Imidazothiazole compounds, pharmaceutical compositions thereof, and uses thereof

Abstract

The present invention provides novel imidazothiazole compounds as ATX (autotaxin) inhibitors, or pharmaceutically acceptable salts, hydrates, solvates, stereoisomers, tautomers, nitroxides, metabolites, prodrugs, or mixtures thereof, pharmaceutical compositions containing said compounds, and uses of said compounds and compositions for treating mammalian diseases having increased expression of ATX (autotaxin) as a pathological feature. The compounds have the structure shown in formula (I), wherein R 1a , R 1c , R 2 , R 3 , R 6 , Cy, Y, Z and t all have the definitions set forth in the present invention. [C51] JPEG2023549203000057.jpg43165

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical chemistry, and particularly to a novel imidazolethiazole compound as an inhibitor of ATX (Autotaxin), a pharmaceutical composition containing the compound, and the use of the compound or composition for treating a disease having an increased expression of ATX (Autotaxin) as a pathological feature.

Background Art

[0002] Autotaxin (abbreviated as ATX) was first isolated from A2058 melanoma cells in 1992 and is a secreted glycoprotein called "autocrine motility factor". ATX has the activity of phosphodiesterase (PDE) and is a member of the extracellular pyrophosphatase / phosphodiesterase (ENPP) family. ATX also has lysophospholipase D (lysoPLD) activity and can catalyze the production of lysophosphatidic acid (abbreviated as LPA) using lysophosphatidylcholine (abbreviated as LPC) as a substrate. LPA is not only a precursor for phospholipid synthesis but can also cause a wide range of biological effects through various signaling pathways. When LPA is produced, it can exert its role through the mediation of six cell surface-specific receptor proteins (LPA1 - 6), namely G protein-coupled receptors (GPCRs). LPA1 - 6 are named LPA1 / Edg-2 / VZG-1, LPA2 / Edg-4, LPA3 / Edg-7, LPA4 / p2y9 / GPR23, LPA5 / GPR92, and LPA6 / p2Y5 based on the endothelial differentiation gene (Edg) and genes in the ventricular region, respectively. All of these receptors mediate a series of cell signal cascades through Gα proteins (Gs, Gi, Gq, and G12 / 13). The main pathways include the hydrolysis of phosphatidylinositol bisphosphate (PIP2) that causes the release of intracellular calcium ions and the activation of protein kinase C (PKC), the adenylate cyclase (cAMP) inhibitory signaling pathway, the Ras-MAPK, MERK, ERK activation pathways that regulate cell proliferation, the phosphoinositide PI3K-AKT activation pathway that regulates cell survival and apoptosis, and the Rho activation pathway that regulates cytoskeleton remodeling, shape change, and cell migration. In various pathological conditions, especially in tumor cells, ATX is highly expressed, so the concentration of LPA is very high. In tumor cells, the concentration of LPA can exceed 100 nmol / L, the normal level, and can even rise to 10 μmol / L.When LPA increases excessively, the production of vascular endothelial growth factor (VEGF) increases, angiogenesis is promoted, the expression of tumor suppressor p53 is reduced, and the survival and migration of tumor cells are promoted. Since the ATX-LPA signaling pathway is involved in many physiological and pathological processes, it is closely related to many serious diseases such as cardiovascular diseases, autoimmune diseases, cancer, fibrotic diseases, inflammation, neurological diseases, and pain. In tumorigenesis, LPA plays various functions such as promoting tumor cell proliferation, angiogenesis, migration, and the emergence of drug resistance. Therefore, reducing the concentration of LPA is helpful for tumor treatment and palliation. As a result, inhibiting the activity of AXT and blocking the production pathway of LPA have become a hot spot in the research on the treatment of various serious diseases.

[0003] As research on ATX has deepened, new inhibitors targeting it have been developed. The areas where research is most concentrated are cancer and fibrotic diseases. Fibrotic diseases mainly include idiopathic pulmonary fibrosis (IPF) and liver fibrosis. IPF is a fatal disease characterized by diffuse alveolitis and alveolar structure damage, which causes the progression of interstitial pulmonary fibrosis. The average survival period is 2 - 5 years, and the prognosis is poor. The highest expression of ATX in lung tissue is in bronchial epithelial cells and alveolar macrophages. Since these cells develop into fibroblast foci, it can be said that IPF is most closely related to the ATX-LPA pathway.

[0004] Currently, as an autotaxin inhibitor, GLPG-1690 for the treatment of idiopathic pulmonary fibrosis has already reached the phase II clinical trial stage. The ATX concentration in serum is closely related to liver fibrosis and liver stiffness, and it is one of the most useful indicators for predicting liver cirrhosis. In addition, ATX is highly expressed in various tumor tissues including melanoma, non-small cell lung cancer, liver cancer, kidney cancer, breast cancer, thyroid cancer, ovarian cancer, and Hodgkin lymphoma. During the proliferation of tumor cells, LPA / ATX promotes cell invasion and migration. Therefore, ATX inhibitors that block the signaling pathway provide a new approach for the clinical treatment of cancer and fibrotic diseases.

[0005] Compared with conventional kinase inhibitors, ATX inhibitors inhibit ATX activity and simultaneously affect multiple signaling pathways related to cell proliferation, growth, apoptosis, etc., show good inhibitory effects on some resistant tumors, and are closely related to the occurrence of fibrosis in multiple organs. Therefore, they are important targets in the research and development of new therapeutic drugs for fibrotic diseases.

[0006] The present invention provides a novel imidazolothiazole compound having good inhibitory activity against ATX, and in terms of in vitro enzyme activity, many of them are superior to Comparative Example 1. Also, from the results of the pharmacokinetic study, it can be seen that the compounds of the present invention have high exposure and bioavailability. In short, since the compounds of the present invention have excellent efficacy, pharmacokinetic properties and / or toxicological properties, good clinical use is expected.

[0007] (Summary of the Invention) Hereinafter, some aspects of the present invention will be briefly described, but the present invention is not limited thereto. These aspects and other parts will be more fully described below. All of the references in this specification are hereby incorporated by reference in their entirety into the present invention. In case of any conflict between the disclosure of this specification and the cited references, the disclosure of this specification shall prevail.

[0008] The present invention provides a novel imidazolothiazole compound having excellent inhibitory activity against ATX, having high exposure and bioavailability in the body of rats, and can be used for producing therapeutic drugs for diseases having an increased expression of ATX as a pathological feature, such as cancer, fibrotic diseases (e.g., pulmonary fibrosis or hepatic fibrosis), metabolic diseases, myelodysplastic syndromes, cardiovascular diseases, autoimmune diseases, inflammation, neurological diseases or pain. The present invention further provides a method for producing the compounds described in the present invention, a method for treating the above-mentioned diseases in mammals, particularly humans, using these compounds, and a pharmaceutical composition containing these compounds.

[0009] In one aspect of the present invention, there is provided a novel imidazolothiazole compound having the structure represented by formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, N-oxide, metabolite, prodrug, or mixture thereof.

Chemical formula

Chemical formula

[0010] In another aspect of the present invention, there is provided a pharmaceutical composition comprising a compound according to the present invention or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, N-oxide, metabolite, prodrug thereof, and a pharmaceutically acceptable additive, diluent or carrier.

[0011] In some embodiments, the pharmaceutical composition according to the present invention further comprises an additional therapeutic agent.

[0012] In another aspect of the present invention, there is provided the use of a compound according to the present invention or a pharmaceutical composition according to the present invention for the manufacture of a medicament for preventing or treating a mammalian disease having an increased expression of ATX as a pathological feature.

[0013] In some embodiments, the disease having an increased expression of ATX as the pathological feature includes cancer, fibrotic disease, metabolic disease, myelodysplastic syndrome, cardiovascular disease, autoimmune disease, inflammation, neurological disease or pain.

[0014] In some embodiments, the disease having an increased expression of ATX as the pathological feature is pulmonary fibrosis or hepatic fibrosis.

[0015] (Detailed Description of the Invention) (Definitions and General Terms) Unless otherwise specified, all technical terms used in the present invention have the same meaning as commonly understood by those skilled in the art. All patents and publications referred to in the present invention are hereby incorporated by reference in their entirety into the present invention.

[0016] Unless otherwise specified, the definitions set forth hereinafter in this specification are used. For the purposes of the present invention, chemical elements are in accordance with the descriptions in the CAS version of the Periodic Table, CRC Handbook of Chemistry and Physics, 75th Ed, 1994. Further, the general principles of organic chemistry can be referred to the descriptions in Organic Chemistry, Thomas Sorrell, University Science Books, Sausalito: 1999, and March’s Advanced Organic Chemistry, by Michael B. Smith and Jerry March, John Wiley & Sons, New York: 2007, the entire contents of which are incorporated herein by reference.

[0017] Unless otherwise specified or unless there is an obvious contradiction in the context, the modifiers “a,” “one (kind),” and “the” as used in this specification are intended to include “at least one” or “one or more.” Accordingly, these modifiers as used in this specification are modifiers that refer to one or more (i.e., at least one) objects. For example, “one component” refers to one or more components, that is, it is contemplated that one or more components are employed or used in the embodiments of the said implementation.

[0018] “Stereoisomer” refers to compounds that have the same chemical structure but different spatial arrangements of atoms or groups. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotational isomers), geometric (cis / trans) isomers, atropisomers, and the like.

[0019] Generally, the term “substituted” refers to the replacement of one or more hydrogen atoms in the target structure by a specific substituent. Unless otherwise specified, in one substituted group, one substituent can substitute at each substitutable position of the group. When one or more positions in the target structural formula can be substituted by one or more substituents selected from a specific group, the substituents can substitute at each position as the same or different ones.

[0020] The term "unsubstituted" refers to a given group having no substituents.

[0021] The term "optionally substituted by..." can be used interchangeably with the term "unsubstituted or substituted by...", i.e., the said structure is either unsubstituted or substituted by one or more substituents described in the present invention, and the substituents described in the present invention include, but are not limited to, H, D, oxo (C=O), -CN, -NO2, -OH, -NH2, -N3, F, Cl, Br, I, an alkyl group, a haloalkyl group, a cyanoalkyl group, a hydroxyalkyl group, an aminoalkyl group, an alkoxy group, an alkylamino group, a haloalkoxy group, or a haloalkoxyalkyl group, etc.

[0022] In addition, unless otherwise specified, the expressions "each... is independently", "each... is, independently of one another, ~", and "... independently, ~" used in the present invention can be used interchangeably, and all should be understood in a broad sense, which may refer to the fact that specific options represented by the same symbol with different groups do not affect each other, or specific options represented by the same symbol with the same group do not affect each other.

[0023] In each part of this specification, the substituents of the compounds disclosed in the present invention are disclosed in terms of the type or range of the groups. In particular, the present invention includes each of the independent secondary combinations of the members of these types and ranges of groups. For example, the term "C 1~6 alkyl group" particularly refers to a methyl group, an ethyl group, a C3 alkyl group, a C4 alkyl group, a C5 alkyl group, and a C6 alkyl group independently disclosed.

[0024] As used herein, the term "alkyl group" or "alkyl moiety" refers to a saturated straight-chain or branched-chain monovalent hydrocarbon group containing 1 to 20 carbon atoms, provided that the alkyl group may optionally be substituted by one or more substituents described herein. Unless otherwise specified in detail, the alkyl group contains 1 to 20 carbon atoms. In one embodiment, the alkyl group contains 1 to 12 carbon atoms; in another embodiment, the alkyl group contains 1 to 6 carbon atoms; in yet another embodiment, the alkyl group contains 1 to 4 carbon atoms; and in still another embodiment, the alkyl group contains 1 to 3 carbon atoms. The alkyl group may optionally be substituted by one or more substituents described herein.

