CN113831337A - 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
CN113831337A
CN113831337A CN202110697757.0A CN202110697757A CN113831337A CN 113831337 A CN113831337 A CN 113831337A CN 202110697757 A CN202110697757 A CN 202110697757A CN 113831337 A CN113831337 A CN 113831337A
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radical
alkyl
heteroaryl
cycloalkyl
methyl
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CN113831337B (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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Guangzhou Henovcom Bioscience Co ltd
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Abstract

The invention provides a heteroaryl compound shown in a formula (I) as a GLP-1 receptor agonist, or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, regioisomer, nitrogen 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. The compound provided by the invention shows excellent agonism on a GLP-1 receptor and has a very good development prospect.

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 act on lowering blood glucose to treat type II Diabetes (Hampp, C.et al (2014) Diabetes Care,37: 1367-: 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(SGLT2) inhibitors 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 trialsTMFDA (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 depth of the gut-brain axisIn research, 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 glucose-dependent manner to increase peripheral absorption of blood glucose to regulate postprandial blood glucose, decrease glucagon secretion to decrease hepatic glucose production, inhibit gastric emptying and small bowel motility to delay food absorption, reduce appetite, and stimulate beta cell proliferation (Meier, et al. (2003) Biodrugs,17.2:93-102. Vilsball, T.et al. (2001) Diabetes,50: 609-. The GLP-1R agonist drugs available at present comprise exenatide, liraglutide and somaglutide which are all polypeptide drugs simulating the structure of natural GLP-1, so that the drugs can only be injected and are expensive, and the cost is up to $1,500 to $2,500 per year (https:// www.ncbi.nlm.nih.gov/books/NBK543967 /). Although the norshanode company has developed oral formulations of somaglutide, due to the limited physicochemical properties of polypeptide drugs, its oral availability is only 1-2%, the daily dose also increases from less than 1mg per day to 14mg per day of the original injected dose, and the cost also rises 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" is used interchangeably with the term "unsubstituted or … substituted", i.e., the structure is unsubstituted or substituted with one or more substituents described herein, including but not limited to, H, D, F, Cl, Br, I, -OH, SH, -NH2、-NO2-CN, -oxo (-O), N 3Alkyl, alkenyl, alkynyl, hydroxyAlkyl, haloalkyl, aminoalkyl, cyanoalkyl, alkoxy, haloalkoxy, alkylthio, alkylamino, haloalkylamino, -NR1bR1cCycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl and the like, wherein R is1bAnd R1cAll have the definitions as set forth herein.
In addition, unless otherwise expressly indicated, the descriptions of "… independently" and "… independently" and "… independently" used in this disclosure are to be construed broadly, and they are intended to mean that the particular elements expressed between the same symbols in different groups do not affect each other, or that the particular elements 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 invention includes each and every independent subcombination of the various members of these groups and ranges. For example, the term "C1-6Alkyl "means in particular independently disclosed methyl, ethyl, C 3Alkyl radical, C4Alkyl radical, C5Alkyl and C6An 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 to be understood as 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)2CH3) N-propyl (n-Pr, -CH)2CH2CH3) Isopropyl group (i-Pr, -CH (CH)3)2) N-butyl (n-Bu, -CH)2CH2CH2CH3) Isobutyl (i-Bu, -CH)2CH(CH3)2) Sec-butyl (s-Bu, -CH (CH)3)CH2CH3) Tert-butyl (t-Bu, -C (CH)3)3) N-pentyl (-CH)2CH2CH2CH2CH3) 2-pentyl (-CH (CH)3)CH2CH2CH3) 3-pentyl (-CH (CH)2CH3)2) 2-methyl-2-butyl (-C (CH)3)2CH2CH3) 3-methyl-2-butyl (-CH (CH)3)CH(CH3)2) 3-methyl-1-butyl (-CH)2CH2CH(CH3)2) 2-methyl-1-butyl (-CH)2CH(CH3)CH2CH3) N-hexyl (-CH)2CH2CH2CH2CH2CH3) 2-hexyl (-CH (CH)3)CH2CH2CH2CH3) 3-hexyl (-CH (CH)2CH3)(CH2CH2CH3) 2-methyl-2-pentyl (-C (CH))3)2CH2CH2CH3) 3-methyl-2-pentyl (-CH (CH)3)CH(CH3)CH2CH3) 4-methyl-2-pentyl (-CH (CH)3)CH2CH(CH3)2) 3-methyl-3-pentyl (-C (CH)3)(CH2CH3)2) 2-methyl-3-pentyl (-CH (CH)2CH3)CH(CH3)2) 2, 3-dimethyl-2-butyl (-C (CH)3)2CH(CH3)2) 3, 3-dimethyl-2-butyl (-CH (CH)3)C(CH3)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 sp2Double 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)2CH＝CH2) And so on. The alkenyl group may be optionally substituted with one or more substituents described herein.
The term "alkynyl" 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. 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.ident.CH), propargyl (-CH)2C.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)2CH3) 1-propoxy (n-PrO, n-propoxy, -OCH)2CH2CH3) 2-propoxy (i-PrO, i-propoxy, -OCH (CH)3)2) 1-butoxy (n-BuO, n-butoxy, -OCH)2CH2CH2CH3) 2-methyl-l-propoxy (i-BuO, i-butoxy, -OCH)2CH(CH3)2) 2-butoxy (s-BuO, s-butoxy, -OCH (CH)3)CH2CH3) 2-methyl-2-propoxy (t-BuO, t-butoxy, -OC (CH)3)3) 1-pentyloxy (n-pentyloxy, -OCH)2CH2CH2CH2CH3) 2-pentyloxy (-OCH (CH)3)CH2CH2CH3) 3-pentyloxy (-OCH (CH))2CH3)2) 2-methyl-2-butoxy (-OC (CH))3)2CH2CH3) 3-methyl-2-butoxy (-OCH (CH)3)CH(CH3)2) 3-methyl-l-butoxy (-OCH)2CH2CH(CH3)2) 2-methyl-l-butoxy (-OCH)2CH(CH3)CH2CH3) 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, 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., C3To C10A cycloalkyl group. In some embodiments, the cycloalkyl has 3-15 (C)3-15)、3-10(C3-10) 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 a cycloalkyl group is substituted, it may be independently substituted on either ring, i.e., on any aromatic or non-aromatic ring comprised by the cycloalkyl group, with one or more substituents 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)0-2And 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)0-2And N, and the remaining ring atoms are all carbon atoms. In some embodiments, the heterocyclic ring contains 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 in an aromatic ring, orContaining two heteroatoms, one in the aromatic ring and the other in the 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 be attached to the main structure through any ring thereof, including any aromatic or non-aromatic ring, regardless of whether the ring contains heteroatoms. 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, piperidyl, and the like Morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, dithianyl, thiazaalkyl, homopiperazinyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepanyl
Figure BDA0003128505470000042
Radical, diaza
Figure BDA0003128505470000043
Radical, S-N-aza
Figure BDA0003128505470000044
A group, a benzodioxanyl group, a benzodioxolyl group, a benzofuranonyl group, a benzopyranonyl group, a benzopyranyl group, a dihydrobenzofuranyl group, a benzothiophenyl group, a benzoxazinyl group, a β -carbolinyl group, a chromanyl group, a chromonyl group, a cinnolinyl group, a coumarinyl group, a decahydroquinolinyl group, a decahydroisoquinolinyl group, a dihydrobenzisothiazinyl group, a dihydrobenzisoxazinyl group, a dihydrofuranyl group, a dihydroisoindolyl group, a dihydropyranyl group, a dihydropyrazolyl group, a dihydropyrazinyl group, a dihydropyridinyl group, a dihydropyrimidyl group, a dihydropyrrolyl group, a dioxolanyl group, a 1, 4-dithianyl group, a furanonyl group, an imidazolidinyl group, a 2, 4-dioxo-imidazolidinyl group, an imidazolinyl group, an indolinyl group, a 2-oxo-indolinyl group, an isobenzotetrahydrofuranyl group, an isobenzotetrahydrothiophenyl group, isochromanyl, isocoumarin, isoindolinyl (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-piperidonyl, 2-oxopyrrolidinyl, 2, 5-dioxopyrrolidinyl, quinuclidinyl, tetrahydroisoquinolinyl, 3, 5-dioxo-thiomorpholinyl, thiazolidinyl, 2, 4-dioxo-thiazolidinyl, tetrahydroquinolinyl, phenothiazinyl, phenoxazinyl, xanthenyl and 1,3, 5-trithiohexanyl. In heterocyclic radicals of-CH 2Examples of-groups substituted by-C (═ O) -include, but are not limited to, 2-oxopyrrolidinyl, oxo-1, 3-thiazolidinyl, 2-piperidinonyl, 3, 5-dioxopiperidinyl and pyrimidinedione. 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 as 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-CH2-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, 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, thiepanyl, oxacycloheptanyl, oxazepanyl, thiazepanyl, and the like
Figure BDA0003128505470000045
Radical, diaza
Figure BDA0003128505470000046
Radical, S-N-aza
Figure BDA0003128505470000047
And (4) a base. In heterocyclic radicals of-CH2Examples of-radicals substituted by-C (═ O) -include, but are not limited to, 2-oxopyrrolidinyl, oxo-1, 3-thiazolidinyl, 2-piperidinonyl3, 5-dioxopiperidinyl and pyrimidinedionyl 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-CH2-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 containing 5-6 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 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 consisting of 5 to 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 consisting of 5 to 6 atoms may optionally be substituted by a groupSubstituted with one or more substituents 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 remainder 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 (a1), 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 ] compounds ]Furan, 2,3,3a,4,7,7 a-hexahydro-1H-indene, 7-azabicyclo [2.3.0 ]]Heptane, fused bicyclo [3.3.0]Octane, fused 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, -NH2、-NO2、-CNOxo (═ O), N3Alkyl, alkenyl, alkynyl, hydroxyalkyl, haloalkyl, aminoalkyl, cyanoalkyl, alkoxy, haloalkoxy, alkylthio, alkylamino, haloalkylamino, -NR1bR1cCycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl and the like, wherein R is1bAnd R1cAll 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 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，PO2Examples 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 ] and]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, -NH2、-NO2-CN, -oxo (-O), N3Alkyl, alkenyl, alkynyl, hydroxyalkyl, haloalkyl, aminoalkyl, cyanoalkyl, alkoxy, haloalkoxy, alkylthio, alkylamino, haloalkylamino, -NR1bR1cCycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl and the like, wherein R is1bAnd R1cAll have the inventionThe above definitions are provided.
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, -NH2、-NO2-CN, -oxo (-O), N3Alkyl, alkenyl, alkynyl, hydroxyalkyl, haloalkyl, aminoalkyl, cyanoalkyl, alkoxy, haloalkoxy, alkylthio, alkylamino, haloalkylamino, -NR1bR1cCycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl and the like, wherein R is1bAnd R1cAll have the definitions as set forth herein.
Figure BDA0003128505470000061
The term "spiroheterobicyclic group" means that one ring originates from a specific 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，PO2Examples 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, -NH2、 -NO2-CN, -oxo (-O), N3Alkyl, alkenyl, alkynyl, hydroxyalkyl, haloalkyl, aminoalkyl, cyanoalkyl, alkoxy, haloalkoxy, alkylthio, alkylamino, haloalkylamino, -NR1bR1cCycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl and the like, wherein R is1bAnd R1cAll have the definitions as set forth herein.
The term "bridged ring group" as used herein denotes a saturated or unsaturated bridged ring system, relating to a non-aromatic bridged ring system, as shown in formula (a2), i.e. ring a1 shares an alkyl or a heteroalkyl chain with ring a2, 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, 1,2,3,4,4a,5,8,8 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, -NH2、-NO2-CN, -oxo (-O), N3Alkyl, alkenyl, alkynyl, hydroxyalkyl, haloalkyl, aminoalkyl, cyanoalkyl, alkoxy, haloalkoxy, alkylthio, alkylamino, haloalkylamino, -NR1bR1cCycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, or heteroarylAlkyl, etc., wherein R1bAnd R1cAll 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，PO2Examples 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-diazabicyclo [2.2.1]Heptane, (1R,5S) -8-azabicyclo [3.2.1]Octane, and the like. And the 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, -NH2、 -NO2-CN, -oxo (-O), N3Alkyl, alkenyl, alkynyl, hydroxyalkyl, haloalkyl, aminoalkyl, cyanoalkyl, alkoxy, haloalkoxy, alkylthio, alkylamino, haloalkylamino, -NR1bR1cCycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl and the like, wherein R is1bAnd R1cAll 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 (a3) or (a4), which means 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-C14A 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]An oct-1, 3, 5-trienyl group, an indanyl group, a fluorenyl group, or a tetrahydronaphthyl group. 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 groups optionally substituted with said aryl group may be independently optionally substituted with one or more substituents described herein, including in some embodiments independently selected from H, D, F, Cl, Br, I, -OH, SH, -NH2、-NO2-CN, -oxo (-O), N3Alkyl, alkenyl, alkynyl, hydroxyalkyl, haloalkyl, aminoalkyl, cyanoalkyl, alkoxy, haloalkoxy, alkylthio, alkylamino, haloalkylamino, -NR1bR1cCycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl, and the like, wherein R is substituted with a substituent 1bAnd R1cAll 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 said 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 atoms are independently selected from O, S (O) in said ring0-2And 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, furyl, 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, pyridyl, phenanthrolinyl, phenanthridinyl, and phenazinyl. In some or any of the embodiments of the present invention, Heteroaryl is indolyl, furyl, pyridyl, 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, -NH2、 -NO2-CN, -oxo (-O), N3Alkyl, alkenyl, alkynyl, hydroxyalkyl, haloalkyl, aminoalkyl, cyanoalkyl, alkoxy, haloalkoxy, alkylthio, alkylamino, haloalkylamino, -NR1bR1cCycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl and the like, wherein R is substituted with a substituent1bAnd R1cAll 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 C1-6Lower alkylamino groups in which the alkyl group is attached to the nitrogen atom. In other embodiments, the alkylamino group is C1-3Lower 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 groups1-10A straight or branched alkyl group. In some of these embodiments, aminoalkyl is C substituted with one or more amino groups1-6"lower aminoalkyl" and other examples are aminoalkyl which is C substituted with one or more amino groups1-4Examples 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 1-10A straight or branched alkyl group. In some of these embodiments, cyano-substituted alkyl is C substituted with one or more cyano groups1-6"lower cyanoalkyl", other embodiments are where the cyano-substituted alkyl is C substituted with one or more cyano groups1-4"lower cyanoalkyl", examples of which include, but are not limited to, CNCH2-、CNCH2CH2-、CNCH2CH2CH2-、CNCH2CHCNCH2-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,1977,66:1-19. Pharmaceutically acceptable non-toxic acid forming salts include, but are not limited to, salts of inorganic acids such as hydrochloride, hydrobromide, phosphate, sulfate, perchlorate, and salts of organic acids such as acetate, oxalate, maleate, Tartrate, citrate, succinate, malonate, or 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, malates, malonates, methanesulfonates, 2-naphthalenesulfonates, nicotinates, nitrates, oleates, palmitates, pamoates, pectinates, persulfates, 3-phenylpropionates, picrates, pivalates, propionates, stearates, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like. Salts obtained by reaction with a suitable base include alkali metals, alkaline earth metals, ammonium and N +(C1-C4Alkyl radical)4A 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, C1-8Sulfonates 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,
L1is O, S, -N (R)c) -, -C (═ O) -, or-C (R)a)(Rb)-；
L2Is O, S, -N (R)c)-、-C(＝O)-、-(C(Ra)(Rb))t1-、-X-(C(Ra)(Rb))t1-, or- (C (R)a)(Rb))t1-X-(C(Ra)(Rb))t2-；
Z1And Z2Each independently is N or CH;
Ar1is C6-10Aryl radical, C1-9Heteroaryl group, C3-8Cycloalkyl radical, C2-9Heterocyclic group, C5-12Condensed bicyclic group, or C5-12Fused heterobicyclic group wherein said Ar1Optionally substituted by 0, 1, 2, 3 or 4R2Substitution;
cy is C3-8Cycloalkyl radical, C2-9Heterocyclic group, C5-12Spiro bicyclic group, C5-12Spiro-heterobicyclic radical, C5-12Condensed bicyclic group, C5-12Fused heterobicyclic radical, C5-12Bridged ring radical, or C5-12Bridged heterocyclyl, wherein said Cy is optionally substituted with 0, 1, 2, 3, or 4R3Substitution;
Ar2is a fused heteroaryl 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 is2Optionally substituted by 0, 1, 2, 3 or 4R6Substitution;or Ar2The method comprises the following steps:
Figure BDA0003128505470000092
Figure BDA0003128505470000093
wherein Ar is2Optionally substituted by 0, 1, 2, 3 or 4R6Substitution;
x is O, S, -N (R)d) -, or-C (═ O) -;
X1、X2and X3Are each independently N or-C (R)6)-；
X5Is O or S;
w is-C (═ O) OR7a、-S(＝O)1-2OR7a、-P(＝O)(OR7a)(OR7b)、-P(＝O)(OR7a)(R7c)、-S(＝O)1-2R7d、-C(＝O)R7d、 -C(＝O)N(R7c)R7d、-S(＝O)1-2N(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、-C(＝O)N(R7c)C(＝S)N(R7c)R7d、 -C(＝O)N(R7c)S(＝NR7a)1-2R7d、-C(＝O)N(R7c)S(＝O)(＝NR7a)R7d、
Figure BDA0003128505470000094
Figure BDA0003128505470000095
Each R1Are respectively and independently H, D, F, Cl, Br, I, -OH, -NH 2、-NO2-CN, -oxo (-O), C1-6Alkyl radical, C1-6Hydroxyalkyl radical, C1-6Haloalkyl, C1-6Aminoalkyl radical, C1-6Cyanoalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, C1-6Alkylthio radical, C1-6Alkylamino radical, C3-8Cycloalkyl radical, C3-8Cycloalkyl radical C1-6Alkyl radical, C3-8Cycloalkyl radical C2-6Alkenyl radical, C3-8Cycloalkyl radical C2-6Alkynyl, C2-7Heterocyclic group, C2-7Heterocyclyl radical C1-6Alkyl radical, C6-12Aryl radical, C6-12Aryl radical C1-6Alkyl radical, C1-9Heteroaryl, or C1-9Heteroaryl C1-6Alkyl, -S (═ O)1-2R1a、-C(＝O)R1a、 -C(＝O)OR1b、-OS(＝O)1-2R1a、-OC(＝O)R1a、-N(R1b)C(＝O)R1a、-OC(＝O)NR1bR1c、-NR1bR1c、-N(R1b)S(＝O)1-2R1aor-N (R)1b)C(＝O)NR1bR1c；
R5Is H, D, F, Cl, Br, I, -OH, -NH2、-NO2-CN, -oxo (-O), C1-6Alkyl radical, C1-6Haloalkyl, C1-6Cyanoalkyl, C1-6Aminoalkyl radical, C1-6Alkoxy radical C1-6Alkyl radical, C3-10Cycloalkyl radical, C2-9Heterocyclic group, C6-10Aryl radical, C1-9Heteroaryl, R5c-C(＝O)-、 R5c-OC(＝O)-、R5c-C(＝O)O-、R5c-NHC(＝O)-、R5c-C(＝O)NH-、R5c-L3-C1-6Alkyl-, R5a-C1-6Alkyl, or R5a-C1-6Hydroxyalkyl-, wherein said C is1-6Alkyl radical, C1-6Haloalkyl, C1-6Cyanoalkyl, C1-6Aminoalkyl radical, C1-6Alkoxy radical C1-6Alkyl radical, C3-10Cycloalkyl radical, C2-9Heterocyclic group, C6-10Aryl radical, C1-9Heteroaryl, R5c-C(＝O)-、R5c-OC(＝O)-、R5c-C(＝O)O-、R5c-NHC(＝O)-、 R5c-C(＝O)NH-、R5c-L3-C1-6Alkyl-, R5a-C1-6Alkyl and R5a-C1-6Hydroxyalkyl-is independently optionally substituted with 0, 1, 2, 3 or 4R5bSubstitution;
R5ais C3-10Cycloalkyl radical, C2-9Heterocycloalkyl radical, C6-10Aryl, or C1-9Heteroaryl, wherein R is5aOptionally substituted by 0, 1, 2, 3 or 4R5bSubstitution;
R5cis H, C1-6Alkyl radical, C3-10Cycloalkyl radical, C2-9Heterocyclic group, C6-10Aryl, or C 1-9Heteroaryl, wherein R is5cOptionally substituted by 0, 1, 2, 3 or 4R5bSubstitution;
L3is O, S, -N (R)d) -, or-C (═ O) -;
each R1a、R2、R3、R4、R5b、R6、RaAnd RbAre respectively and independently H, D, F, Cl, Br, I, -OH, -NH2、-NO2-CN, -oxo (-O), C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Hydroxyalkyl radical, C1-6Haloalkyl, C1-6Aminoalkyl radical, C1-6Cyanoalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, C1-6Alkylthio radical, C1-6Alkylamino radical, C1-6Haloalkylamino, -NR1bR1c、C3-8Cycloalkyl radical, C3-8Cycloalkyl radical C1-6Alkyl radical, C2-7Heterocyclic group, C2-7Heterocyclyl radical C1-6Alkyl radical, C6-12Aryl radical, C6-12Aryl radical C1-6Alkyl radical, C1-9Heteroaryl, or C1-9Heteroaryl C1-6An alkyl group; wherein C is3-8Cycloalkyl radical, C3-8Cycloalkyl radical C1-6Alkyl radical, C2-7Heterocyclic group, C2-7Heterocyclyl radical C1-6Alkyl radical, C6-12Aryl radical, C6-12Aryl radical C1-6Alkyl radical, C1-9Heteroaryl and C1-9Heteroaryl radicalC1-6Alkyl is optionally substituted by 0, 1, 2, 3 or 4 substituents independently selected from H, F, Cl, Br, I, -OH, -NH2、-NO2-CN, -oxo (-O), C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Hydroxyalkyl radical, C1-6Haloalkyl, C1-6Aminoalkyl radical, C1-6Cyanoalkyl, C1-6Alkoxy and C1-6Substituted with a halo alkoxy group;
each R1b、R1c、Rc、Rd、R7a、R7cAnd R7dEach independently is H, D, -OH, -CN, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Hydroxyalkyl radical, C1-6Haloalkyl, C 1-6Aminoalkyl radical, C1-6Cyanoalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, C1-6Alkylthio radical, C1-6Alkylamino radical, C1-6Haloalkylamino, C3-8Cycloalkyl radical, C3-8Cycloalkyl radical C1-6Alkyl radical, C2-7Heterocyclic group, C2-7Heterocyclyl radical C1-6Alkyl radical, C6-12Aryl radical, C6-12Aryl radical C1-6Alkyl radical, C1-9Heteroaryl, or C1-9Heteroaryl C1-6An alkyl group; wherein C is3-8Cycloalkyl radical, C3-8Cycloalkyl radical C1-6Alkyl radical, C2-7Heterocyclic group, C2-7Heterocyclyl radical C1-6Alkyl radical, C6-12Aryl radical, C6-12Aryl radical C1-6Alkyl radical, C1-9Heteroaryl and C1-9Heteroaryl C1-6Alkyl is optionally substituted by 0, 1, 2, 3 or 4 substituents independently selected from H, F, Cl, Br, I, -OH, -NH2、-NO2-CN, -oxo (-O), C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Hydroxyalkyl radical, C1-6Haloalkyl, C1-6Aminoalkyl radical, C1-6Cyanoalkyl, C1-6Alkoxy and C1-6Substituted with a halo alkoxy group;
R7aand R7bEach independently is H, alkali goldMetal ion, alkaline earth metal ion, -OH, -CN, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Hydroxyalkyl radical, C1-6Haloalkyl, C1-6Aminoalkyl radical, C1-6Cyanoalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, C1-6Alkylthio radical, C1-6Alkylamino radical, C1-6Haloalkylamino, C3-8Cycloalkyl radical, C3-8Cycloalkyl radical C1-6Alkyl radical, C2-7Heterocyclic group, C2-7Heterocyclyl radical C1-6Alkyl radical, C6-12Aryl radical, C6-12Aryl radical C1-6Alkyl radical, C1-9Heteroaryl, or C 1-9Heteroaryl C1-6An alkyl group; wherein C is3-8Cycloalkyl radical, C3-8Cycloalkyl radical C1-6Alkyl radical, C2-7Heterocyclic group, C2-7Heterocyclyl radical C1-6Alkyl radical, C6-12Aryl radical, C6-12Aryl radical C1-6Alkyl radical, C1-9Heteroaryl and C1-9Heteroaryl C1-6Alkyl is optionally substituted by 0, 1, 2, 3 or 4 substituents independently selected from H, F, Cl, Br, I, -OH, -NH2、-NO2-CN, -oxo (-O), C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Hydroxyalkyl radical, C1-6Haloalkyl, C1-6Aminoalkyl radical, C1-6Cyanoalkyl, C1-6Alkoxy and C1-6Substituted 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, respectively.
