CN108495852B

CN108495852B - 2-amido thiazole derivatives, preparation method and application thereof

Info

Publication number: CN108495852B
Application number: CN201780005306.8A
Authority: CN
Inventors: 蔡家强; 刘钢; 郁楠; 曾宏; 宋宏梅; 卿燕; 宋帅; 邓汉文; 唐祖建; 段小凡; 黄海涛; 王利春; 王晶翼
Original assignee: Sichuan Kelun Biotech Biopharmaceutical Co Ltd
Current assignee: Sichuan Kelun Biotech Biopharmaceutical Co Ltd
Priority date: 2016-09-08
Filing date: 2017-08-31
Publication date: 2021-06-15
Anticipated expiration: 2037-08-31
Also published as: CN108495852A; WO2018045906A1

Abstract

The invention provides a 2-amido thiazole derivative, or pharmaceutically acceptable salt, ester, solvate, hydrate, isomer, or any crystal form or racemic matter thereof, or metabolite form thereof, or a mixture thereof, which is used for the treatment in the medical field, in particular for promoting thrombopoiesis and megakaryocytopoiesis, thereby treating or preventing diseases mediated by thrombopoietin.

Description

2-amido thiazole derivatives, preparation method and application thereof

Technical Field

The present invention relates to 2-acylaminothiazole derivatives, and more particularly, to 2-acylaminothiazole derivatives useful as thrombopoietin receptor agonists. The invention also relates to a preparation method of the 2-amido thiazole derivative, a pharmaceutical composition and application thereof in treating diseases mediated by thrombopoietin.

Background

The Thrombopoietin (TPO) receptor is one of the members of the thrombopoietin growth factor receptor family. This family of receptors is characterized by a common extracellular structure, including the N-terminal portion of similar C residues and the WSXWS characteristics near the transmembrane region. Expression of the TPO receptor is restricted to spleen, bone marrow, fetal liver in mice and megakaryocytes, platelets, CD34+ cells in humans. These evidences suggest that the TPO receptor plays a role in the hematopoietic process.

Platelets are important in physiological hemostasis and pathological thrombosis. It is produced continuously by megakaryocytes in the body of an organism. Megakaryocytes are cells that are polyploid in nature produced by nuclear replication of bone marrow cells through endomitosis without cell division. When the number of platelets decreases, the endomitotic rate increases, forming more polyploid megakaryocytes, which may increase in number by a factor of 3. Conversely, when platelet counts are increased, the rate of endomitosis decreases, the formation of polyploid megakaryocytes decreases, and the number of megakaryocytes may decrease by 50%. Although the exact mechanism by which circulating platelets regulate the endomitotic rate and the number of megakaryocytes in the bone marrow is not clear, thrombopoietin is currently considered to be a hematopoietic factor involved in mediating this feedback mechanism. TPO has been shown to play a major humoral regulatory role in the context of thrombocytopenia. Some studies have shown that TPO increases platelet count and increases platelet volume. More specifically, TPO affects megakaryocytes in several ways: (1) it can increase the size and number of megakaryocytes; (2) it can increase the DNA content in the form of polyploid megakaryocyte; (3) increasing the endomitosis of megakaryocytes; (4) it can increase megakaryocyte maturation; (5) it produces a percentage of acetylcholinesterase-positive precursor cells in the bone marrow.

Since platelets are essential for blood clotting, patients may be at risk of catastrophic bleeding when their numbers are very low. TPO also has potential applications in the diagnosis and treatment of various hematological disorders, such as those caused primarily by platelet defects. To this end, researchers have developed and synthesized a series of compounds targeting thrombopoietin receptor, and have desired to prevent or treat diseases or disorders caused by platelet deficiency or depletion by promoting platelet production.

For example, WO 2005/014561, WO 2009/017098 and WO 2007/004038 disclose the use of analogous 2-aminothiazole derivatives for the treatment of thrombocytopenia. Although all of the above compounds exhibit some pharmacological activity against thrombocytopenia to varying degrees, their activity has not been sufficiently satisfactory. Moreover, some of the drugs currently approved for marketing also exhibit a degree of side effects that prevent their widespread clinical use. For example, Eltrombopag (eltrombopag) and Lusutrombopag (lusutrombopag), which are recently approved as TPO receptor small molecule agonist drugs for oral administration, play a role in the treatment of targeted severe aplastic anemia and chronic idiopathic Immune Thrombocytopenia (ITP) via TPO receptors (Ali et al; Blood diagnosis & Fibrinolysis, 27(1), 4-52, (2016)). However, despite its good tolerance in humans, eltrombopag has severe hepatotoxic side effects, which greatly limits its clinical use. Therefore, there is an urgent need and great significance in clinical practice to find a more potent TPO receptor agonist with fewer side effects.

Disclosure of Invention

The present inventors have intensively studied to obtain a novel 2-acylaminothiazole derivative, in which the 5-carbon of the novel 2-acylaminothiazole derivative is substituted with a cyclic nitrogen-containing group. As a result, the compound of the present invention has very excellent TPO receptor agonistic activity, and simultaneously shows excellent metabolic stability of liver microsomal P450 oxidase.

Specifically, the present invention includes the following inventions:

1) a compound represented by formula I, or a pharmaceutically acceptable salt, ester, solvate, hydrate, isomer, or any crystal form or racemate thereof, or a metabolite form thereof, or a mixture thereof;

wherein the content of the first and second substances,

m is an integer of 0 to 4,

n is an integer of 1 to 4;

part represents a single bond or a double bond;

R₅，R₆each independently selected from H, substituted or unsubstituted C1-C12 alkyl, substituted or unsubstituted C3-C12 cycloalkyl, substituted or unsubstituted C6-C10 aryl, each R₅、R₆May be the same or different; or

R₅And R₆May form, together with the carbon atom to which they are attached together, a substituted or unsubstituted 3-8 membered saturated carbocyclic ring, or contain at least one group selected from R₇N, O, S, a substituted or unsubstituted 4-to 10-membered saturated heterocyclic ring of the heteroatom;

R₁selected from H, substituted or unsubstituted C1-C12 alkyl, substituted or unsubstituted C2-C12 alkenyl, substituted or unsubstituted C3-C12 cycloalkyl, substituted or unsubstituted C4-C12 cycloalkenyl, substituted or unsubstituted C5-C12 polycycloalkyl, substituted or unsubstituted C6-C12 polycycloalkenyl, substituted or unsubstituted C4-C12 cycloalkylene, substituted or unsubstituted C6-C12 cycloalkenylene, containing at least one substituent selected from R, C, B, C₇N, O, S, a substituted or unsubstituted 4-10 membered saturated heterocyclic group containing 1-4 heteroatoms selected from N, O, S, a substituted or unsubstituted C6-C10 aryl group, a substituted or unsubstituted 5-or 6-or 8-10-membered heteroaryl group containing 1-4 heteroatoms which are the same or different;

R₂selected from the group consisting of₁₁Substituted C6-C10 aryl, optionally substituted with R₁₁Substituted 5-or 6-membered heteroaryl containing 1-3 heteroatoms, which may be the same or different, selected from N, O, S, optionally substituted by R₁₁Substituted 8-to 10-membered heteroaryl containing 1-4 heteroatoms, which may be the same or different, selected from N, O, S,

R₁₁selected from H, substituted or unsubstituted C1-C12 alkyl, substituted or unsubstituted C2-C12 alkoxyalkyl, halogen, cyano, nitro, substituted or unsubstituted C1-C12 alkoxy, substituted or unsubstituted C3-C12 cycloalkyl, carboxylic acid group-substituted C2-C6 alkenyl, ester group-substituted C2-C12 alkenyl, R₇R₈N-, (C1-C12 alkyl) C (═ O) N (R)₇)-，R₇R₈NC(＝O)-，R₇S(＝O)-，R₇S(＝O)₂-，R₇R₈NS(＝O)₂-；

Wherein R is₇、R₈Each independently selected from H, C1-C12 alkyl and C3-C12 cycloalkyl,

R₃represents an aryl or heteroaryl group selected from those represented by formula II, or a heteroaryl group selected from those represented by formula III:

wherein J, L, G, E, Y are each independently selected from N, O, S, CH or C,

in the formula R₂₀，R₂₁，R₂₂Each independently selected from H, halogen, OH, cyano, nitro, carboxylic acid group, ester group, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C2-C4 alkenyl, substituted or unsubstituted C1-C4 alkoxy, R₇R₈N-, a substituted or unsubstituted 4-to 8-membered saturated heterocyclic group containing at least one heteroatom selected from N, O, S, S (O) r, r represents 1 or 2.

2) The compound of the above 1), or a pharmaceutically acceptable salt, ester, solvate, hydrate, isomer, or any crystal form or racemate thereof, or a metabolite form thereof, or a mixture thereof, wherein m is 1 or 2; n is 1 or 2.

3) The compound of the above 1) or 2), or a pharmaceutically acceptable salt, ester, solvate, hydrate, isomer, or any crystal form or racemate thereof, or a metabolite form thereof, or a mixture thereof,

is a double bond.

4) The compound of 1) to 3), or a pharmaceutically acceptable salt, ester, solvate, hydrate, isomer, or any crystal form or racemate thereof, or a metabolite form thereof, or a mixture thereof,

wherein R is₅，R₆Each independently selected from H, CH₃，CHpFq, p and q are integers of 1 or more and p + q is 3.

5) The compound of 1) to 4) above, or a pharmaceutically acceptable salt, ester, solvate, hydrate, isomer, or any crystal form or racemate thereof, or a metabolite form thereof, or a mixture thereof,

wherein R is₁Selected from substituted or unsubstituted C3-C10 alkyl, substituted or unsubstituted C3-C10 alkenyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C4-C10 cycloalkenyl, substituted or unsubstituted C5-C12 polycycloalkyl, substituted or unsubstituted C6-C12 polycycloalkenyl, substituted or unsubstituted C4-C12 cycloalkylene, substituted or unsubstituted C6-C12 cycloalkenylene, containing at least one substituent selected from R₇N, O, S, a substituted or unsubstituted 4-8 membered saturated heterocyclic group containing 1-4 heteroatoms selected from N, O, S, a substituted or unsubstituted C6-C10 aryl group, a substituted or unsubstituted 5-or 6-or 8-10-membered heteroaryl group containing 1-4 heteroatoms selected from the group consisting of the same or different heteroatoms.

