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CN113831337B - GLP-1 receptor agonist, and pharmaceutical composition and use thereof - Google Patents

GLP-1 receptor agonist, and pharmaceutical composition and use thereof Download PDF

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Publication number
CN113831337B
CN113831337B CN202110697757.0A CN202110697757A CN113831337B CN 113831337 B CN113831337 B CN 113831337B CN 202110697757 A CN202110697757 A CN 202110697757A CN 113831337 B CN113831337 B CN 113831337B
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methyl
reaction
ethyl
mixture
added
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CN113831337A (en
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张健存
陈晖旋
陈家锋
何小溪
张菊福
郭琛
李德耀
张礼军
吴烽
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Guangzhou Henovcom Bioscience Co ltd
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Abstract

本发明提供了作为GLP‑1受体激动剂的式(I)所示的杂芳基化合物、或其药学上可接受的盐、水合物、溶剂化物、立体异构体、互变异构体、区域异构体、氮氧化物、或混合物，和包含所述化合物的药物组合物以及使用所述化合物或其药物组合物在制备治疗哺乳动物心血管代谢性疾病和相关病症的药物中的用途。本发明提供的化合物对GLP‑1受体显示出优异的激动作用，具有非常好的开发前景。

Figure DDA0003128505480000011
The present invention provides a heteroaryl compound represented by formula (I) as a GLP-1 receptor agonist, or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer thereof , regioisomers, nitrogen oxides, or mixtures, and pharmaceutical compositions comprising said compounds and uses of said compounds or their pharmaceutical compositions in the preparation of medicines for treating mammalian cardiometabolic diseases and related disorders . The compound provided by the invention shows an excellent agonistic effect on the GLP-1 receptor, and has very good development prospects.
Figure DDA0003128505480000011

Description

GLP-1 receptor agonist, and pharmaceutical composition and use thereof
Technical Field
The invention belongs to the field of medicines, and particularly relates to a novel GLP-1 receptor agonist, or pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, regioisomer, nitric oxide or a mixture thereof, a pharmaceutical composition containing the compound, and application of the compound or the pharmaceutical composition in preparing medicines for treating cardiovascular metabolic diseases and related symptoms of mammals. More specifically, the compounds provided by the present invention exhibit excellent agonistic effects at the GLP-1 receptor.
Background
Diabetes is one of the common chronic diseases, the incidence rate increases year by year, the age of the disease becomes younger, and cardiovascular diseases and respiratory diseases are called as three major chronic killers. In recent years, the prevalence of diabetes in our country has increased from 1% in 1980 to 11% in 2017. Up to now, china has become the country with the largest number of diabetics. Diabetes is a group of metabolic diseases characterized by hyperglycemia. Hyperglycemia is caused by a defect in insulin secretion or an impaired biological action, or both. Hyperglycemia occurring in the long term of diabetes results in chronic damage to, and dysfunction of, various tissues, particularly the eyes, kidneys, heart, blood vessels, nerves. Diabetes mellitus is largely classified into type one diabetes and type two diabetes. Type one diabetes is the loss of insulin secretion due to the autoimmune system attacking the beta cells of the islets of langerhans. Type II diabetes begins with abnormal insulin resistance or cellular unresponsiveness to insulin; obesity is one of the major causes of insulin resistance, and thus obesity can be said to be a major risk factor for type two diabetes. Type ii diabetes accounts for about 90% of diabetics, and thus is a major public health problem in developed countries with severe obesity problems, and in china where the number of obese people is rising.
There are currently several classes of drugs that truly pair blood glucose lowering to treat type two Diabetes (Hampp, c.et al (2014) Diabetes Care,37: 1367-1374), mainly the following six classes: 1) Insulinotropic agents, including sulphonylurea, meglumine, dipeptidyl peptidase-4 (DPP-IV) inhibitors, and glucagon-like peptide-1 receptor (GLP-1R) agonists, promote insulin secretion by acting on the pancreatic beta cells. However, sulphonylurea, meglumine and DPP-IV inhibitors lack effectiveness, while GLP-1R agonists currently on the market are mainly subcutaneously injected polypeptide drugs, liraglutide is additionally approved for the treatment of obesity; 2) Biguanides (e.g., metformin) primarily reduce hepatic glucose production and thereby control blood glucose. Biguanides often cause gastrointestinal reactions and lactations; 3) Alpha-glucosidase inhibitors (e.g., acarbose), can reduce intestinal glucose absorption, but often cause intestinal reactions; 4) Thiazolidinedione drugs act on specific receptors (peroxisome proliferator-activated receptor-gamma) in liver, muscle and adipose tissues to regulate fat metabolism, thereby increasing the sensitivity of these tissues to insulin. Frequent use of such drugs can lead to weight gain, even edema and ischemia; 5) Insulin, used alone or in combination with the above drugs, is used for treating severe diabetes, and may cause weight gain and hypoglycemia in long-term use; 6) Sodium-glucose cotransporter 2 (SGLT 2) inhibitors can inhibit glucose reabsorption in the kidney, thereby lowering blood glucose levels. Such drugs may be associated with ketoacidosis and urinary tract infections.
The first GLP-1R agonist exenatide was approved by the FDA for diabetes treatment in 2005, and later GLP-1R agonists such as liraglutide and somaglutide were subsequently marketed sequentially. GLP-1R agonists are less at risk for hypoglycemia than traditional insulinotropic agents. At the same time, liraglutide and somaglutide also showed good hypoglycemic effects, reduced glycosylated hemoglobin, reduced body weight and cardiovascular benefits (fda. (2013) pharmacological review of saxenda) in clinical trials TM Fda. (2016) pharmacological review of semaglutide.). The medicines for treating diabetes mainly comprise insulin and analogues thereof, chemical oral hypoglycemic agents and GLP-1R agonists. From the market share of GLP-1R agonists, the global rate reaches 17%, and China only has 2%, so that the increasing space of the medicaments in China is large. With the intensive research on the gut-brain axis, GLP-1R agonists are also being studied for the treatment of Parkinson's disease (Kim, D.S.et al. (2017) Cell transplantation,26.9: 1560-1571), which makes GLP-1R agonists more promising market and application scenarios in the future.
Glucagon-like peptide-1 (GLP-1) is a long chain incretin consisting of 30 amino acids secreted by L cells, promoting the digestion of food by the intestinal tract. Under physiological conditions, GLP-1 has been shown to stimulate insulin production in a blood glucose-dependent manner to increase peripheral absorption of blood glucose to regulate postprandial blood glucose, reduce glucagon secretion and thus hepatic glucose production, inhibit gastric emptying and small bowel motility to delay absorption of food, reduce appetite, and stimulate beta cell proliferation (Meier, et al, (2003) Biodrugs, 17.2. The currently available GLP-1R agonist drugs including exenatide, liraglutide and somaglutide are all polypeptide drugs that mimic the structure of native GLP-1, and therefore can only be administered by injection, and are expensive, costing up to $1,500 to $2,500 dollars a year (https:// www.ncbi.nlm.nih.gov/books/NBK543967 /). Although the company noh and nord has developed oral formulations of somaglutide, the oral availability of polypeptide drugs is only 1-2% due to the limited physicochemical properties, the daily dose is also increased from less than 1mg per day to 14mg per day of the original injected dose, and the cost is also rising to $9,264 per year. Thus, the need for developing GLP-1R agonist drugs that are orally available and more cost-effective is particularly apparent.
There remains a great need for easy-to-administer prevention and/or treatment of cardiovascular metabolic diseases and related conditions. The compound has good GLP-1R agonistic effect, good liver microsome stability in human and rats, good pharmacokinetic property, quick oral absorption and good bioavailability, can be used for oral administration, and has good clinical application prospect.
Detailed Description
Definitions and general terms
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. All patents and publications referred to herein are incorporated by reference in their entirety.
The term "mammal" as used herein refers to, for example, primates (e.g., humans, male or female), cows, sheep, goats, horses, pigs, dogs, cats, rabbits, rats, mice, fish, birds, and the like. In certain embodiments, the mammal is a primate. In other embodiments, the mammal is a human.
"stereoisomers" refers to compounds having the same chemical structure, but differing in the arrangement of atoms or groups in space. Stereoisomers include enantiomers, diastereomers, conformers (rotamers), geometric isomers (cis/trans), atropisomers, and the like.
As described herein, the compounds of the present invention may be optionally substituted with one or more substituents, such as those of the general formula above, or as specifically exemplified, sub-classes, and classes of compounds encompassed by the present invention within the examples/embodiments.
In general, the term "substituted" means that one or more hydrogen atoms in a given structure are replaced with a particular substituent. Unless otherwise indicated, a substituted group may have one substituent substituted at each substitutable position of the group. When more than one position in a given formula can be substituted with one or more substituents selected from a particular group, the substituents may be substituted at each position, identically or differently.
The term "unsubstituted" means that the specified group bears no substituents.
The term "optionally substituted with (8230) \ 8230; substituted" is used interchangeably with the term "unsubstituted or substituted with (8230; i.e., the structure may be unsubstituted or substituted with one or more substituents described herein, including, but not limited to, H, D, F, cl, br, I, -OH, SH, -NH 2 、-NO 2 -CN, oxo (= O), N 3 Alkyl, alkenyl, alkynyl, hydroxyalkyl, haloalkyl, aminoalkyl, cyanoalkyl, alkoxy, haloalkoxy, alkylthio, alkylamino, haloalkylamino, -NR 1b R 1c Cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl and the like, wherein R is 1b And R 1c All have the definitions as set forth herein.
In addition, unless otherwise explicitly indicated, the description of "each of" \8230, independently "and" \8230, each/each of "\8230, independently" and "\8230, independently" used in the present invention may be interchanged and should be broadly understood to mean that specific items expressed between the same symbols in different groups do not affect each other, or that specific items expressed between the same symbols in the same groups do not affect each other.
In the various parts of this specification, substituents of the disclosed compounds are disclosed in terms of group type or range. It is specifically intended that the present invention includes such groupsEach independent sub-combination of the individual members of the class and range. For example, the term "C 1-6 Alkyl "means in particular independently disclosed methyl, ethyl, C 3 Alkyl radical, C 4 Alkyl radical, C 5 Alkyl and C 6 An alkyl group.
In each of the parts of the invention, linking substituents are described. Where the structure clearly requires a linking group, the markush variables listed for the group are understood to be linking groups. For example, if the structure requires a linking group and the markush group definition for the variable recites "alkyl" or "aryl," it is understood that the "alkyl" or "aryl" represents an attached alkylene group or arylene group, respectively.
The term "alkyl" or "alkyl group" as used herein, denotes a saturated, straight or branched chain monovalent hydrocarbon radical containing from 1 to 20 carbon atoms, wherein the alkyl group may be optionally substituted with one or more substituents as described herein. Unless otherwise specified, alkyl groups contain 1-20 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; in yet another embodiment, the alkyl group contains 1 to 3 carbon atoms. The alkyl group may be optionally substituted with one or more substituents described herein.
Examples of alkyl groups include, but are not limited to, methyl (Me, -CH) 3 ) Ethyl group (Et, -CH) 2 CH 3 ) N-propyl (n-Pr, -CH) 2 CH 2 CH 3 ) Isopropyl group (i-Pr, -CH (CH) 3 ) 2 ) N-butyl (n-Bu, -CH) 2 CH 2 CH 2 CH 3 ) Isobutyl (i-Bu, -CH) 2 CH(CH 3 ) 2 ) Sec-butyl (s-Bu, -CH (CH) 3 )CH 2 CH 3 ) Tert-butyl (t-Bu, -C (CH) 3 ) 3 ) N-pentyl (-CH) 2 CH 2 CH 2 CH 2 CH 3 ) 2-pentyl (-CH (CH) 3 )CH 2 CH 2 CH 3 ) 3-pentyl (-CH (CH) 2 CH 3 ) 2 ) 2-methyl-2-butyl (-C (CH) 3 ) 2 CH 2 CH 3 ) 3-methyl-2-butyl (-CH (CH) 3 )CH(CH 3 ) 2 ) 3-methyl-1-butyl (-CH) 2 CH 2 CH(CH 3 ) 2 ) 2-methyl-1-butyl (-CH) 2 CH(CH 3 )CH 2 CH 3 ) N-hexyl (-CH) 2 CH 2 CH 2 CH 2 CH 2 CH 3 ) 2-hexyl (-CH (CH) 3 )CH 2 CH 2 CH 2 CH 3 ) 3-hexyl (-CH (CH) 2 CH 3 )(CH 2 CH 2 CH 3 ) 2-methyl-2-pentyl (-C (CH)) 3 ) 2 CH 2 CH 2 CH 3 ) 3-methyl-2-pentyl (-CH (CH) 3 )CH(CH 3 )CH 2 CH 3 ) 4-methyl-2-pentyl (-CH (CH) 3 )CH 2 CH(CH 3 ) 2 ) 3-methyl-3-pentyl (-C (CH) 3 )(CH 2 CH 3 ) 2 ) 2-methyl-3-pentyl (-CH (CH) 2 CH 3 )CH(CH 3 ) 2 ) 2, 3-dimethyl-2-butyl (-C (CH) 3 ) 2 CH(CH 3 ) 2 ) 3, 3-dimethyl-2-butyl (-CH (CH) 3 )C(CH 3 ) 3 ) N-heptyl, n-octyl, and the like.
The term "alkenyl" denotes a straight or branched chain monovalent hydrocarbon radical containing 2 to 12 carbon atoms, wherein there is at least one site of unsaturation, i.e. one carbon-carbon sp 2 Double bonds, which include both "cis" and "trans" orientations, or "E" and "Z" orientations. In one embodiment, the alkenyl group contains 2 to 8 carbon atoms; in another embodiment, the alkenyl group contains 2 to 6 carbon atoms; in yet another embodiment, the alkenyl group contains 2 to 4 carbon atoms. Examples of alkenyl groups include, but are not limited to, vinyl (-CH = CH) 2 ) Allyl (-CH) 2 CH＝CH 2 ) And so on. The alkenyl group may be optionally substituted with one or more substituents described herein.
The term "alkynyl" denotes a compound containingA straight or branched chain monovalent hydrocarbon radical of 2 to 12 carbon atoms having at least one site of unsaturation, i.e., a carbon-carbon sp triple bond. In one embodiment, alkynyl groups contain 2-8 carbon atoms; in another embodiment, alkynyl groups contain 2-6 carbon atoms; in yet another embodiment, alkynyl groups contain 2-4 carbon atoms. Examples of alkynyl groups include, but are not limited to, ethynyl (-C ≡ CH), propargyl (-CH) 2 C.ident.CH), 1-propynyl (-C.ident.C-CH) 3 ) And so on. The alkynyl group may be optionally substituted with one or more substituents described herein.
The term "alkoxy" means an alkyl group attached to the rest of the molecule through an oxygen atom, wherein the alkyl group has the definition as described herein. Unless otherwise specified, 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; in yet another embodiment, the alkoxy group contains 1 to 3 carbon atoms. The alkoxy group may be optionally substituted with one or more substituents described herein.
Examples of alkoxy groups include, but are not limited to, methoxy (MeO, -OCH) 3 ) Ethoxy (EtO, -OCH) 2 CH 3 ) 1-propoxy (n-PrO, n-propoxy, -OCH) 2 CH 2 CH 3 ) 2-propoxy (i-PrO, i-propoxy, -OCH (CH) 3 ) 2 ) 1-butoxy (n-BuO, n-butoxy, -OCH) 2 CH 2 CH 2 CH 3 ) 2-methyl-l-propoxy (i-BuO, i-butoxy, -OCH) 2 CH(CH 3 ) 2 ) 2-butoxy (s-BuO, s-butoxy, -OCH (CH) 3 )CH 2 CH 3 ) 2-methyl-2-propoxy (t-BuO, t-butoxy, -OC (CH) 3 ) 3 ) 1-pentyloxy (n-pentyloxy, -OCH) 2 CH 2 CH 2 CH 2 CH 3 ) 2-pentyloxy (-OCH (CH) 3 )CH 2 CH 2 CH 3 ) 3-pentyloxy (-OCH (CH)) 2 CH 3 ) 2 ) 2-methyl-2-butoxy (-OC (CH)) 3 ) 2 CH 2 CH 3 ) 3-methyl-2-butoxy (-OCH (CH)) 3 )CH(CH 3 ) 2 ) 3-methyl-l-butoxy (-OCH) 2 CH 2 CH(CH 3 ) 2 ) 2-methyl-l-butoxy (-OCH) 2 CH(CH 3 )CH 2 CH 3 ) And so on.
The terms "haloalkyl", "haloalkenyl" or "haloalkoxy" denote alkyl, alkenyl or alkoxy groups substituted with one or more halogen atoms, examples of which include, but are not limited to, trifluoromethyl, trifluoroethyl, 2, 3-tetrafluoropropyl, trifluoromethoxy, and the like.
The term "hydroxyalkyl" as used herein means an alkyl group substituted with one or more hydroxyl groups, wherein the alkyl group has the definition as set forth herein, examples of which include, but are not limited to, hydroxyethyl, 2-hydroxypropyl, hydroxymethyl, and the like.
The term "cycloalkyl", as used herein, unless otherwise specified, refers to a monovalent saturated or partially unsaturated (but not aromatic) monocyclic or polycyclic hydrocarbon. In some embodiments, the cycloalkyl group may be a bridged or unbridged, spiro or unbridged, and/or fused or unfused bicyclic group. In some embodiments, the cycloalkyl group includes 3 to 10 carbon atoms, i.e., C 3 To C 10 A cycloalkyl group. In some embodiments, the cycloalkyl has 3-15 (C) 3-15 )、3-10(C 3-10 ) Or 3-7 (C) 3-7 ) 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 cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclo [2.1.1]Hexyl, bicyclo [2.2.1]Heptyl, decahydronaphthyl, or adamantyl. When the cycloalkyl group is substituted, it may be on any ring I.e., on any aromatic or non-aromatic ring comprised by a cycloalkyl group, may be independently substituted with one or more substituents as described herein.
The terms "heterocyclyl" and "heterocycle" are used interchangeably herein and, unless otherwise specified, refer to monovalent monocyclic non-aromatic ring systems and/or polycyclic ring systems comprising at least one non-aromatic ring; wherein one or more (in certain embodiments, 1, 2, 3, or 4) of said non-aromatic monocyclic atoms is independently selected from O, S (O) 0-2 And N, and the remaining ring atoms are carbon atoms; and wherein one or more (in certain embodiments, 1, 2, 3, or 4) of the ring atoms of the polycyclic ring system is independently selected from O, S (O) 0-2 And N, and the remaining ring atoms are all carbon atoms. In some embodiments, the heterocyclic ring comprises 1 or 2 heteroatoms, each of which is a nitrogen atom. In some embodiments, the heterocyclic group is polycyclic and contains one heteroatom in a non-aromatic ring, or one heteroatom in an aromatic ring, or two heteroatoms with one in an aromatic ring and the other in a non-aromatic ring. In some embodiments, the heterocyclyl group has 3-20, 3-15, 3-10, 3-8, 4-7, or 5-6 ring atoms. In some embodiments, the heterocyclyl is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system. In some embodiments, the heterocyclyl group may be a bridged or unbridged, spiro or unbridged, and/or fused or unfused bicyclic group. One or more nitrogen and sulfur atoms may optionally be oxidized, one or more nitrogen atoms may optionally be quaternized, one or more carbon atoms may optionally be oxidized
Figure BDA0003128505470000041
And (6) replacing. Some rings may be partially or fully saturated or aromatic, provided that the heterocyclic ring is not fully aromatic. The monocyclic heterocycle and polycyclic heterocycle may be attached to the main structure at any heteroatom or carbon atom that results in the creation of a stable compound. The polycyclic heterocyclic group may pass through any of its rings, including anyAromatic or non-aromatic rings, whether or not such rings contain heteroatoms, may be attached to the main structure. In some embodiments, heterocyclyl is "heterocycloalkyl" which is 1) a saturated or partially unsaturated (but not aromatic) monovalent monocyclic group containing at least one ring heteroatom as described herein, or 2) a saturated or partially unsaturated (but not aromatic) monovalent bicyclic or tricyclic group in which at least one ring contains at least one heteroatom as described herein. When the heterocyclyl and heterocycloalkyl group are substituted, they may be substituted on either ring, i.e., on any aromatic or non-aromatic ring contained by the heterocyclyl and heterocycloalkyl groups. In some embodiments, such heterocyclyl groups include, but are not limited to, oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, 1, 3-dioxolanyl, dithiocyclopentyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, dithianyl, thioxanyl, homopiperazinyl, homopiperidinyl, oxepanyl, thietanyl, oxazepanyl, oxazepinyl, and oxazepinyl >
Figure BDA0003128505470000042
Base, diaza->
Figure BDA0003128505470000043
Based on the sulfur and nitrogen impurity->
Figure BDA0003128505470000044
A benzodioxanyl group, benzodioxolyl group, benzofuranonyl group, benzopyranonyl group, benzopyranyl group, dihydrobenzofuranyl group, benzothiophenyl group, benzoxazinyl group, beta-carbolinyl, chromanyl, chromonyl, cinnolinyl, coumarinyl, decahydroquinolinyl, decahydroisoquinolinyl, dihydrobenzisothiazinyl, dihydrobenzisoxazinyl, dihydrofuranyl, dihydroisoquinonylIndolyl, dihydropyranyl, dihydropyrazolyl, dihydropyrazinyl, dihydropyridinyl, dihydropyrimidinyl, dihydropyrrolyl, dioxolanyl, 1, 4-dithianyl, furanonyl, imidazolidinyl, 2, 4-dioxo-imidazolidinyl, imidazolinyl, indolinyl, 2-oxo-indolinyl, isobenzotetrahydrofuryl, isobenzotetrahydrothienyl, isobenzodihydropyranyl, isocoumarinyl, isoindolyl (isoindolinyl), 1-oxo-isoindolinyl, 1, 3-dioxo-isoindolinyl, isothiazolidinyl, isoxazolidinyl, 3-oxo-isoxazolidinyl, morpholinyl, 3, 5-dioxo-morpholinyl, octahydroindolyl, octahydroisoindolyl, 1-oxo-octahydroisoindolyl, 1, 3-dioxo-hexahydroisoindolyl, oxazolidinone, oxazolidinyl, oxiranyl, piperazinyl, 2, 6-dioxo-piperazinyl, piperidinyl, 2, 6-dioxo-piperidinyl, 4-piperidinonyl, 2-oxopyrrolidinyl, 2, 5-dioxopyrrolidinyl, quinuclidinyl, tetrahydroisoquinolinyl, 3, 5-dioxo-thiomorpholinyl, thiazolidinyl, 2, 4-dioxo-thiazolidinyl, tetrahydroquinolinyl, phenothiazinyl, phenoxazinyl, oxaanthracyl and 1,3, 5-trithiahexonyl. In heterocyclic radicals of-CH 2 Examples of the substitution of the-group by-C (= O) -include, but are not limited to, 2-oxopyrrolidinyl, oxo-1, 3-thiazolidinyl, 2-piperidinonyl, 3, 5-dioxopiperidinyl and pyrimidinedione groups. Examples of the sulfur atom in the heterocyclic group being oxidized include, but are not limited to, sulfolane group, 1-dioxothiomorpholinyl group. The heterocyclyl group may be optionally substituted with one or more substituents described herein.
In some embodiments, heterocyclyl is a 3-8 atom heterocyclyl and refers to a saturated or partially unsaturated monocyclic ring containing 3-8 ring atoms, wherein at least one ring atom is selected from the group consisting of nitrogen, sulfur, and oxygen atoms. Unless otherwise specified, a heterocyclic group of 3 to 8 atoms may be carbon-based or nitrogen-based, and-CH 2 The-group may optionally be replaced by-C (= O) -. The sulfur atom of the ring may optionally be oxidized to the S-oxide. The nitrogen atom of the ring may optionally be oxidized to an N-oxygen compound. Examples of heterocyclic groups consisting of 3 to 8 atoms include, but are not limited to: azetidinyl, oxetanyl, thietanyl, pyrrolidinyl2-pyrrolinyl, 3-pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, 1, 3-dioxolanyl, dithiocyclopentyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, dithianyl, thiaxanyl, homopiperazinyl, homopiperidinyl, oxepanyl, thiacycloheptanyl, oxazepanyl, and dihydrofuranyl
Figure BDA0003128505470000045
Based on, diaza->
Figure BDA0003128505470000046
Based on, thiazepine>
Figure BDA0003128505470000047
And (4) a base. In heterocyclic radicals of-CH 2 Examples of the substitution of the-group by-C (= O) -include, but are not limited to, 2-oxopyrrolidinyl, oxo-1, 3-thiazolidinyl, 2-piperidinonyl, 3, 5-dioxopiperidinyl and pyrimidinedione groups. Examples of the sulfur atom in the heterocyclic group being oxidized include, but are not limited to, sulfolane group, 1-dioxothiomorpholinyl group. Said heterocyclyl group of 3 to 8 atoms may be optionally substituted by one or more substituents as described herein.
In some embodiments, heterocyclyl is a 3-6 atom heterocyclyl and refers to a saturated or partially unsaturated monocyclic ring containing 3-6 ring atoms, wherein at least one ring atom is selected from the group consisting of nitrogen, sulfur, and oxygen atoms. Unless otherwise specified, a heterocyclic group of 3 to 6 atoms may be carbon-based or nitrogen-based, and-CH 2 The-group may optionally be replaced by-C (= O) -. The sulfur atom of the ring may optionally be oxidized to the S-oxide. The nitrogen atom of the ring may optionally be oxidized to an N-oxygen compound. Said heterocyclyl group of 3 to 6 atoms may be optionally substituted by one or more substituents as described herein.
In another embodiment, heterocyclyl is a 5-6 atom heterocyclyl and refers to A saturated or partially unsaturated monocyclic ring comprising 5 to 6 ring atoms, wherein at least one ring atom is selected from nitrogen, sulphur and oxygen atoms. Unless otherwise specified, a heterocyclic group of 5 to 6 atoms may be carbon-based or nitrogen-based, and-CH 2 The-group may optionally be replaced by-C (= O) -. The sulfur atom of the ring may optionally be oxidized to the S-oxide. The nitrogen atom of the ring may optionally be oxidized to an N-oxygen compound. Examples of heterocyclic groups of 5-6 atoms include, but are not limited to: pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, 1, 3-dioxolanyl, dithiocyclopentyl, 2-oxopyrrolidinyl, oxo-1, 3-thiazolidinyl, sulfolane, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, dithianyl, thiaxanyl, 2-piperidinonyl, 3, 5-dioxopiperidinyl and pyrimidinedione, 1-dioxothiomorpholinyl. Said heterocyclyl group of 5 to 6 atoms may be optionally substituted by one or more substituents as described herein.
The term "cycloalkylalkyl" denotes an alkyl group which may be substituted with one or more cycloalkyl groups, wherein cycloalkyl and alkyl have the meaning as described herein, examples of which include, but are not limited to, cyclopropylmethyl, cyclopropylethyl, cyclopropylpropyl, cyclobutylmethyl, cyclobutylethyl, cyclopentylmethyl, cyclopentylethyl, cyclopentylpropyl, cyclohexylethyl and the like.
The term "heterocyclylalkyl" includes heterocyclyl-substituted alkyl groups; the term "heterocyclylalkoxy" includes heterocyclyl-substituted-alkoxy groups in which an oxygen atom is attached to the rest of the molecule; the term "heterocyclylalkylamino" includes heterocyclyl-substituted alkylamino groups in which the nitrogen atom is attached to the remainder of the molecule. Where heterocyclyl, alkyl, alkoxy and alkylamino all have the meanings as described herein, such examples include, but are not limited to, azetidin-1-ylmethyl, azetidin-1-ylethyl, azetidin-1-ylpropyl, pyrrol-1-ylmethyl, pyrrol-1-ylethyl, pyrrol-1-ylpropyl, morpholin-4-ylethyl, piperazin-4-ylethyl, piperidin-4-ylethylamino and the like.
The terms "fused bicyclic ring", "fused bicyclic group", "fused ring group" denote a saturated or unsaturated fused ring system, referring to a non-aromatic bicyclic ring system, as shown in formula (a 1), i.e. ring B shares a bond with ring B'. Such systems may contain independent or conjugated unsaturation, but the core structure does not contain aromatic or heteroaromatic rings (although aromatics may be substituents thereon). Each ring in the fused bicyclic ring is either a carbocyclic or a heteroalicyclic, examples of which include, but are not limited to, hexahydro-furo [3,2-b ]]Furan, 2, 3a,4,7 a-hexahydro-1H-indene, 7-azabicyclo [2.3.0 ]]Heptane, condensed bicyclo [3.3.0]Octane, condensed bicyclo [3.1.0]Hexane, these are contained within a fused bicyclic ring. And the fused bicyclic group may be substituted or unsubstituted, wherein the substituent may be, but is not limited to, H, D, F, cl, br, I, -OH, SH, -NH 2 、-NO 2 CN, oxo (= O), N 3 Alkyl, alkenyl, alkynyl, hydroxyalkyl, haloalkyl, aminoalkyl, cyanoalkyl, alkoxy, haloalkoxy, alkylthio, alkylamino, haloalkylamino, -NR 1b R 1c Cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl and the like, wherein R is 1b And R 1c All have the definitions as set forth herein.
Figure BDA0003128505470000051
The term "fused heterobicyclic group" denotes a saturated or unsaturated fused ring system or bridged ring system, involving a non-aromatic bicyclic ring system or bridged ring system. Such systems may contain independent or conjugated unsaturation, but the core structure does not contain aromatic or heteroaromatic rings (although aromatics may be substituents thereon). And at least one ring system comprising one or moreA ring system comprising 3-7 membered rings, i.e. comprising 1-6 carbon atoms and 1-3 heteroatoms selected from N, O, P, S, where S or P is optionally substituted by one or more oxygen atoms to give, for example, SO 2 ，PO，PO 2 Examples of such include, but are not limited to hexahydro-furo [3,2-b ]]Furan, 7-azabicyclo [2.3.0]Heptane, 2-azabicyclo [2.2.1]Heptane, octahydropyrrole [3,2-b ]]Pyrrole, octahydropyrrole [3,4-c ]]Pyrrole, octahydro-1H-pyrrole [3,2-b ]]Pyridine, and the like. And the fused heterobicyclic group can be substituted or unsubstituted, wherein the substituents can be, but are not limited to, H, D, F, cl, br, I, -OH, SH, -NH 2 、-NO 2 -CN, oxo (= O), N 3 Alkyl, alkenyl, alkynyl, hydroxyalkyl, haloalkyl, aminoalkyl, cyanoalkyl, alkoxy, haloalkoxy, alkylthio, alkylamino, haloalkylamino, -NR 1b R 1c Cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl and the like, wherein R is 1b And R 1c All have the definitions as set forth herein.
The terms "spirocyclic", "spiro", "spirobicyclic group", "spirobicyclic ring" indicate that one ring originates from a particular cyclic carbon on the other ring. For example, ring a and ring B share a carbon atom in two saturated ring systems, which are referred to as "spirocycles. Each ring within the spiro ring is either a carbocyclic or a heteroalicyclic. Examples include, but are not limited to, 2, 7-diazaspiro [4.4 ]]Nonan-2-yl, 7-oxo-2-azaspiro [4.5 ]]Decan-2-yl, 4-azaspiro [2.4 ]]Heptane-5-yl, 4-oxaspiro [2.4 ]]Heptane-5-yl, 5-azaspiro [2.4 ]]Heptane-5-yl, spiro [2.4 ]]Heptylalkyl, spiro [4.4 ]]Nonanyl, 7-hydroxy-5-azaspiro [2.4 ]]Heptane-5-yl, and the like. And said spirobicyclic group may be substituted or unsubstituted, wherein the substituents may be, but are not limited to, H, D, F, cl, br, I, -OH, SH, -NH 2 、-NO 2 -CN, oxo (= O), N 3 Alkyl, alkenyl, alkynyl, hydroxyalkyl, haloalkyl, aminoalkyl, cyanoalkyl, alkoxy, haloalkoxy, alkylthio, alkylamino Haloalkylamino, -NR 1b R 1c Cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl and the like, wherein R is 1b And R 1c All have the definitions as set forth herein.
Figure BDA0003128505470000061
The term "spiroheterobicyclic group" means that one ring originates from a particular cyclic carbon on the other ring. For example, as described above, ring a and ring B share a carbon atom in two saturated ring systems, and are referred to as "spirocycles. And at least one ring system comprises one or more heteroatoms, wherein each ring system comprises a 3-7 membered ring, i.e. comprising 1-6 carbon atoms and 1-3 heteroatoms selected from N, O, P, S, whereby S or P is optionally substituted by one or more oxygen atoms to give, for example, SO 2 ，PO，PO 2 Examples of such include, but are not limited to, 4-azaspiro [2.4 ]]Heptane-5-yl, 4-oxaspiro [2.4 ]]Heptane-5-yl, 5-azaspiro [2.4 ]]Heptane-5-yl, 7-hydroxy-5-azaspiro [2.4 ]]Heptane-5-yl, 2, 6-diazaspiro [3.3]Heptane, 2, 6-diazaspiro [3.4 ]]Octane, 1, 6-diazaspiro [3.4 ]]Octane, 2, 7-diazaspiro [3.5 ]]Nonane, 1, 7-diazaspiro [3.5 ]]Nonane, 3, 9-diazaspiro [5.5 ]]Undecane, and the like. And the spiroheterobicyclic group can be substituted or unsubstituted, wherein the substituents can be, but are not limited to, H, D, F, cl, br, I, -OH, SH, -NH 2 、 -NO 2 -CN, oxo (= O), N 3 Alkyl, alkenyl, alkynyl, hydroxyalkyl, haloalkyl, aminoalkyl, cyanoalkyl, alkoxy, haloalkoxy, alkylthio, alkylamino, haloalkylamino, -NR 1b R 1c Cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl and the like, wherein R is 1b And R 1c All have the definitions as set forth herein.
The term "bridged ring group" as used herein denotes a saturated or unsaturated bridged ring system,relates to non-aromatic bridged ring systems, as shown in formula (A2), i.e. ring A1 and ring A2 share an alkyl chain or a heteroalkyl chain, wherein j is 1,2,3 or 4. Such systems may contain independent or conjugated unsaturation, but the core structure does not contain aromatic or heteroaromatic rings (although aromatics may be substituents thereon). Each ring in the bridged ring is either a carbocyclic or a heteroalicyclic, examples of which include, but are not limited to, bicyclo [2.2.1]Heptane, 2-azabicyclo [2.2.1]Heptane, 1,2,3, 4a,5,8 a-octahydronaphthalene, which are contained within a fused bicyclic or bridged ring system. And the bridging group may be substituted or unsubstituted, wherein the substituents may be, but are not limited to, H, D, F, cl, br, I, -OH, SH, -NH 2 、-NO 2 -CN, oxo (= O), N 3 Alkyl, alkenyl, alkynyl, hydroxyalkyl, haloalkyl, aminoalkyl, cyanoalkyl, alkoxy, haloalkoxy, alkylthio, alkylamino, haloalkylamino, -NR 1b R 1c Cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl and the like, wherein R is 1b And R 1c All have the definitions as set forth herein.
Figure BDA0003128505470000062
The term "bridged heterocyclyl" denotes a saturated or unsaturated bridged ring system, involving a non-aromatic bridged ring system. Such systems may contain independent or conjugated unsaturation, but the core structure does not contain aromatic or heteroaromatic rings (although aromatics may be substituents thereon). And at least one ring system comprises one or more heteroatoms, wherein each ring system comprises a 3-7 membered ring, i.e. comprising 1-6 carbon atoms and 1-3 heteroatoms selected from N, O, P, S, whereby S or P is optionally substituted by one or more oxygen atoms to give, for example, SO 2 ，PO，PO 2 Examples of such include, but are not limited to, 2-azabicyclo [2.2.1 ]]Heptane, (1R, 5S) -3, 6-diazabicyclo [3.1.1]Heptane, 2, 5-diaza bisRing [2.2.1]Heptane, (1R, 5S) -8-azabicyclo [3.2.1 ]Octane, and the like. And said bridged heterocyclic group may be substituted or unsubstituted, wherein the substituents may be, but are not limited to, H, D, F, cl, br, I, -OH, SH, -NH 2 、 -NO 2 -CN, oxo (= O), N 3 Alkyl, alkenyl, alkynyl, hydroxyalkyl, haloalkyl, aminoalkyl, cyanoalkyl, alkoxy, haloalkoxy, alkylthio, alkylamino, haloalkylamino, -NR 1b R 1c Cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl and the like, wherein R is 1b And R 1c All have the definitions as set forth herein.
As described herein, there are two attachment points in the ring system that are attached to the rest of the molecule, as shown in formula (a 3) or (a 4), meaning that either the E or E' end is attached to the rest of the molecule, i.e., the attachment of the two ends can be reversed.
Figure BDA0003128505470000063
The term "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).
The term "aryl" as used herein, unless otherwise specified, refers to a monovalent C group comprising at least one aromatic ring 6 -C 14 A carbocyclic ring system, wherein the aromatic ring system is monocyclic, bicyclic, or tricyclic. The aryl radical may be attached to the main structure through any ring thereof, i.e., any aromatic or non-aromatic ring. In some embodiments, aryl is phenyl, naphthyl, bicyclo [4.2.0 ]Oct-1, 3, 5-trienyl, indanyl, fluorenyl, or tetrahydronaphthyl. When the aryl group is substituted, it may be substituted on any ring, i.e., on any aromatic or non-aromatic ring comprised by the aryl group. In some or any embodiment, aryl is phenyl, naphthyl, tetrahydronaphthyl, fluorenyl, or indanyl; each of said phenyl, naphthyl, tetrahydronaphthyl, fluorenyl, and indanyl is optionally substituted with said aryl group independently optionally with one or more substituents described hereinIn some embodiments, including being independently selected from H, D, F, cl, br, I, -OH, SH, -NH 2 、-NO 2 -CN, oxo (= O), N 3 Alkyl, alkenyl, alkynyl, hydroxyalkyl, haloalkyl, aminoalkyl, cyanoalkyl, alkoxy, haloalkoxy, alkylthio, alkylamino, haloalkylamino, -NR 1b R 1c Cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl, and the like, wherein R is substituted with a substituent 1b And R 1c All have the definitions as set forth herein.
The term "aralkyl" as used herein, unless otherwise specified, refers to an alkyl group substituted with one or two aryl groups as defined herein, wherein the alkyl group is the point of attachment to the rest of the molecule. In some embodiments, aralkyl is benzyl, phenethyl-1-yl, phenethyl-2-yl, diphenylmethyl, 2-diphenylethyl, 3-diphenylpropyl, or 3-phenylpropyl; each of the benzyl, phenethyl-1-yl, phenethyl-2-yl, diphenylmethyl, 2-diphenylethyl, 3-diphenylpropyl, and 3-phenylpropyl is optionally substituted on the ring with one or more substituents described herein.
The term "heteroaryl", as used herein, unless otherwise specified, refers to a monovalent monocyclic or polycyclic aromatic group wherein said at least one (and in certain embodiments, 1, 2, 3, or 4) ring atom is independently selected from O, S (O) in said ring 0-2 And heteroatoms of N. The heteroaryl group is attached to the rest of the molecule through any atom in the ring system whose valency rules allow. In some embodiments, each ring of a heteroaryl group can contain 1 or 2O atoms, 1 or 2S atoms, and/or 1 to 4N atoms, or a combination thereof, provided that the total number of heteroatoms in each ring is 4 or less, and each ring contains at least 1 carbon atom. In some embodiments, the heteroaryl group has 5-20, 5-15, 5-10, or 5-8 ring atoms. When the heteroaryl group is substituted, it may be substituted on either ring. In certain embodiments, monocyclic heteroaryl groups include, but are not limited to, furansA group selected from the group consisting of imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, thiadiazolyl, thiazolyl, thienyl, tetrazolyl, triazinyl, and triazolyl. In certain embodiments, bicyclic heteroaryl groups include, but are not limited to, benzofuranyl, benzimidazolyl, benzisoxazolyl, benzopyranyl, benzothiadiazolyl, benzothiazolyl, benzothienyl, benzotriazolyl, benzoxazolyl, furopyridinyl, imidazopyridinyl, imidazothiazolyl, indolizinyl, indolyl, indazolyl, isobenzofuranyl, isobenzothienyl, isoindolyl, isoquinolyl, isothiazolyl, naphthyridinyl, oxazolopyridinyl, phthalazinyl, pteridinyl, purinyl, pyridopyridinyl, pyrrolopyridinyl, quinolinyl, quinoxalinyl, quinazolinyl, thiadiazolopyrimidyl, and thienopyridinyl. In certain embodiments, tricyclic heteroaryl groups include, but are not limited to, acridinyl, benzindolyl, carbazolyl, dibenzofuranyl, \21663pyridinyl, phenanthrolinyl, phenanthridinyl, and phenazinyl. In some or any embodiment, heteroaryl is indolyl, furyl, pyridinyl, pyrimidinyl, imidazolyl, or pyrazolyl; each of which is optionally substituted with 1, 2, 3 or 4 groups as defined throughout the specification, including in some embodiments independently selected from H, D, F, cl, br, I, -OH, SH, -NH 2 、 -NO 2 -CN, oxo (= O), N 3 Alkyl, alkenyl, alkynyl, hydroxyalkyl, haloalkyl, aminoalkyl, cyanoalkyl, alkoxy, haloalkoxy, alkylthio, alkylamino, haloalkylamino, -NR 1b R 1c Cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl and the like, wherein R is substituted with a substituent 1b And R 1c All have the definitions as set forth herein.
The term "heteroarylalkyl" as used herein, unless otherwise indicated, refers to an alkyl group substituted with one or two heteroaryl groups as defined herein, wherein the alkyl group is the point of attachment to the rest of the molecule. Examples of said heteroarylalkyl group include, but are not limited to, imidazole-2-methyl, thiazole-2-methyl, furan-2-ethyl, indole-3-methyl, etc.; each of which is optionally substituted on any ring with one or more substituents described herein.
The term "alkylamino" includes "N-alkylamino" and "N, N-dialkylamino" in which the amino groups are each independently substituted with one or two alkyl groups. In some of these embodiments, the alkylamino group is one or two C 1-6 Lower alkylamino groups in which the alkyl group is attached to the nitrogen atom. In other embodiments, the alkylamino group is C 1-3 Lower alkylamino groups of (a). Suitable alkylamino groups can be monoalkylamino or dialkylamino, and such examples include, but are not limited to, N-methylamino, N-ethylamino, N-dimethylamino, N-diethylamino, and the like.
The term "aminoalkyl" includes C substituted with one or more amino groups 1-10 A straight or branched alkyl group. In some of these embodiments, aminoalkyl is C substituted with one or more amino groups 1-6 "lower aminoalkyl" and other examples are aminoalkyl which is C substituted with one or more amino groups 1-4 Examples of "lower aminoalkyl" radicals include, but are not limited to, aminomethyl, aminoethyl, aminopropyl, aminobutyl, and aminohexyl.
The term "cyanoalkyl" or "cyano-substituted alkyl" includes C substituted with one or more cyano groups 1-10 A straight or branched alkyl group. In some of these embodiments, cyano-substituted alkyl is C substituted with one or more cyano groups 1-6 "lower cyanoalkyl", other embodiments are where the cyano-substituted alkyl is C substituted with one or more cyano groups 1-4 "lower cyanoalkyl", such examples include, but are not limited to, CNCH 2 -、CNCH 2 CH 2 -、CNCH 2 CH 2 CH 2 -、CNCH 2 CHCNCH 2 -and the like.
As described herein, the ring system formed by the substituents on the ring with a bond to the center (as shown below) represents that the substituents may be substituted at any substitutable position on either ring. For example, formula B represents that any possible substituted position on the A or B ring may be substituted as shown in formulas c, d, e, f, g, h, i, j, k, l, m, n, o, p, q, etc.
Figure BDA0003128505470000081
As used herein, "pharmaceutically acceptable salts" refer to organic and inorganic salts of the compounds of the present invention. Pharmaceutically acceptable salts are well known in the art, as are: berge et al, descriptive minor soluble salts in detail in J. Pharmaceutical Sciences,1977, 66. Pharmaceutically acceptable non-toxic acid salts include, but are not limited to, salts of inorganic acids such as hydrochlorides, hydrobromides, phosphates, sulfates, perchlorates, and salts of organic acids such as acetates, oxalates, maleates, tartrates, citrates, succinates, malonates, which are formed by reaction with amino groups, or which are obtained by other methods described in the literature, such as ion exchange. Other pharmaceutically acceptable salts include adipates, alginates, ascorbates, aspartates, benzenesulfonates, benzoates, bisulfates, borates, butyrates, camphorates, camphorsulfonates, cyclopentylpropionates, digluconates, dodecylsulfates, ethanesulfonates, formates, fumarates, glucoheptonates, glycerophosphates, gluconates, hemisulfates, heptanoates, hexanoates, hydroiodides, 2-hydroxy-ethanesulfonates, lactobionates, lactates, laurates, lauryl sulfates, malates, malonates, methanesulfonates, 2-naphthalenesulfonates, nicotinates, nitrates, oleates, palmitates, pamoates, pectinates, persulfates, 3-phenylpropionates, picrates, pivalates, propionates, stearates, thiocyanates, p-toluenesulfonates, undecanoates, valeric acid salts, and the like. By reaction with a suitable base The obtained salt comprises alkali metal, alkaline earth metal, ammonium and N + (C 1 -C 4 Alkyl radical) 4 A salt. The present invention also contemplates quaternary ammonium salts formed from compounds containing groups of N. Water-soluble or oil-soluble or dispersion products can be obtained by quaternization. Alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Pharmaceutically acceptable salts further include suitable, non-toxic ammonium, quaternary ammonium salts and amine cations resistant to formation of counterions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C 1-8 Sulfonates and aromatic sulfonates.
Disclosure of Invention
The invention provides a novel class of GLP-1 receptor agonists, or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, regioisomer, nitroxide, or mixture thereof, and pharmaceutical compositions comprising the compounds, and uses of the compounds or pharmaceutical compositions thereof in the preparation of medicaments for treating cardiovascular metabolic diseases and related disorders in mammals. More specifically, the compounds provided by the present invention exhibit excellent agonistic effects at the GLP-1 receptor.