In some embodiments, wherein L1Is O, NH, or CH2；L2Is O, S, -N (R)c) -, or-CH2-。
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 Ar1Is that
Figure BDA0003128505470000112
Wherein the content of the first and second substances,
Y1and Y2Are each independently N or-C (R)2)-；
Y3And Y4Are each independently-C (═ O) -, O, S, -N (R)2a)-、-(C(R2)2)t3-, or-W1-(C(R2)2)t3-；
W1is-C (═ O) -, O, S, or-N (R)2a)-；
Each R2aAre each independently H, C1-6Alkyl radical, C1-6Hydroxyalkyl radical, C1-6Haloalkyl, C 1-6Aminoalkyl radical, C1-6Cyanoalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, C1-6Alkylthio radical, C1-6Alkylamino radical, C1-6Haloalkylamino, C3-8Cycloalkyl radical, C3-8Cycloalkyl radical C1-6Alkyl radical, C2-7Heterocyclic group, C2-7Heterocyclyl radical C1-6Alkyl radical, C6-12Aryl radical, C6-12Aryl radical C1-6Alkyl radical, C1-9Heteroaryl, or C1-9Heteroaryl C1-6An alkyl group; and t3 is 1, 2, or 3.
In some embodiments, wherein Ar1Is 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 is1And Y2Are 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 1And Y2Are each independently N or-C (R)2) -; and m is 0, 1, 2, or 3.
In some embodiments, wherein Cy is
Figure BDA0003128505470000123
Wherein the content of the first and second substances,
Z3、Z4and Z5Each independently being-O-, -S-, -NH-, - (CH)2)m1-NH-(CH2)m2-、-(CH2)m1-O-(CH2)m2-、-(CH2)m1-S-(CH2)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 is6And Z7Each independently 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 4R3And (4) substitution.
In some embodiments, the first and second substrates are, among others,
Figure BDA0003128505470000132
is that
Figure BDA0003128505470000133
Figure BDA0003128505470000141
Wherein the content of the first and second substances,
X1、X2and X3Are each independently N or-C (R)6)-；
X4Is O, S, -N (R)6a) -, or-C (R)6)2-；
X5Is O or S; and
each R6aAre each independently H, C1-6Alkyl radical, C1-6Hydroxyalkyl radical, C1-6Haloalkyl, C1-6Aminoalkyl radical, C1-6Cyanoalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, C1-6Alkylthio radical, C1-6Alkylamino radical, C1-6Haloalkylamino, C3-8Cycloalkyl radical, C3-8Cycloalkyl radical C1-6Alkyl radical, C2-7Heterocyclic group, C2-7Heterocyclyl radical C1-6Alkyl radical, C6-12Aryl radical, C6-12Aryl radical C1-6Alkyl radical, C1-9Heteroaryl, or C1-9Heteroaryl C1-6An alkyl group.
In some embodiments, the first and second substrates are, among others,
Figure BDA0003128505470000142
Is that
Figure BDA0003128505470000143
Figure BDA0003128505470000151
Figure BDA0003128505470000161
Figure BDA0003128505470000171
In some embodiments, wherein W is-COOH, -COOCH3、-COOCH2CH3、-COOCH2CH2CH3、-COOCH(CH3)2、 -COOCH2CH(CH3)2、-P(＝O)(OH)2、-P(＝O)(OCH3)(OCH3)、-P(＝O)(O-Na+)(O-Na+)、-P(＝O)(O-NH4 +)(O-NH4 +)、 -P(＝O)(OH)(OCH3)、-P(＝O)(OH)(OPh)、-P(＝O)(OH)(OCH2CH3)、-P(＝O)(OCH2CH3)(OCH2CH3)、
Figure BDA0003128505470000172
Wherein R is7dIs H, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, -CF3、-CH2CF3、-CH2CN、-CH2CH2CN、-CH2OH、 -CH2CH2OH, cyclopropyl, cyclobutyl, cyclopentyl, phenyl, pyridinyl, pyridazinyl, pyrazinyl, pyrimidinyl, pyrazolyl, triazolyl, or tetrazolyl, wherein R7dOptionally substituted with 0, 1, 2, 3 or 4 substituents independently selected from H, D, F, Cl, Br, I, -OH, -NH2、-NO2-CN, -oxo (-O), C1-4Alkyl radical, C2-4Alkenyl radical, C2-4Alkynyl, C1-4Hydroxyalkyl radical, C1-4Haloalkyl, C1-4Aminoalkyl radical, C1-4Cyanoalkyl, C1-4Alkoxy and C1-4A substituent of a haloalkoxy group.
In some embodiments, wherein each R is1Are respectively and independently H, D, F, Cl, Br, -OH, -NH2、-NO2-CN, methyl, ethyl, -CF3、-CH2CF3、-CH2CN、-CH2CH2CN、-CH2OH, or-CH2CH2OH; n is 0, 1, 2, 3 or 4.
In some embodiments, wherein R5Is H, D, F, Cl, Br, I, -OH, -NH2、-NO2-CN, -oxo (-O), C1-4Alkyl radical, C1-4Haloalkyl, C1-4Cyanoalkyl, C1-4Alkoxy radical C1-4Alkyl radical, C3-6Cycloalkyl radical, C3-6Heterocyclic group, C6-10Aryl radical, C1-9Heteroaryl, R5c-C(＝O)-、R5c-OC(＝O)-、R5c-C(＝O)O-、R5c-NHC(＝O)-、R5c-C(＝O)NH-、R5c-L3-C1-4Alkyl-, R5a-C1-4Alkyl, or R5a-C1-4Hydroxyalkyl-, wherein said C is1-4Alkyl radical, C1-4Haloalkyl, C1-4Cyanoalkyl, C1-4Alkoxy radical C 1-4Alkyl radical, C3-6Cycloalkyl radical, C3-6Heterocyclic group, C6-10Aryl radical, C1-9Heteroaryl, R5c-C(＝O)-、R5c-OC(＝O)-、R5c-C(＝O)O-、R5c-NHC(＝O)-、 R5c-C(＝O)NH-、R5c-L3-C1-4Alkyl-, R5a-C1-4Alkyl and R5a-C1-4Hydroxyalkyl-is independently optionally substituted with 0, 1, 2, 3 or 4R5bSubstitution;
R5ais C3-6Cycloalkyl radical, C3-6Heterocycloalkyl radical, C6-10Aryl, or C1-9Heteroaryl, wherein R is5aOptionally substituted by 0, 1, 2, 3 or 4R5bSubstitution;
R5cis H, C1-4Alkyl radical, C3-6Cycloalkyl radical, C3-6Heterocyclic group, C6-10Aryl, or C1-9Heteroaryl, wherein R is5cOptionally substituted by 0, 1, 2, 3 or 4R5bSubstitution; and
L3is O, S, -NH-, or-C (═ O) -.
In some embodiments, wherein R5Is H, D, F, Cl, Br, I, -OH, -NH2、-NO2-CN, oxo (═ O), methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, methoxymethyl, methoxyethyl, -CF3、-CH2CF3、-CH2CH2CN、 -CH2CH2OH、-COOH、H2NC(＝O)-、R5c-C(＝O)-、R5c-OC(＝O)-、R5c-NHC(＝O)-、R5c-L3-C1-3Alkyl-, R5a、R5a-C1-3Hydroxyalkyl, or R5a-C1-3An alkyl group;
L3is O, S, -NH-, or-C (═ O) -; and
R5aand R5cEach independently is
Figure BDA0003128505470000181
Wherein said R5aAnd R5cEach optionally substituted by 0, 1, 2 or 3 substituents independently selected from the group consisting of H, D, F, Cl, Br, I, -OH, -NH2、
-NO2-CN, -oxo (-O), C1-4Alkyl radical, C1-4Haloalkyl, C1-4Cyanoalkyl, C1-4Hydroxyalkyl radical, C1-4Alkoxy, and C1-4Alkoxy radical C1-4Alkyl groups.
In some embodiments, wherein said R is5aAnd R5cEach optionally substituted by 0, 1, 2 or 3 substituents independently selected from the group consisting of H, D, F, Cl, Br, I, -OH, -NH2、-NO2-CN, oxo (═ O), methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, -CF3、 -CH2CF3、-CH2CHF2Methoxy, ethoxy, propoxy, methoxymethyl, cyclopropyl, cyclopropylmethyl, and cyclobutyl.
In some embodiments, wherein each R is1a、R2、R3、R4、R5b、R6、RaAnd RbAre respectively and independently H, D, F, Cl, Br, I, -OH, -NH2、-NO2-CN, -oxo (-O), C1-4Alkyl radical, C2-4Alkenyl radical, C2-4Alkynyl, C1-4Hydroxyalkyl radical, C1-4Haloalkyl, C1-4Aminoalkyl radical, C1-4Cyanoalkyl, C1-4Alkoxy radical, C1-4Haloalkoxy, C1-4Alkylthio radical, C1-4Alkylamino radical, C1-4Haloalkylamino, -NR1bR1c、C3-6Cycloalkyl radical, C3-6Cycloalkyl radical C1-4Alkyl radical, C3-6Heterocyclic group, C3-6Heterocyclyl radical C1-4Alkyl radical, C6-10Aryl radical, C6-10Aryl radical C1-4Alkyl radical, C1-9Heteroaryl, or C1-9Heteroaryl C1-4An alkyl group; wherein C is3-6Cycloalkyl radical, C3-6Cycloalkyl radical C1-4Alkyl radical, C3-6Heterocyclic group, C3-6Heterocyclyl radical C1-4Alkyl radical, C6-10Aryl radical, C6-10Aryl radical C1-4Alkyl radical, C1-9Heteroaryl and C1-9Heteroaryl C1-4Alkyl is optionally substituted by 0, 1, 2, 3 or 4 substituents independently selected from H, F, Cl, Br, I, -OH, -NH 2、-NO2-CN, -oxo (-O), C1-4Alkyl radical, C2-4Alkenyl radical, C2-4Alkynyl, C1-4Hydroxyalkyl radical, C1-4Haloalkyl, C1-4Aminoalkyl radical, C1-4Cyanoalkyl, C1-4Alkoxy and C1-4A substituent of a haloalkoxy group.
In some embodiments, each R is5bAre respectively and independently H, D, F, Cl, Br, I, -OH, -NH2、-NO2-CN, oxo (═ O), methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, -CF3、-CH2CF3、-CH2CHF2Methoxy, ethoxy, propoxy, methoxymethyl, cyclopropyl, cyclopropylmethyl, or cyclobutyl.
In some embodiments, wherein each R is1b、R1c、Rc、Rd、R2a、R6a、R7cAnd R7dAre respectively and independently H, D, OH, C1-4Alkyl radical, C2-4Alkenyl radical, C2-4Alkynyl, C1-4Hydroxyalkyl radical, C1-4Haloalkyl, C1-4Aminoalkyl radical, C1-4Cyanoalkyl, C1-4Alkoxy radical, C1-4Haloalkoxy, C1-4Alkylthio radical, C1-4Alkylamino radical, C1-4Haloalkylamino, C3-6Cycloalkyl radical, C3-6Cycloalkyl radical C1-4Alkyl radical, C3-6Heterocyclic group, C3-6Heterocyclyl radical C1-4Alkyl radical, C6-10Aryl radical, C6-10Aryl radical C1-4Alkyl radical, C1-9Heteroaryl, or C1-9Heteroaryl C1-4An alkyl group; wherein C is3-6Cycloalkyl radical, C3-6Cycloalkyl radical C1-4Alkyl radical, C3-6Heterocyclic group, C3-6Heterocyclyl radical C1-4Alkyl radical, C6-10Aryl radical, C6-10Aryl radical C1-4Alkyl radical, C1-9Heteroaryl and C1-9Heteroaryl C1-4Alkyl is optionally substituted by 0, 1, 2, 3 or 4 substituents independently selected from H, F, Cl, Br, I, -OH, -NH 2、-NO2-CN, -oxo (-O), C1-4Alkyl radical, C2-4Alkenyl radical, C2-4Alkynyl, C1-4Hydroxyalkyl radical, C1-4Haloalkyl, C1-4Aminoalkyl radical, C1-4Cyanoalkyl, C1-4Alkoxy and C1-4A substituent of a haloalkoxy group.
In some embodiments, wherein R7aAnd R7bEach independently is H, Li+、Na+、K+、NH4 +、Mg2+、Ca2+、C1-4Alkyl radical, C2-4Alkenyl radical, C2-4Alkynyl, C1-4Hydroxyalkyl radical, C1-4Haloalkyl, C1-4Aminoalkyl radical, C1-4Cyanoalkyl, C3-6Cycloalkyl radical, C3-6Cycloalkyl radical C1-4Alkyl radical, C3-6Heterocyclic group, C3-6Heterocyclyl radical C1-4Alkyl radical, C6-10Aryl radical, C6-10Aryl radical C1-4Alkyl radical, C1-9Heteroaryl, or C1-9Heteroaryl C1-4An alkyl group; wherein C is3-6Cycloalkyl radical, C3-6Cycloalkyl radical C1-4Alkyl radical, C3-6Heterocyclic group, C3-6Heterocyclyl radical C1-4Alkyl radical, C6-10Aryl radical, C6-10Aryl radical C1-4Alkyl radical, C1-9Heteroaryl and C1-9Heteroaromatic compoundsRadical C1-4Alkyl is optionally substituted by 0, 1, 2, 3 or 4 substituents independently selected from H, F, Cl, Br, I, -OH, -NH2、-NO2-CN, -oxo (-O), C1-4Alkyl radical, C2-4Alkenyl radical, C2-4Alkynyl, C1-4Hydroxyalkyl radical, C1-4Haloalkyl, C1-4Aminoalkyl radical, C1-4Cyanoalkyl, C1-4Alkoxy and C1-4A 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 present invention provides a pharmaceutical composition comprising a compound of the present 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.