6) The compound of 1) to 5) above, or a pharmaceutically acceptable salt, ester, solvate, hydrate, isomer, or any crystal form or racemate thereof, or a metabolite form thereof, or a mixture thereof,

wherein R is₂Selected from the group consisting of₁₁Substituted C6-C10 aryl, optionally substituted with R₁₁Substituted 5-or 6-membered heteroaryl containing 1 to 3 identical or different heteroatoms from N, O, S, optionally substituted by R₁₁An 8-to 10-membered heteroaryl group that is substituted and contains 1-4 heteroatoms, which may be the same or different, selected from N, O, S;

R₁₁selected from H, halogen, cyano, nitro, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 alkoxy, substituted or unsubstituted C3-C12 cycloalkyl, and substituted or unsubstituted C2-C12 alkoxyalkyl.

7) The compound of any one of the above 1) to 6), or a pharmaceutically acceptable salt, ester, solvate, hydrate, isomer, or any crystal form or racemate thereof, or a metabolite form thereof, or a mixture thereof,

R₃selected from formula IV, formula V or formula VI

Wherein R is₂₀，R₂₁，R₂₂Each independently selected from H, halogen, OH, cyano, nitro, carboxylic acid group, ester group, C₃-C₆Cycloalkyl, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C2-C4 alkenyl, substituted or unsubstituted C1-C4 alkoxy, R₇R₈N, a substituted or unsubstituted 4-8 membered saturated heterocyclic group containing at least one heteroatom selected from N, O, S, S (O) r, r represents 1 or 2.

8) The compound of any one of the above 1) to 7), or a pharmaceutically acceptable salt, ester, solvate, hydrate, isomer, or any crystal form or racemate thereof, or a metabolite form thereof, or a mixture thereof, wherein the sum of m and n is 3.

9) The compound of any one of the above 1) to 8), or a pharmaceutically acceptable salt, ester, solvate, hydrate, isomer, or any crystal form or racemate thereof, or a metabolite form thereof, or a mixture thereof, wherein R is₅，R₆Is H.

10) The compound of any one of the above 1) to 9), or a pharmaceutically acceptable salt, ester, solvate, hydrate, isomer, or any crystal form or racemate thereof, or a metabolite form thereof, or a mixture thereof, wherein,

R₁represents C1-C10 alkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C5-C12 polycycloalkyl, substituted or unsubstituted C4-C12 cycloalkylalkyl, substituted or unsubstituted C6-C10 aryl.

11) The compound of any one of the above 1) to 10), or a pharmaceutically acceptable salt, ester, solvate, hydrate, isomer, or any crystal form or racemate thereof, or a metabolite form thereof, or a mixture thereof, wherein,

R₁selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 2,2, 2-trifluoroethyl,

12) the compound of any one of the above 1) to 11), or a pharmaceutically acceptable salt, ester, solvate, hydrate, isomer, or any crystal form or racemate thereof, or a metabolite form thereof, or a mixture thereof, wherein,

R₁is cyclohexyl.

13) The compound of 1) -12) above, or a pharmaceutically acceptable salt, ester, solvate, hydrate, isomer, or any crystal form or racemate thereof, or a metabolite form thereof, or a mixture thereof,

R₂₀，R₂₁，R₂₂each independently selected from C1-C4 alkyl substituted with one or more halogens, C1-C4 alkoxy substituted with one or more halogens.

14) The compound of the above 1) -13) of the present invention, or a pharmaceutically acceptable salt, ester, solvate, hydrate, isomer, or any crystal form or racemate thereof, or a metabolite form thereof, or a mixture thereof,

R₁₁each independently selected from C1-C4 alkyl substituted by one or more halogens, C1-C4 alkoxy substituted by one or more halogens, C2-C12 alkoxyalkyl substituted by one or more halogens, and C2-C12 alkoxyalkyl substituted by C3-C12 cycloalkyl.

15) The compound of the above 1) -13) of the present invention, or a pharmaceutically acceptable salt, ester, solvate, hydrate, isomer, or any crystal form or racemate thereof, or a metabolite form thereof, or a mixture thereof,

R₂selected from the group consisting of₁₁Substituted phenyl, naphthyl; optionally substituted by R₁₁Substituted furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, indolyl, quinolinyl, purinyl,

R₁₁each independently selected from H, Cl, F, CH₃，CF₃。

16) The compound of 1) to 15) above, or a pharmaceutically acceptable salt, ester, solvate, hydrate, isomer, or any crystal form or racemate thereof, or a metabolite form thereof, or a mixture thereof,

R₂is selected from

17) The compound of the above 1) -16), or a pharmaceutically acceptable salt, ester, solvate, hydrate, isomer, or any crystal form or racemate thereof, or a metabolite form thereof, or a mixture thereof,

R₂is selected from

18) The compound of any one of the above 1) to 17), or a pharmaceutically acceptable salt, ester, solvate, hydrate, isomer, or any crystal form or racemate thereof, or a metabolite form thereof, or a mixture thereof,

R₃is selected from

In the formula R₂₀，R₂₁Each independently selected from CH₃-，CH₃CH₂-，CF₃Cl, Br, F, cyclopropyl; r₂₂Selected from carboxyl, ester, OH, NH₂Halogen, C1-C10 alkyl substituted by carboxyl or ester group, C2-C10 alkenyl substituted by carboxyl or ester group, C1-C10 alkoxy substituted by carboxyl or ester group, C1-C10 alkylamino substituted by carboxyl or ester group, C1-C10 alkylthio substituted by carboxyl or ester group, and C4-C10 heterocyclic group substituted by carboxyl or ester group.

19) The compound of any one of the above 1) to 18), or a pharmaceutically acceptable salt, ester, solvate, hydrate, isomer, or any crystal form or racemate thereof, or a metabolite form thereof, or a mixture thereof, wherein,

r3 is selected from

20) The compound of any one of the above 1) to 19), or a pharmaceutically acceptable salt, ester, solvate, hydrate, isomer, or any crystal form or racemate thereof, or a metabolite form thereof, or a mixture thereof, wherein the compound is shown as follows:

or

21) A pharmaceutical composition comprising a compound, ester, solvate, hydrate, isomer, or any crystalline form or racemate thereof, or a metabolite form thereof, or a mixture thereof, of any one of 1) to 20) above.

22) A compound according to any one of 1) to 20) above, or a pharmaceutically acceptable salt, ester, solvate, hydrate, isomer, or any crystal form or racemate thereof, or a metabolite form thereof, or mixtures thereof, alone or in combination with other active compounds, including other TPO receptor agonists; the use includes use for the preparation of a pharmaceutical combination.

23) Use of a compound according to any one of the above 1) to 20), or a pharmaceutically acceptable salt, ester, solvate, hydrate, isomer, or any crystal form or racemate thereof, or a metabolite form thereof, or a mixture thereof, for the manufacture of a medicament for the prevention or treatment of a thrombopoietin-mediated disease.

24) The use of the pharmaceutical composition of the present invention described in the above 21) -22) for the preparation of a medicament for preventing or treating a thrombopoietin-mediated disease.

25) A method for preparing the compound of any one of 1) to 20) above, comprising the steps of:

step 1: reacting compound VI with thiourea in the presence of a halogenating agent to obtain compound VII;

step 2: halogenating the obtained compound VII by using a halogenating reagent to obtain a compound VIII;

and step 3: reacting said compound VIII with compound Y to give compound IX;

and 4, step 4: using R₃-COOH with compound IX to give a compound of the formula I,

wherein Y is a compound represented by the formula:

R₁、R₂、R₃、R₅and R₆M and n are as defined above for R in 1) to 19)₁、R₂、R₃、R₅、R₆M and n are as defined, X is halogen and M is a boronic acid group or a boronic ester group.

26) A method for preparing the compound of any one of 1) to 20) above, further comprising the steps of:

and step 3: reacting said compound VIII with compound Y 'to give compound IX';

and 4, step 4: subjecting the compound IX' to condensation and/or substitution reaction to obtain a compound shown as a formula X;

and 5: subjecting the compound X to deprotection and reductive amination reaction to obtain a compound shown as a formula XI;

step 6: carrying out hydrolysis reaction on the compound XI to obtain a compound shown as a formula I;

wherein Y' is a compound represented by the formula:

R₁、R₂、R₃、R₅and R₆M and n are as defined above for R in 1) to 19)₁、R₂、R₃、R₅、R₆M and n are as defined, R₁' is an amino protecting group or hydrogen, R₃' is a substituted or unsubstituted C6-C10 aryl, a substituted or unsubstituted 5-or 6-or 8-to 10-membered heteroaryl group containing 1 to 4 identical or different heteroatoms selected from N, O, S, X is halogen, and M is a boronic acid group or a boronic ester group.

Effects of the invention

The present invention provides a novel 2-acylaminothiazole compound, which can be used for the therapeutic use in the medical field, particularly for promoting thrombopoiesis and megakaryocytopoiesis, thereby treating or preventing diseases. The 2-acylaminothiazole compound of the invention has excellent thrombopoietic effect and excellent metabolic stability to liver microsome P450 oxidase.

Detailed Description

The meaning of each term used in the present specification is explained below. Each term is used in a generic sense and is used in the same sense when used alone or in combination with other terms.

In the present invention, the expression "Ca-Cb group" (a and b are integers of 1 or more, a < b) means that the "group" has a to b carbon atoms, for example, C1-C4 alkyl group which means an alkyl group having 1 to 4 carbon atoms, C1-C4 alkoxy group which means an alkoxy group having 1 to 4 carbon atoms, C3-C10 cycloalkyl group which means a cycloalkyl group having 3 to 10 carbon atoms, C1-C4 alkoxy C1-C4 alkyl group which means a group in which an alkoxy group having 1 to 4 carbon atoms and an alkyl group having 1 to 4 carbon atoms are bonded.

In the present invention, "halogen" represents a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.

The "C1-C12 alkyl group" refers to a linear or branched alkyl group having 1 to 12 carbon atoms, and examples thereof include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, n-heptyl, n-octyl, n-nonyl and n-decyl groups. The alkyl group is preferably an alkyl group having 3 to 10 carbon atoms (i.e., C3-C10 alkyl group) or an alkyl group having 1 to 6 carbon atoms (i.e., C1-C6 alkyl group), more preferably an alkyl group having 1 to 4 carbon atoms (i.e., C1-C4 alkyl group), and examples thereof include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl and isohexyl groups.

"C1-C12 alkoxy" refers to alkoxy groups wherein the alkyl moiety is as described above. Examples of the alkoxy group include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentyloxy, neopentyloxy, and hexyloxy. C1-C6 alkoxy, i.e. alkoxy having 1 to 6 carbon atoms in the alkyl moiety, is preferred. More preferably C1-C4 alkoxy, i.e. alkoxy having 1-4 carbon atoms in the alkyl moiety.