In one aspect, the invention provides a novel GLP-1 receptor agonist having the formula (I):
Figure BDA0003128505470000091
Or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, regioisomer, nitroxide, or mixture thereof, wherein,
L 1 is O, S, -N (R) c ) -, -C (= O) -, or-C (R) a )(R b )-；
L 2 Is O, S, -N (R) c )-、-C(＝O)-、-(C(R a )(R b )) t1 -、-X-(C(R a )(R b )) t1 -, or- (C (R) a )(R b )) t1 -X-(C(R a )(R b )) t2 -；
Z 1 And Z 2 Each independently is N or CH;
Ar 1 is C 6-10 Aryl radical, C 1-9 Heteroaryl group, C 3-8 Cycloalkyl radical, C 2-9 Heterocyclic group, C 5-12 Fused bicyclic group, or C 5-12 Fused heterobicyclic group wherein said Ar 1 Optionally substituted by 0, 1, 2, 3 or 4R 2 Substitution;
cy is C 3-8 Cycloalkyl radical, C 2-9 Heterocyclic group, C 5-12 Spiro bicyclic group, C 5-12 Spiro-heterobicyclic radical, C 5-12 Condensed bicyclic group, C 5-12 Fused heterobicyclic radical, C 5-12 Bridged ring radical, or C 5-12 Bridged heterocyclyl, wherein said Cy is optionally substituted with 0, 1, 2, 3, or 4R 3 Substitution;
Ar 2 is a fused heteroaryl group consisting of 8 ring atoms and said ring atoms contain 1, 2, 3, or 4 heteroatoms independently selected from O, S and/or N, and Ar 2 Optionally substituted by 0, 1, 2, 3 or 4R 6 Substitution; or Ar 2 The method comprises the following steps:
Figure BDA0003128505470000092
Figure BDA0003128505470000093
wherein Ar is 2 Optionally substituted by 0, 1, 2, 3 or 4R 6 Substitution;
x is O, S, -N (R) d ) -, or-C (= O) -;
X 1 、X 2 and X 3 Are each independently N or-C (R) 6 )-；
X 5 Is O or S;
w is-C (= O) OR 7a 、-S(＝O) 1-2 OR 7a 、-P(＝O)(OR 7a )(OR 7b )、-P(＝O)(OR 7a )(R 7c )、-S(＝O) 1-2 R 7d 、-C(＝O)R 7d 、 -C(＝O)N(R 7c )R 7d 、-S(＝O) 1-2 N(R 7c )R 7d 、-C(＝O)N(R 7c )S(＝O) 1-2 R 7d 、-C(＝O)N(R 7c )S(＝O) 1-2 N(R 7c )R 7d 、 -C(＝O)N(R 7c )C(＝O)R 7d 、-C(＝O)N(R 7c )C(＝O)N(R 7c )R 7d 、-C(＝O)N(R 7c )C(＝S)N(R 7c )R 7d 、 -C(＝O)N(R 7c )S(＝NR 7a ) 1-2 R 7d 、-C(＝O)N(R 7c )S(＝O)(＝NR 7a )R 7d 、
Figure BDA0003128505470000094
Figure BDA0003128505470000095
Each R 1 Are respectively and independently H, D, F, cl, br, I, -OH, -NH 2 、-NO 2 -CN, oxo (= O), C 1-6 Alkyl radical, C 1-6 Hydroxyalkyl radical, C 1-6 Haloalkyl, C 1-6 Aminoalkyl radical, C 1-6 Cyanoalkyl, C 1-6 Alkoxy radical, C 1-6 Haloalkoxy, C 1-6 Alkylthio radical, C 1-6 Alkylamino radical, C 3-8 Cycloalkyl radical, C 3-8 Cycloalkyl radical C 1-6 Alkyl radical, C 3-8 Cycloalkyl radical C 2-6 Alkenyl radical, C 3-8 Cycloalkyl radical C 2-6 Alkynyl, C 2-7 Heterocyclic group, C 2-7 Heterocyclyl radical C 1-6 Alkyl radical, C 6-12 Aryl radical, C 6-12 Aryl radical C 1-6 Alkyl radical, C 1-9 Heteroaryl, or C 1-9 Heteroaryl C 1-6 Alkyl, -S (= O) 1-2 R 1a 、-C(＝O)R 1a 、 -C(＝O)OR 1b 、-OS(＝O) 1-2 R 1a 、-OC(＝O)R 1a 、-N(R 1b )C(＝O)R 1a 、-OC(＝O)NR 1b R 1c 、-NR 1b R 1c 、-N(R 1b )S(＝O) 1-2 R 1a or-N (R) 1b )C(＝O)NR 1b R 1c ；
R 5 Is H, D, F, cl, br, I, -OH, -NH 2 、-NO 2 -CN, oxo (= O), C 1-6 Alkyl radical, C 1-6 Haloalkyl, C 1-6 Cyanoalkyl, C 1-6 Aminoalkyl radical, C 1-6 Alkoxy radical C 1-6 Alkyl radical, C 3-10 Cycloalkyl radical, C 2-9 Heterocyclic group, C 6-10 Aryl radical, C 1-9 Heteroaryl, R 5c -C(＝O)-、 R 5c -OC(＝O)-、R 5c -C(＝O)O-、R 5c -NHC(＝O)-、R 5c -C(＝O)NH-、R 5c -L 3 -C 1-6 Alkyl-, R 5a -C 1-6 Alkyl, or R 5a -C 1-6 Hydroxyalkyl-, wherein said C 1-6 Alkyl radical, C 1-6 Haloalkyl, C 1-6 Cyanoalkyl, C 1-6 Aminoalkyl radical, C 1-6 Alkoxy radical C 1-6 Alkyl radical, C 3-10 Cycloalkyl, C 2-9 Heterocyclic group, C 6-10 Aryl radical, C 1-9 Heteroaryl, R 5c -C(＝O)-、R 5c -OC(＝O)-、R 5c -C(＝O)O-、R 5c -NHC(＝O)-、 R 5c -C(＝O)NH-、R 5c -L 3 -C 1-6 Alkyl-, R 5a -C 1-6 Alkyl and R 5a -C 1-6 Hydroxyalkyl-is independently optionally substituted with 0, 1, 2, 3 or 4R 5b Substitution;
R 5a is C 3-10 Cycloalkyl, C 2-9 Heterocycloalkyl radical, C 6-10 Aryl, or C 1-9 Heteroaryl, wherein R is 5a Optionally substituted by 0, 1, 2, 3 or 4R 5b Substitution;
R 5c is H, C 1-6 Alkyl radical, C 3-10 Cycloalkyl radical, C 2-9 Heterocyclic group, C 6-10 Aryl, or C 1-9 Heteroaryl, wherein R is 5c Optionally substituted by 0, 1, 2, 3 or 4R 5b Substitution;
L 3 is O, S, -N (R) d ) -, or-C (= O) -;
each R 1a 、R 2 、R 3 、R 4 、R 5b 、R 6 、R a And R b Are respectively and independently H, D, F, cl, br, I, -OH, -NH 2 、-NO 2 -CN, oxo (= O), C 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 1-6 Hydroxyalkyl radical, C 1-6 Haloalkyl, C 1-6 Aminoalkyl radical, C 1-6 Cyanoalkyl, C 1-6 Alkoxy radical, C 1-6 Haloalkoxy, C 1-6 Alkylthio radical, C 1-6 Alkylamino radical, C 1-6 Haloalkylamino, -NR 1b R 1c 、C 3-8 Cycloalkyl, C 3-8 Cycloalkyl radical C 1-6 Alkyl radical, C 2-7 Heterocyclic group, C 2-7 Heterocyclyl radical C 1-6 Alkyl radical, C 6-12 Aryl radical, C 6-12 Aryl radical C 1-6 Alkyl radical, C 1-9 Heteroaryl, or C 1-9 Heteroaryl C 1-6 An alkyl group; wherein C is 3-8 Cycloalkyl, C 3-8 Cycloalkyl radical C 1-6 Alkyl radical, C 2-7 Heterocyclic group, C 2-7 Heterocyclyl radical C 1-6 Alkyl radical, C 6-12 Aryl radical, C 6-12 Aryl radical C 1-6 Alkyl radical, C 1-9 Heteroaryl and C 1-9 Heteroaryl C 1-6 Alkyl is optionally substituted by 0, 1, 2, 3 or 4 substituents independently selected from H, F, cl, br, I, -OH, -NH 2 、-NO 2 -CN, oxo (= O), C 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 1-6 Hydroxyalkyl radical, C 1-6 Haloalkyl, C 1-6 Aminoalkyl radical, C 1-6 Cyanoalkyl, C 1-6 Alkoxy and C 1-6 Substituted with a halo alkoxy group;
each R 1b 、R 1c 、R c 、R d 、R 7a 、R 7c And R 7d Are each independently H, D, -OH, -CN, C 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 1-6 Hydroxyalkyl radical, C 1-6 Haloalkyl, C 1-6 Aminoalkyl radical, C 1-6 Cyanoalkyl, C 1-6 Alkoxy radical, C 1-6 Haloalkoxy, C 1-6 Alkylthio radical, C 1-6 Alkylamino radical, C 1-6 Haloalkylamino, C 3-8 Cycloalkyl radical, C 3-8 Cycloalkyl radical C 1-6 Alkyl radical, C 2-7 Heterocyclic group, C 2-7 Heterocyclyl radical C 1-6 Alkyl radical, C 6-12 Aryl radical, C 6-12 Aryl radical C 1-6 Alkyl radical, C 1-9 Heteroaryl, or C 1-9 Heteroaryl C 1-6 An alkyl group; wherein C is 3-8 Cycloalkyl radical, C 3-8 Cycloalkyl radical C 1-6 Alkyl radical, C 2-7 Heterocyclic group, C 2-7 Heterocyclyl radical C 1-6 Alkyl radical, C 6-12 Aryl radical, C 6-12 Aryl radical C 1-6 Alkyl radical, C 1-9 Heteroaryl and C 1-9 Heteroaryl C 1-6 Alkyl is optionally substituted by 0, 1, 2, 3 or 4 substituents independently selected from H, F, cl, br, I, -OH, -NH 2 、-NO 2 -CN, oxo (= O), C 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 1-6 Hydroxyalkyl radical, C 1-6 Haloalkyl, C 1-6 Aminoalkyl radical, C 1-6 Cyanoalkyl, C 1-6 Alkoxy and C 1-6 Halo-alkoxy substituents;
R 7a and R 7b Each independently of the other is H, an alkali metal ion, an alkaline earth metal ion, -OH, -CN, C 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 1-6 Hydroxyalkyl radical, C 1-6 Haloalkyl, C 1-6 Aminoalkyl radical, C 1-6 Cyanoalkyl, C 1-6 Alkoxy radical, C 1-6 Haloalkoxy, C 1-6 Alkylthio radical, C 1-6 Alkylamino radical, C 1-6 Haloalkylamino, C 3-8 Cycloalkyl radical, C 3-8 Cycloalkyl radical C 1-6 Alkyl radical, C 2-7 Heterocyclic group, C 2-7 Heterocyclyl radical C 1-6 Alkyl radical, C 6-12 Aryl radical, C 6-12 Aryl radical C 1-6 Alkyl radical, C 1-9 Heteroaryl, or C 1-9 Heteroaryl C 1-6 An alkyl group; wherein C is 3-8 Cycloalkyl radical, C 3-8 Cycloalkyl radical C 1-6 Alkyl radical, C 2-7 Heterocyclic group, C 2-7 Heterocyclyl radical C 1-6 Alkyl radical, C 6-12 Aryl radical, C 6-12 Aryl radical C 1-6 Alkyl radical, C 1-9 Heteroaryl and C 1-9 Heteroaryl C 1-6 Alkyl radical orOptionally substituted by 0, 1, 2, 3 or 4 groups independently selected from H, F, cl, br, I, -OH, -NH 2 、-NO 2 -CN, oxo (= O), C 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 1-6 Hydroxyalkyl radical, C 1-6 Haloalkyl, C 1-6 Aminoalkyl radical, C 1-6 Cyanoalkyl, C 1-6 Alkoxy and C 1-6 Substituted with a halo alkoxy group;
n is 0, 1, 2, 3, 4 or 5; and
each t1 and t2 is independently 1, 2, 3 or 4.
In some embodiments, wherein L 1 Is O, NH, or CH 2 ；L 2 Is O, S, -N (R) c ) -, or-CH 2 -。
In some embodiments, the compounds of the present invention have the structure of formula (II):
Figure BDA0003128505470000111
or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, regioisomer, nitroxide, or mixture thereof.
In some embodiments, wherein Ar 1 Is that
Figure BDA0003128505470000112
Wherein,
Y 1 and Y 2 Are each independently N or-C (R) 2 )-；
Y 3 And Y 4 Are each independently-C (= O) -, O, S, -N (R) 2a )-、-(C(R 2 ) 2 ) t3 -, or-W 1 -(C(R 2 ) 2 ) t3 -；
W 1 is-C (= O) -, O, S, or-N (R) 2a )-；
Each R 2a Are respectively and independently H and C 1-6 Alkyl radical, C 1-6 Hydroxyalkyl radical, C 1-6 Haloalkyl, C 1-6 Aminoalkyl radical, C 1-6 Cyanoalkyl, C 1-6 Alkoxy radical, C 1-6 Haloalkoxy, C 1-6 Alkylthio radical, C 1-6 Alkylamino radical, C 1-6 Haloalkylamino, C 3-8 Cycloalkyl radical, C 3-8 Cycloalkyl radical C 1-6 Alkyl radical, C 2-7 Heterocyclic group, C 2-7 Heterocyclyl radical C 1-6 Alkyl radical, C 6-12 Aryl radical, C 6-12 Aryl radical C 1-6 Alkyl radical, C 1-9 Heteroaryl, or C 1-9 Heteroaryl C 1-6 An alkyl group; and t3 is 1, 2, or 3.
In some embodiments, wherein Ar 1 Is that
Figure BDA0003128505470000113
In some embodiments, the compounds of the present invention have the structure of formula (III):
Figure BDA0003128505470000114
or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, regioisomer, nitroxide, or mixture thereof, wherein Y is 1 And Y 2 Are each independently N or-C (R) 2 ) -; and m is 0, 1, 2, or 3.
In some embodiments, the compounds of the present invention have a structure represented by formula (IIIa):
Figure BDA0003128505470000121
or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, regioisomer, nitroxide, or mixture thereof, wherein m is 0, 1, 2, or 3.
In some embodiments, the compounds of the present invention have the structure of formula (IV):
Figure BDA0003128505470000122
or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, regioisomer, nitroxide, or mixture thereof, wherein Y is 1 And Y 2 Are each independently N or-C (R) 2 ) -; and m is 0, 1, 2, or 3.
In some embodiments, wherein Cy is
Figure BDA0003128505470000123
Wherein,
Z 3 、Z 4 and Z 5 Each independently is-O-) -S-, -NH-, - (CH) 2 ) m1 -NH-(CH 2 ) m2 -、-(CH 2 ) m1 -O-(CH 2 ) m2 -、-(CH 2 ) m1 -S-(CH 2 ) m2 -, or- (CH) 2 ) m3 -；
Each m1 is independently 1, 2, 3 or 4;
each m2 is independently 0, 1, 2, 3 or 4;
each m3 is independently 1, 2, 3 or 4; and
n1 is 0, 1, 2, 3 or 4.
In some embodiments, wherein Cy is
Figure BDA0003128505470000124
Wherein Z is 6 And Z 7 Each independently is N, C or-CH-, provided that a chemically stable structure is formed.
In some embodiments, wherein Cy is
Figure BDA0003128505470000131
Wherein said Cy is optionally substituted with 0, 1, 2, 3 or 4R 3 And (4) substitution.
In some embodiments, the first and second substrates are, among others,
Figure BDA0003128505470000132
is that
Figure BDA0003128505470000133
Figure BDA0003128505470000141
Wherein,
X 1 、X 2 and X 3 Are each independently N or-C (R) 6 )-；
X 4 Is O, S, -N (R) 6a ) -, or-C (R) 6 ) 2 -；
X 5 Is O or S; and
each R 6a Are respectively and independently H and C 1-6 Alkyl radical, C 1-6 Hydroxyalkyl radical, C 1-6 Haloalkyl, C 1-6 Aminoalkyl radical, C 1-6 Cyanoalkyl, C 1-6 Alkoxy radical, C 1-6 Haloalkoxy, C 1-6 Alkylthio radical, C 1-6 Alkylamino radical, C 1-6 Haloalkylamino, C 3-8 Cycloalkyl radical, C 3-8 Cycloalkyl radical C 1-6 Alkyl radical, C 2-7 Heterocyclic group, C 2-7 Heterocyclyl radical C 1-6 Alkyl radical, C 6-12 Aryl radical, C 6-12 Aryl radical C 1-6 Alkyl radical, C 1-9 Heteroaryl, or C 1-9 Heteroaryl C 1-6 An alkyl group.
In some embodiments, the method further comprises, among others,
Figure BDA0003128505470000142
Is that
Figure BDA0003128505470000143
Figure BDA0003128505470000151
Figure BDA0003128505470000161
Figure BDA0003128505470000171
In some embodiments, wherein W is-COOH, -COOCH 3 、-COOCH 2 CH 3 、-COOCH 2 CH 2 CH 3 、-COOCH(CH 3 ) 2 、 -COOCH 2 CH(CH 3 ) 2 、-P(＝O)(OH) 2 、-P(＝O)(OCH 3 )(OCH 3 )、-P(＝O)(O - Na + )(O - Na + )、-P(＝O)(O - NH 4 + )(O - NH 4 + )、 -P(＝O)(OH)(OCH 3 )、-P(＝O)(OH)(OPh)、-P(＝O)(OH)(OCH 2 CH 3 )、-P(＝O)(OCH 2 CH 3 )(OCH 2 CH 3 )、
Figure BDA0003128505470000172
Wherein R is 7d Is H, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, -CF 3 、-CH 2 CF 3 、-CH 2 CN、-CH 2 CH 2 CN、-CH 2 OH、 -CH 2 CH 2 OH, cyclopropyl, cyclobutyl, cyclopentyl, phenyl, pyridinyl, pyridazinyl, pyrazinyl, pyrimidinyl, pyrazolyl, triazolyl, or tetrazolyl, wherein R 7d Optionally substituted with 0, 1, 2, 3 or 4 substituents independently selected from H, D, F, cl, br, I, -OH, -NH 2 、-NO 2 -CN, oxo (= O), C 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, C 1-4 Hydroxyalkyl radical, C 1-4 Haloalkyl, C 1-4 Aminoalkyl radical, C 1-4 Cyanoalkyl, C 1-4 Alkoxy and C 1-4 A substituent of a haloalkoxy group.
In some embodiments, wherein each R is 1 Are respectively and independently H, D, F, cl, br, -OH, -NH 2 、-NO 2 -CN, methyl, ethyl, -CF 3 、-CH 2 CF 3 、-CH 2 CN、-CH 2 CH 2 CN、-CH 2 OH, or-CH 2 CH 2 OH; n is 0, 1, 2, 3 or 4.
In some embodiments, wherein R 5 Is H, D, F, cl, br, I, -OH, -NH 2 、-NO 2 -CN, oxo (= O), C 1-4 Alkyl radical, C 1-4 Haloalkyl, C 1-4 Cyanoalkyl, C 1-4 Alkoxy radical C 1-4 Alkyl radical, C 3-6 Cycloalkyl radical, C 3-6 Heterocyclic group, C 6-10 Aryl radical, C 1-9 Heteroaryl, R 5c -C(＝O)-、R 5c -OC(＝O)-、R 5c -C(＝O)O-、R 5c -NHC(＝O)-、R 5c -C(＝O)NH-、R 5c -L 3 -C 1-4 Alkyl-, R 5a -C 1-4 Alkyl, or R 5a -C 1-4 Hydroxyalkyl-, wherein said C is 1-4 Alkyl radical, C 1-4 Haloalkyl, C 1-4 Cyanoalkyl, C 1-4 Alkoxy radical C 1-4 Alkyl radical, C 3-6 Cycloalkyl radical, C 3-6 Heterocyclic group, C 6-10 Aryl radical, C 1-9 Heteroaryl, R 5c -C(＝O)-、R 5c -OC(＝O)-、R 5c -C(＝O)O-、R 5c -NHC(＝O)-、 R 5c -C(＝O)NH-、R 5c -L 3 -C 1-4 Alkyl-, R 5a -C 1-4 Alkyl and R 5a -C 1-4 Hydroxyalkyl-is independently optionally substituted with 0, 1, 2, 3 or 4R 5b Substitution;
R 5a is C 3-6 Cycloalkyl radical, C 3-6 Heterocyclic ringsAlkyl radical, C 6-10 Aryl, or C 1-9 Heteroaryl, wherein R is 5a Optionally substituted by 0, 1, 2, 3 or 4R 5b Substitution;
R 5c is H, C 1-4 Alkyl radical, C 3-6 Cycloalkyl, C 3-6 Heterocyclic group, C 6-10 Aryl, or C 1-9 Heteroaryl, wherein R is 5c Optionally substituted by 0, 1, 2, 3 or 4R 5b Substitution; and
L 3 is O, S, -NH-, or-C (= O) -.
In some embodiments, wherein R 5 Is H, D, F, cl, br, I, -OH, -NH 2 、-NO 2 -CN, oxo (= O), methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, methoxymethyl, methoxyethyl, -CF 3 、-CH 2 CF 3 、-CH 2 CH 2 CN、 -CH 2 CH 2 OH、-COOH、H 2 NC(＝O)-、R 5c -C(＝O)-、R 5c -OC(＝O)-、R 5c -NHC(＝O)-、R 5c -L 3 -C 1-3 Alkyl-, R 5a 、R 5a -C 1-3 Hydroxyalkyl, or R 5a -C 1-3 An alkyl group;
L 3 is O, S, -NH-, or-C (= O) -; and
R 5a and R 5c Each independently is
Figure BDA0003128505470000181
Wherein said R 5a And R 5c Each optionally substituted by 0, 1, 2 or 3 substituents independently selected from the group consisting of H, D, F, cl, br, I, -OH, -NH 2 、
-NO 2 -CN, oxo (= O), C 1-4 Alkyl radical, C 1-4 Haloalkyl, C 1-4 Cyanoalkyl, C 1-4 Hydroxyalkyl radical, C 1-4 Alkoxy, and C 1-4 Alkoxy radical C 1-4 Alkyl groups.
In some embodiments, wherein said R is 5a And R 5c Each optionally substituted by 0, 1, 2 or 3 substituents independently selected from the group consisting of H, D, F, cl, br, I, -OH, -NH 2 、-NO 2 -CN, oxo (= O), methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, -CF 3 、 -CH 2 CF 3 、-CH 2 CHF 2 Methoxy, ethoxy, propoxy, methoxymethyl, cyclopropyl, cyclopropylmethyl, and cyclobutyl.
In some embodiments, wherein each R is 1a 、R 2 、R 3 、R 4 、R 5b 、R 6 、R a And R b Are respectively and independently H, D, F, cl, br, I, -OH, -NH 2 、-NO 2 -CN, oxo (= O), C 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, C 1-4 Hydroxyalkyl radical, C 1-4 Haloalkyl, C 1-4 Aminoalkyl radical, C 1-4 Cyanoalkyl, C 1-4 Alkoxy radical, C 1-4 Haloalkoxy, C 1-4 Alkylthio radical, C 1-4 Alkylamino radical, C 1-4 Haloalkylamino, -NR 1b R 1c 、C 3-6 Cycloalkyl radical, C 3-6 Cycloalkyl radical C 1-4 Alkyl radical, C 3-6 Heterocyclic group, C 3-6 Heterocyclyl radical C 1-4 Alkyl radical, C 6-10 Aryl radical, C 6-10 Aryl radical C 1-4 Alkyl radical, C 1-9 Heteroaryl, or C 1-9 Heteroaryl C 1-4 An alkyl group; wherein C is 3-6 Cycloalkyl radical, C 3-6 Cycloalkyl radical C 1-4 Alkyl radical, C 3-6 Heterocyclic group, C 3-6 Heterocyclyl radical C 1-4 Alkyl radical, C 6-10 Aryl radical, C 6-10 Aryl radical C 1-4 Alkyl radical, C 1-9 Heteroaryl and C 1-9 Heteroaryl C 1-4 Alkyl is optionally substituted by 0, 1, 2, 3 or 4 substituents independently selected from H, F, cl, br, I, -OH, -NH 2 、-NO 2 -CN, oxo (= O), C 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, C 1-4 Hydroxyalkyl radical, C 1-4 Haloalkyl, C 1-4 Aminoalkyl radical, C 1-4 Cyanoalkyl, C 1-4 Alkoxy and C 1-4 A substituent of a haloalkoxy group.
In some embodiments, each R is 5b Are respectively and independently H, D, F, cl, br, I, -OH, -NH 2 、-NO 2 -CN, oxo (= O), methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, -CF 3 、-CH 2 CF 3 、-CH 2 CHF 2 Methoxy, ethoxy, propoxy, methoxymethyl, cyclopropyl, cyclopropylmethyl, or cyclobutyl.
In some embodiments, wherein each R is 1b 、R 1c 、R c 、R d 、R 2a 、R 6a 、R 7c And R 7d Are respectively and independently H, D, OH, C 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, C 1-4 Hydroxyalkyl radical, C 1-4 Haloalkyl, C 1-4 Aminoalkyl radical, C 1-4 Cyanoalkyl, C 1-4 Alkoxy radical, C 1-4 Haloalkoxy, C 1-4 Alkylthio radical, C 1-4 Alkylamino radical, C 1-4 Haloalkylamino, C 3-6 Cycloalkyl radical, C 3-6 Cycloalkyl radical C 1-4 Alkyl radical, C 3-6 Heterocyclic group, C 3-6 Heterocyclyl radical C 1-4 Alkyl radical, C 6-10 Aryl radical, C 6-10 Aryl radical C 1-4 Alkyl radical, C 1-9 Heteroaryl, or C 1-9 Heteroaryl C 1-4 An alkyl group; wherein C is 3-6 Cycloalkyl radical, C 3-6 Cycloalkyl radical C 1-4 Alkyl radical, C 3-6 Heterocyclic group, C 3-6 Heterocyclyl radical C 1-4 Alkyl radical, C 6-10 Aryl radical, C 6-10 Aryl radical C 1-4 Alkyl radical, C 1-9 Heteroaryl and C 1-9 Heteroaryl C 1-4 Alkyl is optionally substituted by 0, 1, 2, 3 or 4 substituents independently selected from H, F, cl, br, I, -OH, -NH 2 、-NO 2 -CN, oxo (= O), C 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, C 1-4 Hydroxyalkyl radical, C 1-4 Haloalkyl, C 1-4 Aminoalkyl radical, C 1-4 Cyanoalkyl, C 1-4 Alkoxy and C 1-4 A substituent of a haloalkoxy group.
In some embodiments, wherein R 7a And R 7b Each independently is H, li + 、Na + 、K + 、NH 4 + 、Mg 2+ 、Ca 2+ 、C 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, C 1-4 Hydroxyalkyl radical, C 1-4 Haloalkyl, C 1-4 Aminoalkyl radical, C 1-4 Cyanoalkyl, C 3-6 Cycloalkyl radical, C 3-6 Cycloalkyl radical C 1-4 Alkyl radical, C 3-6 Heterocyclic group, C 3-6 Heterocyclyl radical C 1-4 Alkyl radical, C 6-10 Aryl radical, C 6-10 Aryl radical C 1-4 Alkyl radical, C 1-9 Heteroaryl, or C 1-9 Heteroaryl C 1-4 An alkyl group; wherein C is 3-6 Cycloalkyl radical, C 3-6 Cycloalkyl radical C 1-4 Alkyl radical, C 3-6 Heterocyclic group, C 3-6 Heterocyclyl radical C 1-4 Alkyl radical, C 6-10 Aryl radical, C 6-10 Aryl radical C 1-4 Alkyl radical, C 1-9 Heteroaryl and C 1-9 Heteroaryl C 1-4 Alkyl is optionally substituted by 0, 1, 2, 3 or 4 substituents independently selected from H, F, cl, br, I, -OH, -NH 2 、-NO 2 -CN, oxo (= O), C 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, C 1-4 Hydroxyalkyl radical, C 1-4 Haloalkyl, C 1-4 Aminoalkyl radical, C 1-4 Cyanoalkyl, C 1-4 Alkoxy and C 1-4 A substituent of a haloalkoxy group.
In some embodiments, wherein it is a compound having one of the following structures:
Figure BDA0003128505470000191
Figure BDA0003128505470000201
Figure BDA0003128505470000211
Figure BDA0003128505470000221
Figure BDA0003128505470000231
Figure BDA0003128505470000241
Figure BDA0003128505470000251
Figure BDA0003128505470000261
Figure BDA0003128505470000271
Figure BDA0003128505470000281
Figure BDA0003128505470000291
Figure BDA0003128505470000301
Figure BDA0003128505470000311
Figure BDA0003128505470000321
Figure BDA0003128505470000331
Figure BDA0003128505470000341
Figure BDA0003128505470000351
Figure BDA0003128505470000361
or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, regioisomer, nitroxide, or mixture thereof.
In another aspect, the invention provides a pharmaceutical composition comprising a compound of the invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable adjuvant, diluent or carrier.
In some embodiments, the pharmaceutical composition further comprises an additional therapeutic agent.
In another aspect, the present invention provides the use of a compound of the present invention or a pharmaceutical composition of the present invention for the manufacture of a medicament for the prevention and/or treatment of cardiovascular metabolic diseases and related conditions in a mammal.
<xnotran> , , T1D, T2DM, , T1D, LADA, EOD, YOAD, MODY, , , , , , , , , , , , , , , , , , , , NAFLD, NASH, , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , X, , , , , , , , , , , , , , , , apo B , , , , , </xnotran> Short bowel syndrome, crohn's disease, colitis, irritable bowel syndrome, polycystic ovary syndrome, or addiction.
In some embodiments, a compound of the invention or a pharmaceutical composition thereof may be administered in combination with an additional therapeutic agent.
In some embodiments, the use of the invention comprises administering to a mammal an amount of a compound or pharmaceutical composition of the invention sufficient to effect said treatment or prevention.
Pharmaceutical composition, preparation and use
When used as a medicament, the compounds of the present invention are typically administered in the form of a pharmaceutical composition. The compositions may be prepared in a manner well known in the pharmaceutical art and comprise at least one compound according to the invention according to formula I, II or III. Typically, the compounds of the present invention are administered in a pharmaceutically effective amount. The amount of the compound of the invention actually administered will generally be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound of the invention administered, the age, weight and response of the individual patient, the severity of the patient's symptoms, and the like.
In some embodiments, the invention comprises a pharmaceutical composition. Such pharmaceutical compositions comprise a compound of the invention in a pharmaceutically acceptable carrier. Other pharmacologically active substances may also be present. As used herein, "pharmaceutically acceptable carrier" includes any and all solvents, dispersion media, envelopes, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like that are physiologically compatible. Examples of pharmaceutically acceptable carriers include one or more of water, saline, phosphate buffered saline, dextrose, glycerol, ethanol, and the like, and combinations thereof, and isotonic agents, for example, sugars, sodium oxide, or polyalcohols such as mannitol or sorbitol, may be included in the composition. Pharmaceutically acceptable substances (such as wetting agents) or minor amounts of auxiliary substances (such as wetting or emulsifying agents, preservatives or buffers) enhance the shelf life or effectiveness of the antibody or antibody portion.
The compositions of the present invention may take a variety of forms. These forms include, for example, liquid, semi-solid, and solid dosage forms, such as liquid solutions (e.g., injectable and infusible solutions), dispersions or suspensions, tablets, pills, powders, liposomes, and suppositories. The form depends on the intended mode of administration and therapeutic application.
Typical compositions are in the form of injectable and infusible solutions, such as compositions similar to those commonly used for passive immunization of humans with antibodies. One mode of administration is parenteral (e.g., intravenous, subcutaneous, intraperitoneal, intramuscular). In another embodiment, the antibody is administered by intravenous infusion or injection. In yet another embodiment, the antibody is administered by intramuscular or subcutaneous injection.
Oral administration of solid dosage forms can be presented, for example, as individual units, such as hard or soft capsules, pills, cachets, chains, or tablets, each containing a predetermined amount of at least one compound of the invention. In another embodiment, oral administration may be in the form of a powder or granules. In another embodiment, the oral dosage form is a sublingual form, such as a chain agent. In such solid dosage forms, the compounds of formula I are conventionally combined with one or more accessory ingredients. Such capsules or tablets may contain controlled release formulations. In the case of capsules, tablets and pills, the dosage forms may also contain buffering agents or may be prepared with an enteric coating.
Compositions for parenteral administration may be emulsions or sterile solutions. In certain embodiments, propylene glycol, polyethylene glycol, vegetable oils, particularly olive oil, or injectable organic esters may be used as a solvent or carrier, and in some embodiments, ethyl oleate may be used as a solvent or carrier. These compositions may also comprise adjuvants, in particular wetting agents, isotonicity agents, emulsifiers, dispersants and stabilizers. Sterilization can be performed in several ways, in certain embodiments, using bacteriological filters, by radiation or by heating. They may also be prepared in the form of sterile solid compositions which may be dissolved in sterile water or any other injectable sterile medium at the time of use.
Compositions for rectal administration are suppositories or rectal capsules which, in addition to the active ingredient, contain adjuvants such as cocoa butter, semi-synthetic glycerides or polyethylene glycols.
In certain embodiments, the compositions provided herein are pharmaceutical compositions or single unit dosage forms. Pharmaceutical compositions and single unit dosage forms provided herein comprise a prophylactically or therapeutically effective amount of one or more prophylactic or therapeutic agents (e.g., a compound provided herein or other prophylactic or therapeutic agent) and typically one or more pharmaceutically acceptable carriers or excipients. In particular embodiments and within the present invention, the term "pharmaceutically acceptable" refers to a drug approved by a regulatory agency of the federal or a state government or listed in the U.S. pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans. The term "carrier" includes diluents, adjuvants (e.g., freund's adjuvant (complete and incomplete)), adjuvants or vehicles with which the therapeutic agent is administered. Such pharmaceutical carriers can be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. Water may be used as a carrier when the pharmaceutical composition is administered intravenously. Saline and aqueous dextrose and glycerol solutions can also be employed as liquid carriers, particularly for injectable solutions. Examples of suitable pharmaceutical carriers are described in Remington, the Science and practice of pharmacy; pharmaceutical press (pharmaceutical press); version 22 (9/15/2012).
Typical pharmaceutical compositions and dosage forms contain one or more excipients. Suitable excipients are well known to those skilled in the art of pharmacy and in certain embodiments include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol and the like. Whether a particular excipient is suitable for incorporation into a pharmaceutical composition or dosage form depends on a variety of factors well known in the art, including, but not limited to, the manner in which the dosage form is administered to a subject and the particular active ingredient in the dosage form. The compositions or single unit dosage forms may also contain minor amounts of wetting or emulsifying agents, or pH buffering agents, if desired.
Suitable compositions for oral administration comprise an effective amount of a compound of the invention, which may be in the form of: tablets, troches, aqueous or oily suspensions, powders or granules, emulsions, hard or soft capsules or syrups or elixirs. Compositions for oral use may be prepared according to any method known in the art for the manufacture of pharmaceutical compositions, and such compositions may contain one or more ingredients selected from the group consisting of: sweetening agents, flavoring agents, coloring agents and preserving agents, thereby providing a pharmaceutically elegant and palatable preparation. Tablets may contain the active ingredient in combination with non-toxic pharmaceutically acceptable excipients which are used in the manufacture of tablets. These adjuvants include: for example, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, such as corn starch or alginic acid; binding agents, such as starch, gelatin or acacia; lubricants, for example magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated according to known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material may be used, such as glyceryl monostearate or glyceryl distearate.
The dosage regimen for the compounds of the invention and/or compositions containing them is based on a number of factors, including the type, age, weight, sex and medical condition of the patient; the severity of the symptoms; the route of administration; and the activity of the particular compound used. Thus, the dosage regimen may vary widely. In one embodiment, the total daily dose of a compound of the invention for use in the treatment of the indications discussed herein is typically from about 0.001 to about 100 mg/kg (i.e., mg of a compound of the invention per kg body weight). In another embodiment, the total daily dose of a compound of the invention is from about 0.01 to about 30 mg/kg, and in another embodiment from about 0.03 to about 10 mg/kg, and in yet another embodiment from about 0.1 to about 3 mg/kg. It is not uncommon to administer the compounds of the invention repeatedly many times in a day (usually no more than 4 times). Multiple doses per day are typically used to increase the total daily dose, if desired.
Compositions for oral administration may be provided in the form of tablets containing 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 30.0, 50.0, 75.0, 100, 125, 150, 175, 200, 250 or 500 milligrams of the active ingredient in a dose that will symptomatically modify the patient. The medicaments typically contain from about 0.01 mg to about 500 mg of the active ingredient, or in another embodiment from about 1 mg to about 100 mg of the active ingredient. Intravenous dosages during a fixed rate infusion may range from about 0.01 to about 10 mg/kg/min.
In another aspect, the present invention provides a compound of the invention or a pharmaceutical composition comprising a compound of the invention for use in medicine. <xnotran> , , / , T1D, T2DM, , T1D, LADA, EOD, YOAD, MODY, , , , , , , , , , , , , , , , , , , , NAFLD, NASH, , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , X, , , , , , , , , , , , , , </xnotran> Prevention and/or treatment of foot theft, ulcerative colitis, hyperpapo B lipoproteinemia, alzheimer's disease, schizophrenia, impaired cognitive function, inflammatory bowel disease, short bowel syndrome, crohn's disease, colitis, irritable bowel syndrome, polycystic ovary syndrome, or addiction.
The compounds of the present invention may be administered simultaneously with, or before or after, one or more other therapeutic ingredients. The compounds of the invention may be administered separately from the other component, by the same or different routes of administration, or both together in the same pharmaceutical composition.
In some embodiments, the compounds of the present invention may be administered with antidiabetic agents including, but not limited to, biguanides (e.g., metformin), sulfonylureas (e.g., tolbutamide, glibenclamide, gliclazide, chlorpropamide, tolazamide, acetohexamide, glipizide, glimepiride or glipizide), thiazolidinediones (e.g., pioglitazone, rosiglitazone or lobeliglitazone), gliclazide
(glitazar) (e.g. saxaglitazar, aleglitazar, muraglitazar or tesaglitazar), meglitinides (e.g. nateglinide, rapagliptin), dipeptidyl peptidase 4 (DPP-4) inhibitors (e.g. sitagliptin, vildagliptin, saxagliptin, linagliptin, gemagliptin (gemagliptin), anagliptin (anagliptin), teigliptin (teneliptin), alogliptin, emeragliptin (trelagliptin) duloxetine or omagliptin (omarigliptin)), glitazones (glitazones) (e.g. pioglitazone, rosiglitazone, balaglitazone (balaglitazone), rivoglitazone (rivoglitazone) or lobeglitazone), sodium-glucose linked transporter 2 (SGLT 2) inhibitors (e.g. engeletin, canagliflozin, dapagliflozin, exagliflozin (ipragliflozin), trogliflozin (tofoglazin), segregatin (sergliflozin etabonate), segregatin (remog 1if1ozin etabonate) or segregatin, SGLTL1 inhibitors, GPR40 agonists (FFAR 1/FFA1 agonists, e.g. fabry's square (fasiglifam)), glucose-dependent insulinotropic peptide (GIP) and analogs thereof, alpha glucosidase inhibitors, e.g. voglibose (voglibose), acarbose or miglitol (miglitol), or insulin analogs, including pharmaceutically acceptable salts of the specifically identified agents and pharmaceutically acceptable solvates of said agents and salts.
Detailed Description
To illustrate the invention, the following examples are set forth. It is to be understood that the invention is not limited to these embodiments, but is provided as a means of practicing the invention.
In general, the compounds of the invention can be prepared by the processes described herein, unless otherwise indicated, wherein the substituents are as defined in formula I, II, III, IIIa or IV. The following reaction schemes and examples serve to further illustrate the context of the invention.
Those skilled in the art will recognize that: the chemical reactions described herein may be used to suitably prepare a number of other compounds of the invention, and other methods for preparing the compounds of the invention are considered to be within the scope of the invention. For example, the synthesis of those non-exemplified compounds according to the present invention can be successfully accomplished by those skilled in the art by modification, such as appropriate protection of interfering groups, by the use of other known reagents in addition to those described herein, or by some routine modification of reaction conditions. In addition, the reactions disclosed herein or known reaction conditions are also recognized as being applicable to the preparation of other compounds of the present invention.
The examples described below, unless otherwise indicated, are all temperatures set forth in degrees Celsius. Reagents were purchased from commercial suppliers such as Aldrich Chemical Company, arco Chemical Company, annage Chemical Company (Energy-Chemical Company), shanghai Shaoyuan Company, J & K Chemical Company, alradin Chemical Company (Addin Chemical Company), meryer Chemical Company, TCI Chemical Company, xiya Reagent Company, bidepharrm Company, macklin Company and Alfa Chemical Company, and were used without further purification unless otherwise indicated. General reagents were purchased from Shantou Wen Long chemical reagent factory, guangdong Guanghua chemical reagent factory, guangzhou chemical reagent factory, tianjin Haojian Yunyu chemical Co., ltd, tianjin Shucheng chemical reagent factory, wuhan Xin Huayuan scientific and technological development Co., ltd, qingdao Tenglong chemical reagent Co., ltd, and Qingdao Kaolingyi factory.
The anhydrous tetrahydrofuran, dioxane, toluene and ether are obtained through reflux drying of metal sodium. The anhydrous dichloromethane and chloroform are obtained by calcium hydride reflux drying. Ethyl acetate, petroleum ether, N-hexane, N, N-dimethylacetamide and N, N-dimethylformamide were used as they were previously dried over anhydrous sodium sulfate.
The following reactions are generally carried out under positive pressure of nitrogen or argon or by sleeving a dry tube over an anhydrous solvent (unless otherwise indicated), the reaction vial being stoppered with a suitable rubber stopper and the substrate being injected by syringe. The glassware was dried.
The column chromatography is performed using a silica gel column. Silica gel (300-400 mesh) was purchased from Qingdao oceanic plants.
1 HNMR spectra were recorded using a Bruker 400MHz or 600MHz NMR spectrometer. 1 H NMR spectrum CDC1 3 、DMSO-d 6 、CD 3 OD or acetone-d 6 TMS (0 ppm) or chloroform (7.26 ppm) was used as a reference standard for the solvent (in ppm). When multiple peaks occur, the following abbreviations will be used: s (singleton), d (doublet), t (triplet), m (multiplet), br (broad), dd (doublet of doublets), dt (doublet of doublets), and dt (doublet of triplets). Coupling constants are expressed in hertz (Hz).
The conditions for determining low resolution Mass Spectrometry (MS) data were: agilent 6120 four-stage rod HPLC-M (column model: zorbax SB-C18, 2.1x 30mm,3.5 micron, 6min, flow rate 0.6mL/min. Mobile phase: 5% -95% ((CH with 0.1% formic acid) 3 CN) in (H containing 0.1% formic acid) 2 O) by electrospray ionization (ESI) at 210nm/254nm, with UV detection.
Pure compounds were detected by UV at 210nm/254nm using Agilent 1260pre-HPLC or Calesepupmp 250pre-HPLC (column model: NOVASEP 50/80mm DAC).
The following acronyms are used throughout the invention:
CD 3 OD deuterated methanol
CDC1 3 Deuterated chloroform
DMF N, N-dimethylformamide
DMSO-d 6 Deuterated dimethyl sulfoxide
BINAP bis (trimethylsilyl) amino lithium
BINAP 1,1 '-binaphthyl-2, 2' -bisdiphenylphosphine
LDA lithium diisopropylamide
x-phos 2-dicyclohexylphospho-2 ',4',6' -triisopropylbiphenyl
g
h hours
mL, mL
RT, RT, r.t. Room temperature
Typical synthetic procedures for preparing the disclosed compounds of the invention are shown in scheme 1 or 2 below
Synthesis scheme 1:
Figure BDA0003128505470000401
the intermediate 1-1 and the intermediate 1-2 are subjected to coupling reaction under the catalysis of metal palladium to generate an intermediate 1-3; carrying out metal catalytic reduction reaction on the intermediate 1-3 to obtain an intermediate 1-4;1-4 and 1-5 are subjected to coupling reaction under the condition of metal catalysis to obtain an intermediate 1-6; under the action of strong acid, 1-6 removes protective group to form intermediate 1-7;1-7 and 1-8 are subjected to substitution reaction under alkaline condition to obtain 1-9. Wherein Z is 1 、Z 2 、X 1 、X 4 、W、 R 1 、R 2 、R 3 、R 4 、R 5 N, m and n1 have the definitions given in the description; PG is a protecting group.
Synthesis scheme 2
Figure BDA0003128505470000402
Under the action of strong alkali, the intermediate 2-1 and the intermediate 2-2 generate an intermediate 2-3 through substitution reaction; the intermediate 2-3 and 2-4 are subjected to coupling reaction under the condition of metal catalysis to obtain an intermediate 2-5; under the action of strong acid, 2-5 removes protective group to form intermediate 2-6;2-6 and 2-7 are subjected to substitution reaction under alkaline conditions to obtain 2-8. Wherein Z is 1 、Z 2 、X 1 、X 2 、X 3 、W、R 1 、R 2 、R 3 、R 4 、R 5 N, m and n1 have the definitions given in the description; PG is a protecting group.
Examples
Synthesis of intermediates
Intermediate 1-fluoro-4- ((6- (piperidin-4-yl) pyridin-2-yl) oxymethyl) benzonitrile hydrochloride
Figure BDA0003128505470000411
Step 1) N-t-Butyloxycarbonyl-4- (6-chloropyridin-2-yl) piperidine-4-carboxylic acid methyl ester
Diisopropylamine (1.47ml, 10.0 mmol) was dissolved in tetrahydrofuran (10 mL), and 2.5M n-butyllithium (4.2mL, 10.5 mmol) was slowly added dropwise thereto under a low-temperature cooling bath at-30 ℃. Then, a solution of methyl N-t-butyloxycarbonyl-4-piperidinecarboxylate (2.43g, 10.0 mmol) in tetrahydrofuran (10 mL) was slowly dropped into the reaction flask, and after completion of the dropping, the mixture was stirred for 10 minutes. A solution of 2, 6-dichloropyridine (1.48g, 10.0 mmol) in tetrahydrofuran (10 mL) was added dropwise to the reaction flask, and the mixture was allowed to warm to room temperature naturally and stirred for 3 hours. When TLC shows that the reaction is unchanged, the reaction is quenched by saturated ammonium chloride aqueous solution, extracted by ethyl acetate, an organic phase is collected, dried and concentrated under reduced pressure, and the residue is purified by column chromatography to obtain 350mg of the product with the yield of 10%. LC-MS [ M + H ]] + :356.8。
Step 2) N-tert-Butyloxycarbonyl-4- (6-chloropyridin-2-yl) piperidine-4-carboxylic acid
Intermediate methyl N-tert-butyloxycarbonyl-4- (6-chloropyridin-2-yl) piperidine-4-carboxylate (350mg, 1.0 mmol) was dissolved in methanol (5.0 mL) and placed in an ice-water bath to which were added water (1.0 mL) and solid sodium hydroxide (460mg, 11.5 mmol) which was then allowed to stir at room temperature for 1h. After TLC monitoring disappearance of starting material, adjusted to pH =6 with 1.0N hydrochloric acid, the mixture was extracted with ethyl acetate and concentrated under reduced pressure to give the title compound as a light yellow solid 320mg, yield 94%, used directly in the next step. LC-MS [ M + H ] ] + :341.6。
Step 3) 4- (6-Chloropyridin-2-yl) piperidine-1-carboxylic acid tert-butyl ester
By reacting N-tert-butyloxycarbonyl-4- (6-Chloropyridin-2-yl) piperidine-4-carboxylic acid (320 mg) was dissolved in 1, 2-dichloroethane (10 mL), and the mixture was heated to 80 ℃ with stirring. After the reaction was monitored by LC-MS to be complete, the solvent was removed by concentration under reduced pressure to give 260mg of the product in 100% yield. LCMS (liquid Crystal display Module) [ M + H ]] + :297.8。
Step 4) 4- (6- (4-cyano-2-fluorobenzyloxy) pyridin-2-yl) piperidine-1-carboxylic acid tert-butyl ester
4-cyano-2-fluorobenzyl alcohol (101mg, 0.67mmol) and tert-butyl 4- (6-chloropyridin-2-yl) piperidine-1-carboxylate (166mg, 0.56mmol) were dissolved in 1, 4-dioxane (15 mL), followed by the addition of tris (dibenzylideneacetone) dipalladium (26mg, 0.035 mmol), 2-dicyclohexylphosphonium-2, 4, 6-triisopropylbiphenyl (28mg, 0.07mmol) and cesium carbonate (293mg, 1.07mmol), and the mixture was heated to 100 ℃ and stirred for reaction. After the completion of the reaction was monitored by TLC, it was quenched with saturated aqueous ammonium chloride, extracted with ethyl acetate, concentrated under reduced pressure, and the residue was purified by column chromatography to give 200mg of the product in 81% yield.
Step 5) 3-fluoro-4- ((6- (piperidin-4-yl) pyridin-2-yl) oxymethyl) benzonitrile hydrochloride
Tert-butyl 4- (6- (4-cyano-2-fluorobenzyloxy) pyridin-2-yl) piperidine-1-carboxylate (200mg, 0.49mmol) was dissolved in methanol (3 mL), followed by dropwise addition of an ethanol solution of hydrochloric acid (1.2 mL,4.9mmol,4 mol/L), and the mixture was stirred at room temperature for reaction. After the disappearance of the starting material, concentration was performed under reduced pressure to obtain the title compound as an oil (161 mg, yield 95%). LCMS (liquid Crystal display Module) [ M + H ] ] + :312.2。
Intermediate 2- (6- (4-chloro-2-benzyloxy) pyridin-2-yl) piperazine trifluoroacetate
Figure BDA0003128505470000412
Step 1) 4- (6-chloropyridin-2-yl) piperazine-1-carboxylic acid tert-butyl ester
2, 6-dichloropyridine (2g, 13.5 mmol) and piperazine-1-carboxylic acid tert-butyl ester (3.02g, 16.2mmol) were placed in a 100mL single-neck flask, followed by addition of cesium carbonate (8.8g, 27mmol) and acetonitrile (30 mL), and the mixture was stirred at 85 ℃ for 12 hours. Cooling to room temperature, filtering to remove insoluble matter, concentrating the mixture under reduced pressure, and purifying the residue by column chromatography to give the product 500mg in 12% yield.
Step 2) 4- (6- (4-chloro-2-fluorobenzyloxy) pyridin-2-yl) piperazine-1-carboxylic acid tert-butyl ester
Tert-butyl 4- (6-chloropyridin-2-yl) piperazine-1-carboxylate (450mg, 1.51mmol), 4-chloro-2-fluorobenzyl alcohol (243mg, 1.51mmol), cesium carbonate (984mg, 3.02mmol), tris (dibenzylideneacetone) dipalladium (138mg, 0.15mmol), 1 '-binaphthyl-2, 2' -bis-diphenylphosphine (188 mg, 0.30mmol), and toluene (10 mL) were placed in a 50mL single-neck flask, and the mixture was reacted at 110 ℃ for 12 hours under nitrogen. Cooled to room temperature, filtered to remove insoluble matter, concentrated under reduced pressure, and the resulting residue was purified by column chromatography to give the desired product 330mg, yield 52%.
