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

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

 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. Background technique

 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.

 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.

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.

 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.

 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.

 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.

 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.

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.

 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.

 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

 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

 I

 among them:

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;

Wherein R ^{2 is} independently selected from the group consisting of -H, -F, -Cl, -Br, -1, -CN, -OH, d- ₄ alkyl,

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;

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;

 Where A and B rings can be directly connected, J and W are both -N=;

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 -;

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;

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 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 and Τ are independently selected from

; 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 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 ;

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:

(la)

 among them:

The above J and W are independently selected from -C(R ⁴ )- and -N -, and constitute a substituted or unsubstituted six-membered aromatic ring;

Wherein R ^{4 is} independently selected from the group consisting of -H, -F, -Cl, -Br, -1, -CN, -0Η, CH alkyl,

. 2 a 4 ^ ^ > 3⁄4 ^, . 2-4 ^ and Cl-4

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;

The A ring and the B ring can be directly connected or connected through G;

 Where A and B rings can be directly connected, J and W are both -N=;

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 -;

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;

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 and Z are independently selected from -C(R ⁴ )=, -C(=R ⁵ )-, - 0-, -N=, -N(R ⁶ )-, -S - and -Se-

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,. 2-6 blocks, Cl-alkyl, C3-6 ring base. 2-6 women's base Ϊ ^,

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 ;

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. In another embodiment of the invention, the compound of formula I is a compound of formula I b or is pharmaceutically acceptable

( 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;

Wherein R ^{4 is} independently selected from the group consisting of -H, -F, -Cl, -Br, -1, -CN, -0H, CH alkyl,

C2-4 ^3⁄4-> C2-4 ^ and Cl-4 ^^α-3⁄4-)

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;

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;

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 and Z are independently selected from - C (R ⁵ ) = and one N =;

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. 2-6 women's base,. 2-6 blocks, Cl-alkyl,. 3-6 ring-burning base,. 2-6 women's base Ϊ ^,

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. This hair

 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:

3- (4- (4-(3-chloro-4- CI H propoxyphenyl)thiazole)

- 2 -imino)phenyl)propyl

Acid

 3-(4- (4-(3-chloro-4- CI H-n-butoxyphenyl)-pyrazole

- 2 -imino)phenyl)propyl

Acid

 3- (4- (4-chloro-4-isobutoxyphenyl)thiazole

- 2 -imino)phenyl)propyl

Acid

 3- (4- (4-chloro-4-cyclopentyloxyphenyl)thiazole

- 2 -imino)phenyl)propyl

Acid

 3- (4- (4-chloro-4-isopentyloxyphenyl)thiazole

- 2 -imino)phenyl)propyl

Acid

 3- (4- (4-chloro-4-benzyloxyphenyl)thiazole

- 2 -imino)phenyl)propyl

Acid

 2-(4- (4-(3-chloro-4- CI H decyloxyphenyl)thiazole

-2-imine)phenyl)acetic acid

 2-(4- (4-(3-chloro-4-cyclopentyloxyphenyl)thiazole

-2-imine)phenyl)acetic acid

3- (4- (4- (4-cyclobutoxy)

Phenyl)thiazole-2A

Amine)phenyl)propane-1-ol

 3- (4- (4- (4-propoxy)

Phenyl) azole-2-imine)

Phenyl)propane-1-ol

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.

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.

 Further, the immunomodulatory abnormality is bone marrow or organ transplant rejection or graft versus host disease.

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.

 Specifically, wherein the immunomodulatory abnormality is selected from

 1) Multiple sclerosis,

 2) Rheumatoid arthritis,

 3) Systemic lupus erythematosus,

 4) Psoriasis,

 5) rejection of transplanted organs or tissues,

 6) Inflammatory bowel disease,

 7) malignant tumors derived from lymph,

 8) Acute and chronic lymphocytic leukemia and lymphoma

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.

 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.

 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.

 This embodiment is also included in the above method, wherein the patient also has a respiratory disease or condition.

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.

 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.

 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. 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.

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.

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.

 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.

 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.

 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.

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.

 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.

 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.

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.

 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. 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.

 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.

 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.

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.

 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.

 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.

 The present invention also includes any one of the following items (1) to (4):

 (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) 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) 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) 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

 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;

 1

 Reaction route 2

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.

Reaction route 3

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.

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.

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.