"alkoxyalkyl" refers to a group formed by inserting an oxygen atom into the non-terminal carbon chain of an alkyl group; the C1-C12 alkoxyalkyl group is a group in which an oxygen atom is inserted into the non-terminal end of an alkyl group having 1 to 12 carbon atoms. Among them, preferred is a C2-C12 alkoxyalkyl group. Examples of C1-C12 alkoxyalkyl are CH₃OCH₂-、CH₃(CH₂)₃OCH₂-、CH₃OCH(CH₃) -and the like.

The "C2-C12 alkenyl group" refers to a linear or branched alkenyl group having 2 to 12 carbon atoms and having 1 or more double bonds in the alkyl group, and examples thereof include vinyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1, 3-butadienyl, 3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl, 1-hexenyl, and 2-hexenyl. The "C2-C6 alkenyl group" refers to a linear or branched alkenyl group having 2 to 6 carbon atoms and having 1 or more double bonds in the alkyl group, and examples thereof include a vinyl group, a 1-propenyl group, a 2-propenyl group, a 1-butenyl group, a 1-pentenyl group, a 2-pentenyl group, a 1-hexenyl group, and a 2-hexenyl group. Among them, preferred is a C3-C10 alkenyl group, and more preferred is a C2-C4 alkenyl group.

The "C3-C12 cycloalkyl group" refers to a cyclic saturated alkyl group having 3 to 12 carbon atoms, and examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. Preferred examples include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. The "C3-C10 cycloalkyl group" refers to a cyclic saturated alkyl group having 3 to 10 carbon atoms.

"C4-C12 cycloalkenyl" refers to a C4-12 cyclic alkenyl group having at least one double bond in the ring of a C4-12 cycloalkyl group, and examples thereof include cyclopentenyl and cyclohexenyl. Preferably, C4-C10 cycloalkenyl.

"C5-C12 polycycloalkyl" refers to a cycloalkyl group having 5 to 12 total carbon atoms, wherein two carbon atoms which are not adjacent to each other in the cycloalkyl group are connected to each other by a bridge, and examples thereof include adamantyl, norbornyl and cubic alkyl; or a cycloalkyl group having 5 to 12 carbon atoms in total in which two cycloalkyl groups are bonded through a common carbon atom, and examples thereof include a spiropentyl group and a spiro [3.5] nonanyl group.

"C6-C12 polycycloalkenyl" refers to a group having at least one double bond in a polycycloalkyl group having 6 to 12 carbon atoms in total, and examples thereof include norbornenyl and indenyl.

"C4-C12 cycloalkylene" refers to a group having 4 to 12 carbon atoms in total in which two or more of the above-mentioned cycloalkanes are fused together with two adjacent carbon atoms in common, and examples thereof include a decalinyl group.

"C6-C12 cycloalkenylene" refers to a C6-12 cycloalkylene group having at least one double bond, and examples thereof include a hexahydronaphthalene group and the like.

"aryl" refers to monocyclic aromatic hydrocarbon groups (e.g., phenyl) and polycyclic aromatic hydrocarbon groups (e.g., 1-naphthyl, 2-naphthyl, 1-anthryl, 2-anthryl, 9-anthryl, 1-phenanthryl, 2-phenanthryl, 3-phenanthryl, 4-phenanthryl, 9-phenanthryl, etc.). Preferred are phenyl or naphthyl (1-naphthyl, 2-naphthyl).

"C6-C10 aryl" refers to monocyclic aryl (e.g., phenyl) and polycyclic aromatic hydrocarbon (e.g., 1-naphthyl, 2-naphthyl) groups having 6 to 10 carbon atoms. Preferred are phenyl or naphthyl (1-naphthyl, 2-naphthyl).

The "3-to 8-membered saturated carbocyclic ring" means a cyclic saturated cycloalkane having 3 to 8 carbon atoms, and examples thereof include cyclopropane, cyclobutane, cyclopentane, cyclohexane and cycloheptane. Preferred are cyclopropane, cyclobutane, cyclopentane and cyclohexane. "3-to 8-membered saturated carbocyclic group" means a monovalent group derived from "3-to 8-membered saturated carbocyclic ring", and examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. Preferred examples include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

The "4-to 10-membered saturated heterocyclic ring" refers to a saturated heterocyclic ring having 4 to 10 ring-constituting atoms and containing at least one heteroatom selected from N, O, S in the ring, and examples thereof include ethylene oxide, oxetane, azetidine, thietane, tetrahydrofuran, pyrrolidine, imidazolidine, and dioxane. Among them, the N atom as a ring-forming atom may have a substituent. The "4-to 10-membered saturated heterocyclic group" is a monovalent group derived from the "4-to 10-membered saturated heterocyclic ring", and examples thereof include an oxiranyl group, an oxetanyl group, an azetidinyl group, a thietanyl group, a tetrahydrofuranyl group, a pyrrolidinyl group, an imidazolidinyl group, a dioxanyl group and the like. Wherein, it may be "4-to 8-membered saturated heterocyclic group" or "4-to 8-membered saturated heterocyclic group" means a monovalent group derived from "4-to 8-membered saturated heterocyclic group".

The "3-to 8-membered saturated heterocyclic group" refers to a heterocyclic group having 3 to 8 ring atoms which may contain at least one heteroatom selected from N, O, S in the ring, and examples thereof include an oxiranyl group, an oxetanyl group, an azetidinyl group, a thietanyl group, a tetrahydrofuryl group, a pyrrolidinyl group, an imidazolidinyl group, a dioxanyl group, a piperidyl group, a tetrahydropyranyl group and a morpholinyl group. Among them, the N atom as a ring-forming atom may have a substituent.

The "5-or 6-membered heteroaryl group" refers to a 5-or 6-membered aromatic cyclic group having 1 to 4 identical or different heteroatoms selected from N, O, S in the ring, and examples thereof include pyrrolyl, pyrazinyl, pyrazolyl, indolyl, tetrazolyl, furyl, thienyl, pyridyl, imidazolyl, triazolyl, tetrazolyl, triazinyl, pyridazinyl, pyrimidinyl, pyrazinyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, oxadiazolyl, and the like.

The "8-10 membered heteroaryl group" refers to an 8-10 membered aromatic cyclic group having 1 to 4 identical or different heteroatoms selected from N, O, S in the ring, and examples thereof include isoindolyl, indazolyl, indolizinyl, isoindolinyl, quinolyl, isoquinolyl, cinnolinyl, 2, 3-naphthyridinyl, quinazolinyl, naphthyridinyl, quinoxalinyl, purinyl, pteridinyl, benzimidazolyl, benzisoxazolyl, benzoxazolyl, benzooxadiazolyl, benzisothiazolyl, benzothiazolyl, benzothiadiazolyl, benzofuranyl, isobenzofuranyl, benzothiophenyl, benzotriazolyl, imidazopyridinyl, triazolopyridinyl, imidazopyridinyl, imidazothiazolyl, pyrazinopyridazinyl, benzimidazolinyl and the like.

"acyl" includes groups represented by R — C (═ O) - (, for example, R is "hydrogen", "C1-C12 alkyl", "C2-C12 alkenyl", "C3-C12 cycloalkyl", "C3-C12 cycloalkenyl", "C6-C10 aryl", or "5-or 6-or 8-10-membered heteroaryl").

"amino protecting group" refers to a chemical group that is bonded to an amino group to protect the amino group and that is easily removed under certain conditions, and includes, but is not limited to, alkoxycarbonyl, acyl, alkyl; for example, t-butoxycarbonyl, benzyloxycarbonyl, fluorenylmethyloxycarbonyl, allyloxycarbonyl, phthaloyl, benzyl, p-methoxybenzyl, trityl and the like. Those skilled in the art can refer to the textbook Greene's Protective Groups in Organic Synthesis (4)^thedition) to make appropriate selections and operations.

As the above-mentioned "C1-C12 alkyl", "C1-C4 alkyl", "C3-C12 cycloalkyl", "aryl", "3-8 membered saturated carbocyclic ring", "4-10 membered saturated heterocyclic group", "3-8 membered saturated heterocyclic group", "4-8 membered saturated heterocyclic group", "C2-C12 alkenyl", "C2-C4 alkenyl", "C4-C12 cycloalkenyl", "C5-C12 polycycloalkyl", "C7-C12 polycycloalkenyl", "C4-C12 cycloalkylene", "C6-C12 cycloalkenyl", "C6-C10 aryl", "5-or 6-membered heteroaryl", "8-10 membered heteroaryl", "C1-C12 alkoxy", "C2-C12 alkoxyalkyl"), The substituents of "C1-C4 alkoxy", "C2-C6 alkenyl", and substituents in the description and claims as "substituted or unsubstituted", may be one or more groups independently selected from:

H. cyano, hydroxy, carboxyl, halogen (F, Cl, Br, I), C1-C6 alkyl, halo-C1-C12 alkoxy (e.g. CF)₃O), C3-C12 cycloalkyl (e.g., cyclopropyl), C4-C12 cycloalkenyl (e.g., cyclobutenyl), C1-C12 alkoxy (e.g., methoxy, ethoxy, propoxy, butoxy, etc.), C2-C12 alkenyloxy (e.g., vinyloxy, allyloxy, etc.), C1-C12 alkoxycarbonyl(e.g., methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, etc.), nitro, nitroso, amino, aminocarbonylamino, alkylaminocarbonylamino, aminocarbonyl C1-C6 alkyl, C1-C6 alkylaminocarbonyl C1-C6 alkyl, aminocarbonyloxy, amino C1-C6 alkoxycarbonyl, C1-C6 alkoxycarbonylamino, C1-C6 alkoxy C1-C6 alkylamino, C2-C6 alkenyl, C2-C6 alkynyl, C1-C12 alkylamino (e.g., methylamino, ethylamino, dimethylamino, etc.), acylamino (e.g., acetylamino, benzoylamino, etc.), C6-C10 arylalkylamino (e.g., benzylamino, tritylamino), hydroxyamino, C1-C12 alkylsulfonylamino (e.g., methylsulfonylamino), C1-C12 alkylsulfinylamino (e.g., methylsulfinylamino), Imino, hydroxyimino, C1-C12 alkylimino (e.g., methylimino, ethylimino, dimethylimino, etc.), C1-C12 alkoxyimino (e.g., methoxyimino, ethoxyimino, etc.), acylimino (e.g., acetylimino, benzoylimino, etc.), azido, C6-C10 aryl (e.g., phenyl, etc.), C6-C10 aryl C1-C12 alkyl (e.g., benzyl, phenylethyl, etc.), C6-C10 arylalkoxy (e.g., benzyloxy), alkylcarbonyloxy, non-aromatic heterocyclic (e.g., pyrrolinyl, piperidyl, piperazinylpyrrolidino, pyrrolidinyl, morpholinyl, morpholino, etc.), heteroaryl (e.g., furyl, thienyl, pyridyl, isoxazolyl, thiazolyl, thiadiazolyl, oxazolyl, oxadiazolyl, tetrazolyl, isoxazolyl, thiazolyl, thiadiazolyl, oxazolyl, etc.), oxadiazole, and the like, Indolyl, benzofuranyl, etc.), heteroarylalkyl (pyridylmethyl, pyridylethyl, etc.), cyano, isocyano, isocyanato, thiocyanato, isothiocyanato, mercapto, alkylthio (e.g., methylthio, etc.), alkylsulfonyl (e.g., methylsulfonyl, ethylsulfonyl), alkylsulfinyl, aminocarbonyl, alkylaminocarbonyl, (e.g., methylaminocarbonyl, ethylaminocarbonyl, dimethylaminocarbonyl, etc.), sulfamoyl, alkylsulfamoyl, acyl (e.g., formyl, acetyl, etc.), formyloxy, thiocarbonyl, thiocarboxyl, dithiocarboxyl, thiocarbamoyl, sulfinyl, sulfo, hydrazino, azido, ureido, amidino, guanidino, phthaloyl, etc.), and the likeImino, trialkylsilyl (trimethylsilyl and the like) and oxo;