In some embodiments, wherein the cardiometabolic diseases and related disorders are T1D, T2DM, pre-diabetes, idiopathic T1D, LADA, EOD, YOAD, MODY, malnutrition-related diabetes, gestational diabetes, hyperglycemia, insulin resistance, hepatic insulin resistance, glucose intolerance, diabetic neuropathy, diabetic nephropathy, kidney disease, diabetic retinopathy, adipocyte dysfunction, visceral adipocyte accumulation, sleep apnea, obesity, eating disorders, weight gain using other agents, excessive glycemia, dyslipidemia, hyperinsulinemia, NAFLD, NASH, fibrosis, cirrhosis, hepatocellular carcinoma, cardiovascular disease, atherosclerosis, coronary artery disease, peripheral vascular disease, hypertension, endothelial dysfunction, impaired vascular compliance, congestive heart failure, diabetes mellitus, obesity, eating disorders, elevated body weight due to the use of other agents, excessive glycemia, dyslipidemia, hyperinsulinemia, NAFLD, NASH, fibrosis, cirrhosis, hepatocellular carcinoma, cardiovascular disease, atherosclerosis, coronary artery disease, peripheral vascular disease, hypertension, endothelial dysfunction, impaired vascular compliance, congestive heart failure, and other diseases, Myocardial infarction, stroke, hemorrhagic stroke, ischemic stroke, traumatic brain injury, pulmonary hypertension, restenosis following angioplasty, intermittent claudication, postprandial lipemia, metabolic acidosis, ketosis, arthritis, osteoporosis, Parkinson's disease, left ventricular hypertrophy, peripheral arterial disease, macular degeneration, cataracts, glomerulosclerosis, chronic renal failure, metabolic syndrome, syndrome X, premenstrual syndrome, angina pectoris, thrombosis, atherosclerosis, transient ischemic attacks, vascular restenosis, impaired glucose metabolism, impaired fasting glucose conditions, hyperuricemia, gout, erectile dysfunction, skin and connective tissue abnormalities, psoriasis, foot theft, ulcerative colitis, hyperpao B lipoprotein hemotopathy, Alzheimer's disease, schizophrenia, impaired cognitive function, inflammatory bowel disease, ulcerative colitis, and inflammatory bowel disease, 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 pharmaceutically elegant and palatable preparations. 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. In a particular embodiment, the present invention provides a compound of the invention or a pharmaceutical composition comprising a compound of the invention for use in the prevention and/or treatment of cardiovascular metabolic diseases and related conditions in a mammal, particularly T1D, T2DM, pre-diabetes, idiopathic T1D, LADA, EOD, YOAD, MODY, malnutrition-related diabetes, gestational diabetes, hyperglycemia, insulin resistance, hepatic insulin resistance, glucose intolerance, diabetic neuropathy, diabetic nephropathy, renal disease, diabetic retinopathy, adipocyte dysfunction, visceral adipocyte accumulation, sleep apnea, obesity, eating disorders, weight gain due to use of other agents, excessive glycemia, dyslipidemia, hyperinsulinemia, NAFLD, NASH, fibrosis, cirrhosis, hepatocellular carcinoma, cardiovascular diseases, Atherosclerosis, coronary artery disease, peripheral vascular disease, hypertension, endothelial dysfunction, impaired vascular compliance, congestive heart failure, myocardial infarction, stroke, hemorrhagic stroke, ischemic stroke, traumatic brain injury, pulmonary hypertension, restenosis following angioplasty, intermittent claudication, postprandial lipemia, metabolic acidosis, ketosis, arthritis, osteoporosis, parkinson's disease, left ventricular hypertrophy, peripheral arterial disease, macular degeneration, cataracts, glomerulosclerosis, chronic renal failure, metabolic syndrome, syndrome X, premenstrual syndrome, angina pectoris, thrombosis, atherosclerosis, transient ischemic attacks, vascular restenosis, impaired glucose metabolism, impaired fasting glucose conditions, hyperuricemia, gout, erectile dysfunction, skin and connective tissue abnormalities, psoriasis, impaired vascular and other conditions, 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 (saroglitazar), aleglitazar (aleglitazar), muraglitazar (muraglitazar) or telaglitazar (tesaglitazar)), meglitinides (e.g. nateglinide (nateglinide), rapagliptin), dipeptidyl peptidase 4(DPP-4) inhibitors (e.g. sitagliptin, vildagliptin, saxagliptin (saxagliptin), linagliptin, gimeragliptin (gemagliptin), anagliptin (anagliptin), teigliptin (teneligliptin), alogliptin (trelagliptin), dulagliptin (trelagliptin), or omagliclatin (omagliptin), glitazone (e.g. pioglitazone, roside, balaglitazone (e.g. flazaglitazone, balaglitazone (vilaglitazone), vilaglitazone (vildagliptin), glitazone (e) or glitazone (e.g. glitazone), glitazone (e.g. a), glitazobactam (e.g. a) inhibitors (e.g. glitazobactam), glitazobactam (e.g. glitazobactam), glitazobactam (e.g. a), glitazobactam (e.g. glitazobactam), glitazobactam (e.g. a (e.g. glitazobactam), glitazobactam (e.g. glitazobactam), glitazobactam (e.g. glitazobactam), glitazobactam (e.g. glitazobact (e.g. glitazobactam), glitazobact (e.g. glitazobactam), glitazobactam (e.g. glitazobactam), glitazobact (e.g. glitazobactam), glitazobactam, glitazobact (e.g. glitazobactam), glitazobact (e.g. glitazobact) inhibitors (e.g. glitazobact) or glitazobact (e.g. glitazobact, glitazobact (e.g. glitazobactam), glitazobact) or glitazobact (e.g. glitazobactam), glitazobact) inhibitors (e.g. glitazobactam), glitazobact) or glitazobactam, glitazobact (e.g. glitazobactam), remogliflozin (remog1if1ozin etabonate) or remogliflozin), SGLTL1 inhibitors, GPR40 agonists (FFAR1/FFA1 agonists, such as, for example, fasilifam (fasiglifam)), glucose-dependent insulinotropic peptide (GIP) and analogs thereof, alpha glucosidase inhibitors (such as, for example, voglibose, acarbose or miglitol) or insulin analogs, including pharmaceutically acceptable salts of the specified 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 methods described herein, wherein the substituents are as defined in formula I, II, III, IIIa or IV, unless otherwise specified. 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 and 400 meshes) was purchased from Qingdao oceanic chemical plants.
1HNMR spectra were recorded using a Bruker 400MHz or 600MHz NMR spectrometer.1H NMR Spectrum in CDC13、DMSO-d6、CD3OD or acetone-d6TMS (0ppm) or chloroform (7.26ppm) 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).
Low resolution Mass Spectrometry (MS) dataThe measurement conditions of (1) were: agilent 6120 four-stage rod HPLC-M (column model: Zorbax SB-C18, 2.1X 30mm,3.5 micron, 6min, flow rate 0.6 mL/min. mobile phase: 5% -95% ((CH with 0.1% formic acid)3CN) in (H containing 0.1% formic acid)2O) 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:
CD3OD deuterated methanol
CDC13Deuterated chloroform
DMF N, N-dimethylformamide
DMSO-d6Deuterated 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 under alkaline condition through substitution reactionTo obtain 1-9. Wherein Z is1、Z2、X1、X4、W、 R1、R2、R3、R4、R5N, m and n1 are all as defined herein; 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 condition to obtain 2-8. Wherein Z is 1、Z2、X1、X2、X3、W、R1、R2、R3、R4、R5N, m and n1 are all as defined herein; PG is a protecting group.
Examples
Synthesis of intermediates
Intermediate 13-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, 10.0mmol) was dissolved in tetrahydrofuran (10mL) and placed in a low temperature cooling bath at-30 ℃ to which 2.5M n-butyllithium (4.2mL, 10.5mmol) was slowly added dropwise. Then, a solution of methyl N-t-butyloxycarbonyl-4-piperidinecarboxylate (2.43g, 10.0mmol) in tetrahydrofuran (10mL) was slowly dropped into the reaction flask, and after the dropping, the mixture was stirred for 10 minutes. A solution of 2, 6-dichloropyridine (1.48g, 10.0mmol) in tetrahydrofuran (10mL) was added dropwise to the flask, and the mixture was allowed to warm to room temperature and stirred for 3 hours. After TLC shows reverseWhen the reaction solution is not changed, the reaction solution 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 a product with the yield of 10%. LC-MS [ M + H ]]+:356.8。
Step 2) N-t-butyloxycarbonyl-4- (6-chloropyridin-2-yl) piperidine-4-carboxylic acid
Intermediate methyl N-tert-butyloxycarbonyl-4- (6-chloropyridin-2-yl) piperidine-4-carboxylate (350mg, 1.0mmol) was dissolved in methanol (5.0mL) and placed in an ice-water bath to which were added water (1.0mL) and sodium hydroxide solid (460mg, 11.5mmol) and then allowed to stir at room temperature for 1 h. After TLC monitored 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 pale yellow solid 320mg, 94% yield, 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
N-t-Butyloxycarbonyl-4- (6-chloropyridin-2-yl) piperidine-4-carboxylic acid (320mg) was dissolved in 1, 2-dichloroethane (10mL), and the mixture was heated to 80 ℃ and stirred. 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) tert-butyl 4- (6- (4-cyano-2-fluorobenzyloxy) pyridin-2-yl) piperidine-1-carboxylate
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 (15mL), followed by the addition of tris (dibenzylideneacetone) dipalladium (26mg, 0.035mmol), 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 completion of the reaction monitored by TLC, it was quenched with saturated aqueous ammonium chloride solution, 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
4- (6- (4-cyano-2-fluorobenzyloxy) pyridin-2-yl) piperidineTert-butyl (1-carboxylate) (200mg, 0.49mmol) was dissolved in methanol (3mL), followed by dropwise addition of a solution of hydrochloric acid in ethanol (1.2mL, 4.9mmol, 4mol/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 (161mg, yield 95%). LCMS (liquid Crystal display Module) [ M + H ] ]+:312.2。
Intermediate 21- (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, 13.5mmol) and piperazine-1-carboxylic acid tert-butyl ester (3.02g, 16.2mmol) were placed in a 100mL single-neck flask, and cesium carbonate (8.8g, 27mmol) and acetonitrile (30mL) were added 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 (10mL) were placed in a 50mL single-neck flask, protected with nitrogen, and the mixture was reacted at 110 ℃ for 12 hours. 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 (5mL), trifluoroacetic acid (1mL) 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 33-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 (6g, 39.7mmol) is dissolved in tetrahydrofuran (120mL), cooled to 0 deg.C, sodium hydride (3.18g, 79.4mmol, 60%) is added, and the mixture is stirred for 0.5 h. Dichloropyridine (11.75g, 79.4mmol) was then added and the mixture was 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 (150mL), extracted with ethyl acetate (150mL × 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 (7.19g, yield 69%). LCMS (liquid Crystal display Module) [ 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 (9.9g, 30.36mmol) were placed in a 250mL single-neck flask, toluene (80mL) was added, and the mixture was allowed to warm to 100 ℃ under nitrogen for reaction overnight. The reaction was stopped, cooled to room temperature, washed with water (50mL), 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 (5mL), ethanol hydrochloride (1mL, 4mmol, 4mol/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 (30mL) was added, and the mixture was stirred at 100 ℃ for reaction overnight; after the TLC detected the starting material had reacted substantially completely, the system was allowed to cool to room temperature, saturated brine/ethyl acetate (60mL, v/v ═ 1:1) 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
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) were dissolved in N, N-dimethylformamide (10mL) and heated 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 (10mL), extracted with dichloromethane (10 mL. multidot.3), combined and dried over anhydrous sodium sulfate, concentrated to dryness under reduced pressure, and the residue was purified by column chromatography (PE: EA: 10:1) to give 283mg of colorless oil in 58% yield.
Step 3) (S) -1- (6- (4-chloro-2-fluorobenzyloxy) -3, 5-difluoropyridin-2-yl) -3-methylpiperazine hydrochloride
Tert-butyl (S) -4- (6- ((4-chloro-2-fluorobenzyl) oxy) -3, 5-difluoropyridin-2-yl) -2-methylpiperazine-1-carboxylate (283mg,0.6mmol) was dissolved in ethanol (6mL), a 30% ethanol solution of hydrochloric acid (2.8mL) 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 51- (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), N-methylpyrrole (30mL) was added, and the mixture was stirred at 100 ℃ for reaction overnight; after the TLC detected the starting material had reacted substantially completely, the system was allowed to cool to room temperature, saturated brine/ethyl acetate (60mL, v/v ═ 1:1) 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
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) were dissolved in N, N-dimethylformamide (4mL) and heated to 110 ℃ for reaction overnight; after TLC detection of the completion of the reaction of the starting material, the reaction mixture was poured into water (5mL), extracted with dichloromethane (5 mL. multidot.3), combined and dried over anhydrous sodium sulfate, concentrated to dryness under reduced pressure, and the residue was purified by column chromatography (PE: EA: 15:1) to give 236mg of a colorless oily substance in a yield of 57%.
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 (6mL), and a 30% ethanol solution of hydrochloric acid (2.0mL) 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 64- ((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, 230.6mmol) and phosphorus oxychloride (105.8g, 690.2mmol) are placed in a 500mL three-necked flask, the temperature is raised to 95 ℃ and stirred, dimethylaniline (55.9g, 461.2mmol) is added dropwise, and the temperature is kept for reaction overnight after the addition. Cooled to room temperature, slowly poured into diluted hydrochloric acid (122mL, 3N) at-10 ℃ and stirred for 1 hour, added with dichloromethane (300mL) for extraction, the organic phase is washed to neutrality by water, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain 31.5g of a pale yellow solid product with the yield of 83 percent.
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 (75mL), cooled to 0 deg.C, sodium hydride (790mg, 32.93mmol, 60%) was added and the mixture was stirred for 30 minutes, and a solution of 2, 4-dichloro-5-fluoropyrimidine (5g, 29.94mmol) in tetrahydrofuran (25mL) was added dropwise and stirred at room temperature overnight. Pouring the reaction solution into saturated ammonium chloride (200mL), extracting with ethyl acetate (200mL x 3), combining organic phases, washing with saturated salt solution, drying with anhydrous sodium sulfate, and purifying by column chromatography to obtain a white-like solid product 3.65g with the 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 (10mL), triethylamine (348mg, 3.44mmol) was added, and the mixture was warmed to 100 ℃ for reaction overnight. Cooling to room temperature, adding water (15mL), extracting with ethyl acetate (20 mL. times.3), combining organic phases, washing with saturated salt water, 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), and an ethanol solution of hydrochloric acid (2mL, 30%) was added to stir the mixture at room temperature overnight. Concentration under reduced pressure gave 285mg of the product as an off-white solid in > 99% yield.
Intermediate 72- ((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 dichloromethane (50mL), 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 (50mL) is added for washing, anhydrous sodium sulfate is dried, and ethyl acetate is pulped 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 (20mL) were placed in a 50mL single-neck flask, purged with nitrogen 3 times, and warmed to 110 ℃ for reaction overnight. Cooling to room temperature, adding water (20mL), extracting with ethyl acetate (25 mL. 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 (9mL), 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 82- ((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 (5.0g, 19.3mmol) in dry tetrahydrofuran (50mL), 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 and reacting at-40 ℃ for 0.5 hour; dissolving 2-methylthio-4-chloropyrimidine (3.0g,18.7mmol) in dry tetrahydrofuran (15mL), slowly dropping the mixture into the mixed system, and naturally heating the mixture to room temperature for reaction for 1 hour after the dropping is finished; after TLC detection of the completion of the basic reaction of the starting materials, the reaction system was placed in an ice-water bath to a temperature below 10 ℃ and 5% citric acid aqueous solution (75mL) and saturated brine (30mL) were added, followed by extraction with ethyl acetate (100 mL. times.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: 1) to give 7.2g of a yellow oily product with a yield of 99%.
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-dicarboxylate (7.2g, 18.6mmol) was dissolved in methanol/tetrahydrofuran (69mL, v/v ═ 2:1), 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 by ethyl acetate (50mL x 2), organic phase is combined, dried by 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, 18.6mmol) in dichloromethane (140mL), 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 raw materials are detected by LC-MS to be basically reacted completely, the reaction liquid passes through a layer of diatomite, filter residues are washed by dichloromethane, organic phases are combined, dried by anhydrous sodium sulfate, decompressed and concentrated to be dry, and residues are purified by column chromatography (PE: EA is 1: 1) to obtain 4.9g of white solid with the yield of 77%.
Step 4) tert-butyl 4- (2- ((4-chloro-2-fluorobenzyl) oxy) pyrimidin-4-yl) piperidine-1-carboxylate
Dissolving 2-fluoro-4-chlorobenzyl alcohol (2.2g, 13.68mmol) in anhydrous tetrahydrofuran (140mL), adding HMDSNa (13.7mL, 27.3mmol, 2.0M) dropwise under the protection of nitrogen, stirring the mixture for 15 minutes, adding a tetrahydrofuran (100mL) solution of 4- (2- (methylsulfonyl) pyrimidin-4-yl) piperidine-1-carboxylic acid tert-butyl ester (4.9 g,14.37mmol) dropwise into the system, continuing to stir for 2 hours after completion, after TLC detection of the completion of the reaction of the raw materials, adding water (50mL) and saturated saline (50mL), separating an organic phase, drying the organic phase with anhydrous sodium sulfate, concentrating under reduced pressure to dryness, and purifying by column chromatography (PE: EA: 2: 1) to obtain a yellow oily product, 4.94g, and the yield is 86%.
Step 5)2- ((4-chloro-2-fluorobenzyl) oxy) -4- (piperidin-4-yl) pyrimidine hydrochloride
Dissolving tert-butyl 4- (2- ((4-chloro-2-fluorobenzyl) oxy) pyrimidin-4-yl) piperidine-1-carboxylate (4.94g, 11.76mmol) in ethanol (20mL), adding a 30% ethanol hydrochloride solution (49mL), 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 94- (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 (15mL), 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 mixture was heated to 60 ℃ for reaction 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 104- (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 (150mL) was added, and the mixture was allowed to warm to 88 ℃ under nitrogen 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 (10mL), wet palladium on carbon (0.2g, 10%) was added, and the mixture was replaced with hydrogen 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 (15mL), potassium carbonate (1.51g, 10.92mmol) was added, the mixture was stirred at room temperature for 10 minutes, 4-chloro-2-fluorobenzyl bromide (853mg, 3.82mmol) was added, and the mixture was heated to 60 ℃ for reaction 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 (10mL), ethanol hydrochloride solution (5mL, 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 112- ((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 (200mL), stirring at-40 ℃ for 10 minutes, slowly dropping LDA (49mL, 98mmol, 2.0M THF solution) into the system, after the dropping is completed, continuing to stir the mixture at-40 ℃ for 0.5 hour, then dissolving 2, 6-dibromopyridine (23.5g, 98.7mmol) in tetrahydrofuran (200mL), slowly dropping the mixture into the mixed system, after the dropping is completed, naturally raising the temperature to room temperature, and continuing to react for 3 hours; then, the reaction system was cooled to 0 ℃ again, water (50mL) was slowly added dropwise to the reaction system, the temperature was raised to room temperature, the organic layer was separated, the aqueous layer was extracted with ethyl acetate (50mL × 3), the organic phases were combined, 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 (PE: EA ═ 20: 1) to give a pale yellow solid, 23g, yield 70%.
Step 2)4- (6-bromopyridin-2-yl) -1- (tert-butoxycarbonyl) piperidine-4-carboxylic acid
Dissolving tert-butyl 4- (methoxycarbonyl) -4- (6-bromopyridin-2-yl) piperidine-1-carboxylate (23g, 58mmol) in tetrahydrofuran (200mL), adding 1.0M sodium hydroxide solution (116mL, 116mmol), heating the mixture to 50 ℃ and stirring for reaction overnight; after the reaction was complete, 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), 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 (150mL), the mixture was warmed to 80 ℃ for 12 hours, after completion of the reaction, the solvent was evaporated by concentration under reduced pressure, and the obtained 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
4- (6-Bromopyridin-2-yl) piperidine-1-carboxylic acid tert-butyl ester (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 (65mL), 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: 1) to give 6.8g of a white solid in 85% yield.
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-tert-butyl formate (2.1g, 5mmol) in 30% hydrochloric acid ethanol solution (20mL), stirring the mixture at room temperature for reaction, directly concentrating under reduced pressure after TLC detection of complete reaction of raw materials, and evaporating to remove the solvent to obtain 1.6g of yellow solidYield of>99％，LC-MS[M+H]+:321.1。
Intermediate 124- (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 (50mL), N-iodosuccinimide (5.15g, 22.9 mmol) was added, and the mixture was reacted 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 resulting 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 give 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, 16.7mmol) 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 (10mL) 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 × 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 ═ 10:1) to give the desired product (4.54g, > 99%) as a pale yellow transparent oily liquid.
Step 3)1- ((4-chloro-2-fluorobenzyl) oxy) -2, 4-difluoro-5-iodobenzene
2, 4-difluoro-5-iodophenol (4.54g, 17.7mmol) was dissolved in acetonitrile (120 mL). To the reaction system were added potassium carbonate (7.34g, 53.1mmol) and 1- (bromomethyl) -4-chloro-2-fluorobenzene (4.35g, 19.5mmol) in this order. The reaction was warmed to 60 ℃ and stirred overnight. After completion of the conversion 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 desired 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 of2N, N-dimethylacetamide (1.5mL) 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: 0.6mol/L) is preserved under the protection of nitrogen.