[0025] Examples of alkyl groups include, but are not limited to, methyl group (Me, -CH3), ethyl group (Et, -CH2CH3), n-propyl group (n-Pr, -CH2CH2CH3), isopropyl group (i-Pr, -CH(CH3)2), n-butyl group (n-Bu, -CH2CH2CH2CH3), isobutyl group (i-Bu, -CH2CH(CH3)2), sec-butyl group (s-Bu, -CH(CH3)CH2CH3), tert-butyl group (t-Bu, -C(CH3)3), n-pentyl group (-CH2CH2CH2CH2CH3), 2-pentyl group (-CH(CH3)CH2CH2CH3), 3-pentyl group (-CH(CH2CH3)2), 2-methyl-2-butyl group (-C(CH3)2CH2CH3), 3-methyl-2-butyl group (-CH(CH3)CH(CH3)2), 3-methyl-1-butyl group (-CH2CH2CH(CH3)2), 2-methyl-1-butyl group (-CH2CH(CH3)CH2CH3), n-hexyl group (-CH2CH2CH2CH2CH2CH3), 2-hexyl group (-CH(CH3)CH2CH2CH2CH3), 3-hexyl group (-CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl group (-C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl group (-CH(CH3)CH(CH3)CH2CH3), 4-methyl-2-pentyl group (-CH(CH3)CH2CH(CH3)2), 3-methyl-3-pentyl group (-C(CH3)(CH2CH3)2), 2-methyl-3-pentyl group (-CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl group (-C(CH3)2CH(CH3)2), 3,3-dimethyl-2-butyl group (-CH(CH3)C(CH3)3), n-heptyl group, n-octyl group, etc.

[0026] The term "deuterated alkyl group" or "deuterated ethyl group" refers to an alkyl group or an ethyl group substituted by one, two, three, four, five or six D atoms, provided that the alkyl group has the definition described in the present invention. Examples of deuterated alkyl groups or deuterated ethyl groups include, but are not limited to, -CD3, -CH2D, -CHD2, -CD2CD3, -CH2CD3, -CD2CH3, etc.

[0027] The term "alkoxy group" refers to an alkyl group linked to the remainder of the molecule through an oxygen atom, where the alkyl group has the definition described in the present invention. Unless otherwise specified in detail, the alkoxy group contains 1 to 12 carbon atoms. In one embodiment, the alkoxy group contains 1 to 6 carbon atoms; in another embodiment, the alkoxy group contains 1 to 4 carbon atoms; and in a further embodiment, the alkoxy group contains 1 to 3 carbon atoms. The alkoxy group may optionally be substituted by one or more substituents described in the present invention.

[0028] Examples of alkoxy groups include, but are not limited to, methoxy group (MeO, -OCH3), ethoxy group (EtO, -OCH2CH3), 1-propoxy group (n-PrO, n-propoxy group, -OCH2CH2CH3), 2-propoxy group (i-PrO, i-propoxy group, -OCH(CH3)2), 1-butoxy group (n-BuO, n-butoxy group, -OCH2CH2CH2CH3), 2-methyl-l-propoxy group (i-BuO, i-butoxy group, -OCH2CH(CH3)2), 2-butoxy group (s-BuO, s-butoxy group, -OCH(CH3)CH2CH3), 2-methyl-2-propoxy group (t-BuO, t-butoxy group, -OC(CH3)3), 1-pentoxy group (n-pentoxy group, -OCH2CH2CH2CH2CH3), 2-pentoxy group (-OCH(CH3)CH2CH2CH3), 3-pentoxy group (-OCH(CH2CH3)2), 2-methyl-2-butoxy group (-OC(CH3)2CH2CH3), 3-methyl-2-butoxy group (-OCH(CH3)CH(CH3)2), 3-methyl-l-butoxy group (-OCH2CH2CH(CH3)2), 2-methyl-l-butoxy group (-OCH2CH(CH3)CH2CH3), etc.

[0029] The term "haloalkyl group" or "haloalkoxy group" refers to an alkyl group or an alkoxy group substituted by one or more halogen atoms (e.g., F, Cl, Br, or I), and examples thereof include, but are not limited to, a trifluoromethyl group, a trifluoroethyl group, a 2,2,3,3-tetrafluoropropyl group, a trifluoromethoxy group, and the like.

[0030] The term "hydroxyalkyl group" used in the present invention refers to an alkyl group substituted by one or more hydroxy groups, where the alkyl group has the definition described in the present invention. Examples thereof include, but are not limited to, a hydroxyethyl group, a 2-hydroxypropyl group, a hydroxymethyl group, and the like.

[0031] The term "cycloalkyl group" used in the present invention, unless otherwise specified, refers to a monocyclic or polycyclic hydrocarbon that is monovalent, saturated or partially unsaturated (but not aromatic). In some embodiments, the cycloalkyl group may be a bridged or unbridged, spirocyclic or non-spirocyclic, and / or fused or non-fused bicyclic group. In some embodiments, the cycloalkyl group contains 3 to 10 carbon atoms, i.e., C3-C 10 is a cycloalkyl group. In some embodiments, the cycloalkyl group is 3 to 15 (C 3~15 ), 3 to 10 (C 3~10 ) or 3 to 7 (C 3~7) has carbon atoms. In some embodiments, the cycloalkyl group is monocyclic or bicyclic. In some embodiments, the cycloalkyl group is monocyclic. In some embodiments, the cycloalkyl group is bicyclic. In some embodiments, the cycloalkyl group is tricyclic. In some embodiments, the cycloalkyl group is fully saturated. In some embodiments, the cycloalkyl group is partially saturated. In some embodiments, the cycloalkyl group is a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a bicyclo[2.1.1]hexyl group, a bicyclo[2.2.1]heptyl group, a decahydronaphthyl group, or an adamantyl group. When the cycloalkyl group is substituted, any of its rings, i.e., any aromatic or non-aromatic ring contained in the cycloalkyl group, may be independently substituted by one or more substituents described in the present invention.

[0032] The terms "heterocyclyl group" and "heterocycle" can be used interchangeably herein and, unless otherwise specified, refer to a monovalent monocyclic non-aromatic ring system and / or a polycyclic ring system containing at least one non-aromatic ring, 0~2 wherein one or more (in some embodiments, 1, 2, 3, or 4) of the atoms of the non-aromatic monocyclic ring are heteroatoms independently selected from O, S(O) 0~2is a heteroatom independently selected from N, and the remaining ring atoms are all carbon atoms. In some embodiments, the heterocyclic ring contains 1 or 2 heteroatoms, and all of the heteroatoms are nitrogen atoms. In some embodiments, the heterocyclyl group is polycyclic and contains 1 heteroatom in a non-aromatic ring, or contains 1 heteroatom in an aromatic ring, or contains 2 heteroatoms in an aromatic ring, or contains 2 heteroatoms, one of which is in an aromatic ring and the other is in a non-aromatic ring. In some embodiments, the heterocyclyl group has 3 to 20, 3 to 15, 3 to 10, 3 to 8, 4 to 7, or 5 or 6 ring atoms. In some embodiments, the heterocyclyl group is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system. In some embodiments, the heterocyclyl group may be a bridged or unbridged, spiro or non-spiro, and / or fused or non-fused bicyclic group. One or more nitrogen atoms and sulfur atoms may be optionally oxidized, one or more nitrogen atoms may be optionally quaternized, and one or more carbon atoms may be optionally,

Chemical formula

[0033] In one embodiment, the heterocyclic group is a heterocyclic group consisting of 3 to 8 atoms, referring to a saturated or partially unsaturated monocyclic ring containing 3 to 8 ring atoms, and at least one of its ring atoms is selected from nitrogen, sulfur, and oxygen atoms. Unless otherwise specified, the heterocyclic group consisting of 3 to 8 atoms may be a carbon group or a nitrogen group, and the -CH2- group may optionally be replaced by -C(=O)-. The sulfur atom of the ring may optionally be oxidized to form an S-oxide. The nitrogen atom of the ring may optionally be oxidized to form an N-oxide. Examples of the heterocyclic group consisting of 3 to 8 atoms include, but are not limited to, azetidinyl group, oxetanyl group, thietanyl group, pyrrolidinyl group, 2-pyrrolinyl group, 3-pyrrolinyl group, pyrazolinyl group, pyrazolidinyl group, imidazolinyl group, imidazolidinyl group, tetrahydrofuryl group, dihydrofuryl group, tetrahydrothienyl group, dihydrothienyl group, 1,3-dioxocyclopentyl group, dithiocyclopentyl group, tetrahydropyranyl group, dihydropyranyl group, 2H-pyranyl group, 4H-pyranyl group, tetrahydrothiopyranyl group, piperidinyl group, morpholinyl group, thiomorpholinyl group, piperazinyl group, dioxanyl group, dithianyl group, thioxanyl group, homopiperazinyl group, homopiperidinyl group, oxepanyl group, thiepanyl group, oxazepinyl group, diazepanyl group, thiazepinyl group. Examples of the -CH2- group of the heterocyclic group being replaced by -C(=O)- include, but are not limited to, 2-oxopyrrolidinyl group, oxo-1,3-thiazolidinyl group, 2-piperidonyl group, 3,5-dioxopiperidinyl group, and pyrimidinedionyl group. Examples of the sulfur atom of the heterocyclic group being oxidized include, but are not limited to, sulfolanyl group, 1,1-dioxothiomorpholinyl group. The heterocyclic group consisting of 3 to 8 atoms may optionally be substituted by one or more substituents described in the present invention.

[0034] In one embodiment, the heterocyclic group is a heterocyclic group consisting of 3 to 6 atoms, which refers to a saturated or partially unsaturated monocyclic ring containing 3 to 6 ring atoms, and at least one of the ring atoms is selected from nitrogen, sulfur, and oxygen atoms. Unless otherwise specified, the heterocyclic group consisting of 3 to 6 atoms may be a carbon group or a nitrogen group, and the -CH2- group may optionally be replaced by -C(=O)-. The sulfur atom of the ring may optionally be oxidized to form an S-oxide. The nitrogen atom of the ring may optionally be oxidized to form an N-oxide. The heterocyclic group consisting of 3 to 6 atoms may optionally be substituted by one or more substituents described in the present invention.

[0035] In another embodiment, the heterocyclyl group is a heterocyclyl group consisting of 5 or 6 atoms, referring to a saturated or partially unsaturated monocyclic ring containing 5 or 6 ring atoms, at least one of which is selected from nitrogen, sulfur and oxygen atoms. Unless otherwise specified, the heterocyclyl group consisting of 5 or 6 atoms may be a carbon group or a nitrogen group, and the -CH2- group may optionally be replaced by -C(=O)-. The sulfur atom of the ring may optionally be oxidized to form an S-oxide. The nitrogen atom of the ring may optionally be oxidized to form an N-oxide. Examples of the heterocyclyl group consisting of 5 or 6 atoms include, but are not limited to, pyrrolidinyl group, 2-pyrrolinyl group, 3-pyrrolinyl group, pyrazolinyl group, pyrazolidinyl group, imidazolinyl group, imidazolidinyl group, tetrahydrofuryl group, dihydrofuryl group, tetrahydrothienyl group, dihydrothienyl group, 1,3-dioxocyclopentyl group, dithiocyclopentyl group, 2-oxopyrrolidinyl group, oxo-1,3-thiazolidinyl group, sulfolanyl group, tetrahydropyranyl group, dihydropyranyl group, 2H-pyranyl group, 4H-pyranyl group, tetrahydrothiopyranyl group, piperidinyl group, morpholinyl group, thiomorpholinyl group, piperazinyl group, dioxanyl group, dithianyl group, thioxanyl group, 2-piperidonyl group, 3,5-dioxopiperidinyl group and pyrimidinedionyl group, 1,1-dioxothiomorpholinyl group. The heterocyclyl group consisting of 5 or 6 atoms may optionally be substituted by one or more substituents described in the present invention.