Step 3) 1- (6- (4-chloro-2-benzyloxy) pyridin-2-yl) piperazine trifluoroacetate salt
Tert-butyl 4- (6- (4-chloro-2-fluorobenzyloxy) pyridin-2-yl) piperazine-1-carboxylate (200mg, 0.47mmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (1 mL) was added, and the mixture was stirred at room temperature for 4 hours. The reaction was stopped and concentrated under reduced pressure to give 245mg of crude product. LCMS (liquid Crystal display Module) [ M + H ]] + : 322.7。
Intermediate 3-fluoro-4- ((6- (piperazin-1-yl) pyridin-2-yl) oxymethyl) benzonitrile hydrochloride
Figure BDA0003128505470000421
Step 1) 4- ((6-Chloropyridin-2-yl) oxymethyl) -3-fluorobenzonitrile
3-fluoro-4-hydroxymethylbenzonitrile (6 g, 39.7mmol) was dissolved in tetrahydrofuran (120 mL) and cooled to 0 deg.C, sodium hydride (3.18 g,79.4mmol, 60%) was added and the mixture stirred for 0.5 h. Dichloropyridine (11.75g, 79.4 mmol) was then added and the mixture stirred at room temperature for 0.5 h. The temperature was raised to 50 ℃ and the reaction was continued for 1 hour. The reaction was stopped, cooled to room temperature, poured into ice water (150 mL), extracted with ethyl acetate (150 mL × 3), the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting residue was purified by column chromatography to give the objective compound as a white solid (7.19 g, yield 69%). LCMS[M+H] + :263.6。
Step 2) 4- (6- (4-cyano-2-fluorobenzyloxy) pyridin-2-yl) piperazine-1-carboxylic acid tert-butyl ester
4- ((6-Chloropyridin-2-yl) oxymethyl) -3-fluorobenzonitrile (4g, 15.18mmol), piperazine-1-carboxylic acid tert-butyl ester (3.68g, 19.73mmol), tris (dibenzylideneacetone) dipalladium (0.7g, 0.76mmol), 1 '-binaphthyl-2, 2' -bis-diphenylphosphine (0.95g, 1.52mmol) and cesium carbonate (9.9 g, 30.36 mmol) were placed in a 250mL single-neck flask, toluene (80 mL) was added and the mixture was allowed to warm to 100 ℃ under nitrogen overnight. The reaction was stopped, cooled to room temperature, washed with water (50 mL), the aqueous phase was extracted with ethyl acetate (50 mL. Times.2), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and purified by column chromatography to give the product 3.9g, 62% yield. LCMS (liquid Crystal display Module) [ M + H ] ] + :413.5。
Step 3) 3-fluoro-4- ((6- (piperazin-1-yl) pyridin-2-yl) oxymethyl) benzonitrile hydrochloride
Tert-butyl 4- (6- (4-cyano-2-fluorobenzyloxy) pyridin-2-yl) piperazine-1-carboxylate (500mg, 1.21mmol) was dissolved in ethanol (5 mL), ethanol hydrochloride (1mL, 4mmol,4 mol/L) was added, and the mixture was stirred at room temperature for 4.5 hours. The reaction was stopped and concentrated under reduced pressure to give 550mg of the product.
Intermediate 4 (S) -1- (6- (4-chloro-2-fluorobenzyloxy) -3, 5-difluoropyridin-2-yl) -3-methylpiperazine hydrochloride
Figure BDA0003128505470000422
Step 1) 2- (4-chloro-2-fluorobenzyl) oxy) -3,5, 6-trifluoropyridine
To a mixed sample of 2,3,5, 6-tetrafluoropyridine (4.5g, 30mmol), 2-fluoro-4-chlorobenzyl alcohol (4.8g, 30mmol) and potassium carbonate (12.3g, 90mmol), N-methylpyrrole (30 mL) was added, and the mixture was stirred at 100 ℃ for reaction overnight; after the TLC checked that the starting material was substantially completely reacted, the system was allowed to cool to room temperature, saturated brine/ethyl acetate (60ml, v/v = 1) was added, the organic phase was separated, the aqueous phase was extracted with ethyl acetate (30ml × 2), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated to dryness under reduced pressure, and the residue was purified by column chromatography (PE) to give 4.67g of product in 53% yield.
Step 2) (S) -4- (6- ((4-chloro-2-fluorobenzyl) oxy) -3, 5-difluoropyridin-2-yl) -2-methylpiperazine-1-carboxylic acid tert-butyl ester
Dissolving 2- (4-chloro-2-fluorobenzyl) oxy) -3,5, 6-trifluoropyridine (511mg, 1.75mmol), 2S-N-Boc-piperazine (387mg, 1.93mmol) and potassium carbonate (266mg, 1.93mmol) in N, N-dimethylformamide (10 mL), and heating to 110 ℃ for reaction overnight; after TLC detection of the completion of the reaction of the starting materials, the reaction mixture was poured into water (10 mL), extracted with dichloromethane (10 mL. Multidot.3), the organic phases were combined and dried over anhydrous sodium sulfate, concentrated to dryness under reduced pressure, and the residue was purified by column chromatography (PE: EA = 10) to obtain 283mg of colorless oil in 58% yield.
Step 3) (S) -1- (6- (4-chloro-2-fluorobenzyloxy) -3, 5-difluoropyridin-2-yl) -3-methylpiperazine hydrochloride
(S) -4- (6- ((4-chloro-2-fluorobenzyl) oxy) -3, 5-difluoropyridin-2-yl) -2-methylpiperazine-1-carboxylic acid tert-butyl ester (283mg, 0.6 mmol) was dissolved in ethanol (6 mL), a 30% ethanol solution (2.8 mL) of hydrochloric acid was added, and the reaction was stirred at room temperature for 2 hours; TLC detection raw material reaction is complete, direct concentration, white solid 244mg, yield 99%.
Intermediate 5- (6- ((4-chloro-2-fluorobenzyl) oxy) -3, 5-difluoropyridin-2-yl) piperazine hydrochloride
Figure BDA0003128505470000431
Step 1) 2- ((4-chloro-2-fluorobenzyl) oxy) -3,5, 6-trifluoropyridine
To a mixture of 2,3,5, 6-tetrafluoropyridine (4.5g, 30mmol), 2-fluoro-4-chlorobenzyl alcohol (4.8g, 30mmol) and potassium carbonate (12.3g, 90mmol) was added N-methylpyrrole (30 mL), and the above-mentioned mixture was stirred at 100 ℃ for reaction overnight; after the TLC checked that the starting material was substantially completely reacted, the system was allowed to cool to room temperature, saturated brine/ethyl acetate (60ml, v/v = 1) was added, the organic phase was separated, the aqueous phase was extracted with ethyl acetate (30ml × 2), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated to dryness under reduced pressure, and the residue was purified by column chromatography (PE) to give 4.67g of product in 53% yield.
Step 2) tert-butyl 4- (6- ((4-chloro-2-fluorobenzyl) oxy) -3, 5-difluoropyridin-2-yl) piperazine-1-carboxylate
Dissolving 2- ((4-chloro-2-fluorobenzyl) oxy) -3,5, 6-trifluoropyridine (265mg, 0.91mmol), N-Boc-piperazine (188mg, 1.01mmol) and potassium carbonate (139mg, 1.01mmol) in N, N-dimethylformamide (4 mL), and heating to 110 ℃ for reaction overnight; after the TLC detection of the starting material reaction was complete, the reaction solution was poured into water (5 mL), extracted with dichloromethane (5 mL × 3), the organic phases were combined and dried over anhydrous sodium sulfate, concentrated to dryness under reduced pressure, and the residue was purified by column chromatography (PE: EA = 15) to give 236mg of a colorless oil in 57% yield.
Step 3) 1- (6- ((4-chloro-2-fluorobenzyl) oxy) -3, 5-difluoropyridin-2-yl) piperazine hydrochloride
Tert-butyl 4- (6- ((4-chloro-2-fluorobenzyl) oxy) -3, 5-difluoropyridin-2-yl) piperazine-1-carboxylate (236mg, 0.51mmol) was dissolved in ethanol (6 mL), and a 30% ethanol solution (2.0 mL) of hydrochloric acid was added, and the reaction was stirred at room temperature for 2 hours; TLC detection raw material reaction is complete, direct concentration, white solid 174mg, yield 95%.
Intermediate 6- ((4-chloro-2-fluorobenzyl) oxy) -5-fluoro-2- (piperazin-1-yl) pyridine hydrochloride
Figure BDA0003128505470000432
Step 1) 2, 4-dichloro-5-fluoropyrimidine
5-fluorouracil (30g, 230.6 mmol) and phosphorus oxychloride (105.8g, 690.2mmol) are placed in a 500mL three-necked flask, the temperature is increased to 95 ℃, stirring is carried out, dimethylaniline (55.9g, 461.2mmol) is added dropwise, and the temperature is kept for reaction overnight after the dropwise addition. Cooled to room temperature, slowly poured into diluted hydrochloric acid (122mL, 3N) at-10 ℃ and stirred for 1 hour, added with dichloromethane (300 mL) for extraction, the organic phase washed to neutrality with water, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 31.5g of light yellow solid product with yield of 83%.
Step 2) 2-chloro-4- ((4-chloro-2-fluorobenzyl) oxy) -5-fluoropyrimidine
4-chloro-2-fluorobenzyl alcohol (5.29g, 32.93mmol) was dissolved in tetrahydrofuran (75 mL), the temperature was reduced to 0 ℃, sodium hydride (790mg, 32.93mmol, 60%) was added to the mixture, the mixture was stirred for 30 minutes, a solution of 2, 4-dichloro-5-fluoropyrimidine (5 g, 29.94mmol) in tetrahydrofuran (25 mL) was added dropwise, and the mixture was stirred at room temperature overnight. The reaction solution was poured into saturated ammonium chloride (200 mL), extracted with ethyl acetate (200ml × 3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and purified by column chromatography to give a off-white solid product 3.65g with a yield of 38%.
Step 3) tert-butyl 4- (4- ((4-chloro-2-fluorobenzyl) oxy) -5-fluoropyrimidin-2-yl) piperazine-1-carboxylate
2-chloro-4- ((4-chloro-2-fluorobenzyl) oxy) -5-fluoropyrimidine (0.5g, 1.72mmol), 1-Boc-piperazine (352mg, 1.89mmol) was dissolved in DMF (10 mL), triethylamine (348mg, 3.44mmol) was added, and the mixture was warmed to 100 ℃ and reacted overnight. Cooling to room temperature, adding water (15 mL), extracting with ethyl acetate (20mL × 3), mixing the organic phases, washing with saturated saline solution, drying over anhydrous sodium sulfate, and purifying by column chromatography to obtain 326mg of yellow oily product with yield of 43%.
Step 4) 4- ((4-chloro-2-fluorobenzyl) oxy) -5-fluoro-2- (piperazin-1-yl) pyridine hydrochloride
Tert-butyl 4- (4- ((4-chloro-2-fluorobenzyl) oxy) -5-fluoropyrimidin-2-yl) piperazine-1-carboxylate (326mg, 0.74mmol) was dissolved in ethanol (2 mL), a solution of hydrochloric acid in ethanol (2ml, 30%) was added, and the mixture was stirred at room temperature overnight. Concentration under reduced pressure gave 285mg of the product as an off-white solid in >99% yield.
Intermediate 7- ((4-chloro-2-fluorobenzyl) oxy) -5-fluoro-4- (piperazin-1-yl) pyridine hydrochloride
Figure BDA0003128505470000441
Step 1) 4- (2-chloro-5-fluoropyrimidin-4-yl) piperazine-1-carboxylic acid tert-butyl ester
2, 4-dichloro-5-fluoropyrimidine (3g, 17.96mmol) was dissolved in methylene chloride (50 mL), triethylamine (3.64g, 35.92mmol) and 1-Boc-piperazine (3.51g, 18.86mmol) were added, and the mixture was reacted at room temperature overnight. After TLC detection reaction is completed, water (50 mL) is added for washing, anhydrous sodium sulfate is used for drying, and ethyl acetate is used for pulping to obtain 5g of off-white solid product with the yield of 88%.
Step 2) tert-butyl 4- (2- ((4-chloro-2-fluorobenzyl) oxy) -5-fluoropyrimidin-4-yl) piperazine-1-carboxylate
4-chloro-2-fluorobenzyl alcohol (608mg, 3.79mmol), tert-butyl 4- (2-chloro-5-fluoropyrimidin-4-yl) piperazine-1-carboxylate (1g, 3.16mmol), x-phos (2-dicyclohexylphosphorus-2 ',4',6' -triisopropylbiphenyl, 300mg, 0.63mmol), palladium acetate (70mg, 0.32mmol), cesium carbonate (2.57g, 7.9mmol), and toluene (20 mL) were placed in a 50mL single vial, purged with nitrogen 3 times, and warmed to 110 ℃ for reaction overnight. Cooling to room temperature, adding water (20 mL), extracting with ethyl acetate (25mL. Times.3), combining the organic phases, washing with saturated brine, drying over anhydrous sodium sulfate, concentrating under reduced pressure to remove the solvent by evaporation, and purifying the residue by column chromatography to give 900mg of a yellow oily product in 65% yield.
Step 3) 2- ((4-chloro-2-fluorobenzyl) oxy) -5-fluoro-4- (piperazin-1-yl) pyridine hydrochloride
Tert-butyl 4- (2- ((4-chloro-2-fluorobenzyl) oxy) -5-fluoropyrimidin-4-yl) piperazine-1-carboxylate (900mg, 2.04) was dissolved in ethanol (9 mL), and an ethanol solution of hydrochloric acid (9ml, 35%) was added to stir the mixture at room temperature overnight. The ethanol was evaporated by concentration under reduced pressure to give 220mg of a colorless oily product with a yield of 32%.
Intermediate 8- ((4-chloro-2-fluorobenzyl) oxy) -4- (piperidin-4-yl) pyrimidine hydrochloride
Figure BDA0003128505470000442
Step 1) 1-tert-butyl-4-methyl-4- (2- (methylthio) pyrimidin-4-yl) piperidine-1, 4-dicarboxylate
Dissolving N-Boc-4-piperidinecarboxylic acid methyl ester (5.0 g,19.3 mmol) in dry tetrahydrofuran (50 mL), stirring the mixture at-40 ℃ under the protection of nitrogen, slowly dropping HMDSLi (23mL, 23mmol, 1.0M) into the system, and after the dropping is completed, stirring the mixture at-40 ℃ for reaction for 0.5 hour; dissolving 2-methylthio-4-chloropyrimidine (3.0g, 18.7mmol) in dry tetrahydrofuran (15 mL), slowly dropping the solution into the mixed system, and naturally heating the mixture to room temperature to react for 1 hour after the dropping is finished; after the TLC detected that the reaction of the raw materials was substantially complete, the reaction system was placed in an ice-water bath to make the temperature in the system lower than 10 ℃, 5% citric acid aqueous solution (75 mL) and saturated brine (30 mL) were added, followed by extraction with ethyl acetate (100ml × 3), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated to dryness under reduced pressure, and the residue was purified by column chromatography (PE: EA = 3.
Step 2) 4- (2- (methylthio) pyrimidin-4-yl) piperidine-1-carboxylic acid tert-butyl ester
1-tert-butyl-4-methyl 4- (2- (methylthio) pyrimidin-4-yl) piperidine-1, 4-dicarboxylic acid ester (7.2g, 18.6 mmol) was dissolved in methanol/tetrahydrofuran (69ml, v/v =2 1), a 2M sodium hydroxide solution (18ml, 36mmol) was added, and the mixture was stirred at room temperature for reaction for 2 hours; detecting more raw materials by TLC, heating to 40 ℃ and reacting for 2 hours; TLC detection raw material reaction is complete, 1M citric acid aqueous solution is used to adjust pH to 4, the mixture is extracted with ethyl acetate (50mL x 2), organic phase is combined, dried with anhydrous sodium sulfate, reduced pressure concentration to dryness, yellow oily crude product, 5.95g, yield >99%.
Step 3) 4- (2- (methylsulfonyl) pyrimidin-4-yl) piperidine-1-carboxylic acid tert-butyl ester
Dissolving 4- (2- (methylthio) pyrimidin-4-yl) piperidine-1-carboxylic acid tert-butyl ester (5.95g, 18.6 mmol) in dichloromethane (140 mL), adding m-chloroperoxybenzoic acid (7.55g, 37.2mmol) to the system at 0 ℃, and naturally raising the temperature to room temperature for reaction overnight; after the basic reaction of the raw materials was detected by LC-MS to be complete, the reaction solution was passed through a layer of celite, the filter residue was washed with dichloromethane, the organic phases were combined, dried over anhydrous sodium sulfate, concentrated to dryness under reduced pressure, and the residue was purified by column chromatography (PE: EA = 1) to obtain 4.9g of a white solid in 77% yield.
Step 4) tert-butyl 4- (2- ((4-chloro-2-fluorobenzyl) oxy) pyrimidin-4-yl) piperidine-1-carboxylate
Dissolving 2-fluoro-4-chlorobenzyl alcohol (2.2 g, 13.68mmol) in anhydrous tetrahydrofuran (140 mL), adding dropwise HMDSNa (13.7ml, 27.3mmol, 2.0M) under nitrogen protection, stirring the mixture for 15 minutes, adding a tetrahydrofuran (100 mL) solution of 4- (2- (methylsulfonyl) pyrimidin-4-yl) piperidine-1-carboxylic acid tert-butyl ester (4.9 g, 14.37mmol) into the system, stirring the mixture for 2 hours after completion, detecting the reaction by TLC, adding water (50 mL) and saturated saline (50 mL), separating an organic phase, drying the organic phase with anhydrous sodium sulfate, concentrating the organic phase under reduced pressure to dryness, and purifying by column chromatography (PE: EA =2 1) to obtain a yellow oily product, 4.94g, wherein the yield is 86%.
Step 5) 2- ((4-chloro-2-fluorobenzyl) oxy) -4- (piperidin-4-yl) pyrimidine hydrochloride
Dissolving 4- (2- ((4-chloro-2-fluorobenzyl) oxy) pyrimidin-4-yl) piperidine-1-carboxylic acid tert-butyl ester (4.94g, 11.76mmol) in ethanol (20 mL), adding 30% ethanol hydrochloride solution (49 mL), stirring the mixture at room temperature for 1 hour, detecting by LC-MS that the raw materials are completely reacted, and directly concentrating under reduced pressure for later use to obtain the title compound 3.08g with the yield of 82%.
Intermediate 9- (3- ((4-chloro-2-fluorobenzyl) oxy) phenyl) -1,2,3, 6-tetrahydropyridine hydrochloride
Figure BDA0003128505470000451
Step 1) tert-butyl 4- (3- ((4-chloro-2-fluorobenzyl) oxy) phenyl) -3, 6-dihydropyridine-1 (2H) -carboxylate
Tert-butyl 4- (3-hydroxyphenyl) -3, 6-dihydropyridine-1 (2H) -carboxylate (850mg, 3.1mmol) was dissolved in acetonitrile (15 mL), potassium carbonate (1.16g, 8.4mmol) was added, the mixture was stirred at room temperature for 10 minutes, 4-chloro-2-fluorobenzyl bromide (628mg, 2.8mmol) was added, and then the temperature was raised to 60 ℃ to react overnight. Insoluble matter was removed by filtration, and the residue was concentrated under reduced pressure, and purified by column chromatography to give 500mg of a colorless oily product, yield 43%.
Step 2) 4- (3- ((4-chloro-2-fluorobenzyl) oxy) phenyl) -1,2,3, 6-tetrahydropyridine hydrochloride
Tert-butyl 4- (3- ((4-chloro-2-fluorobenzyl) oxy) phenyl) -3, 6-dihydropyridine-1 (2H) -carboxylate (500mg, 1.19mmol) was dissolved in ethanol (5 mL), and an ethanol solution of hydrochloric acid (5mL, 30%) was added, and the mixture was stirred at room temperature for 3 hours. Vacuum concentrating, adding methyl tert-butyl ether and pulping to obtain white solid product 190mg with yield of 45%.
Intermediate 10- (3- ((4-chloro-2-fluorobenzyl) oxy) phenyl) piperidine hydrochloride
Figure BDA0003128505470000452
Step 1) 4- (3-hydroxyphenyl) -3, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester
3-bromophenol (3g, 17.34mmol), N-Boc-1,2,5, 6-tetrahydropyridine-4-boronic acid pinacol ester (5.9g, 19.07mmol), cesium carbonate (11.3g, 34.68mmol) and Pd (dppf) Cl 2 (1.25g, 1.73mmol) was placed in a 250mL two-necked flask, 1, 4-dioxane (150 mL) was added, and the mixture was heated to 88 ℃ under nitrogen atmosphere for reaction overnight. Insoluble matter was removed by filtration, and the residue was concentrated under reduced pressure, and the residue was purified by column chromatography to give 3.9g of an off-white solid product in 82% yield.
Step 2) 4- (3-hydroxyphenyl) piperidine-1-carboxylic acid tert-butyl ester
Tert-butyl 4- (3-hydroxyphenyl) -3, 6-dihydropyridine-1 (2H) -carboxylate (1g, 3.64mmol) was dissolved in tetrahydrofuran (10 mL), wet palladium on carbon (0.2 g, 10%) was added, and the mixture was replaced with hydrogen gas 3 times and stirred at room temperature overnight. Insoluble matter was removed by filtration and concentrated under reduced pressure to give 1.05g of colorless oily product in >99% yield.
Step 3) tert-butyl 4- (3- ((4-chloro-2-fluorobenzyl) oxy) phenyl) piperidine-1-carboxylate
Tert-butyl 4- (3-hydroxyphenyl) piperidine-1-carboxylate (1.05g, 3.64mmol) was dissolved in acetonitrile (15 mL), potassium carbonate (1.51 g, 10.92 mmol) was added, the mixture was stirred at room temperature for 10 minutes, 4-chloro-2-fluorobenzyl bromide (853mg, 3.82mmol) was added, and the reaction was allowed to warm to 60 ℃ for 3.5 hours. Insoluble matter was removed by filtration, and the residue was concentrated under reduced pressure, and the residue was purified by column chromatography to give 1.48g of a colorless oily product in 97% yield.
Step 4) 4- (3- ((4-chloro-2-fluorobenzyl) oxy) phenyl) piperidine hydrochloride
Tert-butyl 4- (3- ((4-chloro-2-fluorobenzyl) oxy) phenyl) piperidine-1-carboxylate (1.48g, 3.52mmol) was dissolved in ethanol (10 mL), and an ethanol solution of hydrochloric acid (5 mL, 30%) was added, and the mixture was stirred at room temperature overnight. Vacuum concentrating, adding methyl tert-butyl ether, and pulping to obtain white solid product 1.15g, >99%.
Intermediate 11- ((4-chloro-2-fluorobenzyl) oxy) -6- (piperidin-4-yl) pyridine hydrochloride
Figure BDA0003128505470000453
Step 1) 4- (methoxycarbonyl) -4- (6-bromopyridin-2-yl) piperidine-1-carboxylic acid tert-butyl ester
Dissolving 4- (methoxycarbonyl) -piperidine-1-carboxylic acid tert-butyl ester (20g, 82.3mmol) in tetrahydrofuran (200 mL), stirring at-40 ℃ for 10 minutes, slowly dropping LDA (49mL, 98mmol,2.0M THF solution) into the system, after the dropping is finished, continuously stirring the mixture at-40 ℃ for 0.5 hour, then dissolving 2, 6-dibromopyridine (23.5g, 98.7mmol) in tetrahydrofuran (200 mL), slowly dropping the mixture into the mixed system, after the dropping is finished, naturally raising the temperature to room temperature, and continuously reacting for 3 hours; then the reaction system was cooled to 0 ℃ again, water (50 mL) was slowly added dropwise to the reaction system, and the reaction system was warmed to room temperature, the organic layer was separated, the aqueous layer was extracted with ethyl acetate (50ml × 3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the solvent, and the residue was purified by column chromatography (PE: EA = 20) to give a pale yellow solid, 23g, yield 70%.
Step 2) 4- (6-bromopyridin-2-yl) -1- (tert-butoxycarbonyl) piperidine-4-carboxylic acid
Dissolving 4- (methoxycarbonyl) -4- (6-bromopyridin-2-yl) piperidine-1-carboxylic acid tert-butyl ester (23g, 58mmol) in tetrahydrofuran (200 mL), adding 1.0M sodium hydroxide solution (116mL, 116mmol), heating the mixture to 50 ℃ and stirring for reaction overnight; after the reaction was completed, the organic phase was separated, the aqueous phase was adjusted to pH 4-5 with 1.0M aqueous hydrochloric acid, extracted with dichloromethane (100ml × 3), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the solvent by evaporation to give a white solid, 19g of crude product, 85% yield of crude product.
Step 3) 4- (6-Bromopyridin-2-yl) piperidine-1-carboxylic acid tert-butyl ester
4- (6-bromopyridin-2-yl) -1- (tert-butoxycarbonyl) piperidine-4-carboxylic acid (19g, 49mmol) was dissolved in 1, 2-dichloroethane (150 mL), the mixture was warmed to 80 ℃ to react for 12 hours, after completion of the reaction, the solvent was evaporated by concentration under reduced pressure, and the resulting residue was purified by column chromatography (PE: EA =20: 1) to give 14g of a white solid in 84% yield.
Step 4) tert-butyl 4- (6- ((4-chloro-2-fluorobenzyl) oxy) pyridin-2-yl) piperidine-1-carboxylate
Tert-butyl 4- (6-bromopyridin-2-yl) piperidine-1-carboxylate (6.5g, 19mmol), 2-fluoro-4-chlorobenzyl alcohol (3.5g, 22mmol), pd 2 (dba) 3 (0.87g, 0.95mmol), BINAP (1.18g, 1.9mmol) and cesium carbonate (12.3g, 38mmol) were dissolved in toluene (65 mL), the mixture was stirred at 100 ℃ for 10 hours under nitrogen protection, after completion of the reaction, the solvent was directly evaporated by concentration under reduced pressure, and the residue was purified by column chromatography (PE: EA = 8.
Step 5) 2- ((4-chloro-2-fluorobenzyl) oxy) -6- (piperidin-4-yl) pyridine hydrochloride
Dissolving 4- (6- ((4-chloro-2-fluorobenzyl) oxy) pyridine-2-yl) piperidine-1-formic acid tert-butyl ester (2.1g, 5 mmol) in 30% hydrochloric acid ethanol solution (20 mL), stirring the mixture at room temperature for reaction, directly concentrating under reduced pressure and evaporating to remove the solvent after TLC detection of complete reaction of raw materials to obtain 1.6g of yellow solid, wherein the yield is high>99％，LC-MS[M+H] + :321.1。
Intermediate 12- (5- ((4-chloro-2-fluorobenzyl) oxy) -2, 4-difluorophenyl) piperidine hydrochloride
Step 1) 1, 5-difluoro-2-iodo-4-anisole
2, 4-difluoro-1-anisole (3g, 20.8mmol) was dissolved in trifluoroacetic acid (50 mL), and N-iodosuccinimide (5.15g, 22.9 mmol) was added to react the mixture at room temperature overnight. After the reaction was completed, the reaction system was cooled to room temperature, poured into 200g of crushed ice, and after the ice was completely melted, the solid was collected by filtration. The obtained solid was redissolved in methylene chloride, dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the solvent, and the residue was separated and purified by column chromatography (PE) to obtain the objective product (4.52g, 80%) as a pale yellow solid.
Step 2) 2, 4-difluoro-5-iodophenol
1, 5-difluoro-2-iodo-4-anisole (4.52g, 16.7 mmol) was dissolved in dichloromethane (75 mL). Boron tribromide (12.5g, 50.2mmol) was slowly added dropwise to the reaction system in an ice bath. The reaction system is slowly heated to room temperature and stirred for reaction for 2 hours. After TLC monitored the conversion was complete, the reaction was quenched by addition of methanol (10 mL) to the reaction (note HBr tail absorption). After the reaction was quenched, it was extracted with dichloromethane, and the organic phase was washed with water (3 x 100ml) and then with saturated brine (100 mL). The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the solvent, and the residue was isolated and purified by column chromatography (PE: EA = 10) to give the objective product (4.54 g, > 99%) as a light yellow transparent oily liquid.
Step 3) 1- ((4-chloro-2-fluorobenzyl) oxy) -2, 4-difluoro-5-iodobenzene
2, 4-difluoro-5-iodophenol (4.54g, 17.7 mmol) was dissolved in acetonitrile (120 mL). To the reaction system were added potassium carbonate (7.34 g, 53.1 mmol) and 1- (bromomethyl) -4-chloro-2-fluorobenzene (4.35g, 19.5 mmol) in this order. The reaction was warmed to 60 ℃ and stirred overnight. After completion of the conversion was monitored by TLC, insoluble matter was removed by filtration, the filtrate was concentrated under reduced pressure to remove the reaction solvent, and the residue was separated and purified by column chromatography (PE) to give the objective product (6.06g, 86%) as a white solid.
Step 4) tert-butyl 4- (5- ((4-chloro-2-fluorobenzyl) oxy) -2, 4-difluorophenyl) piperidine-1-carboxylate
Freshly activated Zn powder (262mg, 4.02mmol) was charged to a round bottom flask. N is a radical of 2 N, N-dimethylacetamide (1.5 mL) was added to a round-bottom flask under an atmosphere, and a mixture of trimethylchlorosilane (70. Mu.L) and 1, 2-dibromoethane (50. Mu.L) was slowly added dropwise to the system, and the reaction was stirred until no gas was generated in the system. Tert-butyl 4-iodopiperidine-1-carboxylate (1g, 3.21mmol) was dissolved in anhydrous N, N-dimethylacetamide, and then slowly added dropwise to the reaction system. After the dropwise addition, the reaction is placed in a 55 ℃ metal sand bath for heating for 2h until the Zn powder in the system is completely dissolved, the solution system is clarified, and after the solution system is cooled to room temperature, the prepared Zn reagent (the concentration: 0.6 mol/L) is preserved under the protection of nitrogen.
Adding Pd (dppf) into a round-bottom flask 2 Cl 2 (46.8mg, 0.064mmol), cuprous iodide (24.4mg, 0.128mmol), 1- ((4-chloro-2-fluorobenzyl) oxy) -2, 4-difluoro-5-iodobenzene (853mg, 2.14mmol). Under nitrogen, N-dimethylacetamide (10 mL) was added, andzn reagent (0.6 mol/L) prepared in the previous step. After the addition, the reaction system was placed in a 80 ℃ metal sand bath and heated for reaction overnight. After the reaction, water (30 mL) was added, extraction was performed with ethyl acetate, and the organic phase was washed with water (3 × 20ml) and then with a saturated sodium chloride solution (50 mL). The organic phase was dried over anhydrous sodium sulfate, the solvent was removed by concentration under reduced pressure, and the residue was isolated and purified by column chromatography (PE: EA = 10) to give the objective product (420mg, 43%) as a colorless transparent oily liquid.
Step 5) 4- (5- ((4-chloro-2-fluorobenzyl) oxy) -2, 4-difluorophenyl) piperidine hydrochloride
Tert-butyl 4- (5- ((4-chloro-2-fluorobenzyl) oxy) -2, 4-difluorophenyl) piperidine-1-carboxylate (420mg, 0.92mmol) was dissolved in methanol (10 mL). To the reaction system was added 30% methanol hydrochloride solution (10 mL), and the mixture was stirred at room temperature for 3h. After the reaction was completed, the solvent was concentrated under reduced pressure to remove it, and the resulting white solid was slurried with diethyl ether, filtered, and vacuum-dried by an oil pump to obtain the objective product (291mg, 81%) as a white solid. LCMS (liquid Crystal display Module) [ M + H ]] + :356)。
Example 1- ((4- (6- (4-cyano-2-fluorobenzyloxy) pyridin-2-yl) piperidin-1-yl) methyl) -1- (cyclobut-2-ylmethyl) -1H-imidazo
[1,2-b ] [1,2,4] triazole-6-carboxylic acid
Figure BDA0003128505470000471
Step 1) Ethyl 2- ((tert-Butoxycarbonyl) amino) -1H-imidazole-5-carboxylate
Ethyl 2-aminoimidazole-5-carboxylate (3.1g, 20mmol) was dissolved in methylene chloride (100 mL), triethylamine (4.18mL, 30 mmol) was added thereto, the mixture was stirred in an ice-water bath, and then di-tert-butyl dicarbonate (4.8g, 22mmol) was slowly added thereto, and the mixture was stirred at room temperature overnight. After completion of the TLC detection reaction, the reaction mixture was poured into a saturated sodium bicarbonate solution, an organic layer was separated, an aqueous layer was extracted with methylene chloride (100 mL. Times.2), organic layers were combined and dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the obtained residue was purified by column chromatography to obtain 4.5g of a product in 88% yield. LCMS (liquid Crystal display Module) [ M + H ] ] + :256.2。
Step 2) 1-amino-2- ((tert-butoxycarbonyl) amino) -1H-imidazole-5-carboxylic acid ethyl ester
Ethyl 2- ((tert-butoxycarbonyl) amino) -1H-imidazole-5-carboxylate (3.8g, 15mmol) was dissolved in dry N, N-dimethylformamide (40 mL), the mixture was stirred at-10 ℃ and lithium bis (trimethylsilyl) amide (16.5mL, 16.5mmoL, 1.0mol/L) was slowly added dropwise to the above system, and after stirring for 10 minutes, a solution of O- (diphenylphosphinoyl) hydroxylamine (4.2g, 18mmol) in N, N-dimethylformamide (5 mL) was added dropwise to the above reaction system, followed by slowly raising to room temperature and stirring for 6 hours. After TLC detection reaction is completed, adding a proper amount of water until the system is clear, concentrating under reduced pressure, adding ethyl acetate (20 mL) into the residue to dissolve, concentrating under reduced pressure again until the residue is dry, and purifying the obtained residue by column chromatography to obtain 2.8g of a product with the yield of 70%. LCMS (liquid Crystal display Module) [ M + H ]] + :271.1。
Step 3) Ethyl 2- ((tert-Butoxycarbonyl) amino) -1- ((oxetan-2-ylmethyl) amino) -1H-imidazole-5-carboxylate
Ethyl 1-amino-2- ((tert-butoxycarbonyl) amino) -1H-imidazole-5-carboxylate (2.7g, 10mmol) was dissolved in acetonitrile (30 mL), and potassium carbonate (2.7g, 20mmol) and methanesulfonic acid- (oxetan-2-yl) methyl ester (2.0g, 12mmol) were added to stir the mixture at 50 ℃ for 6 hours. After completion of the TLC detection reaction, the reaction mixture was cooled to room temperature, saturated brine (30 mL) and dichloromethane (30 mL) were added, the organic layer was separated, the aqueous layer was extracted with dichloromethane (30 mL. Times.2), the organic layers were combined and dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography to give 2.7g of a product with a yield of 80%. LCMS (liquid Crystal display Module) [ M + H ] ] + :341.2。
Step 4) Ethyl 2- (chloromethyl) -1- (oxetan-2-ylmethyl) -1H-imidazole [1,2-b ] [1,2,4] triazole-6-carboxylate
Ethyl 2- ((tert-butoxycarbonyl) amino) -1- ((oxetan-2-ylmethyl) amino) -1H-imidazole-5-carboxylate (1.5g, 4.4 mmol) was dissolved in tetrahydrofuran (30 mL), acetic acid (0.26g, 4.4 mmol) was added, and nitrogen was bubbled through for 1 minute, followed by addition of 2-chloro-1, 1-trimethoxyethane (1.4 g,8.8 mmol), and the mixture was allowed to react at 100 ℃ for 12 hours with tube closure. Then, p-toluenesulfonic acid monohydrate (84mg, 0.44mmol) was added to the reaction mixture, and reacted at 75 ℃ for 1 hour. The reaction was stopped, water (15 mL) was added, extraction was performed with ethyl acetate (20 mL. Times.3), and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 1.3g of crude product, which was used directly in the next reaction.
Step 5) Ethyl 2- ((4- (6- (4-cyano-2-fluorobenzyloxy) pyridin-2-yl) piperidin-1-yl) methyl) -1- (oxetan-2-ylmethyl) -1H-imidazo [1,2-b ] [1,2,4] triazole-6-carboxylate
3-fluoro-4- ((6- (piperidin-4-yl) pyridin-2-yl) oxymethyl) benzonitrile hydrochloride (108mg, 0.31mmol) was dissolved in acetonitrile (3 mL), potassium carbonate (83mg, 0.6 mmol) was added, and after the mixture was stirred at room temperature for 10 minutes, 2- (chloromethyl) -1- (oxetan-2-ylmethyl) -1H-imidazo [1,2-b ] was added ][1,2,4]Ethyl triazole-6-carboxylate (130mg, 0.44mmol), heated to 50 ℃ and reacted overnight. The reaction was stopped, the mixture was cooled to room temperature, quenched by addition of water (5 mL), extracted with ethyl acetate (10 mL. Times.3), washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting residue was purified by column chromatography to give the product 89mg with a yield of 50%. LCMS (liquid Crystal display Module) [ M + H ]] + :574.7。
Step 6) 2- ((4- (6- (4-cyano-2-fluorobenzyloxy) pyridin-2-yl) piperidin-1-yl) methyl) -1- (cyclobut-2-ylmethyl) -1H-imidazo [1,2-b ] [1,2,4] triazole-6-carboxylic acid
2- ((4- (6- (4-cyano-2-fluorobenzyloxy) pyridin-2-yl) piperidin-1-yl) methyl) -1- (oxetan-2-ylmethyl) -1H-imidazo [1, 2-b)][1,2,4]Ethyl triazole-6-carboxylate (89mg, 0.155mmol) was dissolved in ethanol (1 mL), followed by addition of sodium hydroxide solution (1.0 mL, 1.0mmol, 1mol/L) and reaction of the mixture at 50 ℃ overnight. The reaction was stopped, concentrated under reduced pressure to remove ethanol, added 1N HCl to adjust pH to about 5, then extracted with ethyl acetate (3 mL × 3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography (dichloromethane: methanol =10 1) to obtain the title compound (40 mg, yield 47%). LCMS (liquid Crystal display Module) [ M + H ]] + :546.6。 1 HNMR(500MHz,DMSO-d 6 ) δ7.90(s,1H),7.64(t,J＝8.2Hz,1H),7.54(d,J＝8.7Hz,1H),7.46(d,J＝8.3Hz,1H),7.37(d,J＝8.3Hz,1H), 6.76(d,J＝8.0Hz,1H),6.66(d,J＝7.7Hz,1H),5.50(s,2H),5.25(m,1H),4.75(m,2H),4.68–4.60(m,1H), 4.43(m,1H),3.98(s,2H),3.05–2.93(m,2H),2.82–2.71(m,1H),2.62(m,1H),2.49(m,1H),2.29(m,2H), 1.85–1.82(m,2H).1.71–1.63(m,2H)。
Example 2- ((4- (6- (4-chloro-2-fluorobenzyloxy) pyridin-2-yl) piperazin-1-yl) methyl) -1- (oxetan-2-ylmethyl) -1H-thieno [2,3-d ] imidazole-5-carboxylic acid
Figure BDA0003128505470000481
Step 1) 5-bromo-4-nitrothiophene-2-carboxylic acid ethyl ester
5-bromothiophene-2-carboxylic acid ethyl ester (4.5g, 19.14mmol) was placed in a 50mL two-necked flask, and H was added 2 SO 4 Then, the temperature was lowered to 0 ℃ in an ice water bath, nitric acid (6.3 mL, 65%) was added dropwise, and after completion of the addition, the mixture was slowly warmed to room temperature and reacted for 1 hour. TLC detection shows that the raw materials are completely reacted and the reaction is stopped. The reaction solution was poured into ice water (50 mL), extracted with ethyl acetate (30 mL × 3), the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography to give the objective compound 3.36g, yield 63%. LCMS (liquid Crystal display Module) [ M + H ]] + : 279.2。
Step 2) 5- ((2, 4-dimethoxybenzyl) amino) -4-negative thiophene-2-carboxylic acid ethyl ester
Ethyl 5-bromo-4-nitrothiophene-2-carboxylate (2g, 7.14mmol), 2, 4-dimethoxybenzylamine (1.55g, 9.28mmol) were placed in a single-necked flask, potassium carbonate (3.95g, 28.56mmol) and acetonitrile (45 mL) were added, and the mixture was stirred at room temperature for 2.5 hours. The reaction was stopped, the reaction solution was poured into ice water (50 mL), extracted with ethyl acetate (60 mL. Times.3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography to give 2.7g of a product with a yield of 79%. LCMS (liquid Crystal display Module) [ M + H ] ] + :367.2。
Step 3) 5-amino-4-nitrothiophene-2-carboxylic acid ethyl ester
Ethyl 5- ((2, 4-dimethoxybenzyl) amino) -4-negative thiophene-2-carboxylate (2.7g, 7.4mmol) was dissolved in dichloromethane (30 mL), trifluoroacetic acid (3 mL) was added and the mixture was stirred at room temperature overnight. TLC shows the originalAfter the reaction, the reaction was stopped, and the mixture was poured into ice water (100 mL), extracted with ethyl acetate (150 mL. Times.3), and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 1.9g of a product. LCMS (liquid Crystal display Module) [ M + H ]] + :217.2。
Step 4) 5- ((tert-Butoxycarbonyl) amino) -4-nitrothiophene-2-carboxylic acid ethyl ester
Ethyl 5-amino-4-nitrothiophene-2-carboxylate (1.9g, 8.79mmol) was dissolved in tetrahydrofuran (40 mL), triethylamine (1.34 g, 13.2 mmol) and di-tert-butyl dicarbonate (2.3g, 10.55mmol) were added, and the mixture was stirred at room temperature overnight. TLC detects that the raw material stops reacting after completely reacting, and the reaction is concentrated under reduced pressure, and the residue is purified by column chromatography to obtain 1.45g of product with the yield of 52%. LCMS (liquid Crystal display Module) [ M + H ]] + :317.3。
Step 5) 4-amino-5- ((tert-butoxycarbonyl) amino) thiophene-2-carboxylic acid ethyl ester
Ethyl 5- ((tert-butoxycarbonyl) amino) -4-nitrothiophene-2-carboxylate (1.18g, 3.73mmol) was dissolved in methanol (7.5 mL), water (2.5 mL), iron powder (1.04g, 18.65mmol), and ammonium chloride (400mg, 7.46mmol) were added, and the mixture was reacted at 60 ℃ for 2 hours. After completion of the TLC detection reaction, the reaction was stopped, cooled to room temperature, filtered to remove insoluble matter, concentrated under reduced pressure to remove methanol, added with water (10 mL), extracted with ethyl acetate (20 mL. Times.3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography to give 800mg of the product in 75% yield. LCMS (liquid Crystal display Module) [ M + H ] ] + :287.1。
Step 6) Ethyl 5- ((tert-Butoxycarbonyl) amino) -4- ((oxetan-2-ylmethyl) amino) thiophene-2-carboxylate
Ethyl 4-amino-5- ((tert-butoxycarbonyl) amino) thiophene-2-carboxylate (632mg, 2.2mmol) was dissolved in dichloromethane (18 mL), and to the resulting mixture was added oxetanyl-2-carbaldehyde (228mg, 2.65mmol), followed by 3 drops of acetic acid, and the mixture was stirred at room temperature for 20 minutes. Sodium triacetoxyborohydride (933mg, 4.4 mmol) was added to the reaction mixture, and stirred at room temperature for 1 hour. The reaction mixture was diluted with dichloromethane (30 mL), washed with water (20 mL), then brine, dried over anhydrous sodium sulfate, and concentratedConcentration under reduced pressure and purification of the residue by column chromatography gave 330mg of the product in 42% yield. LCMS (liquid Crystal display Module) [ M + H ]] + :357.1。
Step 7) Ethyl 2- (chloroethyl) -1- (oxetan-2-ylmethyl) -1H-thieno [2,3-d ] imidazole-5-carboxylate
Ethyl 5- ((tert-butoxycarbonyl) amino) -4- ((oxetan-2-ylmethyl) amino) thiophene-2-carboxylate (130mg, 0.365mmol) was dissolved in tetrahydrofuran (6.5 mL), followed by addition of acetic acid (22mg, 0.365mmol), aeration with nitrogen for 1 minute, addition of 2-chloro-1, 1-methoxyethane (113mg, 0.733mmol), and tube-sealing reaction of the resulting mixture at 100 ℃ for 12 hours. P-toluenesulfonic acid monohydrate (7 mg,0.036 mmol) was added to the mixture and reacted at 75 ℃ for 1 hour. The reaction was stopped, water (15 mL) was added, extraction was performed with ethyl acetate (20 mL. Times.3), and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 140mg of crude product, which was used directly in the next reaction.
Step 8) Ethyl 2- ((4- (6- (4-chloro-2-fluorobenzyloxy) pyridin-2-yl) piperazin-1-yl) methyl) -1- (oxetan-2-ylmethyl) -1H-thieno [2,3-d ] imidazole-5-carboxylate
1- (6- (4-chloro-2-benzyloxy) pyridin-2-yl) piperazine trifluoroacetate (112mg, 0.255mmol) was dissolved in acetonitrile (3 mL), potassium carbonate (202mg, 1.46mmol) was added, and the mixture was stirred at room temperature for 10 minutes. Then adding 2- (chloroethyl) -1- (oxetan-2-ylmethyl) -1H-thieno [2,3-d ] to the mixture]Ethylimidazole-5-carboxylic acid (140mg, 0.365mmol) was reacted overnight at 50 ℃. The reaction was stopped, cooled to room temperature, quenched with water (5 mL), extracted with ethyl acetate (10 mL. Times.3), washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the solvent, and the residue was purified by column chromatography to give the product 40mg, yield 26%. LCMS (liquid Crystal display Module) [ M + H ]] + :601.1。
Step 9) 2- ((4- (6- (4-chloro-2-fluorobenzyloxy) pyridin-2-yl) piperazin-1-yl) methyl) -1- (oxetan-2-ylmethyl) -1H-thieno [2,3-d ] imidazole-5-carboxylic acid
2- ((4- (6- (4-chloro-2-fluorobenzyloxy) pyridin-2-yl) piperazin-1-yl) methyl) -1- (oxetan-2-ylmethyl) -1H-thieno [2, 3-d)]Imidazole-5-carboxylic acid ethyl ester (40mg, 0.067mmol) was dissolved in ethanol (1.0)mL), a sodium hydroxide solution (1mL, 1mmol, 1mol/L) was added, and the mixture was reacted at 50 ℃ overnight. After TLC detection of the completion of the reaction of the raw materials, the reaction was stopped, concentrated under reduced pressure to remove ethanol, then 1N HCl was added to adjust pH to about 5, the mixture was extracted with ethyl acetate (3 mL × 3), the organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography (dichloromethane: methanol = 10) to obtain the product (10.7 mg, yield: 28%). LCMS (liquid Crystal display Module) [ M + H ] ] + :573.0。 1 HNMR(500 MHz,DMSO-d 6 )δ7.79(s,1H),7.52(t,J＝8.2Hz,1H),7.45(d,J＝8.7Hz,2H),7.30(d,J＝8.3Hz,1H),6.33 (d,J＝8.0Hz,1H),6.09(d,J＝7.7Hz,1H),5.30(s,2H),5.09(d,J＝7.5Hz,1H),4.65(dd,J＝15.1,6.8Hz,1H), 4.58–4.45(m,2H),4.41–4.33(m,1H),3.83(d,J＝13.6Hz,1H),3.73(d,J＝13.6Hz,1H),3.55–3.41(m,8H), 2.69(t,J＝9.1Hz,1H),2.42–2.35(m,1H)。
Example 3- ((4- (6- (4-cyano-2-fluorobenzyloxy) pyridin-2-yl) piperidin-1-yl) methyl) -3- (oxetan-2-ylmethyl) -3H-thiazolo [2,3-d ] imidazole-5-carboxylic acid
Figure BDA0003128505470000491
Step 1) 4-Nitro-5- ((oxetan-2-ylmethyl) amino) thiophene-2-carboxylic acid ethyl ester
Ethyl 5-bromo-4-nitrothiophene-2-carboxylate (2.0g, 7.14mmol) was added to a solution of oxetan-2-ylmethylamine (0.93g, 10.71mmol) in N, N-dimethylformamide (20 mL), and then triethylamine (3.0mL, 21.4mmol) was added, and the mixture was stirred at 45 ℃ for reaction overnight. After TLC detection of the starting material reaction was complete, the solvent was removed by concentration under reduced pressure and the residue was purified by column chromatography to give 1.6g of product, yield: 80 percent. LCMS (liquid Crystal display Module) [ M + H ]] + :287.0。
Step 2) Ethyl 5- ((tert-Butoxycarbonyl) (oxetan-2-ylmethyl) amino) -4-nitrothiophene-2-carboxylate
Ethyl 4-nitro-5- ((oxetan-2-ylmethyl) amino) thiophene-2-carboxylate (1.6 g,5.6 mmol) was dissolved in tetrahydrofuran (30 mL), the mixture was stirred in an ice-water bath, then di-tert-butyl dicarbonate (1.46 g,6.72 mmol) and triethylamine (1.56mL, 11.2mmol), then allowed to spontaneously warm to room temperature and stirred for 8 hours. After TLC detection of the starting material reaction was complete, the reaction was poured into saturated sodium bicarbonate (30 mL), extracted with dichloromethane (30 mL × 3), the combined organic phases washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the solvent, and the residue was purified by column chromatography to give the product 1.9g, yield: 88 percent. LCMS (liquid Crystal display Module) [ M + H ] ] + :387.0。
Step 3) Ethyl 4-amino-5- ((tert-butoxycarbonyl) (oxetan-2-ylmethyl) amino) thiophene-2-carboxylate
Ethyl 5- ((t-butoxycarbonyl) amino) -4-nitrothiophene-2-carboxylate (1.9 g,4.9 mmol) was dissolved in methanol (7.5 mL), and water (2.5 mL), iron powder (1.38g, 24.6 mmol) and ammonium chloride (524mg, 9.8mmol) were added thereto, and the mixture was reacted at 60 ℃ for 2 hours. After completion of the TLC detection reaction, the reaction was stopped, cooled to room temperature, filtered to remove insoluble matter, concentrated under reduced pressure to remove methanol, added with water (10 mL), extracted with ethyl acetate (20 mL. Times.3), the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography to give 1.22g of a product with a yield of 70%. LCMS (liquid Crystal display Module) [ M + H ]] + :357.1。
Step 4) Ethyl 2- (chloromethyl) -3- (oxetan-2-ylmethyl) -3H-thieno [2,3-d ] imidazole-5-carboxylate
Ethyl 4-amino-5- ((tert-butoxycarbonyl) (oxetan-2-ylmethyl) amino) thiophene-2-carboxylate (356 mg,1.0 mmol) was dissolved in tetrahydrofuran (10 mL), acetic acid (60mg, 1.0 mmol) was added thereto and bubbling with nitrogen for 1 minute, then 2-chloro-1, 1-methoxyethane (309mg, 2.0 mmol) was added, and the mixture was allowed to react under a sealed tube at 100 ℃ for 12 hours. Then, p-toluenesulfonic acid monohydrate (19 mg,0.1 mmol) was added to the reaction mixture, and reacted at 75 ℃ for 1 hour. The reaction was stopped, water (15 mL) was added, extraction was performed with ethyl acetate (20 mL. Times.3), and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 310mg of crude product, which was used directly in the next reaction.