Adding Pd (dppf) into a round-bottom flask2Cl2(46.8mg, 0.064mmol), cuprous iodide (24.4mg, 0.128mmol), 1- ((4-chloro-2-fluorobenzyl) oxy) -2, 4-difluoro-5-iodobenzene (853mg, 2.14 mmol). N, N-dimethylacetamide (10mL), and the Zn reagent prepared in the previous step (0.6mol/L) were added under nitrogen atmosphere. After the addition, the reaction system was placed in a 80 ℃ metal sand bath and heated for reaction overnight. After the reaction, water (30mL) was added, extracted with ethyl acetate, and the organic phase was washed with water (3 × 20mL) and then with saturated sodium chloride solution (50 mL). The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the solvent, and the residue was separated and purified by column chromatography (PE: EA ═ 10:1) 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 (10mL), and the mixture was stirred at room temperature for 3 h. 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 with an oil pump to obtain the objective product (291mg, 81%) as a white solid. LCMS (liquid Crystal display Module) [ M + H ]]+:356)。
Example 12- ((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 dichloromethane (100mL), triethylamine (4.18mL, 30 mmol) was added, stirring was performed in an ice-water bath, di-tert-butyl dicarbonate (4.8g, 22mmol) was then slowly added, 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), the organic layer was 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 (40mL), the mixture was stirred at-10 ℃, lithium bis (trimethylsilyl) amide (16.5mL, 16.5mmoL, 1.0mol/L) was slowly added dropwise to the above system, after stirring for 10 minutes, a solution of O- (diphenylphosphinoyl) hydroxylamine (4.2g, 18mmoL) in N, N-dimethylformamide (5mL) was added dropwise to the above reaction 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, adding ethyl acetate (20mL) 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 (30mL) and potassium carbonate (2.7g, 20 m) was addedmol) and methanesulfonic acid- (oxetan-2-yl) methyl ester (2.0g, 12mmol), the mixture was stirred at 50 ℃ for 6 hours. After completion of the TLC detection reaction, the reaction mixture was cooled to room temperature, saturated brine (30mL) and dichloromethane (30mL) were added, the organic layer was separated, the aqueous layer was extracted with dichloromethane (30 mL. times.2), the organic layer was 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, 4.4mmol) was dissolved in tetrahydrofuran (30mL), acetic acid (0.26g, 4.4mmol) was added, and nitrogen was bubbled through for 1 minute, followed by addition of 2-chloro-1, 1, 1-trimethoxyethane (1.4g,8.8mmol), and the mixture was allowed to tube-seal at 100 ℃ for 12 hours. 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 (15mL) 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 (3mL), potassium carbonate (83mg, 0.6mmol) 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 (5mL), 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 (1mL), then sodium hydroxide solution (1.0mL, 1.0mmol,1mol/L) was added and the mixture was reacted at 50 ℃ overnight. The reaction was stopped, concentrated under reduced pressure to remove ethanol, adjusted to pH about 5 by addition of 1N HCl, then extracted with ethyl acetate (3mL × 3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography (dichloromethane: methanol ═ 10: 1) to give the title compound (40mg, yield 47%). LCMS (liquid Crystal display Module) [ M + H ]]+:546.6。1HNMR(500MHz,DMSO-d6) 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 22- ((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 added2SO4The temperature of the mixture is reduced to 0 ℃ in an ice water bath, nitric acid (6.3mL, 65%) is added dropwise, and after complete addition, the mixture is 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. Pouring the reaction solution into ice water (50mL), extracting with ethyl acetate (30 mL. times.3), washing the combined organic phases with saturated brine, drying over anhydrous sodium sulfate, concentrating under reduced pressure, and purifying the residue by column chromatography to obtain the target compound3.36g, 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 (45mL) 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 (50mL), 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 (30mL), trifluoroacetic acid (3mL) was added, and the mixture was stirred at room temperature overnight. TLC showed the starting material was reacted completely, the reaction was stopped, poured into ice water (100mL), extracted with ethyl acetate (150 mL. times.3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 1.9g of the 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 (40mL), triethylamine (1.34g, 13.2mmol) 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 (7.5mL), 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. TLC detection reaction After completion, the reaction was stopped, cooled to room temperature, filtered to remove insoluble matter, concentrated under reduced pressure to remove methanol, added with water (10mL), extracted with ethyl acetate (20mL × 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 (18mL), 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, 4.4mmol) was added to the reaction mixture, and the mixture was stirred at room temperature for 1 hour. Then, the reaction mixture was diluted with dichloromethane (30mL), washed with water (20mL), then with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography to give 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 (6.5mL), then acetic acid (22mg, 0.365mmol) was added, and nitrogen was bubbled through for 1 minute, 2-chloro-1, 1, 1-methoxyethane (113mg, 0.733mmol) was added, and the resulting mixture was tube-sealed at 100 ℃ for 12 hours. To the mixture was added p-toluenesulfonic acid monohydrate (7mg, 0.036mmol), and the reaction was carried out at 75 ℃ for 1 hour. The reaction was stopped, water (15mL) 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 (3mL), 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]Imidazole-5-carboxylic acid ethyl ester (140mg, 0.365mmol), heated to 50 ℃ and reacted overnight. The reaction was stopped, cooled to room temperature, quenched with water (5mL), 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 (1.0mL), sodium hydroxide solution (1mL, 1mmol, 1mol/L) was added, and the mixture was reacted at 50 ℃ overnight. After the TLC detection of the completion of the reaction of the starting materials, the reaction was stopped, and 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 (3 mL. times.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 product (10.7mg, yield: 28%). LCMS (liquid Crystal display Module) [ M + H ]]+:573.0。1HNMR(500 MHz,DMSO-d6)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 32- ((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- ((Oxetadin-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 (20mL), followed by triethylamine (3.0mL, 21.4mmol), and the mixture was stirred at 45 ℃ 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 (1.6g, 5.6mmol) was dissolved in tetrahydrofuran (30mL), and the mixture was stirred in an ice-water bath, followed by addition of di-tert-butyl dicarbonate (1.46g, 6.72mmol) and triethylamine (1.56mL,11.2mmol), and then allowed to naturally warm to room temperature and stirred for reaction for 8 hours. After TLC detection of the completion of the reaction of the starting materials, the reaction solution was poured into saturated sodium bicarbonate (30mL) and extracted with dichloromethane (30 mL. times.3), the combined organic phases were 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- ((tert-butoxycarbonyl) amino) -4-nitrothiophene-2-carboxylate (1.9g, 4.9mmol) was dissolved in methanol (7.5mL), to which were added water (2.5mL), iron powder (1.38g, 24.6mmol) and ammonium chloride (524mg,9.8mmol), 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 (10mL), 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 (356mg, 1.0mmol) was dissolved in tetrahydrofuran (10mL), acetic acid (60mg, 1.0mmol) was added thereto and bubbling with nitrogen gas was continued for 1 minute, followed by addition of 2-chloro-1, 1, 1-methoxyethane (309mg,2.0mmol), and the mixture was subjected to a tube-sealing reaction at 100 ℃ for 12 hours. Then, p-toluenesulfonic acid monohydrate (19 mg, 0.1mmol) was added to the reaction mixture, and reacted at 75 ℃ for 1 hour. The reaction was stopped, water (15mL) 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, 0.7mmol) is dissolved in acetonitrile (3mL), potassium carbonate (483mg, 3.5mmol) is added to it, the mixture is stirred at room temperature for 10 minutes, and 2- (chloromethyl) -3- (oxetan-2-ylmethyl) -3H-thieno [2,3-d ] is added ]Imidazole-5-carboxylic acid ethyl ester (310mg, 0.98mmol), was reacted overnight with warming to 50 ℃. The reaction was stopped, cooled to room temperature, quenched with water (10mL) and the reaction mixture 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 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]Imidazole-5-carboxylic acid ethyl ester (100mg, 0.17mmol) was dissolved in ethanol (1.0mL), to which was added sodium hydroxide solution (1mL, 1mmol, 1mol/L), mixedThe mixture was reacted at 50 ℃ overnight. After the completion of the reaction of the starting materials by TLC, the reaction was stopped, concentrated under reduced pressure to remove ethanol, adjusted to pH about 5 by addition of 1N HCl, the reaction mixture was extracted with ethyl acetate (3mL × 3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the obtained residue was purified by column chromatography (dichloromethane: methanol ═ 10: 1) to obtain the product (24mg, yield 25%). LCMS (liquid Crystal display Module) [ M + H ] ]+:562.6。1H NMR(500MHz,DMSO-d6)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 45- ((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 (45mL), 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 (2.4g, 6.53mmol) was dissolved in dichloromethane (24mL), trifluoroacetic acid (2.4mL) was then added, and the mixture was stirred at room temperature for reaction for 8 hours. After TLC detection of the complete reaction of the raw materials, the reaction is mixedThe mixture was poured into ice water (100mL), ethyl acetate (100 mL. times.3) was added and extracted, and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 1.5g of a crude product. 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 (30mL), 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 (liquid Crystal display Module) [ 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 (7.5mL), followed by addition of water (2.5mL), iron powder (1.04g, 18.65mmol) and ammonium chloride (400mg, 7.46mmol), and the mixture 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 (10mL) was added, the mixture was extracted with ethyl acetate (20mL × 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 (16mL), 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, 5.5mmol) was added to the reaction mixture, and stirred at room temperature for 1 hour. Then, dichloromethane (30mL) was added for dilution, the mixture was washed with water (20mL) and saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography to give 498mg of a product, yield 50％。LCMS[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 (10mL), followed by addition of acetic acid (60mg,1.0mmol) and bubbling with nitrogen for 1 minute, followed by addition of 2-chloro-1, 1, 1-methoxyethane (309 mg, 2.0mmol), and the mixture was allowed to react at 100 ℃ for 12 hours with tube closure. To the reaction mixture was added p-toluenesulfonic acid monohydrate (19mg, 0.1mmol), and the mixture was reacted at 75 ℃ for 1 hour. The reaction was stopped, water (15mL) 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, 0.7mmol) is dissolved in acetonitrile (3mL), then potassium carbonate (483mg, 3.5mmol) is added and the mixture is stirred at room temperature for 10 minutes, then 2- (chloromethyl) -3- (oxetan-2-ylmethyl) -3H-thieno [2,3-d ] is added]Imidazole-5-carboxylic acid ethyl ester (320mg, 1.0mmol), and the mixture was warmed to 50 ℃ for reaction overnight. The reaction was stopped, cooled to room temperature, quenched with water (10mL) 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]Thiazole-2-carboxylic acid ethyl ester (120mg, 0.20mmol) was dissolved in ethanol (1.0mL) and sodium hydroxide solution (1 mL) was added 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, ethanol was removed by concentration under reduced pressure, 1 NHCl was added to the mixture to adjust pH to about 5, and the mixture was extracted with ethyl acetate (3mL × 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 (35mg, yield 31%). LCMS (liquid Crystal display Module) [ M + H ]]+:563.4。1H NMR(500 MHz,DMSO-d6)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, then potassium carbonate (3.49g, 25.32mmol) and acetonitrile (40mL) were added and the mixture stirred at room temperature for 2.5 hours. The reaction was stopped, the reaction solution was poured into ice water (50mL), 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 (22mL), then trifluoroacetic acid (2.2mL) was added and the mixture stirred at room temperature for 8 hours. After TLC detection of the completion of the reaction of the starting materials, the reaction mixture was poured into ice water (100mL) 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 (24mL), then triethylamine (1.0mL, 7.2mmol) was added and 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 ═ 1:1), 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 (10mL) 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
(3-amino-5- (dimethoxyphosphono) thiophen-2-yl) carbamic acid tert-butyl ester (0.89g, 2.76mmol) was dissolved in tetrahydrofuran (5mL) and methanesulfonic acid- (1-ethyl-1H-imidazol-5-yl) methyl ester (0.8) was added4g, 4.14mmol) and potassium carbonate (0.76g, 5.52mmol), the mixture being stirred at room temperature for 6 hours. After completion of the TLC reaction, the reaction mixture was cooled to room temperature, poured into water (20mL), extracted with ethyl acetate (20mL × 3), combined with organic phase, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography (water: methanol ═ 5: 1) 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, 1.6mmol) was dissolved in tetrahydrofuran (10mL), then acetic acid (96mg, 1.6mmol) was added and nitrogen was bubbled through for 5 minutes, then 2-chloro-1, 1, 1-trimethoxyethane (495mg, 3.2mmol) was added and the mixture was allowed to react at 100 ℃ in a tube-sealed condition for 12 hours, p-toluenesulfonic acid monohydrate (30mg,0.16mmol) was added and the mixture was allowed to react at 75 ℃ for 1 hour, the reaction was stopped, water (20mL) was added, ethyl acetate (20 mL. times.3) was extracted, the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure to give 590mg, directly used for the next reaction. Step 7 Synthesis of dimethyl 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) phosphonate
1- (6- (4-chloro-2-benzyloxy) pyridin-2-yl) piperazine trifluoroacetate (387mg, 0.92mmol) is dissolved in acetonitrile (5mL) followed by the addition of potassium carbonate (635mg, 4.6mmol), the mixture is stirred at room temperature for 30 minutes, then (2- (chloromethyl) -1- ((1-ethyl-1H-imidazol-5-yl) methyl) -1H-thieno [2,3-d ] is added ]Imidazol-5-yl) phosphonate 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 (10mL), 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]Imidazol-5-yl) phosphonic acid dimethyl ester (150mg, 0.22mmol) was dissolved in dichloromethane (5mL), the mixture was stirred in an ice water bath, 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 (85.2mg, yield 60%). LCMS (liquid Crystal display Module) [ M + H ] ]+。 647.0。1H NMR(500MHz,DMSO-d6)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 62- ((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- ((Oxetadin-2-ylmethyl) amino) -1H-imidazole-5-carboxylate
Ethyl 2-amino-1H-imidazole-5-carboxylate (2.0g, 12.9mmol) was dissolved in acetonitrile (30mL), followed by the addition of potassium carbonate (3.6g, 25.8 mmol) and methanesulfonic acid- (oxetan-2-yl) methyl ester (2.58g, 15.5mmol), and the mixture was stirred at 50 ℃ for 6 hours. After completion of TLC detection, the reaction mixture was cooled to room temperature, saturated brine (30mL) and dichloromethane (30mL) were added to the mixture, 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 chromatographyThe yield was 82% and 2.38g of the product was obtained. 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 (2.3g, 10.2mmol) was dissolved in dichloromethane (50mL), triethylamine (2.84mL, 20.4mmol) was then added, the mixture was stirred under a bath of ice water, di-tert-butyl dicarbonate (2.67g, 12.2mmol) was then slowly added, and the reaction mixture was stirred at room temperature overnight. After completion of the TLC detection reaction, the mixture was poured into a saturated sodium bicarbonate solution, the organic layer was separated, the aqueous layer was extracted with dichloromethane (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 with a yield of 85%. 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, 8.6mmoL) was dissolved in dry N, N-dimethylformamide (50mL), the mixture was stirred at-10 ℃ and then lithium bis (trimethylsilyl) amide (9.5mL,9.5mmoL,1.0 mol/L) was slowly dropped into the above system, and after the mixture was stirred for reaction for 10 minutes, a solution of O- (diphenylphosphinoyl) hydroxylamine (2.4g,10.3mmoL) in N, N-dimethylformamide (5mL) was dropped into the above system, and then slowly warmed to room temperature and stirred for reaction 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 (30mL), 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 (2.0g, 5.88mmol) was dissolved in tetrahydrofuran (40mL), then acetic acid (0.35g, 5.88mmol) was added and nitrogen was bubbled through for 5 minutes, then 2-chloro-1, 1, 1-trimethoxyethane (1.87g, 11.76mmol) was added and the mixture was tube-sealed 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 (20mL) 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 (5mL), followed by the addition of potassium carbonate (331mg, 2.4mmol), 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. The reaction was stopped, cooled to room temperature, quenched with water (10mL) and 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 resulting residue was purified by column chromatography to give 330mg of the product in 48% yield. LCMS (liquid Crystal display Module) [ 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 (1mL), then sodium hydroxide solution (1.0mL, 1.0mmol, 1mol/L) was added 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 (3mL × 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 give the title compound (43mg, yield 30%). LCMS (liquid Crystal display Module) [ M + H ] ]+:547.5。1H NMR(500 MHz,DMSO-d6)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 72- ((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 (10mL), 1, 3-dichloroacetone (1.12g, 8.8mmol) was then added, and the mixture was stirred at room temperature for 2 hours, then stirred at reflux and reacted overnight. After TLC detection of essentially complete reaction of starting materials, the reaction mixture was allowed to cool to room temperature, saturated sodium carbonate (10mL) 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 (liquid Crystal display Module) [ 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 (5mL), followed by the addition of potassium carbonate (331mg, 2.4mmol), the mixture was 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 (10mL), and the reaction mixture 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, yield 55%. 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 (1mL), then sodium hydroxide solution (1.0mL, 1.0mmol, 1 mol/L) was added 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 (3mL × 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 give the title compound (48mg, yield 25%). LCMS (liquid Crystal display Module) [ M + H ] ]+:546.5。1H NMR(500MHz,DMSO-d6) 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 82- ((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 (2.0g, 14.58mmol) was dissolved in acetonitrile (20mL), O- (2, 4-dinitrophenyl) hydroxylamine (2.90 g, 14.58mmol) was added and the mixture was stirred at 40 ℃ for 24 h. 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 (50mL), 1, 8-diazabicycloundec-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 8 hours, the reaction solution was poured into saturated brine (30mL), extraction was performed with dichloromethane (30 mL. times.3), the organic phases were combined and concentrated under reduced pressure, and the resulting residue was purified by column chromatography to give 1.98g of product in 45% yield. 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 (20mL), 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 (0.2g) 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 (20mL), trifluoroacetic acid (2.0mL) was added, the mixture was stirred at room temperature for 8 hours, after completion of the reaction by LCMS, the reaction mixture was poured into saturated sodium bicarbonate (20mL), the organic layer was separated, and the aqueous layer was washed with dichloromethane (20 mL. times.2) ) Extraction, combined organic phases were dried over anhydrous sodium sulphate, concentrated under reduced pressure and the residue was purified by column chromatography to give 0.69g of 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 dichloromethane (5mL), triethylamine (0.61mL, 4.4mmol) was added, the mixture was stirred in an ice-water bath, methanesulfonyl chloride (0.20mL, 2.64mmol) was added dropwise, and the reaction mixture was allowed to slowly warm to room temperature and stirred. After TLC detection of the completion of the reaction of the starting materials, water (10mL) 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 (5.0mL), 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 (10mL) 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 (1mL), followed by addition of sodium hydroxide solution (1.0mL, 1.0mmol, 1 mol/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 (3mL × 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 give the title compound (43mg, yield 22%). LCMS (liquid Crystal display Module) [ M + H ] ]+:694.7。1H NMR(500MHz,DMSO-d6) 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 92- ((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
Methyl 5-amino-4-cyano-3-methylthiophene-2-carboxylate (1.96g, 10mmol) was dissolved in acetonitrile (20mL), 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 stop the reaction, and cooled to room temperature, saturated brine (30mL) was added to the reaction mixture, followed by dichloromethane (30mL), the organic layer was separated, the aqueous layer was extracted with dichloromethane (30mL × 2), the combined organic phases were dried over sodium sulfate and concentrated under reduced pressure, and the resulting residue was purified by column chromatography to give 2.14g of a product in 80% yield. LCMS (liquid Crystal display Module) [ M + H ]]+:267.2。
Step 2) 4-carbamoyl-3-methyl-5- ((oxetan-2-ylmethyl) amino) thiophene-2-carboxylic acid methyl ester
Methyl 4-cyano-3-methyl-5- ((oxetan-2-ylmethyl) amino) thiophene-2-carboxylate (2.14g, 8.0mmol) was dissolved in methanol (40mL), sodium methoxide (432mg, 8.0mmol) was added, the mixture was stirred at 50 ℃ for 6 hours to stop the reaction, the reaction was cooled to room temperature, methanol was removed by concentration under reduced pressure, dichloromethane/water (40mL, v/v ═ 1:1) was added, the organic layer was separated, the aqueous layer was extracted with dichloromethane (20mL × 2), the combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude product, which was used directly in the next reaction.
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, 1-trimethoxyethane (1.4g,8.8mmol) was added, nitrogen was used for protection, and the reaction was carried out at 120 ℃ for 12 hours with a sealed tube. The reaction was stopped, water (15mL) 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 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 (10mL), 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 (500mg) was allowed to warm to 50 ℃ for reaction overnight. The reaction was stopped, cooled to room temperature, quenched with water (10mL), 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 (2mL), sodium hydroxide solution (1.0mL, 1.0mmol, 1mol/L) was added, 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 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。1H NMR(500MHz,DMSO-d6)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 102- ((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 (10mL), adding sufficient triethylamine and stirring until the system is clear, adding saturated sodium chloride (10mL), separating the organic phase, extracting the aqueous phase with dichloromethane (10mL), combining the organic phases, and then concentrating under reduced pressure to give a free sample (905mg, 2.89 mmol); the free sample was redissolved in acetonitrile (20mL), added with 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, heated to 50 ℃ for reaction overnight; the reaction was cooled to room temperature, poured into saturated sodium chloride (20mL), extracted with ethyl acetate (20mL × 3), the organic phases were combined and dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography (PE: EA ═ 1: 1to EA) to give the product 895mg as a pale yellow solid in 79% yield.