[0036] The term "cycloalkylalkyl group" represents a group in which the alkyl group may be substituted by one or more cycloalkyl groups, where the cycloalkyl group and the alkyl group have the definitions described in the present invention. Examples thereof include, but are not limited to, cyclopropylmethyl group, cyclopropylethyl group, cyclopropylpropyl group, cyclobutylmethyl group, cyclobutylethyl group, cyclopentylmethyl group, cyclopentylethyl group, cyclopentylpropyl group, cyclohexylethyl group, etc.

[0037] The term "heterocyclylalkyl group" includes an alkyl group substituted by a heterocyclyl group. The term "heterocyclylalkoxy group" includes an alkoxy group substituted by a heterocyclyl group, wherein the oxygen atom is linked to the remainder of the molecule. The term "heterocyclylalkylamino group" includes an alkylamino group substituted by a heterocyclyl group, wherein the nitrogen atom is linked to the remainder of the molecule. Here, the heterocyclyl group, alkyl group, alkoxy group, and alkylamino group all have the definitions described in the present invention. Examples thereof include, but are not limited to, azetidin-1-ylmethyl group, azetidin-1-ylethyl group, azetidin-1-ylpropyl group, pyrrol-1-ylmethyl group, pyrrol-1-ylethyl group, pyrrol-1-ylpropyl group, morpholin-4-ylethyl group, morpholin-4-yl ethoxy group, piperazin-4-yl ethoxy group, piperidin-4-ylethylamino group, and the like.

[0038] In the present invention, for a ring system in which two sites are linked to the remainder of the molecule, as shown in the following formula (a1) or formula (a2), the linkage to the remainder of the molecule may be at the E terminus or at the E' terminus, that is, the linkages at both ends may be interchanged.

Chemical formula

[0039] The term "consisting of n atoms (n is an integer)" is a typical expression for explaining the number of ring atoms in a molecule, and the number of ring atoms in the molecule is n. For example, the piperidinyl group is a heterocycloalkyl group consisting of 6 atoms, and 1,2,3,4-tetrahydronaphthalene is a cycloalkyl group consisting of 10 atoms.

[0040] The term "heteroatom" refers to O, S, N, P, and Si, and includes all oxidation states of N, S, and P, primary, secondary, tertiary, and quaternary ammonium salts, or those in which the hydrogen adjacent to the nitrogen atom in a heterocyclic ring is substituted. For example, N (e.g., N of the 3,4-dihydro-2H-pyrrolyl group), NH (e.g., NH of the pyrrolidinyl group), or NR (e.g., NR of the N-substituted pyrrolidinyl group).

[0041] The term "cyano-substituted alkyl group" or "cyanoalkyl group" includes a C 1~10 linear or branched alkyl group substituted by one or more cyano groups. In some embodiments, the cyano-substituted alkyl group is a C 1~6 "lower cyanoalkyl group", and in some embodiments, the cyano-substituted alkyl group is a C 1~4 "lower cyanoalkyl group", examples of which include, but are not limited to, CNCH2-, CNCH2CH2-, CNCH2CH2CH2-, CNCH2CHCNCH2-, etc.

[0042] As described in the present invention, the ring system formed by removing a bond from a substituent and connecting it to the central ring (see the figure below) represents that the substituent can be substituted at any substitutable position in any ring. For example, formula b represents that it can be substituted at any substitutable position in ring A or ring B, as shown in formula c, formula d, formula e, formula f, formula g, formula h, formula i, formula j, formula k, formula l, formula m, formula n, formula o, formula p, formula q, etc.

Chemical formula

[0043] The "pharmaceutically acceptable salts" used in the present invention refer to the organic and inorganic salts of the compounds of the present invention. Pharmaceutically acceptable salts are well-known in the art as described in the literature: S.M. Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66: 1-19. Salts formed from pharmaceutically acceptable non-toxic acids include inorganic acid salts (e.g., hydrochloride, hydrobromide, phosphate, sulfate, perchlorate) formed by reacting with amino groups, and organic acid salts (e.g., acetate, oxalate, maleate, tartrate, citrate, succinate, malonate), or salts obtained by other methods described in books and literature (e.g., ion exchange method), but are not limited thereto. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, besylate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, digalacturonate, lactate, laurate, lauryl sulfate, malate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, stearate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, etc. Salts obtained by reacting with appropriate bases include alkali metal salts, alkaline earth metal salts, ammonium salts and N +It contains a (C1-C4 alkyl)4 salt. The present invention contemplates any quaternary ammonium salt formed from a compound containing a group of N. The water-soluble or oil-soluble or dispersion is obtained by quaternization. The alkali metal salt or alkaline earth metal salt includes sodium salt, lithium salt, potassium salt, calcium salt, magnesium salt, etc. The pharmaceutically acceptable salts further include appropriate non-toxic ammonium salts, quaternary ammonium salts and amine cations formed from counterions, for example, halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C 1~8 sulfonates and aromatic sulfonates.

[0044] In the present invention, the term "solvate" refers to a compound formed from one or more solvent molecules and a compound of the present invention. The solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid and aminoethanol. The term "hydrate" refers to a compound formed when the solvent molecule is water.

[0045] When the solvent is water, the term "hydrate" can be used. In some embodiments, one molecule of a compound of the present invention can bind to one water molecule, for example, a monohydrate. In some other embodiments, one molecule of a compound of the present invention can bind to one or more water molecules, for example, a dihydrate. In some other embodiments, one molecule of a compound of the present invention can bind to less than one water molecule, for example, a hemihydrate. It should be noted that the biological availability of the compound in the non-hydrated form is maintained in the hydrates described in the present invention.

Summary of the Invention

[0046] The imidazothiazole compound provided by the present invention can effectively inhibit ATX activity, and most of them are superior to Comparative Example 1 in terms of in vitro enzyme activity. It has a high exposure amount and bioavailability in the body of rats, and can be used to manufacture therapeutic drugs for diseases having an increased expression of ATX as a pathological feature, such as cancer, fibrotic diseases (e.g., pulmonary fibrosis or liver fibrosis), metabolic diseases, myelodysplastic syndromes, cardiovascular diseases, autoimmune diseases, inflammation, neurological diseases or pain.

[0047] In one aspect of the present invention, there is provided a novel imidazothiazole compound having the structure represented by formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, N-oxide, metabolite, prodrug, or mixture thereof.

Chemical formula

Chemical formula

[0048] In some embodiments, for the compound of the present invention, or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, N-oxide, metabolite, prodrug, or mixture thereof, the compound has a structure represented by formula (II).

Chemical formula

[0049] In some embodiments, R 1a is H, C 2~4 alkyl group, C 1~4 haloalkyl group, C 1~4 hydroxyalkyl group, C 3~6 cycloalkyl group, or C 3~6 cycloalkyl C 1~4 alkyl group, provided that the C 2~4 alkyl group, C 1~4 haloalkyl group, C 1~4 hydroxyalkyl group, C 3~6 cycloalkyl group and C 3~6 cycloalkyl C 1~4 alkyl group is optionally substituted by one, two, three, four or five substituents independently selected from H, D, oxo (C=O), -CN, -NO2, -OH, -NH2, -N3, F, Cl, Br and I.

[0050] In some embodiments, R 1a is H, ethyl group, deuterated ethyl group, isopropyl group, trifluoroethyl group, trifluoromethyl group, hydroxyethyl group, cyclopropyl group, or cyclopropylmethyl group.

[0051] In some embodiments, Cy is [Chemical formula] (wherein X 3 is -NH-, or -(CH2) 1~2 -, m3 is 1, 2 or 3, and n1 is 0, 1, 2, 3 or 4.)

[0052] In some embodiments, Cy is [Chemical formula] is

[0053] In some embodiments, R 1b is H, a methyl group, or an ethyl group.

[0054] In some embodiments, Z is C 1~6 alkyl group, C 1~6 haloalkyl group, C 1~6 hydroxyalkyl group, C 1~6 cyanoalkyl group, C 3~6 heterocyclyl C 1~4 alkyl group, or C 3~6 cycloalkyl C 1~4 alkyl group, provided that the C 1~6 alkyl group, C 1~6 haloalkyl group, C 1~6 hydroxyalkyl group, C 1~6 cyanoalkyl group, C 3~6 heterocyclyl C 1~4 alkyl group and C 3~6 cycloalkyl C 1~4 alkyl group is optionally substituted by one or more R 5 , or Z is [Chemical formula] (wherein X 4 is N, or -CH- is, X 5is -O-, -S-, -NH-, -(CH2) m4 -NH-(CH2) m5 -, -(CH2) m4 -O-(CH2) m5 -, -(CH2) m4 -S-(CH2) m5 -, or -(CH2) m6 - and each m4 is independently 1, 2, 3 or 4, each m5 is independently 0, 1, 2, 3 or 4, each m6 is independently 1, 2, 3 or 4, and n2 is 0, 1, 2, 3 or 4.)

[0055] In some embodiments, Z is -CH2CH2OH, -CH2C(CH3)2OH, -CH2C(CH3)2CH2OH, -CH2CH2CN, -CH2CHF2, -CH(CH3)CH2OH, -C(CH3)2CH2OH, -CH2C(CH3)3,

Chemical formula

[0056] In some embodiments, R 4 , R 5 , R 6 , R 7 and R 8 each independently, every time they appear, is H, D, oxo (C=O), -CN, -NO2, -OH, -NH2, F, Cl, Br, I, methyl, ethyl, propyl, isopropyl, tert-butyl, methoxy, ethoxy, -OCH2CF3, -OCH2CH2F, -CF3, -CH2F, -CH2CF3, -CH2CH2F, -CH2CH2CN, CHF2-O-CH2-, CF3-O-CH2-, -CH2OH, or -CH2CH2OH.

[0057] In some embodiments, the compound of the present invention, or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, N-oxide, metabolite, prodrug, or mixture thereof, is a compound having any of the following structures. [Chemical formula] [Chemical formula] [Chemical formula]

[0058] In another aspect of the present invention, there is provided a pharmaceutical composition comprising the compound described in the present invention or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, N-oxide, metabolite, prodrug thereof, and a pharmaceutically acceptable additive, diluent or carrier.

[0059] In some embodiments, the pharmaceutical composition described in the present invention further comprises an additional therapeutic agent.

[0060] In some embodiments, in the composition described in the present invention, the additional therapeutic agent is a therapeutic agent for treating fibrotic diseases, proliferative diseases, inflammatory diseases, autoimmune diseases, respiratory diseases, cardiovascular diseases, neurodegenerative diseases, skin diseases and / or diseases associated with abnormal angiogenesis.

[0061] In some embodiments, in the pharmaceutical composition described in the present invention, the additional therapeutic agent includes, but is not limited to, immunomodulators, analgesics, non-steroidal anti-inflammatory drugs, steroids, synthetic DMARDs, therapeutic agents for proliferative diseases, glucocorticoids, cell growth inhibitors, alkylating agents, antimetabolites, cytotoxic antibiotics, antibodies and the like.