Step 5) Ethyl 2- ((4- (6- (4-cyano-2-fluorobenzyloxy) pyridin-2-yl) piperidin-1-yl) methyl) -3- (oxetan-2-ylmethyl) -3H-thieno [2,3-d ] imidazole-5-carboxylate
1- (6- (4-chloro-2-benzyloxy) pyridin-2-yl) piperazine trifluoroacetate (243mg, 0.7 mmol) is dissolved in acetonitrile (3 mL), potassium carbonate (483mg, 3.5mmol) is added thereto, the mixture is stirred at room temperature for 10 minutes, and 2- (chloromethyl) -3- (oxetan-2-ylmethyl) -3H-thieno [2,3-d ] is added]Ethyl imidazole-5-carboxylate (310mg, 0.98mmol) was reacted overnight by warming to 50 ℃. The reaction was stopped, cooled to room temperature, quenched by addition of water (10 mL) and the reaction mixture extracted with ethyl acetate (10 mL. Times.3), washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent, and the residue was purified by column chromatography to give 124mg of the product in 30% yield. LCMS (liquid Crystal display Module) [ M + H ]] + :589.6。
Step 6) 2- ((4- (6- (4-cyano-2-fluorobenzyloxy) pyridin-2-yl) piperidin-1-yl) methyl) -3- (oxetan-2-ylmethyl) -3H-thieno [2,3-d ] imidazole-5-carboxylic acid
2- ((4- (6- (4-cyano-2-fluorobenzyloxy) pyridin-2-yl) piperidin-1-yl) methyl) -3- (oxetan-2-ylmethyl) -3H-thieno [2,3-d]Ethyl imidazole-5-carboxylate (100mg, 0.17mmol) was dissolved in ethanol (1.0 mL), to which was added sodium hydroxide solution (1mL, 1mmol, 1mol/L), and the mixture was reacted at 50 ℃ overnight. After the TLC detected the reaction of the starting materials was completed, the reaction was stopped, concentrated under reduced pressure to remove ethanol, added 1N HCl to adjust pH to about 5, the reaction mixture was extracted with ethyl acetate (3 mL × 3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting residue was purified by column chromatography (dichloromethane: methanol =10 1) to obtain the product (24 mg, 25% yield). LCMS (liquid Crystal display Module) [ M + H ] ] + :562.6。 1 H NMR(500MHz,DMSO-d 6 )δ7.80(s,1H),7.64(t,J＝8.2Hz,1H),7.54(d,J＝8.7Hz,1H),7.46(d,J＝8.3 Hz,1H),7.37(d,J＝8.3Hz,1H),6.76(d,J＝8.0Hz,1H),6.66(d,J＝7.7Hz,1H),5.48(s,2H),5.12(m,1H), 4.79(m,1H),4.65(m,1H),4.49(m,1H),4.40(m,1H),3.94(d,J＝13.5Hz,1H),3.78(d,J＝13.5Hz,1H),2.98 (d,J＝11.3Hz,1H),2.85(d,J＝11.3Hz,1H),2.71(p,J＝7.8Hz,1H),2.64–2.55(m,2H),2.31–2.10(m,2H), 1.77–1.64(m,4H)。
Example 4- ((4- (6- (4-cyano-2-fluorobenzyloxy) pyridin-2-yl) piperidin-1-yl) methyl) -4- (oxetan-2-ylmethyl) -4H-imidazo [4,5-d ] thiazole-2-carboxylic acid
Figure BDA0003128505470000501
Step 1) 4-Nitro-5- ((2, 4-Dimethoxybenzyl) amino) thiazole-2-carboxylic acid ethyl ester
Ethyl 5-bromo-4-nitrothiazole-2-carboxylate (2.0g, 7.14mmol, ref. Eur. J. Inorg. Chem.,2011, 539) and 2, 4-dimethoxybenzylamine (1.55g, 8.28mmol) were dissolved in acetonitrile (45 mL), potassium carbonate (3.95g, 28.56mmol) was added thereto, and the mixture was stirred at room temperature for reaction for 3 hours. After TLC detection of the starting material reaction was complete, the solvent was removed by concentration under reduced pressure and the residue was purified by column chromatography to give 2.4g of product, yield: 92 percent. LCMS (liquid Crystal display Module) [ M + H ]] + :368.4。
Step 2) 5-amino-4-nitrothiazole-2-carboxylic acid ethyl ester
Ethyl 4-nitro-5- ((2, 4-dimethoxybenzyl) amino) thiazole-2-carboxylate (2.4 g, 6.53mmol) was dissolved in dichloromethane (24 mL), trifluoroacetic acid (2.4 mL) was then added, and the mixture was stirred at room temperature for 8 hours. TLC check raw material reaction is complete, the reaction mixture is poured into ice water (100 mL), ethyl acetate (100 mL. Times.3) is added for extraction, the combined organic phase is washed with saturated salt water, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain crude product 1.5g. LCMS (liquid Crystal display Module) [ M + H ] ] + :218.0。
Step 3) 5- ((tert-Butoxycarbonyl) amino) -4-nitrothiazole-2-carboxylic acid ethyl ester
Ethyl 5-amino-4-nitrothiazole-2-carboxylate (1.4g, 6.53mmol) was dissolved in tetrahydrofuran (30 mL), and triethylamine (1.36 mL, 9.8mmol) and di-tert-butyl dicarbonate (1.7g, 7.84mmol) were added to stir the mixture at room temperature overnight. After TLC detection, the raw material is completely reacted, the solvent is removed by concentration under reduced pressure, and the obtained residue is purified by column chromatography to obtain 1.5g of the product with the yield of 72%. LCMS [ M + H ]] + :318.0。
Step 4) 4-amino-5- ((tert-butoxycarbonyl) amino) thiazole-2-carboxylic acid ethyl ester
Ethyl 5- ((tert-butoxycarbonyl) amino) -4-nitrothiazole-2-carboxylate (1.5g, 4.73mmol) was dissolved in methanol (7.5 mL), followed by addition of water (2.5 mL), ironThe mixture of powder (1.04 g, 18.65 mmol) and ammonium chloride (400mg, 7.46mmol) was reacted at 60 ℃ for 2 hours. The reaction was stopped, cooled to room temperature, filtered to remove insoluble matter, concentrated under reduced pressure to remove the solvent, water (10 mL) was added, the mixture was extracted with ethyl acetate (20 mL × 3), the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting residue was purified by column chromatography to give 817mg of the product in 60% yield. LCMS (liquid Crystal display Module) [ M + H ]] + :288.0。
Step 5) Ethyl 5- ((tert-Butoxycarbonyl) amino) -4- ((oxetan-2-ylmethyl) amino) thiazole-2-carboxylate
Ethyl 4-amino-5- ((tert-butoxycarbonyl) amino) thiazole-2-carboxylate (800mg, 2.79mmol) was dissolved in dichloromethane (16 mL), and to the resulting mixture was added oxetanyl-2-carbaldehyde (288mg, 3.35mmol), followed by 5 drops of acetic acid and stirred at room temperature for 20 minutes. Sodium triacetoxyborohydride (1.17g, 5.5 mmol) was added to the reaction mixture, and stirred at room temperature for 1 hour. Then, dichloromethane (30 mL) was added to dilute the mixture, the mixture was washed with water (20 mL) and saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography to give 498mg, yield 50%. LCMS (liquid Crystal display Module) [ M + H ]] + :358.1。
Step 6) Ethyl 5- (chloromethyl) -4- (oxetan-2-ylmethyl) -4H-imidazo [4,5-d ] thiazole-2-carboxylate
Ethyl 4-amino-5- ((tert-butoxycarbonyl) (oxetan-2-ylmethyl) amino) thiazole-2-carboxylate (358mg, 1.0mmol) was dissolved in tetrahydrofuran (10 mL), followed by addition of acetic acid (60mg, 1.0mmol) and bubbling with nitrogen for 1 minute, followed by addition of 2-chloro-1, 1-methoxyethane (309 mg, 2.0mmol), and the mixture was allowed to react at 100 ℃ for 12 hours while being sealed. To the reaction mixture was added p-toluenesulfonic acid monohydrate (19 mg, 0.1 mmol), and the mixture was reacted at 75 ℃ for 1 hour. The reaction was stopped, water (15 mL) was added, the mixture was extracted with ethyl acetate (20 mL. Times.3), and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 320mg of crude product, which was used directly in the next reaction.
Step 7) Ethyl 5- ((4- (6- (4-cyano-2-fluorobenzyloxy) pyridin-2-yl) piperidin-1-yl) methyl) -4- (oxetan-2-ylmethyl) -4H-imidazo [4,5-d ] thiazole-2-carboxylate
1- (6- (4-chloro-2-benzyloxy) pyridin-2-yl) piperazine trifluoroacetate (243mg, 0.7 mmol) is dissolved in acetonitrile (3 mL), followed by the addition of potassium carbonate (483mg, 3.5 mmol), the mixture is stirred at room temperature for 10 minutes, then 2- (chloromethyl) -3- (oxetan-2-ylmethyl) -3H-thieno [2,3-d ] is added]Ethyl imidazole-5-carboxylate (320mg, 1.0 mmol), the mixture was warmed to 50 ℃ and reacted overnight. The reaction was stopped, cooled to room temperature, quenched by addition of water (10 mL) and extracted with ethyl acetate (10 mL. Times.3), washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the solvent, and the residue was purified by column chromatography to give 140mg of the product in 34% yield. LCMS (liquid Crystal display Module) [ M + H ]] + :591.0。
Step 8) 5- ((4- (6- (4-cyano-2-fluorobenzyloxy) pyridin-2-yl) piperidin-1-yl) methyl) -4- (oxetan-2-ylmethyl) -4H-imidazo [4,5-d ] thiazole-2-carboxylic acid
Reacting 5- ((4- (6- (4-cyano-2-fluorobenzyloxy) pyridin-2-yl) piperidin-1-yl) methyl) -4- (oxetan-2-ylmethyl) -4H-imidazo [4,5-d]Ethyl thiazole-2-carboxylate (120mg, 0.20mmol) was dissolved in ethanol (1.0 mL), followed by addition of a sodium hydroxide solution (1mL, 1mmol, 1mol/L), and the mixture was reacted at 50 ℃ overnight. After completion of the reaction of the starting materials by TLC, the reaction was stopped, and concentrated under reduced pressure to remove ethanol, and 1 NHCl was added to the mixture to adjust the pH to about 5, extracted with ethyl acetate (3 mL × 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the obtained residue was purified by column chromatography (dichloromethane: methanol =10 1) to obtain the product (35 mg, yield 31%). LCMS (liquid Crystal display Module) [ M + H ] ] + :563.4。 1 H NMR(500 MHz,DMSO-d 6 )δ7.64(t,J＝8.2Hz,1H),7.54(d,J＝8.7Hz,1H),7.46(d,J＝8.3Hz,1H),7.37(d,J＝8.3Hz, 1H),6.76(d,J＝8.0Hz,1H),6.66(d,J＝7.7Hz,1H),5.48(s,2H),5.12(m,1H),4.79(m,1H),4.65(m,1H), 4.49(m,1H),4.40(m,1H),3.94(d,J＝13.5Hz,1H),3.78(d,J＝13.5Hz,1H),2.98(d,J＝11.3Hz,1H),2.85(d, J＝11.3Hz,1H),2.71(p,J＝7.8Hz,1H),2.64–2.55(m,2H),2.30–2.11(m,2H),1.76–1.62(m,4H)。
Example 5 (2- ((4- (6- (4-chloro-2-fluorobenzyloxy) pyridin-2-yl) piperazin-1-yl) methyl) -1- ((1-ethyl-1H-imidazol-5-yl) methyl) -1H-thieno [2,3-d ] imidazol-5-yl) phosphonic acid
Figure BDA0003128505470000521
Step 1) dimethyl 5- ((2, 4-dimethoxybenzyl) amino) -4-nitrothiophen-2-yl) phosphonate
Dimethyl (5-bromo-4-nitrothiophen-2-yl) phosphonate (2g, 6.33mmol, ref. Chem. Commu. 2014,50, 10622.) and 2, 4-dimethoxybenzylamine (1.48g, 8.86mmol) were placed in a single vial, followed by the addition of potassium carbonate (3.49g, 25.32mmol) and acetonitrile (40 mL) and the mixture stirred at room temperature for 2.5 hours. The reaction was stopped, the reaction solution was poured into ice water (50 mL), extracted with ethyl acetate (50 mL. Times.3), the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting residue was purified by column chromatography to give 2.29g of a product with a yield of 90%. LCMS (liquid Crystal display Module) [ M + H ]] + :403.4。
Step 2) (5-amino-4-nitrothiophen-2-yl) phosphonic acid dimethyl ester
Dimethyl (5- ((2, 4-dimethoxybenzyl) amino) -4-nitrothiophen-2-yl) phosphonate (2.2g, 5.47mmol) was dissolved in dichloromethane (22 mL), trifluoroacetic acid (2.2 mL) was then added, and the mixture was stirred at room temperature for reaction for 8 hours. After TLC detection of the completion of the reaction of the starting materials, the reaction mixture was poured into ice water (100 mL) and extracted with ethyl acetate (100 mL. Times.3), the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography to give 1.24g of the product in 90% yield. LCMS (liquid Crystal display Module) [ M + H ] ] + :253.2。
Step 3) (3-Nitro-5- (Dimethoxyphosphonyl) thiophen-2-yl) carbamic acid tert-butyl ester
Dimethyl (5-amino-4-nitrothiophen-2-yl) phosphonate (1.2g, 4.76mmol) was dissolved in tetrahydrofuran (24 mL), then triethylamine (1.0 mL, 7.2mmol) was added, the mixture was stirred in an ice-water bath, then di-tert-butyl dicarbonate (1.24g, 5.71mmol) was added, and the resulting mixture was stirred at room temperature for 8 hours. After completion of the TLC detection reaction, concentration was carried out under reduced pressure, and the residue was purified by column chromatography to give 1.5g of a product in 90% yield. LCMS (liquid Crystal display Module) [ M + H ]] + :353.2。
Step 4) (3-amino-5- (dimethoxyphosphono) thiophen-2-yl) carbamic acid tert-butyl ester
Tert-butyl (3-nitro-5- (dimethoxyphosphono) thiophen-2-yl) carbamate (1.5g, 4.26mmol) was dissolved in methanol/water (10ml, v/v = 1), and then iron powder (1.19g, 21.3mmol) and ammonium chloride (451mg, 8.52mmol) were added, and the mixture was reacted at 60 ℃ for 2 hours. After completion of the reaction of the starting materials by TLC, the mixture was cooled to room temperature, insoluble materials were removed by filtration, the mixture was concentrated under reduced pressure, and water (10 mL) was added to the residue to conduct extraction with ethyl acetate (10 mL. Times.3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography to give 0.89g of the product in 65% yield. LCMS (liquid Crystal display Module) [ M + H ] ] + :323.2。
Step 5) (tert-butyl 5- (dimethoxyphosphono-3- (((1-ethyl-1H-imidazol-5-yl) methyl) amino) thiophen-2-yl) carbamate
Tert-butyl (3-amino-5- (dimethoxyphosphono) thiophen-2-yl) carbamate (0.89g, 2.76mmol) was dissolved in tetrahydrofuran (5 mL), followed by addition of methanesulfonic acid- (1-ethyl-1H-imidazol-5-yl) methyl ester (0.84g, 4.14mmol) and potassium carbonate (0.76g, 5.52mmol), and the mixture was stirred at room temperature for 6 hours. After the TLC detection reaction was complete, it was allowed to cool to room temperature, poured into water (20 mL), extracted with ethyl acetate (20 mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography (water: methanol = 5) to give 0.83 g of product in 70% yield. LCMS (liquid Crystal display Module) [ M + H ]] + :431.4。
Step 6) dimethyl 2- (chloromethyl) -1- ((1-ethyl-1H-imidazol-5-yl) methyl) -1H-thieno [2,3-d ] imidazol-5-yl) phosphonate
Tert-butyl (5- (dimethoxyphosphono-3- (((1-ethyl-1H-imidazol-5-yl) methyl) amino) thiophen-2-yl) carbamate (0.7g, 1.6 mmol) was dissolved in tetrahydrofuran (10 mL), then acetic acid (96mg, 1.6 mmol) was added and nitrogen was bubbled through for 5 minutes, then 2-chloro-1, 1-trimethoxyethane (495mg, 3.2mmol) was added and the mixture was allowed to tube-seal at 100 ℃ for 12 hours, p-toluenesulfonic acid monohydrate (30mg, 0.116mmol) was added and the mixture was allowed to react at 75 ℃ for 1 hour, the reaction was stopped, water (20 mL) was added, ethyl acetate (20 mL. Times.3) was extracted, the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure to give 590mg, which was used directly in the next reaction step 7, crude 2- ((4- (6- (4-chloro-2-fluorobenzyloxy) pyridin-2-yl) piperazin-1-yl) methyl) -1-ethyl-1-thiophen-2-yl) dimethyl ester was synthesized
1- (6- (4-chloro-2-benzyloxy) pyridin-2-yl) piperazine trifluoroacetate (387mg, 0.92mmol) was dissolved in acetonitrile (5 mL), followed by the addition of potassium carbonate (635mg, 4.6 mmol), the mixture was stirred at room temperature for 30 minutes, followed by the addition of (2- (chloromethyl) -1- ((1-ethyl-1H-imidazol-5-yl) methyl) -1H-thieno [2, 3-d)]Imidazol-5-yl) phosphonic acid dimethyl ester (500mg, 1.29mmol) and the mixture was warmed to 50 ℃ for reaction overnight. The reaction was stopped, cooled to room temperature, quenched with water (10 mL), extracted with ethyl acetate (10 mL. Times.3), the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent, and the resulting residue was purified by column chromatography to give 186mg of the product in 30% yield. LCMS (liquid Crystal display Module) [ M + H ]] + : 675.1。
Step 8) (2- ((4- (6- (4-chloro-2-fluorobenzyloxy) pyridin-2-yl) piperazin-1-yl) methyl) -1- ((1-ethyl-1H-imidazol-5-yl) methyl) -1H-thieno [2,3-d ] imidazol-5-yl) phosphonic acid
(2- ((4- (6- (4-chloro-2-fluorobenzyloxy) pyridin-2-yl) piperazin-1-yl) methyl) -1- ((1-ethyl-1H-imidazol-5-yl) methyl) -1H-thieno [2,3-d]Dimethyl imidazol-5-yl) phosphonate (150mg, 0.22mmol) was dissolved in methylene chloride (5 mL), the mixture was stirred in an ice-water bath, and trimethylbromosilane (0.11mL, 0.88mmol) was added dropwise to the reaction system, and the reaction was allowed to warm to room temperature and stirred for 12 hours. After the TLC detection of the completion of the reaction of the starting materials, the reaction mixture was poured into saturated brine (20 mL. Times.3), extracted with dichloromethane (20 mL. Times.3), the combined organic phases were dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting residue was purified by column chromatography to give the product (85.2 mg, yield 60%). LCMS (liquid Crystal display Module) [ M + H ] ] + 。 647.0。 1 H NMR(500MHz,DMSO-d 6 )δ9.10(s,1H),8.20(s,1H),8.11(s,1H),7.63(t,J＝8.2Hz,1H),7.55(d, J＝8.7Hz,1H),7.46(d,J＝8.3Hz,1H),7.37(d,J＝8.3Hz,1H),6.76(d,J＝8.0Hz,1H),6.66(d,J＝7.7Hz, 1H),5.88(s,2H)5.15(s,2H),4.79(s,2H),4.36(q,J＝8Hz,2H),3.55–3.41(m,8H),1.58(t,J＝8Hz,3H)。
Example 6- ((4- (6- (4-cyano-2-fluorobenzyloxy) pyridin-2-yl) piperazin-1-yl) methyl) -3- (cyclobut-2-ylmethyl) -3H-imidazo [1,2-b ] [1,2,4] triazole-6-carboxylic acid
Figure BDA0003128505470000531
Step 1) Ethyl 2- ((oxetan-2-ylmethyl) amino) -1H-imidazole-5-carboxylate
2-amino-1H-imidazole-5-carboxylic acid ethyl ester (2.0 g,12.9 mmol) was dissolved in acetonitrile (30 mL), followed by addition of potassium carbonate (3.6 g,25.8 mmol) and methanesulfonic acid- (oxetan-2-yl) methyl ester (2.58g, 15.5 mmol), and the mixture was stirred at 50 ℃ for 6 hours. After completion of the TLC detection reaction, the reaction mixture was cooled to room temperature, and a saturated common salt solution (30 mL) and methylene chloride (30 mL) were added to the mixture, and the organic layer was separated, and the aqueous layer was extracted with methylene chloride (30 mL. Times.2), and the organic layers were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography to obtain 2.38g of a product with a yield of 82%. LCMS (liquid Crystal display Module) [ M + H ]] + :226.2。
Step 2) Ethyl 2- ((tert-Butoxycarbonyl) (oxetan-2-ylmethyl) amino) -1H-imidazole-5-carboxylate
Ethyl 2- ((oxetan-2-ylmethyl) amino) -1H-imidazole-5-carboxylate (2.3 g,10.2 mmol) was dissolved in dichloromethane (50 mL), triethylamine (2.84mL, 20.4 mmol) was then added, the mixture was stirred in an ice-water bath, di-tert-butyl dicarbonate (2.67 g, 12.2 mmol) was then slowly added, and the reaction mixture was stirred at room temperature overnight. After the completion of the TLC detection reaction, the mixture was poured into saturated sodium bicarbonate solution, the organic layer was separated, the aqueous layer was extracted with methylene chloride (50 mL. Times.2), the organic layers were combined and dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography to give 2.82g of a product in 85% yield. LCMS (liquid Crystal display Module) [ M + H ] ] + :326.2。
Step 3) Ethyl 1-amino-2- ((tert-Butoxycarbonyl) (oxetan-2-ylmethyl) amino) -1H-imidazole-5-carboxylate
Ethyl 2- ((tert-butoxycarbonyl) (oxetan-2-ylmethyl) amino) -1H-imidazole-5-carboxylate (2.8g, 8.6 mmol) was dissolved in dry N, N-dimethylformamide (50 mL), and the mixture was stirred at-10 ℃ and then slowly dropped into the above system over lithium bis (trimethylsilyl) amide (9.5mL, 9.5mmoL,1.0 mol/L), and after the mixture was stirred for 10 minutes, a solution of O- (diphenylphosphinoyl) hydroxylamine (2.4g, 10.3mmol) in N, N-dimethylformamide (5 mL) was dropped into the above system, and then slowly warmed to room temperature and stirred for 6 hours. After TLC detection reaction is completed, adding a proper amount of water until the system is clear, concentrating under reduced pressure, dissolving the residue with ethyl acetate (30 mL), concentrating under reduced pressure again until the residue is dry, and purifying the obtained residue by column chromatography to obtain 2.05g of a product with the yield of 70%. LCMS (liquid Crystal display Module) [ M + H ]] + :341.1。
Step 4) Ethyl 2-chloromethyl-3- (oxetan-2-ylmethyl) -3H-imidazo [1,2-b ] [1,2,4] triazole-6-carboxylate
Ethyl 1-amino-2- ((tert-butoxycarbonyl) (oxetan-2-ylmethyl) amino) -1H-imidazole-5-carboxylate (2.0 g, 5.88mmol) was dissolved in tetrahydrofuran (40 mL), then acetic acid (0.35g, 5.88mmol) was added and nitrogen was bubbled through for 5 minutes, then 2-chloro-1, 1-trimethoxyethane (1.87g, 11.76mmol) was added and the mixture was allowed to tube-seal at 100 ℃ for 12 hours. To the reaction mixture was added p-toluenesulfonic acid monohydrate (112mg, 0.59mmol), and the reaction was carried out at 75 ℃ for 1 hour. The reaction was stopped, water (20 mL) was added, extraction was performed with ethyl acetate (20 mL. Times.3), and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 1.7g of crude product, which was used directly in the next reaction.
Step 5) Ethyl 2- ((4- (6- (4-cyano-2-fluorobenzyloxy) pyridin-2-yl) piperazin-1-yl) methyl) -3- (oxetan-2-ylmethyl) -3H-imidazo [1,2-b ] [1,2,4] triazole-6-carboxylate
3-fluoro-4- ((6- (piperazin-4-yl) pyridin-2-yl) oxymethyl) benzonitrile hydrochloride (417mg, 1.2mmol) was dissolved in acetonitrile (5 mL), followed by the addition of potassium carbonate (331mg, 2.4 mmol), the mixture stirred at room temperature for 10 minutes, 2-chloromethyl-3- (oxetan-2-ylmethyl) -3H-imidazo [1,2-b ] was added][1,2,4]Triazole-6-ethyl formate (500mg, 1.67mmol) is heated to 50 ℃ for reaction overnight. Stopping the reaction, cooling toAt room temperature, water (10 mL) was added thereto for quenching, the mixture was extracted with ethyl acetate (10 mL. Times.3), the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the resulting residue was purified by column chromatography to give the product 330mg, yield 48%. LCMS [ M + H ]] + :575.7。
Step 6) 2- ((4- (6- (4-cyano-2-fluorobenzyloxy) pyridin-2-yl) piperazin-1-yl) methyl) -3- (cyclobut-2-ylmethyl) -3H-imidazo [1,2-b ] [1,2,4] triazole-6-carboxylic acid
2- ((4- (6- (4-cyano-2-fluorobenzyloxy) pyridin-2-yl) piperazin-1-yl) methyl) -3- (oxetan-2-ylmethyl) -3H-imidazo [1, 2-b)][1,2,4]Ethyl triazole-6-carboxylate (150mg, 0.26mmol) was dissolved in ethanol (1 mL), followed by addition of sodium hydroxide solution (1.0 mL, 1.0mmol, 1mol/L) and reaction of the mixture at 50 ℃ overnight. The reaction was stopped, concentrated under reduced pressure to remove ethanol, then 1n hcl was added to adjust pH to about 5, the mixture was extracted with ethyl acetate (3 mL × 3), the organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography (dichloromethane: methanol =10 1) to obtain the title compound (43 mg, yield 30%). LCMS (liquid Crystal display Module) [ M + H ] ] + :547.5。 1 H NMR(500 MHz,DMSO-d 6 )7.95(s,1H),7.63(t,J＝8.2Hz,1H),7.55(d,J＝8.7Hz,1H),7.46(d,J＝8.3Hz,1H),7.37(d, J＝8.3Hz,1H),6.76(d,J＝8.0Hz,1H),6.66(d,J＝7.7Hz,1H),5.50(s,2H),5.12(m,1H),4.79(m,1H),4.65 (m,1H),4.49(m,1H),4.40(m,1H),3.94(d,J＝13.5Hz,1H),3.83(d,J＝13.6Hz,1H),3.55–3.41(m,8H), 2.69(t,J＝9.1Hz,1H),2.42–2.35(m,1H)。
Example 7- ((4- (6- (4-cyano-2-fluorobenzyloxy) pyridin-2-yl) piperazin-1-yl) methyl) -1- (oxetan-2-ylmethyl) -1H-imidazo [1,2-a ] imidazole-5-carboxylic acid
Figure BDA0003128505470000541
Step 1) Ethyl 2- (chloromethyl) -1- (oxetan-2-ylmethyl) -1H-imidazo [1,2-a ] imidazole-5-carboxylate
Ethyl 2- ((oxetan-2-ylmethyl) amino) -1H-imidazole-5-carboxylate (1.0g, 4.4mmol) was dissolved in ethylene glycol dimethyl ether (1.0g, 4.4mmol)0 mL), 1, 3-dichloroacetone (1.12g, 8.8mmol) was added thereto, and the mixture was stirred at room temperature for 2 hours, followed by stirring at reflux overnight. After TLC detection of essentially complete reaction of starting materials, the reaction mixture was allowed to cool to room temperature, saturated sodium carbonate (10 mL) was added, extraction was performed with dichloromethane (20 mL. Times.3), the combined organic phases were dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography to give 0.78g of product in 60% yield. LCMS [ M + H ]] + :298.6。
Step 2) Ethyl 2- ((4- (6- (4-cyano-2-fluorobenzyloxy) pyridin-2-yl) piperazin-1-yl) methyl) -1- (oxetan-2-ylmethyl) -1H-imidazo [1,2-a ] imidazole-5-carboxylate
3-fluoro-4- ((6- (piperazin-4-yl) pyridin-2-yl) oxymethyl) benzonitrile hydrochloride (417mg, 1.2mmol) was dissolved in acetonitrile (5 mL), followed by the addition of potassium carbonate (331mg, 2.4 mmol), the mixture stirred at room temperature for 10 minutes, then 2- (chloromethyl) -1- (oxetan-2-ylmethyl) -1H-imidazo [1,2-a ] was added ]Imidazole-5-carboxylic acid ethyl ester (500mg, 1.68mmol), and the mixture was warmed to 50 ℃ for reaction overnight. The reaction was stopped, cooled to room temperature, quenched by addition of water (10 mL) and the reaction mixture was extracted with ethyl acetate (10 mL. Times.3), the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure and the residue was purified by column chromatography to give 379mg of a product in 55% yield. LCMS (liquid Crystal display Module) [ M + H ]] + :574.6。
Step 3) Synthesis of 2- ((4- (6- (4-cyano-2-fluorobenzyloxy) pyridin-2-yl) piperazin-1-yl) methyl) -1- (oxetan-2-ylmethyl) -1H-imidazo [1,2-a ] imidazole-5-carboxylic acid
2- ((4- (6- (4-cyano-2-fluorobenzyloxy) pyridin-2-yl) piperazin-1-yl) methyl) -1- (oxetan-2-ylmethyl) -1H-imidazo [1, 2-a)]Ethyl imidazole-5-carboxylate (200mg, 0.34mmol) was dissolved in ethanol (1 mL), followed by addition of sodium hydroxide solution (1.0 mL,1.0mmol,1 mol/L) and the mixture was reacted at 50 ℃ overnight. The reaction was stopped, concentrated under reduced pressure to remove ethanol, then 1N HCl was added to adjust pH to about 5, the mixture was extracted with ethyl acetate (3 mL × 3), the organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography (dichloromethane: methanol =10 1) to obtain the title compound (48 mg, yield 25%). LCMS (liquid Crystal display Module) [ M + H ] ] + :546.5。 1 H NMR(500MHz,DMSO-d 6 ) 7.95(s,1H),7.70(s,1H),7.63(t,J＝8.2Hz,1H),7.55(d,J＝8.7Hz,1H),7.46(d,J＝8.3Hz,1H),7.37(d,J＝ 8.3Hz,1H),6.76(d,J＝8.0Hz,1H),6.66(d,J＝7.7Hz,1H),5.50(s,2H),5.09(m,1H),4.77(m,1H),4.63(m, 1H),4.45(m,1H),4.39(m,1H),3.95(d,J＝13.5Hz,1H),3.85(d,J＝13.6Hz,1H),3.55–3.41(m,8H),2.68(t, J＝9.1Hz,1H),2.41–2.34(m,1H)。
Example 8- ((4- (6- (4-cyano-2-fluorobenzyloxy) pyridin-5-yl) piperidin-1-yl) methyl) -3- ((1-ethyl-1H-imidazol-2-yl) methyl) pyrazolo [1,5-a ] pyridine-5-carboxylic acid
Figure BDA0003128505470000551
Step 1) 1-amino-4- (methoxycarbonyl) pyridine-2, 4-dinitrophenol composite salt
Methyl 4-picolinate (2.0 g, 14.58mmol) was dissolved in acetonitrile (20 mL), O- (2, 4-dinitrophenyl) hydroxylamine (2.90 g, 14.58mmol) was added, and the mixture was stirred at 40 ℃ for 24 hours. After the TLC detection reaction was almost complete, the reaction was cooled to room temperature and the sample was concentrated to dryness under reduced pressure to give 4.9g of crude product which was used without further purification.
Step 2) methyl 3- (1-ethyl-1H-imidazole-2-carbonyl) -2- ((4-methoxybenzyloxy) methyl) pyrazolo [1,5-a ] pyridine-5-carboxylate
1-amino-4- (methoxycarbonyl) pyridine-2, 4-dinitrophenol complex salt (3.3g, 9.8mmol) was dissolved in tetrahydrofuran (50 mL), and then 1, 8-diazabicycloundecen-7-ene (2.2g, 14.7mmol) and 1- (1-ethyl-1H-imidazol-5-yl) -4- (4-methoxybenzyloxy) but-2-yn-1-one (3.5g, 11.76mmol) were added, the mixture was stirred at room temperature for reaction for 8 hours, the reaction solution was poured into saturated brine (30 mL), extraction was performed with dichloromethane (30 mL. Times.3), the organic phases were combined, concentration was performed under reduced pressure, and the obtained residue was purified by column chromatography to give 1.98g of a product with a yield of 45%. LCMS (liquid Crystal display Module) [ M + H ] ] + :449.5。
Step 3) methyl 3- (1-ethyl-1H-imidazol-5-methyl) -2- ((4-methoxybenzyloxy) methyl) pyrazolo [1,5-a ] pyridine-5-carboxylate
Methyl 3- (1-ethyl-1H-imidazole-5-carbonyl) -2- ((4-methoxybenzyloxy) methyl) pyrazolo [1,5-a ] pyridine-5-carboxylate (1.98g, 4.4 mmol) was dissolved in tetrahydrofuran (20 mL), and p-toluenesulfonic acid monohydrate (84mg, 0.44mmol) and p-methylbenzenesulfonyl hydrazide (0.98g, 5.28mmol) were added, and the mixture was stirred at room temperature for 2 hours. TLC check the starting material reaction was complete, filtered and the residue was washed with tetrahydrofuran (5.0 mL). Pd/C (0.2 g) was added to the combined organic phases and the mixture was stirred under hydrogen atmosphere for reaction overnight. After TLC detection of the intermediate, the intermediate was essentially completely reacted and filtered, the filter residue was washed with dichloromethane (5.0 mL. Times.2), the combined organic phases were concentrated under reduced pressure and the residue was used directly in the next reaction.
Step 4) methyl 3- (1-ethyl-1H-imidazol-5-methyl) -2- (hydroxymethyl) pyrazolo [1,5-a ] pyridine-5-carboxylate
The residual sample obtained in the previous step was redissolved in dichloromethane (20 mL), trifluoroacetic acid (2.0 mL) was then added, the mixture was stirred at room temperature for 8 hours, after completion of the reaction was detected by LCMS, the reaction solution was poured into saturated sodium bicarbonate (20 mL), the organic layer was separated, the aqueous layer was extracted with dichloromethane (20 mL × 2), the combined organic phases were dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography to give 0.69g of the product in 50% yield. LCMS (liquid Crystal display Module) [ M + H ] ] + :315.1。
Step 5) methyl 3- ((1-ethyl-1H-imidazol-5-yl) methyl) -2- ((methanesulfonyl) oxymethyl) pyrazolo [1,5-a ] pyridine-5-carboxylate
Reacting 3- (1-ethyl-1H-imidazole-5-methyl) -2- ((4-methoxybenzyloxy) methyl) pyrazolo [1,5-a]Pyridine-5-carboxylic acid methyl ester (0.69g, 2.2 mmol) was dissolved in methylene chloride (5 mL), triethylamine (0.61mL, 4.4 mmol) was added, the mixture was stirred in an ice-water bath, followed by dropwise addition of methanesulfonyl chloride (0.20mL, 2.64mmol), and the reaction mixture was slowly warmed to room temperature and stirred. After TLC detection of the completion of the reaction of the starting materials, water (10 mL) was added, the organic layer was separated, the aqueous layer was extracted with methylene chloride (10 mL. Times.3), the organic layers were combined, concentrated under reduced pressure, and the residue was purified by column chromatography to give 0.73g of the product in 85% yield. LCMS (liquid Crystal display Module) [ M + H ]] + :393.4。
Step 6) methyl 2- ((4- (6- (4-cyano-2-fluorobenzyl) pyridin-2-yl) piperidin-1-yl) methyl) -3- ((1-ethyl-1H-imidazol-5-yl) methyl) pyrazolo [1,5-a ] pyridine-5-carboxylate
3-fluoro-4- ((6- (piperidin-4-yl) pyridin-2-yl) oxymethyl) benzonitrile hydrochloride (317mg, 0.91mmol) was dissolved in acetonitrile (5.0 mL), followed by addition of potassium carbonate (251mg, 1.82mmol), the mixture was stirred at room temperature for 10 minutes, and then 3- ((1-ethyl-1H-imidazol-5-yl) methyl) -2- ((methanesulfonyl) oxymethyl) pyrazolo [1,5-a ] was added ]Pyridine-5-carboxylic acid methyl ester (500mg, 1.27mmol), and the mixture was warmed to 50 ℃ for reaction overnight. The reaction was stopped, cooled to room temperature, quenched by addition of water (10 mL) and the reaction mixture was extracted with ethyl acetate (10 mL. Times.3), the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure and the residue was purified by column chromatography to give 276mg of the product in 50% yield. LCMS (liquid Crystal display Module) [ M + H ]] + :608.3。
Step 7) 2- ((4- (6- (4-cyano-2-fluorobenzyl) pyridin-2-yl) piperidin-1-yl) methyl) -3- ((1-ethyl-1H-imidazol-5-yl) methyl) pyrazolo [1,5-a ] pyridine-5-carboxylic acid
2- ((4- (6- (4-cyano-2-fluorobenzyl) pyridin-2-yl) piperidin-1-yl) methyl) -3- ((1-ethyl-1H-imidazol-5-yl) methyl) pyrazolo [1,5-a]Pyridine-5-carboxylic acid methyl ester (200mg, 0.33mmol) was dissolved in ethanol (1 mL), followed by addition of sodium hydroxide solution (1.0 mL,1.0mmol,1 mol/L), and the mixture was reacted at 50 ℃ overnight. The reaction was stopped, concentrated under reduced pressure to remove ethanol, then 1N HCl was added to adjust pH to about 5, the mixture was extracted with ethyl acetate (3 mL × 3), the organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography (dichloromethane: methanol =10 1) to obtain the title compound (43 mg, yield 22%). LCMS (liquid Crystal display Module) [ M + H ] ] + :694.7。 1 H NMR(500MHz,DMSO-d 6 ) δ9.10(s,1H),8.20(s,1H),8.25(s,1H),8.07(t,J＝8.2Hz,1H),7.55(d,J＝8.7Hz,1H),7.46(d,J＝8.3Hz, 1H),7.37(d,J＝8.3Hz,1H),7.28–7.21(m,2H),6.76(d,J＝8.0Hz,1H),6.66(d,J＝7.7Hz,1H),5.88(s,2H) 5.15(s,2H),4.79(s,2H),4.36(q,J＝8Hz,2H),2.71(m,1H),2.64–2.55(m,2H),2.30–2.11(m,2H),1.76– 1.62(m,4H).1.58(t,J＝8Hz,3H)。
Example 9- ((4- (6- (4-cyano-2-fluorobenzyloxy) pyridin-2-yl) piperidin-1-yl) methyl) -5-methyl-1- (oxetan-2-ylmethyl) -4-oxo-1, 4-dihydrothieno [2,3-d ] pyrimidine-6-carboxylic acid
Figure BDA0003128505470000561
Step 1) methyl 4-cyano-3-methyl-5- ((oxetan-2-ylmethyl) amino) thiophene-2-carboxylate
5-amino-4-cyano-3-methylthiophene-2-carboxylic acid methyl ester (1.96g, 10mmol) was dissolved in acetonitrile (20 mL), methanesulfonic acid- (oxetan-2-yl) methyl ester (2.0g, 12mmol) and potassium carbonate (2.7g, 20mmol) were added, the mixture was stirred at 50 ℃ for 6 hours to terminate the reaction, and cooled to room temperature, a saturated saline solution (30 mL) was added to the reaction mixture, followed by dichloromethane (30 mL) to separate an organic layer, a water layer was extracted with dichloromethane (30 mL. Times.2), the combined organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the obtained residue was purified by column chromatography to obtain 2.14g of a product in 80% yield. LCMS [ M + H ]] + :267.2。
Step 2) methyl 4-carbamoyl-3-methyl-5- ((oxetan-2-ylmethyl) amino) thiophene-2-carboxylate
Methyl 4-cyano-3-methyl-5- ((oxetan-2-ylmethyl) amino) thiophene-2-carboxylate (2.14g, 8.0mmol) was dissolved in methanol (40 mL), sodium methoxide (432mg, 8.0mmol) was added, the mixture was stirred at 50 ℃ for reaction for 6 hours, the reaction was stopped, cooled to room temperature, concentrated under reduced pressure to remove methanol, dichloromethane/water (40ml, v/v = 1).
Step 3) methyl 2- (chloromethyl) -5-methyl-1- (oxetan-2-ylmethyl) -4-oxo-1, 4-dihydrothieno [2,3-d ] pyrimidine-6-carboxylate
The crude methyl 4-carbamoyl-3-methyl-5- ((oxetan-2-ylmethyl) amino) thiophene-2-carboxylate was dissolved in 1, 4-dioxane (20 mL), 2-chloro-1, 1-trimethoxyethane (1.4g, 8.8mmol) was added, nitrogen was added, and the reaction was carried out at 120 ℃ with tube sealing for 12 hours. The reaction was stopped, water (15 mL) was added, extraction was performed with ethyl acetate (20 mL. Times.3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 1.0g of crude product, which was used directly in the next reaction.
Step 4) methyl 2- ((4- (6- (4-cyano-2-fluorobenzyloxy) pyridin-2-yl) piperidin-1-yl) methyl) -5-methyl-1- (oxetan-2-ylmethyl) -4-oxo-1, 4-dihydrothieno [2,3-d ] pyrimidine-6-carboxylate
3-fluoro-4- ((6- (piperidin-4-yl) pyridin-2-yl) oxymethyl) benzonitrile hydrochloride (0.36g, 1.0mmol) was dissolved in acetonitrile (10 mL), potassium carbonate (276mg, 2.0mmol) was added, the mixture was stirred at room temperature for 10 minutes, and then 2- (chloromethyl) -5-methyl-1- (oxetan-2-ylmethyl) -4-oxo-1, 4-dihydrothieno [2,3-d ] was added]The crude product of pyrimidine-6-carboxylic acid methyl ester (500 mg) was allowed to warm to 50 ℃ for reaction overnight. The reaction was stopped, cooled to room temperature, quenched with water (10 mL), extracted with ethyl acetate (10 mL. Times.3), washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting residue was purified by column chromatography to give 308mg of the product in 50% yield. LCMS (liquid Crystal display Module) [ M + H ] ] + :618.7。
Step 5) 2- ((4- (6- (4-cyano-2-fluorobenzyloxy) pyridin-2-yl) piperidin-1-yl) methyl) -5-methyl-1- (oxetan-2-ylmethyl) -4-oxo-1, 4-dihydrothieno [2,3-d ] pyrimidine-6-carboxylic acid
2- ((4- (6- (4-cyano-2-fluorobenzyloxy) pyridin-2-yl) piperidin-1-yl) methyl) -5-methyl-1- (oxetan-2-ylmethyl) -4-oxo-1, 4-dihydrothieno [2, 3-d)]Pyrimidine-6-carboxylic acid methyl ester (200mg, 0.32mmol) was dissolved in methanol (2 mL), and sodium hydroxide solution (1.0 mL, 1.0mmol, 1mol/L) was added to react the mixture at 50 ℃ overnight. The reaction was stopped, concentrated under reduced pressure to remove ethanol, then 1N HCl was added to adjust the pH to about 5, the mixture was extracted with ethyl acetate (5 mL. Times.3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified to give the product (58 mg, yield 30%). LCMS (liquid Crystal display Module) [ M + H ]] + :604.7。 1 H NMR(500MHz,DMSO-d 6 )δ7.64(t,J＝8.2Hz,1H),7.54(d,J＝ 8.7Hz,1H),7.46(d,J＝8.3Hz,1H),7.37(d,J＝8.3Hz,1H),6.76(d,J＝8.0Hz,1H),6.66(d,J＝7.7Hz,1H), 5.51(s,2H),5.25(m,1H),4.75(m,2H),4.68–4.60(m,1H),4.43(m,1H),3.98(s,2H),3.05–2.93(m,2H), 2.82–2.71(m,1H),2.63(m,1H),2.52(s,3H),2.48(m,1H),2.31(m,2H),1.85–1.63(m,4H)。
Example 10- ((4- (6- (4-cyano-2-fluorobenzyloxy) pyridin-2-yl) piperazin-1-yl) methyl) -3- (4-methoxyphenyl) imidazo [1,2-a ] pyridine-6-carboxylic acid
Figure BDA0003128505470000571
Step 1) methyl 2- ((4- (6- (4-cyano-2-fluorobenzyloxy) pyridin-2-yl) piperazin-1-yl) methyl) -3-bromoimidazo [1,2-a ] pyridine-6-carboxylate
Dissolving 3-fluoro-4- ((6- (piperazin-1-yl) pyridin-2-yl) oxymethyl) benzonitrile hydrochloride (1.05g, 2.89mmol) in dichloromethane (10 mL), adding sufficient triethylamine and stirring until the system is clear, adding saturated sodium chloride (10 mL), separating the organic phase, extracting the aqueous phase with dichloromethane (10 mL), combining the organic phases, then concentrating under reduced pressure to give a free sample (905mg, 2.89mmol); the free sample was redissolved in acetonitrile (20 mL), methyl 3-bromo-2- (chloromethyl) imidazo [1,2-a ] pyridine-6-carboxylate (800mg, 2.63mmol), potassium carbonate (727mg, 5.26 mmol) and catalytic amount of potassium iodide were added, heated to 50 ℃ for reaction overnight; the reaction was cooled to room temperature, poured into saturated sodium chloride (20 mL), extracted with ethyl acetate (20 mL × 3), the organic phases combined and dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue purified by column chromatography (PE: EA =1, 1to EA) to give the product as a light yellow solid 895mg, yield 79%.
