物活性评价  'H-NMR (400MHz, DMS0-d6) δ (ppm): 10. 34 (s, IH), 8. 10 (q, J= 2. 0, IH), 7. 94 (m, 2H), 7 59 (d, J=8. 4, IH) , 7. 50 (d, J=8. 4, IH), 7. 30 (s , IH) , 7. 26 (d, J=8. 8) , 7. 20 (m, 2H), 3. 89 (s, 3H), 3. 59 (m, IH), 2. 69 (m, 2H) ; ESI- MS m/z (M+H+) 405. 1. Example 76: Evaluation of biological activity
一、 材料与仪器：  1. Materials and instruments:
1. 1 仪器： IN Cel l Analyzer 1000活细胞成像系统（美国 GE公司） 1. 2 细^ 表达 EGFP-S1P1融合蛋白的 U20S细 JJ&^ (美国 Thermo 公司 Biolmage子公司）  1. 1 Instrument: IN Cel l Analyzer 1000 Live Cell Imaging System (GE, USA) 1. 2 U20S Fine EJ-S1P1 Fusion Protein JJ&^ (US Thermo Company Biolmage Subsidiary)
1. 3 试剂配制：  1. 3 reagent preparation:
细胞培养液： 含 0. 5mg/ml G418和 10% FBS的 DMEM高糖培养液 分析培养液： 含 lOmM HEPES、 0. 1%脱脂 BSA的 F12培养液  Cell culture medium: DMEM high glucose medium containing 0.5 mg/ml G418 and 10% FBS Analytical medium: F12 medium containing lOmM HEPES, 0.1% defatting BSA
3 固定液： 12%甲酸溶液（ PBS配）  3 fixative: 12% formic acid solution (PBS)
染色液： 含 Ι μ Μ Hoechs t 33342 (美国 Invi trogen公司）的 PBS 1. 4 化合物的配制：  Staining solution: Preparation of PBS 1. 4 compound containing Ι μ Μ Hoechs t 33342 (Invitrogen, USA):
以含 4%。DMS0的分析培养液作为 4 Control对照工作液，终浓度 1%。  Including 4%. The analytical medium of DMS0 was used as a 4 Control control working solution at a final concentration of 1%.
DMS0。 DMS0.
激动剂鞘氨醇 -1-磷酸 SIP (天然配体， Sigma, MW=379. 5， EC5。~ 25nM， 下文中有时简称为 S1P )用 10mM NaOH水溶液配成 3mM母液， 使用时用 含 4%。DMS0的分析培养液配成 4 工作液， 给予终浓度 10nM、 250nM和 1 μΜ。 The agonist sphingosine-1-phosphate SIP (natural ligand, Sigma, MW=379. 5, EC 5 .~ 25 nM, hereinafter sometimes abbreviated as S1P) is formulated with 3 mM mother liquor in 10 mM NaOH aqueous solution. %. Analytical culture solution of DMS0 is formulated into 4 working fluids, and the final concentration is 10nM, 250nM and 1 μΜ.
送筛化合物用 DMS0配成 30mM的母液，使用时用 DMS0倍比稀释成连 续浓度梯度的 1000 X母液， 再用分析培养液配成 4 X工作液。 初歸选用 ΙΟΟηΜ和 3 μΜ两个终浓度， 复筛根据化合物活性按梯度分别选用终浓度 30ρΜ、 ΙΟΟρΜ, 300ρΜ、 1ηΜ、 3nM、 10nM、 30nM、 100nM、 300nM、 1μΜ、 3 μΜ、 10 μΜ中的连续六到八个浓度做量效关系。  The sieved compound was formulated into a 30 mM mother liquor by DMS0, and diluted to a continuous concentration gradient of 1000 X mother liquor by DMS0 ratio, and then analyzed to prepare a 4 X working solution. The final concentration of ΙΟΟηΜ and 3 μΜ was selected for the initial selection. The final concentration of 30 Μ, ΙΟΟρΜ, 300ρΜ, 1ηΜ, 3nM, 10nM, 30nM, 100nM, 300nM, 1μΜ, 3μΜ, 10 μΜ was selected according to the gradient of the compound activity. A dose-effect relationship is made for six to eight consecutive concentrations.
二、 实验方法：  Second, the experimental method:
将稳定表达 EGFP- SlPi融合蛋白的 U20S细胞， 5%C02培养于含 0.5mg/ml G418和 10% FBS的 DMEM高糖培养液中。 按照细胞 0.8x104个 八 ΟΟμΙ/孔种于 96孔黑色底透细胞培养板中， 5% C02培养 18-24h。 细胞用 200μ1/孔分析培养液洗一次， 加入 150μ1/孔分析培养液， 37 5%C02孵育 60min。 配制激动剂和化合物工作液， 加入 50μ1/孔 4 χ激动 剂或 4 X化合物或 4 X Control对照工作液， 37"€ 5% C02孵育 60min， 化 合物每个浓度平行重复 3孔。加入室温预暖的 3 固定液 ΙΟΟμΙ/孔混匀， 室温孵育 20min。 细胞用染色液 200μ1/孔洗三次， 并留在 200μ1/孔染色 液中室温染色 lh。 细胞在 IN Cell Analyzer 1000活细胞成像系统上进 行测定，测定条件为： 20倍物镜，激发波长 Ex=460nm，发射波长 Em=535nm， 曝光 300ms 检测细胞核通道蓝色荧光； 激发波长 Ex=475nm， 发射波长 Em=535nm， 曝光 800ms检测细胞质通道绿色荧光 EGFP, 每孔 5个视野连 续拍照。 使用 GE公司 IN Cell Analyzer 1000 Multi Target Analysis Module软件分析细胞质中的颗粒形成，计算化合物激动 SlPi受体内吞的 活性。 U20S cells stably expressing the EGFP-SPiPi fusion protein, 5% CO 2 were cultured in DMEM high glucose medium containing 0.5 mg/ml G418 and 10% FBS. The cells were seeded in a 96-well black-bottomed cell culture plate according to the cells at 0.8x10 4 ΟΟμΙ/well, and cultured in 5% CO 2 for 18-24 hours. The cells were washed once with 200 μl/well assay medium, and 150 μl/well assay medium was added and incubated for 37 min at 37 5% CO 2 . Prepare the agonist and compound working solution, add 50μ1/well 4 χ agonist or 4 X compound or 4 X Control control working solution, incubate for 37 min at 37" € 5% C0 2 , repeat the compound 3 times in each concentration. Add room temperature pre- Warm the 3 fixative ΙΟΟμΙ/well and mix for 20 min at room temperature. The cells were washed three times with 200 μl/well of staining solution and left in 200 μl/well staining solution for 1 h at room temperature. Cells were plated on IN Cell Analyzer 1000 live cell imaging system. The measurement conditions were as follows: 20 times objective lens, excitation wavelength Ex=460 nm, emission wavelength Em=535 nm, exposure for 300 ms, detection of nuclear fluorescence of the nuclear channel; excitation wavelength Ex=475 nm, emission wavelength Em=535 nm, exposure for 800 ms, detection of cytoplasmic channel green fluorescence EGFP, 5 fields per well were photographed continuously. Particle formation in the cytoplasm was analyzed using GE IN Cell Analyzer 1000 Multi Target Analysis Module software, and the activity of the compound stimulating SlPi receptor endocytosis was calculated.
化合物激动强度= (化合物处理组平均每细胞所含颗粒的总面积 -Control对照处理组平均每细胞所含颗粒的总面积） I Control对照处 理组平均每细胞所含颗粒的总面积。  Compound agonistic intensity = (the total area of particles per cell contained in the compound-treated group - the total area of particles per cell contained in the Control control treatment group) I Control The total area of particles per cell contained in the control treatment group.
2.6 数据统计与分析：  2.6 Data Statistics and Analysis:
在化合物每个受试浓度点平行测定的 3孔中， 取 15个视野（每孔 5 个）数据的平均值， 计算激动强度。  The excitation intensity was calculated by taking the average of 15 fields (5 per well) in 3 wells measured in parallel for each test concentration point of the compound.
三、 实验结果 验结果Third, the experimental results Test result
Μ和 3 μ M两个终浓度进行了第一次初筛，实验结果如表 2。 The first initial screening was carried out at two final concentrations of Μ and 3 μM. The experimental results are shown in Table 2.