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. detailed description

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

 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. Example 2: Preparation of 4-benzyloxythiobenzamide

 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),

7. 94 (d, J=8. 8, 2H), 7. 31-7. 47 (brs, 5H), 7. 17 (d, J=9. 2, 2H), 5. 18 (S,

1H). Example 3: Preparation of ethyl 2-(4-benzyloxyphenyl)-4-thiazole

 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

(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). Example 4: Preparation of ethyl 3-(4-(2-(4-benzyloxyphenyl)-4-thiazolecarboxamido)phenyl)propionate

 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. 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

( 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). Example 5: Preparation of ethyl 3-(4-(2-(4-hydroxyphenyl)-4-ylthiazolecarboxamide) phenyl) propionate

 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) ,

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

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, C ₂₂ H ₂₄ N ₂ 0 ₄ S. Example 7: Preparation of 3-(4-(2-(4-benzyloxyphenyl)-4-thiazolecarboxamide)phenyl)propionic acid

 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, C ₂₆ H ₂₃ N ₂ 0 ₄ S. Example 8: Preparation of 3-(4-(2-(4-cyclopentyloxyphenyl)-4-thiazolecarboxamide)phenyl)propionic acid

 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, C ₂₂ H ₂₄ N ₂ 0 ₄ S. Example 9: Preparation of 3-(4-(2-(4-isobutoxyphenyl)-4-thiazolecarboxamide)phenyl)propionic acid

 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, C ₂₃ H ₂₅ N ₂ 0 ₄ S. Example 10: Preparation of 3-(4-(2-(4-cyclobutoxyphenyl)-4thiazolecarboxamide)phenyl)propionic acid

 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, C ₂₃ H ₂₃ N ₂ 0 ₄ S. Example 11: Preparation of 3-(4-(2-(4-butoxyphenyl)-4-thiazolecarboxamide)phenyl)propionic acid

 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, C ₂₃ H ₂₅ N ₂ 0 ₄ S. Example 12: Preparation of 3-(4-(2-(4-propoxyphenyl)-4-thiazolylcarboxamide)phenyl)propionic acid

 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, C ₂₃ H ₂₅ N ₂ 0 ₄ S. Example 13: Preparation of 3-(4-thioureidophenyl)propionic acid

 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),

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

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)„ Example 15: Preparation of 3-(4-((5-(4-isopropoxyphenyl)thiazole-2)amino)phenyl)propanoic acid

 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, C ₂₁ H ₂₃ N ₂ 0 ₃ S. Example 16: Preparation of 3-(4-((5-(4-isobutoxyphenyl)thiazole-2)amino)phenyl)propanoic acid

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) ,

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

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=

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

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

(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

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, 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

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, 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

 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 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

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

(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

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, C ₂ .H ₁₉ N ₂ 04S. Example 24: Preparation of 3-(4-((5-(4-chlorophenyl)thiazol-2)amino)phenyl)propanoic acid

 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

(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

 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, C ₂₄ H ₂₉ N ₂ 0 ₃ S. Example 26: Preparation of 5-bromo salicylaldoxime

 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). Example 27: Preparation of 5-bromo-2-hydroxybenzonitrile

 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). Example 28: Preparation of 5-bromo-2-isopropoxybenzonitrile

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). Example 29: Preparation of 3-cyano-4-isopropoxybenzeneboronic acid

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: 206.0 _o Example 30: 3-methyl 4 -Preparation of bromo-benzoic acid ethyl ester

 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

 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, 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, 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

 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 ) Separation. 6%。 The yield of 1. 36g ( 5. 50mmol) of compound ( 10 ), yield 48.4%.

'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. 75

(s, 3H), 1.43 (t, J=7.2, 3H). Example 34: Preparation of 3-methyl-4-(thiazol-2-yl)benzylidene

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

 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

 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). Example 37: Preparation of 3-methyl-4-(thiazol-2-yl)benzenepropionic acid

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

 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=7.2 Hz, 3H). Example 40: Preparation of ethyl 3-methyl-4-(3-(3-cyano-4-isopropoxy-1-phenyl)thiazole-2-yl)benzenepropanoate

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). Example 41: Preparation of 3-methyl-4-(5-(3-cyano-4-isopropoxy- 1-phenyl)thiazole-2-yl)benzenepropionic acid

 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, 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

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). Example 43: Preparation of 3-(4-aminophenyl)propionic acid

 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.

 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=

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

 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.

 After the reaction, a large amount of solid precipitated, cooled, filtered, washed 3 times, dried white powdery solid 12. 5g.