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 (250mg, 0.43mmol), 4-methoxyphenylboronic acid (98mg, 0.65mmol), palladium acetate (9.6mg, 0.043mmol), triphenylphosphine (33.8mg, 0.129mmol) and potassium carbonate (118.6mg, 0.86mmol) were dissolved in toluene (5mL) and reacted at 70 ℃ overnight under nitrogen; after the raw materials are completely reacted by LC-MS detection, the reaction solution is directly concentrated under reduced pressure, and the obtained residue is purified by column chromatography (PE: EA is 1: 2to 1: 3) to obtain a product which is 212mg of white solid with the yield of 81%.1H NMR(500MHz,CDCl3)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 ═ 4:1), and the mixture was stirred at 100 ℃ for reaction; after TLC checked complete conversion of starting material, it was purified directly by separation 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。1H NMR(500MHz, DMSO-D6)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 112- ((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-Imidazaldehyde (5g, 52.03mmol), potassium carbonate (14.3g, 104.6mmol) and acetonitrile (60mL) 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 complete, 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 (100mL) was added for dilution, water (100mL) was added, the organic phase was separated, the aqueous phase was extracted with dichloromethane (100mL), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the solvent by evaporation, and the residue was purified by column chromatography (PE: EA: 1) to give 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 (10mL), added sodium borohydride (613mg, 16.1mmol) in an ice bath, and stirred at room temperature for 1 hour. TLC detection raw material reaction is complete, adding ice water (3mL) to quench, vacuum concentration to remove methanol, adding ethyl acetate (15mL x 3) to extract, combining organic phase, anhydrous sodium sulfate drying, filtering, vacuum concentration to remove solvent, colorless oily product 500mg, yield 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 one-necked flask, and thionyl chloride (5mL) was added to the flask to react 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 (20mL), ethyl 4-amino-5- ((tert-butoxycarbonyl) amino) thiophene-2-carboxylate (500mg, 1.75mmol) and DIPEA (903mg, 7.00mmol) were added, and the reaction was stirred at room temperature for 12H. After TLC detection reaction was complete, the reaction was stopped, and concentrated under reduced pressure to remove acetonitrile, water (10mL) 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, concentrated under reduced pressure to remove the solvent by evaporation, and the obtained residue was purified by column chromatography to give 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 and dichloromethane (25mL), trifluoroacetic acid (0.5mL) and 2-chloro-1, 1, 1-trimethoxyethane (294mg, 1.90mmol) were added and the mixture was stirred at room temperature 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 (5mL), potassium carbonate (235mg, 1.7mmol) 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, water (5mL) 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 give 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]Imidazole-5-carboxylic acid ethyl ester (30mg, 0.047mmol) was dissolved in ethanol (2mL), and sodium hydroxide (1mL, 1M) solution was added and the reaction stirred at room temperature for 15 h. After TLC detection reaction, decompression concentration to remove ethanol, adding water (2mL), ethyl acetate (2mL x 2) extraction, separating the aqueous phase, adjusting the pH of the aqueous phase to about 5, then ethyl acetate (3mL x 3) extraction, organic phase through anhydrous sodium sulfate drying, filtration, decompression concentration, freeze drying to get white solid product 14.3mg, yield 50%. Purity: 97.0 percent. 1HNMR(500MHz,DMSO-d6) 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 122- ((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 (5mL) and intermediate 2 hydrochloride (140mg, crude, 0.35mmol) were added, and the temperature was raised to 60 ℃ for reaction for 2.5H. After cooling to room temperature, water (5mL) was added, extraction was performed with ethyl acetate (10mL × 3), and the organic phases were combined, then washed with saturated brine, dried over anhydrous sodium sulfate, and purified by preparative TLC to give the title compound as a colorless transparent oil 60mg, yield 22%.
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 ]Imidazole-5-carboxylic acid ethyl ester (75mg, 0.12mmol) was dissolved in ethanol (3mL), and sodium hydroxide (1.5mL, 1M) solution was added and the reaction stirred at room temperature for 15 h. After TLC detection raw material reaction is completed, concentrating under reduced pressure to remove ethanol, adding water (2mL), extracting with ethyl acetate (2mL x 2), separating out an aqueous phase, adjusting the pH of the aqueous phase to be about 5, extracting with ethyl acetate (3mL x 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.1H NMR (500MHz,MeOH-d4)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 132- ((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
Intermediate 2 hydrochloride (30mg, 0.085mmol) was dissolved in acetonitrile (1.5mL) and K was added2CO3(30mg, 0.213mmol) and 2- (chloromethyl) -1- ((1-ethyl-1H-imidazol 5-yl) methyl) -1H-thieno [2,3-d]Imidazole-5-carboxylic acid ethyl ester (25mg, 0.071mmol), heating to 60 deg.C, stirring and reacting for 12 h. After TLC detection, water (5mL) was added, extraction was performed with ethyl acetate (15 mL. times.3), and the organic phases were combined and saturated Washed with brine, dried over anhydrous sodium sulfate, and purified by preparative TLC to give 30mg of a pale yellow oily product in 66% yield.
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]Imidazole-5-carboxylic acid ethyl ester (30mg, 0.047mmol) was dissolved in ethanol (4mL), and sodium hydroxide (1.5mL, 1M) solution was added and reacted at room temperature for 8.5 h. After the TLC detection reaction is completed, the mixture is concentrated under reduced pressure to remove ethanol. Water (2mL) was added, ethyl acetate extracted (2mL x 2), the organic phase was discarded, the pH of the aqueous phase was adjusted to about 5, ethyl acetate extracted (3mL x 3), the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, lyophilized to give 14.3mg of off-white solid product with 50% yield. Purity: 97.7 percent.1H NMR(500MHz,MeOH-d4)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 (760mg,8.64mmol) was dissolved in dichloromethane (10mL), Dess-martin (5.5g, 12.96mmol) 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 added2SO4Then placing the reaction system in an ice water bath to reduce the temperature to 0 ℃, and dropwise adding 65% of HNO3(6.3mL), 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 (50mL), extracted with ethyl acetate (30mL × 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-neck flask, potassium carbonate (3.95g, 28.56mmol) and acetonitrile (45mL) were added, and stirred at room temperature for 2.5 h. After TLC detection reaction was completed, the reaction was stopped, the reaction solution was poured into ice water (50mL), 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 (2.7g, 7.1mmol) was dissolved in dichloromethane (30mL), trifluoroacetic acid (3mL) 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 (100mL), 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 (1.9g, 8.79mmol) was dissolved in tetrahydrofuran (40mL), and triethylamine (1.34g, 13.2mmol) and (Boc) were added2O (2.3g, 10.55mmol), 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 (7.5mL), water (2.5 mL), iron powder (1.04g, 18.65mmol) and ammonium chloride (400mg, 7.46mmol) were added, and the mixture was heated to 60 ℃ for 2 h. After TLC detection reaction was completed, the reaction was stopped, cooled to room temperature, concentrated under reduced pressure to remove methanol, filtered to remove insoluble matter, added with water (10mL), 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, 75% of a yellowish brown oily product.
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 (18mL), and (S) -oxetanyl-2-carbaldehyde (228mg,2.65mmol) was added thereto and dropwise added to 3 drops of acetic acid, followed by stirring at room temperature for 20 minutes. Sodium triacetoxyborohydride (933mg, 4.4mmol) was added and the reaction stirred at room temperature for an additional 1 h. Diluting with dichloromethane (30mL), washing with water (20mL), separating organic phase, washing with saturated salt solution, drying with anhydrous sodium sulfate, concentrating under reduced pressure, evaporating to remove solvent, and purifying the residue by column chromatography to obtain dark brown oily product 330mg, 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 (6.5mL), acetic acid (22mg, 0.365mmol) was added and nitrogen was bubbled for 1 min, 2-chloro-1, 1, 1-trimethoxyethane (113mg, 0.733mmol) was added and the reaction was allowed to proceed for 12h at 100 ℃ with tube closure. After 12h, p-toluenesulfonic acid monohydrate (7mg, 0.036mmol) was added and the reaction was carried out at 75 ℃ for 1 h. The reaction was stopped, water (15mL) was added, extraction was performed with ethyl acetate (20mL × 3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, 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 (3mL), potassium carbonate (202mg, 1.46mmol) was added, stirring was carried out at room temperature for 10 minutes, ethyl (S) -2- (chloromethyl) -1- (oxetan-2-ylmethyl) -1H-thieno [2,3-d ] imidazole-5-carboxylate (140mg, 0.365 mmol) was added, and the mixture was allowed to warm to 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 (5mL), extracted with ethyl acetate (10 mL. times.3), the organic phase washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the solvent, and the residue purified by column chromatography to give 40mg, 26% as 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]Imidazole-5-carboxylic acid ethyl ester (40mg, 0.067mmol) was dissolved in ethanol (1mL), 1N sodium hydroxide solution (1mL) 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。1HNMR(500MHz,DMSO-d6)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 temperature was raised to 70 ℃ and stirred 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 (5mL) was added, extracted with ethyl acetate (3 × 5mL), 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, 0.087mmol) was dissolved in ethanol (2mL), lithium hydroxide (1mL, 1M) was added, and the mixture was stirred at room temperature overnight. Concentrating under reduced pressure to remove ethanol, adding water (3mL), extracting with ethyl acetate (3mL), discarding the organic phase, adjusting pH of the aqueous phase to about 5, extracting with ethyl acetate (3X 5mL), 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.1H NMR(500MHz,MeOH-d4)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 162- ((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 ethyl ester
Figure BDA0003128505470000621
Ethyl 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 (3mL) 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 give 60mg, 31% of the product as a yellow oil.
Example 172- ((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]Imidazole-5-carboxylic acid ethyl ester (60mg, 0.089mmol) was dissolved in ethanol (2mL), and lithium hydroxide (1mL, 1M) was added and stirred at room temperature overnight. Concentrating under reduced pressure to remove ethanol, adding water (2mL), extracting with ethyl acetate (2mL), discarding organic phase, adjusting pH of water phase to about 5, extracting with ethyl acetate (5mL × 3), mixing organic phases, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, adding 2 drops of trifluoroacetic acid, and lyophilizing to obtain white-like solid product 36.0mg, 63%. Purity: 98 percent.1H NMR(500MHz,MeOH-d4)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 182 Ethyl- ((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 (156mg, 1.132mmol) and acetonitrile (3mL) 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 at 70 ℃ overnight. 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 192- ((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 trifluoroacetate complex
Figure BDA0003128505470000631
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 ethyl ester (50mg, 0.076mmol) was dissolved in ethanol (2mL), and lithium hydroxide (1mL, 1M) was added and stirred at room temperature overnight. Concentrating under reduced pressure to remove ethanol, adding water (2mL), extracting with ethyl acetate (2mL), discarding the organic phase, adjusting pH of the aqueous phase to about 5, extracting with ethyl acetate (5mL × 3), combining the organic phases, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, adding 2 drops of trifluoroacetic acid,freeze-drying to obtain white solid product 32mg, 67%. Purity: 94 percent.1H NMR(500MHz,MeOH-d4)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 206 Ethyl- ((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)6- (chloromethyl) -5-imidazo [2,1-b ] thiazole-2-carboxylic acid ethyl ester
Ethyl 2-aminothiazole-5-carboxylate (1.72g, 10mmol) and dichloroacetone (2.54mg, 20mmol) were placed in a 30mL sealed tube, chlorobenzene (20mL) was added, the mixture was stirred at 130 ℃ for 2 hours, cooled to room temperature, the solvent was evaporated off by concentration under reduced pressure, and the resulting residue was purified by column chromatography to give 1.02g of a pale yellow solid product with a yield of 42%.
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 (0.6g,2.45mmol) and iodosuccinimide (0.6g, 2.7mmol) were dissolved in acetonitrile (20mL), 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
The hydrochloride salt of intermediate 2 (1.07g, 3mmol) and ethyl 6- (chloromethyl) -5-iodoimidazo [2,1-b ] thiazole-2-carboxylate (1.22g, 3.3mmol) were dissolved in acetonitrile (30mL), triethylamine (0.9g, 9mmol) was added, and the reaction was carried out at 60 ℃ for 14 h. Cooling to room temperature, concentrating under reduced pressure and evaporating to remove the solvent, 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 (5mL), 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 (5mL) 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 216- ((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
Mixing 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 (1.2mL), lithium hydroxide (8.4mg, 0.2mmol) and water (0.4mL) were added, and the mixture was reacted at room temperature for 3 h. 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.1H NMR(500MHz,CD3OD)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 222 methyl- ((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 (50mL) 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 (40mL), the reaction was stirred at room temperature overnight, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography to give 4.4g of a white solid product 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 salt of intermediate 2 (0.54g, 1.5mmol) and methyl 2- (chloromethyl) -3-iodoimidazo [1,2-a ] pyridine-6-carboxylate (0.63g, 1.8mmol) were dissolved in acetonitrile (15mL), triethylamine (530mg, 5.3mmol) was added, and the reaction was carried out at 60 ℃ for 14 h. 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 (15mL), 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 (15mL) 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 232- ((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 (3.6mL), lithium hydroxide (21mg, 0.5mmol) and water (1.2mL) were added, and the mixture was reacted at room temperature for 3 h. The reaction was stopped, pH adjusted to approximately 5 with 1N HCl, purified by preparative TLC and lyophilized to give 10.8mg, 17% as a white solid. Purity: 92.3 percent.1HNMR(500MHz,CD3OD)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 246 Ethyl- ((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 (5mL) 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 69% yield.
Example 256- ((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
Mixing 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 (2.4mL), LiOH (16.8mg, 0.4mmol) and water (0.6mL) were added, and the mixture was reacted at room temperature for 3 h. 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: 87.3 percent.1H NMR(500MHz,CD3OD)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 262- ((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 (321mg, 2.32mmol) and acetonitrile (5mL) 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
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 (3mL), 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 (3mL), extracting with ethyl acetate (3mL), discarding organic phase, adjusting pH of 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 solid product 97mg with yield of 72%. Purity: 93.8 percent.1H NMR(500MHz,MeOH-d4)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 272- ((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, 0.5mmol), potassium carbonate (276mg, 2.0mmol), acetonitrile (3mL) 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. Cooling to room temperature, filtering to remove insoluble substances, concentrating under reduced pressure to remove the solvent, and purifying the residue by column chromatography to obtain 30mg of yellow oily product with yield of 9%.
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 (2mL), lithium hydroxide (1mL, 1M) was added, and the mixture was stirred at room temperature overnight. Concentrating under reduced pressure to remove ethanol, adding water (3mL), extracting with ethyl acetate (3mL), discarding the organic phase, adjusting pH of the aqueous phase to about 5, extracting with ethyl acetate (5mL × 3), combining the organic phases, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure to remove the solvent, adding 2 drops of trifluoroacetic acid, and lyophilizing to obtain a white-like solid product 45mg with a yield of 79%. Purity: 97.8 percent.1H NMR(500MHz,MeOH-d4) 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 286- ((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 (3g, 18.7mmol) was dissolved in THF (30mL), sodium hydride (1.12g, 28.05mmol, 60%) was added under ice-water bath, the mixture was stirred for 0.5 h, 2, 6-dichloropyridine (3.32g,22.4mmol) was added, and the mixture was stirred at room temperature for 12 h. The reaction was stopped, ice water (30mL) was added, ethyl acetate (30mL × 3) was 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 (100mL), concentrated sulfuric acid (2.5mL) 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 (200mL) was added, and the mixture was washed with water (100mL), a saturated sodium bicarbonate solution (100mL) and a saturated sodium chloride solution 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]Methyl isothiazole-3-carboxylate (2g, 7.36mmol), 1-Boc-4-aminopiperidine (1.77g, 8.84mmol), cesium carbonate (4.8g, 14.72mmol), x-phos (702mg, 1.47mmol), Pd2(dba)3(674mg, 0.74mmol) was placed in a 100mL single-neck flask, toluene (50mL) 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 (4mL) 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)，Pd2(dba)3(181mg, 0.198mmol) was placed in a 100mL single neck flask, toluene (50mL) 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-chloromethylimidazole hydrochloride (98mg, 0.54mmol), potassium carbonate (271mg, 1.96mmol) were placed in a 48 mL sealed tube, acetonitrile (5mL) was added, and the mixture was warmed to 70 ℃ for reaction overnight. Insoluble material was removed by filtration and purified by preparative TLC to give 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 (3mL), 1M aqueous lithium hydroxide (1.5mL) 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 (3 × 5mL), combining organic phases, drying over anhydrous sodium sulfate, concentrating, purifying the residue by preparative TLC, and lyophilizing to obtain 18mg, 30% beige product. Purity: 95.8 percent.1H NMR (500MHz,DMSO-d6)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 292- ((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) was dissolved in thionyl chloride (27mL) and reacted overnight at reflux; after the raw materials completely react, concentrating under reduced pressure to dryness, adding dichloromethane (10mL) into the residue, dripping a dichloromethane (10mL) 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 completely finished, diluting with dichloromethane (83mL), washing the obtained solution with saturated sodium bicarbonate (100mL x 3), then washing with water (100mL x 3), drying the organic phase with anhydrous sodium sulfate, and concentrating under reduced pressure to obtain 3.04g of brown solid with yield of 46%; 1H NMR(500MHz,CDCl3)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, 28.15mmol) in dimethyl sulfoxide (80mL), reacting the mixture at 120 ℃ overnight, performing TLC detection on the complete conversion of the raw materials at 100 ℃ for the weekend, cooling, adding 1.0M hydrochloric acid solution (20mL), and continuing to react the mixture at 120 ℃ for 1 hour; after cooling to room temperature, 1.0M hydrochloric acid solution (20mL) was added, water (100mL) 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), the obtained ethyl acetate layer was washed with water (100mL), washed with saturated brine (100mL), dried over anhydrous sodium sulfate, and concentrated to dryness to obtain 2.15g of a yellow oily substance with a yield of 79%.1H NMR(500MHz,CDCl3)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 (40mL), ethyl 2, 4-dichloroacetoacetate (3.07g, 15.4mmol) was added, and the mixture was refluxed overnight; after TLC monitoring the complete conversion of the starting material, it was directly concentrated to dryness under reduced pressure and the residue was purified by column chromatography (PE: EA: 1: 0to 2: 1) to give 920mg of a white solid in 25% yield. 1H NMR(500MHz,CDCl3)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 (20mL), 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 ester (0.62g, 1.83mmol), reacted at 50 ℃ overnight; TLC monitored complete conversion of starting material, cooled to room temperature, diluted with ethyl acetate (20mL), added water (20mL), separated the organic layer, the aqueous layer extracted with ethyl acetate (20mL), the combined organic layers dried over anhydrous sodium sulfate, concentrated, and the residue purified by column chromatography (PE: EA ═ 1: 2) to give 1.03g of yellow oil in 90% yield.1H NMR(500MHz,CDCl3)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
Mixing 6- (tert-butyl) 3-ethyl 2- ((4- (6- ((4-chloro-2-fluorobenzyl) oxy) pyridine-2-yl) piperidine-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 1) to this mixture was added lithium hydroxide monohydrate (28mg, 0.61mmol) and the mixture was reacted at room temperature overnight; after the reaction of the starting material was monitored by LC-MS to be complete, the pH was adjusted to about 4, extracted with dichloromethane (15mL x 3), dried over anhydrous sodium sulfate, and concentrated to dryness to give 151mg of a foamy solid in 62% yield. 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 (1.2mL) 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％。1H NMR(500MHz, DMSO-d6)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 305- ((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, 105.6mmol) was dissolved in methanol (150mL), sulfuric acid (3mL) was added, and the mixture was warmed to 90 ℃ for reaction overnight. The reaction was stopped, cooled to room temperature, concentrated under reduced pressure to remove methanol, water (100mL), extracted with ethyl acetate (50mL x 3), the organic phases combined, washed successively with 5% sodium hydroxide solution (50mL x 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, 97.4mmol) in sulfuric acid (34mL), cooling the mixture to 0 ℃, dropwise adding a sulfuric acid solution of nitric acid (8.2mL of nitric acid in 23mL of sulfuric acid), reacting for 1 hour, slowly pouring the reaction solution into ice water (400mL), extracting with ethyl acetate (3 x 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 (35mL), 1-dimethoxy-N, N-dimethylethylamine (7.05g, 52.95mmol) was added, and the mixture was heated to 100 ℃ for reaction 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 (100mL), iron powder (5.27g, 94.35mmol), ammonium chloride (2.02g, 37.74mmol) and water (30mL) 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 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) dissolved in THF (10mL) and triethylamine (518 mg, 5.12mmol), (Boc)2O (1.12g, 5.12mmol) and DMAP (312mg, 2.56mmol), heating the mixture to 50 ℃ to react for 4 hours, stopping the reaction, concentrating under reduced pressure, purifying the residue by column chromatography to obtain 530mg of light yellow solid product,the yield thereof was found to be 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 (400mg, crude, 0.68mmol), intermediate 11 trifluoroacetate salt (600mg, 0.75mmol), potassium carbonate (376mg, 2.72mmol) were placed in a 48 mL sealed tube, acetonitrile (15mL) was added, and the reaction was allowed to warm to 60 ℃ overnight. The reaction was stopped, water (15mL) and ethyl acetate (15mL × 3) were added and 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 (10mL), trifluoroacetic acid (3mL) was added and the mixture was stirred at room temperature overnight. The reaction was stopped, concentrated under reduced pressure, dissolved in ethyl acetate (10mL), washed with saturated sodium bicarbonate (10mL), the aqueous phase was extracted with ethyl acetate (2 x 10mL), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to yield 189 mg of a light brown oily product in > 99% yield.