[0062] In another aspect of the present invention, there is provided the use of the compound described in the present invention or the pharmaceutical composition described in the present invention for the manufacture of a drug for preventing or treating a mammalian disease having an increased expression of ATX as a pathological feature.

[0063] In some embodiments, the disease having increased expression of ATX as the pathological feature includes cancer, fibrotic disease, metabolic disease, myelodysplastic syndrome, cardiovascular disease, autoimmune disease, inflammation, neurological disease or pain.

[0064] In some embodiments, the disease having increased expression of ATX as the pathological feature is pulmonary fibrosis or hepatic fibrosis.

[0065] In some embodiments, the compound or pharmaceutical composition thereof of the present invention may be administered in combination with other therapeutic agents.

[0066] In some embodiments, the use described in the present invention includes administering to a mammal a compound or pharmaceutical composition described in the present invention in an amount sufficient to effect said treatment or prevention.

[0067] Pharmaceutical compositions, formulations and their uses When used as a drug, the compound of the present invention is generally administered in the form of a pharmaceutical composition. The composition can be manufactured by methods well known in pharmaceutical technology and contains at least one compound of the present invention of formula I or formula II. Generally, the compound of the present invention is administered in a pharmaceutically effective amount. The amount of the compound of the present invention actually administered is generally determined by a physician from relevant circumstances such as the medical condition being treated, the administration route selected, the specific compound of the present invention being administered, the age, weight and response of the individual patient, and the severity of the patient's symptoms.

[0068] The pharmaceutical composition of the present invention may be administered by various routes such as oral, rectal, transdermal, subcutaneous, intra-articular, intravenous, intramuscular, intranasal, etc. Depending on the predetermined administration route, the compound of the present invention is preferably formulated as an injectable or oral composition, or as an ointment, lotion or patch (for transdermal administration).

[0069] As a liquid composition for oral administration, pharmaceutically acceptable solutions, suspensions, emulsions, syrups and elixirs containing an inert diluent (e.g., water or liquid paraffin) can be used. These compositions may further contain substances other than the diluent, and in some embodiments, contain a wetting agent, a sweetening agent or a flavoring agent.

[0070] The composition for parenteral administration may be an emulsion or a sterile solution. In some embodiments, propylene glycol, polyethylene glycol, vegetable oil, particularly olive oil or an injectable organic ester can be used as a solvent or a carrier, and in some embodiments, ethyl oleate is used as a solvent or a carrier. These compositions may further contain adjuvants (particularly a wetting agent, an isotonic agent, an emulsifying agent, a dispersing agent, a stabilizing agent). They can be sterilized by multiple methods, and in some embodiments, are sterilized by irradiation or heating using a bacteriological filter. They are manufactured in the form of a sterile solid composition and may be dissolved in sterile water or any other injectable sterile medium at the time of use.

[0071] The composition may be an aerosol. For use in the form of a liquid aerosol, the composition may be a stable sterile solution or a solid composition that dissolves in sterile water, physiological saline or any other pharmaceutically acceptable carrier that does not contain a pyrogenic substance at the time of use. For use in the form of a dry aerosol for direct inhalation, the active ingredient is accurately divided and combined with a water-soluble solid diluent or a carrier, and in some embodiments, combined with dextran, mannitol or lactose.

[0072] Typical pharmaceutical compositions and dosage forms include one or more additives. Suitable additives are well-known to those skilled in the pharmaceutical art, and in some embodiments, suitable additives include starch, glucose, lactose, sucrose, gelatin, malt, rice, wheat flour, chalk, silica gel, sodium stearate, glyceryl monostearate, talc, sodium chloride, nonfat dry milk, glycerol, propylene glycol, water, ethanol, and the like. Whether a particular additive should be included in a pharmaceutical composition or dosage form depends on various factors well-known in the art, including but not limited to the mode of administration of the dosage form to a subject and the particular active ingredient(s) in the dosage form. If necessary, the composition or single unit dosage form may contain a small amount of wetting or emulsifying agent, or a pH buffering agent.

[0073] In another aspect of the invention, there is provided a compound of the invention for medical use or a pharmaceutical composition comprising a compound of the invention. In certain embodiments of the invention, there is provided a compound of the invention or a pharmaceutical composition comprising a compound of the invention for preventing and / or treating a fibrotic disease, a proliferative disease, an inflammatory disease, an autoimmune disease, a respiratory disease, a cardiovascular disease, a neurodegenerative disease, a skin disease, and / or a disease associated with abnormal angiogenesis.

[0074] In some embodiments of the invention, there is provided a compound of the invention or a pharmaceutical composition comprising a compound of the invention for manufacturing a drug for preventing and / or treating a fibrotic disease, a proliferative disease, an inflammatory disease, an autoimmune disease, a respiratory disease, a cardiovascular disease, a neurodegenerative disease, a skin disease, and / or a disease associated with abnormal angiogenesis.

[0075] In some embodiments of the invention, there is provided a pharmaceutical composition comprising a compound of the invention and another therapeutic agent. In certain embodiments of the invention, the other therapeutic agent is an agent for treating a fibrotic disease, a proliferative disease, an inflammatory disease, an autoimmune disease, a respiratory disease, a cardiovascular disease, a neurodegenerative disease, a skin disease, and / or a disease associated with abnormal angiogenesis.

[0076] In some embodiments of the present invention, there is provided a compound of the present invention or a pharmaceutical composition comprising the compound of the present invention for preventing and / or treating fibrotic diseases. In certain embodiments of the present invention, the fibrotic disease is idiopathic pulmonary fibrosis (IPF), cystic fibrosis, other diffuse parenchymal lung diseases due to various etiologies (including drug-induced fibrosis, occupational and / or environmental-induced fibrosis), granulomatous diseases (sarcoidosis, allergic pneumonia), collagen vascular diseases, alveolar proteinosis, Langerhans cell histiocytosis, lymphangioleiomyomatosis, genetic diseases (Hermansky-Pudlak syndrome, tuberous sclerosis, neurofibroma, storage metabolic disorders, familial interstitial pneumonia), radiation-induced fibrosis, chronic obstructive pulmonary disease (COPD), scleroderma, bleomycin-induced pulmonary fibrosis, chronic asthma, silicosis, asbestos-induced pulmonary fibrosis, acute respiratory distress syndrome (ARDS), renal fibrosis, tubulointerstitial nephritis, glomerulonephritis, focal segmental glomerulosclerosis, IgA nephropathy, hypertension, Alport syndrome, intestinal fibrosis, liver fibrosis, cirrhosis, alcoholic liver fibrosis, toxin / drug-induced liver fibrosis, hemochromatosis, non-alcoholic steatohepatitis (NASH), bile duct injury, primary biliary cirrhosis, infection-induced liver fibrosis, virus-induced liver fibrosis and autoimmune hepatitis, corneal scar, hypertrophic scar, Dupuytren's contracture, keloid, dermatofibroma, scleroderma of the skin, systemic sclerosis, spinal cord injury / fibrosis, myelofibrosis, vascular restenosis, atherosclerosis, arteriosclerosis, polyangiitis granulomatosa, Peyronie's disease or chronic lymphocytic leukemia. In particular, the fibrotic disease is idiopathic pulmonary fibrosis (IPF).

[0077] In some other embodiments, the present invention provides a compound of the present invention or a pharmaceutical composition comprising the compound of the present invention for use in the manufacture of a medicament for preventing and / or treating fibrotic diseases. In certain embodiments, the fibrotic disease is idiopathic pulmonary fibrosis (IPF), cystic fibrosis, other diffuse parenchymal lung diseases of various etiologies (including drug-induced fibrosis, occupational and / or environmental-induced fibrosis), granulomatous diseases (sarcoidosis, allergic pneumonia), collagen vascular diseases, alveolar proteinosis, Langerhans cell histiocytosis, lymphangioleiomyomatosis, genetic diseases (Hermansky-Pudlak syndrome, tuberous sclerosis, neurofibroma, storage metabolic disorders, familial interstitial pneumonia), radiation-induced fibrosis, chronic obstructive pulmonary disease (COPD), scleroderma, bleomycin-induced pulmonary fibrosis, chronic asthma, silicosis, asbestos-induced pulmonary fibrosis, acute respiratory distress syndrome (ARDS), renal fibrosis, tubulointerstitial nephritis, glomerulonephritis, focal segmental glomerulosclerosis, IgA nephropathy, hypertension, Alport syndrome, intestinal fibrosis, liver fibrosis, cirrhosis, alcoholic liver fibrosis, toxin / drug-induced liver fibrosis, hemochromatosis, non-alcoholic steatohepatitis (NASH), bile duct injury, primary biliary cirrhosis, infection-induced liver fibrosis, virus-induced liver fibrosis and autoimmune hepatitis, corneal scar, hypertrophic scar, Dupuytren's contracture, keloid, dermatofibroma, scleroderma of the skin, systemic sclerosis, spinal cord injury / fibrosis, myelofibrosis, vascular restenosis, atherosclerosis, arteriosclerosis, polyangiitis granulomatosa, Peyronie's disease or chronic lymphocytic leukemia. In particular, the fibrotic disease is idiopathic pulmonary fibrosis (IPF).

[0078] As another method of treatment, the present invention provides a prophylactic and / or treatment method comprising administering to a mammal suffering from a fibrotic disease an effective amount of one or more of the compounds or pharmaceutical compositions described in the present invention for the treatment or prevention of said disease. In certain embodiments, the fibrotic disease is idiopathic pulmonary fibrosis (IPF), cystic fibrosis, other diffuse parenchymal lung diseases of various etiologies (including drug-induced fibrosis, occupational and / or environmental-induced fibrosis), granulomatous diseases (sarcoidosis, allergic pneumonia), collagen vascular diseases, alveolar proteinosis, Langerhans cell histiocytosis, lymphangioleiomyomatosis, genetic diseases (Hermansky-Pudlak syndrome, tuberous sclerosis, neurofibromatosis, storage metabolic disorders, familial interstitial lung disease), radiation-induced fibrosis, chronic obstructive pulmonary disease (COPD), scleroderma, bleomycin-induced pulmonary fibrosis, chronic asthma, silicosis, asbestos-induced pulmonary fibrosis, acute respiratory distress syndrome (ARDS), renal fibrosis, tubulointerstitial nephritis, glomerulonephritis, focal segmental glomerulosclerosis, IgA nephropathy, hypertension, Alport syndrome, intestinal fibrosis, liver fibrosis, cirrhosis, alcoholic liver fibrosis, toxin / drug-induced liver fibrosis, hemochromatosis, non-alcoholic steatohepatitis (NASH), bile duct injury, primary biliary cirrhosis, infection-induced liver fibrosis, virus-induced liver fibrosis and autoimmune hepatitis, corneal scar, hypertrophic scar, Dupuytren's contracture, keloid, dermatofibroma, scleroderma of the skin, systemic sclerosis, spinal cord injury / fibrosis, myelofibrosis, vascular restenosis, atherosclerosis, arteriosclerosis, polyangiitis granulomatosa, Peyronie's disease or chronic lymphocytic leukemia. In particular, the fibrotic disease is idiopathic pulmonary fibrosis (IPF).

[0079] Certain embodiments of the method of the present invention involve administering to an individual suffering from a fibrotic disease an effective amount of a compound of the present invention of Formula I, Formula Ia, Formula II or Formula IIa for a time sufficient to reduce the degree of fibrosis in the individual and preferably to halt the events that induce said fibrosis. Certain embodiments of the method involve continuously administering to a patient suffering from progressive idiopathic pulmonary fibrosis an effective amount of a compound of the present invention of Formula I, Formula Ia, Formula II or Formula IIa for a time sufficient to reduce idiopathic pulmonary fibrosis in the patient and preferably to halt the events that induce said idiopathic pulmonary fibrosis.

