CN112789277B - Guanidine derivatives and use thereof - Google Patents

Guanidine derivatives and use thereof Download PDF

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CN112789277B
CN112789277B CN201980065364.9A CN201980065364A CN112789277B CN 112789277 B CN112789277 B CN 112789277B CN 201980065364 A CN201980065364 A CN 201980065364A CN 112789277 B CN112789277 B CN 112789277B
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disease
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顾峥
黎健豪
刘建余
王伟华
李峥
覃浩雄
王绪礼
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Guangdong HEC Pharmaceutical
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Abstract

The invention belongs to the field of medicines, particularly relates to a guanidine derivative serving as a VAP-1 inhibitor and application thereof, and further relates to a pharmaceutical composition containing the compound. The compounds or pharmaceutical compositions of the invention are useful for treating inflammation and/or inflammation-related disorders, diabetes and/or diabetes-related disorders, ischemic disorders, vascular disease, fibrosis, or tissue transplant rejection.

Description

Guanidine derivatives and use thereof
Cross Reference to Related Applications
This application claims priority to chinese patent application No. 201811228252.4 filed on 22/10/2018, which is hereby incorporated by reference in its entirety.
Technical Field
The invention belongs to the field of medicines, and particularly relates to a guanidine derivative serving as a VAP-1 (Vascular adhesion protein-1, VAP-1) inhibitor, and a preparation method and application thereof. More specifically, the invention relates to a compound shown in a general formula (I) or a pharmaceutically acceptable salt thereof or a stereoisomer and a geometric isomer thereof, and a pharmaceutical composition containing the compound, and further relates to application of the compound and the pharmaceutical composition in preparation of medicines for preventing, treating or relieving inflammatory diseases and/or inflammation-related diseases, diabetes and/or diabetes-related diseases, ischemic diseases, vascular diseases, fibrosis or tissue transplantation rejection.
Background
Amine Oxidase (AO) is a protein with special biological functions, widely exists in organisms, participates in metabolism of biological Amine, and causes Amine to be oxidized and cracked into aldehyde and ammonia. Two major classes of amine oxidases are known, one being copper-containing amine oxidases (COAs) with quinones as coenzymes; another class is flavin-containing amine oxidase with Flavin Adenine Dinucleotide (FAD) as a coenzyme. The flavin-containing amine oxidases mainly include Monoamine oxidases (MAOs) and Polyamine Oxidases (POs). There are 2 subtypes of MAOs, monoamine oxidase A (MAO-A) and Monoamine oxidase B (MAO-B), which are mainly present in the mitochondrial outer membrane of mammalian cells and can selectively metabolize (oxidatively deaminate) primary, secondary and tertiary amines. The medicine for inhibiting MAOs can be used for treating depression. There are 3 subtypes of POs, which are involved in the regulation of cell growth through the oxidation of polyamines such as spermine and spermidine. Copper-containing amine oxidases can be further divided into: 2,4,5-Trihydroxyphenylalaninequinone (TPQ) -dependent copper-containing amine oxidase family and Lysine Tyrosinylaminoquinone (LTQ) -dependent lysyl oxidase family. Among them, 2,4,5-trihydroxyphenylalanine quinone (TPQ) dependent copper-containing amine oxidase families include diamine oxidase (DAO), retina specific amine oxidase (RAO), vascular adhesion protein-1 (Vascular adhesion protein-1, VAP-1), and Serum Amine Oxidase (SAO).
Mammalian copper-containing amine oxidases are encoded primarily by the AOC1, AOC2, AOC3, and AOC4 genes. Wherein, AOC1 codes DAO, AOC2 codes RAO, AOC3 codes VAP-1, AOC4 codes SAO. DAO is expressed mainly in kidney, placenta, intestine and seminal vesicle, and it acts only on diamines, especially histamine, and is also known as histamine oxidase. RAO was cloned from human retina in 1997 with retinal specificity, with overall folding of its three-dimensional structure similar to VAP-1. RAO can oxidize 2-phenylethylamine, tryptamine, and tyramine. SAO is highly expressed only in bovines, equines, porcines and ovines and, in humans, is a protein lacking functionality.
Vascular adhesion protein-1 (VAP-1) is encoded by the AOC3 gene located on human chromosome 17 and is an amine oxidase sensitive to semicarbazide. VAP-1 is widely found in tissues of mammalian bodies that are rich in vascular content, primarily in two forms, one being a soluble form, primarily in circulating blood; one is the membrane-bound form, which is widely distributed in organs and tissues, especially in adipocytes, vascular endothelial cells and smooth muscle cells. VAP-1 has double functions, on one hand, is an adhesion molecule of lymphocytes, can promote the adhesion of the lymphocytes to vascular endothelium, and can also regulate an inflammation microenvironment by regulating transcription factors, chemotactic factors and other adhesion molecules; on the other hand, VAP-1 also has enzymatic efficiency and is capable of catalyzing primary amines to the corresponding aldehydes, ammonia and hydrogen peroxide.
Inflammation is the first response of the immune system to infection or irritation. The movement of leukocytes into the tissue circulation is important to this process. Inappropriate inflammatory responses can lead to local inflammation of otherwise healthy tissue, which can lead to diseases such as rheumatoid arthritis, inflammatory bowel disease, multiple sclerosis, asthma, chronic Obstructive Pulmonary Disease (COPD), eczema, psoriasis and the like. Leukocytes need to adhere to the endothelium by binding adhesion molecules before passing through the vessel wall. VAP-1, as an endothelial adhesion molecule, is abundantly expressed in vascular endothelial cells such as high-potency venous endothelial cells (HVEs) of lymphoid organs, and is also expressed in Hepatic Sinus Endothelial Cells (HSECs), smooth muscle cells and adipocytes, and is capable of inducing cell adhesion, regulating leukocyte trafficking, participating in granulocyte extravasation, and its level is elevated during inflammation. Migration of neutrophils from the blood to the site of inflammation is achieved by the binding of adhesion molecules to vascular endothelial cells. Therefore, VAP-1 plays an important role in diseases related to inflammation, and is widely regarded by researchers.