as the above-mentioned substituent, further preferred are:

halogen, cyano, nitro, carboxyl, hydroxyl, amino, aminocarbonyl, C1-C6 alkyl, C3-C10 cycloalkyl, C1-C6 alkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkylthio, C1-C6 alkylsulfinyl, C1-C6 alkylsulfonyl, C1-C6 alkylaminosulfonyl, C6-C6 alkylsulfonamido, C6-C6 alkylamino, C6-C6 alkylcarbonyloxy, C6-C6 alkylaminocarbonyl, aminocarbonylamino, C6-C6 alkylaminocarbonylamino, aminocarbonyl C6-C6 alkyl, C6-C6 alkylaminocarbonyl C6 alkyl, aminocarbonyloxy, amino C6-C6 alkoxycarbonyl, C6-C6 alkoxycarbonylamino, C6-C6 alkoxyalkenylC 6-6 alkyl, 6-C6 alkyl, C2-C6 alkynyl, C6-C20 aryl, C5-C20 heterocyclyl (including aliphatic heterocyclyl and heteroaryl);

wherein the C1-C6 alkyl, C3-C12 cycloalkyl, C1-C6 alkoxy, C1-C6 alkoxycarbonyl, C6-C6 alkylthio, C6-C6 alkylsulfinyl, C6-C6 alkylsulfonyl, C6-C6 alkylaminosulfonyl, C6-C6 alkylsulfonamide, C6-C6 alkylamino, C6-C6 alkylcarbonyloxy, C6-C6 alkylaminocarbonyl, aminocarbonylamino, C6-C6 alkylaminocarbonylamino, aminocarbonyl C6-C6 alkyl, C6-C6 alkylaminocarbonyl C6-C6 alkyl, aminocarbonyloxy, amino C6-C6 alkoxycarbonyl, C6-C6 alkoxycarbonylamino, C6-C6 alkoxy C6-C6 alkylamino, C6 alkenyl, C6-C6 alkynyl, C6 alkynyl 6 aryl 6-C6 alkynyl, The C3-C20 heterocyclyl (including aliphatic heterocyclyl and heteroaryl) groups may be optionally substituted with one or more of the same or different groups selected from: carboxyl, ester group, cyano, C1-C6 alkyl, halogen, C1-C6 haloalkyl, phosphoric acid group, phosphate group; preferably a carboxyl group, an ester group, a phosphoric acid group or a phosphate group;

the above-mentioned substituent is particularly preferably halogen, methyl, ethyl, propyl, butyl, halomethyl, haloethyl, halopropyl, halobutyl, carboxyl, cyano, nitro or hydroxyl.

The compound of the invention has a structure shown in the following formula I;

wherein m is an integer of 0 to 4. n is an integer of 1 to 4.

The compound of formula I of the present invention preferably has m of 1 or 2.

The compound of formula I of the present invention, preferably, n is 1 or 2.

More preferably, the sum of m and n is 3.

The compounds of the above formula I of the present invention,

and a moiety represents a single bond or a double bond. It is preferable that the first and second liquid crystal layers are formed of,

the moiety represents a double bond.

R₅，R₆Each independently selected from H, substituted or unsubstituted C1-C12 alkyl, substituted or unsubstituted C3-C12 cycloalkyl, substituted or unsubstituted C6-C10 aryl, each R₅、R₆May be the same or different.

Or, R₅And R₆May form, together with the carbon atom to which they are attached together, a substituted or unsubstituted 3-8 membered saturated carbocyclic ring, or contain at least one group selected from R₇N, O, S, or a substituted or unsubstituted 4-to 10-membered saturated heterocyclic ring.

Preferably, R is₅，R₆Each independently selected from H, substituted or unsubstituted C1-C12 alkyl, substituted or unsubstituted C3-C12 cycloalkyl.

Preferably, R is₅，R₆Each independently selected from H; methyl, ethyl, propyl, butyl, pentyl, hexyl, optionally substituted by halogen; cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, optionally substituted by halogen.

Preferably, R is₅And R₆Together with the carbon atom to which they are jointly attached formCyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, optionally substituted by halogen.

Preferably, R is₅And R₆Together with the carbon atom to which they are attached form an oxetanyl, azetidinyl, thietanyl, oxolanyl, aziridinyl, thietanyl, oxocyclohexyl, azacyclohexyl, thiacyclohexyl, optionally substituted with halogen.

More preferably, R₅，R₆Each independently selected from H, CH₃CHpFq, p and q are integers of 1 or more and p + q is 3.

It is particularly preferred that R₅And R₆And is also hydrogen.

R₁Selected from H, substituted or unsubstituted C1-C12 alkyl, substituted or unsubstituted C2-C12 alkenyl, substituted or unsubstituted C3-C12 cycloalkyl, substituted or unsubstituted C4-C12 cycloalkenyl, substituted or unsubstituted C5-C12 polycycloalkyl, substituted or unsubstituted C6-C12 polycycloalkenyl, substituted or unsubstituted C4-C12 cycloalkylene, substituted or unsubstituted C6-C12 cycloalkenylene, containing at least one substituent selected from R, C, B, C₇N, O, S, a substituted or unsubstituted 4-to 10-membered saturated heterocyclic group containing 1 to 4 heteroatoms selected from N, O, S, a substituted or unsubstituted C6-to C10 aryl group, a substituted or unsubstituted 5-or 6-or 8-to 10-membered heteroaryl group containing 1 to 4 heteroatoms, which may be the same or different.

Preferably, R is₁Selected from substituted or unsubstituted C3-C10 alkyl, substituted or unsubstituted C3-C10 alkenyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C4-C10 cycloalkenyl, substituted or unsubstituted C5-C12 polycycloalkyl, substituted or unsubstituted C6-C12 polycycloalkenyl, substituted or unsubstituted C4-C12 cycloalkylene, substituted or unsubstituted C6-C12 cycloalkenylene, containing at least one substituent selected from R₇N, O, S, a substituted or unsubstituted 4-to 8-membered heterocyclyl group containing 1 to 4 heteroatoms selected from the group consisting of N, O, S, a substituted or unsubstituted C6-to C10 aryl group, a substituted or unsubstituted 5-or 6-or 8-to 10-membered heteroaryl group containing 1 to 4 heteroatoms selected from the group consisting of the same or different heteroatoms.

Preferably, R is₁Is C1-C10 alkyl, takeSubstituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C5-C12 polycycloalkyl, substituted or unsubstituted C4-C12 cycloalkylalkyl, and substituted or unsubstituted C6-C10 aryl.

More preferably, R1 is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 2,2, 2-trifluoroethyl,

it is particularly preferred that R₁Is cyclohexyl.

In addition, R₁May also be selected from H; methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, optionally substituted by halogen; cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, optionally substituted by halogen; oxetanyl, azetidinyl, thietanyl, oxolanyl, azacyclopentyl, thietanyl, oxocyclohexyl, azacyclohexyl, thietanyl, optionally substituted with halogen; phenyl, naphthyl optionally substituted with halogen; furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, indolyl, quinolinyl, purinyl, optionally substituted with halo.

R₂Selected from the group consisting of₁₁Substituted C6-C10 aryl, optionally substituted with R₁₁Substituted 5-or 6-membered heteroaryl containing 1-3 heteroatoms, which may be the same or different, selected from N, O, S, optionally substituted by R₁₁Substituted 8-to 10-membered heteroaryl containing 1-4 heteroatoms, which may be the same or different, selected from N, O, S.

Preferably, R is₂Selected from the group consisting of₁₁Substituted phenyl, naphthyl; optionally substituted with R₁₁Substituted and containing 1 to 3 identical or different 5-or 6-membered heteroaryl groups from N, O, S heteroatoms, optionally substituted by R₁₁An 8-to 10-membered heteroaryl group which is substituted and which contains 1-4 heteroatoms which are the same or different and are selected from N, O, S;

further preferably, R₂Selected from the group consisting of₁₁Substituted phenyl, naphthyl, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, indolyl, quinolinyl, purinyl.

R₁₁Selected from H, substituted or unsubstituted C1-C12 alkyl, substituted or unsubstituted C2-C12 alkoxyalkyl, halogen, cyano, nitro, substituted or unsubstituted C1-C12 alkoxy, substituted or unsubstituted C3-C12 cycloalkyl, carboxylic acid group-substituted C2-C6 alkenyl, ester group-substituted C2-C12 alkenyl, R₇R₈N-, (C1-C12 alkyl) C (═ O) N (R)₇)-，R₇R₈NC(＝O)-，R₇S(＝O)-，R₇S(＝O)₂-，R₇R₈NS(＝O)₂-。

R₇、R₈Each independently selected from H, C1-C12 alkyl and C3-C12 cycloalkyl.

Preferably, R is₁₁Independently selected from H, halogen, cyano, nitro, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 alkoxy, substituted or unsubstituted C3-C12 cycloalkyl, substituted or unsubstituted C2-C12 alkoxyalkyl.

Preferably, R is₁₁Selected from halogen, C1-C4 alkyl substituted by one or more halogens, C1-C4 alkoxy substituted by one or more halogens, C2-C12 alkoxyalkyl substituted by one or more halogens, and C2-C12 alkoxyalkyl substituted by C3-C12 cycloalkyl.

Preferably, R is₂Selected from the group consisting of₁₁Substituted phenyl, optionally substituted with R₁₁Substituted furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, indolyl, quinolinyl, purinyl.

Preferably, R is₁₁Independently selected from halogen, methyl, ethyl, propyl, butyl, pentyl, halomethyl, haloethyl, halopropyl, halopentyl.