[0080] To those skilled in the art, it is self-evident that co-administration includes any form that involves delivering two or more active agents to a patient as part of the same treatment regimen. The two or more active agents may be co-administered simultaneously (i.e., as a single pharmaceutical composition), but this is not necessarily the case. The active agents may be administered in different formulations or at different times.

Embodiments for Carrying out the Invention

[0081] Hereinafter, examples will be given to explain the present invention. However, it should be understood that the present invention is not limited to these examples and that only a method for carrying out the present invention is provided.

[0082] Generally, the compounds of the present invention can be produced by the methods described in the present invention, and unless otherwise explained, the definitions of their substituents are as shown in Formula I or Formula II. The following reaction schemes and examples are for illustrative purposes to further explain the content of the present invention.

[0083] One skilled in the art can envision that the chemical reactions described in the present invention are suitable for manufacturing many other compounds of the present invention, and all other methods for manufacturing the compounds of the present invention are considered to be within the scope of the present invention. For example, the synthesis of compounds not listed in the present invention can be carried out by methods such as appropriately protecting interfering groups by those skilled in the art, using reagents different from those described in the present invention, or making ordinary modifications to some of the reaction conditions. Also, the reactions or known reaction conditions disclosed in the present invention are generally recognized as suitable for the manufacture of other compounds of the present invention.

[0084] In the examples described below, unless otherwise specified, all temperatures are in degrees Celsius. The reagents are purchased from suppliers such as Aldrich Chemical Company, Arco Chemical Company, Energy-chemical Company, Shanghai Shaoyuan Company, J&K Chemical Company, Aladdin Chemical Company, Meryer Chemical Company, TCI Chemical Company, Xiya Reagent Company, Bidepharm Company, Macklin Company, and Alfa Chemical Company, and are not further purified when used unless otherwise specified. General reagents are purchased from Shantou Xilong Chemical Factory, Guangdong Guanghua Chemical Reagent Factory, Guangzhou Chemical Reagent Factory, Tianjin Haoyu Chemical Co., Ltd., Tianjin Fuchen Chemical Reagent Factory, Wuhan Jinhuayuan Technology Development Co., Ltd., Qingdao Tenglong Chemical Reagent Co., Ltd., and Qingdao Ocean Chemical Factory.

[0085] Anhydrous tetrahydrofuran, dioxane, toluene, and diethyl ether are obtained by refluxing and drying over metallic sodium. Anhydrous dichloromethane and chloroform are obtained by refluxing and drying over calcium hydride. Ethyl acetate, petroleum ether, n-hexane, N,N-dimethylacetamide, and N,N-dimethylformamide are dried over anhydrous sodium sulfate in advance before use.

[0086] The following reactions are generally carried out under a positive pressure of nitrogen or argon (unless otherwise specified), or with a dry tube attached above an anhydrous solvent. All reaction vials are fitted with appropriate rubber stoppers, and the substrate is injected with a syringe. All glass containers are dried.

[0087] A silica gel column is used as the column. The silica gel (300 - 400 mesh) is purchased from Qingdao Marine Chemical Factory.

[0088] 1 1H NMR spectra are recorded using a Bruker 400 MHz or 600 MHz nuclear magnetic resonance spectrometer. 1 1H NMR spectra are referenced to TMS (0 ppm) or chloroform (7.26 ppm) using CDCl3, DMSO-d6, CD3OD, or acetone-d6 as the solvent (in ppm). When multiplets appear, the following abbreviations are used: s (singlet), d (doublet), t (triplet), m (multiplet), br (broadened), dd (doublet of doublets), dt (doublet of triplets). Coupling constants are expressed in Hertz (Hz).

[0089] The measurement conditions for low-resolution mass spectrometry (MS) data are as follows. Agilent 6120 quadrupole HPLC-M (column model: Zorbax SB-C18, 2.1×30 mm, 3.5 μm, 6 minutes, flow rate 0.6 mL / min. Mobile phase: 5% - 95% (ratio in (H2O containing 0.1% formic acid) to (CH3CN containing 0.1% formic acid)), detected by UV at 210 nm / 254 nm using electrospray ionization (ESI).

[0090] Pure compounds are detected by UV at 210 nm / 254 nm using an Agilent 1260 pre-HPLC or a Calesep pump 250 pre-HPLC (column model: NOVASEP 50 / 80 mm DAC).

[0091] Typical synthetic steps for the production of the compounds disclosed in the present invention are as shown in the following Synthetic Scheme 1.

[0092] Synthetic Scheme 1: [Chemical Formula]

[0093] Here, E 1 is selected from Cl, Br or I, E 2 is selected from Cl, Br, I or B(OH)2, E 3 is selected from Cl, Br, I, OMs, OTs or OTf, Pr 1 is selected from Boc, Cbz or PMB, Pr 2 is selected from a tert-butyl group or 2,4,4-trimethylpent-2-yl, R 1a , R 2 , R 3 , R 6 , Y, Z, Cy and t all have the definitions described in the present invention.

[0094] React Intermediate 1-1 with NBS or phenyltrimethylammonium bromide to obtain Intermediate 1-2, perform a ring-closing reaction of Intermediate 1-2 with thiourea to obtain Intermediate 1-3, react Intermediate 1-3 with Pr 2 NC and aldehyde R 2 CHO to generate Intermediate 1-4 through a three-component reaction under the catalysis of a Lewis acid, react Intermediate 1-4 with acetic acid under heating conditions, and react the obtained intermediate with di-tert-butyl dicarbonate or CbzCl to obtain Intermediate 1-5. After reacting Intermediate 1-5 with a strong base, perform a nucleophilic substitution reaction with Intermediate 1-6, and then react with substituted alkyl R 1a E 2 to obtain Intermediate 1-7. Remove the protecting group Pr 1 from Intermediate 1-7 under acidic conditions or by palladium-catalyzed hydrogenation or by reaction with iodotrimethylsilane to obtain Intermediate 1-8. Perform a nucleophilic substitution reaction of Intermediate 1-8 and Intermediate 2-7 under basic and heating conditions to obtain the compound shown in Formula 1-9.

[0095] (Example) (Example 1) Production of 2-(ethyl(6-ethyl-2-(1-(2-(3-hydroxyazetidin-1-yl)-2-oxoethyl)piperidin-4-yl)imidazo[2,1-b]thiazol-5-yl)amino)-4-(4-fluorophenyl)thiazole-5-carbonitrile [Chemical formula]

[0096] Step 1) Benzyl 4-(hydroxyethyl)piperidine-1-carboxylate Triethylamine (1.08 mL, 7.76 mmol) was added to a solution of 2-(piperidin-4-yl)ethanol (0.5 g, 3.88 mmol) in dichloromethane (10 mL), and the mixture was cooled to 0 °C. Benzyl chloroformate (0.6 mL, 4.26 mmol) was added dropwise. After stirring the reaction mixture at 0 °C for 2 hours, it was concentrated under reduced pressure to remove the solvent. Water (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 0.8 g of a crude product, which was used directly in the reaction of the next step.

[0097] Step 2) Benzyl 4-(oxoethyl)piperidine-1-carboxylate Under nitrogen protection, at -70 °C, dimethyl sulfoxide (0.8 mL, 11.2 mmol) was added dropwise to a dichloromethane (5 mL) solution of oxalyl chloride (0.48 mL, 5.67 mmol). After stirring the mixture for 30 minutes, a dichloromethane (8 mL) solution of benzyl 4-(hydroxyethyl)piperidine-1-carboxylate (0.8 g, 3.04 mmol) was added dropwise, and then triethylamine (2.3 mL, 16.6 mmol) was added dropwise. After stirring for 1 hour, the mixture was concentrated under reduced pressure to remove the solvent, water (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting residue was purified by column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain the title compound (0.57 g, 72%) as a pale yellow oil. LCMS [M+1] + : 262.1.

[0098] Step 3) Benzyl 4-(1-bromo-2-oxoethyl)piperidine-1-carboxylate At 0 °C, trimethylphenylammonium tribromide (0.94 g, 2.5 mmol) was added to a tetrahydrofuran (5 mL) solution of benzyl 4-(oxoethyl)piperidine-1-carboxylate (0.57 g, 2.18 mmol). The resulting mixture was stirred at this temperature for 50 minutes. It was concentrated under reduced pressure, water (15 mL) was added to the residue, and the mixture was extracted with ethyl acetate (15 mL × 3). The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the title compound (714 mg) was obtained as a pale yellow oil. It was used directly in the reaction of the next step.

[0099] Step 4) Benzyl 4-(2-aminothiazol-5-yl)piperidine-1-carboxylate A solution of benzyl 4-(1-bromo-2-oxoethyl)piperidine-1-carboxylate (710 mg, 2.09 mmol) in absolute ethanol (12 mL) was added with thiourea (0.33 g, 4.4 mmol). The resulting mixture was reacted at 80 °C for 2 hours. The reaction was stopped, and the reaction solution was cooled to room temperature, concentrated under reduced pressure, water (30 mL) was added, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic layers were combined, washed with saturated sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the obtained residue was purified by column chromatography (petroleum ether:ethyl acetate = 2:1) to obtain the product (0.54 g, 81%). LCMS [M+1] + : 318.1

[0100] Step 5) Benzyl 4-(5-(tert-butylamino)-6-ethylimidazo[2,1-b]thiazol-2-yl)piperidine-1-carboxylate At 0 °C, tert-butyl isocyanide (0.17 g, 2 mmol), n-propionaldehyde (0.1 g, 3.4 mmol) and magnesium chloride (10 mg, 0.08 mmol) were added in this order to a solution of benzyl 4-(2-aminothiazol-5-yl)piperidine-1-carboxylate (0.54 g, 1.7 mmol) in ethylene glycol dimethyl ether (15 mL). The mixture was stirred for 10 minutes, then the temperature was raised to room temperature and stirred for 2 hours. It was filtered, and the reaction solution was concentrated under reduced pressure to obtain the crude product (0.5 g). LCMS [M+1] + : 441.2

[0101] Step 6) tert-Butyl 4-(5-acetamido-6-ethylimidazo[2,1-b]thiazol-2-yl)piperidine-1-carboxylate To a solution of benzyl 4-(5-(tert-butylamino)-6-ethylimidazo[2,1-b]thiazol-2-yl)piperidine-1-carboxylate (0.5 g, 1.14 mmol) in acetic acid (5 mL) was added p-toluenesulfonic acid (0.22 g, 1.14 mmol), and the mixture was reacted at 100 °C overnight. When the reaction solution cooled, it was concentrated under reduced pressure, ethyl acetate (15 mL) and water (15 mL) were added, the aqueous phase was separated, dioxane (10 mL), triethylamine (0.79 mL, 5.7 mmol) and di-tert-butyl dicarbonate (0.39 mL, 1.71 mmol) were added to the aqueous phase, and the mixture was stirred at room temperature for 3 hours. It was concentrated under reduced pressure, water (20 mL) was added to the residue, and it was extracted with ethyl acetate (15 mL × 3). The organic layers were combined, the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting residue was purified by column chromatography (petroleum ether:ethyl acetate = 1:1) to obtain the product (0.2 g, 45%). LCMS [M+1] + : 393.2.