表 2: 初筛实验结果  Table 2: Results of the preliminary screening experiment
初筛  Initial screening
化合物 浓度  Compound concentration
激动强度 土 标准差  Excitatory intensity soil standard deviation
ΙΟηΜ 3.12 土 0.14  ΙΟηΜ 3.12 soil 0.14
S1P  S1P
250nM 6.76 土 0.18  250nM 6.76 soil 0.18
ΙΟΟηΜ -0.06 土 0.19  ΙΟΟηΜ -0.06 soil 0.19
实施例 6  Example 6
3μΜ 1.19 土 0.19  3μΜ 1.19 土 0.19
ΙΟΟηΜ -0.02 土 0.16  ΙΟΟηΜ -0.02 soil 0.16
实施例 7  Example 7
3μΜ 0.51 土 0.17  3μΜ 0.51 soil 0.17
ΙΟΟηΜ 0.03 土 0.16  ΙΟΟηΜ 0.03 soil 0.16
实施例 8  Example 8
3μΜ 0.00 土 0.19  3μΜ 0.00 soil 0.19
ΙΟΟηΜ -0.03 土 0.15  ΙΟΟηΜ -0.03 soil 0.15
实施例 9  Example 9
3μΜ 0.01 土 0.14  3μΜ 0.01 soil 0.14
ΙΟΟηΜ -0.02 土 0.16  ΙΟΟηΜ -0.02 soil 0.16
实施例 10 Example 10
3μΜ 0.05 土 0.18  3μΜ 0.05 soil 0.18
ΙΟΟηΜ -0.03 土 0.14  ΙΟΟηΜ -0.03 soil 0.14
实施例 11 Example 11
3μΜ -0.08 土 0.14  3μΜ -0.08 soil 0.14
ΙΟΟηΜ 0.08 土 0.16  ΙΟΟηΜ 0.08 soil 0.16
实施例 12 Example 12
3μΜ 1.48 土 0.17  3μΜ 1.48 soil 0.17
ΙΟΟηΜ -0.06 土 0.16  ΙΟΟηΜ -0.06 soil 0.16
实施例 15 Example 15
3μΜ 0.00 土 0.18  3μΜ 0.00 soil 0.18
ΙΟΟηΜ -0.07 土 0.16  ΙΟΟηΜ -0.07 soil 0.16
实施例 16 Example 16
3μΜ 0.03 土 0.15  3μΜ 0.03 soil 0.15
ΙΟΟηΜ -0.09 土 0.12  ΙΟΟηΜ -0.09 soil 0.12
实施例 17 Example 17
3μΜ -0.03 土 0.16  3μΜ -0.03 土 0.16
ΙΟΟηΜ -0.02 土 0.14  ΙΟΟηΜ -0.02 soil 0.14
实施例 18 Example 18
3μΜ 0.00 土 0.17  3μΜ 0.00 soil 0.17
ΙΟΟηΜ -0.04 土 0.15  ΙΟΟηΜ -0.04 soil 0.15
实施例 19 Example 19
3μΜ 0.01 土 0.17  3μΜ 0.01 soil 0.17
ΙΟΟηΜ 0.03 土 0.16  ΙΟΟηΜ 0.03 soil 0.16
实施例 20 Example 20
3μΜ -0.04 土 0.15  3μΜ -0.04 soil 0.15
ΙΟΟηΜ 0.04 土 0.18  ΙΟΟηΜ 0.04 soil 0.18
实施例 21 Example 21
3μΜ 1.93 土 0.18 ΙΟΟηΜ 0.02 土 0.19 实施例 22 3μΜ 1.93 土 0.18 ΙΟΟηΜ 0.02 soil 0.19 Example 22
3μΜ 0.63 土 0.14 3μΜ 0.63 soil 0.14
ΙΟΟηΜ -0.13 土 0.13 实施例 23 ΙΟΟηΜ -0.13 soil 0.13 Example 23
3μΜ 0.01 土 0.18 3μΜ 0.01 soil 0.18
ΙΟΟηΜ 0.09 土 0.20 实施例 24 ΙΟΟηΜ 0.09 soil 0.20 Example 24
3μΜ 0.07 土 0.19 3μΜ 0.07 soil 0.19
ΙΟΟηΜ 0.00 土 0.18 实施例 25 ΙΟΟηΜ 0.00 soil 0.18 Example 25
3μΜ -0.03 土 0.16 3μΜ -0.03 土 0.16
ΙΟΟηΜ -0.07 土 0.18 实施例 45 ΙΟΟηΜ -0.07 soil 0.18 Example 45
3μΜ 0.99 土 0.17 3μΜ 0.99 soil 0.17
ΙΟΟηΜ 0.19 土 0.17 实施例 47 ΙΟΟηΜ 0.19 soil 0.17 Example 47
3μΜ 2.80 土 0.17 3μΜ 2.80 soil 0.17
ΙΟΟηΜ -0.05 土 0.17 实施例 48 ΙΟΟηΜ -0.05 soil 0.17 Example 48
3μΜ 1.88 土 0.20 3μΜ 1.88 soil 0.20
ΙΟΟηΜ -0.13 土 0.18 实施例 49 ΙΟΟηΜ -0.13 soil 0.18 Example 49
3μΜ 0.82 土 0.20 3μΜ 0.82 soil 0.20
ΙΟΟηΜ 0.17 土 0.15 实施例 50 ΙΟΟηΜ 0.17 soil 0.15 Example 50
3μΜ 2.82 土 0.16 3μΜ 2.82 soil 0.16
ΙΟΟηΜ 0.29 土 0.17 实施例 51 ΙΟΟηΜ 0.29 soil 0.17 Example 51
3μΜ 0.56 土 0.17 3μΜ 0.56 soil 0.17
ΙΟΟηΜ 0.36 土 0.19 实施例 52 ΙΟΟηΜ 0.36 soil 0.19 Example 52
3μΜ 0.95 土 0.18 3μΜ 0.95 soil 0.18
ΙΟΟηΜ -0.04 土 0.16 实施例 54 ΙΟΟηΜ -0.04 soil 0.16 Example 54
3μΜ -0.02 土 0.16 3μΜ -0.02 soil 0.16
ΙΟΟηΜ 0.14 土 0.16 实施例 56 ΙΟΟηΜ 0.14 soil 0.16 Example 56
3μΜ 3.08 土 0.18 3μΜ 3.08 soil 0.18
ΙΟΟηΜ 0.18 土 0.18 实施例 57 ΙΟΟηΜ 0.18 soil 0.18 Example 57
3μΜ 0.52 土 0.18 3μΜ 0.52 soil 0.18
ΙΟΟηΜ -0.02 土 0.17 实施例 58 ΙΟΟηΜ -0.02 soil 0.17 Example 58
3μΜ 0.03 土 0.19 3μΜ 0.03 soil 0.19
ΙΟΟηΜ 0.01 土 0.17 实施例 59 ΙΟΟηΜ 0.01 soil 0.17 Example 59
3μΜ 1.31 土 0.16 3μΜ 1.31 土 0.16
ΙΟΟηΜ 0.04 土 0.18 实施例 60 ΙΟΟηΜ 0.04 soil 0.18 Example 60
3μΜ 0.05 土 0.15 实施例 61 ΙΟΟηΜ -0.06 土 0.17 3μΜ 0.00 土 0.20 3μΜ 0.05 soil 0.15 Example 61 ΙΟΟηΜ -0.06 Soil 0.17 3μΜ 0.00 soil 0.20
ΙΟΟηΜ 0.10 土 0.16  ΙΟΟηΜ 0.10 soil 0.16
实施例 62  Example 62
3μΜ -0.08 土 0.16  3μΜ -0.08 soil 0.16
ΙΟΟηΜ 0.54 土 0.21  ΙΟΟηΜ 0.54 soil 0.21
实施例 64  Example 64
3μΜ 0.31 土 0.15  3μΜ 0.31 soil 0.15
ΙΟΟηΜ 0.05 土 0.17  ΙΟΟηΜ 0.05 soil 0.17
实施例 66  Example 66
3μΜ -0.05 土 0.17  3μΜ -0.05 soil 0.17
ΙΟΟηΜ -0.04 土 0.16  ΙΟΟηΜ -0.04 soil 0.16
实施例 67  Example 67
3μΜ 0.17 土 0.20  3μΜ 0.17 soil 0.20
ΙΟΟηΜ -0.07 土 0.16  ΙΟΟηΜ -0.07 soil 0.16
实施例 68  Example 68
3μΜ 0.03 土 0.18  3μΜ 0.03 soil 0.18
ΙΟΟηΜ -0.10 土 0.15  ΙΟΟηΜ -0.10 soil 0.15
实施例 69  Example 69
3μΜ -0.02 土 0.16  3μΜ -0.02 soil 0.16
ΙΟΟηΜ -0.12 土 0.17  ΙΟΟηΜ -0.12 soil 0.17
实施例 70  Example 70
3μΜ 0.78 土 0.17  3μΜ 0.78 soil 0.17
ΙΟΟηΜ -0.08 土 0.18  ΙΟΟηΜ -0.08 soil 0.18
实施例 71  Example 71
3μΜ -0.19 土 0.16  3μΜ -0.19 soil 0.16
ΙΟΟηΜ 0.51 土 0.18  ΙΟΟηΜ 0.51 soil 0.18
实施例 72  Example 72
3μΜ 0.00 土 0.17  3μΜ 0.00 soil 0.17
ΙΟΟηΜ 0.06 土 0.16  ΙΟΟηΜ 0.06 soil 0.16
实施例 74  Example 74
3μΜ -0.05 土 0.16  3μΜ -0.05 soil 0.16
ΙΟΟηΜ -0.06 土 0.16  ΙΟΟηΜ -0.06 soil 0.16
实施例 75  Example 75
3μΜ 0.11 土 0.19  3μΜ 0.11 soil 0.19
初筛结果表明， 实施例 6、 实施例 12、 实施例 21、 实施例 22、 实施 例 45、 实施例 47、 实施例 48、 实施例 49、 实施例 50、 实施例 52、 实施 例 56、 实施例 59、 实施例 70分别在 3 μΜ有激动活性达到或超过三倍标 准差， 可以进行进一步筛选。  The preliminary screening results show that the embodiment 6, the embodiment 12, the embodiment 21, the embodiment 22, the embodiment 45, the embodiment 47, the embodiment 48, the embodiment 49, the embodiment 50, the embodiment 52, the embodiment 56, and the implementation In Example 59 and Example 70, respectively, the agonistic activity reached 3 or more standard deviations at 3 μΜ, and further screening was possible.