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 (5mL), 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 (1.5mL) and reacted overnight with 1N aqueous sodium hydroxide (0.5 mL). The reaction was stopped, concentrated under reduced pressure to remove the solvent, water (2mL), 1N diluted hydrochloric acid was added to adjust the pH to about 6, ethyl acetate (5mL × 3) was extracted, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then ethyl acetate (5mL) was added to dissolve it, filtered to remove insoluble matter, concentrated under reduced pressure, and lyophilized to obtain an off-white solid product 14mg, yield 58%. LCMS (liquid Crystal display Module) [ M + H ]]+:608.2。1H NMR(500 MHz,MeOH-d4)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 312- ((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-butyloxycarbonyl) -2- ((4- (6- ((4-chloro-2-fluorobenzyl)Yl) oxy) pyridin-2-yl) piperidin-1-yl) methyl) imidazo [1,2-a]Pyridine-3-carboxylic acid (60mg, 0.1mmol), 3-azetidine (14.6mg, 0.2mmol), HATU (42mg, 0.11mmol), triethylamine (20mg, 0.2mmol) and dichloromethane (2mL) 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 (3mL) and water (1mL), lithium hydroxide (20mg) 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%.1H NMR(500MHz,CD3OD)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 322- ((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(0.6g, 2.7mmol) were dissolved in acetonitrile (2mL), triethylamine (45mg, 0.4mmol) was added, the mixture was stirred at 60 ℃ overnight to stop the reaction, and the residue was directly purified by column chromatography to give 60mg of a white solid 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 (4mL) and water (1mL), and the mixture is stirred at 60 ℃ for 24 h. 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 (38mg, 0.1mmol), triethylamine and dichloromethane (2mL) were placed in a 5mL sample vial 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 (3mL) and water (1mL), lithium hydroxide (11mg) was added, the mixture was stirred at 60 ℃ overnight, concentrated under reduced pressure, water (5mL) was added, the pH was adjusted to between 5 and 6, and a 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%.1HNMR(500MHz,CD3OD)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, 0.987mmol), 1,1' -bis (diphenylphosphino) ferrocene (1.09g, 1.97mmol), potassium acetate (426mg, 4.41mmol) were placed in a 25 mL two-necked flask, tetrahydrofuran (100mL) 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 (5.46g, 39.48mmol) were added, and the mixture was allowed to react overnight. The reaction was stopped, cooled to room temperature, water (100mL) was added, extraction was performed with ethyl acetate (100mL x 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 in 11% yield.
Step 2) 5-bromo-4-nitrothiophene-2-phosphoric acid diethyl ester
Diethyl 5-bromothiophene-2-phosphate (3.7g, 12.32mmol) was dissolved in concentrated sulfuric acid (16.5mL), the mixture was cooled to 0 deg.C, nitric acid (5.5mL, 65%) was added dropwise, the reaction was continued for 0.5 hour, TLC showed disappearance of the starting material, and the reaction was stopped. The reaction solution was poured into ice water (50mL), 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 (40mL), potassium carbonate (3.9g, 28.26 mmol) and 2, 4-dimethoxybenzylamine (2.05g, 12.24mmol) were added, and the mixture was allowed to react at 50 ℃ for 4 hours, and then allowed to react at room temperature overnight. TLC showed disappearance of the starting material, reaction was stopped, water (30mL) was added, extraction was performed with ethyl acetate (30 mL. times.3), and 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
Mixing 5- ((2, 4-dimethoxy)Benzyl) amino) -4-nitrothiophene-2-phospho-diethyl ester (5g, 9.42mmol) was dissolved in dichloromethane (20mL), trifluoroacetic acid (3mL) was added and the mixture was reacted at room temperature for 7 hours, TLC showed disappearance of starting material, concentrated under reduced pressure to give crude product, which was added (Boc)2O (4.1 g,18.84mmol), triethylamine (4.76g, 47.1mmol), DMAP (346mg, 2.83mmol) and tetrahydrofuran (50mL), and the mixture was stirred at room temperature overnight. Stopping reaction, adding water (50mL), extracting with ethyl acetate (50mL × 3), combining organic phases, washing with saturated common salt water, 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
Tert-butyl 5- (diethoxyphosphonyl) -3-nitrothiophene-2-carbamate (1.4g, 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
Tert-butyl 3-amino-5- (diethoxy) phosphonothiophene-2-carbamate (1.2g, 3.42mmol) was dissolved in acetonitrile, 1-ethyl-5-chloromethylimidazole 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 (20mL) 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, 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 (70mL), trifluoroacetic acid (3mL) and 2-chloro-1, 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 (5mL), 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 reaction overnight. The reaction was stopped, the 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
Mixing (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, 0.043mmol) was dissolved in ethanol (1.5mL), 1N sodium hydroxide (1mL) 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 (2mL) was added, pH was adjusted to about 5 with 1N diluted hydrochloric acid, ethyl acetate (2mL x 3) was extracted, the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure to give the crude product, which was dissolved by addition of ethyl acetate (10mL), insoluble matter was removed by filtration, 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。1HNMR(500MHz,MeOH-d4)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 (10mL), 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 (10mL × 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%. 1H NMR(500MHz,MeOH-d4)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 (3mL), 1N sodium hydroxide (1mL) was added, and the mixture was reacted at room temperature overnight. Stopping reaction, concentrating under reduced pressure to remove ethanol, addingAdjusting pH to about 6 with 1N trifluoroacetic acid, extracting with ethyl acetate (5mL x 3), drying with anhydrous sodium sulfate, concentrating under reduced pressure to obtain crude product, adding ethyl acetate (10mL) to dissolve the product, filtering to remove insoluble substance, concentrating under reduced pressure, and lyophilizing to obtain white solid product 152mg with yield of 69%. 97% purity, LCMS [ M + H ]]+:571.0。1H NMR(500MHz,MeOH-d4)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) phosphodiammonium salt
Figure BDA0003128505470000732
Mixing (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, 0.043mmol) 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 (1mL) was added to dissolve it, separation and purification was prepared, concentrated, 0.5 mL of ammonia was added, and lyophilized to give 10.0mg of off-white solid product in 34% yield. 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 (5mL), potassium carbonate (110mg, 0.8mmol) is added followed by (S) -2- (chloromethyl) -1- (oxetan-2-ylmethyl) -1H-thieno [2,3-d ] imidazole-5-carboxylic acid ethyl ester (100mg, 0.197mmol) and the mixture is warmed to 70 ℃ for 4H. The reaction was stopped, cooled to room temperature, 5mL 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 32% yield.
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 ]Ethyl imidazole-5-carboxylate (37mg, 0.063mmol) was dissolved in acetonitrile (1mL), DBU (19.2mg, 0.126mmol) was added, and the mixture was allowed to warm up overnight. Stopping the reaction, concentrating under reduced pressure to remove acetonitrile, adding 10% trifluoroacetic acid to adjust the pH to be about 5-6, extracting with ethyl acetate (5mL 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 freeze-drying to obtain an off-white solid product 15mg with the yield of 42%. 91% purity, LCMS [ M + H ]]+:562.2。1H NMR(500MHz,MeOH-d4)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 382- ((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 (25mL), triethylamine (2mL) 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 with a yield of 71%.
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 (1.5g, 2.8mmol) is dissolved in aqueous formaldehyde (20mL) and acetic acid (2mL), the mixture is stirred at 100 ℃ for reaction overnight, the solvent is evaporated under reduced pressure, and the residue is purified by column chromatography to give 800m g as 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, 1.4mmol) and triethylamine (0.4mL, 2.8mmol) are dissolved in anhydrous dichloromethane (20mL), cooled to-40 ℃, methanesulfonyl chloride (220mg, 2.0mmol) is added dropwise, and after 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 (2mL), triethylamine (40mg, 0.4mmol) is added, and the mixture is stirred at 90 ℃ for 2.5 h. 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, 0.057mmol) was dissolved in methanol (3mL) and water (1mL), lithium hydroxide (6.3mg, 0.22mmol) was added, and the mixture was stirred at 30 ℃ for 2 h. 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 (2mL), filtering, and draining to obtain white solid product 20mg with yield of 66%. Purity 98%, LCMS [ M + H ]]+:600.3。1H NMR(500MHz,CDCl3)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 392- ((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 (14.6mg, 0.2mmol) are dissolved in acetonitrile (2mL), triethylamine (20mg, 0.4mmol) is added, and the mixture is stirred at 90 ℃ for 2.5 h. 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, 0.058mmol) was dissolved in methanol (3mL) and water (1mL), lithium hydroxide (6.3mg, 0.22mmol) was added, and the mixture was stirred at 30 ℃ for reaction overnight. Adjusting pH to about 6 with dilute hydrochloric acid, concentrating most of methanol under reduced pressure to precipitate a large amount of precipitate, adding water (2mL), filtering, and draining to obtain white solid product 13.8mg with yield of 40%. Purity 97%, LCMS [ M + H ] ]+:600.3。1HNMR (500MHz,CDCl3)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 (1.5mL), EDCI (24mg, 0.126mmol), HOBt (9mg, 0.07mol) and aqueous ammonia (3 drops) were added and the mixture was stirred at room temperature for 4 hours. Stopping reaction, concentrating under reduced pressure, purifying the residue by preparative TLC, and lyophilizing to obtain off-white solid15mg of substance (g), yield 38%. LCMS (liquid Crystal display Module) [ M + H ]]+:570.2。1H NMR(500MHz,MeOH-d4)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 (5mL) 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 ]]Imidazole-5-carboxylic acid ethyl ester (36mg, 0.06mmol) was dissolved in ethanol (2mL), 1M aqueous sodium hydroxide (1 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, and extracting with ethyl acetate (5 mL. times.3)Combining organic phases, adding anhydrous sodium sulfate, drying, concentrating, adding ethyl acetate (10mL), filtering, concentrating and freeze-drying to obtain a white solid product 30mg with the yield of 88%. Purity: 99% LCMS [ M + H ]]+:568.2。1HNMR(500MHz,CD3OD)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 (4mL) 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
Reacting (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 ethyl ester (80mg, 0.134mmol) was dissolved in ethanol (3mL), 1M aqueous sodium hydroxide (1.5mL) was added, and the mixture was stirred at room temperature overnight. Concentrating under reduced pressureRemoving ethanol, adjusting pH to about 6 with 1N diluted hydrochloric acid, extracting with ethyl acetate (5 mL. times.3), mixing organic phases, adding anhydrous sodium sulfate, drying, concentrating, adding ethyl acetate (10mL), filtering, concentrating, and lyophilizing to obtain off-white solid product 57mg, yield 74. Purity: 98%, LCMS [ M + H ]]+:570.2。1HNMR(500MHz,CD3OD)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 432- ((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-necked flask and K was added2CO3(41mg, 0.295mmol), acetonitrile (2mL) and 2-bromopropane (18mg, 0.147mmol), and the mixture was warmed to 70 ℃ for reaction overnight. Cooling to room temperature, adding water (5mL), extracting with ethyl acetate (3X 10mL), combining organic phases, washing with saturated brine, drying over anhydrous sodium sulfate, concentrating under reduced pressure to remove the solvent by evaporation, 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。1HNMR(500 MHz,CD3OD)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 442- ((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 isobutyl ester
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-necked flask and K was added2CO3(41mg, 0.295mmol), acetonitrile (2mL) and bromoisobutane (20mg, 0.147mmol), and the mixture was warmed to 70 ℃ for reaction overnight. Cooling to room temperature, adding water (5mL), extracting with ethyl acetate (10mL × 3), combining the organic phases, washing with saturated brine, drying over anhydrous sodium sulfate, concentrating under reduced pressure to remove the solvent by evaporation, purifying the residue by preparative TLC, and lyophilizing to obtain an off-white solid product 40mg, yield 45%. Purity: 99% LCMS [ M + H ]]+:664.1。1HNMR (500MHz,CD3OD)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 452- ((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-necked flask and HATU (94 m) was added g, 0.246mmol), morpholinoethanol (32 mg, 0.246mmol), tetrahydrofuran (5mL) and diisopropylethylamine (42mg, 0.328mmol), and the mixture was warmed to 70 ℃ for reaction overnight. Cooling to room temperature, adding water (5mL), extracting with ethyl acetate (10mL × 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。1H NMR(500MHz,CD3OD)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 462 Ethyl- ((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 (5mL) and intermediate 11(300mg, 0.38mmol) were added, and the mixture was warmed to 60 ℃ for reaction for 2.5 h. Cooled to room temperature, water (5mL), ethyl acetate (10mL x 3) was added for extraction, 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.1H NMR (500MHz, 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 ═ 12.9, 2H),1.84(d, 1.38 Hz,1H), 1.38 (d, 1H), 1.6.38 Hz,1H), 1.6.8 (d, 1H), 1.6.8 Hz,1H), 1H, and 7H H),1.20(t,J＝7.3Hz,3H)。
Example 472- ((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 (50mL) and water (10mL) were added 4- (4,4,5, 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' -bisdiphenylphosphinoferrocelluridinium dichloride palladium (0.7g, 1mmol), and the mixture was stirred at 90 ℃ overnight. After completion of the reaction, ethyl acetate (50mL) 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 give 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 6-chloro-5 ',6' -dihydro- [2,4' -bipyridine ] -1' (2' H) -carboxylic acid tert-butyl ester (1.8g, 6.1mmol) in toluene (60mL) were added (4-chloro-2-fluorophenyl) methanol (1g, 6.25mmol), cesium carbonate (4g, 12.3mmol), tris-dibenzylideneacetone dipalladium (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 (50mL) 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: 1) to obtain a 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 (1g, 6.75mmol) in ethanol (5mL) was added ethanol hydrochloride (5mL), 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 (1mL) and water (1mL) were added ethyl 2- (chloromethyl) -1- (oxetan-2-ylmethyl) -1H-thieno [2,3-d ] imidazole-5-carboxylate (135mg, 0.44mmol) and potassium carbonate (210mg, 1.76mmol), and the mixture was stirred at 60 ℃ overnight. After completion of the reaction, ethyl acetate (5mL) 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 (2mL) was added 1M hydrochloric acid (0.5mL), 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: 1) to obtain a product (25.1mg, 18.9%). LCMS (liquid Crystal display Module) [ M + H ]]+:569.33。1HNMR(500MHz,CD3OD) 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 482- ((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-neck flask, potassium carbonate (147mg, 1.06mmol), acetonitrile (5mL) and intermediate 11(140mg, crude, 0.35 mmol) were added, and the mixture was warmed to 60 ℃ for 2.5H. After cooling to room temperature, water (5mL) was added, extraction was performed with ethyl acetate (10mLX 3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and purified by preparative TLC to give 60mg of a colorless transparent oil, with 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]Imidazole-5-carboxylic acid ethyl ester (100mg, 0.157mmol) was dissolved in 1, 4-dioxane (1mL), water (2mL), 50% aqueous hydroxylamine solution (22 mg, 0.33mmol) and then sodium hydroxide (38mg, 0.95mmol) were added and the mixture was stirred at room temperature for 1 h. 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 10:1) and lyophilized to give 32mg of off-white solid product in 32.6% yield: 95 percent.1H NMR(500MHz,CD3OD)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 492- ((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-neck flask, potassium carbonate (147mg, 1.06mmol), acetonitrile (5mL) and intermediate 11(140mg, crude, 0.35mmol) were added, and the mixture was warmed to 60 ℃ for 2.5H. Cooled to room temperature, added with water (5mL), extracted with ethyl acetate (10mL X3), combined organic phases, washed with saturated brine, dried over anhydrous sodium sulfate, 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 (3mL), a solution of sodium hydroxide (1.5mL, 1M) was added, and the mixture was stirred at room temperature for 15 h. After TLC detection raw material reaction is completed, concentrating under reduced pressure to remove ethanol, adding water (2mL) and ethyl acetate (2mL X2) for extraction, separating out a water phase, adjusting the pH value of the water phase to be equal to 5 approximately, 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 an off-white solid product 28mg, wherein the yield is 38%, and the purity: 85.7 percent. 1H NMR(500MHz,MeOH-d4)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 (5mL), 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 (5mL), and concentrated under reduced pressure to give a crude product, which was prepared, isolated and purified from 1/4 (14.8mg), with yield: 35%, purity: 97 percent. LCMS (liquid Crystal display Module) [ M + H ]]+：686.29。1H NMR(500MHz,CD3OD)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 502- ((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, 0.095mmol) was placed in a 25mL single-necked flask, methyl carbonate (66mg, 0.475mmol) and acetonitrile (3mL) were added, and the mixture was warmed to 60 ℃ for reaction overnight. LCMS indicated product formation, reaction stopped and cooled to room temperature. Adding water (5mL), extracting with ethyl acetate (3X 5mL), combining 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 pale yellow oily product (36mg, 0.057mmol), 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
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, 0.057mmol) was dissolved in ethanol (2.5mL), aqueous sodium hydroxide (1 mL, 1M) was added, and the mixture was stirred at room temperature overnight. LCMS showed reaction was complete, stop reaction, concentrate under reduced pressure to remove ethanol, dissolve with water (2mL), adjust pH to about 6 with 1N dilute hydrochloric acid, extract with ethyl acetate (3X 5mL), combine organic phases, dry over anhydrous sodium sulfate, filter to remove insoluble materials, concentrate under reduced pressure to give crude product, dissolve with ethyl acetate (10mL), filter to remove insoluble materials, concentrate under reduced pressure, lyophilize to give off-white solid product (17.8mg, 0.029mmol), yield: 51.5%, purity: 98 percent. LCMS (liquid Crystal display Module) [ M + H ] ]+：606.19。1H NMR (500MHz,CD3OD)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 512- ((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 (10mL), N-diisopropylethylamine (903mg, 7.00mmol) and 1-isopropyl-1H-5-chloromethylimidazole 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 (10mL), extracting with ethyl acetate (10mL X3), mixing organic phases, washing with saturated saline, drying over anhydrous sodium sulfate, concentrating under reduced pressure to obtain crude product, and purifying by column chromatography to obtain yellow oily product (365mg, 0.89mmol), yield: 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 (20mL), trifluoroacetic acid (0.4mL) and 2-chloro-1, 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 (5mL) 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), combining organic phases, washing with saturated saline, drying over anhydrous sodium sulfate, concentrating under reduced pressure to obtain a crude product, and purifying by column chromatography to obtain a 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 (4mL), a 1M aqueous solution of sodium hydroxide (2mL) 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 (2mL), pH adjusted to about 6 with 1M dilute hydrochloric acid, to precipitate a large amount of solid, filtered, residue washed with water three times, 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。1H NMR(500MHz,CD3OD)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 522- ((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 trifluoroacetate
Figure BDA0003128505470000811
Step 1) Ethyl 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-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-necked flask, potassium carbonate (99mg, 0.715mmol) and acetonitrile (4mL) 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 (2mL), a 1M aqueous solution of sodium hydroxide (1 mL) 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 (0.1% CF) 3Aqueous solution of COOH, MeCN 90:10 to 10:90) to give a yellow oily product, 1.8mg, yield: 11%, LC-MS [ M + H ]]+:607.1。1H NMR(500MHz,CD3OD)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 532- ((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 sequence2CO3(97mg, 0.7mmol) and 2- (chloromethyl) -1- ((1-ethyl-1H-imidazol 5-yl) methyl) -1H-thieno [2,3-d]Imidazole-5-carboxylic acid ethyl ester (50mg, 0.14mmol) and the mixture was heated in a metal sand bath (50 ℃ C.) overnight. After completion of the reaction, the inorganic salt was removed by filtration, the solvent was removed by concentration under reduced pressure, and the residue was separated by thin layer chromatography (DCM: MeOH ═ 20:1) to give the desired 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 (1mL), and sodium hydroxide (1.6mg, 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 completion of the conversion monitored by TLC, the pH of the system was adjusted to 6 with 1N hydrochloric acid, at which time a large amount of white solid was precipitated in the system, and the supernatant was removed by pipetting. The resulting solid crude product was preparative separated by preparative HPLC and lyophilized to give the desired product (4.4mg, 35%) as a pale yellow solid. HPLC purity 95%, LCMS [ M + H ]]+:644。1HNMR(500MHz,MeOH-d4)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 542- ((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 afford 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-bath. 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 Na2SO4The residue was separated by column chromatography (PE: EA ═ 50:1) to give the desired 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 tert-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 48 h. After completion of the conversion 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 give the desired product (920mg, 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 (100mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the solvent, and the residue was separated by column chromatography (PE: EA ═ 20:1 to 10:1) to give the desired product (760mg, 19%) as a colorless oily liquid.