Step 2) methyl 2- ((4- (6- (4-cyano-2-fluorobenzyloxy) pyridin-2-yl) piperazin-1-yl) methyl) -3- (4-methoxyphenyl) imidazo [1,2-a ] pyridine-6-carboxylate
2- ((4- (6- (4-cyano-2-fluorobenzyloxy) pyridin-2-yl) piperazin-1-yl) methyl) -3-bromoimidazo [1, 2-a)]Methyl pyridine-6-carboxylate (250 mg, 0.43 mmol), 4-methoxyphenylboronic acid (98mg, 0.65mmol), palladium acetate (9.6 mg,0.043 mmol), triphenylphosphine (33.8 mg, 0.129 mmol) and potassium carbonate (118.6 mg, 0.86mmol) were dissolved in toluene (5 mL) and reacted overnight at 70 ℃ under nitrogen; after the LC-MS detects that the raw materials completely react, directly decompressing and concentrating to obtain residuesThe residue was purified by column chromatography (PE: EA =1 = 2to 1) to give the product as a white solid 212mg in 81% yield. 1 H NMR(500MHz,CDCl 3 )δ8.79(s,1H),7.74(d,J＝10.0Hz,1H),7.65–7.60 (m,2H),7.49(s,1H),7.47(s,1H),7.45–7.40(m,2H),7.36(d,J＝10.0Hz,1H),7.13(s,1H),7.11(s,1H),6.16 (dd,J＝10.0,5.0Hz,2H),5.43(s,2H),3.93(d,J＝3.5Hz,6H),3.79(s,2H),3.70(s,2H),3.48(s,4H),2.60(s, 4H)。
Step 3) 2- ((4- (6- (4-cyano-2-fluorobenzyloxy) pyridin-2-yl) piperazin-1-yl) methyl) -3- (4-methoxyphenyl) imidazo [1,2-a ] pyridine-6-carboxylic acid
2- ((4- (6- (4-cyano-2-fluorobenzyloxy) pyridin-2-yl) piperazin-1-yl) methyl) -3- (4-methoxyphenyl) imidazo [1, 2-a)]Pyridine-6-carboxylic acid methyl ester (200mg, 0.33mmol), cesium carbonate (538mg, 1.65mmol) were dissolved in 1, 4-dioxane/water (2.0ml, v/v = 4; after TLC checked complete conversion of starting material, it was isolated and purified directly using a thick prep plate (DCM: meOH =15: 1) to give the product as an off-white solid 18mg, yield 9%. HPLC P >94.7％，LCMS[M+H] + :593.2。 1 H NMR(500MHz, DMSO-D 6 )δ8.67(s,1H),7.88(d,J＝10.0Hz,1H),7.70(m,1H),7.66(m,3H),7.63(s,1H),7.61(s,1H),7.46 (t,J＝10.0Hz,1H),7.20(s,1H),7.18(s,1H),6.31(d,J＝8.5Hz,1H),6.11(d,J＝8.5Hz,1H),5.39(s,2H), 3.86(s,3H),2.03–1.97(m,4H)。
Example 11- ((4- (6- ((4-chloro-2-fluorobenzyl) oxy) pyridin-2-yl) piperazin-1-yl) methyl) -1- ((1-ethyl-1H-imidazol-5-yl) methyl) -1H-thieno [2,3-d ] imidazole-5-carboxylic acid
Figure BDA0003128505470000581
Step 1) 1-Ethyl-1H-imidazole-5-carbaldehyde
4-imidazolecarboxaldehyde (5g, 52.03mmol), potassium carbonate (14.3g, 104.6 mmol) and acetonitrile (60 mL) were added to a 250mL single-neck flask, cooled to 0 ℃ in an ice bath, iodoethane (12.2g, 78.04mmol) was added dropwise, after the addition was completed, the mixture was warmed to room temperature and stirred for 30min, and then warmed to 60 ℃ for reaction overnight. After TLC detection of the completion of the reaction of the starting materials, the reaction was stopped, dichloromethane (100 mL) was added for dilution, water (100 mL) was added, the organic phase was separated, the aqueous phase was extracted with dichloromethane (100 mL), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the solvent by evaporation, and the obtained residue was purified by column chromatography (PE: EA = 1) to obtain 1.2g of the product in 18% yield.
Step 2) (1-Ethyl-1H-imidazol-5-yl) methanol
1-Ethyl-1H-imidazole-5-carbaldehyde (1g, 8.06mmol) was dissolved in methanol (10 mL), and sodium borohydride (613 mg, 16.1 mmol) was added under ice-bath, followed by stirring at room temperature for 1 hour. After TLC detection of the reaction of the raw materials, ice water (3 mL) was added to quench, methanol was removed by concentration under reduced pressure, ethyl acetate (15mL. Multidot.3) was added for extraction, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated by concentration under reduced pressure to obtain 500mg of a colorless oily product with a yield of 49%.
Step 3) 5- (chloromethyl) -1-ethyl-1H-imidazole hydrochloride
(1-Ethyl-1H-imidazol-5-yl) methanol (500mg, 3.97mmol) was placed in a 50mL single-necked flask, and thionyl chloride (5 mL) was added and reacted at room temperature for 4 hours. The reaction was stopped and concentrated under reduced pressure to give a crude product as a white solid (800 mg).
Step 4) Ethyl 5- ((tert-Butoxycarbonyl) amino) -4- (((1-ethyl-1H-imidazol-5-yl) methyl) amino) thiophene-2-carboxylate
5- (chloromethyl) -1-ethyl-1H-imidazole hydrochloride (380mg, 2.10mmol) was dissolved in acetonitrile (20 mL), and 4-amino-5- ((tert-butoxycarbonyl) amino) thiophene-2-carboxylic acid ethyl ester (500mg, 1.75mmol) and DIPEA (903mg, 7.00mmol) were added and the reaction stirred at room temperature for 12 hours. After completion of the TLC detection reaction, the reaction was stopped, acetonitrile was removed by concentration under reduced pressure, water (10 mL) was added, extraction was performed with ethyl acetate (20mL × 3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated by concentration under reduced pressure, and the obtained residue was purified by column chromatography to obtain 250mg of a yellow foamy product with a yield of 36%.
Step 5) Ethyl 2- (chloromethyl) -1- ((1-ethyl-1H-imidazol 5-yl) methyl) -1H-thieno [2,3-d ] imidazole-5-carboxylate
Ethyl 5- ((tert-butoxycarbonyl) amino) -4- (((1-ethyl-1H-imidazol-5-yl) methyl) amino) thiophene-2-carboxylate (250mg, 0.63mmol) was placed in a 100mL single-necked flask, dichloromethane (25 mL), trifluoroacetic acid (0.5 mL) and 2-chloro-1, 1-trimethoxyethane (294 mg, 1.90 mmol) were added, and the mixture was stirred at room temperature for reaction for 1H. After TLC detection reaction is completed, the crude product is obtained by decompression and concentration, and the crude product of 260mg is obtained by preparative TLC purification.
Step 6) Ethyl 2- ((4- (6- (4-chloro-2-fluorobenzyloxy) pyridin-2-yl) piperazin-1-yl) methyl) -1- ((1-ethyl-1H-imidazol-5-yl) methyl) -1H-thieno [2,3-d ] imidazole-5-carboxylate
The hydrochloride salt of intermediate 2 (182mg, 0.51mmol) was dissolved in acetonitrile (5 mL), potassium carbonate (235mg, 1.7 mmol) and ethyl 2- (chloromethyl) -1- ((1-ethyl-1H-imidazol 5-yl) methyl) -1H-thieno [2,3-d ] imidazole-5-carboxylate (150mg, 0.425mmol) were added and the reaction was stirred at 50 ℃ for 12H. After completion of the TLC detection reaction, water (5 mL) was added, extraction was performed with ethyl acetate (15ml × 3), and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and then purified by preparative TLC to obtain 30mg of a pale yellow oily product.
Step 7) 2- ((4- (6- ((4-chloro-2-fluorobenzyl) oxy) pyridin-2-yl) piperazin-1-yl) methyl) -1- ((1-ethyl-1H-imidazol-5-yl) methyl) -1H-thieno [2,3-d ] imidazole-5-carboxylic acid
2- ((4- (6- (4-chloro-2-fluorobenzyloxy) pyridin-2-yl) piperazin-1-yl) methyl) -1- ((1-ethyl-1H-imidazol-5-yl) methyl) -1H-thieno [2,3-d]Ethyl imidazole-5-carboxylate (30mg, 0.047 mmol) was dissolved in ethanol (2 mL), and a solution of sodium hydroxide (1mL, 1M) was added, followed by stirring at room temperature for 15 hours. After TLC detection reaction, decompression concentration to remove ethanol, adding water (2 mL), ethyl acetate (2mL x 2) extraction, separating the aqueous phase, adjusting the pH of the aqueous phase to be about 5, then ethyl acetate (3mL x 3) extraction, drying the organic phase with anhydrous sodium sulfate, filtering, decompression concentration, freeze-drying to obtain white solid product 14.3mg, yield 50%. Purity: 97.0 percent. 1 HNMR(500MHz,DMSO-d 6 ) δ7.77(s,1H),7.52(t,J＝8.2Hz,1H),7.45(d,J＝9.4Hz,2H),7.29(d,J＝8.3Hz,1H),7.06(s,1H),7.01(s, 1H),6.32(d,J＝8.1Hz,1H),6.09(d,J＝7.8Hz,1H),5.58(s,2H),5.30(s,2H),3.88(q,J＝7.4Hz,2H),3.80(s, 2H),3.50(s,4H),2.52(s,4H),0.99(t,J＝7.2Hz,3H)。
Example 12- ((1- (6- (4-chloro-2-fluorobenzyloxy) pyridin-2-yl) piperidin-4-yl) -1- ((1-yl-1H-imidazol-5-yl) methyl) -1H-thieno [2,3-d ] imidazole-5-carboxylic acid
Figure BDA0003128505470000591
Step 1) Ethyl 2- ((1- (6- (4-chloro-2-fluorobenzyloxy) pyridin-2-yl) piperidin-4-yl) -1- ((1-yl-1H-imidazol-5-yl) methyl) -1H-thieno [2,3-d ] imidazole-5-carboxylate
Ethyl 2- (chloromethyl) -1- ((1-ethyl-1H-imidazol 5-yl) methyl) -1H-thieno [2,3-d ] imidazole-5-carboxylate (136mg, 0.43mmol) was placed in a 25mL single-necked flask, potassium carbonate (147mg, 1.06mmol), acetonitrile (5 mL) and intermediate 2 hydrochloride (140 mg, crude, 0.35 mmol) were added, and the temperature was raised to 60 ℃ for reaction for 2.5H. After cooling to room temperature, water (5 mL) was added, extraction was performed with ethyl acetate (10 mL × 3), and the organic phases were combined, then washed with saturated brine, dried over anhydrous sodium sulfate, and purified by preparative TLC to give 60mg of the title compound as a colorless transparent oil in 22% yield.
Step 2) 2- ((1- (6- (4-chloro-2-fluorobenzyloxy) pyridin-2-yl) piperidin-4-yl) -1- ((1-yl-1H-imidazol-5-yl) methyl) -1H-thieno [2,3-d ] imidazole-5-carboxylic acid
2- ((1- (6- (4-chloro-2-fluorobenzyloxy) pyridin-2-yl) piperidin-4-yl) -1- ((1-yl-1H-imidazol-5-yl) methyl) -1H-thieno [2,3-d ]Ethyl imidazole-5-carboxylate (75mg, 0.12mmol) was dissolved in ethanol (3 mL), and a solution of sodium hydroxide (1.5mL, 1M) was added thereto, followed by stirring at room temperature for 15 hours. After TLC detection raw material reaction is completed, concentrating under reduced pressure to remove ethanol, adding water (2 mL), extracting with ethyl acetate (2mL × 2), separating out an aqueous phase, adjusting the pH of the aqueous phase to be about 5, extracting with ethyl acetate (3mL × 3), drying an organic phase with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, adding acetonitrile, water and two drops of trifluoroacetic acid, and freeze-drying to obtain an off-white solid product of 28mg, yield 38%, purity: 85.7 percent. 1 H NMR (500MHz,MeOH-d 4 )δ8.94(s,1H),7.72–7.63(m,1H),7.56–7.48(m,2H),7.36(s,1H),7.29–7.20(m,2H), 6.93(d,J＝7.3Hz,1H),6.74(dd,J＝8.4,2.2Hz,1H),5.80(s,2H),5.45(s,2H),4.77–4.70(m,2H),4.24(q,J ＝7.7Hz,2H),3.92–3.81(m,2H),3.37–3.33(m,2H),3.03(s,1H),2.20(d,J＝10.5Hz,4H),2.20(td,J＝7.5 Hz,2.3Hz,3H)。
Example 13- ((4- (6- ((4-chloro-2-fluorobenzyl) oxy) pyridin-2-yl) piperazin-1-yl) methyl) -1- ((1-ethyl-1H-imidazol-4-yl) methyl) -1H-thieno [2,3-d ] imidazole-5-carboxylic acid
Figure BDA0003128505470000592
Step 1) Ethyl 2- ((4- (6- ((4-chloro-2-fluorobenzyl) oxy) pyridin-2-yl) piperazin-1-yl) methyl) -1- ((1-ethyl-1H-imidazol-4-yl) methyl) -1H-thieno [2,3-d ] imidazole-5-carboxylate
The hydrochloride salt of intermediate 2 (30mg, 0.085mmol) was dissolved in acetonitrile (1.5 mL) and K was added 2 CO 3 (30mg, 0.213mmol) and 2- (chloromethyl) -1- ((1-ethyl-1H-imidazol 5-yl) methyl) -1H-thieno [2,3-d]Imidazole-5-ethyl formate (25mg, 0.071mmol), heating to 60 deg.C, stirring and reacting for 12h. After completion of the TLC reaction, water (5 mL) was added, extraction was performed with ethyl acetate (15ml × 3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and purified by preparative TLC to give 30mg of a pale yellow oily product with a yield of 66%.
Step 2) 2- ((4- (6- ((4-chloro-2-fluorobenzyl) oxy) pyridin-2-yl) piperazin-1-yl) methyl) -1- ((1-ethyl-1H-imidazol-4-yl) methyl) -1H-thieno [2,3-d ] imidazole-5-carboxylic acid
2- ((4- (6- ((4-chloro-2-fluorobenzyl) oxy) pyridin-2-yl) piperazin-1-yl) methyl) -1- ((1-ethyl-1H-imidazol-4-yl) methyl) -1H-thieno [2,3-d]Ethyl imidazole-5-carboxylate (30mg, 0.047 mmol) was dissolved in ethanol (4 mL), and a solution of sodium hydroxide (1.5mL, 1M) was added to react at room temperature for 8.5 hours. After the TLC detection reaction is completed, the mixture is concentrated under reduced pressure to remove ethanol. Adding water (2 mL), extracting with ethyl acetate (2mL × 2), discarding the organic phase, adjusting pH of the aqueous phase to about 5, extracting with ethyl acetate (3mL × 3), drying the organic phase with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and lyophilizing to obtain white solid product 14.3mg with yield of 50%. Purity: 97.7 percent. 1 H NMR(500MHz,MeOH-d 4 )δ7.79(s,1H), 7.54–7.44(m,3H),7.33(s,1H),7.21(t,J＝8.7Hz,2H),6.34(d,J＝8.1Hz,1H),6.17(d,J＝7.9Hz,1H),5.52 (s,2H),5.36(s,2H),4.18(s,2H),4.06(q,J＝7.5Hz,2H),3.63(s,4H),2.89(d,J＝5.6Hz,4H),1.43(t,J＝7.4 Hz,3H)。
Example 14 (S) -2- ((4- (6- (4-chloro-2-fluorobenzyloxy) pyridin-2-yl) piperazin-1-yl) methyl) -1- (oxetan-2-ylmethyl) -1H-thieno [2,3-d ] imidazole-5-carboxylic acid
Figure BDA0003128505470000601
Step 1) (S) -Oxetadin-2-yl Formaldehyde
(S) -Oxetadin-2-ylmethanol (760 mg, 8.64mmol) was dissolved in dichloromethane (10 mL), dess-martin (5.5 g, 12.96 mmol) was added, and the mixture was stirred at room temperature overnight. The reaction was stopped and filtered to obtain 60mL of filtrate, which was used in the next reaction without purification.
Step 2) 5-bromo-4-nitrothiophene-2-carboxylic acid ethyl ester
5-bromothiophene-2-carboxylic acid ethyl ester (4.5g, 19.14mmol) was placed in a 50mL two-necked flask, and H was added 2 SO 4 Then placing the reaction system in an ice-water bath to reduce the temperature to 0 ℃, and dropwise adding 65 percent of HNO 3 (6.3 mL), after the dropwise addition was completed, the temperature was slowly raised to room temperature, and the reaction was carried out for 1 hour. After the reaction was completed by TLC detection, the reaction was stopped. The reaction solution was poured into ice water (50 mL), extracted with ethyl acetate (30 mL × 3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the solvent, and the resulting residue was purified by column chromatography to give a pale yellow solid product, 3.36g, yield 63%.
Step 3) 5- ((2, 4-Dimethoxybenzyl) amino) -4-nitrothiophene-2-carboxylic acid ethyl ester
Ethyl 5-bromo-4-nitrothiophene-2-carboxylate (2g, 7.14mmol) and 2, 4-dimethoxybenzylamine (1.55g, 9.28mmol) were placed in a single-necked flask, potassium carbonate (3.95g, 28.56mmol) and acetonitrile (45 mL) were added, and stirred at room temperature for 2.5h. After TLC detection reaction was completed, the reaction was stopped, the reaction solution was poured into ice water (50 mL), extracted with ethyl acetate (60 mL. Times.3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the solvent, and the obtained residue was purified by column chromatography to give a pale yellow solid product, 2.7g, with a yield of >99%.
Step 4) 5-amino-4-nitrothiophene-2-carboxylic acid ethyl ester
Ethyl 5- ((2, 4-dimethoxybenzyl) amino) -4-nitrothiophene-2-carboxylate (2.7 g,7.1 mmol) was dissolved in dichloromethane (30 mL), trifluoroacetic acid (3 mL) was added, and the mixture was stirred at room temperature overnight. After TLC detection of the completion of the reaction, the reaction was stopped, poured into ice water (100 mL), extracted with ethyl acetate (150 mL. Times.3), and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent by evaporation to give a pale yellow solid product, 1.9g, >99%.
Step 5) 5- ((tert-butoxycarbonyl) amino) -4-nitrothiophene-2-carboxylic acid ethyl ester
5-amino-4-nitrothiophene-2-carboxylic acid ethyl ester (1.9 g, 8.79mmol) was dissolved in tetrahydrofuran (40 mL), and triethylamine (1.34 g, 13.2 mmol) and (Boc) were added 2 O (2.3g, 10.55mmol), and stirred at room temperature overnight. After TLC detection reaction is completed, the reaction is stopped, the solvent is evaporated by concentration under reduced pressure, and the obtained residue is purified by column chromatography to obtain 1.45g of the product with the yield of 64%.
Step 6) 4-amino-5- ((tert-butoxycarbonyl) amino) thiophene-2-carboxylic acid ethyl ester
Ethyl 5- ((tert-butoxycarbonyl) amino) -4-nitrothiophene-2-carboxylate (1.18g, 3.73mmol) was dissolved in methanol (7.5 mL), water (2.5 mL), iron powder (1.04g, 18.65mmol) and ammonium chloride (400mg, 7.46mmol) were added, and the temperature was raised to 60 ℃ for 2h. After TLC detection reaction was complete, the reaction was stopped, cooled to room temperature, concentrated under reduced pressure to remove methanol, filtered to remove insoluble matter, water (10 mL) was added, extracted with ethyl acetate (20 mL. Times.3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the solvent, and the resulting residue was purified by column chromatography to give 800mg of a yellowish brown oily product, 75%.
Step 7) Ethyl (S) -5- ((tert-Butoxycarbonyl) amino) -4- ((oxetan-2-ylmethyl) amino) thiophene-2-carboxylate
Ethyl 4-amino-5- ((tert-butoxycarbonyl) amino) thiophene-2-carboxylate (632mg, 2.2mmol) was dissolved in dichloromethane (18 mL), and (S) -oxetanyl-2-carbaldehyde (228mg, 2.65mmol) was added dropwise to the solution, followed by addition of 3 drops of acetic acid and reaction with stirring at room temperature for 20 minutes. Sodium triacetoxyborohydride (933mg, 4.4mmol) was added, and the reaction was stirred at room temperature for additional 1h. Diluting with dichloromethane (30 mL), washing with water (20 mL), separating organic phase, washing with saturated salt water, drying over anhydrous sodium sulfate, concentrating under reduced pressure, evaporating to remove solvent, and purifying the residue by column chromatography to obtain 330mg of dark brown oily product, 38%.
Step 8) (S) -2- (chloromethyl) -1- (oxetan-2-ylmethyl) -1H-thieno [2,3-d ] imidazole-5-carboxylic acid ethyl ester
Ethyl (S) -5- ((tert-butoxycarbonyl) amino) -4- ((oxetan-2-ylmethyl) amino) thiophene-2-carboxylate (130mg, 0.365mmol) was dissolved in tetrahydrofuran (6.5 mL), acetic acid (22mg, 0.365mmol) was added, nitrogen was bubbled for 1 minute, 2-chloro-1, 1-trimethoxyethane (113mg, 0.733mmol) was added, and the reaction was carried out with a tube sealer at 100 ℃ for 12 hours. After 12h, p-toluenesulfonic acid monohydrate (7 mg,0.036 mmol) was added and the reaction was carried out at 75 ℃ for 1h. The reaction was stopped, water (15 mL) was added, extraction was performed with ethyl acetate (20mL × 3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent by evaporation to give 140mg of crude product as a dark brown oil, which was used directly in the next reaction.
Step 9) Ethyl (S) -2- ((4- (6- (4-chloro-2-fluorobenzyloxy) pyridin-2-yl) piperazin-1-yl) methyl) -1- (oxetan-2-ylmethyl) -1H-thieno [2,3-d ] imidazole-5-carboxylate
Intermediate 2 (112mg, 0.255mmol) was dissolved in acetonitrile (3 mL), potassium carbonate (202mg, 1.46mmol) was added thereto, and the mixture was stirred at room temperature for 10 minutes, followed by addition of ethyl (S) -2- (chloromethyl) -1- (oxetan-2-ylmethyl) -1H-thieno [2,3-d ] imidazole-5-carboxylate (140mg, 0.365 mmol), followed by warming of the mixture at 50 ℃ for reaction overnight. After TLC detected that the reaction of the starting material was complete, the reaction was stopped, cooled to room temperature, quenched by addition of water (5 mL), extracted with ethyl acetate (10mL. Multidot.3), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the solvent, and the residue was purified by column chromatography to give 40mg of a yellowish brown oily product.
Step 10) (S) -2- ((4- (6- (4-chloro-2-fluorobenzyloxy) pyridin-2-yl) piperazin-1-yl) methyl) -1- (oxetan-2-ylmethyl) -1H-thieno [2,3-d ] imidazole-5-carboxylic acid
Reacting (S) -2- ((4- (6- (4-chloro-2-fluorobenzyloxy) pyridin-2-yl) piperazin-1-yl) methyl) -1- (oxetan-2-ylmethyl) -1H-thieno [2,3-d]Ethyl imidazole-5-carboxylate (40mg, 0.067mmol) was dissolved in ethanol (1 mL), 1N sodium hydroxide solution (1 mL) was added, and the mixture was reacted at 50 ℃ overnight. After TLC detection raw material reaction is completed, stopping reaction, concentrating under reduced pressure and distilling off ethanol, adjusting pH to be about 5 with 1N Cl, extracting with ethyl acetate (3 mL. Times.3), drying with anhydrous sodium sulfate, concentrating under reduced pressure and distilling off solvent, and purifying the obtained residue by column chromatography to obtain a white-like solid product 10.7mg, yield: 28 percent. 88.9% purity, LCMS [ M + H ] ] + :572.1。 1 HNMR(500MHz,DMSO-d 6 )δ7.79(s,1H),7.52 (t,J＝8.2Hz,1H),7.45(d,J＝8.7Hz,2H),7.30(d,J＝8.3Hz,1H),6.33(d,J＝8.0Hz,1H),6.09(d,J＝7.7Hz, 1H),5.30(s,2H),5.09(d,J＝7.5Hz,1H),4.65(dd,J＝15.1,6.8Hz,1H),4.58–4.45(m,2H),4.41–4.33(m, 1H),3.83(d,J＝13.6Hz,1H),3.73(d,J＝13.6Hz,1H),3.55–3.41(m,8H),2.69(t,J＝9.1Hz,1H),2.42– 2.35(m,1H)。
Example 15 (S) -2- ((4- (6- ((4-chloro-2-fluorobenzyl) oxy) -3, 5-difluoropyridin-2-yl) -2-methylpiperazin-1-yl) methyl) -1- ((1-ethyl-1H-imidazol-5-yl) methyl) -1H-thieno [2,3-d ] imidazole-5-carboxylic acid
Figure BDA0003128505470000611
Step 1) Ethyl (S) -2- ((4- (6- ((4-chloro-2-fluorobenzyl) oxy) -3, 5-difluoropyridin-2-yl) -2-methylpiperazin-1-yl) methyl) -1- ((1-ethyl-1H-imidazol-5-yl) methyl) -1H-thieno [2,3-d ] imidazole-5-carboxylate
(S) -1- (6- (4-chloro-2-fluorobenzyloxy) -3, 5-difluoropyridin-2-yl) -3-methylpiperazine hydrochloride (155mg, 0.38mmol) was dissolved in acetonitrile (3 mL), potassium carbonate (158mg, 1.14mmol) was added, the mixture was stirred at 70 ℃ for 20 minutes, ethyl 2- (chloromethyl) -1- ((1-ethyl-1H-imidazol 5-yl) methyl) -1H-thieno [2,3-d ] imidazole-5-carboxylate (134mg, 0.38mmol) was added, and the reaction was allowed to proceed overnight. The reaction was stopped, cooled to room temperature, water (5 mL) was added, extraction was performed with ethyl acetate (3 × 5 mL), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by preparative TLC to give 60mg,7% of a pale yellow oily product.
Step 2) (S) -2- ((4- (6- ((4-chloro-2-fluorobenzyl) oxy) -3, 5-difluoropyridin-2-yl) -2-methylpiperazin-1-yl) methyl) -1- ((1-ethyl-1H-imidazol-5-yl) methyl) -1H-thieno [2,3-d ] imidazole-5-carboxylic acid
Reacting (S) -2- ((4- (6- ((4-chloro-2-fluorobenzyl) oxy) -3, 5-difluoropyridin-2-yl) -2-methylpiperazin-1-yl) methyl) -1- ((1-ethyl-1H-imidazol-5-yl) methyl) -1H-thieno [2,3-d]Ethyl imidazole-5-carboxylate (60mg, 0.087 mmol) was dissolved in ethanol (2 mL), and lithium hydroxide (1 mL, 1M) was added and stirred at room temperature overnight. Concentrating under reduced pressure to remove ethanol, adding water (3 mL), extracting with ethyl acetate (3 mL), discarding the organic phase, adjusting pH of the aqueous phase to about 5, extracting with ethyl acetate (3X 5 mL), combining the organic phases, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and lyophilizing to obtain white solid product 42.0mg,73%. Purity: 98 percent. 1 H NMR(500MHz,MeOH-d 4 )δ8.03(s,1H),7.47(t,J＝8.1 Hz,1H),7.40(t,J＝10.2Hz,1H),7.27–7.19(m,2H),7.12(s,1H),7.06(s,1H),5.80–5.60(m,2H),5.43(s, 2H),4.36(d,J＝14.0Hz,1H),4.03(q,J＝7.5Hz,2H),3.63(d,J＝14.0Hz,1H),3.54(t,J＝15.3Hz,2H),3.09 (t,J＝10.8Hz,1H),2.97(d,J＝11.1Hz,1H),2.78(d,J＝12.1Hz,1H),2.70(d,J＝8.6Hz,1H),2.45(t,J＝ 10.4Hz,1H),1.28–1.20(m,6H)。
Example 16 Ethyl 2- ((4- (6- ((4-chloro-2-fluorobenzyl) oxy) -3, 5-difluoropyridin-2-yl) piperazin-1-yl) methyl) -1- ((1-ethyl-1H-imidazol-5-yl) methyl) -1H-thieno [2,3-d ] imidazole-5-carboxylate
Figure BDA0003128505470000621
1- (6- ((4-chloro-2-fluorobenzyl) oxy) -3, 5-difluoropyridin-2-yl) piperazine hydrochloride (112mg, 0.283mmol), ethyl 2- (chloromethyl) -1- ((1-ethyl-1H-imidazol 5-yl) methyl) -1H-thieno [2,3-d ] imidazole-5-carboxylate (100mg, 0.283mmol), potassium carbonate (156mg, 1.132 mmol) and acetonitrile (3 mL) were placed in a 15 mL sealed tube and allowed to warm to 70 ℃ for reaction overnight. Cooled to room temperature, filtered to remove insoluble material and purified by preparative TLC to yield 60mg of product as a yellow oil.
Example 17- ((4- (6- ((4-chloro-2-fluorobenzyl) oxy) -3, 5-difluoropyridin-2-yl) piperazin-1-yl) methyl) -1- ((1-ethyl-1H-imidazol-5-yl) methyl) -1H-thieno [2,3-d ] imidazole-5-carboxylic acid trifluoroacetate complex
Figure BDA0003128505470000622
2- ((4- (6- ((4-chloro-2-fluorobenzyl) oxy) -3, 5-difluoropyridin-2-yl) piperazin-1-yl) methyl) -1- ((1-ethyl-1H-imidazol-5-yl) methyl) -1H-thieno [2,3-d]Ethyl imidazole-5-carboxylate (60mg, 0.089mmol) was dissolved in ethanol (2 mL), and lithium hydroxide (1mL, 1M) was added and stirred at room temperature overnight. Concentrating under reduced pressure to remove ethanol, adding water (2 mL), extracting with ethyl acetate (2 mL), discarding the organic phase, adjusting pH of the aqueous phase to about 5, extracting with ethyl acetate (5 mL × 3), combining the organic phases, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, adding 2 drops of trifluoroacetic acid, and lyophilizing to obtain off-white solid product 36.0mg,63%. Purity: 98 percent. 1 H NMR(500MHz,MeOH-d 4 )δ9.08(s,1H), 7.58(d,J＝2.1Hz,1H),7.52–7.45(m,2H),7.43(s,1H),7.26(d,J＝8.0Hz,2H),5.83(s,2H),5.44(s,2H), 4.29(dd,J＝14.9,7.2Hz,4H),3.50(s,4H),3.09(s,4H),1.49–1.43(m,3H)。
Example 18 Ethyl 2- ((4- (4- ((4-chloro-2-fluorobenzyl) oxy) -5-fluoropyrimidin-2-yl) piperazin-1-yl) methyl) -1- ((1-ethyl-1H-imidazol-5-yl) methyl) -1H-thieno [2,3-d ] imidazole-5-carboxylate
Figure BDA0003128505470000623
4- ((4-chloro-2-fluorobenzyl) oxy) -5-fluoro-2- (piperazin-1-yl) pyridine hydrochloride (107mg, 0.283mmol), potassium carbonate (156 mg, 1.132 mmol) and acetonitrile (3 mL) were placed in a 15 mL sealed tube, warmed to 70 ℃ and stirred for 40 minutes, 2- (chloromethyl) -1- ((1-ethyl-1H-imidazol 5-yl) methyl) -1H-thieno [2,3-d ] imidazole-5-carboxylic acid ethyl ester (100mg, 0.283mmol) was added and the mixture was reacted overnight at 70 ℃. Insoluble material was removed by filtration, concentrated and the residue was purified by preparative TLC to give 50mg of a yellow oily product in 27% yield.
Example 19 Complex of trifluoroacetate 2- ((4- (4- ((4-chloro-2-fluorobenzyl) oxy) -5-fluoropyrimidin-2-yl) piperazin-1-yl) methyl) -1- ((1-ethyl-1H-imidazol-5-yl) methyl) -1H-thieno [2,3-d ] imidazole-5-carboxylic acid
Figure BDA0003128505470000631
Reacting 2- ((4- (4- ((4-chloro-2-fluorobenzyl) oxy) -5-fluoropyrimidin-2-yl) piperazin-1-yl) methyl) -1- ((1-ethyl-1H-imidazol-5-yl) methyl) -1H-thieno [2,3-d]Ethyl imidazole-5-carboxylate (50mg, 0.076 mmol) was dissolved in ethanol (2 mL), and lithium hydroxide (1mL, 1M) was added and stirred at room temperature overnight. Concentrating under reduced pressure to remove ethanol, adding water (2 mL), extracting with ethyl acetate (2 mL), discarding the organic phase, adjusting pH of the aqueous phase to about 5, extracting with ethyl acetate (5 mL × 3), combining the organic phases, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, adding 2 drops of trifluoroacetic acid, and lyophilizing to obtain off-white solid product 32mg,67%. Purity: 94 percent. 1 H NMR(500MHz,MeOH-d 4 )δ9.08(s,1H),8.08(s, 1H),7.59(s,1H),7.53(t,J＝8.3Hz,1H),7.42(s,1H),7.28(t,J＝7.8Hz,2H),5.83(s,2H),5.51(s,2H),4.35(s, 2H),4.29(d,J＝7.5Hz,2H),3.88(s,4H),3.07(s,4H),1.46(td,J＝7.4,2.1Hz,3H)。
Example 20 Ethyl 6- ((4- (6- ((4-chloro-2-fluorobenzyl) oxy) piperidin-2-yl) piperazin-1-yl) methyl) -5- ((1-ethyl-1H-imidazol-5-yl) (hydroxy) methyl) imidazo [2,1-b ] thiazole-2-carboxylate
Figure BDA0003128505470000632
Step 1) Ethyl 6- (chloromethyl) -5-imidazo [2,1-b ] thiazole-2-carboxylate
Ethyl 2-aminothiazole-5-carboxylate (1.72g, 10 mmol) and dichloroacetone (2.54mg, 20 mmol) were placed in a 30mL sealed tube, chlorobenzene (20 mL) was added, the mixture was stirred at 130 ℃ for 2 hours, cooled to room temperature, concentrated under reduced pressure to remove the solvent, and the obtained residue was purified by column chromatography to give 1.02g of a pale yellow solid product in 42% yield.
Step 2) 6- (chloromethyl) -5-iodoimidazo [2,1-b ] thiazole-2-carboxylic acid ethyl ester
Ethyl 6- (chloromethyl) -5-imidazo [2,1-b ] thiazole-2-carboxylate (0.6 g, 2.45mmol) and iodosuccinimide (0.6 g,2.7 mmol) were dissolved in acetonitrile (20 mL), reacted overnight with stirring at room temperature, the solvent was evaporated off by concentration under reduced pressure, and the resulting residue was purified by column chromatography to give 0.6g of a white solid product in 66% yield.
Step 3) Ethyl 6- ((4- (6- ((4-chloro-2-fluorobenzyl) oxy) piperidin-2-yl) piperazin-1-yl) methyl) -5-iodoimidazo [2,1-b ] thiazole-2-carboxylate
Intermediate 2 hydrochloride (1.07g, 3mmol) and ethyl 6- (chloromethyl) -5-iodoimidazo [2,1-b ] thiazole-2-carboxylate (1.22g, 3.3mmol) were dissolved in acetonitrile (30 mL), triethylamine (0.9g, 9mmol) was added, and the reaction was carried out at 60 ℃ for 14h. Cooling to room temperature, concentrating under reduced pressure to remove the solvent by evaporation, and purifying the obtained residue by column chromatography to obtain 1.3g of a pale yellow solid product with a yield of 66%.
Step 4) Ethyl 6- ((4- (6- ((4-chloro-2-fluorobenzyl) oxy) piperidin-2-yl) piperazin-1-yl) methyl) -5- ((1-ethyl-1H-imidazol-5-yl) (hydroxy) methyl) imidazo [2,1-b ] thiazole-2-carboxylate
Ethyl 6- ((4- (6- ((4-chloro-2-fluorobenzyl) oxy) piperidin-2-yl) piperazin-1-yl) methyl) -5-iodoimidazo [2,1-b ] thiazole-2-carboxylate (129 mg, 0.2mmol) was dissolved in anhydrous tetrahydrofuran (5 mL), the mixture was cooled to-40 ℃, isopropyl magnesium chloride (0.3mL, 1.3M) was added dropwise, the reaction was stirred for 0.5h, and then 1-ethyl-5-imidazolecarboxaldehyde was added. After stirring at-40 ℃ for 1h, slowly raising the temperature to room temperature and stirring for reaction overnight, adding a saturated ammonium chloride solution (5 mL) to quench the reaction, separating the liquid, drying the organic phase, concentrating under reduced pressure to remove the solvent, and purifying the obtained residue by column chromatography to obtain a pale yellow oily product 70mg with a yield of 54%.
Example 21- ((4- (6- ((4-chloro-2-fluorobenzyl) oxy) piperidin-2-yl) piperazin-1-yl) methyl) -5- ((1-ethyl-1H-imidazol-5-yl) (hydroxy) methyl) imidazo [2,1-b ] thiazole-2-carboxylic acid
Figure BDA0003128505470000641
Reacting 6- ((4- (6- ((4-chloro-2-fluorobenzyl) oxy) piperidin-2-yl) piperazin-1-yl) methyl) -5- ((1-ethyl-1H-imidazol-5-yl) (hydroxy) methyl) imidazo [2,1-b]Ethyl thiazole-2-carboxylate (26mg, 0.04mmol) was dissolved in methanol (1.2 mL), lithium hydroxide (8.4 mg, 0.2mmol) and water (0.4 mL) were added, and the mixture was reacted at room temperature for 3h. The reaction was stopped, pH adjusted to approximately 5 with 1N HCl, purified by preparative TLC and lyophilized to give 12.1mg of a white solid in 48% yield. Purity: 90.4 percent. 1 H NMR(500MHz,CD 3 OD)δ8.02(s,1H),7.82(s,1H),7.45 (dd,J＝12.9,7.3Hz,2H),7.20(t,J＝9.6Hz,2H),6.61(s,1H),6.42(s,1H),6.26(d,J＝7.8Hz,1H),6.13(d,J＝ 7.8Hz,1H),5.33(s,2H),4.27–4.12(m,2H),3.74(dd,J＝55.7,13.6Hz,2H),3.47–3.38(m,4H),2.71–2.58 (m,4H),1.44(t,J＝7.2Hz,3H)。
Example 22 methyl 2- ((4- (6- ((4-chloro-2-fluorobenzyl) oxy) pyridin-2-yl) piperazin-1-yl) methyl) -3- ((1-ethyl-1H-imidazol-5-yl) (hydroxy) methyl) imidazo [1,2-a ] pyridine-6-carboxylate
Figure BDA0003128505470000642
Step 1) methyl 2- (chloromethyl) imidazo [1,2-a ] pyridine-6-carboxylate
Methyl 2-aminopyridine-5-carboxylate (4.08g, 27mmol) and dichloroacetone (6.81g, 54mmol) were placed in a 60mL sealed tube, chlorobenzene (50 mL) was added, the mixture was stirred at 130 ℃ for 3 hours, cooled to room temperature, concentrated under reduced pressure to remove the solvent, and the residue was purified by column chromatography to give 3.02g of a white solid product with a yield of 50%.
Step 2) methyl 2- (chloromethyl) -3-iodoimidazo [1,2-a ] pyridine-6-carboxylate
Methyl 2- (chloromethyl) imidazo [1,2-a ] pyridine-6-carboxylate (3.18g, 14.2mmol) and iodosuccinimide (3.52g, 15.7mmol) were dissolved in acetonitrile (40 mL), and the reaction was stirred at room temperature overnight, concentrated under reduced pressure to remove the solvent, and the residue was purified by column chromatography to give 4.4g of a white solid in 89% yield.
Step 3) methyl 2- ((4- (6- ((4-chloro-2-fluorobenzyl) oxy) pyridin-2-yl) piperazin-1-yl) methyl) -3-iodoimidazo [1,2-a ] pyridine-6-carboxylate
The hydrochloride of intermediate 2 (0.54g, 1.5 mmol) and methyl 2- (chloromethyl) -3-iodoimidazo [1,2-a ] pyridine-6-carboxylate (0.63 g, 1.8 mmol) were dissolved in acetonitrile (15 mL), triethylamine (530mg, 5.3 mmol) was added, and the reaction was carried out at 60 ℃ for 14h. Cooling to room temperature, concentrating under reduced pressure to remove the solvent by evaporation, and purifying the residue by column chromatography to obtain 0.6g of a white solid product with a yield of 63%.
Step 4) methyl 2- ((4- (6- ((4-chloro-2-fluorobenzyl) oxy) pyridin-2-yl) piperazin-1-yl) methyl) -3- ((1-ethyl-1H-imidazol-5-yl) (hydroxy) methyl) imidazo [1,2-a ] pyridine-6-carboxylate
Methyl 2- ((4- (6- ((4-chloro-2-fluorobenzyl) oxy) pyridin-2-yl) piperazin-1-yl) methyl) -3-iodoimidazo [1,2-a ] pyridine-6-carboxylate (635 mg, 1mmol) was dissolved in anhydrous THF (15 mL), the mixture was cooled to-40 ℃, isopropyl magnesium chloride (1.2ml, 1.3m) was added dropwise, the reaction was stirred for 0.5h, and then 1-ethyl-5-imidazolecarboxaldehyde was added. Stirring at-40 deg.C for 1h, slowly heating to room temperature and stirring for reaction overnight, adding saturated ammonium chloride solution (15 mL) to quench the reaction, separating out the organic phase, drying the organic phase with anhydrous sodium sulfate, concentrating under reduced pressure to remove the solvent, and purifying the residue by column chromatography to obtain light yellow solid product 308mg with yield of 49%.
Example 23- ((4- (6- ((4-chloro-2-fluorobenzyl) oxy) pyridin-2-yl) piperazin-1-yl) methyl) -3- ((1-ethyl-1H-imidazol-5-yl) (hydroxy) methyl) imidazo [1,2-a ] pyridine-6-carboxylic acid
Figure BDA0003128505470000643
Reacting 2- ((4- (6- ((4-chloro-2-fluorobenzyl) oxy) pyridin-2-yl) piperazin-1-yl) methyl) -3- ((1-ethyl-1H-imidazol-5-yl) (hydroxy) methyl) imidazo [1,2-a]Pyridine-6-carboxylic acid methyl ester (63mg, 0.1mmol) was dissolved in methanol (3.6 mL), lithium hydroxide (21mg, 0.5mmol) and water (1.2 mL) were added, and the mixture was reacted at room temperatureAnd 3h. The reaction was stopped, pH adjusted to approximately 5 with 1N Cl, purified by preparative TLC and lyophilized to yield 10.8mg of white solid, 17%. Purity: 92.3 percent. 1 HNMR(500MHz,CD 3 OD)δ8.91(s,1H),7.91(d,J＝9.3Hz,1H), 7.80(s,1H),7.54(d,J＝9.1Hz,1H),7.44(q,J＝7.8Hz,2H),7.20(t,J＝9.9Hz,2H),6.59(s,1H),6.38(s,1H), 6.24(d,J＝7.9Hz,1H),6.12(d,J＝7.7Hz,1H),5.32(s,2H),4.29(qd,J＝14.3,7.1Hz,2H),3.85(dd,J＝35.3, 13.8Hz,2H),3.37(s,4H),2.62(dd,J＝35.3,11.1Hz,4H),1.52(t,J＝7.0Hz,3H)。
Example 24 Ethyl 6- ((4- (6- ((4-chloro-2-fluorobenzyl) oxy) piperidin-2-yl) piperazin-1-yl) methyl) -5- (1-ethyl-1H-imidazole-5-carbonyl) imidazo [2,1-b ] thiazole-2-carboxylate
Figure BDA0003128505470000651
Ethyl 6- ((4- (6- ((4-chloro-2-fluorobenzyl) oxy) piperidin-2-yl) piperazin-1-yl) methyl) -5- ((1-ethyl-1H-imidazol-5-yl) (hydroxy) methyl) imidazo [2,1-b ] thiazole-2-carboxylate (26mg, 0.04mmol) and Dess Martin periodinane (25mg, 0.06mmol) were placed in a 25mL single vial, DCM (5 mL) was added, the reaction was stirred at room temperature overnight, the solvent was evaporated by concentration under reduced pressure, and the resulting residue was purified by column chromatography to give 18mg of a white solid product in a yield of 69%.
Example 25- ((4- (6- ((4-chloro-2-fluorobenzyl) oxy) piperidin-2-yl) piperazin-1-yl) methyl) -5- (1-ethyl-1H-imidazole-5-carbonyl) imidazo [2,1-b ] thiazole-2-carboxylic acid
Figure BDA0003128505470000652
Reacting 6- ((4- (6- ((4-chloro-2-fluorobenzyl) oxy) piperidin-2-yl) piperazin-1-yl) methyl) -5- (1-ethyl-1H-imidazole-5-carbonyl) imidazo [2,1-b]Thiazole-2-carboxylic acid (50mg, 0.08mmol) was dissolved in methanol (2.4 mL), liOH (16.8mg, 0.4mmol) and water (0.6 mL) were added, and the mixture was reacted at room temperature for 3h. The reaction was stopped, pH adjusted to about 5 with 1N HCl, purified by preparative TLC and lyophilized to give 13.3mg of a white solid with 27% yield. Purity of：87.3％。 1 H NMR(500MHz,CD 3 OD)δ8.54(s,1H),8.04(s,1H),7.97(s,1H),7.49 –7.40(m,2H),7.21(t,J＝10.5Hz,2H),6.25(d,J＝8.1Hz,1H),6.10(d,J＝7.8Hz,1H),5.33(s,2H),4.43(q, J＝7.0Hz,2H),3.67(s,2H),3.42(s,4H),2.47(s,4H),1.49(t,J＝7.1Hz,3H)。
Example 26- ((4- (2- ((4-chloro-2-fluorobenzyl) oxy) -5-fluoropyrimidin-4-yl) piperazin-1-yl) methyl) -1- ((1-ethyl-1H-imidazol-5-yl) methyl) -1H-thiazolo [2,3-d ] imidazole-5-carboxylic acid
Figure BDA0003128505470000653
Step 1) Ethyl 2- ((4- (2- ((4-chloro-2-fluorobenzyl) oxy) -5-fluoropyrimidin-4-yl) piperazin-1-yl) methyl) -1- ((1-ethyl-1H-imidazol-5-yl) methyl) -1H-thiazolo [2,3-d ] imidazole-5-carboxylate
2- ((4-chloro-2-fluorobenzyl) oxy) -5-fluoro-4- (piperazin-1-yl) pyridine hydrochloride (220mg, 0.58mmol), potassium carbonate (321 mg, 2.32 mmol) and acetonitrile (5 mL) were placed in a 15 mL sealed tube, warmed to 60 ℃ and stirred for 40 minutes, 2- (chloromethyl) -1- ((1-ethyl-1H-imidazol 5-yl) methyl) -1H-thieno [2,3-d ] imidazole-5-carboxylic acid ethyl ester (180mg, 0.51mmol) was added and the mixture was reacted at 60 ℃ overnight. Insoluble material was removed by filtration, concentrated and purified by preparative TLC to give 140mg of a colorless oily product in 42% yield.
Step 2) 2- ((4- (2- ((4-chloro-2-fluorobenzyl) oxy) -5-fluoropyrimidin-4-yl) piperazin-1-yl) methyl) -1- ((1-ethyl-1H-imidazol-5-yl) methyl) -1H-thiazolo [2,3-d ] imidazole-5-carboxylic acid
Reacting 2- ((4- (2- ((4-chloro-2-fluorobenzyl) oxy) -5-fluoropyrimidin-4-yl) piperazin-1-yl) methyl) -1- ((1-ethyl-1H-imidazol-5-yl) methyl) -1H-thiazolo [2,3-d]Ethyl imidazole-5-carboxylate (140mg, 0.213mmol) was dissolved in ethanol (3 mL), lithium hydroxide (1.5mL, 1M) was added, and the mixture was stirred at room temperature overnight. Concentrating under reduced pressure to remove ethanol, adding water (3 mL), extracting with ethyl acetate (3 mL), discarding the organic phase, adjusting pH of the water phase to about 6 with 1M dilute hydrochloric acid, precipitating a large amount of solid, filtering, washing with water twice, and drying to obtain white-like solid product 97mg with yield of 72%. PureDegree: 93.8 percent. 1 H NMR(500MHz,MeOH-d 4 )δ9.11(s,1H),8.10(d,J＝6.9Hz,1H),7.58(d,J＝2.1Hz, 1H),7.52(t,J＝8.1Hz,1H),7.46(s,1H),7.27(t,J＝8.7Hz,2H),5.84(s,2H),5.45(s,2H),4.29(d,J＝7.4Hz, 2H),4.21(s,2H),3.97(s,4H),3.00(s,4H),1.45(td,J＝7.4,2.1Hz,3H)。
Example 27- ((4- (2- ((4-chloro-2-fluorobenzyl) oxy) pyrimidin-4-yl) piperidin-1-yl) methyl) -1- ((1-ethyl-1H-imidazol-5-yl) methyl) -1H-thieno [2,3-d ] imidazole-5-carboxylic acid
Figure BDA0003128505470000661
Step 1) Ethyl 2- ((4- (2- ((4-chloro-2-fluorobenzyl) oxy) pyrimidin-4-yl) piperidin-1-yl) methyl) -1- ((1-ethyl-1H-imidazol-5-yl) methyl) -1H-thieno [2,3-d ] imidazole-5-carboxylate
2- ((4-chloro-2-fluorobenzyl) oxy) -4- (piperidin-4-yl) pyrimidine hydrochloride (180g, 0.5 mmol), potassium carbonate (276 mg,2.0 mmol), acetonitrile (3 mL) were placed in a 15mL sealed tube, the mixture was heated to 70 ℃ and stirred for 30 minutes, and ethyl 2- (chloromethyl) -1- ((1-ethyl-1H-imidazol 5-yl) methyl) -1H-thieno [2,3-d ] imidazole-5-carboxylate (250mg, 0.51mmol) was added to react overnight. Cooled to room temperature, filtered to remove insoluble substances, concentrated under reduced pressure to remove the solvent, and the residue was purified by column chromatography to give 30mg of a yellow oily product in 9% yield.