 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),

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

 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. Example 46: Preparation of 3-(4-(4-(3-bromo-4-hydroxyphenyl)thiazole-2-imino)phenyl)propanoic acid

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. Example 47: Preparation of 3-(4-(4-(3-bromo-4-isopropoxyphenyl)thiazole-2-imino)phenyl)propionic acid

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. Example 48: Preparation of 3-(4-(4-(3-bromo-4-propoxyphenyl)thiazole-2-imino)phenyl)propanoic acid

 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.

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

 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),

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

 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. Example 51: Preparation of 3-(4-(4-(3-bromo-4-n-butoxyphenyl)thiazole-2-imino)phenyl)propanoic acid

 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),

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

 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) ,

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

(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). Example 54: Preparation of 3-(4-(4-(3-chloro-4-methoxyphenyl)thiazole-2-imino)phenyl)propanoic acid

 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. 1 _0. Example 55: 3- (4- (4-(3-chloro-4-hydroxyphenyl)thiazole-2-imino)phenyl) Preparation of propionic acid

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. Example 56: Preparation of 3-(4-(4-(3-chloro-4-isopropoxyphenyl)thiazole-2-imino)phenyl)propionic acid

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);

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

 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

(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. Example 58: Preparation of 3-(4-(4-(3-chloro-4-n-butoxyphenyl)thiazole-2-imino)phenyl)propionic acid

 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),

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

(M+H ⁺ ) 431. 3. Example 60: Preparation of 3-(4-(4-(3-chloro-4-cyclopentyloxyphenyl)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 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. 3 ₀ Example 61: 3- (4- (4- Preparation of 3-chloro-4-isopentyloxyphenyl)thiazole-2-imino)phenyl)propionic 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 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. 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

°2*I ( ₊ H+W) z/ra sw-isa - (Hi 's) es *e ' (HZ ^ ·8=Γ 'Ρ) IZ 'L ' (Hi ^ *8=r ' ) ee 'L

' (HI ⁴ s) L9 *6 ' (HI 's iq) t^ 'Zl '· (^d) g (9P-0SW0 'zHWOOt^) NH _T

 °%s -is :古^ ' ^w

-rn^mn ( -f ^-f 1-^ ) -i Ρ Λ ' [^ ^^

( ₊ 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 NH _T

. %Π·9Ι :古^(f^ Cf3⁄4i3⁄4r-2-

Cf ^-f ^-t^-f -e) -e Ι^ Λ

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);

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

 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),

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

The 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=

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

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. Example 69: Preparation of 3-(4-(4-(4-bromophenyl)thiazole-2-imine)phenyl)propane 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. Example 70: Preparation of 3-(4-(4-(3-chloro-4-isopropoxyphenyl)thiazole-2-imine)phenyl)propan-1-ol

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. Example 71: Preparation of 3-(4-(4-(3-chloro-4-isopentyloxyphenyl)thiazole-2-imine)phenyl)propane-1-ol

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. Example 72: Preparation of 3-(4-(4-(4-isopropylphenyl)thiazole-2-imine)phenyl)propane -1 - leaven

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. Example 73: Preparation of 1-(4-(2-hydroxyethyl)phenyl)thiourea

 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 . Example 74: Preparation of 2-(4-(4-(3-chloro-4-methoxyphenyl)thiazole-2-imine)phenyl)

 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. Example 75: Preparation of 2-(4-(4-(3-bromo-4-methoxyphenyl)thiazole-2-iminamine)phenyl)glycine

 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. Example 76: Evaluation of biological activity

 1. Materials and instruments:

 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 reagent preparation:

 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 fixative: 12% formic acid solution (PBS)

 Staining solution: Preparation of PBS 1. 4 compound containing Ι μ Μ Hoechs t 33342 (Invitrogen, USA):

 Including 4%. The analytical medium of DMS0 was used as a 4 Control control working solution at a final concentration of 1%.

DMS0.

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.

 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.

 Second, the experimental method:

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.

 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 Data Statistics and Analysis:

 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.

Third, the experimental results Test result

The first initial screening was carried out at two final concentrations of Μ and 3 μM. The experimental results are shown in Table 2.