Step 5) methyl 2- (((tert-butyldimethylsilyl) oxy) methyl) -1H-imidazo [1,2-b ] pyrazole-6-carboxylate
Methyl 1- (3- ((tert-butyldimethylsilyl) oxy) -2-oxopropyl) -5-nitro-1H-pyrazole-3-carboxylate (760mg, 2.13mmol) was dissolved in 10mL MeOH. 10% Pd/C (222mg, 0.21mmol) was added to the reaction system, and the inside of the system was replaced with hydrogen gas three times and stirred at room temperature. After TLC monitoring for complete conversion (2h), 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 completion of the conversion monitored by LC-MS, the solvent was removed by concentration under reduced pressure, and the residue was isolated by column chromatography (PE: EA ═ 2:1) to give the desired product (466mg, 71%) 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
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 successively added to the reaction system, and the mixture was placed in a metal sand bath and heated at 50 ℃. After completion of the conversion monitored by TLC, the inorganic salts in the system were removed by filtration, the solvent was removed by concentration under reduced pressure, and the residue was separated by column chromatography (PE: EA ═ 4:1) 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
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). Into a reaction systemTBAF (185mg, 0.71mmol) was added and the mixture was stirred at room temperature. TLC monitored complete conversion (5min), water (50mL) was added, extraction was performed with ethyl acetate, and the combined organic phases were washed with saturated brine (30mL) and Na 2SO4Dried, concentrated under reduced pressure to remove the solvent, and the residue was isolated by thin layer chromatography (DCM: MeOH ═ 20:1) 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 dichloromethane, and the combined organic phases were washed with saturated brine (10mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the solvent, 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 (2mL), 1, 2-dichloroethane (2mL) and sodium bicarbonate (84mg, 1.0mmol) were added to the reaction system, the mixture was stirred at room temperature for 3h, then extracted with dichloromethane, the combined organic phases were washed with saturated brine (10mL), dried over anhydrous sodium sulfate, and the solvent was removed by concentration under reduced pressure to give 2- ((4-chloro-2-fluorobenzyl) oxy) -6- (piperidin-4-yl) pyridine. Dissolving the obtained free compound in 1, 2-dichloroethane (1mL), 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 2 h. After TLC monitored 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 extracted with saturated NaCl solution(10mL) washed with Na2SO4Dried, concentrated under reduced pressure to remove the solvent, and the residue was isolated by thin layer chromatography (DCM: MeOH ═ 20:1) to give the title product (92mg, 66%) as a yellow oil. 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, and the reaction 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 (10mL) and Na2SO4Drying, removal of solvent in vacuo and isolation of the residue by thin layer chromatography (DCM: MeOH 10:1) gave the title product (37mg, 41%) as a white powder. LCMS (liquid Crystal display Module) [ M + H ] ]+:542。1H NMR(500MHz,CH3OH-d4/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 CH3To 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 was carried out overnight, the reaction mixture was,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 ═ 1:1) to give 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 MeOH. Sodium borohydride (831mg, 21.97mmol) was slowly added to the reaction under ice-bath. The reaction was slowly warmed to room temperature and stirred for 1 h. 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 × 50mL) and then with saturated NaCl solution (100 mL). The organic phase is passed through Na2SO4The solvent was removed by drying and concentration under reduced pressure to give the objective product (1.27g, 56%) 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 SOCl with ice-bath cooling2In the reaction system, the reaction is refluxed (metal sand bath 80 ℃) and reacted for 2 hours. After the reaction is finished, concentrating under reduced pressure to remove SOCl2Oil pump vacuum drying gave the title product (920mg, 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 CH3CN (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 ═ 1:1 to DCM: MeOH ═ 20:1) to give the desired product (320mg, 46%) as a brown-black oil. LCMS (liquid Crystal display Module) [ M + H ]]+:395。
Step 5) Ethyl 2- (chloromethyl) -1- ((1-ethyl-1H-imidazol-2-yl) methyl) -1H-thieno [2,3-d ] imidazole-5-carboxylate
Reacting 5- ((tert-butoxycarbonyl) amino) Ethyl-4- (((1-ethyl-1H-imidazol-2-yl) methyl) amino) thiophene-2-carboxylate (200mg, 0.51mmol) was dissolved in dichloromethane (20 mL). Trifluoroacetic acid (0.4mL) and 2-chloro-1, 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 15:1) to give the crude product (180mg) as a brown-black oil. LCMS (liquid Crystal display Module) [ 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 (180mg, crude mixture) was dissolved in acetonitrile (6 mL). Potassium carbonate (415mg, 0.6mmol) and intermediate 11(214mg, 3.0mmol) were added successively to the reaction system, and the mixture was placed in a metal sand bath and heated to react (50 ℃ C.) overnight. After completion of the conversion of the starting material was monitored by LCMS, the inorganic salts were removed by filtration, the solvent was removed by concentration under reduced pressure, and the residue was separated by thin layer chromatography (DCM: MeOH ═ 20:1) to give the desired product (32mg, 9.8%) as a pale yellow oil. LCMS (liquid Crystal display Module) [ 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 THF, 1mL water and LiOH (2.4mg, 0.1mmol) were added to the reaction, and the reaction 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 (10mL) and Na 2SO4Drying, concentration under reduced pressure to remove the solvent, and semipreparative liquid phase separation gave the desired product (25mg, 83%) as a pale yellow powder. LCMS (liquid Crystal display Module) [ M + H ]]+:609。1H NMR(500MHz,MeOH-d4)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, 0.2mmol) was dissolved in dichloromethane (5mL), N' -carbonyldiimidazole (42mg, 0.3mmol) was added, the mixture was stirred at room temperature for 2 hours, then aminosulfonamide (19mg, 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. Washing the reaction solution with water (5mL), concentrating under reduced pressure to obtain a crude product, and preparing, separating and purifying to obtain a product (11mg) with the yield: 8%, purity: 98 percent. LCMS (liquid Crystal display Module) [ M + H ]]+：687.15。1H NMR(500MHz,CD3OD)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 622- ((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 dichloromethane (5mL), 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. Washing the reaction solution with water (5mL), concentrating under reduced pressure to obtain a crude product, and preparing, separating and purifying to obtain a product (8mg) with the yield: 6%, purity: 98 percent. LCMS (liquid Crystal display Module) [ M + H ]]+：701.21。1HNMR(500MHz,CD3OD)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 (5mL) and acetamide (26mg, 0.4 mmol) was added4mmol), 1-ethyl- (3-dimethylaminopropyl) carbonyldiimine hydrochloride (94mg, 0.49mmol) and 4-dimethylaminopyridine (90mg, 0.74mmol), 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 (5mL), and concentrated under reduced pressure to give crude product, which was prepared, separated and purified to give product (48mg, 30%), purity: 98 percent. LCMS (liquid Crystal display Module) [ M + H ] ]+：650.20。1H NMR(500MHz,CD3OD)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 642- ((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, 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 (5mL), 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 (5mL), and concentrated under reduced pressure to give crude product, which was prepared, separated and purified to give product (21mg, 12%), purity: 97 percent. LCMS (liquid Crystal display Module) [ M + H ]]+：704.10。1H NMR(500MHz,CD3OD)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 (5mL), 3,4, 5-trifluorophenylboronic acid (2.2mg, 0.0125mmol), urea (17mg, 0.28mmol), 4A molecular sieves (50mg) 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 (5mL), and concentrated under reduced pressure to give crude product, which was prepared, separated and purified to give product (24mg, 15%), purity: 98 percent. LCMS (liquid Crystal display Module) [ M + H ]]+：651.2。1H NMR(500MHz,CD3OD)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 (5mL), 3,4, 5-trifluorophenylboronic acid (2.2mg, 0.0125mmol), thiourea (21mg, 0.28mmol), 4A molecular sieves (50mg) were added, and the mixture was stirred at reflux overnight. LCMS showed the starting material reaction was complete and the reaction was stopped. Washing the reaction solution with water (5mL), and concentrating under reduced pressure to obtain a crude productIsolation and purification gave the product (18mg, 11%), purity: 98 percent. LCMS (liquid Crystal display Module) [ M + H ]]+：667.2。1H NMR(500MHz,CD3OD)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 672- ((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 (150mg, 0.25mmol) was dissolved in toluene (5mL), 3,4, 5-trifluorophenylboronic acid (2.2mg, 0.0125mmol), N-methylurea (21 mg, 0.28mmol), 4A molecular sieves (50mg) 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 (5mL), 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。1H NMR(500MHz,CD3OD)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 682- ((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 (5mL), 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 (5mL), a 0.5M solution of pyridazine in acetonitrile (2mL) was added dropwise to the above system, stirred for 1 minute, and then N- (tert-butyldimethylsilyl) methylsulfoneimine [ ref.chen, y.; gibson, J.A conditional synthetic routes to sulfenamides from sulfenamides RSC adv.2015,5,4171-4174.](19mg, 0.2mmol) in acetonitrile (1mL) 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 product (35mg, 13% containing the tautomer thereof) is prepared, separated and purified, and has the purity: 98 percent. LCMS (liquid Crystal display Module) [ M + H ]]+：685.20。1H NMR(500MHz, CD3OD)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, 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 strain 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. 10 μ L of cell suspension was added to each well. Secret keySealing plate, 5% CO at 37 ℃2Incubate for 30 minutes. Each well was filled with 5. mu.L of cAMP-d2 working solution, and then 5. mu.L of anti-cAMP labeled antibody working solution was added to detect the cAMP production level. The plate is covered with a cover. Incubate at room temperature for 1 hour. Fluorescence was read at 665 and 615/620nm using a fluorescent microplate reader and the data was saved. Calculation of EC for GLP-1R activation by test Compounds of the invention by Effect Curve fitting Compound concentration and corresponding cAMP levels 50The value is obtained.
GLP-1R agonistic activity (EC) of the test compounds of the invention50) 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 EC50(nM) Test compounds EC50(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 + Practice ofExample 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 ++++
Example 61 ++++ 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, for a person skilled in the art, several variations and modifications can be made without departing from the inventive concept, which falls within the scope of the present invention. Therefore, the protection scope of the present invention should be subject to the appended claims.

Claims (25)

1. A compound of formula (I):
Figure FDA0003128505460000011
or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, regioisomer, nitroxide, or mixture thereof, wherein,
L1is O, S, -N (R)c) -, -C (═ O) -, or-C (R)a)(Rb)-；
L2Is O, S, -N (R)c)-、-C(＝O)-、-(C(Ra)(Rb))t1-、-X-(C(Ra)(Rb))t1-, or- (C (R)a)(Rb))t1-X-(C(Ra)(Rb))t2-；
Z1And Z2Each independently is N or CH;
Ar1is C6-10Aryl radical, C1-9Heteroaryl group, C3-8Cycloalkyl radical, C2-9Heterocyclic group, C5-12Condensed bicyclic group, or C5-12Fused heterobicyclic group wherein said Ar1Optionally substituted by 0, 1, 2, 3 or 4R2Substitution;
cy is C3-8Cycloalkyl radical, C2-9Heterocyclic group, C5-12Spiro bicyclic group, C5-12Spiro-heterobicyclic radical, C5-12Condensed bicyclic group, C5-12Fused heterobicyclic radical, C5-12Bridged ring radical, or C5-12Bridged heterocyclyl, wherein said Cy is optionally substituted with 0, 1, 2, 3, or 4R 3Substitution;
Ar2is a fused heteroaryl 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 is2Optionally substituted by 0, 1, 2, 3 or 4R6Substitution; or Ar2The method comprises the following steps:
Figure FDA0003128505460000012
Figure FDA0003128505460000013
wherein Ar is2Optionally substituted by 0, 1, 2, 3 or 4R6Substitution;
x is O, S, -N (R)d) -, or-C (═ O) -;
X1、X2and X3Are each independently N or-C (R)6)-；
X5Is O or S;
w is-C (═ O) OR7a、-S(＝O)1-2OR7a、-P(＝O)(OR7a)(OR7b)、-P(＝O)(OR7a)(R7c)、-S(＝O)1- 2R7d、-C(＝O)R7d、-C(＝O)N(R7c)R7d、-S(＝O)1-2N(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、-C(＝O)N(R7c)C(＝S)N(R7c)R7d、-C(＝O)N(R7c)S(＝NR7a)1-2R7d、-C(＝O)N(R7c)S(＝O)(＝NR7a)R7d、
Figure FDA0003128505460000014
Figure FDA0003128505460000015
Each R1Are respectively and independently H, D, F, Cl, Br, I, -OH, -NH2、-NO2-CN, -oxo (-O), C1-6Alkyl radical, C1-6Hydroxyalkyl radical, C1-6Haloalkyl, C1-6Aminoalkyl radical, C1-6Cyanoalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, C1-6Alkylthio radical, C1-6Alkylamino radical, C3-8Cycloalkyl radical, C3-8Cycloalkyl radical C1-6Alkyl radical, C3-8Cycloalkyl radical C2-6Alkenyl radical, C3-8Cycloalkyl radical C2-6Alkynyl, C2-7Heterocyclic group, C2-7Heterocyclyl radical C1-6Alkyl radical, C6-12Aryl radical, C6-12Aryl radical C1-6Alkyl radical, C1-9Heteroaryl, or C1-9Heteroaryl C1-6Alkyl, -S (═ O)1-2R1a、-C(＝O)R1a、-C(＝O)OR1b、-OS(＝O)1-2R1a、-OC(＝O)R1a、-N(R1b)C(＝O)R1a、-OC(＝O)NR1bR1c、-NR1bR1c、-N(R1b)S(＝O)1-2R1aor-N (R)1b)C(＝O)NR1bR1c；
R5Is H, D, F, Cl, Br, I, -OH, -NH2、-NO2-CN, -oxo (-O), C1-6Alkyl radical, C1-6Haloalkyl, C1-6Cyanoalkyl, C1-6Aminoalkyl radical, C1-6Alkoxy radical C1-6Alkyl radical, C3-10Cycloalkyl radical, C2-9Heterocyclic group, C6-10Aryl radical, C1-9Heteroaryl, R5c-C(＝O)-、R5c-OC(＝O)-、R5c-C(＝O)O-、R5c-NHC(＝O)-、R5c-C(＝O)NH-、R5c-L3-C1-6Alkyl-, R5a-C1-6Alkyl, or R5a-C1-6Hydroxyalkyl-, wherein said C is 1-6Alkyl radical, C1-6Haloalkyl, C1-6Cyanoalkyl, C1-6Aminoalkyl radical, C3-10Cycloalkyl radical, C2-9Heterocyclic group, C6-10Aryl radical, C1-9Heteroaryl, R5c-C(＝O)-、R5c-OC(＝O)-、R5c-NHC(＝O)-、R5c-L3-C1-6Alkyl-, R5a-C1-6Alkyl-andR5a-C1-6hydroxyalkyl-is independently optionally substituted with 0, 1, 2, 3 or 4R5bSubstitution;
R5ais C3-10Cycloalkyl radical, C2-9Heterocyclic group, C6-10Aryl, or C1-9Heteroaryl, wherein R is5aOptionally substituted by 0, 1, 2, 3 or 4R5bSubstitution;
R5cis H, C1-6Alkyl radical, C3-10Cycloalkyl radical, C2-9Heterocyclic group, C6-10Aryl, or C1-9Heteroaryl, wherein R is5cOptionally substituted by 0, 1, 2, 3 or 4R5bSubstitution;
L3is O, S, -N (R)d) -, or-C (═ O) -;
each R1a、R2、R3、R4、R5b、R6、RaAnd RbAre respectively and independently H, D, F, Cl, Br, I, -OH, -NH2、-NO2-CN, -oxo (-O), C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Hydroxyalkyl radical, C1-6Haloalkyl, C1-6Aminoalkyl radical, C1-6Cyanoalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, C1-6Alkylthio radical, C1-6Alkylamino radical, C1-6Haloalkylamino, -NR1bR1c、C3-8Cycloalkyl radical, C3-8Cycloalkyl radical C1-6Alkyl radical, C2-7Heterocyclic group, C2-7Heterocyclyl radical C1-6Alkyl radical, C6-12Aryl radical, C6-12Aryl radical C1-6Alkyl radical, C1-9Heteroaryl, or C1-9Heteroaryl C1-6An alkyl group; wherein C is3-8Cycloalkyl radical, C3-8Cycloalkyl radical C1-6Alkyl radical, C2-7Heterocyclic group, C2-7Heterocyclyl radical C1-6Alkyl radical, C6-12Aryl radical, C6-12Aryl radical C1-6Alkyl radical, C1-9Heteroaryl and C 1-9Heteroaryl C1-6Alkyl is optionally substituted by 0, 1, 2, 3 or 4 substituents independently selected from H, F, Cl, Br, I, -OH, -NH2、-NO2-CN, -oxo (-O), C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Hydroxyalkyl radical, C1-6Haloalkyl, C1-6Aminoalkyl radical, C1-6Cyanoalkyl, C1-6Alkoxy and C1-6Substituted with a halo alkoxy group;
each R1b、R1c、Rc、Rd、R7cAnd R7dEach independently is H, D, -OH, -CN, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Hydroxyalkyl radical, C1-6Haloalkyl, C1-6Aminoalkyl radical, C1-6Cyanoalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, C1-6Alkylthio radical, C1-6Alkylamino radical, C1-6Haloalkylamino, C3-8Cycloalkyl radical, C3-8Cycloalkyl radical C1-6Alkyl radical, C2-7Heterocyclic group, C2-7Heterocyclyl radical C1-6Alkyl radical, C6-12Aryl radical, C6-12Aryl radical C1-6Alkyl radical, C1-9Heteroaryl, or C1-9Heteroaryl C1-6An alkyl group; wherein C is3-8Cycloalkyl radical, C3-8Cycloalkyl radical C1-6Alkyl radical, C2-7Heterocyclic group, C2-7Heterocyclyl radical C1-6Alkyl radical, C6-12Aryl radical, C6-12Aryl radical C1-6Alkyl radical, C1-9Heteroaryl and C1-9Heteroaryl C1-6Alkyl is optionally substituted by 0, 1, 2, 3 or 4 substituents independently selected from H, F, Cl, Br, I, -OH, -NH2、-NO2-CN, -oxo (-O), C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Hydroxyalkyl radical, C1-6Haloalkyl, C1-6Aminoalkyl radical, C1-6Cyanoalkyl, C1-6Alkoxy and C1-6Substituted with a halo alkoxy group;
R7aAnd R7bEach independently of the other is H, an alkali metal ion, an alkaline earth metal ion, -OH, -CN, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Hydroxyalkyl radical、C1-6Haloalkyl, C1-6Aminoalkyl radical, C1-6Cyanoalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, C1-6Alkylthio radical, C1-6Alkylamino radical, C1-6Haloalkylamino, C3-8Cycloalkyl radical, C3-8Cycloalkyl radical C1-6Alkyl radical, C2-7Heterocyclic group, C2-7Heterocyclyl radical C1-6Alkyl radical, C6-12Aryl radical, C6-12Aryl radical C1-6Alkyl radical, C1-9Heteroaryl, or C1-9Heteroaryl C1-6An alkyl group; wherein C is3-8Cycloalkyl radical, C3-8Cycloalkyl radical C1-6Alkyl radical, C2-7Heterocyclic group, C2-7Heterocyclyl radical C1-6Alkyl radical, C6-12Aryl radical, C6-12Aryl radical C1-6Alkyl radical, C1-9Heteroaryl and C1-9Heteroaryl C1-6Alkyl is optionally substituted by 0, 1, 2, 3 or 4 substituents independently selected from H, F, Cl, Br, I, -OH, -NH2、-NO2-CN, -oxo (-O), C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Hydroxyalkyl radical, C1-6Haloalkyl, C1-6Aminoalkyl radical, C1-6Cyanoalkyl, C1-6Alkoxy and C1-6Substituted 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, respectively.
2. The compound of claim 1, wherein L1Is O, NH, or CH2；L2Is O, S, -N (R)c) -, or-CH2-。
3. The compound of claim 1, having the structure of formula (II):
Figure FDA0003128505460000031
Or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, regioisomer, nitroxide, or mixture thereof.
4. The compound of any one of claims 1-3, wherein Ar1Is that
Figure FDA0003128505460000032
Wherein the content of the first and second substances,
Y1and Y2Are each independently N or-C (R)2)-；
Y3And Y4Are each independently-C (═ O) -, O, S, -N (R)2a)-、-(C(R2)2)t3-, or-W1-(C(R2)2)t3-；
W1is-C (═ O) -, O, S, or-N (R)2a)-；
Each R2aAre each independently H, C1-6Alkyl radical, C1-6Hydroxyalkyl radical, C1-6Haloalkyl, C1-6Aminoalkyl radical, C1-6Cyanoalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, C1-6Alkylthio radical, C1-6Alkylamino radical, C1-6Haloalkylamino, C3-8Cycloalkyl radical, C3-8Cycloalkyl radical C1-6Alkyl radical, C2-7Heterocyclic group, C2-7Heterocyclyl radical C1-6Alkyl radical, C6-12Aryl radical, C6-12Aryl radical C1-6Alkyl radical, C1-9Heteroaryl, or C1-9Heteroaryl C1-6An alkyl group; and
t3 is 1, 2, or 3.
5. The compound of any one of claims 1-3, wherein Ar1Is that
Figure FDA0003128505460000033
6. The compound of claim 1, having the structure of formula (III):
Figure FDA0003128505460000034
or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, regioisomer, nitroxide, or mixture thereof,
wherein Y is1And Y2Are each independently N or-C (R) 2) -; and
m is 0, 1, 2, or 3.