It has been reported that an increase in VAP-1 content has been observed in the following diseases: diabetes (Li, H, y.et al.,2009, clin.chim.acta 404, 149-153), obesity (Meszaros, z.et al.,1999, metabolism 48. For inflammatory Liver diseases, scientists have correlated VAP-1 plasma activity levels with Liver fibrosis and used as a predictor for patients with Nonalcoholic Fatty Liver Disease (NAFLD).
In addition, VAP-1 is also associated with the following diseases: melanoma and lymphoma (Martila-lchihara, f.et., 2010, j.immunol.184, 3164-3173), acute and chronic arthritis (tabo, t.et., 2013, j.neurol.120.
In conclusion, the development of a VAP-1 inhibitor with strong selectivity, strong efficacy and good tolerance would be beneficial for the treatment of various diseases, especially inflammation and/or inflammation-related diseases and diabetes and/or diabetes-related diseases in humans.
Summary of the invention
The invention provides a novel compound with better VAP-1 activity inhibition, and the compound and a pharmaceutical composition thereof can be used for preparing medicaments for preventing, treating or relieving inflammation diseases and/or inflammation-related diseases, diabetes and/or diabetes-related diseases, ischemic diseases, vascular diseases, fibrosis or tissue transplant rejection of patients, and particularly for preparing medicaments for preventing, treating or relieving non-alcoholic fatty liver diseases, diabetic retinopathy, diabetic nephropathy, diabetic neuropathy or diabetic macular edema of the patients.
In one aspect, the invention relates to a compound that is a compound of formula (I) or a stereoisomer, a tautomer, a nitrogen oxide, a solvate, a metabolite, a pharmaceutically acceptable salt, or a prodrug thereof,
Figure GPA0000302900140000031
wherein,
U 1 and U 2 Each independently is CH or N;
R 1 、R 2 and R 3 Each independently is H, D, F, cl, br, I, CN, NO 2 、OH、NH 2 、C 1-6 Alkyl radical, C 1-6 Haloalkyl, C 1-6 Alkoxy radical, C 1-6 Alkylamino radical, C 1-6 Haloalkoxy or hydroxy C 1-6 An alkyl group;
R 4 and R 5 Each independently is H, D, F, cl, br, I, CN, NO 2 、OH、NH 2 、C 1-6 Alkyl radical, C 1-6 Haloalkyl, C 1-6 Haloalkoxy or C 3-6 Cycloalkyl, wherein said C 1-6 Alkyl radical, C 1-6 Haloalkyl, C 1-6 Haloalkoxy and C 3-6 Cycloalkyl is each independently unsubstituted or substituted with 1,2,3 or 4 substituents independently selected from D, F, cl, br, I, CN, NO 2 、OH、NH 2 、-COOH、-SH、C 1-6 Alkyl radical, C 1-6 Haloalkyl, C 1-6 Alkoxy radical, C 1-6 Alkylamino or C 1-6 A haloalkoxy group;
or R 4 、R 5 Together with the carbon atom to which they are attached, form C 3-6 A carbocyclic ring or a heterocyclic ring of 3 to 6 atoms in which said C 3-6 Carbocyclic ring and hetero ring of 3 to 6 atomsEach ring is independently unsubstituted or substituted with 1,2,3 or 4 substituents independently selected from D, F, cl, br, I, CN, NO 2 、OH、NH 2 、-COOH、-SH、C 1-6 Alkyl radical, C 1-6 Haloalkyl, C 1-6 Alkoxy radical, C 1-6 Alkylamino or C 1-6 A haloalkoxy group;
a is a heterocyclic group of 5-14 atoms or a heteroaryl group of 5-14 atoms, wherein A is unsubstituted or substituted with 1,2,3 or 4R 6 Substituted;
each R 6 Independently H, D, F, cl, br, I, CN, NO 2 、OH、-NR c R d 、＝O、-C(＝O)R a 、-C(＝O)OR b 、-C(＝O)NR c R d 、-S(＝O) q R e 、-NR f C(＝O)R a 、-NR f S(＝O) 2 R e 、C 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 1-6 Alkoxy radical, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, C 3-6 Cycloalkyl, 5-6 atom heterocyclic radical, C 6-10 Aryl or heteroaryl of 5 to 6 atoms, wherein said C 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 1-6 Alkoxy radical, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, C 3-6 Cycloalkyl, heterocyclic radical of 5-6 atoms, C 6-10 Aryl and heteroaryl of 5 to 6 atoms are each independently unsubstituted or substituted with 1,2,3 or 4 substituents independently selected from D, F, cl, br, I, CN, NO 2 、OH、NH 2 、-COOH、-SH、C 1-6 Alkyl radical, C 1-6 Haloalkyl, C 1-6 Alkoxy radical, C 1-6 Alkylamino or C 1-6 A haloalkoxy group;
q is 0, 1 or 2;
each R a 、R b 、R c 、R d 、R e And R f Independently H, D, C 1-6 Haloalkyl, C 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 3-6 Cycloalkyl, heterocyclic group consisting of 3 to 6 atoms, C 6-10 Aryl or heteroaryl of 5 to 6 atoms, wherein said C 1-6 Haloalkyl, C 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 3-6 Cycloalkyl, heterocyclic group consisting of 3 to 6 atoms, C 6-10 Aryl and heteroaryl of 5 to 6 atoms are each independently unsubstituted or substituted with 1,2,3 or 4 substituents independently selected from D, F, cl, br, I, CN, -OH, NH 2 、C 1-6 Alkyl radical, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 An alkylamino group;
or Rc, rd and the nitrogen atom to which they are attached, together form a 3-6 atom heterocycle or a 5-6 atom heteroaryl ring, wherein the 3-6 atom heterocycle and the 5-6 atom heteroaryl ring are each independently unsubstituted or substituted with 1,2,3, or 4 substituents independently selected from D, F, cl, br, I, CN, -OH, NH 2 、C 1-6 Alkyl radical, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 An alkylamino group.