Preferably, R is₁₁Independently selected from H; optionally substituted with halogenMethyl, ethyl, propyl, butyl, pentyl, hexyl substituted with an alkyl; halogen; a cyano group; a nitro group; methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, optionally substituted with halogen; carboxylic acid group

Preferably, R is₁₁Independently selected from H; methyl, ethyl, propyl; trifluoromethyl, trifluoroethyl, trifluoropropyl, trifluorobutyl, trifluoropentyl, trifluorohexyl, trichloromethyl, trichloroethyl, trichloropropyl, trichlorobutyl, trichloropentyl, trichlorohexyl; fluorine, chlorine, bromine, iodine.

Preferably, R is₁₁Independently selected from hydrogen, fluorine, chlorine, methyl, trifluoromethyl.

Preferably, R₂Is selected from

Particularly preferably, R₂Is selected from

R₃Selected from aryl or heteroaryl groups of formula II, or, alternatively, from heteroaryl groups of formula III:

wherein J, L, G, E, Y are each independently selected from N, O, S, CH or C,

in the formula R₂₀，R₂₁，R₂₂Each independently selected from H, halogen, OH, cyano, nitro, carboxylic acid group, ester group, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C1-C4 alkyl (especially C1-C4 alkyl substituted with one or more halogens), substituted or unsubstituted C2-C4 alkenyl, substituted or unsubstituted C1-C4 alkoxy (especially C1-C4 alkoxy substituted with one or more halogens), R₇R₈N-containingAt least one substituted or unsubstituted 4-8 membered saturated heterocyclic group selected from the group consisting of N, O, S, S (O) r, r represents 1 or 2.

Preferably, J, L, G, E, Y each independently represent CH.

Preferably, J represents N; l, G, E, Y each independently represents CH.

Preferably, R is₃Selected from formula IV, formula V or formula VI:

preferably, R₂₀，R₂₁，R₂₂Each independently selected from H, halogen, OH, carboxylic acid group, ester group, C₃-C₆Cycloalkyl, C1-C4 alkyl substituted by one or more halogens (in particular C1-C4 alkyl substituted by one or more halogens), substituted or unsubstituted C2-C4 alkenyl, C1-C4 alkoxy substituted by one or more halogens (in particular C1-C4 alkoxy substituted by one or more halogens), R₇R₈N, a substituted or unsubstituted 4-8 membered saturated heterocyclic group containing at least one heteroatom selected from N, O, S (O) r, r represents 1 or 2.

Preferably, R is₃Selected from the group consisting of:

preferably, R₂₀，R₂₁Each independently selected from CH₃-，CH₃CH₂-，CF₃Cl, Br, F, cyclopropyl; r₂₂Selected from carboxyl, ester, OH, NH₂Halogen, C1-C10 alkyl substituted by carboxyl or ester group, C2-C10 alkenyl substituted by carboxyl or ester group, C1-C10 alkoxy substituted by carboxyl or ester group, C1-C10 alkylamino substituted by carboxyl or ester group, C1-C10 alkylthio substituted by carboxyl or ester group, and C4-C10 heterocyclic group substituted by carboxyl or ester group.

It is preferable that the first and second liquid crystal layers are formed of,R₂₀，R₂₁，R₂₂each independently selected from H; halogen; a carboxyl group; methyl, ethyl, propyl, butyl, pentyl, hexyl, optionally substituted by halogen or carboxy; a cyano group; a nitro group; methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy optionally substituted with halogen or carboxy; vinyl, propenyl, butenyl, pentenyl, hexenyl optionally substituted with halogen or carboxy; oxetanyl, azetidinyl, thietanyl, tetrahydrofuryl, pyrrolidinyl, imidazolidinyl, dioxanyl, piperidinyl, tetrahydropyranyl, morpholinyl, optionally substituted with halogen or carboxyl; furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, optionally substituted by halogen or carboxyl.

Particularly preferably, R₃Is selected from

Preferably, the compound of the present invention is a compound selected from the group consisting of, or a pharmaceutically acceptable salt thereof, or a solvate thereof or a solvate of a pharmaceutically acceptable salt thereof.

In the present specification, the term "pharmaceutically acceptable salt" includes salts with inorganic acids such as sulfuric acid, hydrochloric acid, hydrobromic acid, phosphoric acid, or nitric acid, salts with organic acids such as acetic acid, benzoic acid, oxalic acid, lactic acid, malic acid, tartaric acid, fumaric acid, maleic acid, citric acid, malonic acid, mandelic acid, gluconic acid, galactaric acid, glucoheptonic acid, glycolic acid, glutamic acid, trifluoroacetic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, or naphthalene-2-sulfonic acid, salts with 1 or more metal ions such as lithium ion, sodium ion, potassium ion, calcium ion, magnesium ion, zinc ion, aluminum ion, and salts with amines such as ammonia, arginine, lysine, piperazine, choline, diethylamine, 4-phenylcyclohexylamine, 2-aminoethanol, and benzathine. There is no particular limitation as long as it is a pharmaceutically acceptable salt. The conversion from the free form to the salt can be carried out by known methods.

The compound of the present invention may exist as various solvates. In addition, from the viewpoint of applicability as a drug, there are cases of a hydrate, a methanolate, and an ethanolate.

Where the compounds of the present invention contain one or more asymmetric centers, the compounds of the present invention can exist in the form of racemates, racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers, and the like.

In addition, the compounds of the present invention can also exist in various crystal forms, and different single crystal forms and polymorphic mixtures of the compounds can be obtained by recrystallizing the compounds or pharmaceutically acceptable salts thereof in a solvent.

The invention provides a composition comprising a compound of the invention and a pharmaceutically acceptable adjuvant. The excipient may be a carrier, excipient, diluent, or combination thereof, used to form a pharmaceutical formulation. As carriers, excipients and diluents as mentioned above, refer to inactive ingredients in pharmaceutical compositions that do not cause significant irritation to the organism and do not interfere with the properties of the biological activity of the administered compound.

The carrier, excipient and diluent include various oils such as water, lactose, glucose, fructose, sucrose, sorbitol, mannitol, polyethylene glycol, propylene glycol, starch, rubber, gelatin, alginate, calcium silicate, calcium phosphate, cellulose, aqueous syrup, methyl cellulose, polyvinylpyrrolidone, alkyl p-hydroxybenzoates, talc, magnesium stearate, stearic acid, glycerin, sesame oil, olive oil, soybean oil and the like.

The carrier, excipient or diluent may be mixed with additives such as an extender, a binder, a disintegrant, a pH adjuster, and a dissolving agent, which are generally used, if necessary, and may be prepared as an oral or non-oral drug such as a tablet, a pill, a capsule, a granule, a powder, a liquid, an emulsion, a suspension, an ointment, an injection, and a skin patch by a conventional preparation technique. The compound of the present invention can be administered orally or parenterally to an adult patient, 1 time per day or several times per day, in a total amount of 0.001 to 1500 mg/day, preferably 0.01 to 1000 mg/day, more preferably 0.1 to 800 mg/day, particularly preferably 1 to 600 mg/day, for example, 250 mg/day, 400 mg/day, 500 mg/day and 600 mg/day. The dose of the compound of the present invention can be appropriately increased or decreased depending on the type of disease to be treated, the age, weight, symptoms of the patient, and the like.

The compound of the present invention may further contain a compound in which one or more of a hydrogen atom, a fluorine atom, a carbon atom, a nitrogen atom, an oxygen atom, and a sulfur atom is replaced with a radioisotope or a stable isotope. These labeled compounds are useful for metabolic or pharmacokinetic studies, biological analyses as ligands for receptors, and the like.

The compounds of the present invention may be used in combination with one or more other active ingredients to treat, prevent, inhibit or ameliorate a disease or condition, wherein the combination of drugs is safer or more effective than either drug alone. Such other agents may be administered, by a route and in an amount commonly used therefor, either simultaneously or sequentially with a compound of the present invention. When a compound of the invention is used contemporaneously with one or more other drugs, a pharmaceutical composition containing the other drug and the compound of the invention in unit dosage form is preferred, particularly in combination with a pharmaceutically acceptable carrier. However, combination therapy may also include treatment in which a compound of the invention and one or more other drugs are administered on different overlapping schedules. It is also contemplated that when used in combination with one or more other active ingredients, the compounds of the present invention and the other active ingredients may be used in lower doses than when each is used alone. Thus, in addition to the compounds of the present invention, the pharmaceutical compositions of the present invention also include those compositions that contain one or more other active ingredients.

The composition of the present invention contains 0.01 to 1000mg, suitably 0.1 to 500mg, preferably 0.1 to 200mg, more preferably 1 to 100mg, for example 0.5mg, 1mg, 3mg, 5mg, 10mg, 15mg of the compound of the present invention. The pharmaceutical preparation of the present invention and the like may be in unit dosage form containing 0.01 to 1000mg, suitably 0.1 to 500mg, preferably 0.1 to 200mg, more preferably 1 to 100mg of the compound of the present invention.

The compounds of the invention can be prepared by the following scheme:

wherein, the step 1: compound VI and thiourea in a suitable solvent, such as ethers, alkanes, haloalkanes, aromatics, alcohols and aqueous solvents, and mixtures of the above solvents, in a halogenating agent, such as iodine, bromine, NBS, NIS, NCS, CBr₄And dibromohydantoin, etc., to obtain compound VII.

Step 2: and (2) reacting the compound VII obtained in the step (1) in the presence of a halogenating agent, such as iodine, bromine, NBS, NIS, NCS, CBr4, dibromohydantoin and the like to obtain a compound VIII.

And step 3: and (3) carrying out substitution reaction on the compound VIII obtained in the step (2) and the compound Y in the presence of alkali to obtain a compound IX. The substitution reaction can be a reaction of a compound VIII and a compound Y in the presence of a metal catalyst to form a C-C bond; the base is selected from sodium carbonate, potassium carbonate, cesium carbonate, potassium phosphate, sodium tert-butoxide, potassium tert-butoxide, lithium hydroxide, sodium hydroxide, potassium hydroxide and the like, preferably sodium carbonate; the metal catalyst may be a metal catalyst commonly used in the art for the reaction, and may be, for example, a palladium metal catalyst compound, which may be Pd (OAc)₂、Pd(dba)₂、Pd₂(dba)₃、Pd-(pph₃)₄Preferably Pd- (pph)₃)₄。

Y is a compound of the formula:

and 4, step 4: reacting the compound IX and R obtained in step 3₃-COOH to obtain the desired compound I.

Optionally, the above process may comprise a reaction to remove the protecting group.

Wherein R is₁、R₂、R₃、R₅And R₆M and n are as defined above for R in formula (I)₁、R₂、R₃、R₅、R₆M and n are as defined. X represents halogen, and M is a boronic acid group or a boronic ester group.