7. The compound of claim 1, having the structure of formula (IV):
Figure FDA0003128505460000041
or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, regioisomer, nitroxide, or mixture thereof,
wherein Y is1And Y2Are each independently N or-C (R)2) -; and
m is 0, 1, 2, or 3.
8. The compound of any one of claims 1-3 and 6-7, wherein Cy is
Figure FDA0003128505460000042
Wherein the content of the first and second substances,
Z3、Z4and Z5Each independently being-O-, -S-, -NH-, - (CH)2)m1-NH-(CH2)m2-、-(CH2)m1-O-(CH2)m2-、-(CH2)m1-S-(CH2)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.
9. The compound of any one of claims 1-3 and 6-7, wherein Cy is
Figure FDA0003128505460000043
Wherein the content of the first and second substances,
Z6and Z7Each independently N, C or-CH-, provided that a chemically stable structure is formed.
10. The compound of any one of claims 1-3 and 6-7, wherein Cy is
Figure FDA0003128505460000044
Figure FDA0003128505460000051
Wherein said Cy is optionally substituted with 0, 1, 2, 3 or 4R3And (4) substitution.
11. The compound according to any one of claims 1-3 and 6, wherein,
Figure FDA0003128505460000052
is that
Figure FDA0003128505460000053
Figure FDA0003128505460000061
Wherein the content of the first and second substances,
X1、X2and X3Are each independently N or-C (R) 6)-；
X4Is O, S, -N (R)6a) -, or-C (R)6)2-；
X5Is O or S; and
each R6aIndependently H, C1-6Alkyl radical, C1-6Hydroxyalkyl radical, C1-6Haloalkyl, C1-6Aminoalkyl radical, C1-6Cyanoalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, C1-6Alkylthio radical, C1-6Alkylamino radical, C1-6Haloalkylamino, C3-8Cycloalkyl radical, C3-8Cycloalkyl radical C1-6Alkyl radical, C2-7Heterocyclic group, C2-7Heterocyclyl radical C1-6Alkyl radical, C6-12Aryl radical, C6-12Aryl radical C1-6Alkyl radical, C1-9Heteroaryl, or C1-9Heteroaryl C1-6An alkyl group.
12. The compound according to any one of claims 1-3 and 6, wherein,
Figure FDA0003128505460000062
is that
Figure FDA0003128505460000063
Figure FDA0003128505460000071
Figure FDA0003128505460000081
Figure FDA0003128505460000091
13. The compound of any one of claims 1-3 and 6-7, wherein W is-COOH, -COOCH3、-COOCH2CH3、-COOCH2CH2CH3、-COOCH(CH3)2、-COOCH2CH(CH3)2、-P(＝O)(OH)2、-P(＝O)(OCH3)(OCH3)、-P(＝O)(ONa+)(ONa+)、-P(＝O)(ONH4 +)(ONH4 +)、-P(＝O)(OH)(OCH3)、-P(＝O)(OH)(OPh)、-P(＝O)(OH)(OCH2CH3)、-P(＝O)(OCH2CH3)(OCH2CH3)、
Figure FDA0003128505460000092
Figure FDA0003128505460000093
Wherein R is7dIs H, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, -CF3、-CH2CF3、-CH2CN、-CH2CH2CN、-CH2OH、-CH2CH2OH, cyclopropyl, cyclobutyl, cyclopentyl, phenyl, pyridinyl, pyridazinyl, pyrazinyl, pyrimidinyl, pyrazolyl, triazolyl, or tetrazolyl, wherein R7dOptionally substituted with 0, 1, 2, 3 or 4 substituents independently selected from H, D, F, Cl, Br, I, -OH, -NH2、-NO2-CN, -oxo (-O), C1-4Alkyl radical, C2-4Alkenyl radical, C2-4Alkynyl, C1-4Hydroxyalkyl radical, C1-4Haloalkyl group、C1-4Aminoalkyl radical, C1-4Cyanoalkyl, C1-4Alkoxy and C1-4A substituent of a haloalkoxy group.
14. The compound of any one of claims 1-3 and 6-7, wherein each R 1Are respectively and independently H, D, F, Cl, Br, -OH, -NH2、-NO2-CN, methyl, ethyl, -CF3、-CH2CF3、-CH2CN、-CH2CH2CN、-CH2OH, or-CH2CH2OH; n is 0, 1, 2, 3 or 4.
15. The compound according to any one of claims 1-3 and 6-7, wherein,
R5is H, D, F, Cl, Br, I, -OH, -NH2、-NO2-CN, -oxo (-O), C1-4Alkyl radical, C1-4Haloalkyl, C1-4Cyanoalkyl, C1-4Alkoxy radical C1-4Alkyl radical, C3-6Cycloalkyl radical, C3-6Heterocyclic group, C6-10Aryl radical, C1-9Heteroaryl, R5c-C(＝O)-、R5c-OC(＝O)-、R5c-C(＝O)O-、R5c-NHC(＝O)-、R5c-C(＝O)NH-、R5c-L3-C1-4Alkyl-, R5a-C1-4Alkyl-, or R5a-C1-4Hydroxyalkyl-, wherein said C is1-4Alkyl radical, C1-4Haloalkyl, C1-4Cyanoalkyl, C1-4Alkoxy radical C1-4Alkyl radical, C3-6Cycloalkyl radical, C3-6Heterocyclic group, C6-10Aryl radical, C1-9Heteroaryl, R5c-C(＝O)-、R5c-OC(＝O)-、R5c-C(＝O)O-、R5c-NHC(＝O)-、R5c-C(＝O)NH-、R5c-L3-C1-4Alkyl-, R5a-C1-4Alkyl-and R5a-C1-4Hydroxyalkyl-is independently optionally substituted with 0, 1, 2, 3 or 4R5bSubstitution;
R5ais C3-6Cycloalkyl radical, C3-6Heterocyclic group, C6-10Aryl, or C1-9Heteroaryl, wherein R is5aOptionally substituted by 0, 1, 2, 3 or 4R5bSubstitution;
R5cis H, C1-4Alkyl radical, C3-6Cycloalkyl radical, C3-6Heterocyclic group, C6-10Aryl, or C1-9Heteroaryl, wherein R is5cOptionally substituted by 0, 1, 2, 3 or 4R5bSubstitution; and
L3is O, S, -NH-, or-C (═ O) -.
16. The compound according to any one of claims 1-3 and 6-7, wherein,
R5is H, D, F, Cl, Br, I, -OH, -NH 2、-NO2-CN, oxo (═ O), methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, methoxymethyl, methoxyethyl, -CF3、-CH2CF3、-CH2CH2CN、-CH2CH2OH、-COOH、H2NC(＝O)-、R5c-C(＝O)-、R5c-OC(＝O)-、R5c-NHC(＝O)-、R5c-L3-C1-3Alkyl-, R5a、R5a-C1-3Hydroxyalkyl-, or R5a-C1-3Alkyl-;
L3is O, S, -NH-, or-C (═ O) -; and
R5aand R5cEach independently is
Figure FDA0003128505460000101
Wherein said R5aAnd R5cEach optionally substituted by 0, 1, 2 or 3 substituents independently selected from the group consisting of H, D, F, Cl, Br, I, -OH, -NH2、-NO2-CN, -oxo (-O), C1-4Alkyl radical, C1-4Haloalkyl, C1-4Cyanoalkyl, C1-4Hydroxy alkaneBase, C1-4Alkoxy radical, C1-4Alkoxy radical C1-4Alkyl and C3-6Cycloalkyl groups.
17. The compound of any one of claims 1-3 and 6-7, wherein each R1a、R2、R3、R4、R5b、R6、RaAnd RbAre respectively and independently H, D, F, Cl, Br, I, -OH, -NH2、-NO2-CN, -oxo (-O), C1-4Alkyl radical, C2-4Alkenyl radical, C2-4Alkynyl, C1-4Hydroxyalkyl radical, C1-4Haloalkyl, C1-4Aminoalkyl radical, C1-4Cyanoalkyl, C1-4Alkoxy radical, C1-4Haloalkoxy, C1-4Alkylthio radical, C1-4Alkylamino radical, C1-4Haloalkylamino, -NR1bR1c、C3-6Cycloalkyl radical, C3-6Cycloalkyl radical C1-4Alkyl radical, C3-6Heterocyclic group, C3-6Heterocyclyl radical C1-4Alkyl radical, C6-10Aryl radical, C6-10Aryl radical C1-4Alkyl radical, C1-9Heteroaryl, or C1-9Heteroaryl C1-4An alkyl group; wherein C is3-6Cycloalkyl radical, C 3-6Cycloalkyl radical C1-4Alkyl radical, C3-6Heterocyclic group, C3-6Heterocyclyl radical C1-4Alkyl radical, C6-10Aryl radical, C6-10Aryl radical C1-4Alkyl radical, C1-9Heteroaryl and C1-9Heteroaryl C1-4Alkyl is optionally substituted by 0, 1, 2, 3 or 4 substituents independently selected from H, F, Cl, Br, I, -OH, -NH2、-NO2-CN, -oxo (-O), C1-4Alkyl radical, C2-4Alkenyl radical, C2-4Alkynyl, C1-4Hydroxyalkyl radical, C1-4Haloalkyl, C1-4Aminoalkyl radical, C1-4Cyanoalkyl, C1-4Alkoxy and C1-4A substituent of a haloalkoxy group.
18. The compound according to any one of claims 1-3 and 6-7, whereinEach R5bAre respectively and independently H, D, F, Cl, Br, I, -OH, -NH2、-NO2-CN, oxo (═ O), methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, -CF3、-CH2CF3、-CH2CHF2Methoxy, ethoxy, propoxy, methoxymethyl, cyclopropyl, cyclopropylmethyl, or cyclobutyl.
19. The compound of any one of claims 1-3 and 6-7, wherein each R1b、R1c、Rc、Rd、R2a、R6a、R7cAnd R7dAre respectively and independently H, OH, D, C1-4Alkyl radical, C2-4Alkenyl radical, C2-4Alkynyl, C1-4Hydroxyalkyl radical, C1-4Haloalkyl, C1-4Aminoalkyl radical, C1-4Cyanoalkyl, C1-4Alkoxy radical, C1-4Haloalkoxy, C1-4Alkylthio radical, C1-4Alkylamino radical, C1-4Haloalkylamino, C3-6Cycloalkyl radical, C3-6Cycloalkyl radical C 1-4Alkyl radical, C3-6Heterocyclic group, C3-6Heterocyclyl radical C1-4Alkyl radical, C6-10Aryl radical, C6-10Aryl radical C1-4Alkyl radical, C1-9Heteroaryl, or C1-9Heteroaryl C1-4An alkyl group; wherein C is3-6Cycloalkyl radical, C3-6Cycloalkyl radical C1-4Alkyl radical, C3-6Heterocyclic group, C3-6Heterocyclyl radical C1-4Alkyl radical, C6-10Aryl radical, C6-10Aryl radical C1-4Alkyl radical, C1-9Heteroaryl and C1-9Heteroaryl C1-4Alkyl is optionally substituted by 0, 1, 2, 3 or 4 substituents independently selected from H, F, Cl, Br, I, -OH, -NH2、-NO2-CN, -oxo (-O), C1-4Alkyl radical, C2-4Alkenyl radical, C2-4Alkynyl, C1-4Hydroxyalkyl radical, C1-4Haloalkyl, C1-4Aminoalkyl radical, C1-4Cyanoalkyl, C1-4Alkoxy and C1-4A substituent of a haloalkoxy group.
20. The compound of any one of claims 1-3 and 6-7, wherein R7aAnd R7bEach independently is H, Li+、Na+、K+、NH4 +、Mg2+、Ca2+、C1-4Alkyl radical, C2-4Alkenyl radical, C2-4Alkynyl, C1-4Hydroxyalkyl radical, C1-4Haloalkyl, C1-4Aminoalkyl radical, C1-4Cyanoalkyl, C3-6Cycloalkyl radical, C3-6Cycloalkyl radical C1-4Alkyl radical, C3-6Heterocyclic group, C3-6Heterocyclyl radical C1-4Alkyl radical, C6-10Aryl radical, C6-10Aryl radical C1-4Alkyl radical, C1-9Heteroaryl, or C1-9Heteroaryl C1-4An alkyl group; wherein C is3-6Cycloalkyl radical, C3-6Cycloalkyl radical C1-4Alkyl radical, C3-6Heterocyclic group, C3-6Heterocyclyl radical C1-4Alkyl radical, C6-10Aryl radical, C6-10Aryl radical C1-4Alkyl radical, C1-9Heteroaryl and C1-9Heteroaryl C1-4Alkyl is optionally substituted by 0, 1, 2, 3 or 4 substituents independently selected from H, F, Cl, Br, I, -OH, -NH 2、-NO2-CN, -oxo (-O), C1-4Alkyl radical, C2-4Alkenyl radical, C2-4Alkynyl, C1-4Hydroxyalkyl radical, C1-4Haloalkyl, C1-4Aminoalkyl radical, C1-4Cyanoalkyl, C1-4Alkoxy and C1-4A substituent of a haloalkoxy group.
21. The compound according to any one of claims 1, wherein it is a compound having one of the following structures:
Figure FDA0003128505460000111
Figure FDA0003128505460000121
Figure FDA0003128505460000131
Figure FDA0003128505460000141
Figure FDA0003128505460000151
Figure FDA0003128505460000161
Figure FDA0003128505460000171
Figure FDA0003128505460000181
Figure FDA0003128505460000191
Figure FDA0003128505460000201
Figure FDA0003128505460000211
Figure FDA0003128505460000221
Figure FDA0003128505460000231
Figure FDA0003128505460000241
Figure FDA0003128505460000251
Figure FDA0003128505460000261
Figure FDA0003128505460000271
Figure FDA0003128505460000281
Figure FDA0003128505460000291
or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, regioisomer, nitroxide, or mixture thereof.
22. A pharmaceutical composition comprising a compound of any one of claims 1-21, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable adjuvant, diluent, or carrier.
23. The pharmaceutical composition of claim 22, further comprising an additional therapeutic agent.
24. Use of a compound according to any one of claims 1 to 21 or a pharmaceutical composition according to any one of claims 22 to 23 in the manufacture of a medicament for the prevention and/or treatment of cardiovascular metabolic diseases and related conditions in a mammal.
25. The use of claim 24, wherein the cardiometabolic diseases and related conditions are T1D, T2DM, pre-diabetes, idiopathic T1D, LADA, EOD, YOAD, MODY, malnutrition-related diabetes, gestational diabetes, hyperglycemia, insulin resistance, hepatic insulin resistance, glucose intolerance, diabetic neuropathy, diabetic nephropathy, kidney disease, diabetic retinopathy, adipocyte dysfunction, visceral adipocyte accumulation, sleep apnea, obesity, eating disorders, weight gain using other agents, excessive glycemia, dyslipidemia, hyperinsulinemia, NAFLD, NASH, fibrosis, cirrhosis, hepatocellular carcinoma, cardiovascular disease, atherosclerosis, coronary artery disease, peripheral vascular disease, hypertension, endothelial dysfunction, impaired vascular compliance, diabetes mellitus, diabetic retinopathy, obesity, elevated blood pressure, obesity, diabetes mellitus, or a combination thereof, Congestive heart failure, myocardial infarction, stroke, hemorrhagic stroke, ischemic stroke, traumatic brain injury, pulmonary hypertension, restenosis following angioplasty, intermittent claudication, postprandial lipemia, metabolic acidosis, ketosis, arthritis, osteoporosis, parkinson's disease, left ventricular hypertrophy, peripheral arterial disease, macular degeneration, cataracts, glomerulosclerosis, chronic renal failure, metabolic syndrome, syndrome X, premenstrual syndrome, angina pectoris, thrombosis, atherosclerosis, transient ischemic attacks, vascular restenosis, impaired glucose metabolism, impaired fasting glucose conditions, hyperuricemia, gout, erectile dysfunction, skin and connective tissue abnormalities, psoriasis, foot ulceration, ulcerative colitis, hyperpapob lipoproteinemia, alzheimer's disease, schizophrenia, impaired cognitive function, impaired cardiac function, peripheral vascular disease, peripheral vascular disease, Inflammatory bowel disease, short bowel syndrome, crohn's disease, colitis, irritable bowel syndrome, polycystic ovary syndrome, or addiction.
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Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113801136A (en) * 2020-06-16 2021-12-17 江苏恒瑞医药股份有限公司 Imidazo heteroaryl derivative, preparation method and application thereof in medicine
CN114230556A (en) * 2022-01-05 2022-03-25 广州安岩仁医药科技有限公司 Preparation method of CDK4/6 inhibitor intermediate
CN115536638A (en) * 2022-08-15 2022-12-30 上海交通大学 Triazole compound and application thereof
CN115667238A (en) * 2020-12-25 2023-01-31 四川海思科制药有限公司 Five-membered ring derivative and application thereof in medicine
WO2023057427A1 (en) 2021-10-05 2023-04-13 Astrazeneca Ab Certain 2,5-diazabicyclo[4.2.0]octanes as glp-1 receptor modulators
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WO2023111145A1 (en) 2021-12-16 2023-06-22 Astrazeneca Ab Certain 3-azabicyclo[3.1.0]hexanes as glp-1 receptor modulators
WO2023222124A1 (en) * 2022-05-20 2023-11-23 中国科学院上海药物研究所 5,6-dihydro-1,2,4-triazine compound and pharmaceutical use thereof as glp-1 receptor agonist
US11897851B2 (en) 2020-08-06 2024-02-13 Gasherbrum Bio, Inc. Heterocyclic GLP-1 agonists
US11926626B2 (en) 2020-08-28 2024-03-12 Gasherbrum Bio, Inc. Heterocyclic GLP-1 agonists

Families Citing this family (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPWO2022202864A1 (en) 2021-03-24 2022-09-29
TW202310838A (en) 2021-05-20 2023-03-16 美商美國禮來大藥廠 Glucagon-like peptide 1 receptor agonists
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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019184955A1 (en) * 2018-03-28 2019-10-03 Fochon Pharmaceuticals, Ltd. Macrocyclic compounds as trk kinases inhibitors
CN110325530A (en) * 2016-12-16 2019-10-11 辉瑞大药厂 GLP-1 receptor stimulating agent and application thereof
WO2020103815A1 (en) * 2018-11-22 2020-05-28 Qilu Regor Therapeutics Inc. Glp-1r agonists and uses thereof
WO2020117987A1 (en) * 2018-12-05 2020-06-11 Viking Therapeutics, Inc. Compositions and methods for the treatment of liver disorders

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2006510600A (en) * 2002-10-04 2006-03-30 ラボラトワール フルニエ エス・アー Compounds derived from 2-thiohydantoin and their use in therapy
EP3806855B1 (en) * 2018-06-15 2023-03-01 Pfizer Inc. Glp-1 receptor agonists and uses thereof
CR20210562A (en) * 2019-04-12 2022-02-18 Qilu Regor Therapeutics Inc Glp-1r agonists and uses thereof
WO2021018023A1 (en) * 2019-08-01 2021-02-04 济南泰达领创医药技术有限公司 Small molecule glp-1 receptor modulator
KR20220101092A (en) * 2019-11-15 2022-07-19 일동제약(주) GLP-1 receptor agonists and uses thereof

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110325530A (en) * 2016-12-16 2019-10-11 辉瑞大药厂 GLP-1 receptor stimulating agent and application thereof
WO2019184955A1 (en) * 2018-03-28 2019-10-03 Fochon Pharmaceuticals, Ltd. Macrocyclic compounds as trk kinases inhibitors
WO2020103815A1 (en) * 2018-11-22 2020-05-28 Qilu Regor Therapeutics Inc. Glp-1r agonists and uses thereof
WO2020117987A1 (en) * 2018-12-05 2020-06-11 Viking Therapeutics, Inc. Compositions and methods for the treatment of liver disorders

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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US11897851B2 (en) 2020-08-06 2024-02-13 Gasherbrum Bio, Inc. Heterocyclic GLP-1 agonists
US11926626B2 (en) 2020-08-28 2024-03-12 Gasherbrum Bio, Inc. Heterocyclic GLP-1 agonists
CN115667238A (en) * 2020-12-25 2023-01-31 四川海思科制药有限公司 Five-membered ring derivative and application thereof in medicine
WO2023057429A1 (en) 2021-10-05 2023-04-13 Astrazeneca Ab Certain 2,5-diazabicyclo[4.2.0]octanes and octahydrofuro[3,4- b]pyrazines as glp-1 receptor modulators
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WO2023057427A1 (en) 2021-10-05 2023-04-13 Astrazeneca Ab Certain 2,5-diazabicyclo[4.2.0]octanes as glp-1 receptor modulators
WO2023111144A1 (en) 2021-12-16 2023-06-22 Astrazeneca Ab Certain 3-azabicyclo[3.1.0]hexanes as glp-1 receptor modulators
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CN115536638A (en) * 2022-08-15 2022-12-30 上海交通大学 Triazole compound and application thereof

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