[0102] Step 7) tert-Butyl 4-(5-((5-cyano-4-(4-fluorophenyl)thiazol-2-yl)(ethyl)amino)-6-ethylimidazo[2,1-b]thiazol-2-yl)piperidine-1-carboxylate Under an ice bath and nitrogen protection, 60% NaH (46 mg, 1.14 mmol) was added to a solution of tert-butyl 4-(5-acetamido-6-ethylimidazo[2,1-b]thiazol-2-yl)piperidine-1-carboxylate (150 mg, 0.38 mmol) in tetrahydrofuran (6 mL). After the mixture was stirred for 15 minutes, a solution of 2-chloro-4-(4-fluorophenyl)thiazole-5-carbonitrile (91 mg, 0.38 mmol) in tetrahydrofuran (3 mL) was slowly added dropwise. The temperature of the mixture was raised to room temperature and reacted for 30 minutes. As a result of monitoring by TLC plate and complete reaction, iodomethane (89 mg, 0.57 mmol) was added and the reaction was continued for 3 hours. As a result of detection by LC-MS, the reaction was complete. The reaction solution was poured into water (20 mL) and extracted with ethyl acetate (15 mL×3). The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether:ethyl acetate = 3:1) to obtain the title compound (137 mg, 62%) as a white solid. LCMS [M+1] + : 581.2.

[0103] Step 8) 2-((6-Ethyl-2-(piperidin-4-yl)imidazo[2,1-b]thiazol-5-yl)(ethyl)amino)-4-(4-fluorophenyl)thiazole-5-carbonitrile 4-(5-((5-Cyano-4-(4-fluorophenyl)thiazol-2-yl)(ethyl)amino)-6-ethylimidazo[2,1-b]thiazol-2-yl)piperidine-1-carboxylic acid tert-butyl (137 mg, 0.24 mmol) in dichloromethane (3 mL), trifluoroacetic acid (0.5 mL) was added. After the mixture was stirred at room temperature for 3 hours and the reaction was complete as a result of detection by LC-MS, it was concentrated under reduced pressure. The residue was dissolved in methanol (6 mL), NaHCO3 (50 mg) was added and stirred for 30 minutes for neutralization, then concentrated under reduced pressure. Dichloromethane (10 mL) was added to the residue to dissolve it, filtered, and concentrated under reduced pressure to obtain the title compound (112 mg, 98%) as a white solid. MS (m / z): 481.2 [M+1].

[0104] Step 9) 2-(Ethyl(6-ethyl-2-(1-(2-(3-hydroxyazetidin-1-yl)-2-oxoethyl)piperidin-4-yl)imidazo[2,1-b]thiazol-5-yl)amino)-4-(4-fluorophenyl)thiazole-5-carbonitrile To a solution of 2-((6-ethyl-2-(piperidin-4-yl)imidazo[2,1-b]thiazol-5-yl)(ethyl)amino)-4-(4-fluorophenyl)thiazole-5-carbonitrile (112 mg, 0.23 mmol) in acetonitrile (3 mL) were added K2CO3 (96 mg, 0.70 mmol), KI (19 mg, 0.12 mmol) and 2-chloro-1-(3-hydroxyazetidin-1-yl)ethanone (35 mg, 0.23 mmol). The temperature of the resulting mixture was raised to 65 °C and reacted for 5 hours. As a result of detection by LC-MS, the reaction was completed. It was filtered, concentrated under reduced pressure, and the residue was purified by a thick preparative plate (dichloromethane:methanol = 20:1) to obtain the title compound (66 mg, 48%) as a white solid. 1 H NMR (400 MHz, CDCl3) δ: 8.13 (m, 2H), 7.16 (m, 2H), 6.94 (m, 1H), 4.68 (m, 1H), 4.44 (m, 1H), 4.28 (m, 1H), 4.11 (m, 2H), 3.94 (m, 2H), 3.21 (m, 4H), 2.76 (m, 1H), 2.60 (m, 2H), 2.47 (m, 2H), 2.04 (m, 2H), 1.31 (m, 6H), 1.25 (s, 3H). LCMS [M+1] + : 594.2.

[0105] (Example 2) Production of 2-(Cyclopropylmethyl(6-ethyl-2-(1-(2-(3-hydroxyazetidin-1-yl)-2-oxoethyl)piperidin-4-yl)imidazo[2,1-b]thiazol-5-yl)amino)-4-(4-fluorophenyl)thiazole-5-carbonitrile

Chemical formula

[0106] (Example 3) Preparation of 2-(4-(5-((5-cyano-4-(4-fluorophenyl)thiazol-2-yl)(ethyl)amino)-6-ethylimidazo[2,1-b]thiazol-2-yl)piperidin-1-yl)-N-(2-hydroxyethyl)acetamide

Chemical Structure

[0107] Step 1) Ethyl 2-(4-(5-((5-cyano-4-(4-fluorophenyl)thiazol-2-yl)(ethyl)amino)-6-ethylimidazo[2,1-b]thiazol-2-yl)piperidin-1-yl)acetate 2-((6-Ethyl-2-(piperidin-4-yl)imidazo[2,1-b]thiazol-5-yl)(ethyl)amino)-4-(4-fluorophenyl)thiazole-5-carbonitrile (2.8 g, 5.83 mmol) in acetonitrile (25 mL) was added potassium carbonate (2.42 g, 17.5 mmol). After cooling the mixture in an ice-water bath, ethyl bromoacetate (1.16 g, 6.95 mmol) was added, and after stirring for 2 hours, the result detected by LC-MS showed that the reaction was complete. The reaction solution was poured into water (30 mL), extracted with ethyl acetate (30 mL × 3), the organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether:ethyl acetate = 1:2) to obtain the title compound (2.31 g, 70%) as a white solid. LCMS [M+1] + : 567.2.

[0108] Step 2) 2-(4-(5-((5-Cyano-4-(4-fluorophenyl)thiazol-2-yl)(ethyl)amino)-6-ethylimidazo[2,1-b]thiazol-2-yl)piperidin-1-yl)acetic acid To a solution of ethyl 2-(4-(5-((5-cyano-4-(4-fluorophenyl)thiazol-2-yl)(ethyl)amino)-6-ethylimidazo[2,1-b]thiazol-2-yl)piperidin-1-yl)acetate (2.31 g, 4.08 mmol) in tetrahydrofuran (10 mL) and water (10 mL) was added lithium hydroxide monohydrate (514 mg, 12.2 mmol). The mixture was reacted at room temperature for 3 hours, and the result detected by LC-MS showed that the reaction was complete. It was concentrated under reduced pressure, water (50 mL) was added to the residue, the pH was adjusted to about 5 with 1N HCl, filtered, the filter cake was washed with water, and baked to obtain the title compound (1.98 g, 90%) as a white solid. LCMS [M+1] + : 539.2.

[0109] Step 3) 2-(4-(5-((5-Cyano-4-(4-fluorophenyl)thiazol-2-yl)(ethyl)amino)-6-ethylimidazo[2,1-b]thiazol-2-yl)piperidin-1-yl)-N-(2-hydroxyethyl)acetamide To a solution of 2-(4-(5-((5-Cyano-4-(4-fluorophenyl)thiazol-2-yl)(ethyl)amino)-6-ethylimidazo[2,1-b]thiazol-2-yl)piperidin-1-yl)acetic acid (50 mg, 0.093 mmol) in dichloromethane (3 mL) were added HATU (46 mg, 0.12 mmol), DIPEA (36 mg, 0.28 mmol) and ethanolamine (11 mg, 0.18 mmol) in this order. The resulting mixture was stirred at room temperature for 2 hours and then concentrated under reduced pressure. The residue was purified by thick preparative plate (DCM:MeOH = 15:1) to give the title compound (50 mg, 93%) as a white solid. 1 1H NMR (400 MHz, CD3OD) δ: 8.12 (m, 2H), 7.52 (m, 1H), 7.25 (m, 2H), 4.17 (m, 1H), 4.01 (m, 1H), 3.73 (m, 2H), 3.61 (m, 2H), 3.35 (m, 2H), 3.24 (m, 2H), 3.11 (m, 2H), 3.03 (m, 1H), 2.88 (m, 1H), 2.60 (m, 2H), 2.37 (m, 1H), 2.03 (m, 2H), 1.88 (m, 2H), 1.30 (m, 6H). LCMS [M+1] + : 582.3.

[0110] (Example 4) Preparation of 2-(4-(5-((5-Cyano-4-(4-fluorophenyl)thiazol-2-yl)(ethyl)amino)-6-ethylimidazo[2,1-b]thiazol-2-yl)piperidin-1-yl)-N-(2-hydroxyethyl)-N-methylacetamide

Chemical formula

[0111] (Example 5) Preparation of 2-(4-(5-((5-cyano-4-(4-fluorophenyl)thiazol-2-yl)(ethyl)amino)-6-ethylimidazo[2,1-b]thiazol-2-yl)piperidin-1-yl)-N-(3-hydroxycyclobutyl)acetamide

Chemical Structure

[0112] (Example 6) Preparation of 2-((6-Ethyl-2-(1-(2-(3-hydroxyazetidin-1-yl)-2-oxoethyl)piperidin-4-yl)imidazo[2,1-b]thiazol-5-yl)(2,2,2-trifluoroethyl)amino)-4-(4-fluorophenyl)thiazole-5-carbonitrile [Chemical Structure] The synthesis steps of 2-((6-Ethyl-2-(1-(2-(3-hydroxyazetidin-1-yl)-2-oxoethyl)piperidin-4-yl)imidazo[2,1-b]thiazol-5-yl)(2,2,2-trifluoroethyl)amino)-4-(4-fluorophenyl)thiazole-5-carbonitrile refer to Example 1, except that 2,2,2-trifluoroethyl methanesulfonate was used instead of ethyl iodide to obtain the title compound (96 mg, 87%) as a white solid. 1 1H NMR (400 MHz, CD3OD) δ: 8.15 (m, 2H), 7.51 (m, 1H), 7.27 (m, 2H), 4.88 (m, 1H), 4.75 (m, 1H), 4.51 (m, 1H), 4.47 (m, 1H), 4.21 (m, 1H), 4.05 (m, 1H), 3.78 (m, 1H), 3.14 (m, 2H), 3.02 (m, 2H), 2.84 (m, 1H), 2.61 (m, 2H), 2.26 (m, 2H), 2.03 (m, 2H), 1.82 (m, 2H), 1.30 (m, 3H). LCMS [M+1] + : 648.1

[0113] (Example 7) Preparation of 2-((ethyl-d5)(6-ethyl-2-(1-(2-(3-hydroxyazetidin-1-yl)-2-oxoethyl)piperidin-4-yl)imidazo[2,1-b]thiazol-5-yl)amino)-4-(4-fluorophenyl)thiazole-5-carbonitrile

Chemical Structure

[0114] (Example 8) Preparation of 2-(4-(5-((5-cyano-4-(4-fluorophenyl)thiazol-2-yl)(ethyl)amino)-6-ethylimidazo[2,1-b]thiazol-2-yl)piperidin-1-yl)-N-(2-hydroxy-2-methylpropyl)acetamide

Chemical Structure

[0115] (Example 9) Preparation of 2-(4-(5-((5-cyano-4-(4-fluorophenyl)thiazol-2-yl)(ethyl)amino)-6-ethylimidazo[2,1-b]thiazol-2-yl)piperidin-1-yl)-N-(3-hydroxy-2,2-dimethylpropyl)acetamide

Chemical Structure

[0116] (Example 10) Preparation of 2-(4-(5-((5-Cyano-4-(4-fluorophenyl)thiazol-2-yl)(ethyl)amino)-6-ethylimidazo[2,1-b]thiazol-2-yl)piperidin-1-yl)-N-(2-cyanoethyl)-N-methylacetamide

Chemical Structure

[0117] (Example 11) Preparation of 2-(4-(5-((5-Cyano-4-(4-fluorophenyl)thiazol-2-yl)(ethyl)amino)-6-ethylimidazo[2,1-b]thiazol-2-yl)piperidin-1-yl)-N-(2,2-difluoroethyl)acetamide

Chem.