In some embodiments, a is the following substructure:
Figure GPA0000302900140000041
wherein,
each E is independently N or CH;
each G is independently-CH 2 -, -NH-, -O-, or-S-, -S (= O) -or-S (= O) 2 -；
U is N, -C = or CH;
each T is independently- (CH) 2 ) x - ；
Each y is independently 0, 1 or 2;
each w is independently 0, 1 or 2;
x is 1,2 or 3;
ring C is C 3-6 A carbocyclic ring, a heterocyclic ring of 3 to 6 atoms,C 6-10 An aromatic ring or a 5-6 atom heteroaromatic ring;
each ring D is independently C 3-6 Carbocyclic ring, heterocyclic ring of 3-6 atoms, C 6-10 An aromatic ring or a heteroaromatic ring of 5 to 6 atoms;
wherein A is unsubstituted or substituted by 1,2,3 or 4R 6 And (4) substituting.
In other embodiments, ring C is cyclopropane, cyclobutane, cyclopentane, cyclohexane, oxirane, azetidine, oxetane, thietane, 1,3-dioxolane, tetrahydrofuran, tetrahydrothiophene, dihydrothiophene, tetrahydropyran, dihydropyran, pyrrolidine, piperidine, morpholine, thiomorpholine, piperazine, benzene, pyrrole, pyridine, pyrimidine, thiazole, thiophene, furan, pyrazole, imidazole, triazole, tetrazole, oxazole, isoxazole, oxadiazole, pyrazine, or pyridazine.
Each ring D is independently cyclopropane, cyclobutane, cyclopentane, cyclohexane, oxirane, azetidine, oxetane, thietane, 1,3-dioxolane, tetrahydrofuran, tetrahydrothiophene, dihydrothiophene, tetrahydropyran, dihydropyran, pyrrolidine, piperidine, morpholine, thiomorpholine, piperazine, benzene, pyrrole, pyridine, pyrimidine, thiazole, thiophene, furan, pyrazole, imidazole, triazole, tetrazole, oxazole, isoxazole, oxadiazole, pyrazine, or pyridazine.
In still other embodiments, A is
Figure GPA0000302900140000051
Figure GPA0000302900140000052
Figure GPA0000302900140000053
Wherein A is unsubstituted or substituted by 1,2,3 or 4R 6 And (4) substituting.
In some embodiments, each R is 6 Independently H, D, F, cl, br, I, CN, NO 2 、OH、-NR c R d 、＝O、-C(＝O)R a 、-C(＝O)OR b 、-C(＝O)NR c R d 、-S(＝O) q R e 、-NR f C(＝O)R a 、-NR f S(＝O) 2 R e 、C 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, C 1-4 Alkoxy radical, C 1-4 Haloalkyl, C 1-4 Haloalkoxy, C 3-6 Cycloalkyl, heterocyclic radical of 5-6 atoms, C 6-10 Aryl or heteroaryl of 5 to 6 atoms, wherein said C 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, C 1-4 Alkoxy radical, C 1-4 Haloalkyl, C 1-4 Haloalkoxy, C 3-6 Cycloalkyl, 5-6 atom heterocyclic radical, C 6-10 Aryl and heteroaryl of 5 to 6 atoms are each independently unsubstituted or substituted with 1,2,3 or 4 substituents independently selected from D, F, cl, br, I, CN, NO 2 、OH、NH 2 、-COOH、-SH、C 1-4 Alkyl radical, C 1-4 Haloalkyl, C 1-4 Alkoxy radical, C 1-4 Alkylamino or C 1-4 A haloalkoxy group;
q is 0, 1 or 2;
each R a 、R b 、R c 、R d 、R e And R f Independently H, D, C 1-4 Haloalkyl, C 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, C 3-6 Cycloalkyl, heterocyclic radical of 5-6 atoms, C 6-10 Aryl or heteroaryl of 5 to 6 atoms, wherein said C 1-4 Haloalkyl, C 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, C 3-6 Cycloalkyl, heterocyclic radical of 5-6 atoms, C 6-10 Aryl and heteroaryl of 5 to 6 atoms are each independently unsubstituted or substituted with 1,2,3 or 4 substituents independently selected from D, F, cl, br, I, CN, -OH, NH 2 、C 1-4 Alkyl radical, C 1-4 Haloalkyl, C 1-4 Alkoxy or C 1-4 An alkylamino group;
or R c 、R d And together with the nitrogen atom to which they are attached, form a 5-6 atom heterocyclic ring or a 5-6 atom heteroaromatic ring, wherein the 5-6 atom heterocyclic ring and the 5-6 atom heteroaromatic ring are each independently unsubstituted or substituted with 1,2,3, or 4 substituents independently selected from D, F, cl, br, I, CN, -OH, NH 2 、C 1-4 Alkyl radical, C 1-4 Haloalkyl, C 1-4 Alkoxy or C 1-4 An alkylamino group.
In yet other embodiments, each R is 6 Independently H, D, F, cl, br, I, CN, NO 2 、OH、NH 2 、-NHCH 3 、-N(CH 3 ) 2 、＝O、-C(＝O)OH、-C(＝O)OCH 3 、-C(＝O)OCH 2 CH 3 、-C(＝O)NH 2 、-C(＝O)N(CH 3 ) 2 、-S(＝O) 2 CH 3 、-S(＝O) 2 CH 2 CH 3 、-NHC(＝O)R a 、-NHS(＝O) 2 R e Methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, trifluoromethyl, trifluoroethyl, trifluoromethoxy, cyclopropyl, cyclobutyl, cyclopentyl, tetrahydrofuryl, tetrahydrothienyl, dihydrothienyl, tetrahydropyranyl, dihydropyranyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, phenyl, pyrrolyl, pyridinyl, pyrimidinyl, thiazolyl, thienyl, furyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, pyrazinyl, or pyridazinyl, wherein said methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, trifluoroethyl, cyclopropyl, cyclobutyl, cyclopentyl, tetrahydrofuryl, tetrahydrothienyl, dihydrothienyl, tetrahydropyranyl, dihydropyranyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, phenyl, pyrrolyl, pyridinyl, pyrimidinyl, thiazolyl, thienyl, furyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, pyrazinyl, and pyridazinyl are each independently unsubstituted or substituted by 1,2,3,4, or 4 independently of said groupsFrom D, F, cl, br, I, CN, NO 2 、OH、NH 2 -COOH, -SH, methyl, ethyl, trifluoromethyl, methoxy or ethoxy.