 Table 2: Results of the preliminary screening experiment

 Initial screening

 Compound concentration

 Excitatory intensity soil standard deviation

 ΙΟηΜ 3.12 soil 0.14

 S1P

 250nM 6.76 soil 0.18

 ΙΟΟηΜ -0.06 soil 0.19

 Example 6

 3μΜ 1.19 土 0.19

 ΙΟΟηΜ -0.02 soil 0.16

 Example 7

 3μΜ 0.51 soil 0.17

 ΙΟΟηΜ 0.03 soil 0.16

 Example 8

 3μΜ 0.00 soil 0.19

 ΙΟΟηΜ -0.03 soil 0.15

 Example 9

 3μΜ 0.01 soil 0.14

 ΙΟΟηΜ -0.02 soil 0.16

Example 10

 3μΜ 0.05 soil 0.18

 ΙΟΟηΜ -0.03 soil 0.14

Example 11

 3μΜ -0.08 soil 0.14

 ΙΟΟηΜ 0.08 soil 0.16

Example 12

 3μΜ 1.48 soil 0.17

 ΙΟΟηΜ -0.06 soil 0.16

Example 15

 3μΜ 0.00 soil 0.18

 ΙΟΟηΜ -0.07 soil 0.16

Example 16

 3μΜ 0.03 soil 0.15

 ΙΟΟηΜ -0.09 soil 0.12

Example 17

 3μΜ -0.03 土 0.16

 ΙΟΟηΜ -0.02 soil 0.14

Example 18

 3μΜ 0.00 soil 0.17

 ΙΟΟηΜ -0.04 soil 0.15

Example 19

 3μΜ 0.01 soil 0.17

 ΙΟΟηΜ 0.03 soil 0.16

Example 20

 3μΜ -0.04 soil 0.15

 ΙΟΟηΜ 0.04 soil 0.18

Example 21

3μΜ 1.93 土 0.18 ΙΟΟηΜ 0.02 soil 0.19 Example 22

 3μΜ 0.63 soil 0.14

ΙΟΟηΜ -0.13 soil 0.13 Example 23

 3μΜ 0.01 soil 0.18

ΙΟΟηΜ 0.09 soil 0.20 Example 24

 3μΜ 0.07 soil 0.19

ΙΟΟηΜ 0.00 soil 0.18 Example 25

 3μΜ -0.03 土 0.16

ΙΟΟηΜ -0.07 soil 0.18 Example 45

 3μΜ 0.99 soil 0.17

ΙΟΟηΜ 0.19 soil 0.17 Example 47

 3μΜ 2.80 soil 0.17

ΙΟΟηΜ -0.05 soil 0.17 Example 48

 3μΜ 1.88 soil 0.20

ΙΟΟηΜ -0.13 soil 0.18 Example 49

 3μΜ 0.82 soil 0.20

ΙΟΟηΜ 0.17 soil 0.15 Example 50

 3μΜ 2.82 soil 0.16

ΙΟΟηΜ 0.29 soil 0.17 Example 51

 3μΜ 0.56 soil 0.17

ΙΟΟηΜ 0.36 soil 0.19 Example 52

 3μΜ 0.95 soil 0.18

ΙΟΟηΜ -0.04 soil 0.16 Example 54

 3μΜ -0.02 soil 0.16

ΙΟΟηΜ 0.14 soil 0.16 Example 56

 3μΜ 3.08 soil 0.18

ΙΟΟηΜ 0.18 soil 0.18 Example 57

 3μΜ 0.52 soil 0.18

ΙΟΟηΜ -0.02 soil 0.17 Example 58

 3μΜ 0.03 soil 0.19

ΙΟΟηΜ 0.01 soil 0.17 Example 59

 3μΜ 1.31 土 0.16

ΙΟΟηΜ 0.04 soil 0.18 Example 60

3μΜ 0.05 soil 0.15 Example 61 ΙΟΟηΜ -0.06 Soil 0.17 3μΜ 0.00 soil 0.20

 ΙΟΟηΜ 0.10 soil 0.16

 Example 62

 3μΜ -0.08 soil 0.16

 ΙΟΟηΜ 0.54 soil 0.21

 Example 64

 3μΜ 0.31 soil 0.15

 ΙΟΟηΜ 0.05 soil 0.17

 Example 66

 3μΜ -0.05 soil 0.17

 ΙΟΟηΜ -0.04 soil 0.16

 Example 67

 3μΜ 0.17 soil 0.20

 ΙΟΟηΜ -0.07 soil 0.16

 Example 68

 3μΜ 0.03 soil 0.18

 ΙΟΟηΜ -0.10 soil 0.15

 Example 69

 3μΜ -0.02 soil 0.16

 ΙΟΟηΜ -0.12 soil 0.17

 Example 70

 3μΜ 0.78 soil 0.17

 ΙΟΟηΜ -0.08 soil 0.18

 Example 71

 3μΜ -0.19 soil 0.16

 ΙΟΟηΜ 0.51 soil 0.18

 Example 72

 3μΜ 0.00 soil 0.17

 ΙΟΟηΜ 0.06 soil 0.16

 Example 74

 3μΜ -0.05 soil 0.16

 ΙΟΟηΜ -0.06 soil 0.16

 Example 75

 3μΜ 0.11 soil 0.19

 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 Re-screening experiment results

 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.