Step 2) 2- ((4- (2- ((4-chloro-2-fluorobenzyl) oxy) pyrimidin-4-yl) piperidin-1-yl) methyl) -1- ((1-ethyl-1H-imidazol-5-yl) methyl) -1H-thieno [2,3-d ] imidazole-5-carboxylic acid
Reacting 2- ((4- (2- ((4-chloro-2-fluorobenzyl) oxy) pyrimidin-4-yl) piperidin-1-yl) methyl) -1- ((1-ethyl-1H-imidazol-5-yl) methyl) -1H-thieno [2,3-d]Ethyl imidazole-5-carboxylate (60mg, 0.094mmol) was dissolved in ethanol (2 mL), lithium hydroxide (1mL, 1M) was added, and the mixture was stirred at room temperature overnight. Concentrating under reduced pressure to remove ethanol, adding water (3 mL), extracting with ethyl acetate (3 mL), discarding the organic phase, adjusting pH of the aqueous phase to about 5, extracting with ethyl acetate (5 mL × 3), mixing the organic phases, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, evaporating to remove solvent, adding 2 drops of threeFluoroacetic acid, freeze-dried to obtain the white solid product 45mg, yield 79%. Purity: 97.8 percent. 1 H NMR(500MHz,MeOH-d 4 ) δ9.05(s,1H),8.54(d,J＝5.1Hz,1H),7.62–7.53(m,2H),7.39(s,1H),7.27(t,J＝10.3Hz,2H),7.11(d,J＝ 5.1Hz,1H),5.81(s,2H),5.51(s,2H),4.65(s,2H),4.27(q,J＝7.3Hz,2H),3.77(d,J＝12.0Hz,2H),3.22(s, 2H),3.06(s,1H),2.17(d,J＝23.1Hz,4H),1.48(t,J＝7.3Hz,3H)。
Example 28- ((1- (6- ((4-chloro-2-fluorobenzyl) oxy) pyridin-2-yl) piperidin-4-yl) ((1-ethyl-1H-imidazol-5-yl) methyl) amino) benzo [ d ] isothiazole-3-carboxylic acid
Figure BDA0003128505470000662
Step 1) 2-chloro-6- ((4-chloro-2-fluorobenzyl) oxy) pyridine
4-chloro-2-fluorobenzyl alcohol (3 g,18.7 mmol) was dissolved in THF (30 mL), and sodium hydride (1.12g, 28.05mmol, 60%) was added under ice-water bath, and the mixture was stirred for 0.5 hour, then 2, 6-dichloropyridine (3.32g, 22.4 mmol) was added, and stirred at room temperature for 12 hours. The reaction was stopped, ice water (30 mL) and ethyl acetate (30ml × 3) were added and extracted, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the solvent by evaporation, and the residue was purified by column chromatography to give 2g,85% of a white solid product.
Step 2) 6-Bromobenzo [ d ] isothiazole-3-carboxylic acid methyl ester
6-bromobenzo [ d ] isothiazole-3-carboxylic acid (10g, 38.75mmol) was dissolved in methanol (100 mL), concentrated sulfuric acid (2.5 mL) was added, and the mixture was allowed to warm to 70 ℃ for reaction overnight. After the reaction was terminated, the reaction mixture was concentrated under reduced pressure to remove methanol, ethyl acetate (200 mL) was added, and the mixture was washed with water (100 mL), a saturated sodium bicarbonate solution (100 mL) and saturated sodium chloride in this order, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain 7.4 g of a pale yellow solid product with a yield of 70%.
Step 3) methyl 6- ((1- (tert-butoxycarbonyl) piperidin-4-yl) amino) benzo [ d ] isothiazole-3-carboxylate
Reacting 6-bromobenzo [ d]Isothiazole-3-carboxylic acid methyl ester (2g, 7.36mmol), 1-Boc-4-aminopiperidine (1.77g, 8.84mmol), cesium carbonate (4.8g，14.72mmol)，x-phos(702mg，1.47mmol)，Pd 2 (dba) 3 (674mg, 0.74mmol) was placed in a 100mL single-neck flask, toluene (50 mL) was added, and the mixture was allowed to warm to 110 ℃ under nitrogen overnight. The reaction was stopped, cooled to room temperature, filtered, the filtrate was concentrated, and the residue was purified by column chromatography to give 1.8g of a pale yellow solid product in 63% yield.
Step 4) trifluoroacetic acid salt of methyl 6- (piperidin-4-ylamino) benzo [ d ] isothiazole-3-carboxylate
Methyl 6- ((1- (tert-butoxycarbonyl) piperidin-4-yl) amino) benzo [ d ] isothiazole-3-carboxylate (1.55g, 3.96mmol) was dissolved in dichloromethane (20 mL), trifluoroacetic acid (4 mL) was added, and the mixture was stirred at room temperature overnight. Concentration to obtain 2.0g, yield >99%.
Step 5) methyl 6- ((1- (6- ((4-chloro-2-fluorobenzyl) oxy) pyridin-2-yl) piperidin-4-yl) amino) benzo [ d ] isothiazole-3-carboxylate
Reacting 6- (piperidin-4-ylamino) benzo [ d]Trifluoroacetic acid salt of methyl isothiazole-3-carboxylate (2.0g, 3.96mmol), 2-chloro-6- ((4-chloro-2-fluorobenzyl) oxy) pyridine (1.08g, 3.96mmol), cesium carbonate (5.4g, 46.63mmol), x-phos (189mg, 0.396mmol), pd 2 (dba) 3 (181mg, 0.198mmol) was placed in a 100mL single vial, toluene (50 mL) was added, and the mixture was allowed to warm to 110 ℃ under nitrogen overnight. The reaction was stopped, cooled to room temperature, filtered, the filtrate was concentrated, and the residue was purified by column chromatography to give 260mg, 12% as a colorless transparent oily product.
Step 6) methyl 6- ((1- (6- ((4-chloro-2-fluorobenzyl) oxy) pyridin-2-yl) piperidin-4-yl) ((1-ethyl-1H-imidazol-5-yl) methyl) amino) benzo [ d ] isothiazole-3-carboxylate
Methyl 6- ((1- (6- ((4-chloro-2-fluorobenzyl) oxy) pyridin-2-yl) piperidin-4-yl) amino) benzo [ d ] isothiazole-3-carboxylate (260mg, 0.49 mmol), 1-oxy-5-chloromethylimidazolyl hydrochloride (98mg, 0.54mmol), and potassium carbonate (271mg, 1.96mmol) were placed in a 48 mL sealed tube, acetonitrile (5 mL) was added, and the mixture was warmed to 70 ℃ for reaction overnight. Insoluble material was removed by filtration and purified by preparative TLC to yield 60mg,19% as a yellow oily product.
Step 7) 6- ((1- (6- ((4-chloro-2-fluorobenzyl) oxy) pyridin-2-yl) piperidin-4-yl) ((1-ethyl-1H-imidazol-5-yl) methyl) amino) benzo [ d ] isothiazole-3-carboxylic acid
Reacting 6- ((1- (6- ((4-chloro-2-fluorobenzyl) oxy) pyridin-2-yl) piperidin-4-yl) ((1-ethyl-1H-imidazol-5-yl) methyl) amino) benzo [ d]Methyl isothiazole-3-carboxylate (60mg, 0.094mmol) was dissolved in ethanol (3 mL), 1M aqueous lithium hydroxide solution (1.5 mL) was added, and the mixture was stirred at room temperature overnight. Concentrating under reduced pressure to remove ethanol, adjusting pH to about 5, extracting with ethyl acetate (3X 5 mL), combining organic phases, drying with anhydrous sodium sulfate, concentrating, purifying the residue by preparative TLC, and lyophilizing to obtain beige product of 18mg,30%. Purity: 95.8 percent. 1 H NMR (500MHz,DMSO-d 6 )δ9.11(s,1H),8.37(d,J＝9.3Hz,1H),7.57(s,1H),7.51(t,J＝8.2Hz,1H),7.45(d,J＝ 9.2Hz,2H),7.35(s,1H),7.28(d,J＝8.4Hz,1H),7.18(d,J＝9.4Hz,1H),6.39(d,J＝8.2Hz,1H),6.06(d,J＝7.8Hz,1H),5.31(s,2H),4.65(s,2H),4.41(d,J＝12.8Hz,2H),4.26(q,J＝7.6Hz,3H),2.97(t,J＝12.6Hz, 2H),1.88(d,J＝11.9Hz,2H),1.70(dd,J＝12.0,3.9Hz,2H),1.48(t,J＝7.3Hz,3H)。
Example 29- ((4- (6- ((4-chloro-2-fluorobenzyl) oxy) pyridin-2-yl) piperidin-1-yl) methyl) imidazo [1,2-a ] pyridine-3, 6-dicarboxylic acid
Figure BDA0003128505470000671
Step 1) 6-Chloronicotinic acid tert-butyl ester
6-Chlorhydric acid (4.9g, 31mmol) is dissolved in thionyl chloride (27 mL) and the reaction is refluxed overnight; after the reaction of the raw materials is completed, concentrating under reduced pressure to dryness, adding dichloromethane (10 mL) into the residue, dripping a dichloromethane (10 mL) solution of tert-butyl alcohol (28mL, 310mmol) into the system, adding triethylamine (43mL, 310mmol) and a catalytic amount of 4-dimethylaminopyridine (244mg, 2mmol), continuing the reaction, monitoring by TLC, after the conversion is completed, diluting with dichloromethane (83 mL), washing the obtained solution with saturated sodium bicarbonate (100mL × 3), then washing with water (100mL × 3), drying the organic phase with anhydrous sodium sulfate, and concentrating under reduced pressure to obtain 3.04g of brown solid with a yield of 46%; 1 H NMR(500MHz,CDCl 3 )δ8.94(s,1H),8.19(d,J＝8.0Hz,1H),7.39(d,J＝8.0Hz,1H),1.61(s,9H)。
Step 2) 6-Carbamic acid tert-butyl ester
Dissolving tert-butyl 6-chloronicotinate (3.04g, 14.09mmol), sodium azide (1.83g, 28.15mmol) and triphenylphosphine (14.38g, 28.15 mmol) in dimethyl sulfoxide (80 mL), reacting the mixture at 120 ℃ overnight, detecting the complete conversion of the raw materials at 100 ℃ by TLC, cooling, adding 1.0M hydrochloric acid solution (20 mL), and reacting the mixture at 120 ℃ for 1 hour; after cooling to room temperature, 1.0M hydrochloric acid solution (20 mL) was added, water (100 mL) was added, extraction was performed with ethyl acetate (100ml × 3), the PH of the aqueous layer was adjusted to moderately basic, extraction was performed with ethyl acetate (100ml × 3), and the obtained ethyl acetate layer was washed with water (100 mL), saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated to dryness to obtain 2.15g of a yellow oily substance with a yield of 79%. 1 H NMR(500MHz,CDCl 3 )δ8.67(s,1H),7.96 (d,J＝8.5Hz,1H),6.46(d,J＝8.5Hz,1H),5.04(br,2H),1.57(s,9H)。
Step 3) 2- (chloromethyl) -3- (ethoxycarbonyl) -imidazo [1,2-a ] pyridine-6-carboxylic acid tert-butyl ester
Tert-butyl 6-aminonicotinate (2.15g, 11mmol) was dissolved in toluene (40 mL), and ethyl 2, 4-dichloroacetoacetate (3.07 g, 15.4 mmol) was added and reacted with reflux overnight; after TLC monitored that the starting material was substantially completely converted, it was directly concentrated to dryness under reduced pressure, and the residue was purified by column chromatography (PE: EA =1, 0to 2. 1 H NMR(500MHz,CDCl 3 )δ9.95(s,1H),7.99(d,J＝9.0 Hz,1H),7.72(d,J＝9.0Hz,1H),5.08(s,2H),4.54(q,J＝7.0Hz,2H),1.66(s,9H),1.52(t,J＝7.0Hz,3H)。
Step 4) tert-butyl 2- ((4- (6- ((4-chloro-2-fluorobenzyl) oxy) pyridin-2-yl) piperidin-1-yl) methyl) imidazo [1,2-a ] pyridine-3- (ethoxycarbonyl) -6-carboxylate
2- (4-chloro-2-fluorobenzyloxy) -6- (piperidin-4-yl) pyridine hydrochloride (1.0g, 2.8mmol) was dissolved in acetonitrile (20 mL), potassium carbonate (1.5g, 10.88mmol) was added, the mixture was stirred at room temperature for 5 minutes, and then 6- (tert-butyl) 3-ethyl 2- (chloromethyl) imidazo [1,2-a ] was added]Pyridine-3, 6-dicarboxylic acid esters(0.62g, 1.83mmol), reaction at 50 ℃ overnight; TLC monitored complete conversion of starting material, cooled to room temperature, diluted with ethyl acetate (20 mL), added water (20 mL), separated the organic layer, the aqueous layer was extracted with ethyl acetate (20 mL), the organic layers were combined and dried over anhydrous sodium sulfate, concentrated, and the residue was purified by column chromatography (PE: EA = 1) to afford 1.03g of a yellow oil in 90% yield. 1 H NMR(500MHz,CDCl 3 )δ9.98(s,1H),7.94(d,J＝9.0Hz,1H),7.72(d,J＝9.0Hz,1H),7.53-7.43(m,2H), 7.12(m,2H),6.75(d,J＝7.5Hz,1H),6.60(d,J＝7.5Hz,1H),5.41(s,2H),4.51(q,J＝7.0Hz,2H),4.12(s, 2H),3.24(d,J＝10.5Hz,2H),2.60(t,J＝10.0Hz,1H),2.34(t,J＝11.5Hz,2H),1.99(q,J＝12.5Hz,1H),1.89 (d,J＝12.0Hz,2H),1.65(s,9H),1.52(t,J＝7.0Hz,3H)。
Step 5) 6- (tert-Butoxycarbonyl) -2- ((4- (6- ((4-chloro-2-fluorobenzyl) oxy) pyridin-2-yl) piperidin-1-yl) methyl) imidazo [1,2-a ] pyridine-3-carboxylic acid
Reacting 6- (tert-butyl) 3-ethyl 2- ((4- (6- ((4-chloro-2-fluorobenzyl) oxy) pyridin-2-yl) piperidin-1-yl) methyl) imidazo [1,2-a]Pyridine-3, 6-dicarboxylic acid ester (255mg, 0.41mmol) was dissolved in ethanol/water (10ml, v/v = 3; after monitoring the completion of the reaction of the starting materials by LC-MS, the pH was adjusted to about 4, extracted with dichloromethane (15ml × 3), dried over anhydrous sodium sulfate, and concentrated to dryness to obtain 151mg of a foamy solid with a yield of 62%. LC-MS ESI [ M + H ] ] + :595.2。
Step 6) 2- ((4- (6- ((4-chloro-2-fluorobenzyl) oxy) pyridin-2-yl) piperidin-1-yl) methyl) imidazo [1,2-a ] pyridine-3, 6-dicarboxylic acid
Reacting 6- (tert-butoxycarbonyl) -2- ((4- (6- ((4-chloro-2-fluorobenzyl) oxy) pyridin-2-yl) piperidin-1-yl) methyl) imidazo [1,2-a]Pyridine-3-carboxylic acid (30mg, 0.05mmol) was dissolved in 20% trifluoroacetic acid in dichloromethane (1.2 mL) and the mixture was stirred at room temperature overnight; after LC-MS monitors that the raw material is completely converted, directly concentrating, then adding acetonitrile, and freeze-drying to obtain yellow solid 28.1mg with yield>99％。 1 H NMR(500MHz, DMSO-d 6 )δ9.96(s,1H),8.01(d,J＝10.0Hz,1H),7.91(d,J＝9.5Hz,1H),7.70(t,J＝7.5Hz,1H),7.62(t,J＝ 8.5Hz,1H),7.50(d,J＝10.0Hz,1H),7.34(d,J＝7.5Hz,1H),6.91(d,J＝7.0Hz,1H),6.75(d,J＝9.0Hz,1H), 5.41(s,2H),4.84(s,2H),3.30(br,4H),2.93(br,1H),2.01(br,4H)。
Example 30- ((4- (6- ((4-chloro-2-fluorobenzyl) oxy) pyridin-2-yl) piperidin-1-yl) methyl) -4- ((1-ethyl-1H-imidazol-5-yl) methyl) -4H-thieno [3,2-b ] pyrrole-2-carboxylic acid
Figure BDA0003128505470000681
Step 1) 5-methylthiophene-2-carboxylic acid methyl ester
5-methyl-2-thiophenecarboxylic acid (15g, 105.6 mmol) was dissolved in methanol (150 mL), sulfuric acid (3 mL) was added, and the mixture was warmed to 90 ℃ and reacted overnight. The reaction was stopped, cooled to room temperature, concentrated under reduced pressure to remove methanol, water (100 mL), extracted with ethyl acetate (50ml × 3), the organic phases combined, washed successively with 5% sodium hydroxide solution (50ml × 2), saturated brine, dried over anhydrous sulfuric acid, filtered, and concentrated under reduced pressure to give 15.2g of a yellow oily product in 92% yield.
Step 2) 5-methyl-4-nitrothiophene-2-carboxylic acid methyl ester
Dissolving 5-methylthiophene-2-carboxylic acid methyl ester (15.2g, 97.4 mmol) in sulfuric acid (34 mL), cooling the mixture to 0 ℃, dropwise adding a sulfuric acid solution of nitric acid (8.2 mL of nitric acid is dissolved in 23mL of sulfuric acid), reacting for 1 hour, slowly pouring the reaction solution into ice water (400 mL), extracting with ethyl acetate (3X 200mL), combining organic phases, washing with saturated common salt water, drying with anhydrous sodium sulfate, concentrating under reduced pressure, and purifying the residue by column chromatography to obtain a light yellow solid product 8.3g with the yield of 39%.
Step 3) 5- (2- (dimethylamino) prop-1-en-1-yl) -4-nitrothiophene-2-carboxylic acid methyl ester
Methyl 5-methyl-4-nitrothiophene-2-carboxylate (7.1g, 35.3mmol) was dissolved in N, N-dimethylacetamide (35 mL), 1-dimethoxy-N, N-dimethylethylamine (7.05g, 52.95mmol) was added, and the mixture was heated at 100 ℃ for 1 hour. The reaction is stopped, the reaction is cooled to room temperature, a large amount of solid is separated out, the reaction product is filtered, filter residue is washed by ethyl acetate and dried, and brick red solid products 5.1g are obtained, and the yield is 53%.
Step 4) 5-methyl-4H-thieno [3,2-b ] pyrrole-2-carboxylic acid methyl ester
Methyl 5- (2- (dimethylamino) prop-1-en-1-yl) -4-nitrothiophene-2-carboxylate (5.1g, 18.87mmol) was dissolved in methanol (100 mL), iron powder (5.27g, 94.35mmol), ammonium chloride (2.02g, 37.74mmol) and water (30 mL) were added, and the mixture was warmed to 60 ℃ and reacted overnight. The reaction was stopped, cooled to room temperature, filtered to remove insoluble matter, concentrated under reduced pressure to remove methanol, extracted with ethyl acetate (3 × 50ml), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography to give a pale yellow solid product 1.66g with a yield of 45%.
Step 5) methyl 4- (tert-Butoxycarbonyl) -5-methyl-4H-thieno [3,2-b ] pyrrole-2-carboxylate
Reacting 5-methyl-4H-thieno [3,2-b ]]Pyrrole-2-carboxylic acid methyl ester (500mg, 2.56mmol) was dissolved in THF (10 mL), triethylamine (518 mg, 5.12mmol), (Boc) 2 O (1.12g, 5.12mmol) and DMAP (312mg, 2.56mmol) were mixed and the mixture was heated to 50 ℃ to react for 4 hours, the reaction was stopped, concentrated under reduced pressure, and the residue was purified by column chromatography to give 530mg of a pale yellow solid product with a yield of 70%.
Step 6) methyl 4- (tert-Butoxycarbonyl) -5- (bromomethyl) -4H-thieno [3,2-b ] pyrrole-2-carboxylate
Methyl 4- (tert-butoxycarbonyl) -5-methyl-4H-thieno [3,2-b ] pyrrole-2-carboxylate (200mg, 0.68mmol) was dissolved in carbon tetrachloride (4 mL), N-bromosuccinimide (145mg, 0.81mmol) and azobisisobutyronitrile (11mg, 0.068mmol) were added, and the mixture was heated to 50 ℃ for reaction for 2.5 hours. The reaction was stopped and concentrated under reduced pressure to give 400mg of crude yellow solid product which was used directly in the next reaction.
Step 7) methyl 4- (tert-Butoxycarbonyl) -5- ((4- (6- ((4-chloro-2-fluorobenzyl) oxy) pyridin-2-yl) piperidin-1-yl) methyl) -4H-thieno [3,2-b ] pyrrole-2-carboxylate
Methyl 4- (tert-butoxycarbonyl) -5- (bromomethyl) -4H-thieno [3,2-b ] pyrrole-2-carboxylate (400 mg, crude, 0.68 mmol), intermediate 11 trifluoroacetate (600mg, 0.75mmol), potassium carbonate (376 mg, 2.72mmol) were placed in a 48 mL sealed tube, acetonitrile (15 mL) was added, and the reaction was allowed to warm to 60 ℃ overnight. The reaction was stopped, water (15 mL) was added, ethyl acetate (15ml × 3) was extracted, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to give 200mg of a light brown oily product with a yield of 48%.
Step 8) methyl 5- ((4- (6- ((4-chloro-2-fluorobenzyl) oxy) pyridin-2-yl) piperidin-1-yl) methyl) -4H-thieno [3,2-b ] pyrrole-2-carboxylate methyl 4- (tert-butoxycarbonyl) -5- ((4- (6- ((4-chloro-2-fluorobenzyl) oxy) pyridin-2-yl) piperidin-1-yl) methyl) -4H-thieno [3,2-b ] pyrrole-2-carboxylate (200mg, 0.326mmol) was dissolved in dichloromethane (10 mL), trifluoroacetic acid (3 mL) was added and the mixture was stirred at room temperature overnight. The reaction was stopped, concentrated under reduced pressure, dissolved in ethyl acetate (10 mL), washed with saturated sodium bicarbonate (10 mL), the aqueous phase was extracted with ethyl acetate (2 × 10ml), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 189 mg of a light brown oily product with a yield of >99%.
Step 9) methyl 5- ((4- (6- ((4-chloro-2-fluorobenzyl) oxy) pyridin-2-yl) piperidin-1-yl) methyl) -4- ((1-ethyl-1H-imidazol-5-yl) methyl) -4H-thieno [3,2-b ] pyrrole-2-carboxylate
Methyl 5- ((4- (6- ((4-chloro-2-fluorobenzyl) oxy) pyridin-2-yl) piperidin-1-yl) methyl) -4H-thieno [3,2-b ] pyrrole-2-carboxylate (180 mg, 0.35mmol) was dissolved in N, N-dimethylformamide (5 mL), cesium carbonate (342mg, 1.05mmol) and 1-ethyl-5 chloromethylimidazole (82.4mg, 0.455mmol) were added and the mixture was warmed to 100 ℃ for reaction overnight. The reaction was stopped, concentrated under reduced pressure and the residue was purified by column chromatography to give 25mg of the product in 11% yield.
Step 10) 5- ((4- (6- ((4-chloro-2-fluorobenzyl) oxy) pyridin-2-yl) piperidin-1-yl) methyl) -4- ((1-ethyl-1H-imidazol-5-yl) methyl) -4H-thieno [3,2-b ] pyrrole-2-carboxylic acid
Reacting 5- ((4- (6- ((4-chloro-2-fluorobenzyl) oxy) pyridin-2-yl) piperidin-1-yl) methyl) -4- ((1-ethyl-1H-imidazol-5-yl) methyl) -4H-thieno [3,2-b]Pyrrole-2-carboxylic acid methyl ester (25mg, 0.04mmol) was dissolved in MeOH (1.5 mL), and 1N aqueous sodium hydroxide (0.5 mL) was added to react overnight. Stopping the reaction, concentrating under reduced pressure to remove the solvent, adding water (2 mL), adjusting pH to about 6 with 1N dilute hydrochloric acid, andextracting with ethyl acetate (5 mL × 3), mixing organic phases, washing with saturated salt water, drying with anhydrous sodium sulfate, concentrating under reduced pressure, adding ethyl acetate (5 mL) to dissolve, filtering to remove insoluble substances, concentrating under reduced pressure, and lyophilizing to obtain a white-like solid product 14mg with a yield of 58%. LCMS [ M + H ]] + :608.2。 1 H NMR(500 MHz,MeOH-d 4 )δ7.83(s,1H),7.60(t,J＝7.8Hz,1H),7.48(t,J＝8.0Hz,1H),7.31(s,1H),7.20(ddd,J＝11.0, 9.1,2.0Hz,2H),6.85(d,J＝7.3Hz,1H),6.81(s,1H),6.67(d,J＝8.2Hz,1H),6.55(s,1H),5.56(s,2H),5.40(s, 2H),4.00(s,2H),3.97(q,J＝7.3Hz,2H),3.32(s,0H),2.78(p,J＝7.7Hz,1H),2.57(s,2H),1.98(q,J＝7.4,6.7 Hz,4H),1.15(t,J＝7.3Hz,3H)。
Example 31- ((4- (6- ((4-chloro-2-fluorobenzyl) oxy) pyridin-2-yl) piperidin-1-yl) methyl) -3- (oxetan-3-ylcarbamoyl) imidazo [1,2-a ] pyridine-6-carboxylic acid
Figure BDA0003128505470000701
Reacting 6- (tert-butoxycarbonyl) -2- ((4- (6- ((4-chloro-2-fluorobenzyl) oxy) pyridin-2-yl) piperidin-1-yl) methyl) imidazo [1,2-a]Pyridine-3-carboxylic acid (60mg, 0.1mmol), 3-azetidine (14.6 mg, 0.2mmol), HATU (42mg, 0.11mmol), triethylamine (20 mg,0.2 mmol) and dichloromethane (2 mL) were placed in a 5mL sample vial, and the mixture was stirred at room temperature overnight. The solvent was evaporated by concentration under reduced pressure, and the obtained residue was purified by column chromatography to give 35mg of an intermediate product. The intermediate was then dissolved in a mixture of methanol (3 mL) and water (1 mL), lithium hydroxide (20 mg) was added, the mixture was stirred at 60 ℃ overnight, most of the methanol was removed under reduced pressure, 5mL of water was added, the pH was adjusted to between 5 and 6, and a precipitate precipitated, filtered, and dried to give 30mg of the product as a white solid in 50% yield over two steps. LCMS (liquid Crystal display Module) [ M + H ] ] + :594.2. The purity is 95%. 1 H NMR(500MHz,CD 3 OD)δ11.62(s,1H),10.11(s,1H),7.85–7.83(m,1H),7.73(d,J＝3.0Hz, 1H),7.65(t,J＝6.0Hz,1H),7.55(t,J＝8.0Hz,1H),7.48–7.46(m,2H),7.23–7.30(m,1H),6.90(d,J＝5.0 Hz,1H),6.68(d,J＝5.0Hz,1H),5.34(s,2H),5.22–5.18(m,1H),4.90(t,J＝5.0Hz,2H),4.63(t,J＝5.0Hz, 2H),4.06–4.02(m,1H),3.95(s,2H),3.08(d,J＝5.8Hz,2H),2.77–2.73(m,1H),2.34–2.29(m,2H),1.95– 1.89(m,4H)。
Example 32- ((4- (4- ((4-chloro-2-fluorobenzyl) oxy) -5-fluoropyrimidin-2-yl) piperazin-1-yl) methyl) -3- (3-hydroxyazetidiyl-1-carbonyl) imidazo [1,2-a ] pyridine-6-carboxylic acid
Figure BDA0003128505470000702
Step 1) tert-butyl 2- ((4- (4- ((4-chloro-2-fluorobenzyl) oxy) -5-fluoropyrimidin-2-yl) piperazin-1-yl) methyl) -3- (ethoxycarbonyl) imidazo [1,2-a ] pyridine-6-carboxylate
Tert-butyl 2- (chloromethyl) -3- (ethoxycarbonyl) -imidazo [1,2-a ] pyridine-6-carboxylate (50mg, 0.15mmol) and intermediate 6 (0.6 g, 2.7 mmol) were dissolved in acetonitrile (2 mL), triethylamine (45mg, 0.4 mmol) was added, the mixture was stirred at 60 ℃ overnight to terminate the reaction, and the residue was directly purified by column chromatography to give 60mg of a white solid product in 4% yield.
Step 2) 6- (tert-Butoxycarbonyl) -2- ((4- (4- ((4-chloro-2-fluorobenzyl) oxy) -5-fluoropyrimidin-2-yl) piperazin-1-yl) methyl) -3- (ethoxycarbonyl) imidazo [1,2-a ] pyridine-3-carboxylic acid
Tert-butyl 2- ((4- (4- ((4-chloro-2-fluorobenzyl) oxy) -5-fluoropyrimidin-2-yl) piperazin-1-yl) methyl) -3- (ethoxycarbonyl) imidazo [1,2-a ] pyridine-6-carboxylate (90mg, 0.14mmol) is dissolved in a mixture of ethanol (4 mL) and water (1 mL), and the mixture is stirred at 60 ℃ for 24h. Cooled to room temperature, concentrated under reduced pressure, and the residue purified by column chromatography to give 50mg of a white solid product in 57% yield.
Step 3) 2- ((4- (4- ((4-chloro-2-fluorobenzyl) oxy) -5-fluoropyrimidin-2-yl) piperazin-1-yl) methyl) -3- (3-hydroxyazetidiyl-1-carbonyl) imidazo [1,2-a ] pyridine-6-carboxylic acid
Reacting 6- (tert-butoxycarbonyl) -2- ((4- (4- ((4-chloro-2-fluorobenzyl) oxy) -5-fluoropyrimidin-2-yl) piperazin-1-yl) methyl) -3- (ethoxycarbonyl) imidazo [1,2-a]Pyridine-3-carboxylic acid (40mg, 0.065mmol), azetidine-3-ol hydrochloride (11mg, 0.1mmol), HATU (38 mg, 0).1 mmol), triethylamine and dichloromethane (2 mL) were placed in a 5mL sample bottle and the mixture was stirred at room temperature overnight. After the reaction was stopped, the residue was directly purified by column chromatography to give 35mg of an intermediate product. The intermediate was then dissolved in a mixture of methanol (3 mL) and water (1 mL), lithium hydroxide (11 mg) was added, the mixture was stirred at 60 ℃ overnight, concentrated under reduced pressure, water (5 mL) was added, the pH adjusted to between 5 and 6, and the precipitate precipitated, filtered, and dried to give 15mg of the product as a white solid in 38% yield. LCMS (liquid Crystal display Module) [ M + H ]] + :614.2. The purity is 95%. 1 HNMR(500MHz,CD 3 OD)δ9.21(s,1H),8.04(d,J＝3.0Hz,1H),8.01–7.99(m,1H),7.67(d,J＝9.4 Hz,1H),7.52(t,J＝8.1Hz,1H),7.29–7.25(m,2H),5.49(s,2H),4.72–4.67(m,1H),4.46–4.43(m,2H),4.10 (s,2H),4.05–4.02(m,2H),3.87–3.84(m,4H),2.85–2.84(m,4H)。
Example 33 monoethyl (2- ((4- (6- ((4-chloro-2-fluorobenzyl) oxy) pyridin-2-yl) piperidin-1-yl) methyl) -1- ((1-ethyl-1H-imidazol-5-yl) methyl) -1H-thieno [2,3-d ] imidazol-5-yl) phosphate
Figure BDA0003128505470000711
Step 1) 5-bromothiophene-2-phosphoric acid diethyl ester
Palladium acetate (231mg, 0.987 mmol), 1' -bis (diphenylphosphino) ferrocene (1.09g, 1.97mmol) and potassium acetate (426 mg, 4.41 mmol) were placed in a 25 mL two-necked flask, tetrahydrofuran (100 mL) and triethylamine (4.79g, 47.46mmol) were added, the mixture was allowed to react under nitrogen at 68 ℃ for 25 minutes, 2, 5-dibromothiophene (10.5g, 43.47mmol) and diethyl phosphite (5.46 g, 39.48 mmol) were added, and the mixture was allowed to react overnight. The reaction was stopped, cooled to room temperature, water (100 mL) was added, extraction was performed with ethyl acetate (100ml × 3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography to give 3.7g of a yellow cloudy product, yield 11%.
Step 2) 5-bromo-4-nitrothiophene-2-phosphoric acid diethyl ester
5-bromothiophene-2-phosphoric acid diethyl ester (3.7g, 12.32mmol) was dissolved in concentrated sulfuric acid (16.5 mL), the mixture was cooled to 0 deg.C, nitric acid (5.5mL, 65%) was added dropwise, the reaction was carried out for 0.5 hour, TLC showed disappearance of the starting material, and the reaction was stopped. The reaction solution was poured into ice water (50 mL), extracted with ethyl acetate (50ml × 3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography to give 3.24g of a pale yellow oily product in 77% yield.
Step 3) 5- ((2, 4-dimethoxybenzyl) amino) -4-nitrothiophene-2-phosphoric acid diethyl ester
Diethyl 5-bromo-4-nitrothiophene-2-phosphate (3.24g, 9.42mmol) was dissolved in acetonitrile (40 mL), potassium carbonate (3.9g, 28.26 mmol) and 2, 4-dimethoxybenzylamine (2.05g, 12.24mmol) were added, and the mixture was allowed to warm to 50 ℃ for reaction for 4 hours, and then allowed to react at room temperature overnight. TLC showed the starting material disappeared, the reaction was stopped, water (30 mL) was added, ethyl acetate (30ml × 3) was extracted, the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 5g of crude product as a yellowish brown oil.
Step 4) 5- (diethoxyphosphonyl) -3-nitrothiophene-2-carbamic acid tert-butyl ester
Dissolving 5- ((2, 4-dimethoxybenzyl) amino) -4-nitrothiophene-2-phosphoric acid diethyl ester (5g, 9.42mmol) in dichloromethane (20 mL), adding trifluoroacetic acid (3 mL), reacting the mixture at room temperature for 7 hours, TLC shows disappearance of the raw material, concentrating under reduced pressure to obtain a crude product, adding (Boc) 2 O (4.1 g, 18.84mmol), triethylamine (4.76g, 47.1mmol), DMAP (346mg, 2.83mmol) and tetrahydrofuran (50 mL), and the mixture was stirred at room temperature overnight. Stopping reaction, adding water (50 mL), extracting with ethyl acetate (50mL × 3), combining organic phases, washing with saturated brine, drying over anhydrous sodium sulfate, concentrating under reduced pressure, and purifying the residue by column chromatography to obtain pale yellow solid product 3.42g, yield >99％。
Step 5) 3-amino-5- (diethoxy) phosphonothiophene-2-carbamic acid tert-butyl ester
5- (diethoxyphosphonyl) -3-nitrothiophene-2-carbamic acid tert-butyl ester (1.4 g, 3.68mmol) was dissolved in ethanol, raney nickel (200 mg) was added, the mixture was replaced 3 times with hydrogen, and the mixture was reacted for 4.5 hours under hydrogen balloon protection. The reaction was stopped, insoluble matter was removed by filtration, and the reaction mixture was concentrated under reduced pressure to give 1.2g of a brown solid product in a yield of 93%.
Step 6) tert-butyl 5- (diethoxyphosphonyl) -3- (((1-ethyl-1H-imidazol-5-yl) methyl) amino) thiophene-2-carbamate
3-amino-5- (diethoxy) phosphonothiophene-2-carbamic acid tert-butyl ester (1.2g, 3.42mmol) was dissolved in acetonitrile, and 1-ethyl-5-chloromethylimidazolyl hydrochloride (744mg, 4.11mmol) and diisopropylethylamine (1.76g, 13.68mmol) were added, and the mixture was reacted at room temperature overnight. The reaction was stopped, water (20 mL) was added, extraction was performed with ethyl acetate (20ml × 3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, the solvent was concentrated under reduced pressure, and the residue was purified by column chromatography to give a crude product as pale yellow oil, 1.4g, in 89% yield.
Step 7) (2- (chloromethyl) -1- ((1-ethyl-1H-imidazol-5-yl) methyl) -1H-thieno [2,3-d ] imidazol-5-yl) phosphoric acid diethyl ester
Tert-butyl 5- (diethoxyphosphonyl) -3- (((1-ethyl-1H-imidazol-5-yl) methyl) amino) thiophene-2-carbamate (700mg, 1.53 mmol) was dissolved in dichloromethane (70 mL), trifluoroacetic acid (3 mL) and 2-chloro-1, 1-trimethoxyethane (945mg, 6.11mmol) were added, and the mixture was stirred at room temperature overnight. Vacuum concentrating to obtain crude product, and purifying by column chromatography to obtain product 300mg with yield of 47%.
Step 8) diethyl 2- ((4- (6- ((4-chloro-2-fluorobenzyl) oxy) pyridin-2-yl) piperidin-1-yl) methyl) -1- ((1-ethyl-1H-imidazol-5-yl) methyl) -1H-thieno [2,3-d ] imidazol-5-yl) phosphate
Diethyl (2- (chloromethyl) -1- ((1-ethyl-1H-imidazol-5-yl) methyl) -1H-thieno [2,3-d ] imidazol-5-yl) phosphate (190mg, 0.45 mmol) was dissolved in acetonitrile (5 mL), potassium carbonate (248mg, 1.8mmol) and the trifluoroacetate salt of intermediate 11 (236mg, 0.54mmol) were added, and the mixture was warmed to 70 ℃ for overnight reaction. The reaction was stopped, insoluble material was removed by filtration, concentrated under reduced pressure, and the residue was purified by column chromatography to give 100mg of the product in 32% yield.
Step 9) monoethyl 2- ((4- (6- ((4-chloro-2-fluorobenzyl) oxy) pyridin-2-yl) piperidin-1-yl) methyl) -1- ((1-ethyl-1H-imidazol-5-yl) methyl) -1H-thieno [2,3-d ] imidazol-5-yl) phosphate
Will (2-((4- (6- ((4-chloro-2-fluorobenzyl) oxy) pyridin-2-yl) piperidin-1-yl) methyl) -1- ((1-ethyl-1H-imidazol-5-yl) methyl) -1H-thieno [2,3-d]Imidazol-5-yl) phosphoric acid diethyl ester (30mg, 0.043 mmol) was dissolved in ethanol (1.5 mL), 1N sodium hydroxide (1 mL) was added, and the mixture was reacted at room temperature for 2 days, and then heated to 70 ℃ for overnight reaction. TLC showed disappearance of the starting material, reaction was stopped, solvent was removed by concentration under reduced pressure, water (2 mL) was added, pH was adjusted to about 5 with 1N diluted hydrochloric acid, ethyl acetate (2mL. Times.3) was extracted, the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure to give a crude product, which was dissolved by addition of ethyl acetate (10 mL), filtered to remove insoluble matter, concentrated under reduced pressure, and lyophilized to give 13.6mg of beige solid product in 43% yield. Purity: 94 percent. LCMS (liquid Crystal display Module) [ M + H ]] + :673.1。 1 HNMR(500MHz,MeOH-d 4 )δ7.78(s,1H),7.59 (t,J＝7.8Hz,1H),7.50(t,J＝8.0Hz,1H),7.30–7.16(m,2H),7.04(s,1H),6.96(d,J＝8.1Hz,1H),6.83(d,J ＝7.3Hz,1H),6.65(d,J＝8.2Hz,1H),5.67(s,2H),5.43(s,2H),4.01(q,J＝7.3Hz,2H),3.81(q,J＝7.3Hz, 4H),3.02(d,J＝11.3Hz,2H),2.66(s,1H),2.32–2.24(m,2H),1.91–1.77(m,4H),1.16(dt,J＝12.6,7.1Hz, 6H)。
Example 34 Ethyl (S) -2- ((4- (6- (4-chloro-2-fluorobenzyloxy) pyridin-2-yl) piperidin-1-yl) methyl) -1- (oxetan-2-ylmethyl) -1H-thieno [2,3-d ] imidazole-5-carboxylate
Figure BDA0003128505470000721
Intermediate 11 trifluoroacetate salt (360mg, 1.01mmol) is dissolved in acetonitrile (10 mL), potassium carbonate (558mg, 1.46mmol) is added, the mixture is stirred at room temperature for 10 minutes, and (S) -2- (chloromethyl) -1- (oxetan-2-ylmethyl) -1H-thieno [2,3-d ] is added]Imidazole-5-carboxylic acid ethyl ester (400mg, 1.01mmol) was reacted overnight at 50 ℃. The reaction was stopped, cooled to room temperature, 5mL of water was added, extraction was performed with ethyl acetate (10 mL × 3), washing was performed with saturated brine, drying was performed with anhydrous sodium sulfate, concentration was performed under reduced pressure, and the residue was purified by column chromatography to give 230mg of a light brown oily product with a yield of 38%. 1 H NMR(500MHz,MeOH-d 4 )δ7.89(s,1H),7.59(t,J＝7.8Hz,1H),7.51(t,J＝8.1Hz,1H),7.22 (ddd,J＝15.1,8.9,2.0Hz,2H),6.84(d,J＝7.4Hz,1H),6.65(d,J＝8.2Hz,1H),5.44(s,2H),5.30–5.22(m, 1H),4.74(dd,J＝15.1,6.9Hz,1H),4.63(td,J＝15.1,13.3,4.8Hz,2H),4.46(dt,J＝9.4,6.0Hz,1H),4.37(q,J ＝7.1Hz,2H),3.94–3.75(m,2H),3.04(d,J＝11.3Hz,1H),2.95(d,J＝11.4Hz,1H),2.80(dq,J＝11.8,7.7Hz, 1H),2.70–2.61(m,1H),2.57–2.47(m,1H),2.33–2.20(m,2H),1.91–1.82(m,4H),1.39(t,J＝7.1Hz,3H)。
Example 35 (S) -2- ((4- (6- (4-chloro-2-fluorobenzyloxy) pyridin-2-yl) piperidin-1-yl) methyl) -1- (oxetan-2-ylmethyl) -1H-thieno [2,3-d ] imidazole-5-carboxylic acid
Figure BDA0003128505470000731
Reacting (S) -2- ((4- (6- (4-chloro-2-fluorobenzyloxy) pyridin-2-yl) piperidin-1-yl) methyl) -1- (oxetan-2-ylmethyl) -1H-thieno [2,3-d]Ethyl imidazole-5-carboxylate (230mg, 0.384mmol) was dissolved in ethanol (3 mL), 1N sodium hydroxide (1 mL) was added, and the mixture was reacted at room temperature overnight. Stopping reaction, concentrating under reduced pressure to remove ethanol, adding 1N trifluoroacetic acid to adjust pH to be about 6, extracting with ethyl acetate (5 mL x 3), drying with anhydrous sodium sulfate, concentrating under reduced pressure to obtain crude product, adding ethyl acetate (10 mL) to dissolve product, filtering to remove insoluble substance, concentrating under reduced pressure, and lyophilizing to obtain white solid product 152mg with yield of 69%. Purity 97%, LCMS [ M + H ]] + :571.0。 1 H NMR(500MHz,MeOH-d 4 )δ7.64 –7.58(m,2H),7.50(t,J＝8.0Hz,1H),7.21(ddd,J＝12.2,8.8,2.0Hz,2H),6.87(d,J＝7.3Hz,1H),6.68(d,J ＝8.2Hz,1H),5.42(s,2H),5.22(dd,J＝7.2,2.6Hz,1H),4.73–4.62(m,2H),4.59(dd,J＝15.3,2.7Hz,1H), 4.43(dt,J＝9.3,5.9Hz,1H),4.27(d,J＝2.6Hz,2H),3.46(dd,J＝27.6,11.9Hz,2H),2.88–2.75(m,4H),2.56 –2.45(m,1H),2.03(q,J＝8.4,6.9Hz,4H)。
Example 36 (2- ((4- (6- ((4-chloro-2-fluorobenzyl) oxy) pyridin-2-yl) piperidin-1-yl) methyl) -1- ((1-ethyl-1H-imidazol-5-yl) methyl) -1H-thieno [2,3-d ] imidazol-5-yl) diammonium phosphate
Figure BDA0003128505470000732
Reacting (2- ((4- (6- ((4-chloro-2-fluorobenzyl) oxy) pyridin-2-yl) piperidin-1-yl) methyl) -1- ((1-ethyl-1H-imidazol-5-yl) methyl) -1H-thieno [2,3-d]Imidazol-5-yl) phosphoric acid diethyl ester (30mg, 0.043 mmol) was dissolved in hydrobromic acid-acetic acid (1.5ml, 33%), and the mixture was reacted at room temperature for 2 days. The reaction was stopped, the solvent was removed by concentration under reduced pressure, water (1 mL) was added to dissolve it, preparative separation and purification, concentration, addition of 0.5 mL of ammonia water, lyophilization to give an off-white solid product 10.0mg, yield 34%. Purity: 94%, LCMS [ M-H ] ] - :677.2。
Example 37 (S) -2- ((4- (6- ((4-cyano-2-fluorobenzyl) oxy) pyridin-2-yl) piperidin-1-yl) methyl) -1- (oxetan-2-ylmethyl) -1H-thieno [2,3-d ] imidazole-5-carboxylic acid
Figure BDA0003128505470000733
Step 1) Ethyl (S) -2- ((4- (6- ((4-cyano-2-fluorobenzyl) oxy) pyridin-2-yl) piperidin-1-yl) methyl) -1- (oxetan-2-ylmethyl) -1H-thieno [2,3-d ] imidazole-5-carboxylate
Intermediate 1, trifluoroacetate (68mg, 0.197mmol), is dissolved in acetonitrile (5 mL), potassium carbonate (110mg, 0.8mmol) is added followed by ethyl (S) -2- (chloromethyl) -1- (oxetan-2-ylmethyl) -1H-thieno [2,3-d ] imidazole-5-carboxylate (100mg, 0.197mmol), and the mixture is warmed to 70 ℃ for 4H. The reaction was stopped, cooled to room temperature, 5mL of water was added, extracted with ethyl acetate (3 × 10ml), washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by preparative TLC to give 37mg of a light brown oily product in a yield of 32%.
Step 2) (S) -2- ((4- (6- ((4-cyano-2-fluorobenzyl) oxy) pyridin-2-yl) piperidin-1-yl) methyl) -1- (oxetan-2-ylmethyl) -1H-thieno [2,3-d ] imidazole-5-carboxylic acid
Reacting (S) -2- ((4- (6- ((4-cyano-2-fluorobenzyl) oxy) pyridin-2-yl) piperidin-1-yl) methyl) -1- (oxetan-2-ylmethyl) -1H-thieno [2,3-d ]Imidazole-5-carboxylic acid ethyl ester(37mg, 0.063mmol) was dissolved in acetonitrile (1 mL), DBU (19.2mg, 0.126mmol) was added, and the mixture was allowed to warm up overnight. Stopping reaction, concentrating under reduced pressure to remove acetonitrile, adding 10% trifluoroacetic acid to adjust the pH value to be about 5-6, extracting with ethyl acetate (5 mL x 3), combining organic phases, drying with anhydrous sodium sulfate, concentrating under reduced pressure to obtain a crude product, purifying the residue by preparative TLC, and lyophilizing to obtain a white-like solid product 15mg with the yield of 42%. 91% purity, LCMS [ M + H ]] + :562.2。 1 H NMR(500MHz,MeOH-d 4 )δ7.69 (t,J＝7.6Hz,1H),7.65–7.60(m,2H),7.59–7.54(m,2H),6.88(d,J＝7.3Hz,1H),6.72(d,J＝8.2Hz,1H), 5.54(s,2H),5.28–5.21(m,1H),4.68(td,J＝16.6,16.0,6.9Hz,2H),4.60(dd,J＝15.2,2.7Hz,1H),4.45(q,J ＝6.8,6.4Hz,1H),4.13(d,J＝3.9Hz,2H),3.37(d,J＝8.0Hz,1H),3.26(d,J＝11.9Hz,1H),2.79(dd,J＝17.5, 9.3Hz,2H),2.65(d,J＝26.0Hz,2H),2.55–2.48(m,1H),1.94(s,4H)。
Example 38- ((4- (4- ((4-chloro-2-fluorobenzyl) oxy) -5-fluoropyrimidin-2-yl) piperazin-1-yl) methyl) -3- ((3-hydroxyazetidin-1-yl) methyl) imidazo [1,2-a ] pyridine-6-carboxylic acid
Figure BDA0003128505470000741
Step 1) methyl 2- ((4- (4- ((4-chloro-2-fluorobenzyl) oxy) -5-fluoropyrimidin-2-yl) piperazin-1-yl) methyl) imidazo [1,2-a ] pyridine-6-carboxylate
Methyl 2- (chloromethyl) imidazo [1,2-a ] pyridine-6-carboxylate (0.9g, 4mmol) and intermediate 6 (1.5g, 4mmol) were dissolved in anhydrous acetonitrile (25 mL), triethylamine (2 mL) was added, and the mixture was stirred at 115 ℃ for 3 hours, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography to give 1.5g of a yellow solid product in 71% yield.