In some embodiments, R 1 、R 2 And R 3 Each independently is H, D, F, cl, br, I, CN, NO 2 、OH、NH 2 Methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, trifluoroethyl, methoxy, ethoxy, methylamino, trifluoromethoxy, or hydroxymethyl.
In some embodiments, R 4 And R 5 Each independently is H, D, F, cl, br, I, CN, NO 2 、OH、NH 2 Methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, trifluoroethyl, trifluoromethoxy, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, wherein said methyl, ethyl, n-propyl, isopropyl, trifluoroethyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl are each independently unsubstituted or substituted with 1,2,3, or 4 substituents independently selected from D, F, cl, br, I, CN, NO 2 、OH、NH 2 -COOH, -SH, methyl, ethyl, trifluoromethyl, methoxy or ethoxy;
or R 4 、R 5 And together with the carbon atom to which they are attached form a cyclopropane, cyclobutane, cyclopentane, cyclohexane, oxirane, azetidine, oxetane, thietane, 1,3-dioxolane, tetrahydrofuran, tetrahydrothiophene, dihydrothiophene, tetrahydropyran, dihydropyran, pyrrolidine, piperidine, morpholine, thiomorpholine, or piperazine, wherein the cyclopropane, cyclobutane, cyclopentane, cyclohexane, oxirane, azetidine, oxetane, thietane, 1,3-dioxolane, tetrahydrofuran, tetrahydrothiophene, dihydrothiophene, tetrahydropyran, dihydropyran, pyrrolidine, piperidine, morpholine, thiomorpholine, and piperazine are each independently unsubstituted or substituted with 1,2,3, or 4 substituents independently selected from D, F, cl, br, I, CN, NO 2 、OH、NH 2 -COOH, -SH, methyl, ethyl, trifluoromethyl, methoxy or ethoxy.
In yet other embodiments, each R is a 、R b 、R c 、R d 、R e And R f Independently H, D, trifluoromethyl, methyl, ethyl, n-propyl, isopropyl, tert-butyl, cyclopropyl, cyclobutyl, 5-6 atom heterocyclyl, phenyl, or 5-6 atom heteroaryl, wherein said methyl, ethyl, n-propyl, isopropyl, tert-butyl, cyclopropyl, cyclobutyl, 5-6 atom heterocyclyl, phenyl, and 5-6 atom heteroaryl are each independently unsubstituted or substituted with 1,2,3, or 4 substituents independently selected from D, F, cl, br, I, -CN, -OH, -NH, and 2 methyl, ethyl, n-propyl, isopropyl, trifluoromethyl or methoxy;
or R c 、R d And the nitrogen atom to which they are attached, form a 5-6 atom heterocyclic ring or a 5-6 atom heteroaromatic ring, wherein the 5-6 atom heterocyclic ring and the 5-6 atom heteroaromatic ring are each independently unsubstituted or substituted with 1,2,3, or 4 substituents independently selected from D, F, cl, br, I, -CN, -OH, -NH 2 Methyl, ethyl, n-propyl, isopropyl, trifluoromethyl or methoxy.
In another aspect, the present invention relates to a pharmaceutical composition comprising a compound of the present invention, optionally further comprising a pharmaceutically acceptable carrier, excipient, adjuvant, vehicle, or combination thereof.
In another aspect, the invention relates to the use of a compound or pharmaceutical composition according to the invention for the preparation of a medicament, wherein the medicament is for inhibiting VAP-1.
In another aspect, the invention relates to the use of a compound or pharmaceutical composition according to the invention for inhibiting the activity of VAP-1.
In another aspect, the invention relates to a method of inhibiting VAP-1 activity using a compound or pharmaceutical composition described herein, comprising administering to a patient a therapeutically effective amount of a compound or pharmaceutical composition described herein.
In another aspect, the invention relates to the use of a compound or pharmaceutical composition of the invention in the manufacture of a medicament for the prevention, treatment or amelioration of diseases associated with VAP-1 protein or modulated by VAP-1.
In another aspect, the invention relates to the use of a compound or pharmaceutical composition according to the invention for the prevention, treatment or alleviation of diseases related to the VAP-1 protein or modulated by VAP-1.
In another aspect, the invention relates to a method of preventing, treating or ameliorating a disease associated with or modulated by VAP-1 protein using a compound or pharmaceutical composition of the invention by administering to a patient a therapeutically effective amount of a compound or pharmaceutical composition of the invention.
In some embodiments, wherein the disease associated with or modulated by a VAP-1 protein is an inflammatory and/or inflammation-related disease, diabetes and/or diabetes-related disease, ischemic disease, vascular disease, fibrosis, or tissue transplant rejection.
In other embodiments, the inflammatory disease and/or inflammation-related disease of the present invention is arthritis, systemic inflammatory syndrome, sepsis, synovitis, crohn's disease, ulcerative colitis, inflammatory bowel disease, liver disease, respiratory disease, eye disease, skin disease, or neuroinflammatory disease.
In still other embodiments, the arthritis of the invention is osteoarthritis, rheumatoid arthritis, or juvenile rheumatoid arthritis.