2.2复筛实验结果  2.2 Re-screening experiment results
对初筛 3μΜ 浓度下激动活性达到或超过三倍标准差的化合物进行 了复筛， 结果见表 3。  Compounds with an agonistic activity of 3 μΜ at or below the standard deviation of three times the standard sieve were rescreened. The results are shown in Table 3.
表 3: 复筛实验结果  Table 3: Results of the rescreening experiment
化合物 浓度 激动强度 标准差 EC50  Compound concentration agonistic intensity standard deviation EC50
ΙΟΟρΜ - 0.04 0.12  ΙΟΟρΜ - 0.04 0.12
S1P 24.49 ±  S1P 24.49 ±
300pM - 0.03 0.14 300pM - 0.03 0.14
Figure imgf000058_0001
ΐΐΐ9εΐ Z OAV OT ·0 ι\ ·0-
Figure imgf000058_0001
Ϊ́ΐΐ9εΐ Z OAV OT ·0 ι\ ·0-
IT ·0 ί\ ·0-IT ·0 ί\ ·0-
ΖΖΌ ΖΖΌ
oro 'ς  Oro 'ς
u'o SO 'Ζ  U'o SO 'Ζ
OS  OS
St ·0 SO ·Ι  St ·0 SO ·Ι
ί  ί
91 ·0 Α8·0 W Ol  91 ·0 Α8·0 W Ol
81 ·0 se ·ο W0£  81 ·0 se ·ο W0£
LI ·0 π ·0 WOl  LI ·0 π ·0 WOl
81 ·0 ΖΙ Ί  81 ·0 ΖΙ Ί
ι\ ·0 92*0  ι\ ·0 92*0
π ·ο Οΐ ·0- et ·ο π ·ο- et ·ο St ·0- W Ol ex ·ο 80 ·0- π ·ο Οΐ ·0- et ·ο π ·ο- et ·ο St ·0- W Ol ex ·ο 80 ·0-
ΖΖΌ xe *e ΖΖΌ xe *e
£1 ·0 30 *e w^e  £1 ·0 30 *e w^e
in^n 'i 60 ·0 00 Ί In^n 'i 60 ·0 00 Ί
+ Z,6*8 ·0 S6'0 w«ooe  + Z,6*8 ·0 S6'0 w«ooe
01 ·0 LZ'O  01 ·0 LZ'O
91 ·0 H ·0  91 ·0 H ·0
xe ·ο  Xe ·ο
OT *e w^  OT *e w^
91 ·0  91 ·0
91 ·0 w«ooe 91 ·0 w«ooe
+ 9L'l + 9L'l
8ΐ ·0 16*0 ί ¥ ·0 xe ·ο W0£  8ΐ ·0 16*0 ί ¥ ·0 xe ·ο W0£
St ·0 81 ·0 WOl  St ·0 81 ·0 WOl
1\ ·0 ΠΊ  1\ ·0 ΠΊ
91 ·0 U'O w^  91 ·0 U'O w^
·0 e9*o  ·0 e9*o
ex ·ο 92*0 w«ooe  Ex ·ο 92*0 w«ooe
·0 ST ·0 ί ¥ ι\ ·0 80 ·0  ·0 ST ·0 ί ¥ ι\ ·0 80 ·0
ι\ ·0 SO ·0— ΐΐΐ9εΐ Z OAV 52 ΙΟΟηΜ -0.17 0.12 ι\ ·0 SO ·0— ΐΐΐ9εΐ Z OAV 52 ΙΟΟηΜ -0.17 0.12
300nM -0.16 0.10  300nM -0.16 0.10
ΙμΜ -0.06 0.12  ΙμΜ -0.06 0.12
3μΜ 0.45 0.13  3μΜ 0.45 0.13
ΙΟηΜ 0.38 0.20  ΙΟηΜ 0.38 0.20
30ηΜ 1.29 0.19  30ηΜ 1.29 0.19
ΙΟΟηΜ 1.32 0.17  ΙΟΟηΜ 1.32 0.17
实施例 1.02 ±  Example 1.02 ±
300ηΜ 1.32 0.16  300ηΜ 1.32 0.16
56 ΙμΜ 3.63 0.20 0.24μΜ  56 ΙμΜ 3.63 0.20 0.24μΜ
3μΜ 5.01 0.19  3μΜ 5.01 0.19
ΙΟμΜ 5.71 0.19  ΙΟμΜ 5.71 0.19
3ηΜ -0.08 0.17  3ηΜ -0.08 0.17
ΙΟηΜ -0.04 0.18  ΙΟηΜ -0.04 0.18
30ηΜ 0.38 0.20  30ηΜ 0.38 0.20
实施例  Example
ΙΟΟηΜ 0.83 0.16 ~ 3 μΜ 59 300ηΜ 0.92 0.18  ΙΟΟηΜ 0.83 0.16 ~ 3 μΜ 59 300ηΜ 0.92 0.18
ΙμΜ 2.15 0.17  ΙμΜ 2.15 0.17
3μΜ 3.04 0.20  3μΜ 3.04 0.20
30ηΜ -0.07 0.15  30ηΜ -0.07 0.15
ΙΟΟηΜ -0.11 0.13  ΙΟΟηΜ -0.11 0.13
实施例 300ηΜ -0.07 0.12 8.13土  Example 300ηΜ -0.07 0.12 8.13 soil
70 ΙμΜ 0.29 0.15 0.26μΜ  70 ΙμΜ 0.29 0.15 0.26μΜ
3μΜ 1.30 0.17  3μΜ 1.30 0.17
ΙΟμΜ 4.03 0.20  ΙΟμΜ 4.03 0.20
上表中， "~" 表示大约。  In the above table, "~" means approx.
四、 实猃结论:  Fourth, the actual conclusion:
EGFP-S1P!_U20S细胞为美国 Thermo公司用于筛 S1P1受体具有 影响的化合物的商品化细胞株， SIP 受体激活后内吞， 表现为绿色荧光 蛋白报告基因在胞质形成颗粒聚集。 因此， 对 SI 受体具有激动活性的 化合物在此细 能够引起报告分子 £0??-31?1的变化。 The EGFP-S1P!_U20S cell is a commercial cell strain of a compound used by the American company to screen for the S1P1 receptor, and the SIP receptor is activated after endocytosis, which is represented by the aggregation of the green fluorescent protein reporter gene in the cytoplasmic granule. Therefore, a compound having an agonistic activity on the SI receptor can cause a change in the reporter molecule £0??-31? 1 .