 Table 3: Results of the rescreening experiment

 Compound concentration agonistic intensity standard deviation EC50

 ΙΟΟρΜ - 0.04 0.12

 S1P 24.49 ±

300pM - 0.03 0.14

Ϊ́ΐΐ9εΐ Z OAV OT ·0 ι\ ·0-

IT ·0 ί\ ·0-

ΖΖΌ

 Oro 'ς

 U'o SO 'Ζ

 OS

 St ·0 SO ·Ι

 ί

 91 ·0 Α8·0 W Ol

 81 ·0 se ·ο W0£

 LI ·0 π ·0 WOl

 81 ·0 ΖΙ Ί

 ι\ ·0 92*0

 π ·ο Οΐ ·0- et ·ο π ·ο- et ·ο St ·0- W Ol ex ·ο 80 ·0-

ΖΖΌ xe *e

 £1 ·0 30 *e w^e

In^n 'i 60 ·0 00 Ί

 + Z,6*8 ·0 S6'0 w«ooe

 01 ·0 LZ'O

 91 ·0 H ·0

 Xe ·ο

 OT *e w^

 91 ·0

 91 ·0 w«ooe

+ 9L'l

 8ΐ ·0 16*0 ί ¥ ·0 xe ·ο W0£

 St ·0 81 ·0 WOl

 1\ ·0 ΠΊ

 91 ·0 U'O w^

 ·0 e9*o

 Ex ·ο 92*0 w«ooe

 ·0 ST ·0 ί ¥ ι\ ·0 80 ·0

ι\ ·0 SO ·0— ΐΐΐ9εΐ Z OAV 52 ΙΟΟηΜ -0.17 0.12

 300nM -0.16 0.10

 ΙμΜ -0.06 0.12

 3μΜ 0.45 0.13

 ΙΟηΜ 0.38 0.20

 30ηΜ 1.29 0.19

 ΙΟΟηΜ 1.32 0.17

 Example 1.02 ±

 300ηΜ 1.32 0.16

 56 ΙμΜ 3.63 0.20 0.24μΜ

 3μΜ 5.01 0.19

 ΙΟμΜ 5.71 0.19

 3ηΜ -0.08 0.17

 ΙΟηΜ -0.04 0.18

 30ηΜ 0.38 0.20

 Example

 ΙΟΟηΜ 0.83 0.16 ~ 3 μΜ 59 300ηΜ 0.92 0.18

 ΙμΜ 2.15 0.17

 3μΜ 3.04 0.20

 30ηΜ -0.07 0.15

 ΙΟΟηΜ -0.11 0.13

 Example 300ηΜ -0.07 0.12 8.13 soil

 70 ΙμΜ 0.29 0.15 0.26μΜ

 3μΜ 1.30 0.17

 ΙΟμΜ 4.03 0.20

 In the above table, "~" means approx.

 Fourth, the actual conclusion:

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 .

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.

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

Rights request

General formula (I

 among them:

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;

Wherein R ^{2 is} independently selected from the group consisting of -H, -F, -Cl, -Br, -1, -CN, -OH, d- ₄ alkyl,

C2-4 ^3⁄4-> C2-4 ^ and Cl-4 ^^α-3⁄4-)

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;

The A ring and the B ring can be directly connected or connected through G;

 Where A and B rings can be directly connected, J and W are both -N=;

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 -;

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;

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 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 and T are independently selected from

, where Q and Τ are not the same

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;

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 ;

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;

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.