In still other embodiments, the systemic inflammatory syndrome of the invention is systemic inflammatory sepsis.
In still other embodiments, the inflammatory bowel disease of the present invention is irritable bowel disease.
In still other embodiments, the liver disease of the present invention is liver autoimmune disease, autoimmune hepatitis, primary biliary cirrhosis, sclerosing cholangitis, autoimmune cholangitis, alcoholic liver disease, or non-alcoholic fatty liver disease.
In still other embodiments, the respiratory disease of the present invention is asthma, acute lung injury, acute respiratory distress syndrome, pulmonary inflammation, chronic obstructive pulmonary disease, bronchitis, or bronchiectasis.
In still other embodiments, the ocular disease of the present invention is uveitis, iritis, retinitis, autoimmune ocular inflammation, inflammation due to angiogenesis and/or lymphogenesis, or macular degeneration.
In still other embodiments, the skin disease of the present invention is contact dermatitis, skin inflammation, psoriasis, or eczema.
In still other embodiments, the neuroinflammatory disorder of the invention is parkinson's disease, alzheimer's disease, vascular dementia, multiple sclerosis or chronic multiple sclerosis.
In still other embodiments, the non-alcoholic fatty liver disease of the invention is non-alcoholic simple fatty liver, non-alcoholic steatohepatitis, non-alcoholic fatty liver disease phase Guan Yin-derived cirrhosis, or primary liver cancer.
In other embodiments, the diabetes and/or diabetes related disorders of the present invention are type I diabetes, type II diabetes, syndrome X, diabetic retinopathy, diabetic nephropathy, diabetic neuropathy, or diabetic macular edema.
In other embodiments, the ischemic disease of the invention is stroke and/or its complications, myocardial infarction and/or its complications, or destruction of tissue by inflammatory cells after stroke.
In other embodiments, the fibrosis of the present invention is liver fibrosis, cystic fibrosis, kidney fibrosis, idiopathic pulmonary fibrosis, or radiation-induced fibrosis.
In other embodiments, the vascular disease of the present invention is atherosclerosis, chronic heart failure, or congestive heart failure.
The foregoing merely summarizes certain aspects of the invention, but is not limited to such aspects. These and other aspects will be more fully described below.
Detailed description of the invention
The invention provides a guanidine derivative with VAP-1 activity inhibition, a preparation method and application thereof. Those skilled in the art can modify the process parameters appropriately to achieve the desired results with reference to the disclosure herein. It is expressly intended that all such similar substitutes and modifications apparent to those skilled in the art are deemed to be within the scope of the invention.
Definitions and general terms
Reference will now be made in detail to certain embodiments of the invention, examples of which are illustrated by the accompanying structural and chemical formulas. The invention is intended to cover alternatives, modifications and equivalents, which may be included within the scope of the invention. Those skilled in the art will recognize that many methods and materials similar or equivalent to those described herein can be used in the practice of the present invention. The present invention is in no way limited to the methods and materials described herein. In the event that one or more of the incorporated documents, patents, and similar materials differ or contradict this application (including but not limited to defined terminology, application of terminology, described techniques, and the like), this application controls.
It will be further appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination.
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 following definitions as used herein should be applied unless otherwise indicated. For the purposes of the present invention, the chemical elements are in accordance with the CAS version of the periodic Table of the elements, and the handbook of chemistry and Physics, 75 th edition, 1994. In addition, reference may be made to the general principles of Organic Chemistry, thomas Sorrell, university Science Books, sausaltito: 1999, and "March's Advanced Organic Chemistry" by Michael B.Smith and Jerry March, john Wiley & Sons, new York:2007, the entire contents of which are incorporated herein by reference.
The articles "a," "an," and "the" as used herein are intended to include "at least one" or "one or more" unless otherwise indicated or clearly contradicted by context. Thus, as used herein, the articles refer to articles of one or more than one (i.e., at least one) object. For example, "a component" refers to one or more components, i.e., there may be more than one component contemplated to be employed or used in embodiments of the described embodiments.
The term "subject" as used herein refers to an animal. Typically the animal is a mammal. Subjects also refer to primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, and the like. In certain embodiments, the subject is a primate. In still other embodiments, the subject is a human.
The terms "subject" and "patient" as used herein are used interchangeably. The terms "subject" and "patient" refer to animals (e.g., birds or mammals such as chickens, quails or turkeys), particularly "mammals" including non-primates (e.g., cows, pigs, horses, sheep, rabbits, guinea pigs, rats, cats, dogs, and mice) and primates (e.g., monkeys, chimpanzees, and humans), and more particularly humans. In one embodiment, the subject is a non-human animal, such as a farm animal (e.g., a horse, cow, pig, or sheep) or a pet (e.g., a dog, cat, guinea pig, or rabbit). In other embodiments, the "patient" refers to a human.
The term "comprising" is open-ended, i.e. including what is specified in the invention, but not excluding other aspects.
The present invention also includes isotopically-labelled compounds of the present invention which are identical to those recited herein, except for the fact that: one or more atoms by atomsAn atom substitution of a mass or mass number different from the natural usual atomic mass or mass number. Exemplary isotopes that can also be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as 2 H， 3 H， 13 C， 14 C， 15 N， 16 O， 17 O， 31 P， 32 P， 36 S， 18 F and 37 Cl。
compounds of the present invention that contain the aforementioned isotopes and/or other isotopes of other atoms, as well as pharmaceutically acceptable salts of such compounds, are included within the scope of the present invention. Isotopically-labelled compounds of the invention, e.g. radioisotopes, e.g. 3 H and 14 incorporation of C into the compounds of the invention can be used in drug and/or substrate tissue distribution assays. Tritiated, i.e., 3 h, and carbon-14, i.e 14 C, an isotope is particularly preferred. In addition, heavy isotopes are used, such as deuterium, i.e. 2 H substitution may provide some therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements. Thus, it may be preferable in some situations.
The term "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 isomers), atropisomers, and the like.