在 EGFP-SlPi-MOS细 型上， 激动剂 S1P激活 Sl^并导致其内吞 形成颗粒聚集， 其在 10nM的激动活性约为 2- 3倍， 在 250nM的激动活性 约为 5-6倍， 在 1 μΜ的激动活性约为 7-8倍， 其 EC5。值约为 25nM。 送筛化合物中实施例 6、 实施例 12、 实施例 21、 实施例 22、 实施例 45、 实施例 47、 实施例 48、 实施例 49、 -实施例 50、 实施例 52、 实施 例 56、 实施例 59、 实施例 70在 3 μΜ激动活性达到或超过三倍标准差。 对初筛在 3μΜ 浓度下激动活性达到或超过三倍标准差的化合物进行了 复筛，其中实施例 47 (EC5。=1.76 ± 0.88 μ M)、实施例 50 (EC50=1.56 ± 0.23 μΜ) 和实施例 56(EC50=1.02 ±0.24μΜ) 有激动活性。 On the EGFP-SlPi-MOS fine form, the agonist S1P activates S1 and causes its endocytic formation of particle aggregation, which is about 2- to 3-fold at 10 nM and about 5-6 times at 250 nM. The agonistic activity at 1 μΜ is approximately 7-8 times its EC 5 . The value is approximately 25 nM. Example 6, Example 12, Example 21, Example 22, Example 45, Example 47, Example 48, Example 49, Example 50, Example 52, Example 56, Implementation Example 59, Example 70 achieved or exceeded three standard deviations at 3 μΜ agonistic activity. Compounds were screened for compounds with a priming activity of 3 or more standard deviations at a concentration of 3 μΜ, Example 47 (EC 5 = 1.76 ± 0.88 μ M), Example 50 (EC50 = 1.56 ± 0.23 μΜ) And Example 56 (EC50 = 1.02 ± 0.24 μΜ) had agonistic activity.
尽管本发明的具体实施方式已经得到详细的描述。 本领域技术人 员将会理解。 根据已经公开的所有教导， 可以对那些细节进行各种修 改和替换， 这些改变均在本发明的保护范围之内。 本发明的全部范围 由所附权利要求及其任何等同物给出。 Although specific embodiments of the invention have been described in detail. Those skilled in the art will understand. Various modifications and alterations may be made to those details in accordance with the teachings of the invention, which are within the scope of the invention. The full scope of the invention is indicated by the appended claims and any equivalents thereof.

Claims

权利要求 Rights request
1. 通式（I General formula (I
Figure imgf000062_0001
Figure imgf000062_0001
其中：  among them:
K独立地选自 - C00H, -P03H, -P02H2, - S03H， -0 (P03) H; K is independently selected from - C00H, -P0 3 H, -P0 2 H 2 , - S0 3 H, -0 (P0 3 ) H;
U、 V、 W和 J独立地选自- C(R2)-和 - N-， 构成取代或者未被取代的 六元芳香环； U, V, W and J are independently selected from -C(R 2 )- and -N-, and constitute a substituted or unsubstituted six-membered aromatic ring;
其中 R2独立地选自 -H、 - F、 - Cl、 -Br, -1、 - CN、 -OH, d-4烷基、Wherein R 2 is independently selected from the group consisting of -H, -F, -Cl, -Br, -1, -CN, -OH, d- 4 alkyl,
C2-4 ^¾-> C2-4 ^和 Cl-4 ^^α-¾-) C2-4 ^3⁄4-> C2-4 ^ and Cl-4 ^^α-3⁄4-)
上述的 CH烷基、 CH烯基、 C2-4炔基和 CH烷氧基各自任选被独立 地选自以下的取代基取代： - F、 - Cl、 -Br, -1、 -OH和 d—8烷氧基；The above CH alkyl, CH alkenyl, C 2 -4 alkynyl and CH alkoxy groups are each optionally substituted with a substituent independently selected from the group consisting of: - F, - Cl, -Br, -1, -OH and D- 8 alkoxy;
A环和 B环可以直接连接或者通过 G连接； The A ring and the B ring can be directly connected or connected through G;
其中 A环和 B环可以直接连接时， J和 W同时为 -N=;  Where A and B rings can be directly connected, J and W are both -N=;
其中 G可以是 d-3烷基， C2-4烯基， C2-4炔基， - N- R3-、 - 0- R3-、 -S- R3 -、 - Se- R3-、 - C(=0)- R3-、 - C (=0) NH- R3-、 - C(=0)0- R3-、 -C (=S) - R3 -、 - C(=S)NH- R3-、 -C (=Se) - R3-、 -C (=Se) NH- R3-; Wherein G may be d- 3 alkyl, C 2 -4 alkenyl, C 2 -4 alkynyl, -N-R 3 -, - 0- R 3 -, -S-R 3 -, - Se- R 3 -, - C(=0)- R 3 -, - C (=0) NH- R 3 -, - C(=0)0- R 3 -, -C (=S) - R 3 -, - C (=S)NH-R 3 -, -C (=Se) - R 3 -, -C (=Se) NH- R 3 -;
其中所述 d-4烷基， C2-4烯基， C2-4炔基各自任选被 -F、 - Cl、 -Br、 - 1、 -OH, - CN、 CH烷基及 CH烷氧基取代； Wherein the d- 4 alkyl, C 2 -4 alkenyl, C 2 -4 alkynyl are each optionally -F, -Cl, -Br, -1, -OH, -CN, CH alkyl and CH alkane Oxygen substitution;
R3可以是 H、 d-3烷基， C2-4烯基， C2-4炔基， 其中所述的 d-3烷基， C2-4烯基， C2-4炔基各自任选被- F、 - Cl、 -Br, -1、 -OH, - CN、 CH烷基 及 CH烷氧基取代； R 3 may be H, d- 3 alkyl, C 2 -4 alkenyl, C 2 -4 alkynyl, wherein the d- 3 alkyl, C 2 -4 alkenyl, C 2 -4 alkynyl are each Optionally substituted with -F, -Cl, -Br, -1, -OH, -CN, CH alkyl and CH alkoxy;
X、 Y和 Z独立地选自- C(R4)=、 - C(=R5)-、 - 0-、 - N=、 - N(R6)-、 -S -和 -Se-， 这样所得 Q和 T构成杂环； X, Y and Z are independently selected from -C(R 4 )=, -C(=R 5 )-, - 0-, -N=, -N(R 6 )-, -S - and -Se-, The Q and T thus obtained constitute a heterocyclic ring;
Q和 T独立地选自
Figure imgf000062_0002
,其中 Q和 Τ不同时为 Q and T are independently selected from
Figure imgf000062_0002
, where Q and Τ are not the same
R\ R5和 R6各自独立地选自- H、 d—6烷基、 C2—6烯基、 C2—6炔基和 烷氧基， 上述 d-6烷基、 C2-6烯基、 C2-6炔基和 d-6烷氧基各自任选被- F、 - Cl、 -Br , -1、 -OH, - CN、 d-4烷基及 d-4烷氧基取代； R \ R 5 and R 6 are each independently selected from - H, d- 6 alkyl, C 2 - 6 alkenyl, C 2 - 6 alkynyl group, and Alkoxy, the above d- 6 alkyl, C 2 -6 alkenyl, C 2 -6 alkynyl and d- 6 alkoxy are each optionally -F, -Cl, -Br, -1, -OH, - CN, d- 4 alkyl and d- 4 alkoxy substituted;
R1选自苯基、 嘧啶基、 吡啶基、 吡嗪基、 哒嗪基、 噻吩基和噻唑 基， 其中所述各基团任选自以下取代基取代： - F、 - Cl、 -Br , -1、 -0H、 - CN、 - NR7R8、 - N02、 苯基、 苄基、 苄氧基、 d—6烷基、 （：3—6环烷基、 C2—6 婦基、 C2-6块基、 Cl-6 氧¾^、 C3-6环燒 基、 。2—6婦 基基、 。2—6块氧Ϊ^、 d-6烷硫基、 C3-6环烷硫基和 C2-6酰氧基， 可选地， 上述苯基、 苄基和苄 氧基独立地被 1 - 3个以下的取代基取代： - F、 - Cl、 -Br , -1、 -CN、 -NR7R8、 -N02; R 1 is selected from the group consisting of phenyl, pyrimidinyl, pyridyl, pyrazinyl, pyridazinyl, thienyl and thiazolyl, wherein each of the groups is optionally substituted with the following substituents: - F, - Cl, -Br, -1, -0H, - CN, - NR 7 R 8, - N0 2, phenyl, benzyl, benzyloxy, d- 6 alkyl, (: 3 - 6 cycloalkyl group, C 2 - 6 women yl , C2-6 block base, Cl-6 oxygen 3⁄4^, C3-6 cycloalkyl, .2-6 base, 2. 6 oxo, d- 6 alkylthio, C 3 - 6 ring An alkylthio group and a C 2 -6 acyloxy group, optionally, the above phenyl group, benzyl group and benzyloxy group are each independently substituted with 1 to 3 substituents: - F, - Cl, -Br, -1 , -CN, -NR 7 R 8 , -N0 2 ;
R7和 R8独立地选自- H、 d-6烷基、 C2-6烯基和 C2-6炔基， 其中所述的 d-6烷基、 C2-6烯基和 C2-6炔基各自任选被独立地选自以下的取代基取 代： - F、 - Cl、 - Br、 -1、 -OH, - CN和 d—6烷氧基； R 7 and R 8 are independently selected from -H, d- 6 alkyl, C 2 -6 alkenyl and C 2 -6 alkynyl, wherein said d- 6 alkyl, C 2 - 6 alkenyl and C The 2 - 6 alkynyl groups are each optionally substituted with a substituent independently selected from the group consisting of: - F, - Cl, - Br, -1, -OH, - CN and d- 6 alkoxy;
或 R7和 R8独立为饱和单环， 或与它们连接的氮原子一起构成 3-8 个原子的饱和单环， 其中任选包含 1-2个氧原子， 所述环任选独立地 选自以下的取代基取代： - F、 - Cl、 -Br , -1、 -OH, - CN和 d—6烷氧基。 Or R 7 and R 8 are independently saturated monocyclic rings, or together with the nitrogen atom to which they are attached form a saturated monocyclic ring of 3-8 atoms, optionally containing 1-2 oxygen atoms, optionally independently selected Substituted from the following substituents: - F, - Cl, -Br, -1, -OH, - CN and d- 6 alkoxy.