 The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is represented by the following formula I a:

 among them:

J and W are independently selected from -C(R ⁴ ) - and -N -, and constitute a substituted or unsubstituted six-membered aromatic ring;

Wherein R ^{4 is} independently selected from the group consisting of -H, -F, -Cl, -Br, -1, -CN, -0Η, CH alkyl,

. 2 a 4 ^^>3⁄4^, . 2—4^ and

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=;

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 -;

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;

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 and Z are independently selected from -C(R ⁴ )=, -C(=R ⁵ )-, - 0-, -N=, -N(R ⁶ )-, -S - and -Se-

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,. 2-6 blocks, Cl-alkyl, C3-6 ring base. 2-6 women's base Ϊ ^,

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 ;

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 compound according to claim 2 or a pharmaceutically acceptable salt thereof, wherein the compound is represented by the following formula Ib:

 ( l b )

 among them:

The above J and W are independently selected from -C(R ⁴ )- and -N -, and constitute a substituted or unsubstituted six-membered aromatic ring;

Wherein R ^{4 is} independently selected from the group consisting of -H, -F, -Cl, -Br, -1, -CN, -0H, CH alkyl,

. 2 a 4 ^^3⁄4^, . 2-4 ^ and Cl-4 ^^α3⁄4-)

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;

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 -;

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;

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 and Z are independently selected from - C (R ⁵ ) = and one N =;

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

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^,

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 ;

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.

 4. A compound according to any one of claims 1 to 3 or a pharmaceutically acceptable compound thereof

Wherein the compound is selected from the group consisting of

 3-(4-(2-(4-isopropoxyphenyl)-4-thiazolecarboxamide)phenyl)propionic acid,

3-(4-(2-( ⁴ -benzyloxyphenyl) ^-4- thiazolecarboxamide)phenyl)propionic acid,

3-(4-(2-( ⁴ -cyclopentyloxyphenyl) ^-4- thiazolylcarboxamide)phenyl)propionic acid,

3-(4-(2-( ⁴ -isobutoxyphenyl) ^-4- thiazolylcarboxamide)phenyl)propionic acid,

3-(4-(2-( ⁴ -cyclobutoxyphenyl) ^-4- thiazolylcarboxamide)phenyl)propionic acid,

3-(4-(2-(4-Butoxyphenyl)-4 thiazolecarboxamide) phenyl) propionic acid,

3-(4-(2-(4-propoxyphenyl)-4-thiazolylcarboxamide)phenyl)propionic acid,

3-(4-(( ^5- ( ⁴ -isopropoxyphenyl)thiazole- ² )amino)phenyl)propanoic acid,

3-(4-(( ^5- ( ⁴ -isobutoxyphenyl)thiazole- ² )amino)phenyl)propanoic acid,

3-(4-((5-(4-propoxyphenyl)thiazole-2)amino)phenyl)propanoic acid,

3-(4-((5-(4-Butoxyphenyl)thiazole-2)amino)phenyl)propanoic acid,

3-(4-(( ^5- ( ⁴ -cyclopentyloxyphenyl)thiazole- ² )amino)phenyl)propanoic acid,

3-(4-((5-(4-Benzyloxyphenyl)thiazole-2)amino)phenyl)propanoic acid,

3-(4-((5-(4-,4-difluorophenyl)thiazole-2)amino)phenyl)propanoic acid,

3-(4-((5-(4-bromophenyl)thiazole-2)amino)phenyl)propanoic acid,

3-(4-(( ^5- ( ⁴ -methoxyphenyl)thiazole- ² )amino)phenyl)propanoic acid,

3-(4-((5-(4-chlorophenyl)thiazole-2)amino)phenyl)propanoic acid,

3-(4-(( ^5- ( ⁴ -n-hexyloxyphenyl)thiazole- ² )amino)phenyl)propanoic acid,

3-(4-(4-(3-bromo-4-methoxyphenyl)thiazole-2-imino)phenyl)propanoic acid,

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-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-chloro-4-methoxyphenyl)thiazole-2-imino)phenyl)propanoic acid,

 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-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-chloro-4-methoxyphenyl)thiazole-2-imino)phenyl)acetic acid,

 2-(4-(4-(3-chloro-4-cyclopentyloxyphenyl)thiazole-2-imine)phenyl)acetic acid,

 3-(4-(4-(4-cyclobutoxyphenyl)thiazole-2-imine)phenyl)propane-1-ol,

 3-(4-(4-(4-propoxyphenyl)thiazole-2-imine)phenyl)propane-1-ol,

 3-(4-(4-(4-bromophenyl)thiazole-2-imine)phenyl)propane-1-ol,

 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-chloro-4-methoxyphenyl)thiazole-2-imine)phenyl)ethanol, and

 2-(4-(4-(3-Bromo-4-methoxyphenyl)thiazole-2-imine)phenyl)ethanol.

 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. 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. 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.

Wherein I, W as defined in the claims, in the definition of R ² R 3 as claimed in claim.

 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. 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. 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.

 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.