The stereochemical definitions and rules used in the present invention generally follow the general definitions of S.P. Parker, ed., mcGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, new York; and Eliel, E.and Wilen, S., "Stereochemistry of Organic Compounds", john Wiley & Sons, inc., new York,1994. The compounds of the invention may contain asymmetric or chiral centers and thus exist in different stereoisomeric forms. It is contemplated that all stereoisomeric forms of the compounds of the present invention, including but not limited to diastereomers, enantiomers, and atropisomers (atropisomers) and mixtures thereof, such as racemic mixtures, are also within the scope of the present invention. Many organic compounds exist in an optically active form, i.e., they have the ability to rotate the plane of plane polarized light. When describing optically active compounds, the prefixes D and L or R and S are used to denote the absolute configuration of the molecule with respect to the chiral center (or centers) in the molecule. The prefixes d and l or (+) and (-) are the symbols used to specify the rotation of plane polarized light by the compound, where (-) or l indicates that the compound is left-handed. Compounds prefixed with (+) or d are dextrorotatory. A particular stereoisomer is an enantiomer and a mixture of such isomers is referred to as an enantiomeric mixture. A50: 50 mixture of enantiomers is referred to as a racemic mixture or racemate, which can occur when there is no stereoselectivity or stereospecificity in a chemical reaction or process.
Any asymmetric atom (e.g., carbon, etc.) of a compound of the invention can exist in racemic or enantiomerically enriched forms, such as the (R) -, (S) -, (R, R) -, (S, S) -, (S, R) -or (R, S) -configurations. In certain embodiments, each asymmetric atom has at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess in the (R) -or (S) -configuration. Substituents on atoms having unsaturated double bonds may be present in cis- (Z) -or trans- (E) -form, if possible.
Depending on the choice of starting materials and methods, the compounds of the invention may exist as one of the possible isomers or as mixtures thereof, for example as racemates and mixtures of non-corresponding isomers (depending on the number of asymmetric carbon atoms). Optically active (R) -or (S) -isomers may be prepared using chiral synthons or chiral preparations, or resolved using conventional techniques. If the compound contains a double bond, the substituents may be in the E or Z configuration; if the compound contains a disubstituted cycloalkyl group, the substituents of the cycloalkyl group may be in the cis or trans (cis-or trans-) configuration.
Any resulting mixture of stereoisomers may be separated into pure or substantially pure geometric isomers, enantiomers, diastereomers, depending on differences in the physicochemical properties of the components, for example, by chromatography and/or fractional crystallization.
The racemates of any of the resulting end products or intermediates can be resolved into the optical enantiomers by known methods using methods familiar to those skilled in the art, e.g., by separation of the diastereomeric salts obtained. The racemic product can also be separated by chiral chromatography, e.g., high Performance Liquid Chromatography (HPLC) using a chiral adsorbent. In particular, enantiomers can be prepared by asymmetric synthesis, for example, see Jacques, et al, enantiomers, racemates and solutions (Wiley Interscience, new York, 1981); principles of Asymmetric Synthesis (2) nd Ed.Robert E.Gawley，Jeffrey Aubé，Elsevier，Oxford，UK，2012)；Eliel，E.L.Stereochemistry of Carbon Compounds(McGraw-Hill，NY，1962)；Wilen，S.H.Tables of Resolving Agents and Optical Resolutions p.268(E.L.Eliel，Ed.，Univ.of Notre Dame Press，Notre Dame，IN 1972)；Chiral Separation Techniques：A Practical Approach(Subramanian，G.Ed.，Wiley-VCH Verlag GmbH&Co.KGaA，Weinheim，Germany，2007)。
The term "tautomer" or "tautomeric form" refers to structural isomers having different energies that can interconvert by a low energy barrier (low energy barrier). If tautomerism is possible (e.g., in solution), then the chemical equilibrium of the tautomer can be reached. For example, proton tautomers (also known as proton transfer tautomers) include interconversions by proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers (value tautomers) include interconversion by recombination of some of the bonding electrons. A specific example of keto-enol tautomerism is the tautomerism of the pentane-2,4-dione and 4-hydroxypent-3-en-2-one tautomers. Another example of tautomerism is phenol-ketone tautomerism. One specific example of phenol-ketone tautomerism is the tautomerism of pyridin-4-ol and pyridin-4 (1H) -one tautomers. Unless otherwise indicated, all tautomeric forms of the compounds of the invention are within the scope of the invention.
Thus, as described herein, the compounds of the present invention may exist as one of the possible isomers, rotamers, atropisomers, tautomers, or mixtures thereof, for example, as substantially pure geometric (cis or trans) isomers, diastereomers, optical isomers (enantiomers), racemates, or mixtures thereof.
The term "nitroxide" means that when a compound contains several amine functional groups, 1 or more than 1 nitrogen atom can be oxidized to form an N-oxide. Specific examples of N-oxides are N-oxides of tertiary amines or N-oxides of nitrogen-containing heterocyclic nitrogen atoms. The corresponding amines can be treated with an oxidizing agent, such as hydrogen peroxide or a peracid (e.g., peroxycarboxylic acid) to form the N-oxide (see Advanced Organic Chemistry, wiley Interscience, 4 th edition, jerry March). In particular, N-oxides may be prepared by the method of l.w. ready (syn.comm.1977, 7, 509-514) in which an amine compound is reacted with m-chloroperbenzoic acid (MCPBA), for example, in an inert solvent such as dichloromethane.
The term "solvate" refers to an association of one or more solvent molecules with a compound of the invention. Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, aminoethanol. The term "hydrate" refers to an association of solvent molecules with water.
The term "metabolite" refers to the product of the metabolism of a particular compound or salt thereof in vivo. Metabolites of a compound can be identified by techniques well known in the art, and its activity can be characterized by assay methods as described herein. Such products may be obtained by administering the compound by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, defatting, enzymatic cleavage, and the like. Accordingly, the present invention includes metabolites of compounds, including metabolites produced by contacting a compound of the present invention with a mammal for a sufficient period of time.