2. 根据权利要求 1所述的化合物或其药学上可接受的盐， 其中， 所述化合物由如下的式 I a所示：  The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is represented by the following formula I a:
Figure imgf000063_0001
Figure imgf000063_0001
其中：  among them:
J和 W独立地选自- C (R4 ) -和- N -， 构成取代或者未被取代的六元 芳香环； J and W are independently selected from -C(R 4 ) - and -N -, and constitute a substituted or unsubstituted six-membered aromatic ring;
其中 R4独立地选自 -H、 - F、 - Cl、 - Br、 - 1、 - CN、 - 0Η、 CH烷基、Wherein R 4 is independently selected from the group consisting of -H, -F, -Cl, -Br, -1, -CN, -0Η, CH alkyl,
。2一4 ^^>¾^、 。2— 4 ^和
Figure imgf000063_0002
. 2 a 4 ^^>3⁄4^, . 2—4^ and
Figure imgf000063_0002
上述的 CH烷基、 C2-4烯基、 C2-4炔基和 CH烷氧基各自任选被独立 地选自以下的取代基取代： - F、 - C l、 -Br , -1、 -OH和 d—8烷氧基； A环和 B环可以直接连接或者通过 G连接； 其中 A环和 B环可以直接连接时， J和 W同时为 -N=; The above CH alkyl group, C 2 -4 alkenyl group, C 2 -4 alkynyl group and CH alkoxy group are each optionally substituted with a substituent independently selected from the group consisting of: - F, - C l, -Br , -1 , -OH and d- 8 alkoxy; A ring and B ring may be directly linked or linked via G; Where A ring and B ring can be directly connected, J and W are simultaneously -N=;
其中 G可以是 d-3烷基， C2-4烯基， C2-4炔基， - N- R4-、 -0- R4 -、 -S- R4-、 -Se- R4-、 -C (=0) - R4-、 -C (=0) NH- R4-、 -C (=0) 0- R4 -、 -C (=S) - R4-、 -C (=S) H- R4-、 -C (=Se) - R4-、 -C (=Se) NH- R4-; Wherein G may be d- 3 alkyl, C 2 -4 alkenyl, C 2 -4 alkynyl, -N-R 4 -, -0- R 4 -, -S- R 4 -, -Se- R 4 -, -C (=0) - R 4 -, -C (=0) NH- R 4 -, -C (=0) 0- R 4 -, -C (=S) - R 4 -, -C (=S) H- R 4 -, -C (=Se) - R 4 -, -C (=Se) NH- R 4 -;
其中所述 d-3烷基， C2-4烯基， C2-4炔基各自任选被选自以下 - F、- C 1、 -Br, -1、 -OH, - CN、 d-4烷基及 CH烷氧基基团取代； Wherein the d- 3 alkyl group, C 2 -4 alkenyl group, C 2 -4 alkynyl group are each optionally selected from the group consisting of -F, -C1, -Br, -1, -OH, -CN, d- Substituted with a 4- alkyl and CH alkoxy group;
R4可以是 H、 d-3烷基， C2-4烯基， C2-4炔基， 其中所述的 d-3烷基， C2-4烯基， C2-4炔基各自任选被- F、 - Cl、 -Br, -1、 -OH, - CN、 CH烷基 及 CH烷氧基取代； R 4 may be H, d- 3 alkyl, C 2 -4 alkenyl, C 2 -4 alkynyl, wherein the d- 3 alkyl, C 2 -4 alkenyl, C 2 -4 alkynyl are each Optionally substituted with -F, -Cl, -Br, -1, -OH, -CN, CH alkyl and CH alkoxy;
X、 Y和 Z独立地选自- C(R4)=、 - C(=R5)-、 - 0-、 - N=、 - N(R6)-、 - S -和- Se-X, Y and Z are independently selected from -C(R 4 )=, -C(=R 5 )-, - 0-, -N=, -N(R 6 )-, -S - and -Se-
R5、 R6和 R7各自独立地选自 -H、 d-6烷基、 C2-6烯基、 C2-6炔基和 (^-6烷氧基， 上述 d-6烷基、 C2-6烯基、 C2-6炔基和 d-6烷氧基各自任选 被- F、 - Cl、 -Br, -1、 -OH, - CN、 d-4烷基及 d-4烷氧基取代； R 5 , R 6 and R 7 are each independently selected from -H, d- 6 alkyl, C 2 -6 alkenyl, C 2 -6 alkynyl and (^ -6 alkoxy, above d- 6 alkyl , C 2 -6 alkenyl, C 2 -6 alkynyl and d- 6 alkoxy are each optionally -F, -Cl, -Br, -1, -OH, -CN, d- 4 alkyl and d - 4 alkoxy substituted;
U和 V各自任选独立地选自 C和 N;  Each of U and V is optionally independently selected from C and N;
R1 ， R2和 R3各自任选独立地选自以下取代基取代： - F、 - Cl、 -Br、 - 1、 -OH, - CN、 - NR8R9、 - N02、 苯基、 苄基、 苄氧基、 d—6烷基、 C3—6 环燒基、 。2—6婦基、 。2—6块基、 Cl-燒 基、 C3—6环燒 基、 。2—6婦 基Ϊ^、Each of R 1 , R 2 and R 3 is optionally independently selected from the group consisting of: - F, - Cl, -Br, -1, -OH, - CN, -NR 8 R 9 , - N0 2 , phenyl , benzyl, benzyloxy, d- 6 alkyl, C 3 - 6 cycloalkyl group burning. 2-6 women's base,. 2-6 blocks, Cl-alkyl, C3-6 ring base. 2-6 women's base Ϊ ^,
C2-6炔氧基、 d-6烷硫基、 C3-6环烷硫基和 C2-6酰氧基， 可选地， 上述苯 基、苄基和苄氧基独立地被 1 - 3个以下的取代基取代： - F、 - Cl、 -Br, -1、 — CN、 — NR7R8、 -N02; C 2 - 6 alkynyl group, d- 6 alkylthio, C 3 - 6 cycloalkyl group and a C 2 - 6 acyloxy, optionally, where the phenyl, benzyl and benzyloxy are independently 1 - substitution of 3 or less substituents: - F, - Cl, -Br, -1, - CN, - NR 7 R 8 , -N0 2 ;
R8和 R9独立地选自- H、 d-6烷基、 C2-6烯基和 C2-6炔基， 其中所述 的 d-6烷基、 C2-6烯基和 C2-6炔基各自任选被独立地选自以下的取代基 取代： - F、 - Cl、 -Br, -1、 -OH, - CN和 d—6烷氧基； R 8 and R 9 are independently selected from -H, d- 6 alkyl, C 2 -6 alkenyl and C 2 -6 alkynyl, wherein said d- 6 alkyl, C 2 - 6 alkenyl and C The 2 - 6 alkynyl groups are each optionally substituted with a substituent independently selected from the group consisting of: - F, - Cl, -Br, -1, -OH, - CN and d- 6 alkoxy;
R8和 R9可以与它们连接的氮原子一起构成 3-8 个原子的饱和单 环， 其中任选包含 1-2个氧原子， 所述环任选独立地选自以下的取代 基取代： - F、 - Cl、 -Br, -1、 -OH, - CN和 d—6烷氧基。 R 8 and R 9 may, together with the nitrogen atom to which they are attached, form a saturated monocyclic ring of 3-8 atoms, optionally containing 1-2 oxygen atoms, optionally substituted with a substituent selected from the group consisting of: - F, - Cl, -Br, -1, -OH, - CN and d- 6 alkoxy.