[0118] (Example 12) Preparation of 2-(4-(5-((5-Cyano-4-(4-fluorophenyl)thiazol-2-yl)(ethyl)amino)-6-ethylimidazo[2,1-b]thiazol-2-yl)piperidin-1-yl)-N-(1-(hydroxymethyl)cyclopropyl)acetamide

Chem.

[0119] (Example 13) Preparation of 2-(4-(5-((5-cyano-4-(4-fluorophenyl)thiazol-2-yl)(ethyl)amino)-6-ethylimidazo[2,1-b]thiazol-2-yl)piperidin-1-yl)-N-(1-hydroxypropan-2-yl)acetamide

Chemical formula

[0120] (Example 14) Preparation of 2-(4-(5-((5-Cyano-4-(4-fluorophenyl)thiazol-2-yl)(ethyl)amino)-6-ethylimidazo[2,1-b]thiazol-2-yl)piperidin-1-yl)-N-(1-hydroxy-2-methylpropan-2-yl)acetamide [Chemical formula] The synthesis steps of 2-(4-(5-((5-Cyano-4-(4-fluorophenyl)thiazol-2-yl)(ethyl)amino)-6-ethylimidazo[2,1-b]thiazol-2-yl)piperidin-1-yl)-N-(1-hydroxy-2-methylpropan-2-yl)acetamide refer to Example 3, and the title compound (41 mg, 72%) was obtained as a white solid, except that 2-amino-2-methyl-1-propanol was used instead of ethanolamine. 1 1H NMR (400 MHz, CD3OD) δ: 8.13 (m, 2H), 7.53 (m, 1H), 7.24 (m, 2H), 4.19 (m, 1H), 4.01 (m, 1H), 3.73 (m, 1H), 3.54 (m, 2H), 3.22 (m, 1H), 3.04 (m, 4H), 2.88 (m, 1H), 2.61 (m, 2H), 2.40 (m, 2H), 2.08 (m, 2H), 1.84 (m, 2H), 1.30 (m, 12H). LCMS [M+1] + : 610.2

[0121] (Example 15) Preparation of 2-(4-(5-((5-Cyano-4-(4-fluorophenyl)thiazol-2-yl)(ethyl)amino)-6-ethylimidazo[2,1-b]thiazol-2-yl)piperidin-1-yl)-N-((1-hydroxycyclopropyl)methyl)acetamide

Chem.

[0122] (Example 16) Preparation of 2-(4-(5-((5-Cyano-4-(4-fluorophenyl)thiazol-2-yl)(ethyl)amino)-6-ethylimidazo[2,1-b]thiazol-2-yl)piperidin-1-yl)-N-((1-hydroxycyclobutyl)methyl)acetamide

Chem.

[0123] (Example 17) Preparation of 2-(4-(5-((5-cyano-4-(4-fluorophenyl)thiazol-2-yl)(ethyl)amino)-6-ethylimidazo[2,1-b]thiazol-2-yl)piperidin-1-yl)-N-(3,3-difluorocyclobutyl)acetamide

Chemical Structure

[0124] (Example 18) Preparation of 2-(4-(5-((5-Cyano-4-(4-fluorophenyl)thiazol-2-yl)(ethyl)amino)-6-ethylimidazo[2,1-b]thiazol-2-yl)piperidin-1-yl)-N-(cyclopropylmethyl)acetamide

Chemical Structure

[0125] (Example 19) Preparation of 2-(4-(5-((5-Cyano-4-(4-fluorophenyl)thiazol-2-yl)(ethyl)amino)-6-ethylimidazo[2,1-b]thiazol-2-yl)piperidin-1-yl)-N-(cyclobutylmethyl)acetamide

Chem.

[0126] (Example 20) Preparation of 2-(4-(5-((5-Cyano-4-(4-fluorophenyl)thiazol-2-yl)(ethyl)amino)-6-ethylimidazo[2,1-b]thiazol-2-yl)piperidin-1-yl)-N-tert-amylacetamide

Chem.

[0127] (Example 21) Preparation of 2-(4-(5-((5-cyano-4-(4-fluorophenyl)thiazol-2-yl)(ethyl)amino)-6-ethylimidazo[2,1-b]thiazol-2-yl)piperidin-1-yl)-N-(3-oxetanyl)acetamide

Chemical formula

[0128] (Example 22) Preparation of 2-(ethyl(6-ethyl-2-(1-(2-morpholinyl-2-oxoethyl)piperidin-4-yl)imidazo[2,1-b]thiazol-5-yl)amino)-4-(4-fluorophenyl)thiazole-5-carbonitrile [Chemical Structure] The synthesis steps of 2-(ethyl(6-ethyl-2-(1-(2-morpholinyl-2-oxoethyl)piperidin-4-yl)imidazo[2,1-b]thiazol-5-yl)amino)-4-(4-fluorophenyl)thiazole-5-carbonitrile refer to Example 3, except that morpholine was used instead of ethanolamine to obtain the title compound (41 mg, 73%) as a white solid. 1 1H NMR (400 MHz, CD3OD) δ: 8.13 (m, 2H), 7.52 (m, 1H), 7.25 (m, 2H), 4.17 (m, 1H), 4.00 (m, 1H), 3.65 (m, 5H), 3.58 (m, 2H), 3.03 - 3.96 (m, 5H), 2.87 (m, 1H), 2.61 (m, 2H), 2.25 (m, 2H), 2.04 (m, 2H), 1.78 (m, 2H), 1.30 (m, 6H). LCMS [M+1] + : 608.1.

[0129] (Example 23) Preparation of 2-(4-(5-((5-Cyano-4-(4-fluorophenyl)thiazol-2-yl)(ethyl)amino)-6-ethylimidazo[2,1-b]thiazol-2-yl)piperidin-1-yl)-N-(tetrahydro-2H-pyran-4-yl)acetamide

Chem.

[0130] (Example 24) Preparation of 2-(Cyclopropyl(6-ethyl-2-(1-(2-(3-hydroxyazetidin-1-yl)-2-oxoethyl)piperidin-4-yl)imidazo[2,1-b]thiazol-5-yl)amino)-4-(4-fluorophenyl)thiazole-5-carbonitrile

Chem.

[0131] Step 1) tert-Butyl 4-(5-((5-cyano-4-(4-fluorophenyl)thiazol-2-yl)amino)-6-ethylimidazo[2,1-b]thiazol-2-yl)piperidine-1-carboxylate At 0 °C, sodium hydride (306 mg, 7.65 mmol) was added portionwise to a solution of tert-butyl 4-(5-acetamido-6-ethylimidazo[2,1-b]thiazol-2-yl)piperidine-1-carboxylate (1 g, 2.55 mmol) in tetrahydrofuran (15 mL). After stirring the mixture for 10 minutes, a solution of 2-chloro-4-(4-fluorophenyl)thiazole-5-carbonitrile (596 mg, 2.50 mmol) in tetrahydrofuran (5 mL) was added dropwise. The temperature of the mixture was raised to room temperature to allow the reaction to proceed. When the reaction was detected by LCMS to be complete, the reaction solution was poured into water and extracted with ethyl acetate (15 mL × 3). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether:ethyl acetate = 4:1 to 1.5:1) to obtain the title compound (980 mg, 70%) as a yellow foamy solid. LCMS [M+1] + : 553.3.

[0132] Step 2) tert-Butyl 4-(5-((5-cyano-4-(4-fluorophenyl)thiazol-2-yl)(cyclopropyl)amino)-6-ethylimidazo[2,1-b]thiazol-2-yl)piperidine-1-carboxylate To a solution of tert-butyl 4-(5-((5-cyano-4-(4-fluorophenyl)thiazol-2-yl)amino)-6-ethylimidazo[2,1-b]thiazol-2-yl)piperidine-1-carboxylate (330 mg, 0.60 mmol) in 1,2-dichloroethane (10 mL) were added cyclopropylboronic acid (156 mg, 1.8 mmol), copper(II) acetate (108 mg, 0.60 mmol), 2,2'-bipyridyl (96 mg, 0.60 mmol) and sodium carbonate (192 mg, 1.8 mmol). The mixture was reacted overnight at 75 °C under oxygen (balloon). It was filtered through diatomaceous earth and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether:ethyl acetate = 5:1 - 3:1) to give the title compound (287 mg, 71%) as a pale yellow foamy solid. LCMS [M+1] + : 593.3.

[0133] Step 3) 2-(Cyclopropyl(6-ethyl-2-(piperidin-4-yl)imidazo[2,1-b]thiazol-5-yl]amino}-4-(4-fluorophenyl)thiazole-5-carbonitrile To a solution of tert-butyl 4-(5-((5-cyano-4-(4-fluorophenyl)thiazol-2-yl)(cyclopropyl)amino)-6-ethylimidazo[2,1-b]thiazol-2-yl)piperidine-1-carboxylate (287 mg, 0.48 mmol) in dichloromethane (3 mL) was added trifluoroacetic acid (0.5 mL). The mixture was reacted at room temperature for 2 hours and then concentrated under reduced pressure. Water (15 mL) and dichloromethane (15 mL) were added to the residue, and the pH was adjusted to about 8 with sodium bicarbonate solution. It was extracted with dichloromethane (15 mL × 2). The organic layers were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound (230 mg, 96%) as a pale yellow foamy solid. LCMS [M+1] + : 493.3.

[0134] Step 4) 2-(Cyclopropyl(6-ethyl-2-(1-(2-(3-hydroxyazetidin-1-yl)-2-oxoethyl)piperidin-4-yl)imidazo[2,1-b]thiazol-5-yl)amino)-4-(4-fluorophenyl)thiazole-5-carbonitrile To a solution of 2-(cyclopropyl(6-ethyl-2-(piperidin-4-yl)imidazo[2,1-b]thiazol-5-yl]amino}-4-(4-fluorophenyl)thiazole-5-carbonitrile (50 mg, 0.1 mmol) in acetonitrile (3 mL) were added 2-chloro-1-(3-hydroxyazetidin-1-yl)ethanone (15 mg, 0.1 mmol), potassium carbonate (27 mg, 0.2 mmol) and potassium iodide (8.3 mg, 0.050 mmol), and the mixture was reacted at 70 °C for 2 hours. It was concentrated under reduced pressure, and the obtained residue was purified by thick preparative plate (dichloromethane:isopropanol = 12:1) to obtain the title compound (40 mg, 66%) as a white solid. 1 H NMR (500 MHz, CDCl3) δ: 8.09 (m, 2H), 7.15 (m, 2H), 6.89 (m, 1H), 4.93 (m, 1H), 4.68 (m, 1H), 4.45 (m, 1H), 4.30 (m, 1H), 4.10 (m, 1H), 3.99 (m, 1H), 3.07~2.95 (m, 3H), 2.70 (m, 1H), 2.54 (m, 2H), 2.21 (m, 2H), 2.01 (m, 2H), 1.81 (m, 2H), 1.27 (m, 3H), 0.95 (m, 2H), 0.73 (m, 2H). LCMS [M+1] + : 606.3.