The term "pharmaceutically acceptable salts" refers to both organic and inorganic salts of the compounds of the present invention. Pharmaceutically acceptable salts are well known in the art, as are: s.m. berge et al, describe be pharmacological acceptable salts in detail in j. Pharmaceutical Sciences,1977, 66:1-19. Pharmaceutically acceptable non-toxic acid salts include, but are not limited to, salts of inorganic acids formed by reaction with amino groups such as hydrochlorides, hydrobromides, phosphates, sulfates, perchlorates, and salts of organic acids such as acetates, oxalates, maleates, tartrates, citrates, succinates, malonates, or those obtained by other methods described in the literature above, such as ion exchange. Other pharmaceutically acceptable salts include adipates, alginates, ascorbates, aspartates, benzenesulfonates, benzoates, bisulfates, borates, butyrates, camphorsulfonates, cyclopentylpropionates, digluconates, dodecylsulfates, ethanesulfonates, formates, fumarates, glucoheptonates, glycerophosphates, gluconates, hemisulfates, heptanoates, hexanoates, hydroiodides, 2-hydroxy-ethanesulfonates, lactobionates, lactates, laurates, lauryl sulfates, malates, malonates, methanesulfonates, 2-naphthalenesulfonates, nicotinates, nitrates, oleates, palmitates, pamoates, pectinates, persulfates, 3-phenylpropionates, picrates, pivalates, propionates, stearates, thiocyanates, p-toluenesulfonates, undecanoates, valerates, and the like. Salts obtained with appropriate bases include alkali metals, alkaline earth metals, ammonium and N + (C 1-4 Alkyl radical) 4 A salt. The present invention also contemplates quaternary ammonium salts formed from compounds containing groups of N. Water-soluble or oil-soluble or dispersion products can be obtained by quaternization. Alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Pharmaceutically acceptable salts further include suitableNon-toxic ammonium, quaternary ammonium salts and amine cations resistant to formation of counterions, e.g. halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C 1-8 Sulfonates and aromatic sulfonates.
The term "prodrug" denotes a compound which is converted in vivo to a compound of formula (I). Such conversion is effected by hydrolysis of the prodrug in the blood or by enzymatic conversion to the parent structure in the blood or tissue. The prodrug compound of the invention can be ester, and in the prior invention, the ester can be used as the prodrug and comprises phenyl ester and aliphatic (C) 1-24 ) Esters, acyloxymethyl esters, carbonates, carbamates and amino acid esters. For example, a compound of the present invention contains a hydroxy group, i.e., it can be acylated to provide the compound in prodrug form. Other prodrug forms include phosphate esters, such as those obtained by phosphorylation of a hydroxyl group on the parent. For a complete discussion of prodrugs, reference may be made to the following: t.higuchi and v.stella, pro-drugs as Novel Delivery Systems, vol.14 of the a.c.s.symposium Series, edward b.roche, ed., bioreversible Carriers in Drug Delivery Design, american Pharmaceutical Association and Pergamon Press,1987, j.rautio et al, produgs: design and Clinical Applications, nature Review Drug Discovery,2008,7, 255-270, and S.J. Hecker et al, prodrugs of photophates and photophorates, journal of medical Chemistry,2008, 51, 2328-2345.
The term "substituted" means that one or more hydrogen atoms in a given structure is replaced with a particular substituent. The compounds of the invention may be optionally substituted with one or more substituents, as described herein, for example, compounds of formula (I), or as specified in the examples, subclasses, and classes of compounds encompassed by the invention. The term "optionally substituted with … …" is used interchangeably with the term "unsubstituted or substituted with … …", i.e., the structure is unsubstituted or substituted with one or more substituents described herein.
Unless otherwise indicated, oneOptional substituent groups may be 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. Wherein the substituent can be, but is not limited to, H, D, F, cl, br, I, CN, NO 2 、OH、NH 2 Oxo (= O), -COOH, -SH, -NR c R d 、-C(＝O)R a 、-C(＝O)OR b 、-C(＝O)NR c R d 、-S(＝O) q R e 、-NR f C(＝O)R a 、-NR f S(＝O) 2 R e Haloalkyl, alkoxy, alkylthio, alkylamino, haloalkoxy, hydroxyalkyl, alkyl, alkenyl, alkynyl, cycloalkyl, carbocyclyl, heterocyclyl, aryl or heteroaryl, wherein each R is independently selected from the group consisting of a 、R b 、R c 、R d 、R f And q has the meaning as defined in the invention.
In addition, unless otherwise expressly indicated, the terms "each independently" and "each independently" are used interchangeably in this disclosure and should be broadly understood to mean that the particular items expressed between the same symbols in different groups do not affect each other, or that the particular items expressed between the same symbols in the same groups do not affect each other.
In the various parts of this specification, substituents of the disclosed compounds are disclosed in terms of group type or range. It is specifically intended that the invention includes each and every independent subcombination of the various members of these groups and ranges. For example, the term "C 1-6 Alkyl "in particular denotes independently disclosed C 1 Alkyl (methyl), C 2 Alkyl (ethyl), C 3 Alkyl radical, C 4 Alkyl radical, C 5 Alkyl and C 6 Alkyl, and "heteroaryl of 5-6 atoms" refers to heteroaryl of 5 atoms and heteroaryl of 6 atoms.
In the various parts of this specification, linking substituents are described. Where the structure clearly requires a linking group, the markush variables listed for that group are understood to be linking groups. For example, if the structure requires a linking group and the markush group definition for that 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, means a saturated straight or branched chain monovalent hydrocarbon radical containing from 1 to 20 carbon atoms. Unless otherwise specified, alkyl groups contain 1-20 carbon atoms; in some embodiments, the alkyl group contains 1 to 12 carbon atoms; in some embodiments, the alkyl group contains 1 to 10 carbon atoms; in some embodiments, the alkyl group contains 1 to 9 carbon atoms; in some embodiments, the alkyl group contains 1 to 8 carbon atoms; in some embodiments, the alkyl group contains 1 to 6 carbon atoms; in some embodiments, the alkyl group contains 1 to 4 carbon atoms, and in some embodiments, the alkyl group contains 1 to 2 carbon atoms.