3. 根据权利要求 2所述的化合物或其药学上可接受的盐，其中， 所述化合物由如下的式 I b所示：
Figure imgf000065_0001
The compound according to claim 2 or a pharmaceutically acceptable salt thereof, wherein the compound is represented by the following formula Ib:
Figure imgf000065_0001
( l b )  ( l b )
其中：  among them:
上述的 J和 W独立地选自- C(R4)-和- N -， 构成取代或者未被取代 的六元芳香环； The above J and W are independently selected from -C(R 4 )- and -N -, and constitute a substituted or unsubstituted six-membered aromatic ring;
其中 R4独立地选自 -H、 - F、 - Cl、 -Br, -1、 -CN、 -0H、 CH烷基、Wherein R 4 is independently selected from the group consisting of -H, -F, -Cl, -Br, -1, -CN, -0H, CH alkyl,
。2一4 ^^¾^、 。2-4 ^和 Cl-4 ^^α¾-) . 2 a 4 ^^3⁄4^, . 2-4 ^ and Cl-4 ^^α3⁄4-)
上述的 CH烷基、 CH烯基、 C2-4炔基和 CH烷氧基各自任选被独立 地选自以下的取代基取代： - F、 - Cl、 -Br, -1、 -OH和 CH烷氧基； A环和 B环通过 G连接； The above CH alkyl, CH alkenyl, C 2 -4 alkynyl and CH alkoxy groups are each optionally substituted with a substituent independently selected from the group consisting of: - F, - Cl, -Br, -1, -OH and CH alkoxy; A ring and B ring are connected by G;
其中 G有选自以下基团： d—3烷基， C2-4烯基， C2-4炔基， - N- R4 -、 -O-R4-、 - S- R4-、 - Se- R4-、 - C(=0)- R4-、 - C (=0) NH- R4-、 -C (=0) 0- R4 -、 -C(=S)- R4-、 -C (=S) NH- R4-、 -C(=Se)- R4-、 -C (=Se) NH- R4-; Wherein G is selected from the group consisting of: d- 3 alkyl, C 2 -4 alkenyl, C 2 -4 alkynyl, -N-R 4 -, -OR 4 -, -S-R 4 -, - Se - R 4 -, - C(=0)- R 4 -, - C (=0) NH- R 4 -, -C (=0) 0- R 4 -, -C(=S)- R 4 - , -C (=S) NH- R 4 -, -C(=Se)- R 4 -, -C (=Se) NH- R 4 -;
其中所述 d-3烷基， C2-4烯基， C2-4块基各自任选被 -F、 - Cl、 -Br、 - 1、 -OH, - CN、 CH烷基及 CH烷氧基取代； Wherein the d- 3 alkyl group, the C 2 -4 alkenyl group, and the C 2 - 4 block group are each optionally selected from -F, -Cl, -Br, -1, -OH, -CN, CH alkyl and CH alkane Oxygen substitution;
R4可以是 H、 d-3烷基， C2-4烯基， C2-4块基， 其中所述的 d-3烷基， C2-4烯基， C2-4炔基各自任选被- F、 - Cl、 -Br, -1、 -OH, - CN、 CH烷基 及 CH烷氧基取代； R 4 may be H, d- 3 alkyl, C 2 -4 alkenyl, C 2 - 4 block, wherein the d- 3 alkyl, C 2 -4 alkenyl, C 2 -4 alkynyl are each Optionally substituted with -F, -Cl, -Br, -1, -OH, -CN, CH alkyl and CH alkoxy;
Y和 Z独立地选自 - C (R5) =和一 N=; Y and Z are independently selected from - C (R 5 ) = and one N =;
R5可以选自以下基团作为取代基： - H、 d-6烷基、 C2-6烯基、 C2—6 块基和 d-6烷氧基， 上述 d-6烷基、 C2-6烯基、 C2-6炔基和（^-6烷氧基各 自任选被- F、 - Cl、 -Br, -1、 -OH, - CN、 CH烷基及 CH烷氧基取代；R 5 may be selected from the group consisting of: -H, d- 6 alkyl, C 2 -6 alkenyl, C 2 - 6 -block and d- 6 alkoxy, the above-mentioned d- 6 alkyl, C 2 - 6 alkenyl, C 2 -6 alkynyl and (^- 6 alkoxy are each optionally -F, -Cl, -Br, -1, -OH, -CN, CH alkyl and CH alkoxy Replace
R1 ， R2和 R3各自任选独立地选自以下取代基取代： - F、 - Cl、 -Br、 - 1、 -OH, - CN、 - NR6R7、 - N02、 苯基、 苄基、 苄氧基、 d—6烷基、 C3—6 环燒基、 Cl-6婦基、 Cl-6块基、 Cl-6燒 基、 C3-6环燒 基、 C2-6婦 基¾^、Each of R 1 , R 2 and R 3 is optionally independently selected from the group consisting of: - F, - Cl, -Br, -1, -OH, - CN, - NR 6 R 7 , - N0 2 , phenyl , benzyl, benzyloxy, d- 6 alkyl, C 3 - 6 cycloalkyl group burning, Cl-6-yl women, Cl-6 block basis, Cl-6-yl burn, burn a C3-6 cycloalkyl group, a C2-6 Women's base 3⁄4^,
C2-6炔氧基、 （^-6烷硫基、 C3-6环烷硫基和 C2-6酰氧基， 上述苯基、 苄基 和苄氧基可以被 1 - 3个以下的取代基取代： - F、 - Cl、 -Br, -1、 -CN、 -NR7R\ -N02; C 2 - 6 alkynyl group, (^ - 6 alkylthio, C 3 - 6 cycloalkyl group and a C 2 - 6 acyloxy, where the phenyl, benzyl and benzyloxy may be substituted with 1 - 3 or less Replacement of substituents: - F, - Cl, -Br, -1, -CN, -NR 7 R\ -N0 2 ;
R6和 R7独立地选自- H、 d-6烷基、 C2-6烯基和 C2-6炔基， 其中所述 的 d-6烷基、 C2-6烯基和 C2-6炔基各自任选被独立地选自以下的取代基 取代： - F、 - Cl、 -Br, -1、 -OH, - CN和 d—6烷氧基； R 6 and R 7 are independently selected from -H, d- 6 alkyl, C 2 -6 alkenyl and C 2 -6 alkynyl, wherein said d- 6 alkyl, C 2 - 6 alkenyl and C The 2 - 6 alkynyl groups are each optionally substituted with a substituent independently selected from the group consisting of: - F, - Cl, -Br, -1, -OH, - CN and d- 6 alkoxy;
R6和 R7可以与它们连接的氮原子一起构成 3-8 个原子的饱和单 环， 其中任选包含 1-2个氧原子， 所述环任选独立地选自以下的取代 基取代： - F、 - Cl、 -Br, -1、 -OH, - CN和 d—6烷氧基。 R 6 and R 7 may together with the nitrogen atom to which they are attached form a saturated monocyclic ring of 3-8 atoms, optionally containing 1-2 oxygen atoms, optionally substituted with a substituent selected from the group consisting of: - F, - Cl, -Br, -1, -OH, - CN and d- 6 alkoxy.