The compounds of the present invention can also be prepared by the following scheme:

step 1: compound VI and thiourea in a suitable solvent, such as ethers, alkanes, haloalkanes, aromatics, alcohols and aqueous solvents, and mixtures of the above solvents, in a halogenating agent, such as iodine, bromine, NBS, NIS, NCS, CBr₄In the presence of dibromohydantoin and the like to obtain a compound VII;

step 2: reacting said compound VII in the presence of a halogenating agent such as iodine, bromine, NBS, NIS, NCS, CBr4, dibromohydantoin, etc., to give compound VIII;

and step 3: and (b) subjecting the compound VIII to a substitution reaction with a compound Y 'in the presence of a base to obtain a compound IX'. The substitution reaction can be a reaction of the compound VIII and the compound Y' in the presence of a metal catalyst to form a C-C bond; the base is selected from sodium carbonate, potassium carbonate, cesium carbonate, potassium phosphate, sodium tert-butoxide, potassium tert-butoxide, lithium hydroxide, sodium hydroxide, potassium hydroxide and the like, preferably sodium carbonate; the metal catalyst may be a metal catalyst commonly used in the art for the reaction, and may be, for example, a palladium metal catalyst compound, which may be Pd (OAc)₂、Pd(dba)₂、Pd₂(dba)₃、Pd-(pph₃)₄Preferably Pd- (pph)₃)₄；

And 4, step 4: subjecting the compound IX' to condensation and/or substitution reaction to obtain a compound shown as a formula X; the condensation reaction may be carried out in the presence of an activating agent and a base, and the substitution reaction may be carried out in the presence of a base. The activating reagent is a reagent which can convert carboxylic acid into more active anhydride, acyl halide and ester, and is preferably acetic anhydride, oxalyl chloride, NBS, NIS and PCl₃、PBr₃、PPh₃/I₂4-nitrophenol, phenol, diphenyl chlorophosphate, the base being an organic base (e.g. triethylamine, N-diisopropylethylamine, DBU, DBN, DABCO, morpholine, N-methylmorpholine, pyridine) or an inorganic base (e.g. sodium hydroxide, potassium hydroxide, calcium hydroxide, barium hydroxide, sodium carbonate, potassium carbonate, magnesium carbonate, sodium bicarbonate, potassium bicarbonate).

And 5: subjecting the compound X to deprotection and reductive amination reaction to obtain a compound shown as a formula XI; the reductive amination is to react the free amine group of the deprotected compound X with a ketone or aldehyde such as paraformaldehyde, acetone, cyclopentanone, cyclobutanone, 3-methylcyclopentanone, cyclohexanone, N-methyl-4-piperidone, 4-tetrahydropyranone, cycloheptanone, 2-bicyclo [2.2.1] heptanone, adamantanone, 3-difluorocyclobutanone or the like in the presence of a reducing agent to form a C — N bond, wherein the reducing agent may be sodium borohydride, potassium borohydride, borane, sodium cyanoborohydride, sodium triacetoxyborohydride;

step 6: carrying out hydrolysis reaction on the compound XI to obtain a compound shown as a formula I; the above hydrolysis reaction may be carried out in the presence of a base, which is an organic base (triethylamine, N-diisopropylethylamine, DBU, DBN, DABCO, morpholine, N-methylmorpholine, pyridine) or an inorganic base (e.g., lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, barium hydroxide, sodium carbonate, potassium carbonate, magnesium carbonate, sodium bicarbonate, potassium bicarbonate).

Wherein Y' is a compound represented by the formula:

R₁、R₂、R₃、R₅and R₆M and n are as defined above for R in formula (I)₁、R₂、R₃、R₅、R₆M and n are as defined, R₁' is an amino protecting group or hydrogen, R₃' is a substituted or unsubstituted C6-C10 aryl, a substituted or unsubstituted 5-or 6-or 8-to 10-membered heteroaryl group containing 1 to 4 identical or different heteroatoms selected from N, O, S, X is halogen, and M is a boronic acid group or a boronic ester group.

In the compounds of the formula I, R₁、R₂And R₃Further chemical modification may be carried out as required, this being for R₁、R₂And R₃The chemical reaction method OF modification can be carried out with reference to general organic Chemistry textbooks or to (1) Alan R.Katriszly et al, comparative Heterocyclic Chemistry (2) Alan R.Katriszly et al, comparative Veheteric Chemistry II (3) RODD' S CHEMISTRY OF CARBON COMPOSITS VOLUME IV HETEROCYC COMPOSITS, etc.

In the synthesis of the compound, the reaction solvent can be ethers, alkanes, halogenated alkanes, aromatic hydrocarbons, alcohols and the like. Specific examples thereof include N, N-dimethylformamide, dimethylsulfoxide, aromatic hydrocarbons (e.g., toluene, benzene, xylene, etc.), saturated hydrocarbons (e.g., cyclohexane, hexane, etc.), halogenated hydrocarbons (e.g., dichloromethane, chloroform, 1, 2-dichloroethane, etc.), ethers (e.g., tetrahydrofuran, diethyl ether, dioxane, 1, 2-dimethoxyethane, etc.), esters (e.g., methyl acetate, ethyl acetate, etc.), ketones (e.g., acetone, methyl ethyl ketone, etc.), nitriles (e.g., acetonitrile, etc.), alcohols (e.g., methanol, ethanol, t-butanol, etc.), water and a mixed solvent thereof.

As halogenating agents in the synthesis of the compounds of the invention, there may be used, for example, iodine, bromine, NBS, NIS, NCS, CBr₄Dibromohydantoin, and the like.

Examples

The present invention will be described in more detail below with reference to examples and test examples, but these are not intended to limit the present invention and may be modified without departing from the scope of the present invention.

The structures of the compounds described in the following examples were determined by nuclear magnetic resonance (¹HNMR) or Mass Spectrometry (MS).

Nuclear magnetic resonance (¹HNMR) was performed using a JEOL Eclipse 400 nuclear magnetic instrument; the solvent was determined to be deuterated methanol (CD)₃OD), deuterated chloroform (CDCl)₃) Hexadeuterio dimethyl sulfoxide (DMSO-d 6); the internal standard substance is Tetramethylsilane (TMS).

Abbreviations in Nuclear Magnetic Resonance (NMR) spectra used in examples are shown below.

s: unimodal (singlet), d: doublet (doublt), t: triplet (triplet), q: quartet (quartz), dd: doublet (doubledoubledoublet), qd: quartet doubtet, ddd: double doublet (double doublet), ddt: double double triplet (double double triple), dddd: double double doublet (double double doublet), m: multiplet (multiplex), br: broad (broad), J: coupling constant, Hz: hertz, DMSO-d 6: deuterated dimethyl sulfoxide.

All delta values are expressed in ppm.

Mass Spectrometry (MS) was performed using an Agilent (ESI) mass spectrometer.

Example 11- (3-chloro-5- { [4- (4-chlorothien-2-yl) -5- (1-cyclohexyl-1, 2, 3, 6-tetrahydropyridin-4-yl) thiazol-2-yl ] carbamoyl } pyridin-2-yl) piperidine-4-carboxylic acid (Compound L1)

The method comprises the following steps: synthesis of 4- [ 2-amino-4- (4-chlorothien-2-yl) thiazol-5-yl ] -3, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester

5-bromo-4- (4-chlorothien-2-yl) -2-amino-thiazole (900mg, 3.1mmol), N-tert-butoxycarbonyl-1, 2, 5, 6-tetrahydropyridine-4-boronic acid pinacol ester (960mg, 3.1mmol), anhydrous sodium carbonate (920mg, 7.3mmol) and tetrakis triphenylphosphine palladium (180mg, 0.2mmol) were dissolved in a mixed solvent of ethylene glycol dimethyl ether and water (45mL, V: V ═ 2: 1). The reaction is carried out for 1.5h at 70 ℃ under the protection of nitrogen. Cooled to room temperature, filtered, and the filtrate was concentrated to give a crude product, which was purified by silica gel column chromatography to give the title compound 1.1 g.

ESI-MS(m/z)：398.2[M+H]⁺

Step two: synthesis of 4- [4- (4-chlorothien-2-yl) -2- (5, 6-dichloronicotinamide) thiazol-5-yl ] -3, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester

5, 6-Dichloronicotinic acid (811mg, 4.3mmol) was dissolved in pyridine (15mL), and phosphorus oxychloride (650mg, 4.3mmol) was added dropwise. The reaction was carried out at room temperature for 30 min. The reaction mixture was added in portions to 4- [ 2-amino-4- (4-chlorothien-2-yl) thiazol-5-yl ] -3, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester (1.1g, 2.8mmol) at 0 ℃ and reacted at room temperature for 3.5H. The solvent was distilled off under reduced pressure, and ethyl acetate was added to dissolve the residue. Washed with 1N hydrochloric acid and brine. Dried over anhydrous sodium sulfate. Filtration and evaporation of the solvent from the filtrate under reduced pressure gave the title compound. It was used in the next reaction without purification.

ESI-MS(m/z)：571.2[M+H]⁺

Step three: synthesis of 4- [2- { 5-chloro-6- [4- (ethoxycarbonyl) piperidin-1-yl ] nicotinamide } -4- (4-chlorothien-2-yl) thiazol-5-yl ] -3, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester

Tert-butyl 4- [4- (4-chlorothien-2-yl) -2- (5, 6-dichloronicotinamide) thiazol-5-yl ] -3, 6-dihydropyridine-1 (2H) -carboxylate (1.6g, 2.8mmol), ethyl 4-piperidinecarboxylate (885mg, 5.6mmol) and N, N-diisopropylethylamine (717mg, 5.6mmol) were dissolved in tetrahydrofuran (30mL) and refluxed overnight. The reaction solution is cooled to room temperature, and the solvent is removed by evaporation under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography to give the title compound 1.5 g.

ESI-MS(m/z)：692.2[M+H]⁺

Step four: synthesis of ethyl 1- (3-chloro-5- { [4- (4-chlorothien-2-yl) -5- (1, 2, 3, 6-tetrahydropyridin-4-yl) thiazol-2-yl ] carbamoyl } pyridin-2-yl) piperidine-4-carboxylate

Tert-butyl 4- [4- (4-chlorothien-2-yl) -2- (5, 6-dichloronicotinamide) thiazol-5-yl ] -3, 6-dihydropyridine-1 (2H) -carboxylate (69mg, 0.1mmol) was dissolved in dichloromethane (1.5mL), trifluoroacetic acid (0.5mL) was added dropwise, and the reaction was carried out at room temperature for 1.5H. The reaction solution was evaporated under reduced pressure to remove the solvent to give the title compound. It was used in the next reaction without purification.