[0135] (Example 25) Production of 2-((6-ethyl-2-(1-(2-(3-hydroxyazetidin-1-yl)-2-oxoethyl)piperidin-4-yl)imidazo[2,1-b]thiazol-5-yl)(isopropyl)amino)-4-(4-fluorophenyl)thiazole-5-carbonitrile [Chemical formula]

[0136] Step 1) tert-Butyl 4-(5-((5-cyano-4-(4-fluorophenyl)thiazol-2-yl)(isopropyl)amino)-6-ethylimidazo[2,1-b]thiazol-2-yl)piperidine-1-carboxylate Sodium hydride (72 mg, 1.8 mmol) was added to a solution of tert-butyl 4-(5-((5-cyano-4-(4-fluorophenyl)thiazol-2-yl)amino)-6-ethylimidazo[2,1-b]thiazol-2-yl)piperidine-1-carboxylate (330 mg, 0.60 mmol) in DMF (9 mL). The mixture was stirred at room temperature for 5 minutes, then 2-bromopropane (282 μL, 3.0 mmol) was added. The reaction mixture was reacted at 85 °C. When the reaction was complete by TLC, the reaction solution was cooled to 0 °C, water was added dropwise to quench the reaction, water (15 mL) was added, and the mixture was extracted with ethyl acetate (15 mL × 3). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting residue was purified by column chromatography (petroleum ether:ethyl acetate = 4:1 to 3:1) to obtain the title compound (365 mg, 89%) as a pale yellow foamy solid. LCMS [M+1] + : 595.3。

[0137] Step 2) 2-((6-Ethyl-2-(piperidin-4-yl)imidazo[2,1-b]thiazol-5-yl)(isopropyl)amino)-4-(4-fluorophenyl)thiazole-5-carbonitrile To a solution of tert-butyl 4-(5-((5-cyano-4-(4-fluorophenyl)thiazol-2-yl)(isopropyl)amino)-6-ethylimidazo[2,1-b]thiazol-2-yl)piperidine-1-carboxylate (365 mg, 0.61 mmol) in dichloromethane (4 mL) was added trifluoroacetic acid (0.45 mL). The mixture was reacted at room temperature for 2 hours and then concentrated under reduced pressure. Water (15 mL) and dichloromethane (15 mL) were added, and the pH was adjusted to about 8 with sodium bicarbonate solution. The mixture was extracted with dichloromethane (15 mL × 2). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the title compound (290 mg, 96%) as a pale yellow foamy solid. LCMS [M+1] + : 495.3.

[0138] Step 3) 2-((6-Ethyl-2-(1-(2-(3-hydroxyazetidin-1-yl)-2-oxoethyl)piperidin-4-yl)imidazo[2,1-b]thiazol-5-yl)(isopropyl)amino)-4-(4-fluorophenyl)thiazole-5-carbonitrile To a solution of 2-((6-ethyl-2-(piperidin-4-yl)imidazo[2,1-b]thiazol-5-yl)(isopropyl)amino)-4-(4-fluorophenyl)thiazole-5-carbonitrile (50 mg, 0.1 mmol) in acetonitrile (3 mL) were added 2-chloro-1-(3-hydroxyazetidin-1-yl)ethanone (15 mg, 0.1 mmol), sodium bicarbonate (21 mg, 0.25 mmol), and potassium iodide (8.3 mg, 0.050 mmol). The mixture was reacted at 70 °C for 3 hours, then filtered and concentrated under reduced pressure. The resulting residue was purified by thick preparative plate (dichloromethane:isopropanol = 12:1) to obtain the title compound (35 mg, 57%) as a white solid. 11H NMR (500 MHz, CDCl3) δ: 8.15 (m, 2H), 7.18 (m, 2H), 6.94 (m, 1H), 5.11 (m, 1H), 4.71 (m, 1H), 4.47 (m, 1H), 4.30 (m, 1H), 4.12 (m, 1H), 3.92 (m, 1H), 3.11 - 3.05 (m, 4H), 2.73 (m, 1H), 2.60 (m, 3H), 2.30 (m, 2H), 2.03 (m, 2H), 1.86 (m, 2H), 1.33 (m, 6H), 1.27 (m, 3H). LCMS [M+1] + : 608.3.

[0139] (Example 26) Preparation of 2-(4-(5-((5-Cyano-4-(4-fluorophenyl)thiazol-2-yl)(isopropyl)amino)-6-ethylimidazo[2,1-b]thiazol-2-yl)piperidin-1-yl)-N-(tetrahydro-2H-pyran-4-yl)acetamide

Chemical Structure

[0140] (Example 27) Preparation of 2-(4-(5-((5-Cyano-4-(4-fluorophenyl)thiazol-2-yl)(isopropyl)amino)-6-ethylimidazo[2,1-b]thiazol-2-yl)piperidin-1-yl)-N-(oxetan-3-yl)acetamide [Chemical formula] The synthesis steps of 2-(4-(5-((5-Cyano-4-(4-fluorophenyl)thiazol-2-yl)(isopropyl)amino)-6-ethylimidazo[2,1-b]thiazol-2-yl)piperidin-1-yl)-N-(oxetan-3-yl)acetamide refer to Example 25, except that 2-chloro-N-(oxetan-3-yl)acetamide was used instead of 2-chloro-1-(3-hydroxyazetidin-1-yl)ethanone to obtain the title compound (48 mg, 72%) as a white solid. 11H NMR (400 MHz, CDCl3) δ: 8.15 (m, 2H), 7.71 - 7.60 (m, 1H), 7.19 (m, 2H), 6.98 (s, 1H), 5.16 - 5.07 (m, 2H), 4.98 (m, 2H), 4.54 (m, 2H), 3.06 (s, 2H), 3.00 - 2.95 (m, 2H), 2.81 - 2.73 (m, 1H), 2.63 - 2.59 (m, 2H), 2.39 - 2.28 (m, 2H), 2.09 - 2.07 (m, 2H), 1.87 - 1.77 (m, 2H), 1.37 - 1.32 (m, 6H), 1.29 - 1.26 (m, 3H). LCMS [M+1] + : 608.3

[0141] Comparative Example 1: 2-(4-(2-Ethyl-3-((4-(4-Fluorophenyl)thiazol-2-yl)(methyl)amino)-8-methylimidazo[1,2a]pyridin-6-yl)piperazin-1-yl)-1-(3-hydroxyazetidin-1-yl)ethanone

Chemical Structure

[0142] Biological Experiment: In Vitro Analysis: Enzyme Activity Screening Using LPC as Substrate Principle: Utilize the ability of the lysoPLD enzyme activity to hydrolyze the substrate lysophosphatidylcholine (LPC for short) to generate lysophosphatidic acid (LPA) and choline. Choline is oxidized by choline oxidase to produce H2O2. When horseradish peroxidase (HRP) is present, Amplex Red reagent and H2O2 react in a 1:1 stoichiometric ratio to generate a product that emits strong fluorescence, thereby quantitatively detecting the fluorescence

[0143] Experimental steps: The test compound of the present invention and Comparative Example 1 were each dissolved in DMSO to prepare a 10 mM stock solution, and then serially diluted 3-fold with DMSO at 10 concentrations with an initial concentration of 10 mM. A mixed solution 1 containing ATX at a final concentration of 2 ng / μL, HRP at 2 U / mL, and choline oxidase at 0.2 U / mL was prepared with a reaction buffer. 20 μL of the mixed solution 1 was added to each well of a test plate at 10 nL / well, and the compound diluted with DMSO was transferred to the test plate using an Echo550. A mixed solution 2 containing LPC at a final concentration of 60 mM and Amplex Red at 400 μM was prepared with a reaction buffer, and 20 μL of the mixed solution 2 was added to each well of the test plate. After loading the samples, the test plate was shaken on a shaker for 30 seconds and incubated at room temperature for 30 minutes. Fluorescence signals at an excitation wavelength of 530 nm and an emission wavelength of 590 nm were read using an Envision. The inhibition rate of the compound against the enzymatic reaction was calculated from the fluorescence ratio values and analyzed with software to calculate the IC 50 value of the compound. The results are shown in Table 1. [Table 1]

[0144] As can be seen from Table 1, the compounds of the present invention have excellent ATX inhibitory activity, and most of the IC 50 values are less than 100 nM and are clearly superior to Comparative Example 1.

[0145] Rat pharmacokinetic experiment: In this study, male SD rats were used as test animals, and the plasma drug concentrations at different time points after intravenous injection and oral administration of the test compounds to the rats were quantitatively measured using the LC / MS / MS method to evaluate the pharmacokinetic characteristics of the test compounds in the body of SD rats.

[0146] The clear solution of the test compound was injected into the body of SD rats via the femoral vein (without diet restriction, 6 - 8 weeks old), and the suspension of the test compound was administered intragastrically to SD rats (without diet restriction, 6 - 8 weeks old). Blood samples were collected from the tail vein of all animals at 0.083, 0.25, 0.5, 1, 2, 4, 6, 8, 10, and 24 hours after administration. The volume of each blood sample collection was 0.15 mL. All the collected whole blood samples were put into centrifuge tubes containing EDTA-K2, and the centrifuge tubes were inverted up and down to fully mix the anticoagulant and the blood. Within 30 minutes, the samples were centrifuged at 4°C and 1500 g for 10 minutes to separate the plasma. The plasma samples were transferred to new centrifuge tubes and stored at -90~-60°C until analysis. The blood drug concentration of the test compound of the present invention was measured by LC-MS / MS, and the pharmacokinetic parameters were calculated using the non-compartmental model of the software Pharsight Phoenix 8.0, and the absolute bioavailability was calculated and shown in Table 2.

Table 2

[0147] It can be seen from Table 2 that the compounds of the present invention have high exposure and bioavailability.

[0148] In short, the compounds of the present invention have good inhibitory activity against ATX, excellent efficacy and pharmacokinetic properties in vivo or in vitro, and are expected to have good clinical use.

[0149] All publications, patents, and patent applications cited herein are incorporated by reference into the present invention to the same extent as if each individual publication, patent, or patent application was specifically and individually stated to be incorporated by reference. Although the technical features claimed are described using various examples / embodiments, those skilled in the art can envision making various modifications / alterations, substitutions, deletions, and changes / variations without departing from the spirit of the present invention. Therefore, the scope of the technical features claimed is limited only by the claims and is intended to include equivalents thereof.

Claims

1. A compound having any one of the following structures, or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, N-oxide or mixture thereof. 【Chemical Formula 50-1】 【Chemical Formula 50-2】

2. A pharmaceutical composition comprising the compound according to Claim 1 or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, N-oxide thereof and a pharmaceutically acceptable additive, diluent or carrier.

3. The pharmaceutical composition according to Claim 2, further comprising an additional therapeutic agent.

4. The compound according to Claim 1 for preventing or treating a mammalian disease having an increased expression of ATX as a pathological feature.

5. The compound according to Claim 1, wherein the disease having an increased expression of ATX as a pathological feature includes cancer, fibrotic disease, metabolic disease, myelodysplastic syndrome, cardiovascular disease, autoimmune disease, inflammation, neurological disease or pain.

6. The compound according to any one of Claims 1 to 5, wherein the disease having an increased expression of ATX as a pathological feature is pulmonary fibrosis or hepatic fibrosis.

7. The pharmaceutical composition according to Claim 2 or 3 for preventing or treating a mammalian disease having an increased expression of ATX as a pathological feature.

8. The pharmaceutical composition according to Claim 2 or 3, wherein the disease having an increased expression of ATX as a pathological feature includes cancer, fibrotic disease, metabolic disease, myelodysplastic syndrome, cardiovascular disease, autoimmune disease, inflammation, neurological disease or pain.

9. The pharmaceutical composition according to Claim 2 or 3, wherein the disease having an increased expression of ATX as a pathological feature is pulmonary fibrosis or hepatic fibrosis.

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