4. 根据权利要求 1至 3中任一项所述的化合物或其药学上可接受 4. A compound according to any one of claims 1 to 3 or a pharmaceutically acceptable compound thereof
， 其中， 所述化合物选自： Wherein the compound is selected from the group consisting of
3- ( 4- ( 2- (4-异丙氧基苯基） -4-噻唑甲酰胺）苯基） 丙酸， 3-(4-(2-(4-isopropoxyphenyl)-4-thiazolecarboxamide)phenyl)propionic acid,
3- ( 4- ( 2- (4-苄氧基苯基） - 4噻唑甲酰胺）苯基） 丙酸，3-(4-(2-( 4 -benzyloxyphenyl) -4- thiazolecarboxamide)phenyl)propionic acid,
3- ( 4- ( 2- (4-环戊氧基苯基） - 4噻唑甲酰胺）苯基） 丙酸，3-(4-(2-( 4 -cyclopentyloxyphenyl) -4- thiazolylcarboxamide)phenyl)propionic acid,
3- ( 4- ( 2- (4-异丁氧基苯基） - 4噻唑甲酰胺）苯基） 丙酸，3-(4-(2-( 4 -isobutoxyphenyl) -4- thiazolylcarboxamide)phenyl)propionic acid,
3- ( 4- ( 2- (4-环丁氧基苯基） - 4噻唑甲酰胺）苯基） 丙酸，3-(4-(2-( 4 -cyclobutoxyphenyl) -4- thiazolylcarboxamide)phenyl)propionic acid,
3- ( 4- ( 2- (4-丁氧基苯基） -4噻唑甲酰胺）苯基） 丙酸，3-(4-(2-(4-Butoxyphenyl)-4 thiazolecarboxamide) phenyl) propionic acid,
3- ( 4- ( 2- (4-丙氧基苯基） -4噻唑甲酰胺）苯基） 丙酸，3-(4-(2-(4-propoxyphenyl)-4-thiazolylcarboxamide)phenyl)propionic acid,
3- ( 4- ( (5-（4-异丙氧基苯基）噻唑- 2)氨基）苯基） 丙酸，3-(4-(( 5- ( 4 -isopropoxyphenyl)thiazole- 2 )amino)phenyl)propanoic acid,
3- ( 4- ( (5-（4-异丁氧基苯基）噻唑- 2)氨基）苯基） 丙酸，3-(4-(( 5- ( 4 -isobutoxyphenyl)thiazole- 2 )amino)phenyl)propanoic acid,
3- ( 4- ( (5- (4-丙氧基苯基）噻唑- 2)氨基）苯基） 丙酸，3-(4-((5-(4-propoxyphenyl)thiazole-2)amino)phenyl)propanoic acid,
3- ( 4- ( (5- (4-丁氧基苯基）噻唑- 2)氨基）苯基） 丙酸，3-(4-((5-(4-Butoxyphenyl)thiazole-2)amino)phenyl)propanoic acid,
3- ( 4- ( (5-（4-环戊氧基苯基）噻唑- 2)氨基）苯基） 丙酸，3-(4-(( 5- ( 4 -cyclopentyloxyphenyl)thiazole- 2 )amino)phenyl)propanoic acid,
3- ( 4- ( (5- (4-苄氧基苯基）噻唑- 2)氨基）苯基） 丙酸，3-(4-((5-(4-Benzyloxyphenyl)thiazole-2)amino)phenyl)propanoic acid,
3- ( 4- ( ( 5- ( 2, 4-二氟苯基 )噻唑 -2 )氨基）苯基） 丙酸，3-(4-((5-(4-,4-difluorophenyl)thiazole-2)amino)phenyl)propanoic acid,
3- ( 4- ( ( 5- ( 4-溴苯基 )噻唑- 2 )氨基）苯基） 丙酸， 3-(4-((5-(4-bromophenyl)thiazole-2)amino)phenyl)propanoic acid,
3- ( 4- ( (5-（4-甲氧基苯基）噻唑- 2)氨基）苯基） 丙酸，3-(4-(( 5- ( 4 -methoxyphenyl)thiazole- 2 )amino)phenyl)propanoic acid,
3- ( 4- ( ( 5- ( 4-氯苯基 )噻唑- 2 )氨基）苯基） 丙酸， 3-(4-((5-(4-chlorophenyl)thiazole-2)amino)phenyl)propanoic acid,
3- ( 4- ( (5-（4-正己氧苯基）噻唑- 2)氨基）苯基） 丙酸，3-(4-(( 5- ( 4 -n-hexyloxyphenyl)thiazole- 2 )amino)phenyl)propanoic acid,
3- (4-(4- -(3-溴- 4-甲氧基苯基)噻唑- 2-亚胺基)苯基）丙酸， 3-(4-(4-(3-bromo-4-methoxyphenyl)thiazole-2-imino)phenyl)propanoic acid,
3- (4- (4- -(3-溴- 4-异丙氧基苯基)噻唑- 2-亚胺基)苯基）丙酸， 3- (4- (4- (3-溴- 4-丙氧基苯基)噻唑- 2-亚胺基)苯基）丙酸， 3-(4-(4-(3-bromo-4-isopropoxyphenyl)thiazole-2-imino)phenyl)propanoic acid, 3-(4-(4-(3-bromo-4-propoxyphenyl)thiazole-2-imino)phenyl)propanoic acid,
3- (4- (4- (3-溴- 4-环戊氧基苯基)噻唑- 2-亚胺基)苯基）丙酸， 3- (4- (4- (3-溴- 4-环戊氧基苯基)噻唑- 2-亚胺基)苯基）丙酸， 3- (4- (4- (3-溴- 4-正丁氧基苯基）噻唑- 2-亚胺基）苯基）丙酸， 3- (4- (4- (3-溴- 4-卞氧基苯基)噻唑- 2-亚胺基)苯基）丙酸，  3-(4-(4-(3-Bromo-4-cyclopentyloxyphenyl)thiazole-2-imino)phenyl)propionic acid, 3-(4-(4-(3-bromo-4) -cyclopentyloxyphenyl)thiazole-2-imino)phenyl)propionic acid, 3-(4-(4-(3-bromo-4-n-butoxyphenyl)thiazole-2-imine Phenyl)propionic acid, 3-(4-(4-(3-bromo-4-yloxyphenyl)thiazole-2-imino)phenyl)propanoic acid,
3- (4- (4- (3-氯- 4-甲氧基苯基)噻唑- 2-亚胺基)苯基）丙酸，  3-(4-(4-(3-chloro-4-methoxyphenyl)thiazole-2-imino)phenyl)propanoic acid,
3- (4- (4- (3-氯- 4-异丙氧基苯基)噻唑- 2-亚胺基)苯基）丙酸， 3- (4- (4- (3-氯- 4-丙氧基苯基)噻唑- 2-亚胺基)苯基）丙酸，  3-(4-(4-(3-chloro-4-isopropoxyphenyl)thiazole-2-imino)phenyl)propionic acid, 3-(4-(4-(3-chloro- 4 ) -propoxyphenyl)thiazole-2-imino)phenyl)propionic acid,
3- (4- (4- (3-氯- 4-正丁氧基苯基）噻唑- 2-亚胺基）苯基）丙酸， 3- (4- (4- (3-氯- 4-异丁氧基苯基)噻唑- 2-亚胺基)苯基）丙酸， 3- (4- (4- (3-氯- 4-环戊氧基苯基）噻唑- 2-亚胺基）苯基）丙酸， 3- (4- (4- (3-氯- 4-异戊氧基苯基)噻唑- 2-亚胺基)苯基）丙酸， 3- (4- (4- (3-氯- 4-苄氧基苯基)噻唑- 2-亚胺基)苯基）丙酸，  3-(4-(4-(3-chloro-4-n-butoxyphenyl)thiazole-2-imino)phenyl)propionic acid, 3-(4-(4-(3-chloro- 4 ) -isobutoxyphenyl)thiazole-2-imino)phenyl)propionic acid, 3-(4-(4-(3-chloro-4-cyclopentyloxyphenyl)thiazole-2-imine Phenyl)propionic acid, 3-(4-(4-(3-chloro-4-isopentyloxyphenyl)thiazole-2-imino)phenyl)propionic acid, 3- (4- 4-(3-chloro-4-benzyloxyphenyl)thiazole-2-imino)phenyl)propanoic acid,
2- (4- (4- (3-氯- 4-甲氧基苯基)噻唑- 2-亚胺）苯基）乙酸，  2-(4-(4-(3-chloro-4-methoxyphenyl)thiazole-2-imino)phenyl)acetic acid,
2- (4- (4- (3-氯- 4-环戊氧基苯基）噻唑- 2-亚胺）苯基）乙酸，  2-(4-(4-(3-chloro-4-cyclopentyloxyphenyl)thiazole-2-imine)phenyl)acetic acid,
3- (4- (4- (4-环丁氧基苯基)噻唑- 2-亚胺）苯基）丙烷- 1-醇，  3-(4-(4-(4-cyclobutoxyphenyl)thiazole-2-imine)phenyl)propane-1-ol,
3- (4- (4- (4-丙氧基苯基)噻唑- 2-亚胺）苯基）丙烷- 1 -醇，  3-(4-(4-(4-propoxyphenyl)thiazole-2-imine)phenyl)propane-1-ol,
3- (4- (4- (4-溴苯基)噻唑- 2-亚胺）苯基）丙烷- 1-醇，  3-(4-(4-(4-bromophenyl)thiazole-2-imine)phenyl)propane-1-ol,
3- (4- (4- (3-氯- 4-异丙氧基苯基)噻唑- 2-亚胺）苯基）丙烷- 1-醇， 3- (4- (4- (3-氯- 4-异戊氧基苯基)噻唑- 2-亚胺）苯基）丙烷- 1-醇， 3-（4- (4- (4-异丙基苯基）噻唑- 2-亚胺）苯基） 丙烷- 1-醇，  3-(4-(4-(3-chloro-4-isopropoxyphenyl)thiazole-2-imine)phenyl)propane-1-ol, 3-(4-(4-(3-chloro) - 4-isopentyloxyphenyl)thiazole-2-imine)phenyl)propane-1-ol, 3-(4-(4-(4-isopropylphenyl)thiazole-2-imine) Phenyl) propane-1-ol,
2-（4- (4- (3-氯- 4-甲氧基苯基)噻唑- 2-亚胺）苯基）乙醇， 和  2-(4-(4-(3-chloro-4-methoxyphenyl)thiazole-2-imine)phenyl)ethanol, and
2- (4- (4- (3-溴- 4-甲氧基苯基)噻唑- 2-亚胺）苯基）乙醇。  2-(4-(4-(3-Bromo-4-methoxyphenyl)thiazole-2-imine)phenyl)ethanol.