ESI-MS(m/z)：592.2[M+H]⁺

Step five: synthesis of ethyl 1- (3-chloro-5- { [4- (4-chlorothien-2-yl) -5- (1-cyclohexyl-1, 2, 3, 6-tetrahydropyridin-4-yl) thiazol-2-yl ] -carbamoyl } -pyridin-2-yl) -piperidine-4-carboxylate

Ethyl 1- (3-chloro-5- { [4- (4-chlorothien-2-yl) -5- (1, 2, 3, 6-tetrahydropyridin-4-yl) -thiazol-2-yl ] -carbamoyl } -pyridin-2-yl) -piperidine-4-carboxylate was dissolved in 1, 4-dioxane (5mL), glacial acetic acid (0.1mL), cyclohexanone (49mg, 0.5mmol) and sodium cyanoborohydride (32mg, 0.5mmol) were added and reacted at 50 ℃ for 2 h. The reaction solution was filtered, and the filtrate was evaporated under reduced pressure to remove the solvent to give the title compound. It was used in the next reaction without purification.

ESI-MS(m/z)：674.2[M+H]⁺

Step six: synthesis of 1- (3-chloro-5- { [4- (4-chlorothien-2-yl) -5- (1-cyclohexyl-1, 2, 3, 6-tetrahydropyridin-4-yl) thiazol-2-yl ] carbamoyl } pyridin-2-yl) piperidine-4-carboxylic acid

Ethyl 1- (3-chloro-5- { [4- (4-chlorothien-2-yl) -5- (1-cyclohexyl-1, 2, 3, 6-tetrahydropyridin-4-yl) -thiazol-2-yl ] -carbamoyl } -pyridin-2-yl) -piperidine-4-carboxylate was dissolved in a mixed solvent of tetrahydrofuran and water (3mL, V: V ═ 2: 1), and lithium hydroxide monohydrate (25mg, 0.6mmol) was added to react at room temperature for 3.5 h. The reaction solution was adjusted to acidity (pH 3) with a saturated citric acid solution. Extracting with mixed solvent of ethyl acetate and tetrahydrofuran, and combining organic phases. The organic phase was washed successively with water and brine. Dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated to give the crude title compound. The crude title compound was purified by high performance liquid chromatography using a trifluoroacetic acid system to give 36mg of the trifluoroacetate salt of the title compound.

¹H NMR(400MHz，DMSO-d₆)δ12.87(s，1H)，12.31(s，1H)，9.67(s，1H)，8.85(d，J＝2.1Hz，1H)，8.42(d，J＝2.1Hz，1H)，7.64(d，J＝1.4Hz，1H)，7.32(d，J＝1.4Hz，1H)，6.13(s，1H)，4.01-3.87(m，4H)，3.67(s，1H)，3.34-3.29(m，2H)，3.04(t，J＝11.4Hz，2H)，2.78-2.72(m，1H)，2.57-2.53(m，1H)，2.57-2.54(m，1H)，2.14-2.05(s，2H)，1.96-1.93(m，2H)，1.86(d，J＝12.4Hz，2H)，1.72-1.63(m，3H)，1.54-1.41(m，2H)，1.33-1.23(m，3H)，1.18-1.13(s，1H)。

ESI-MS(m/z)：646.2[M+H]⁺。

Example 21- (3-chloro-5- { [4- (4-chlorothien-2-yl) -5- (1-methyl-1, 2, 5, 6-tetrahydropyridin-3-yl) thiazol-2-yl ] carbamoyl } pyridin-2-yl) piperidine-4-carboxylic acid (Compound L2)

Using a method similar to example 1, but starting from 1-tert-butoxycarbonyl-3, 6-dihydro-2H-pyridine-5-boronic acid pinacol ester (960mg, 3.1mmol) in the first step instead of N-tert-butoxycarbonyl-1, 2, 5, 6-tetrahydropyridine-4-boronic acid pinacol ester (960mg, 3.1mmol), paraformaldehyde was used instead of cyclohexanone in the fifth step, the trifluoroacetate salt of the title compound was prepared, 32 mg.

¹H NMR(400MHz，DMSO-d₆)δ12.73(s，1H)，12.31(s，1H)，9.26(s，1H)，8.84(d，J＝2.1Hz，1H)，8.40(d，J＝2.1Hz，1H)，7.62(d，J＝1.5Hz，1H)，7.52(d，J＝1.5Hz，1H)，6.29(s，1H)，4.00-3.97(d，J＝13.1Hz，2H)，3.68(s，1H)，3.60-3.52(m，1H)，3.46(d，J＝11.6Hz，2H)，3.07-3.01(m，2H)，2.93(d，J＝12.1Hz，2H)，2.82(d，J＝3.9Hz，3H)，2.56-2.54(m，1H)，1.95(d，J＝10.5Hz，2H)，1.72-1.63(m，2H)，1.38(s，3H)，1.31-1.18(m，2H)。

ESI-MS(m/z)：578.2[M+H]⁺。

Example 31- (3-chloro-5- { [4- (4-chlorothien-2-yl) -5- (1-cyclohexyl-1, 2, 5, 6-tetrahydropyridin-3-yl) thiazol-2-yl ] carbamoyl } pyridin-2-yl) piperidine-4-carboxylic acid (Compound L3)

Using a method similar to example 1, but using in the first step 1-tert-butoxycarbonyl-3, 6-dihydro-2H-pyridine-5-boronic acid pinacol ester (960mg, 3.1mmol) instead of N-tert-butoxycarbonyl-1, 2, 5, 6-tetrahydropyridine-4-boronic acid pinacol ester (960mg, 3.1mmol) as the starting material, the title compound was prepared as the trifluoroacetate salt at 32 mg.

¹H NMR(400MHz，DMSO-d₆)δ12.89(s，1H)，12.26(s，1H)，9.80(s，1H)，8.85(d，J＝2.1Hz，1H)，8.42(d，J＝2.1Hz，1H)，7.63(s，1H)，7.42(s，1H)，6.30(s，1H)，4.00-3.97(m，3H)，3.82(d，J＝15.4Hz，1H)，3.62(s，1H)，3.29-3.24(m，1H)，3.07-3.01(t，J＝11.9Hz，2H)，2.93(d，J＝12.1Hz，2H)，2.69-2.53(m，2H)，2.09-1.93(m，4H)，1.82(d，J＝10.4Hz，2H)，1.71-1.59(m，3H)，1.48-1.39(m，2H)，1.32-1.23(s，3H)，1.14-1.05(m，2H)。

ESI-MS(m/z)：646.2[M+H]⁺。

Example 4 (E) -3- (2, 6-dichloro-4- { [4- (4-chlorothien-2-yl) -5- (1-cyclohexyl-1, 2, 3, 6-tetrahydropyridin-4-yl) thiazol-2-yl ] carbamoyl } phenyl) -2-methacrylic acid (Compound L4)

The method comprises the following steps: (E) synthesis of tert-butyl (4- {4- (4-chlorothien-2-yl) -2- [3, 5-dichloro-4- (3-ethoxy-2-methyl-3-oxo-1-propenyl) benzamido ] thiazol-5-yl } -3, 6-dihydropyridine-1 (2H) -carboxylate

Tert-butyl 4- [ 2-amino-4- (4-chlorothien-2-yl) thiazol-5-yl ] -3, 6-dihydropyridine-1 (2H) -carboxylate (373mg, 0.9mmol), 3, 5-dichloro-4- (3-ethoxy-2-methyl-3-oxo-1-propenyl) -benzoic acid (426mg, 1.4mmol) were dissolved in chloroform (30mL), diphenyl chlorophosphate (379mg, 1.4mmol), N, N-diisopropylethylamine (179mg, 1.4mmol) were added in that order, and reaction was carried out at 50 ℃ for 4H. The reaction mixture was cooled to room temperature, and washed with water, a sodium hydrogencarbonate solution and brine in that order. Drying with anhydrous sodium sulfate, filtering, and evaporating the filtrate under reduced pressure to remove the solvent to obtain crude product. The crude product was purified by flash column chromatography on silica gel (petroleum ether: ethyl acetate 3: 1) to give the title compound 566 mg.

ESI-MS(m/z)：682.2[M+H]⁺。

Step two: (E) synthesis of ethyl-3- (2, 6-dichloro-4- { [4- (4-chlorothien-2-yl) -5- (1, 2, 3, 6-tetrahydropyridin-4-yl) thiazol-2-yl ] carbamoyl } phenyl) -2-methacrylate

(E) -4- {4- (4-chlorothien-2-yl) -2- [3, 5-dichloro-4- (3-ethoxy-2-methyl-3-oxo-1-propenyl) benzamido ] thiazol-5-yl } -3, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester (68mg, 0.1mmol) was dissolved in methyl chloride (1.5mL), and trifluoroacetic acid (0.5mL) was added dropwise and reacted at room temperature for 1.5H. The reaction solution was evaporated under reduced pressure to remove the solvent to give the title compound. It was used in the next reaction without purification.

ESI-MS(m/z)：582.2[M+H]⁺。

Step three: (E) synthesis of ethyl-3- (2, 6-dichloro-4- { [4- (4-chlorothien-2-yl) -5- (1-cyclohexyl-1, 2, 3, 6-tetrahydropyridin-4-yl) thiazol-2-yl ] carbamoyl } phenyl) -2-methacrylate

Ethyl (E) -3- (2, 6-dichloro-4- { [4- (4-chlorothien-2-yl) -5- (1, 2, 3, 6-tetrahydropyridin-4-yl) thiazol-2-yl ] carbamoyl } phenyl) -2-methacrylate was dissolved in 1, 4-dioxane (5mL), glacial acetic acid (0.1mL), cyclohexanone (49mg, 0.5mmol) and sodium cyanoborohydride (32mg, 0.5mmol) were added and reacted at room temperature for 2 h. The reaction solution was filtered, and the solvent was distilled off from the filtrate under reduced pressure to give the title compound. It was used in the next reaction without purification.

ESI-MS(m/z)：664.2[M+H]⁺。

Step four: (E) synthesis of (E) -3- (2, 6-dichloro-4- { [4- (4-chlorothien-2-yl) -5- (1-cyclohexyl-1, 2, 3, 6-tetrahydropyridin-4-yl) thiazol-2-yl ] carbamoyl } phenyl) -2-methacrylic acid

Ethyl (E) -3- (2, 6-dichloro-4- { [4- (4-chlorothien-2-yl) -5- (1-cyclohexyl-1, 2, 3, 6-tetrahydropyridin-4-yl) thiazol-2-yl ] carbamoyl } phenyl) -2-methacrylate was dissolved in a mixed solvent of tetrahydrofuran and water (3mL, V: V ═ 2: 1), and lithium hydroxide monohydrate (25mg, 0.6mm0l) was added to react at room temperature for 3.5 h. The reaction solution was adjusted to acidity (pH 3) with a saturated citric acid solution. Extracting with mixed solvent of ethyl acetate and tetrahydrofuran, and combining organic phases. The organic phase was washed successively with water and brine. Dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated to give the crude title compound. The crude title compound was purified by high performance liquid chromatography using a trifluoroacetic acid system to give 35mg of the trifluoroacetate salt of the title compound.