Step 2) methyl 2- ((4- (4- ((4-chloro-2-fluorobenzyl) oxy) -5-fluoropyrimidin-2-yl) piperazin-1-yl) methyl) -3- (hydroxymethyl) imidazo [1,2-a ] pyridine-6-carboxylate
Methyl 2- ((4- (4- ((4-chloro-2-fluorobenzyl) oxy) -5-fluoropyrimidin-2-yl) piperazin-1-yl) methyl) imidazo [1,2-a ] pyridine-6-carboxylate (1.5 g, 2.8 mmol) is dissolved in aqueous formaldehyde (20 mL) and acetic acid (2 mL), the mixture is stirred at 100 ℃ overnight, the solvent is evaporated under reduced pressure, and the residue is purified by column chromatography to give 800m g of a yellow oily product in 51% yield.
Step 3) methyl 2- ((4- (4- ((4-chloro-2-fluorobenzyl) oxy) -5-fluoropyrimidin-2-yl) piperazin-1-yl) methyl) -3- (((methylsulfonyl) oxy) methyl) imidazo [1,2-a ] pyridine-6-carboxylate
Methyl 2- ((4- (4- ((4-chloro-2-fluorobenzyl) oxy) -5-fluoropyrimidin-2-yl) piperazin-1-yl) methyl) -3- (hydroxymethyl) imidazo [1,2-a ] pyridine-6-carboxylate (800mg, 1.4 mmol) and triethylamine (0.4ml, 2.8mmol) are dissolved in dry dichloromethane (20 mL), cooled to-40 ℃, methanesulfonyl chloride (220mg, 2.0mmol) is added dropwise, and after completion of dropwise addition, the mixture is slowly warmed to room temperature and stirred for reaction overnight. The solvent was evaporated by concentration under reduced pressure and the residue was purified by column chromatography to give 280mg of the product in 31% yield.
Step 4) methyl 2- ((4- (4- ((4-chloro-2-fluorobenzyl) oxy) -5-fluoropyrimidin-2-yl) piperazin-1-yl) methyl) -3- ((3-hydroxyazetidin-1-yl) methyl) imidazo [1,2-a ] pyridine-6-carboxylate
Methyl 2- ((4- (4- ((4-chloro-2-fluorobenzyl) oxy) -5-fluoropyrimidin-2-yl) piperazin-1-yl) methyl) -3- (((methylsulfonyl) oxy) methyl) imidazo [1,2-a ] pyridine-6-carboxylate (64mg, 0.1mmol) and azetidin-3-ol (22mg, 0.3mmol) are dissolved in acetonitrile (2 mL), triethylamine (40mg, 0.4mmol) is added, and the mixture is stirred at 90 ℃ for 2.5h. The solvent was evaporated by concentration under reduced pressure, and the residue was purified by column chromatography to give 38mg of a product with a yield of 62%.
Step 5) 2- ((4- (4- ((4-chloro-2-fluorobenzyl) oxy) -5-fluoropyrimidin-2-yl) piperazin-1-yl) methyl) -3- ((3-hydroxyazetidin-1-yl) methyl) imidazo [1,2-a ] pyridine-6-carboxylic acid
Reacting 2- ((4- (4- ((4-chloro-2-fluorobenzyl) oxy) -5-fluoropyrimidin-2-yl) piperazin-1-yl) methyl) -3- ((3-hydroxyazetidin-1-yl) methyl) imidazo [1,2-a]Pyridine-6-carboxylic acid methyl ester (35mg, 0.057 mmol) was dissolved in methanol (3 mL) and water (1 mL), lithium hydroxide (6.3mg, 0.22mmol) was added, and the mixture was stirred at 30 ℃ for 2h. Adjusting pH to about 6 with dilute hydrochloric acid, evaporating under reduced pressure to remove most of methanol, precipitating a large amount of precipitate, adding water(2 mL), filtered and dried by suction to obtain 20mg of white solid product with the yield of 66%. Purity 98%, LCMS [ M + H ]] + :600.3。 1 H NMR(500MHz,CDCl 3 )δ9.46(s,1H),7.96–7.91(m,2H),7.51(d,J＝5.0Hz,1H),7.41–7.37(m,1H),7.15– 7.08(m,2H),5.40(s,2H),4.87(s,2H),4.67–4.65(m,1H),4.41(s,2H),4.16–4.05(m,4H),3.86(s,4H),3.67 (s,1H),2.95(s,4H)。
Example 39- ((4- (4- ((4-chloro-2-fluorobenzyl) oxy) -5-fluoropyrimidin-2-yl) piperazin-1-yl) methyl) -3- ((oxetan-3-ylamino) methyl) imidazo [1,2-a ] pyridine-6-carboxylic acid
Figure BDA0003128505470000742
Step 1) methyl 2- ((4- (4- ((4-chloro-2-fluorobenzyl) oxy) -5-fluoropyrimidin-2-yl) piperazin-1-yl) methyl) -3- ((oxetan-3-ylamino) methyl) imidazo [1,2-a ] pyridine-6-carboxylate
Methyl 2- ((4- (4- ((4-chloro-2-fluorobenzyl) oxy) -5-fluoropyrimidin-2-yl) piperazin-1-yl) methyl) -3- (((methylsulfonyl) oxy) methyl) imidazo [1,2-a ] pyridine-6-carboxylate (64mg, 0.1mmol) and 3-oxetane (14.6 mg, 0.2mmol) were dissolved in acetonitrile (2 mL), triethylamine (20mg, 0.4mmol) was added, and the mixture was stirred at 90 ℃ for 2.5h. Cooling to room temperature, concentrating under reduced pressure and evaporating to remove the solvent, and purifying the residue by column chromatography to obtain 35mg of the product with a yield of 57%.
Step 2) 2- ((4- (4- ((4-chloro-2-fluorobenzyl) oxy) -5-fluoropyrimidin-2-yl) piperazin-1-yl) methyl) -3- ((oxetan-3-ylamino) methyl) imidazo [1,2-a ] pyridine-6-carboxylic acid
Reacting 2- ((4- (4- ((4-chloro-2-fluorobenzyl) oxy) -5-fluoropyrimidin-2-yl) piperazin-1-yl) methyl) -3- ((oxetan-3-ylamino) methyl) imidazo [1,2-a]Pyridine-6-carboxylic acid methyl ester (35mg, 0.058 mmol) was dissolved in methanol (3 mL) and water (1 mL), lithium hydroxide (6.3 mg, 0.22 mmol) was added, and the mixture was stirred at 30 ℃ for reaction overnight. Adjusting pH to about 6 with dilute hydrochloric acid, concentrating most methanol under reduced pressure to precipitate a large amount of precipitate, adding water (2 mL), filtering, and draining to obtain white solid product 13.8mg with yield of 40%. Purity 97%, LCMS [M+H] + :600.3。 1 HNMR (500MHz,CDCl 3 )δ9.04(s,1H),8.01(d,J＝5.0Hz,1H),7.60(d,J＝5.0Hz,1H),7.50(d,J＝5.0Hz,1H),7.44 (t,J＝5.0Hz,1H),7.18–7.14(m,2H),5.45(s,2H),4.97(t,J＝5.0Hz,2H),4.66(t,J＝5.0Hz,2H),4.30(d,J＝ 5.0Hz,4H),3.92–3.87(m,6H),2.79–2.77(m,4H)。
Example 40 (S) -2- ((4- (6- (4-chloro-2-fluorobenzyloxy) pyridin-2-yl) piperidin-1-yl) methyl) -1- (oxetan-2-ylmethyl) -1H-thieno [2,3-d ] imidazole-5-carboxamide
Figure BDA0003128505470000751
Reacting (S) -2- ((4- (6- (4-chloro-2-fluorobenzyloxy) pyridin-2-yl) piperidin-1-yl) methyl) -1- (oxetan-2-ylmethyl) -1H-thieno [2,3-d]Imidazole-5-carboxylic acid (40mg, 0.07mmol) was dissolved in dichloromethane (1.5 mL), EDCI (24mg, 0.126mmol), HOBt (9 mg,0.07 mol) and aqueous ammonia (3 drops) were added and the mixture was stirred at room temperature for 4 hours. The reaction was stopped, concentrated under reduced pressure, and the residue was purified by preparative TLC and lyophilized to give 15mg of off-white solid product in 38% yield. LCMS (liquid Crystal display Module) [ M + H ]] + :570.2。 1 H NMR(500MHz,MeOH-d 4 )δ7.81(s,1H), 7.59(t,J＝7.8Hz,1H),7.52(d,J＝8.1Hz,1H),7.22(ddd,J＝14.5,9.0,2.0Hz,2H),6.84(d,J＝7.3Hz,1H), 6.65(d,J＝8.2Hz,1H),5.44(d,J＝2.5Hz,2H),5.27(dd,J＝7.2,2.8Hz,1H),4.76–4.58(m,3H),4.48(dt,J＝ 9.4,6.0Hz,1H),3.94–3.73(m,2H),3.05(d,J＝11.4Hz,1H),2.96(d,J＝11.6Hz,1H),2.82(ddd,J＝11.9,5.9, 2.9Hz,1H),2.65(p,J＝8.0Hz,1H),2.53(dq,J＝11.3,7.5Hz,1H),2.34–2.22(m,2H),1.90–1.80(m,4H)。
Example 41 (S) -2- ((4- (3- ((4-chloro-2-fluorobenzyl) oxy) phenyl) -3, 6-dihydropyridin-1 (2H) -yl) methyl) -1- (oxetan-2-ylmethyl) -1H-thieno [2,3-d ] imidazole-5-carboxylic acid
Figure BDA0003128505470000752
Step 1) Ethyl (S) -2- ((4- (3- ((4-chloro-2-fluorobenzyl) oxy) phenyl) -3, 6-dihydropyridin-1 (2H) -yl) methyl) -1- (oxetan-2-ylmethyl) -1H-thieno [2,3-d ] imidazole-5-carboxylate
Intermediate 9 (100mg, 0.28mmol), (S) -2- (chloromethyl) -1- (oxetan-2-ylmethyl) -1H-thieno [2,3-d ] imidazole-5-carboxylic acid ethyl ester (137mg, 0.28mmol), potassium carbonate (155mg, 1.12mmol) and acetonitrile (5 mL) were placed in a 15 mL sealed tube and allowed to warm to 60 ℃ for reaction overnight. Cooled to room temperature, filtered to remove insoluble material and purified by preparative TLC to give 36mg of product as a yellow oil in 22% yield.
Step 2) (S) -2- ((4- (3- ((4-chloro-2-fluorobenzyl) oxy) phenyl) -3, 6-dihydropyridin-1 (2H) -yl) methyl) -1- (oxetan-2-ylmethyl) -1H-thieno [2,3-d ] imidazole-5-carboxylic acid
Reacting (S) -2- ((4- (3- ((4-chloro-2-fluorobenzyl) oxy) phenyl) -3, 6-dihydropyridin-1 (2H) -yl) methyl) -1- (oxetan-2-ylmethyl) -1H-thieno [2,3-d ]]Ethyl imidazole-5-carboxylate (36mg, 0.06mmol) was dissolved in ethanol (2 mL), and 1M aqueous sodium hydroxide (1 mL) was added to stir the mixture at room temperature overnight. Concentrating under reduced pressure to remove ethanol, adjusting pH to about 6 with 1N diluted hydrochloric acid, extracting with ethyl acetate (5 mL × 3), mixing organic phases, adding anhydrous sodium sulfate, drying, concentrating, adding ethyl acetate (10 mL), filtering, concentrating, and lyophilizing to obtain off-white solid product 30mg with yield of 88%. Purity: 99% LCMS [ M + H ]]+:568.2。 1 HNMR(500MHz,CD 3 OD)δ7.77(s,1H),7.53 (t,J＝8.2Hz,1H),7.30–7.22(m,3H),7.06(t,J＝5.4Hz,2H),6.93(dd,J＝8.1,2.1Hz,1H),6.14(s,1H),5.21 (ddd,J＝14.4,7.0,2.6Hz,1H),5.14(s,2H),4.71(dd,J＝15.2,6.8Hz,1H),4.67–4.62(m,1H),4.60(dd,J＝ 15.2,2.7Hz,1H),4.43(dt,J＝9.2,6.0Hz,1H),4.19(q,J＝14.2Hz,2H),3.53–3.40(m,2H),3.12–3.00(m, 2H),2.81–2.72(m,1H),2.66(s,2H),2.53–2.45(m,1H)。
Example 42 (S) -2- ((4- (3- ((4-chloro-2-fluorobenzyl) oxy) phenyl) piperidin-1-yl) methyl) -1- (oxetan-2-ylmethyl) -1H-thieno [2,3-d ] imidazole-5-carboxylic acid
Figure BDA0003128505470000761
Step 1) Ethyl (S) -2- ((4- (3- ((4-chloro-2-fluorobenzyl) oxy) phenyl) piperidin-1-yl) methyl) -1- (oxetan-2-ylmethyl) -1H-thieno [2,3-d ] imidazole-5-carboxylate
Intermediate 10 (100mg, 0.28mmol), (S) -2- (chloromethyl) -1- (oxetan-2-ylmethyl) -1H-thieno [2,3-d ] imidazole-5-carboxylic acid ethyl ester (137mg, 0.28mmol), potassium carbonate (155mg, 1.12mmol) and acetonitrile (4 mL) were placed in a 15 mL sealed tube and allowed to warm to 60 ℃ for reaction overnight. Cooled to room temperature, filtered to remove insoluble matter, concentrated under reduced pressure to remove the solvent, and the residue was purified by preparative TLC to give 80mg of a yellow oily product in 48% yield.
Step 2) (S) -2- ((4- (3- ((4-chloro-2-fluorobenzyl) oxy) phenyl) piperidin-1-yl) methyl) -1- (oxetan-2-ylmethyl) -1H-thieno [2,3-d ] imidazole-5-carboxylic acid
(S) -2- ((4- (3- ((4-chloro-2-fluorobenzyl) oxy) phenyl) piperidin-1-yl) methyl) -1- (oxetan-2-ylmethyl) -1H-thieno [2, 3-d)]Ethyl imidazole-5-carboxylate (80mg, 0.134mmol) was dissolved in ethanol (3 mL), 1M aqueous sodium hydroxide (1.5 mL) was added, and the mixture was stirred at room temperature overnight. Concentrating under reduced pressure to remove ethanol, adjusting pH to about 6 with 1N diluted hydrochloric acid, extracting with ethyl acetate (5 mL × 3), mixing organic phases, adding anhydrous sodium sulfate, drying, concentrating, adding ethyl acetate (10 mL), filtering, concentrating, and lyophilizing to obtain off-white solid product 57mg, with yield 74. Purity: 98%, LCMS [ M + H ]]+:570.2。 1 HNMR(500MHz,CD 3 OD)δ7.69(s,1H),7.53(t, J＝8.2Hz,1H),7.25(ddd,J＝8.5,5.0,2.2Hz,3H),6.87(dd,J＝12.6,4.5Hz,3H),5.23(qd,J＝7.0,2.6Hz, 1H),5.12(s,2H),4.70(dt,J＝14.2,7.3Hz,2H),4.60(dd,J＝15.3,2.6Hz,1H),4.44(dt,J＝9.2,6.0Hz,1H), 4.25(s,2H),3.42(dd,J＝31.1,12.3Hz,2H),2.86–2.68(m,4H),2.52(ddd,J＝16.4,11.5,7.3Hz,1H),2.04– 1.96(m,2H),1.93–1.80(m,2H)。
Example 43- ((1- (6- (4-chloro-2-fluorobenzyloxy) pyridin-2-yl) piperidin-4-yl) -1- ((1-yl-1H-imidazol-5-yl) methyl) -1H-thieno [2,3-d ] imidazole-5-carboxylic acid isopropyl ester
Figure BDA0003128505470000762
2- ((1- (6- (4-chloro-2-fluorobenzyloxy) pyridin-2-yl) piperidin-4-yl) -1- ((1-yl-1H-imidazol-5-yl) methyl) -1H-thieno [2,3-d]Imidazole-5-carboxylic acid (100mg, 0.134mmol) was placed in a 5mL single-neck bottle and K was added 2 CO 3 (41mg, 0.295mmol), acetonitrile (2 mL), and 2-bromopropane (18mg, 0.147mmol), and the mixture was heated to 70 ℃ to react overnight. Cooling to room temperature, adding water (5 mL), extracting with ethyl acetate (3X 10 mL), combining the organic phases, washing with saturated brine, drying over anhydrous sodium sulfate, concentrating under reduced pressure to remove the solvent, purifying the residue by preparative TLC, and lyophilizing to obtain an off-white solid product 30mg with a yield of 34%. Purity: 99% LCMS [ M + H ] ] + :651.2。 1 HNMR(500 MHz,CD 3 OD)δ7.84(s,1H),7.62–7.58(m,1H),7.50(t,J＝8.0Hz,1H),7.26–7.17(m,2H),7.16–7.08(m, 2H),6.84(d,J＝7.3Hz,1H),6.66(d,J＝8.2Hz,1H),5.69(s,2H),5.43(s,2H),5.16(dt,J＝12.5,6.2Hz,1H), 4.00(q,J＝7.3Hz,2H),3.86(s,2H),3.04(d,J＝11.5Hz,2H),2.72–2.63(m,1H),2.30(dd,J＝11.5,9.2Hz, 2H),1.84(dt,J＝21.4,11.1Hz,4H),1.40–1.28(m,6H),1.21–1.12(m,3H)。
Example 44 isobutyl 2- ((1- (6- (4-chloro-2-fluorobenzyloxy) pyridin-2-yl) piperidin-4-yl) -1- ((1-yl-1H-imidazol-5-yl) methyl) -1H-thieno [2,3-d ] imidazole-5-carboxylate
Figure BDA0003128505470000771
2- ((1- (6- (4-chloro-2-fluorobenzyloxy) pyridin-2-yl) piperidin-4-yl) -1- ((1-yl-1H-imidazol-5-yl) methyl) -1H-thieno [2,3-d]Imidazole-5-carboxylic acid (100mg, 0.134mmol) was placed in a 5mL single-neck bottle and K was added 2 CO 3 (41mg, 0.295mmol), acetonitrile (2 mL) and bromoisobutane (20mg, 0.147mmol), and the mixture was heated to 70 ℃ to react overnight. Cooling to room temperature, adding water (5 mL), extracting with ethyl acetate (10mL × 3), mixing organic phases, washing with saturated salt solution, drying over anhydrous sodium sulfate, concentrating under reduced pressure to remove solvent, purifying the residue by preparative TLC, and lyophilizing to obtain off-white solid product 40mg, yield 45%. Purity: 99% LCMS [ M + H ]] + :664.1。 1 HNMR (500MHz,CD 3 OD)δ7.83(s,1H),7.63–7.57(m,1H),7.50(t,J＝8.1Hz,1H),7.25–7.18(m,2H),7.12(d,J＝3.5Hz,2H),6.84(d,J＝7.3Hz,1H),6.66(d,J＝8.1Hz,1H),5.70(s,2H),5.42(s,2H),4.06(d,J＝6.5Hz,2H), 4.00(q,J＝7.3Hz,2H),3.86(s,2H),3.04(d,J＝11.6Hz,2H),2.73–2.62(m,1H),2.30(td,J＝11.6,2.6Hz, 2H),2.03(dp,J＝13.4,6.7Hz,1H),1.91–1.77(m,4H),1.17(t,J＝7.3Hz,3H),1.01(d,J＝6.7Hz,6H)。
Example 45- ((1- (6- (4-chloro-2-fluorobenzyloxy) pyridin-2-yl) piperidin-4-yl) -1- ((1-yl-1H-imidazol-5-yl) methyl) -1H-thieno [2,3-d ] imidazole-5-carboxylic acid 2- (morpholin-1-yl) ethyl ester
Figure BDA0003128505470000772
2- ((1- (6- (4-chloro-2-fluorobenzyloxy) pyridin-2-yl) piperidin-4-yl) -1- ((1-yl-1H-imidazol-5-yl) methyl) -1H-thieno [2,3-d]Imidazole-5-carboxylic acid (100mg, 0.164mmol) was placed in a 25mL single vial, HATU (94mg, 0.246mmol), morpholinoethanol (32 mg, 0.246mmol), tetrahydrofuran (5 mL) and diisopropylethylamine (42mg, 0.328mmol) were added and the mixture was allowed to warm to 70 ℃ for reaction overnight. Cooling to room temperature, adding water (5 mL), extracting with ethyl acetate (10 mL × 3), combining the organic phases, washing with saturated brine, drying over anhydrous sodium sulfate, concentrating the solvent under reduced pressure, purifying the residue by preparative TLC, and lyophilizing to give 11mg of an off-white solid product in 9% yield. Purity: 98%, LCMS [ M + H ] ] + :722.2。 1 H NMR(500MHz,CD 3 OD)δ7.82(s,1H),7.62–7.57(m,1H),7.50(t,J＝8.2Hz, 1H),7.24–7.18(m,2H),7.16(s,1H),7.11(s,1H),6.84(d,J＝7.3Hz,1H),6.66(d,J＝8.2Hz,1H),5.70(s,2H), 5.43(s,2H),4.43(t,J＝5.6Hz,2H),4.00(q,J＝7.3Hz,2H),3.86(s,2H),3.75–3.67(m,4H),3.04(d,J＝11.5 Hz,2H),2.76(t,J＝5.6Hz,2H),2.71–2.63(m,1H),2.64–2.55(m,4H),2.30(dd,J＝12.5,10.1Hz,2H),1.93 –1.77(m,4H),1.16(t,J＝7.3Hz,3H)。
Example 46 Ethyl 2- ((1- (6- (4-chloro-2-fluorobenzyloxy) pyridin-2-yl) piperidin-4-yl) -1- ((1-yl-1H-imidazol-5-yl) methyl) -1H-thieno [2,3-d ] imidazole-5-carboxylate
Figure BDA0003128505470000773
Reacting 2- (chloromethyl) -1- ((1-ethyl-1H-imidazol 5-yl) methyl) -1H-thieno [2,3-d]Imidazole-5-carboxylic acid ethyl ester (135mg, 0.38mmol) was placed in a 25mL single neck flask, potassium carbonate (210mg, 1.52mmol), acetonitrile (5 mL) and intermediate 11 (300mg, 0.38mmol) were added and the mixture was warmed to 60 ℃ for 2.5h. After cooling to room temperature, water (5 mL) and ethyl acetate (10 mL × 3) were added and extracted, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate and the residue was purified by preparative TLC to give 60mg of a colorless transparent oil in 22% yield. 1 H NMR (500 MHz, chloroform-d) δ 7.62 (s, 1H), 7.53 (t, J =7.7hz, 1h), 7.46 (d, J =7.9hz, 1h), 7.18-7.10 (m, 4H), 6.75 (d, J =7.3hz, 1h), 6.65 (d, J =8.1hz, 1h), 5.55 (s, 2H), 5.42 (s, 2H), 4.35 (q, J =7.1hz, 2h), 3.86 (dd, J =12.8, 5.3hz, 4h), 3.07 (s, 2H), 2.68 (t, J =11.8hz, 1h), 2.35 (s, 2H), 1.95 (d, J =12.9hz, 2h), 1.84 (d, J =12.6, 2H), 1.38 (t = 3.3h, 1.7H), 7.20H, 7.7H, 7H.
Example 47 2- ((6- ((4-chloro-2-fluorobenzyl) oxy) -5',6' -dihydro- [2,4' -bipyridine ] -1' (2 ' H) -yl) methyl) -1- (oxetan-2-ylmethyl) -1H-thieno [2,3-d ] imidazole-5-carboxylic acid
Figure BDA0003128505470000781
Step 1) 6-chloro-5 ',6' -dihydro- [2,4' -bipyridine ] ] ] -1' (2 ' H) -carboxylic acid tert-butyl ester
To a solution of 2, 6-dichloropyridine (1.48g, 10mmol) in dioxane (50 mL) and water (10 mL) were added 4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -5, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester (3.09g, 10mmol), cesium carbonate (7.15g, 22mmol) and 1,1' -bis diphenylphosphinopyrylaferrocene dichloride (0.7g, 1mmol), and the mixture was stirred at 90 ℃ overnight. After completion of the reaction, ethyl acetate (50 mL) was added, washed with saturated sodium chloride, the organic phase was dried over sodium sulfate, the solvent was removed by concentration under reduced pressure, and the resulting residue was purified by column chromatography (PE: EA =10 1) to obtain the product (1.8g, 61%).
Step 2) 6- (((4-chloro-2-fluorobenzyl) oxy) -5',6' -dihydro- [2,4' -bipyridine ] -1' (2 ' H) -carboxylic acid tert-butyl ester
To a solution of tert-butyl 6-chloro-5 ',6' -dihydro- [2,4 '-bipyridine ] -1' (2H) -carboxylate (1.8g, 6.1mmol) in toluene (60 mL) were added (4-chloro-2-fluorophenyl) methanol (1g, 6.25mmol), cesium carbonate (4 g, 12.3mmol), dipalladium tribenzylideneacetone (0.28g, 0.3mmol) and (. + -.) -2,2 '-bis- (diphenylphosphino) -1,1' -binaphthyl (0.38g, 0.6mmol), and the mixture was stirred at 100 ℃ overnight. After completion of the reaction, ethyl acetate (50 mL) was added, washed with saturated sodium chloride, the organic phase was dried over sodium sulfate, the solvent was removed by concentration under reduced pressure, and the obtained residue was purified by column chromatography (PE: EA = 10) to obtain the product (1g, 39%).
Step 3) 6- ((4-chloro-2-fluorobenzyl) oxy) -1',2',3',6' -tetrahydro-2, 4' -bipyridine hydrochloride
To a solution of 6- (((4-chloro-2-fluorobenzyl) oxy) -5',6' -dihydro- [2,4' -bipyridine ] -1' (2 ' H) -carboxylic acid tert-butyl ester (1 g, 6.75mmol) in ethanol (5 mL) was added ethanol hydrochloride (5 mL), the mixture was stirred overnight after completion of the reaction, filtered and dried to give the product (0.56g, 74%).
Step 4) Ethyl 2- ((6- ((4-chloro-2-fluorobenzyl) oxy) -5',6' -dihydro- [2,4' -bipyridine ] -1' (2 ' H) -yl) methyl) -1- (oxetan-2-ylmethyl) -1H-thieno [2,3-d ] imidazole-5-carboxylate
To a solution of 6- ((4-chloro-2-fluorobenzyl) oxy) -1',2',3',6' -tetrahydro-2, 4' -bipyridinium hydrochloride (156mg, 0.44mmol) in acetonitrile (1 mL) and water (1 mL) was added ethyl 2- (chloromethyl) -1- (oxetan-2-ylmethyl) -1H-thieno [2,3-d ] imidazole-5-carboxylate (135mg, 0.44 mmol) and potassium carbonate (210mg, 1.76mmol), and the mixture was stirred at 60 ℃ overnight. After completion of the reaction, ethyl acetate (5 mL) was added, washed with saturated sodium chloride, the organic phase was dried over sodium sulfate, the solvent was removed by concentration under reduced pressure, and the resulting residue was purified by column chromatography (DCM: meOH =20: 1) to give the product (141mg, 15%).
Step 5) 2- ((6- ((4-chloro-2-fluorobenzyl) oxy) -5',6' -dihydro- [2,4' -bipyridine ] -1' (2 ' H) -yl) methyl) -1- (oxetan-2-ylmethyl) -1H-thieno [2,3-d ] imidazole-5-carboxylic acid
To 2- ((6- ((4-chloro-2-fluorobenzyl) oxy) -5',6' -dihydro- [2,4' -bipyridine]-1 '(2' H) -yl) methyl) -1- (oxetan-2-ylmethyl) -1H-thieno [2,3-d]To a solution of imidazole-5-carboxylic acid ethyl ester (141mg, 0.23mmol) in ethanol (2 mL) was added 1M hydrochloric acid (0.5 mL), and the mixture was stirred overnight. After completion of the reaction, the mixture was made neutral with 1M hydrochloric acid, the solvent was removed by concentration under reduced pressure, and the resulting residue was purified by column chromatography (DCM: meOH = 10. LCMS [ M + H ]]+:569.33。 1 HNMR(500MHz,CD 3 OD) δ7.79(s,1H),7.68–7.63(m,1H),7.50(t,J＝8.1Hz,1H),7.26–7.18(m,2H),7.10(d,J＝7.5Hz,1H),6.73(d, J＝8.3Hz,2H),5.47(d,J＝17.0Hz,2H),5.25–5.15(m,1H),4.76–4.54(m,3H),4.43(dt,J＝9.2,5.9Hz,1H), 4.33–4.17(m,2H),3.57(s,2H),3.19–3.04(m,2H),2.76(dd,J＝29.2,11.8Hz,3H),2.56–2.41(m,1H)。
Example 48- ((1- (6- (4-chloro-2-fluorobenzyloxy) pyridin-2-yl) piperidin-4-yl) -1- ((1-yl-1H-imidazol-5-yl) methyl) -N-hydroxy-1H-thieno [2,3-d ] imidazole-5-carboxamide
Figure BDA0003128505470000782
Step 1) Ethyl 2- ((1- (6- (4-chloro-2-fluorobenzyloxy) pyridin-2-yl) piperidin-4-yl) -1- ((1-yl-1H-imidazol-5-yl) methyl) -1H-thieno [2,3-d ] imidazole-5-carboxylate
Ethyl 2- (chloromethyl) -1- ((1-ethyl-1H-imidazol 5-yl) methyl) -1H-thieno [2,3-d ] imidazole-5-carboxylate (136mg, 0.43mmol) was placed in a 25mL single-necked flask, potassium carbonate (147mg, 1.06mmol), acetonitrile (5 mL) and intermediate 11 (140 mg, crude, 0.35 mmol) were added, and the mixture was warmed to 60 ℃ for 2.5H. After cooling to room temperature, water (5 mL) was added, extraction was performed with ethyl acetate (10mLX 3), and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and purified by preparative TLC to obtain 60mg of a colorless transparent oil in a yield of 22%.
Step 2) 2- ((1- (6- (4-chloro-2-fluorobenzyloxy) pyridin-2-yl) piperidin-4-yl) -1- ((1-yl-1H-imidazol-5-yl) methyl) -N-hydroxy-1H-thieno [2,3-d ] imidazole-5-carboxamide
2- ((1- (6- (4-chloro-2-fluorobenzyloxy) pyridin-2-yl) piperidin-4-yl) -1- ((1-yl-1H-imidazol-5-yl) methyl) -1H-thieno [2,3-d]Ethyl imidazole-5-carboxylate (100mg, 0.157mmol) was dissolved in 1, 4-dioxane (1 mL), water (2 mL), 50% aqueous hydroxylamine (22 mg, 0.33mmol) and then sodium hydroxide (38mg, 0.95mmol) were added, and the mixture was stirred at room temperature for 1h. After TLC detection of the starting material reaction was complete, the pH was adjusted to about 6 with dilute hydrochloric acid, ethyl acetate (10mLX 3) was extracted, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by preparative TLC (DCM: meOH = 10) and lyophilized to give 32mg of off-white solid product, 32.6% yield, purity: 95 percent. 1 H NMR(500MHz,CD 3 OD)δ7.81(s,1H),7.60(t,J＝7.8Hz,1H),7.50(t,J＝8.2Hz,1H),7.22(t, J＝8.3Hz,2H),7.09(s,1H),7.07(s,1H),6.84(d,J＝7.3Hz,1H),6.66(d,J＝8.2Hz,1H),5.67(s,2H),5.43(s, 2H),4.02(q,J＝7.2Hz,2H),3.85(s,2H),3.04(d,J＝11.5Hz,2H),2.67(t,J＝11.5Hz,1H),2.29(t,J＝10.6 Hz,2H),1.83(dt,J＝21.5,10.9Hz,4H),1.17(t,J＝7.3Hz,3H)。
Example 49 2- ((1- (6- (4-chloro-2-fluorobenzyloxy) pyridin-2-yl) piperidin-4-yl) -1- ((1-yl-1H-imidazol-5-yl) methyl) -N- (methylsulfonyl) -1H-thieno [2,3-d ] imidazole-5-carboxamide
Figure BDA0003128505470000791
Step 1) Ethyl 2- ((1- (6- (4-chloro-2-fluorobenzyloxy) pyridin-2-yl) piperidin-4-yl) -1- ((1-yl-1H-imidazol-5-yl) methyl) -1H-thieno [2,3-d ] imidazole-5-carboxylate
Ethyl 2- (chloromethyl) -1- ((1-ethyl-1H-imidazol 5-yl) methyl) -1H-thieno [2,3-d ] imidazole-5-carboxylate (136mg, 0.43mmol) was placed in a 25mL single-necked flask, potassium carbonate (147mg, 1.06mmol), acetonitrile (5 mL) and intermediate 11 (140 mg, crude, 0.35 mmol) were added, and the mixture was warmed to 60 ℃ for 2.5H. Cooled to room temperature, added with water (5 mL), extracted with ethyl acetate (10mL X3), combined organic phases, washed with saturated brine, dried over anhydrous sodium sulfate, and purified by preparative TLC to give 60mg of colorless transparent oil in 22% yield.
Step 2) 2- ((1- (6- (4-chloro-2-fluorobenzyloxy) pyridin-2-yl) piperidin-4-yl) -1- ((1-yl-1H-imidazol-5-yl) methyl) -1H-thieno [2,3-d ] imidazole-5-carboxylic acid
2- ((1- (6- (4-chloro-2-fluorobenzyloxy) pyridin-2-yl) piperidin-4-yl) -1- ((1-yl-1H-imidazol-5-yl) methyl) -1H-thieno [2,3-d]Ethyl imidazole-5-carboxylate (75mg, 0.12mmol) was dissolved in ethanol (3 mL), a solution of sodium hydroxide (1.5mL, 1M) was added, and the mixture was stirred at room temperature for reaction for 15h. After TLC detection raw material reaction is completed, concentrating under reduced pressure to remove ethanol, adding water (2 mL), extracting with ethyl acetate (2mL X2), separating out a water phase, adjusting the pH value of the water phase to be equal to 5, extracting with ethyl acetate (3mL X3), drying an organic phase with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, adding acetonitrile, water and two drops of trifluoroacetic acid, and freeze-drying to obtain a white-like solid product 28mg, wherein the yield is 38%, and the purity is as follows: 85.7 percent. 1 H NMR(500MHz,MeOH-d 4 )δ8.94(s,1H),7.72–7.63(m,1H),7.56–7.48(m,2H),7.36(s,1H),7.29–7.20(m, 2H),6.93(d,J＝7.3Hz,1H),6.74(dd,J＝8.4,2.2Hz,1H),5.80(s,2H),5.45(s,2H),4.77–4.70(m,2H),4.24 (q,J＝7.7Hz,2H),3.92–3.81(m,2H),3.37–3.33(m,2H),3.03(s,1H),2.20(d,J＝10.5Hz,4H),2.20(td,J＝ 7.5Hz,2.3Hz,3H)。
Step 3) 2- ((1- (6- (4-chloro-2-fluorobenzyloxy) pyridin-2-yl) piperidin-4-yl) -1- ((1-yl-1H-imidazol-5-yl) methyl) -N- (methylsulfonyl) -1H-thieno [2,3-d ] imidazole-5-carboxamide
2- ((1- (6- (4-chloro-2-fluorobenzyloxy) pyridin-2-yl) piperidin-4-yl) -1- ((1-yl-1H-imidazol-5-yl) methyl) -1H-thieno [2,3-d]Imidazole-5-carboxylic acid (150mg, 0.25mmol) was dissolved in dichloromethane (5 mL), methylsulfonamide (42mg, 0.44mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (94mg, 0.49mmol) and 4-dimethylaminopyridine (90mg, 0.74mmol) were added and the mixture was stirred at room temperature overnight. LCMS showed a small amount of starting material remaining and product formed and reaction stopped. The reaction solution was washed with water (5 mL), and concentrated under reduced pressure to give crude product, which was isolated and purified 1/4 of the way to give product (14.8 mg), yield: 35%, purity: 97 percent. LCMS [ M + H ]] + ：686.29。 1 H NMR(500MHz,CD 3 OD)δ9.00(s,1H),7.71–7.63(m,1H),7.52(t,J＝8.2Hz,1H),7.43(s,1H),7.33(s, 1H),7.26–7.19(m,2H),6.94(d,J＝7.4Hz,1H),6.75(d,J＝8.3Hz,1H),5.80(s,2H),5.45(s,2H),4.66(s, 2H),4.26(q,J＝7.3Hz,2H),3.94(s,2H),3.35(s,2H),3.28(s,3H),3.04(s,1H),2.27(dt,J＝29.6,13.3Hz,4H), 1.48(t,J＝7.3Hz,3H)。
Example 50- ((4- (3- ((4-chloro-2-fluorobenzyl) oxy) phenyl) -3, 6-dihydropyridin-1 (2H) -yl) methyl) -1- ((1-ethyl-1H-imidazol-5-yl) methyl) -1H-thieno [2,3-d ] imidazole-5-carboxylic acid
Figure BDA0003128505470000801
Step 1) Ethyl 2- ((4- (3- ((4-chloro-2-fluorobenzyl) oxy) phenyl) -3, 6-dihydropyridin-1 (2H) -yl) methyl) -1- ((1-ethyl-1H-imidazol-5-yl) methyl) -1H-thieno [2,3-d ] imidazole-5-carboxylate
Ethyl 2- (chloromethyl) -1- ((1-ethyl-1H-imidazol 5-yl) methyl) -1H-thieno [2,3-d ] imidazole-5-carboxylate (24mg, 0.095mmol),
intermediate 9 (34mg, 0.095 mmol) was placed in a 25mL single neck flask, methyl carbonate (66mg, 0.475 mmol) and acetonitrile (3 mL) were added, and the mixture was allowed to warm to 60 ℃ for reaction overnight. LCMS indicated product formation, reaction stopped and cooled to room temperature. Adding water (5 mL), extracting with ethyl acetate (3X 5 mL), mixing organic phases, washing with saturated salt water, drying with anhydrous sodium sulfate, concentrating under reduced pressure to obtain crude product, and purifying by column chromatography to obtain pale yellow oily product (36mg, 0.057 mmol), with yield: and (7) percent.
Step 2) 2- ((4- (3- ((4-chloro-2-fluorobenzyl) oxy) phenyl) -3, 6-dihydropyridin-1 (2H) -yl) methyl) -1- ((1-ethyl-1H-imidazol-5-yl) methyl) -1H-thieno [2,3-d ] imidazole-5-carboxylic acid
Reacting 2- ((4- (3- ((4-chloro-2-fluorobenzyl) oxy) phenyl) -3, 6-dihydropyridin-1 (2H) -yl) methyl) -1- ((1-ethyl-1H-imidazol-5-yl) methyl) -1H-thieno [2,3-d]Ethyl imidazole-5-carboxylate (36mg, 0.057 mmol) was dissolved in ethanol (2.5 mL), an aqueous sodium hydroxide solution (1 mL, 1M) was added, and the mixture was stirred at room temperature overnight. LCMS display reverseWhen the reaction was completed, the reaction was stopped, and the reaction mixture was concentrated under reduced pressure to remove ethanol, dissolved by adding water (2 mL), adjusted to pH 6 with 1N dilute hydrochloric acid, extracted with ethyl acetate (3X 5 mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered to remove insoluble matter, concentrated under reduced pressure to give a crude product, dissolved by adding ethyl acetate (10 mL), filtered to remove insoluble matter, concentrated under reduced pressure, and lyophilized to give an off-white solid product (17.8mg, 0.029mmol), yield: 51.5%, purity: 98 percent. LCMS (liquid Crystal display Module) [ M + H ] ] + ：606.19。 1 H NMR (500MHz,CD 3 OD)δ9.14(s,1H),7.63(s,1H),7.54(t,J＝8.2Hz,1H),7.42(s,1H),7.35(t,J＝7.9Hz,1H), 7.27(t,J＝7.2Hz,2H),7.14(d,J＝8.8Hz,2H),7.03(d,J＝8.2Hz,1H),6.20(s,1H),5.81(s,2H),5.17(s,2H), 4.90(s,2H),4.28(q,J＝7.3Hz,2H),4.21(s,2H),3.82(s,2H),2.99(s,2H),1.50(t,J＝7.3Hz,3H)。
Example 51- ((4- (6- ((4-chloro-2-fluorobenzyl) oxy) pyridin-2-yl) piperidin-1-yl) methyl) -1- ((1-isopropyl-1H-imidazol-5-yl) methyl) -1H-thieno [2,3-d ] imidazole-5-carboxylic acid
Figure BDA0003128505470000802
Step 1) Ethyl 5- ((tert-Butoxycarbonyl) amino) -4- (((1-isopropyl-1H-imidazol-5-yl) methyl) amino) thiophene-2-carboxylate
Ethyl 4-amino-5- ((tert-butoxycarbonyl) amino) thiophene-2-carboxylate (500mg, 1.75mmol) was dissolved in acetonitrile (10 mL), N-diisopropylethylamine (903mg, 7.00mmol) and 1-isopropyl-1H-5-chloromethylimidazolium hydrochloride (511mg, 2.62mmol) were added, and the mixture was stirred at room temperature overnight. TLC showed the starting material remained and new product was formed, stopping the reaction. Concentrating under reduced pressure to remove acetonitrile, adding water (10 mL), extracting with ethyl acetate (10mL X3), mixing organic phases, washing with saturated salt water, drying over anhydrous sodium sulfate, concentrating under reduced pressure to obtain a crude product, and purifying by column chromatography to obtain a yellow oily product (365mg, 0.89mmol), wherein the yield is as follows: 51 percent.
Step 2) Ethyl 2- (chloromethyl) -1- ((1-isopropyl-1H-imidazol-5-yl) methyl) -1H-thieno [2,3-d ] imidazole-5-carboxylate
Ethyl 5- ((tert-butoxycarbonyl) amino) -4- (((1-isopropyl-1H-imidazol-5-yl) methyl) amino) thiophene-2-carboxylate (200mg, 0.49mmol) was dissolved in dichloromethane (20 mL), trifluoroacetic acid (0.4 mL) and 2-chloro-1, 1-trimethoxyethane (227mg, 1.47mmol) were added, and the mixture was stirred at room temperature overnight. LCMS showed product formation and reaction was stopped. Concentration under reduced pressure, and purification of the residue by column chromatography gave a yellow oily product (100mg, 0.27mmol), yield: 55.6 percent.
Step 3) Ethyl 2- ((4- (6- ((4-chloro-2-fluorobenzyl) oxy) pyridin-2-yl) piperidin-1-yl) methyl) -1- ((1-isopropyl-1H-imidazol-5-yl) methyl) -1H-thieno [2,3-d ] imidazole-5-carboxylate
Ethyl 2- (chloromethyl) -1- ((1-isopropyl-1H-imidazol-5-yl) methyl) -1H-thieno [2,3-d ] imidazole-5-carboxylate (107mg, 0.27mmol) was placed in a single-neck flask, potassium carbonate (150mg, 1.09mmol), intermediate 11 (100mg, 0.27mmol) and acetonitrile (5 mL) were added, and the mixture was warmed to 60 ℃ for 5H. LCMS showed reaction complete, stop reaction and cool to room temperature. Concentrating under reduced pressure to remove acetonitrile, adding water (10 mL), extracting with ethyl acetate (3X 15mL), mixing organic phases, washing with saturated salt water, drying with anhydrous sodium sulfate, concentrating under reduced pressure to obtain crude product, purifying by column chromatography to obtain pale yellow oily product (110mg, 0.17mmol), yield: and 63 percent.
Step 4) 2- ((4- (6- ((4-chloro-2-fluorobenzyl) oxy) pyridin-2-yl) piperidin-1-yl) methyl) -1- ((1-isopropyl-1H-imidazol-5-yl) methyl) -1H-thieno [2,3-d ] imidazole-5-carboxylic acid
2- ((4- (6- ((4-chloro-2-fluorobenzyl) oxy) pyridin-2-yl) piperidin-1-yl) methyl) -1- ((1-isopropyl-1H-imidazol-5-yl) methyl) -1H-thieno [2,3-d]Ethyl imidazole-5-carboxylate (110mg, 0.17mmol) was dissolved in ethanol (4 mL), 1M aqueous sodium hydroxide solution (2 mL) was added, and the mixture was stirred at room temperature overnight. LCMS showed reaction completion, concentrated under reduced pressure to remove ethanol, dissolved by addition of water (2 mL), pH adjusted to about 6 with 1M dilute hydrochloric acid, to precipitate a large amount of solid, filtered, and the residue washed with water three times and dried to give off-white solid product (53.8mg, 0.086 mmol), yield: 50.8%, purity: 97 percent. LCMS (liquid Crystal display Module) [ M + H ] ] + :623.23。 1 H NMR(500MHz,CD 3 OD)δ9.27(d,J＝1.3Hz, 1H),7.73–7.65(m,1H),7.59(s,1H),7.52(t,J＝8.2Hz,1H),7.40(s,1H),7.24(dd,J＝12.3,4.3Hz,2H),6.94 (d,J＝7.3Hz,1H),6.76(d,J＝8.2Hz,1H),5.85(s,2H),5.45(s,2H),4.82(s,2H),4.67(dt,J＝13.2,6.6Hz, 1H),3.95(s,2H),3.41(s,2H),3.07(s,1H),2.26(dd,J＝30.5,11.8Hz,4H),1.55(d,J＝6.7Hz,6H)。
Example 52 trifluoroacetic acid 2- ((6- ((4-chloro-2-fluorobenzyl) oxy) -3',6' -dihydro- [2,4' -pyridine ] -1' (2 ' H) -yl) methyl) -1- ((1-ethyl-1H-imidazol-5-yl) methyl) -1H-thieno [2,3-d ] imidazole-5-carboxylate
Figure BDA0003128505470000811
Step 1) Ethyl 2- ((6- ((4-chloro-2-fluorobenzyl) oxy) -3',6' -dihydro- [2,4' -pyridine ] -1' (2 ' H) -yl) methyl) -1- ((1-ethyl-1H-imidazol-5-yl) methyl) -1H-thieno [2,3-d ] imidazole-5-carboxylate
Ethyl 2- (chloromethyl) -1- ((1-ethyl-1H-imidazol 5-yl) methyl) -1H-thieno [2,3-d ] imidazole-5-carboxylate (36mg, 0.143mmol) and intermediate 9 (60mg, 0.143mmol, crude) were placed in a 50 mL single-neck flask, potassium carbonate (99mg, 0.715mmol) and acetonitrile (4 mL) were added, and the mixture was warmed to 60 ℃ for reaction overnight. The reaction was stopped, concentrated under reduced pressure, and the residue was purified by column chromatography to give 18mg of a pale yellow oily product.