5. 一种药物组合物，其包含权利要求 1至 4中任一项所述的化合 物或其可药用盐； 可选地， 还包含药用载体或赋形剂。  A pharmaceutical composition comprising the compound of any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof; optionally, further comprising a pharmaceutically acceptable carrier or excipient.
6. G为- C (=0) NH-的权利要求 3化合物或其可药用盐的制备方法， 其包括如下反应路线， 即首先用溴苄将对羟基苯甲腈的羟基保护， 在 N，N-二甲基甲酰胺， 二甲基亚砜， 二氯甲烷等溶剂中， 在加热或常温 下， 通过使用碳酸钾、 碳酸钠、 碳酸氢钠、 三乙胺中和反应过程中产 生的酸， 制得化合物 ii ; 通过硫氢化钠将氰基硫解得到硫代酰胺类化 合物 iii; 硫代酰胺与溴代酮类化合物在甲醇， 乙醇或者异丙醇等极性 较大的溶剂中环合得到噻唑环 （化合物 iv ) ； 再通过经典的酰氯与氨 缩合制备酰胺方法将两个芳香环连接制得化合物 V， 其中酰氯的制备 方法可以使用二氯亚砜， 草酰氯， 三氯氧磷和五氯氧磷等试剂， 在合 适的溶剂中制备化合物 v， 化合物 V也可以使用 DCC， DIEA， DBU， EDCI 等缩合剂制备； 然后通过常规 Pd- C催化氢化脱苄基方法制得 vi，其中 可以使用环己烯、 氢气或甲酸铵等作为供氢体， 在合适的压力条件下 制备； 通过与制备化合物 ii类似的经典酚羟基烷基化反应； 最后使用 合适 物 i； 6. A process for the preparation of a compound of claim 3 or a pharmaceutically acceptable salt thereof, wherein C is -C(=0)NH-, which comprises the following reaction scheme, i.e. first protecting the hydroxyl group of p-hydroxybenzonitrile with benzyl bromide, in N , N-dimethylformamide, dimethyl sulfoxide, methylene chloride and other solvents, during heating or at room temperature, by neutralization using potassium carbonate, sodium carbonate, sodium hydrogencarbonate, triethylamine The acid is produced to obtain the compound ii; the thio group is thiolated by sodium hydrosulfide to obtain the thioamide compound iii; the thioamide and the bromo ketone compound are in a relatively polar solvent such as methanol, ethanol or isopropanol. The thiazole ring (compound iv) is obtained in the middle ring; the amide method is prepared by condensing a classical acid chloride with ammonia to form a compound V by combining two aromatic rings, wherein the acid chloride can be prepared by using dichlorosulfoxide, oxalyl chloride or trichloroox Compounds such as phosphorus and phosphorus pentoxide are prepared in a suitable solvent. Compound V can also be prepared by using a condensing agent such as DCC, DIEA, DBU, EDCI or the like; and then a conventional Pd-C catalytic hydrogenation debenzylation method is used to prepare vi. , wherein cyclohexene, hydrogen or ammonium formate can be used as a hydrogen donor, prepared under suitable pressure conditions; by classical phenolic hydroxyalkylation reaction similar to the preparation of compound ii; finally using suitable i;
7. G为 -NH-的权利要求 3化合物或其可药用盐的制备方法， 其包 括如下反应路线， 即首先对氨基取代芳基丙酸与硫氰酸钾或者硫氰酸 铵在甲醇、 乙醇或水作为溶剂得到化合物 viii; 化合物 l与 2-溴- 4， - 羟基苯乙酮以各种短链低沸点醇为溶剂， 回流既得到化合物； 化合物 采用权利要求 5中反应路线 1类似的方法处理后， 即得到终产物， 7. A process for the preparation of a compound of claim 3 or a pharmaceutically acceptable salt thereof, which comprises -NH-, which comprises the first reaction to an amino-substituted arylpropionic acid with potassium thiocyanate or ammonium thiocyanate in methanol, Ethanol or water is used as a solvent to obtain a compound viii; the compound 1 and 2-bromo-4,-hydroxyacetophenone are refluxed with various short-chain low-boiling alcohols to obtain a compound; the compound is similar to the reaction scheme 1 in claim 5. After the method is processed, the final product is obtained.
Figure imgf000069_0001
Figure imgf000069_0001
Figure imgf000069_0002
其中 I，W如权利要求中定义， R如权利要求 3中 R2的定义。
Figure imgf000069_0002
Wherein I, W as defined in the claims, in the definition of R 2 R 3 as claimed in claim.
8. 权利要求 1至 4中任一项所述的化合物或其可药用盐在制备用 于治疗和 /或预防哺乳动物患者的免疫调节异常、 呼吸道疾病或症状、 血管相完整关性疾病或症状、 脑水肿或肺水肿相关疾病、 抗炎或止血 的药物中的用途。  The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, for use in the treatment and/or prevention of immunomodulatory disorders, respiratory diseases or symptoms, vascular integrity disorders or Use in medicines for symptoms, cerebral edema or pulmonary edema-related diseases, anti-inflammatory or hemostasis.
9. 权利要求 1至 4中任一项所述的化合物或其可药用盐在制备或 作为 S1P EDG1受体激动剂的药物中的用途。  9. Use of a compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, for the manufacture or use as a medicament for an S1P EDG1 receptor agonist.
10. 一种治疗和 /或预防哺乳动物患者的免疫调节异常、呼吸道疾 病或症状、 血管相完整关性疾病或症状、 脑水肿或肺水肿相关疾病、 或者抗炎或止血的方法， 包括给予有效量的权利要求 1至 4中任一项 所述的化合物或其可药用盐的步骤。  10. A method of treating and/or preventing immunomodulatory abnormalities, respiratory diseases or symptoms, vascular intact diseases or symptoms, cerebral edema or pulmonary edema-related diseases, or anti-inflammatory or hemostasis in a mammalian patient, including effective administration A step of the compound of any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof.
11. 一种在体内或体外调节 S1P EDG1 受体活性的方法， 包括使 用有效量的权利要求 1至 4中任一项所述的化合物或其可药用盐的步  A method of modulating the activity of an S1P EDG1 receptor in vivo or in vitro, comprising the step of using an effective amount of the compound of any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof.
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