¹H NMR(400MHz，DMSO-d₆)δ12.80(s，2H)，8.25(s，2H)，8.16(s，1H)，7.58(d，J＝1.4Hz，1H)，7.38(d，J＝1.4Hz，1H)，7.21(d，J＝1.4Hz，1H)，6.05(s，1H)，3.37(s，1H)，2.88(s，2H)，2.57(s，1H)，2.35(s，2H)，1.87(d，J＝9.6Hz，2H)，1.78(d，J＝10.8Hz，2H)，1.67(d，J＝1.3Hz，3H)，1.60(d，J＝12.3Hz，1H)，1.34-1.09(m，6H)。

ESI-MS(m/z)：636.2[M+H]⁺。

Example 5 (E) -3- (2, 6-dichloro-4- { [4- (4-chlorothien-2-yl) -5- (1-cyclohexyl-1, 2, 3, 6-tetrahydropyridin-3-yl) thiazol-2-yl ] carbamoyl } phenyl) -2-methacrylic acid (Compound L5)

Using a method similar to example 1, but starting from 1-tert-butoxycarbonyl-3, 6-dihydro-2H-pyridine-5-boronic acid pinacol ester (960mg, 3.1mmol) in the first step instead of N-tert-butoxycarbonyl-1, 2, 5, 6-tetrahydropyridine-4-boronic acid pinacol ester (960mg, 3.1mmol), 3, 5-dichloro-4- (3-ethoxy-2-methyl-3-oxo-1-propenyl) -benzoic acid (426mg, 1.4mmol) in the second step instead of 5, 6-dichloronicotinic acid (811mg, 4.3mmol), the title compound was prepared as the trifluoroacetate salt at 37 mg.

¹H NMR(400MHz，DMSO-d₆)δ12.91(s，1H)，8.25(s，2H)，8.16(s，1H)，7.56(d，J＝1.4Hz，1H)，7.38(d，J＝1.4Hz，1H)，7.22(d，J＝1.4Hz，1H)，6.05(s，1H)，3.37(s，1H)，3.23(s，2H)，2.79(s，2H)，2.32(s，2H)，1.74(s，2H)，1.67(d，J＝1.2Hz，3H)，1.54(d，J＝11.6Hz，1H)，1.21-1.03(m，6H)。

ESI-MS(m/z)：636.2[M+H]⁺。

EXAMPLE 61- [ 3-chloro-5- ({5- (1-cyclohexyl-1, 2, 3, 6-tetrahydropyridin-4-yl) -4- [ 2-fluoro-3- (trifluoromethyl) -phenyl ] -thiazol-2-yl } carbamoyl) -pyridin-2-yl ] -piperidine-4-carboxylic acid (Compound L6)

Using a method similar to example 1, starting from 5-bromo-4- (2-fluoro-3-trifluoromethyl-phenyl) -thiazole-2-ammonia (600mg, 1.8mmol) in the first step of example 1 instead of 5-bromo-4- (4-chlorothien-2-yl) -2-amino-thiazole (900mg, 3.1mmol), high performance liquid chromatography purification of the hydrochloric acid system in the sixth step of example 1 instead of the trifluoroacetic acid system prepared 55mg of the hydrochloride of the title compound.

¹H NMR(400MHz，DMSO-d₆)：δ12.89(s，1H)，12.28(s，1H)，10.17(s，1H)，8.86(s，1H)，8.41(d，J＝1.9Hz，1H)，7.89(d，J＝1.5Hz，1H)，7.51(t，J＝2.2Hz，1H)，5.88(s，1H)，4.0(d，J＝10.6Hz，2H)，3.73(m，2H)，3.53(m，1H)，3.25(m，1H)，3.10-2.99(m，3H)，2.68-2.59(m，1H)，2.54-2.48(m，1H)，2.35-2.25(m，2H)，2.15-2.01(m，2H)，1.90-1.78(m，2H)，1.73-1.61(m，2H)，1.55-1.48(m，3H)，1.45-1.37(m，2H)，1.33-1.12(m，3H)

ESI-MS(m/z)：711.2[M+H]⁺。

EXAMPLE 7 (E) -3- [2, 6-dichloro-4- ({5- (1-cyclohexyl-1, 2, 3, 6-tetrahydropyridin-4-yl) -4- [ 2-fluoro-3- (trifluoromethyl) -phenyl ] -thiazol-2-yl } -carbamoyl) phenyl ] -2-methacrylic acid (Compound L7)

Using a method similar to example 4, starting from tert-butyl 4- [ 2-amino-4- (2-fluoro-3-trifluoromethyl-phenyl) -thiazol-5-yl ] -3, 6-dihydro-2H-pyridine-1-carboxylate (140mg, 0.3mmol) instead of tert-butyl 4- [ 2-amino-4- (4-chlorothien-2-yl) thiazol-5-yl ] -3, 6-dihydropyridine-1 (2H) -carboxylate (373mg, 0.9mmol), in the fourth step of example 4 high performance liquid chromatography purification of the hydrochloric acid system instead of high performance liquid chromatography purification of the trifluoroacetic acid system, 48mg of the hydrochloride of the title compound was prepared.

¹H NMR(400MHz，DMSO-d₆)：δ13.15(s，1H)，12.99(s，1H)，10.06(s，1H)，8.27(s，2H)，7.88(t，J＝1.9Hz，2H)，7.54(t，J＝1.5Hz，1H)，7.40(s，1H)，5.90(s，1H)，3.84-3.72(m，2H)，3.65-3.55(m，1H)，3.33-3.22(m，1H)，3.15-2.93(m，2H)，2.75-2.55(m，1H)，2.38-2.21(m，1H)，2.12-1.95(m，2H)，1.88-1.75(m，2H)，1.68(s，3H)，1.63-1.52(m，1H)，1.44-1.34(m，1H)，1.25-1.15(m，2H)，1.09-1.01(m，1H)

ESI-MS(m/z)：682.2[M+H]⁺。

Test examples

Test example 1

Thrombopoietin (TPO) is a glycoprotein involved in platelet production and plays a key role in regulating megakaryocytopoiesis and bone marrow megakaryocytopoiesis. In vitro synthesis of TPO mimetic compounds, which interact with the TPO receptor (TPOR) on cells, stimulate the proliferation and differentiation of cells. The OD490 value was measured by the MTS method, and the larger the number of cells, the larger the OD value, and thereby the response of the compound to the proliferation and differentiation of cells was measured. The concentration of agonist with the signal increasing to the highest level was Emax, and the signal increased to 50% E_maxHas a concentration of EC₅₀. By EC₅₀Determination of the Activity of the Compound, EC₅₀The smaller, the compound is activeThe higher.

Mouse pro-B cell BAF3 stably expressing human TPOR was cultured in 1640 medium containing 10% FBS. On the day of the assay, cells were counted and plated in multi-well plates. The compounds to be tested were added to the well plates at different concentrations to a final concentration of 10000nM, 3000nM, 300nM, 30nM, 3nM, 0.3nM, 0.03nM, respectively, after incubation of the compounds with the cells in an incubator for 24 h. OD490 was measured with a multifunctional full-automatic enzymatic calibrator and EC was fitted with GraphPad Prism5 software₅₀。

TABLE 1 cell proliferation Effect of the Compounds of the invention on BAF3/TPOR

Example numbering	EC₅₀(nM)
		Lutropopa	2.7
Example 1	0.38
		Example 3	1.55
Example 4	1.04
		Example 5	0.73

The data in Table 1 demonstrate that the EC of the compounds L1, L3, L4, L5 of the invention compared to the LD of the positive control compound₅₀Lower value, better displayBAF3/TPOR cell proliferation.

Other compounds of the invention have BAF3/TPOR cell proliferation similar to the compounds described above.

The compound of the invention shows better effect in the aspect of medicine safety when being applied to medicines for diseases mediated by thrombopoietin receptor, and shows good pharmaceutical activity and in vivo metabolic advantage in the pharmacodynamics or pharmacokinetics in vivo or in vitro of animals.

Industrial applicability

The 2-acylaminothiazole derivatives of the invention can be used for the therapeutic application in the medical field, in particular for promoting thrombopoiesis and megakaryocytopoiesis, thereby treating or preventing thrombopoietin-mediated diseases.

Claims

1. A compound of formula I, or a pharmaceutically acceptable salt thereof, or a mixture thereof;

wherein the content of the first and second substances,

m is 1 or 2, n is 1 or 2; and the sum of m and n is 3;

the moiety is a double bond;

R₅，R₆is H;

R₂is selected from

R₃Selected from:

2. the compound of claim 1, or a pharmaceutically acceptable salt thereof, or a mixture thereof,

R₁is cyclohexyl.

3. The compound of any one of claims 1-2, or a pharmaceutically acceptable salt thereof, or a mixture thereof, wherein the compound is represented by:

or

4. A pharmaceutical composition comprising a compound of any one of claims 1-3, or a pharmaceutically acceptable salt thereof, or a mixture thereof.

5. Use of a compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, or a mixture thereof, in the manufacture of a medicament for the prevention or treatment of a thrombopoietin-mediated disorder.

6. Use of the pharmaceutical composition of claim 4 in the manufacture of a medicament for the prevention or treatment of a thrombopoietin-mediated disorder.

7. A process for the preparation of a compound according to any one of claims 1 to 3, comprising the steps of:

and step 3: reacting said compound VIII with compound Y to give compound IX;

wherein Y is a compound represented by the formula:

R₁、R₂、R₃、R₅and R₆M and n are as defined in claims 1 to 3 with respect to R₁、R₂、R₃、R₅、R₆M and n are as defined, X is halogen and M is a boronic acid group or a boronic ester group.

8. A process for the preparation of a compound according to any one of claims 1 to 3, comprising the steps of:

and step 3: reacting said compound VIII with compound Y 'to give compound IX';

wherein Y' is a compound represented by the formula:

R₁、R₂、R₃、R₅and R₆M and n are as defined in claims 1 to 3 with respect to R₁、R₂、R₃、R₅、R₆M and n are as defined, R₁' is an amino protecting group or hydrogen, R₃' is a substituted or unsubstituted C6-C10 aryl, a substituted or unsubstituted 5-or 6-or 8-to 10-membered heteroaryl group containing 1 to 4 identical or different heteroatoms selected from N, O, S, X is halogen, and M is a boronic acid group or a boronic ester group.