Step 2) trifluoroacetic acid salt of 2- ((6- ((4-chloro-2-fluorobenzyl) oxy) -3',6' -dihydro- [2,4' -pyridin ] -1' (2 ' H) -yl) methyl) -1- ((1-ethyl-1H-imidazol-5-yl) methyl) -1H-thieno [2,3-d ] imidazole-5-carboxylic acid
2- ((6- ((4-chloro-2-fluorobenzyl) oxy) -3',6' -dihydro- [2,4' -pyridine]-1 '(2' H) -yl) methyl) -1- ((1-ethyl-1H-imidazol-5-yl) methyl) -1H-thieno [2,3-d]Ethyl imidazole-5-carboxylate (18mg, 0.028mmol) was dissolved in ethanol (2 mL), a 1M aqueous solution (1 mL) of sodium hydroxide was added, and the mixture was reacted at room temperature overnight. Stopping reaction, concentrating under reduced pressure to remove ethanol, adjusting to neutral with 1N diluted hydrochloric acid, adding acetonitrile to dissolve, filtering to remove insoluble substances, and separating the filtrate by preparative separation (0.1% CF) 3 Aqueous solution of COOH MeCN =90: 10-10) to give a yellow oily product, 1.8mg, yield: 11%, LC-MS [ M + H ]] + :607.1。 1 H NMR(500MHz,CD 3 OD)δ8.93(s,1H),7.69(t,J＝7.7Hz,1H), 7.55(s,1H),7.51(t,J＝7.9Hz,1H),7.42(s,1H),7.29–7.19(m,2H),7.14(d,J＝7.6Hz,1H),6.84–6.71(m, 2H),5.79(s,2H),5.46(s,2H),4.57–4.48(m,2H),4.27–4.18(m,2H),3.83(s,2H),3.38(s,2H),2.82(s,2H), 1.40(t,J＝7.1Hz,3H)。
Example 53 2- ((4- (5- ((4-chloro-2-fluorobenzyl) oxy) -2, 4-difluorophenyl) piperidin-1-yl) methyl) -1- ((1-ethyl-1H-imidazol-5-yl) methyl) -1H-thieno [2,3-d ] imidazole-5-carboxylic acid
Figure BDA0003128505470000821
Step 1) Ethyl 2- ((4- (5- ((4-chloro-2-fluorobenzyl) oxy) -2, 4-difluorophenyl) piperidin-1-yl) methyl) -1- ((1-ethyl-1H-imidazol-5-yl) methyl) -1H-thieno [2,3-d ] imidazole-5-carboxylate
Intermediate 12 (61.1mg, 0.16mmol) was dissolved in acetonitrile (2 mL). Adding K into the reaction system in sequence 2 CO 3 (97mg, 0.7mmol) and 2- (chloromethyl) -1- ((1-ethyl-1H-imidazol 5-yl) methyl) -1H-thieno [2,3-d]Ethyl imidazole-5-carboxylate (50mg, 0.14mmol) and the mixture was heated in a metal sand bath (50 ℃ C.) overnight. After completion of the reaction, the inorganic salt in the system was removed by filtration, the solvent was removed by concentration under reduced pressure, and the residue was separated by thin layer chromatography (DCM: meOH = 20) to obtain the objective product (13mg, 14%) as a pale yellow solid. LCMS (liquid Crystal display Module) [ M + H ]] + :672。
Step 2) 2- ((4- (5- ((4-chloro-2-fluorobenzyl) oxy) -2, 4-difluorophenyl) piperidin-1-yl) methyl) -1- ((1-ethyl-1H-imidazol-5-yl) methyl) -1H-thieno [2,3-d ] imidazole-5-carboxylic acid
Reacting 2- ((4- (5- ((4-chloro-2-fluorobenzyl) oxy) -2, 4-difluorophenyl) piperidin-1-yl) methyl) -1- ((1-ethyl-1H-imidazol-5-yl) methyl) -1H-thieno [2,3-d]Imidazole-5-carboxylic acid ethyl ester (13mg, 0.02mmol) was dissolved in tetrahydrofuran (2 mL). Water (1 mL) and sodium hydroxide (1.6 mg, 0.04mmol) were added to the reaction system, and the mixture was placed in a metal sand bath and heated to react (50 ℃ C.) overnight. After TLC monitoring the conversion was complete, the pH of the system was adjusted with 1N hydrochloric acid =6, at which time the system was inA large amount of white solid precipitated out, and the supernatant was removed by pipetting. The obtained solid crude product was subjected to preparative separation by preparative HPLC and lyophilized to obtain the objective product (4.4 mg, 35%) as a pale yellow solid. HPLC purity =95%, LCMS [ M + H] + :644。 1 HNMR(500MHz,MeOH-d 4 )δ9.01(s,1H),7.57(s,1H),7.53(t,J＝8.1Hz,1H),7.41–7.35(m, 1H),7.28(s,1H),7.26(s,1H),7.10–7.05(m,1H),7.02(t,J＝10.6Hz,1H),5.81(s,2H),5.18(s,2H),4.62(s, 2H),4.26(q,J＝7.1Hz,2H),3.81–3.67(m,2H),3.24–3.05(m,3H),2.15–2.01(m,4H),1.47(t,J＝7.3Hz, 3H)。
Example 54- ((4- (6- ((4-chloro-2-fluorobenzyl) oxy) pyridin-2-yl) piperidin-1-yl) methyl) -1- (2-methoxyethyl) -1H-imidazo [1,2-b ] pyrazole-6-carboxylic acid
Figure BDA0003128505470000822
Step 1) 5-Nitro-1H-pyrazole-3-carboxylic acid methyl ester
5-Nitro-1H-pyrazole-3-carboxylic acid (2g, 12.73mmol) was dissolved in methanol (10 mL). Thionyl chloride (2.68g, 20mmol) was slowly added dropwise to the reaction system under ice-cooling. After the addition, the reaction was refluxed (80 ℃ C.) in a metal sand bath. After refluxing for 2h, the reaction was cooled to room temperature, concentrated under reduced pressure to remove the solvent and dried in vacuo to give the desired product (2.18g, 98%) as a white solid.
Step 2) tert-butyldimethyl (oxetan-2-ylmethoxy) silane
(Oxetadin-2-yl) methanol (5g, 67.5mmol) was dissolved in dichloromethane (200 mL). 1H-imidazole (9.2g, 135mmol) and TBSCl (15.26g, 101.2mmol) were added to the reaction sequentially under ice-cooling. The reaction was slowly warmed to room temperature and stirred overnight, after TLC monitored the completion of the conversion, 100mL of water was added to the reaction, followed by liquid separation, and the resulting organic phase was washed with water (3 × 100ml) and then with saturated brine (100 mL). The organic phase is passed through Na 2 SO 4 The solvent was removed by drying and concentration under reduced pressure, and the residue was isolated by column chromatography (PE: EA = 50) to give the objective product (11.1g, 87%) as a colorless oily liquid.
Step 3) methyl 1- (3- ((tert-butyldimethylsilyl) oxy) -2-hydroxypropyl) -5-nitro-1H-pyrazole-3-carboxylate
Methyl 5-nitro-1H-pyrazole-3-carboxylate (500mg, 2.92mmol) was dissolved in toluene (12 mL). 2, 6-lutidine (47mg, 0.44mmol) and t-butyldimethyl (oxetan-2-ylmethoxy) silane (824mg, 4.38mmol) were added to the reaction system in this order. The reaction system is heated to 70 ℃ to react for 48h. After completion of the conversion was monitored by TLC, the reaction solvent was removed by concentration under reduced pressure, and the residue was separated by column chromatography (PE: EA =3, 1) to obtain the objective product (920 mg, crude mixture, 79%) as a colorless oily liquid.
Step 4) methyl 1- (3- ((tert-butyldimethylsilyl) oxy) -2-oxopropyl) -5-nitro-1H-pyrazole-3-carboxylate
Methyl 1- (3- ((tert-butyldimethylsilyl) oxy) -2-oxopropyl) -5-nitro-1H-pyrazole-3-carboxylate (4.02g, 11.2mmol) was dissolved in dichloromethane (120 mL). Dess-Martin reagent (7.13g, 16.8mmol) was added to the reaction system, and the mixture was stirred at room temperature for reaction. After LC-MS monitored the conversion was complete, 100mL of saturated sodium bicarbonate solution and 15g of sodium thiosulfate were added to the reaction and stirred vigorously until the reaction was clear. The aqueous reaction phase was extracted with DCM, and the combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent, and the residue was separated by column chromatography (PE: EA =20, 1 to 10.
Step 5) methyl 2- (((tert-butyldimethylsilyl) oxy) methyl) -1H-imidazo [1,2-b ] pyrazole-6-carboxylate
1- (3- ((tert-butyldimethylsilyl) oxy) -2-oxopropyl) -5-nitro-1H-pyrazole-3-carboxylic acid methyl ester (760mg, 2.13mmol) was dissolved in 10mL of MeOH. 10% of Pd/C (222mg, 0.21mmol) was added to the reaction system, and the inside of the system was replaced with hydrogen gas three times, followed by stirring at room temperature. After TLC monitoring for complete conversion (2 h), the mixture was filtered through Celite to remove Pd/C from the system, and acetic acid (200. Mu.L) was added to the resulting filtrate, which was then placed in a metal sand bath at reflux (80 ℃ C.) overnight. After monitoring the completion of the conversion by LC-MS, the solvent was removed by concentration under reduced pressure, the residue was separated by column chromatography (PE: EA =2, The desired product (466mg, 71%) was obtained as a white solid. LCMS (liquid Crystal display Module) [ M + H ]] + :310。
Step 6) methyl 2- (((tert-butyldimethylsilyl) oxy) methyl) -1- (2-methoxyethyl) -1H-imidazo [1,2-b ] pyrazole-6-carboxylate
Reacting 2- (((tert-butyldimethylsilyl) oxy) methyl) -1H-imidazo [1,2-b]Pyrazole-6-carboxylic acid methyl ester (271mg, 0.88mmol) was dissolved in acetonitrile (11 mL). Potassium carbonate (363mg, 2.64mmol) and 1-bromo-2-methoxyethyl (181mg, 1.31mmol) were added successively to the reaction system, and the mixture was placed in a metal sand bath and heated to react (50 ℃). After TLC monitoring the conversion was complete, the inorganic salts in the system were removed by filtration, the solvent was removed by concentration under reduced pressure, and the residue was isolated by column chromatography (PE: EA = 4) to give the desired product (240mg, 72%) as a white solid. LCMS (liquid Crystal display Module) [ M + H ]] + :368。
Step 7) methyl 2- (hydroxymethyl) -1- (2-methoxyethyl) -1H-imidazo [1,2-b ] pyrazole-6-carboxylate
Reacting 2- (((tert-butyldimethylsilyl) oxy) methyl) -1- (2-methoxyethyl) -1H-imidazo [1, 2-b)]Pyrazole-6-carboxylic acid methyl ester (240mg, 0.65 mmol) was dissolved in tetrahydrofuran (6 mL). TBAF (185mg, 0.71mmol) was added to the reaction system, and the mixture was stirred at room temperature. TLC monitored complete conversion (5 min), water (50 mL) was added, extraction was performed with ethyl acetate, and the combined organic phases were washed with saturated brine (30 mL) and Na 2 SO 4 Dried, concentrated under reduced pressure to remove the solvent, and the residue was isolated by thin layer chromatography (DCM: meOH = 20) to give the desired product (146mg, 89%) as a yellow oily liquid.
Step 8) methyl 2-formyl-1- (2-methoxyethyl) -1H-imidazo [1,2-b ] pyrazole-6-carboxylate
2- (hydroxymethyl) -1- (2-methoxyethyl) -1H-imidazo [1,2-b]Pyrazole-6-carboxylic acid methyl ester (146mg, 0.58mmol) was dissolved in dichloromethane (6 mL). Dess-Martin reagent (294mg, 0.7mmol) was added to the reaction system and the mixture was stirred at room temperature for reaction. After TLC monitoring the conversion was complete, 10mL of saturated sodium bicarbonate solution and 1.5g of sodium thiosulfate were added to the reaction and stirred vigorously until the reaction was clear. The aqueous reaction phase was extracted with methylene chloride, the combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate,the solvent was removed by concentration under reduced pressure, and the residue was separated by column chromatography (EA) to give the objective product (64mg, 44%) as a yellow solid. LCMS (liquid Crystal display Module) [ M + H ]] + :252。
Step 9) methyl 2- ((4- (6- ((4-chloro-2-fluorobenzyl) oxy) pyridin-2-yl) piperidin-1-yl) methyl) -1- (2-methoxyethyl) -1H-imidazo [1,2-b ] pyrazole-6-carboxylate
Intermediate 11 (135mg, 0.38mmol) was dissolved in water (2 mL), 1, 2-dichloroethane (2 mL) and sodium hydrogencarbonate (84mg, 1.0 mmol) were added to the reaction system, and the mixture was stirred at room temperature for 3 hours, followed by extraction with dichloromethane, and the combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent, to give 2- ((4-chloro-2-fluorobenzyl) oxy) -6- (piperidin-4-yl) pyridine. Dissolving the obtained free compound in 1, 2-dichloroethane (1 mL), and sequentially adding 2-formyl-1- (2-methoxyethyl) -1H-imidazo [1,2-b ] to the reaction system ]Pyrazole-6-carboxylic acid methyl ester (64mg, 0.25mmol), sodium tris (acetoxy) borohydride (159mg, 0.75mmol), and the mixture was stirred at room temperature for 2h. After TLC monitoring the conversion was complete, 10mL of water was added to the reaction. The aqueous phase was extracted with DCM and the combined organic phases were washed with saturated NaCl solution (10 mL), na 2 SO 4 Dried, concentrated under reduced pressure to remove the solvent, and the residue was isolated by thin layer chromatography (DCM: meOH = 20). LCMS (liquid Crystal display Module) [ M + H ]] + :556。
Step 10) 2- ((4- (6- ((4-chloro-2-fluorobenzyl) oxy) pyridin-2-yl) piperidin-1-yl) methyl) -1- (2-methoxyethyl) -1H-imidazo [1,2-b ] pyrazole-6-carboxylic acid
2- ((4- (6- ((4-chloro-2-fluorobenzyl) oxy) pyridin-2-yl) piperidin-1-yl) methyl) -1- (2-methoxyethyl) -1H-imidazo [1, 2-b)]Pyrazole-6-carboxylic acid methyl ester (92mg, 0.165mmol) was dissolved in 2mL of THF, 1mL of water and LiOH (8mg, 0.331mmol) were added to the reaction system, and the reaction system was heated in a metal sand bath (50 ℃ C.). After TLC to monitor the completion of the conversion, the reaction was cooled to room temperature, the pH of the aqueous phase was adjusted to about 6 with 1N HCl, extracted with EtOAc and the combined organic phases were washed with saturated NaCl solution (10 mL) and Na 2 SO 4 Drying, removal of solvent in vacuo, and isolation of the residue by thin layer chromatography (DCM: meOH = 10) afforded the target The product (37mg, 41%) was a white powder. LCMS (liquid Crystal display Module) [ M + H ]] + :542。 1 H NMR(500MHz,CH 3 OH-d 4 /TFA)δ7.89(s,1H),7.68(t,J＝7.8Hz,1H),7.50(t,J＝8.2Hz,1H),7.31(s,1H) 7.24(t,J＝8.1Hz,2H),6.94(d,J＝6.8Hz,1H),6.76(d,J＝8.2Hz,1H),5.43(s,2H),4.64(s,2H),4.43(s,2H), 3.89–3.71(m,4H),3.42(s,3H),3.29(s,1H),3.05(s,1H),2.28–2.05(m,4H),1.66–1.56(m,1H)。
Example 552- ((4- (6- ((4-chloro-2-fluorobenzyl) oxy) pyridin-2-yl) piperidin-1-yl) methyl) -1- ((1-ethyl-1H-imidazol-2-yl) methyl) -1H-thieno [2,3-d ] imidazole-5-carboxylic acid
Figure BDA0003128505470000841
Step 1) 1-Ethyl-1H-imidazole-2-carbaldehyde
1H-imidazole-2-carbaldehyde (2g, 20.82mmol) was dissolved in 120mL CH 3 To the reaction system, iodoethane (4.87g, 31.2 mmol) was added dropwise in CN. After the addition, the reaction was heated in a metal sand bath (60 ℃ C.). After the reaction overnight, the reaction system was cooled to room temperature, filtered to remove inorganic salts, concentrated under reduced pressure to remove the solvent from the filtrate, and the residue was purified by column chromatography (PE: EA = 1) to obtain the objective product (2.27g, 88%) as a pale yellow oily liquid.
Step 2) (1-Ethyl-1H-imidazol-2-yl) methanol
1-Ethyl-1H-imidazole-2-carbaldehyde (2.27g, 18.31mmol) was dissolved in 75mL of MyeOH. Sodium borohydride (831mg, 21.97mmol) was added slowly to the reaction under ice-bath. The reaction was slowly warmed to room temperature and stirred for 1h. After TLC monitoring the conversion was complete, the reaction was concentrated under reduced pressure to remove the reaction solution, and extracted with 100mL of EA and 100mL of water. The organic phase was washed with water (3 x 50ml) and then with saturated NaCl solution (100 mL). The organic phase is passed through Na 2 SO 4 The mixture was dried and concentrated under reduced pressure to remove the solvent, whereby the objective product (1.27g, 56%) was obtained as a colorless oily liquid.
Step 3) 2- (chloromethyl) -1-ethyl-1H-imidazole hydrochloride
(1-Ethyl-1H-imidazol-2-yl) methanol (1.27g, 10.07mmol) was dissolved in 30mL of SOCl with ice-bath cooling 2 In the reaction, the reaction system is refluxed (metal sand bath 80 ℃) and reacted for 2 hours. After the reaction is finished, concentrating under reduced pressure to remove SOCl 2 Oil pump vacuum drying gave the title product (920 mg, 56%) as a white solid.
Step 4) Ethyl 5- ((tert-Butoxycarbonyl) amino) -4- (((1-ethyl-1H-imidazol-2-yl) methyl) amino) thiophene-2-carboxylate
Ethyl 4-amino-5- ((tert-butoxycarbonyl) amino) thiophene-2-carboxylate (500mg, 1.75mmol) was dissolved in CH 3 CN (20 mL). 2- (chloromethyl) -1-ethyl-1H-imidazole hydrochloride (217mg, 2.1mmol) and diisopropylethylamine (1.35g, 10.5mmol) were added to the reaction system, and the mixture was stirred at room temperature overnight. After completion of the reaction, the reaction solvent was removed in vacuo and the residue was isolated by column chromatography (PE: EA =1 to DCM: meOH = 20) to give the desired product (320mg, 46%) as a brown-black oil. LCMS [ M + H ]] + :395。
Step 5) Ethyl 2- (chloromethyl) -1- ((1-ethyl-1H-imidazol-2-yl) methyl) -1H-thieno [2,3-d ] imidazole-5-carboxylate
Ethyl 5- ((tert-butoxycarbonyl) amino) -4- (((1-ethyl-1H-imidazol-2-yl) methyl) amino) thiophene-2-carboxylate (200mg, 0.51mmol) was dissolved in dichloromethane (20 mL). Trifluoroacetic acid (0.4 mL), and 2-chloro-1, 1-trimethoxyethane (235mg, 1.53 mmol) were added to the reaction system, and the mixture was reacted at room temperature overnight. After completion of the reaction, the solvent was removed by concentration under reduced pressure, and the residue was isolated by column chromatography (DCM: meOH = 15) to give the crude product (180 mg) as a brown-black oil. LCMS [ M + H ]] + :353。
Step 6) Ethyl 2- ((4- (6- ((4-chloro-2-fluorobenzyl) oxy) pyridin-2-yl) piperidin-1-yl) methyl) -1- ((1-ethyl-1H-imidazol-2-yl) methyl) -1H-thieno [2,3-d ] imidazole-5-carboxylate
Reacting 2- (chloromethyl) -1- ((1-ethyl-1H-imidazol-2-yl) methyl) -1H-thieno [2,3-d]Imidazole-5-carboxylic acid ethyl ester (180 mg, crude mixture) was dissolved in acetonitrile (6 mL). Potassium carbonate (415mg, 0.6 mmol) and intermediate 11 (214mg, 3.0 mmol) were added to the reaction system in this order, and the mixture was placed in a metal sand bath and heated to react (50 ℃ C.) overnight. After LCMS to monitor complete conversion of the starting material, filterThe inorganic salts were removed from the system, the solvent was removed by concentration under reduced pressure, and the residue was separated by thin layer chromatography (DCM: meOH = 20). LCMS [ M + H ] ] + :637。
Step 7) 2- ((4- (6- ((4-chloro-2-fluorobenzyl) oxy) pyridin-2-yl) piperidin-1-yl) methyl) -1- ((1-ethyl-1H-imidazol-2-yl) methyl) -1H-thieno [2,3-d ] imidazole-5-carboxylic acid
2- ((4- (6- ((4-chloro-2-fluorobenzyl) oxy) pyridin-2-yl) piperidin-1-yl) methyl) -1- ((1-ethyl-1H-imidazol-2-yl) methyl) -1H-thieno [2,3-d]Imidazole-5-carboxylic acid ethyl ester (32mg, 0.05mmol) was dissolved in 2mL of THF, 1mL of water and LiOH (2.4 mg,0.1 mmol) were added to the reaction system, and the reaction system was heated in a metal sand bath (50 ℃ C.). After TLC to monitor the completion of the conversion, the reaction was cooled to room temperature, the pH of the aqueous phase was adjusted to about 6 with 1N HCl, then extracted with EtOAc and the combined organic phases were washed with saturated NaCl solution (10 mL) and Na 2 SO 4 Drying, concentration under reduced pressure to remove the solvent, and semi-preparative liquid phase separation gave the desired product (25mg, 83%) as a pale yellow powder. LCMS (liquid Crystal display Module) [ M + H ]] + :609。 1 H NMR(500MHz,MeOH-d 4 )δ7.83(s,1H),7.69(t,J＝7.7Hz,1H),7.51(t,J＝8.1Hz,1H),7.26(dd,J＝22.1, 10.2Hz,3H),7.10(s,1H),6.97(d,J＝7.4Hz,1H),6.78(d,J＝8.1Hz,1H),5.87(s,2H),5.51(s,2H),4.74(s, 2H),4.39(dd,J＝14.7,7.2Hz,2H),3.73(d,J＝12.1Hz,2H),3.34(s,2H),3.10(s,1H),2.21(s,4H),1.52(t,J＝ 7.2Hz,3H)。
Further, according to a method similar to example 49, the compounds shown in Table A were synthesized.
TABLE A. Inventive examples 56 to 60
Figure BDA0003128505470000851
Figure BDA0003128505470000861
Example 612- ((4- (6- ((4-chloro-2-fluorobenzyl) oxy) pyridin-2-yl) piperidin-1-yl) methyl) -1- ((1-ethyl-1H-imidazol-5-yl) methyl) -N-sulfamoyl-1H-thieno [2,3-d ] imidazole-5-carboxamide
Figure BDA0003128505470000862
2- ((1- (6- (4-chloro-2-fluorobenzyloxy) pyridin-2-yl) piperidin-4-yl) -1- ((1-yl-1H-imidazol-5-yl) methyl) -1H-thieno [2,3-d ]Imidazole-5-carboxylic acid (122mg, 0.2 mmol) was dissolved in dichloromethane (5 mL), N' -carbonyldiimidazole (42mg, 0.3 mmol) was added, the mixture was stirred at room temperature for 2 hours, and aminosulfonamide (19mg, 0.2 mmol) was added, and the mixture was stirred at room temperature overnight. LCMS showed the starting material was essentially reacted to completion, stopping the reaction. Washing the reaction solution with water (5 mL), concentrating under reduced pressure to obtain a crude product, and preparing, separating and purifying to obtain a product (11 mg) with the yield: 8%, purity: 98 percent. LCMS (liquid Crystal display Module) [ M + H ]] + ：687.15。 1 H NMR(500MHz,CD 3 OD)δ9.00(s,1H),7.71–7.63(m,1H), 7.52(t,J＝8.2Hz,1H),7.43(s,1H),7.33(s,1H),7.26–7.19(m,2H),6.94(d,J＝7.4Hz,1H),6.75(d,J＝8.3 Hz,1H),5.80(s,2H),5.45(s,2H),4.66(s,2H),4.18(q,J＝7.3Hz,2H),3.94(s,2H),3.35(s,2H),3.04(s,1H), 2.27(m,4H),2.10(s,3H),1.35(t,J＝7.3Hz,3H)。
Example 62- ((4- (6- ((4-chloro-2-fluorobenzyl) oxy) pyridin-2-yl) piperidin-1-yl) methyl) -1- ((1-ethyl-1H-imidazol-5-yl) methyl) -N- (N-methylaminosulfonyl) -1H-thieno [2,3-d ] imidazole-5-carboxamide
Figure BDA0003128505470000863
2- ((1- (6- (4-chloro-2-fluorobenzyloxy) pyridin-2-yl) piperidin-4-yl) -1- ((1-yl-1H-imidazol-5-yl) methyl) -1H-thieno [2,3-d]Imidazole-5-carboxylic acid (122mg, 0.2mmol) was dissolved in methylene chloride (5 mL), N' -carbonyldiimidazole (42mg, 0.3mmol) was added, the mixture was stirred at room temperature for 2 hours, then N-methylsulfonamide (22mg, 0.2mmol) was added, and the mixture was stirred at room temperature overnight. LCMS showed the starting material was essentially reacted to completion, stopping the reaction. The reaction solution was washed with water (5 mL) and concentrated under reduced pressureAnd (3) condensing to obtain a crude product, and carrying out preparation, separation and purification to obtain a product (8 mg) with the yield: 6%, purity: 98 percent. LCMS (liquid Crystal display Module) [ M + H ] ] + ：701.21。 1 HNMR(500MHz,CD 3 OD)δ9.00(s,1H),7.71–7.63(m, 1H),7.52(t,J＝8.2Hz,1H),7.43(s,1H),7.33(s,1H),7.26–7.19(m,2H),6.94(d,J＝7.4Hz,1H),6.75(d,J＝ 8.3Hz,1H),5.80(s,2H),5.45(s,2H),4.66(s,2H),4.19(q,J＝7.3Hz,2H),3.94(s,2H),3.35(s,2H),3.04(s, 1H),2.79(s,3H),2.27(m,4H),2.10(s,3H),1.35(t,J＝7.3Hz,3H)。
Example 63N-acetyl-2- ((4- (6- ((4-chloro-2-fluorobenzyl) oxy) pyridin-2-yl) piperidin-1-yl) methyl) -1- ((1-ethyl-1H-imidazol-5-yl) methyl) -1H-thieno [2,3-d ] imidazole-5-carboxamide
Figure BDA0003128505470000871
2- ((1- (6- (4-chloro-2-fluorobenzyloxy) pyridin-2-yl) piperidin-4-yl) -1- ((1-yl-1H-imidazol-5-yl) methyl) -1H-thieno [2,3-d]Imidazole-5-carboxylic acid (150mg, 0.25mmol) was dissolved in dichloromethane (5 mL), acetamide (26mg, 0.44mmol), 1-ethyl- (3-dimethylaminopropyl) carbonyldiimine hydrochloride (94mg, 0.49mmol) and 4-dimethylaminopyridine (90mg, 0.74mmol) were added and the mixture was stirred at room temperature overnight. LCMS showed a small amount of starting material remaining and product formed and reaction stopped. The reaction solution was washed with water (5 mL), and concentrated under reduced pressure to give crude product, which was isolated and purified to give product (48mg, 30%), purity: 98 percent. LCMS (liquid Crystal display Module) [ M + H ]] + ：650.20。 1 H NMR(500MHz,CD 3 OD)δ8.99 (s,1H),7.71–7.63(m,1H),7.52(t,J＝8.2Hz,1H),7.43(s,1H),7.33(s,1H),7.26–7.19(m,2H),6.94(d,J＝ 7.4Hz,1H),6.75(d,J＝8.3Hz,1H),5.80(s,2H),5.45(s,2H),4.66(s,2H),4.26(q,J＝7.3Hz,2H),3.94(s,2H), 3.35(s,2H),3.04(s,1H),2.27(m,4H),2.10(s,3H),1.48(t,J＝7.3Hz,3H)。
Example 64- ((4- (6- ((4-chloro-2-fluorobenzyl) oxy) pyridin-2-yl) piperidin-1-yl) methyl) -1- ((1-ethyl-1H-imidazol-5-yl) methyl) -N- (2, 2-trifluoroacetyl) -1H-thieno [2,3-d ] imidazole-5-carboxamide
Figure BDA0003128505470000872
2- ((1- (6- (4-chloro-2-fluorobenzyloxy) pyridin-2-yl) piperidin-4-yl) -1- ((1-yl-1H-imidazol-5-yl) methyl) -1H-thieno [2,3-d]Imidazole-5-carboxylic acid (150mg, 0.25mmol) was dissolved in dichloromethane (5 mL), trifluoroacetamide (26mg, 0.44mmol), 1-ethyl- (3-dimethylaminopropyl) carbonyldiimine hydrochloride (94mg, 0.49mmol) and 4-dimethylaminopyridine (90mg, 0.74mmol) were added and the mixture was stirred at room temperature overnight. LCMS showed a small amount of starting material remaining and product formed and reaction stopped. The reaction solution was washed with water (5 mL), and concentrated under reduced pressure to give crude product, which was isolated and purified to give product (21mg, 12%), purity: 97 percent. LCMS (liquid Crystal display Module) [ M + H ] ] + ：704.10。 1 H NMR(500MHz,CD 3 OD)δ9.11 (s,1H),7.70–7.63(m,1H),7.52(t,J＝8.2Hz,1H),7.43(s,1H),7.33(s,1H),7.26–7.19(m,2H),6.94(d,J＝ 7.4Hz,1H),6.75(d,J＝8.3Hz,1H),5.80(s,2H),5.45(s,2H),4.66(s,2H),4.26(q,J＝7.3Hz,2H),3.94(s,2H), 3.35(s,2H),3.04(s,1H),2.27(m,4H),1.39(t,J＝7.3Hz,3H)。
Example 65N-carbamoyl-2- ((4- (6- ((4-chloro-2-fluorobenzyl) oxy) pyridin-2-yl) piperidin-1-yl) methyl) -1- ((1-ethyl-1H-imidazol-5-yl) methyl) -1H-thieno [2,3-d ] imidazole-5-carboxamide
Figure BDA0003128505470000873
2- ((1- (6- (4-chloro-2-fluorobenzyloxy) pyridin-2-yl) piperidin-4-yl) -1- ((1-yl-1H-imidazol-5-yl) methyl) -1H-thieno [2,3-d]Imidazole-5-carboxylic acid (150mg, 0.25mmol) was dissolved in toluene (5 mL), 3,4, 5-trifluorophenylboronic acid (2.2mg, 0.0125 mmol), urea (17 mg, 0.28 mmol), 4A molecular sieves (50 mg) were added, and the mixture was stirred at reflux overnight. LCMS showed a small amount of starting material remaining and product formed and reaction stopped. The reaction solution was washed with water (5 mL), and concentrated under reduced pressure to give crude product, which was isolated and purified to give product (24mg, 15%), purity: 98 percent. LCMS (liquid Crystal display Module) [ M + H ]] + ：651.2。 1 H NMR(500MHz,CD 3 OD)δ8.89(s,1H),7.70–7.63(m,1H),7.50(t,J＝8.2Hz,1H),7.43(s, 1H),7.33(s,1H),7.26–7.19(m,2H),6.94(d,J＝7.4Hz,1H),6.75(d,J＝8.3Hz,1H),5.80(s,2H),5.45(s,2H), 4.66(s,2H),4.22(q,J＝7.3Hz,2H),3.94(s,2H),3.35(s,2H),3.04(s,1H),2.27(m,4H),1.38(t,J＝7.3Hz, 3H)。
Example 66N-Thiocarbamoyl-2- ((4- (6- ((4-chloro-2-fluorobenzyl) oxy) pyridin-2-yl) piperidin-1-yl) methyl) -1- ((1-ethyl-1H-imidazol-5-yl) methyl) -1H-thieno [2,3-d ] imidazole-5-carboxamide
Figure BDA0003128505470000881
2- ((1- (6- (4-chloro-2-fluorobenzyloxy) pyridin-2-yl) piperidin-4-yl) -1- ((1-yl-1H-imidazol-5-yl) methyl) -1H-thieno [2,3-d]Imidazole-5-carboxylic acid (150mg, 0.25mmol) was dissolved in toluene (5 mL), 3,4, 5-trifluorophenylboronic acid (2.2mg, 0.0125 mmol), thiourea (21 mg, 0.28 mmol), 4A molecular sieves (50 mg) were added, and the mixture was stirred at reflux overnight. LCMS showed the starting material reaction was complete and the reaction was stopped. The reaction solution was washed with water (5 mL), and concentrated under reduced pressure to give a crude product, which was isolated and purified to give a product (18mg, 11%) with a purity of: 98 percent. LCMS (liquid Crystal display Module) [ M + H ] ] + ：667.2。 1 H NMR(500MHz,CD 3 OD)δ8.88(s,1H),7.70–7.63(m,1H),7.50(t,J＝8.2Hz,1H),7.43(s,1H),7.33(s, 1H),7.26–7.19(m,2H),6.94(d,J＝7.4Hz,1H),6.75(d,J＝8.3Hz,1H),5.80(s,2H),5.45(s,2H),4.66(s,2H), 4.19(q,J＝7.3Hz,2H),3.94(s,2H),3.35(s,2H),3.04(s,1H),2.27(m,4H),1.35(t,J＝7.3Hz,3H)。
Example 67- ((4- (6- ((4-chloro-2-fluorobenzyl) oxy) pyridin-2-yl) piperidin-1-yl) methyl) -1- ((1-ethyl-1H-imidazol-5-yl) methyl) -N- (N-methylcarbamoyl) -1H-thieno [2,3-d ] imidazole-5-carboxamide
Figure BDA0003128505470000882
2- ((1- (6- (4-chloro-2-fluorobenzyloxy) pyridin-2-yl) piperidin-4-yl) -1- ((1-yl-1H-imidazol-5-yl) methyl) -1H-thieno [2,3-d]Imidazole-5-carboxylic acid (150 mg,0.25 mmol) was dissolved in toluene (5 mL), 3,4, 5-trifluorophenylboronic acid (2.2mg, 0.0125 mmol), N-methylurea (21 mg, 0.28mmol), 4A molecular sieve (50 mg) were added, and the mixture was stirred under reflux overnight. LCMS showed the starting material reaction was complete and the reaction was stopped. The reaction solution was washed with water (5 mL), and concentrated under reduced pressure to give crude product, which was prepared, separated and purified to give product (17mg, 10%), purity: 98 percent. LCMS (liquid Crystal display Module) [ M + H ]] + ： 665.2。 1 H NMR(500MHz,CD 3 OD)δ8.90(s,1H),7.70–7.63(m,1H),7.50(t,J＝8.2Hz,1H),7.43(s,1H), 7.33(s,1H),7.26–7.19(m,2H),6.94(d,J＝7.4Hz,1H),6.75(d,J＝8.3Hz,1H),5.80(s,2H),5.45(s,2H), 4.66(s,2H),4.19(q,J＝7.3Hz,2H),3.94(s,2H),3.35(s,2H),3.04(s,1H),3.02(s,3H),2.27(m,4H),1.38(t,J ＝7.3Hz,3H)。
Example 68- ((4- (6- ((4-chloro-2-fluorobenzyl) oxy) pyridin-2-yl) piperidin-1-yl) methyl) -1- ((1-ethyl-1H-imidazol-5-yl) methyl) -N- (S-methylsulfomimido) -1H-thieno [2,3-d ] imidazole-5-carboxamide (including its tautomer)
Figure BDA0003128505470000883
2- ((1- (6- (4-chloro-2-fluorobenzyloxy) pyridin-2-yl) piperidin-4-yl) -1- ((1-yl-1H-imidazol-5-yl) methyl) -1H-thieno [2,3-d]Imidazole-5-carboxylic acid (122mg, 0.2mmol) was dissolved in thionyl chloride (5 mL), the mixture was stirred at 60 ℃ for 1 hour, the solvent was removed by concentration under reduced pressure, the resulting residue was dissolved in acetonitrile (5 mL), a 0.5M solution of pyridazine in acetonitrile (2 mL) was added dropwise to the above system, stirred for 1 minute, and then N- (tert-butyldimethylsilyl) methylsulfonimide [ ref.chen, y.; gibson, J.A. Derived synthetic routes to amides from amides, RSC adv.2015,5,4171-4174.](19mg, 0.2mmol) in acetonitrile (1 mL), and the mixture was stirred at room temperature overnight. LCMS showed the starting material was essentially reacted to completion, stopping the reaction. The reaction solution is decompressed and concentrated to obtain a crude product, and the crude product is prepared, separated and purified to obtain a product (35mg, 13 percent, containing the tautomer thereof), and has the purity: 98 percent. LCMS (liquid Crystal display Module) [ M + H ]] + ：685.20。 1 H NMR(500MHz, CD 3 OD)δ9.00(br,1H),7.71–7.63(m,1H),7.52(t,J＝8.2Hz,1H),7.43(s,1H),7.33(s,1H),7.26–7.19(m,2H), 6.94(d,J＝7.4Hz,1H),6.75(d,J＝8.3Hz,1H),5.80(s,2H),5.45(s,2H),4.66(s,2H),4.20(q,J＝7.3Hz,2H), 3.94(s,2H),3.35(s,2H),3.10(d,J＝0.5Hz,3H)3.04(s,1H),2.27(m,4H),1.38(t,J＝7.3Hz,3H)。
Biological assay
Test A: GLP-1R agonist activity assay
GLP-1R agonist activity detection is a competitive immunoassay that is calculated by comparing the endogenous cAMP produced by the cells to the exogenous cAMP labeled with the d2 stain. anti-cAMP antibodies conjugated to cryptate can be used to detect cAMP levels, the intensity of the signal detected being inversely proportional to cAMP levels.
The HEK/GLP1R/CRE/Luc cell line capable of expressing human GLP-1R on the cell surface was used for this experiment. Human GLP-1R gene was cloned into HEK cells for expression and cell suspensions were prepared prior to performing the experiments. Working solutions of the test compounds of the present invention diluted 1000-fold in concentration were prepared according to plate type arrangement, and the total 10nl volume of working solution was added to the test plate. Cell suspension was added at 10. Mu.L per well. Sealing plate, at 37 ℃ 5% 2 Incubate for 30 minutes. The level of cAMP production was measured by adding 5. Mu.L of cAMP-d2 working solution to each well, followed by 5. Mu.L of anti-cAMP-labeled antibody working solution. The plate is covered with a cover. Incubate at room temperature for 1 hour. Fluorescence was read with a fluorescent microplate reader at 665 and 615/620nm and the data saved. Calculation of EC for GLP-1R activation by test Compounds of the invention by Effect Curve fitting Compound concentration and corresponding cAMP levels 50 The value is obtained.
GLP-1R agonistic Activity (EC) of test Compounds of the invention 50 ) The test results are listed in table 1, where, +:>100nM；++：50-100 nM；+++：10-50nM；++++：<10nM
TABLE 1 GLP-1R agonistic activity of compounds
Test compounds EC 50 (nM) Test compounds EC 50 (nM)
Example 2 ++++ Example 10 +
Example 11 ++++ Example 12 ++++
Example 13 + Example 14 ++++
Example 15 ++++ Example 17 ++++
Example 19 ++++ Example 21 +
Example 23 + Example 25 ++++
Example 26 ++++ Example 27 ++++
Example 28 + Example 29 +++
Example 30 + Example 31 +++
Example 32 + Example 33 +++
Example 34 ++ Example 35 ++++
Example 36 + Example 37 ++++
Example 38 + Example 39 +
Example 40 + EXAMPLE 41 +++
Example 42 +++ Example 46 ++++
Example 47 ++++ Example 48 +++
Example 49 ++++ Example 50 ++++
Example 51 ++++ Example 53 +++
Example 56 ++++ Example 57 ++++
Example 58 ++++ Example 59 ++++
Examples61 ++++ Example 62 ++++
Example 63 ++++ Example 67 +++
Test B: pharmacokinetic Studies
Liver microsome stability test
After incubation of the test compounds of the invention with human and rat liver microsomes, metabolic stability was evaluated by measuring the decrease in the test compounds of the invention at different incubation times.
Study of absorption pharmacokinetics in rats
In the experiment, rat plasma samples are obtained at different time points after 1mg/kg single intravenous injection (i.v.) and 5mg/kg oral gavage (i.g.) administration research of SD rats; the LC-MS/MS method is used for detecting the concentration of the tested compound in the plasma of the SD rat, so as to evaluate the pharmacokinetic characteristics of the compound in the SD rat.
6 SD rats were randomly divided into 2 groups, and group A animals were administered a 1mg/kg test compound solution of the present invention intravenously and blood was collected intravenously at 0.083, 0.25, 0.5, 1, 2, 4, 8 and 24h before and after administration, respectively; animals in group B were gavaged with 5mg/kg of the test compound formulation of the invention and bled intravenously before and 0.25, 0.5, 1, 2, 4, 8 and 24h post-dose, respectively.
The concentration of the tested compound in the plasma of the SD rat is detected by an LC-MS/MS method, and the obtained blood concentration data adopts a WinNonlin non-atrioventricular model to calculate relevant pharmacokinetic parameters.
Tests show that the compound has better stability of liver microsomes in human and rats, better pharmacokinetic property, quicker oral absorption and better bioavailability.
In a word, the compound has good agonism on a GLP-1 receptor, excellent in-vivo and in-vitro drug effect and pharmacokinetic property, and good clinical application prospect.
The technical features of the embodiments described above may be arbitrarily combined, and for the sake of brevity, all possible combinations of the technical features in the embodiments described above are not described, but should be considered as being within the scope of the present specification as long as there is no contradiction between the combinations of the technical features.
The above-mentioned embodiments only express several embodiments of the present invention, and the description thereof is more specific and detailed, but not construed as limiting the scope of the invention. It should be noted that various changes and modifications can be made by those skilled in the art without departing from the spirit of the invention, and these changes and modifications are all within the scope of the invention. Therefore, the protection scope of the present invention should be subject to the appended claims.

Claims (10)

1.式(II)所示化合物：1. Compound represented by formula (II):
Figure FDA0003949105730000011
Figure FDA0003949105730000011
 或其药学上可接受的盐、水合物，其中，or a pharmaceutically acceptable salt or hydrate thereof, wherein: L2是-N(Rc)-、-CH2-； L2 is -N( Rc )-, -CH2- ; Ar1是Ar 1 is
Figure FDA0003949105730000012
Figure FDA0003949105730000012
 Y1和Y2分别独立地为N或-C(R2)-；且当Ar1是
Figure FDA0003949105730000013
时，Y1和Y2分别独立地为-C(R2)-；Y 1 and Y 2 are each independently N or -C(R 2 )-; and when Ar 1 is
Figure FDA0003949105730000013
When Y1 and Y2 are independently -C( R2 )-; Cy是Cy is
Figure FDA0003949105730000014
Figure FDA0003949105730000014
Figure FDA0003949105730000015
是
Figure FDA0003949105730000015
yes
Figure FDA0003949105730000016
Figure FDA0003949105730000016
Figure FDA0003949105730000021
Figure FDA0003949105730000021
 W是-C(＝O)OR7a、-P(＝O)(OR7a)(OR7b)、-C(＝O)N(R7c)R7d、-C(＝O)N(R7c)S(＝O)1-2R7d、-C(＝O)N(R7c)S(＝O)1-2N(R7c)R7d、-C(＝O)N(R7c)C(＝O)R7d、-C(＝O)N(R7c)C(＝O)N(R7c)R7d；W is -C(=O)OR 7a , -P(=O)(OR 7a )(OR 7b ), -C(=O)N(R 7c )R 7d , -C(=O)N(R 7c )S(＝O) 1-2 R 7d , -C(＝O)N(R 7c )S(＝O) 1-2 N(R 7c )R 7d , -C(＝O)N(R 7c ) C(=O)R 7d , -C(=O)N(R 7c )C(=O)N(R 7c )R 7d ; 各R1分别独立地为H、D、F、Cl、Br、I、-CN；Each R 1 is independently H, D, F, Cl, Br, I, or -CN; R5是H、-COOH、R5c-C(＝O)-、R5c-L3-C1-3烷基-、R5a、R5a-C1-3烷基；R 5 is H, -COOH, R 5c -C(=O)-, R 5c -L 3 -C 1-3 alkyl-, R 5a , R 5a -C 1-3 alkyl; L3是-NH-； L3 is -NH-; R5a和R5c各自独立地为R 5a and R 5c are each independently
Figure FDA0003949105730000022
Figure FDA0003949105730000022
 其中所述R5a和R5c各自任选地被1、2个独立地选自由H、-OH、C1-4烷基C1-4烷氧基的基团取代；wherein R 5a and R 5c are each optionally substituted by 1 or 2 groups independently selected from H, -OH, C 1-4 alkyl, C 1-4 alkoxy; R2独立地为H、F、Cl、Br、I； R2 is independently H, F, Cl, Br, I; R6为H； R6 is H; Rc为C2-7杂环基C1-6烷基；R c is C 2-7 heterocyclyl C 1-6 alkyl; 各R7c和R7d分别独立地为H、-OH、C1-6烷基、C6-12芳基、C6-12芳基C1-6烷基；Each R 7c and R 7d is independently H, -OH, C 1-6 alkyl, C 6-12 aryl, C 6-12 arylC 1-6 alkyl; R7a和R7b各自独立地为H、C1-6烷基；R 7a and R 7b are each independently H, C 1-6 alkyl; n是1、2、3。n is 1, 2, 3. 2.根据权利要求1所述的化合物，其中，Ar1是2. The compound according to claim 1, wherein Ar 1 is
Figure FDA0003949105730000023
Figure FDA0003949105730000023
 3.根据权利要求1所述的化合物，其具有式(III)所示结构：3. The compound according to claim 1, having a structure shown in formula (III):
Figure FDA0003949105730000024
Figure FDA0003949105730000024
 或其药学上可接受的盐，or a pharmaceutically acceptable salt thereof, 其中Y1和Y2分别独立地为N或-C(R2)-；和wherein Y 1 and Y 2 are independently N or -C(R 2 )-; and m是0、1、2、或3。m is 0, 1, 2, or 3. 4.根据权利要求1所述的化合物，其具有式(IV)所示结构：4. The compound according to claim 1, which has a structure shown in formula (IV):
Figure FDA0003949105730000031
Figure FDA0003949105730000031
 或其药学上可接受的盐、水合物、或混合物，or a pharmaceutically acceptable salt, hydrate, or mixture thereof, 其中Y1和Y2分别独立地为N或-C(R2)-；和wherein Y 1 and Y 2 are independently N or -C(R 2 )-; and m是0、1、2、或3。m is 0, 1, 2, or 3. 5.根据权利要求4所述的化合物，其中W是-COOH、-COOCH3、
Figure FDA0003949105730000032
Figure FDA0003949105730000033
其中R7d是H、甲基、乙基、丙基、异丙基、丁基、叔丁基、-CF3、-CH2CF3、环丙基、环丁基、或苯基；5. The compound according to claim 4, wherein W is -COOH, -COOCH 3 ,
Figure FDA0003949105730000032
Figure FDA0003949105730000033
wherein R 7d is H, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, -CF 3 , -CH 2 CF 3 , cyclopropyl, cyclobutyl, or phenyl; 其中R7d任选地被0、1、2、3或4个独立选自D、F、Cl、Br、I或C1-4烷基的取代基取代。wherein R 7d is optionally substituted with 0, 1, 2, 3 or 4 substituents independently selected from D, F, Cl, Br, I or C 1-4 alkyl. 6.根据权利要求4所述的化合物，其中，R5是R5c-C(＝O)-或R5a-C1-3烷基-；R5a和R5c各自独立地为
Figure FDA0003949105730000034
Figure FDA0003949105730000035
6. The compound according to claim 4, wherein R 5 is R 5c -C(=O)- or R 5a -C 1-3 alkyl-; R 5a and R 5c are each independently
Figure FDA0003949105730000034
Figure FDA0003949105730000035
 其中所述R5a和R5c各自任选地被1、2或3个独立地选自由C1-4烷基、C1-4卤代烷基和C3-6环烷基组成的基团取代。wherein R 5a and R 5c are each optionally substituted by 1, 2 or 3 groups independently selected from the group consisting of C 1-4 alkyl, C 1-4 haloalkyl and C 3-6 cycloalkyl. 7.一种化合物，其中，其为具有以下结构之一的化合物：7. A compound, wherein it is a compound having one of the following structures:
Figure FDA0003949105730000036
Figure FDA0003949105730000036
Figure FDA0003949105730000041
Figure FDA0003949105730000041
Figure FDA0003949105730000051
Figure FDA0003949105730000051
Figure FDA0003949105730000061
Figure FDA0003949105730000061
 或其药学上可接受的盐、水合物。or a pharmaceutically acceptable salt or hydrate thereof. 8.药物组合物，所述药物组合物包含权利要求1-7中任一项所述的化合物或其药学上可接受的盐，以及药学上可接受的辅料、稀释剂或载体。8. A pharmaceutical composition comprising the compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, diluent or carrier. 9.使用权利要求1-7任一项所述的化合物或权利要求8所述的药物组合物在制备用于预防和/或治疗哺乳动物心血管代谢性疾病和相关病症的药物中的用途。9. Use of the compound according to any one of claims 1 to 7 or the pharmaceutical composition according to claim 8 in the preparation of a medicament for preventing and/or treating cardiovascular metabolic diseases and related conditions in mammals. 10.根据权利要求9所述的用途，其中，所述心血管代谢性疾病和相关病症是T1D、T2DM、糖尿病前期、特发性T1D、LADA、EOD、YOAD、MODY、营养不良相关性糖尿病、妊娠糖尿病、高血糖症、胰岛素抗性、肝脏胰岛素抗性、葡萄糖耐受不良、糖尿病神经病变、糖尿病肾病变、糖尿病视网膜病变、帕金森病。10. The method of claim 9, wherein the cardiovascular metabolic diseases and related conditions are T1D, T2DM, prediabetes, idiopathic T1D, LADA, EOD, YOAD, MODY, malnutrition-related diabetes, gestational diabetes, hyperglycemia, insulin resistance, hepatic insulin resistance, glucose intolerance, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, Parkinson's disease.
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