Examples of alkyl groups include, but are not limited to, methyl (Me, -CH) 3 ) Ethyl (Et, -CH) 2 CH 3 ) N-propyl (n-Pr, -CH) 2 CH 2 CH 3 ) Isopropyl (i-Pr, -CH (CH) 3 ) 2 ) N-butyl (n-Bu, -CH) 2 CH 2 CH 2 CH 3 ) Isobutyl (i-Bu, -CH) 2 CH(CH 3 ) 2 ) Sec-butyl (s-Bu, -CH (CH) 3 )CH 2 CH 3 ) Tert-butyl (t-Bu, -C (CH) 3 ) 3 ) N-pentyl (-CH) 2 CH 2 CH 2 CH 2 CH 3 ) 2-pentyl (-CH (CH) 3 )CH 2 CH 2 CH 3 ) 3-pentyl (-CH (CH) 2 CH 3 ) 2 ) 2-methyl-2-butyl (-C (CH) 3 ) 2 CH 2 CH 3 ) 3-methyl-2-butyl (-CH (CH) 3 )CH(CH 3 ) 2 ) 3-methyl-1-butyl (-CH) 2 CH 2 CH(CH 3 ) 2 ) 2-methyl-1-butyl (-CH) 2 CH(CH 3 )CH 2 CH 3 ) N-hexyl (-CH) 2 CH 2 CH 2 CH 2 CH 2 CH 3 ) 2-hexyl (-CH (CH) 3 )CH 2 CH 2 CH 2 CH 3 ) 3-hexyl (-CH (CH) 2 CH 3 )(CH 2 CH 2 CH 3 ) 2-methyl-2-pentyl (-C (CH)) 3 ) 2 CH 2 CH 2 CH 3 ) 3-methyl-2-pentyl (-CH (CH) 3 )CH(CH 3 )CH 2 CH 3 ) 4-methyl-2-pentyl (-CH (CH) 3 )CH 2 CH(CH 3 ) 2 ) 3-methyl-3-pentyl (-C (CH) 3 )(CH 2 CH 3 ) 2 ) 2-methyl-3-pentyl (-CH (CH) 2 CH 3 )CH(CH 3 ) 2 ) 2,3-dimethyl-2-butyl (-C (CH) 3 ) 2 CH(CH 3 ) 2 ) 3,3-dimethyl-2-butyl (-CH (CH) 3 )C(CH 3 ) 3 ) N-heptyl, n-octyl, and the like.
The term "alkenyl" denotes a straight or branched chain monovalent hydrocarbon radical containing 2 to 12 carbon atoms, wherein there is at least one site of unsaturation, i.e. one carbon-carbon sp 2 A double bond, wherein the alkenyl group may be optionally substituted with one or more substituents described herein, including the positioning of "cis" and "tan", or the positioning of "E" and "Z". In one embodiment, the alkenyl group contains 2 to 8 carbon atoms; in one embodiment, alkenyl groups contain 2 to 6 carbon atoms; in one embodiment, the alkenyl group contains 2 to 4 carbon atoms. Examples of alkenyl groups include, but are not limited to, vinyl (-CH = CH) 2 ) Allyl (-CH) 2 CH＝CH 2 ) Propenyl (-CH = CH-CH) 3 ) And so on.
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, wherein said alkynyl radical may optionally be substituted with one or more substituents as described herein. In some embodiments, alkynyl groups contain 2-8A carbon atom; in some embodiments, alkynyl groups contain 2-6 carbon atoms; in some embodiments, alkynyl groups contain 2-4 carbon atoms. Examples of alkynyl groups include, but are not limited to, ethynyl (-C ≡ CH), propargyl (-CH) 2 C.ident.CH), 1-propynyl (-C.ident.C-CH) 3 ) 1-butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl, 3-methyl-1-butynyl, 1-hexynyl, 1-heptynyl, 1-octynyl, and the like.
The term "alkoxy" denotes an alkyl group attached to the rest of the molecule via an oxygen atom, i.e. -O-alkyl, wherein the alkyl group has the meaning as described herein. Unless otherwise specified, the alkoxy group contains 1 to 12 carbon atoms. In some embodiments, alkoxy groups contain 1 to 6 carbon atoms; in some embodiments, alkoxy groups contain 1 to 4 carbon atoms; in some embodiments, alkoxy groups contain 1 to 3 carbon atoms.
Examples of alkoxy groups include, but are not limited to, methoxy (MeO, -OCH) 3 ) Ethoxy (EtO, -OCH) 2 CH 3 ) 1-propoxy (n-PrO, n-propoxy, -OCH) 2 CH 2 CH 3 ) 2-propoxy (i-PrO, i-propoxy, -OCH (CH) 3 ) 2 ) 1-butoxy (n-BuO, n-butoxy, -OCH) 2 CH 2 CH 2 CH 3 ) 2-methyl-1-propoxy (i-BuO, i-butoxy, -OCH) 2 CH(CH 3 ) 2 ) 2-butoxy (s-BuO, s-butoxy, -OCH (CH) 3 )CH 2 CH 3 ) 2-methyl-2-propoxy (t-BuO, t-butoxy, -OC (CH) 3 ) 3 ) 1-pentyloxy (n-pentyloxy, -OCH) 2 CH 2 CH 2 CH 2 CH 3 ) 2-pentyloxy (-OCH (CH) 3 )CH 2 CH 2 CH 3 ) 3-pentyloxy (-OCH (CH)) 2 CH 3 ) 2 ) 2-methyl-2-butoxy (-OC (CH)) 3 ) 2 CH 2 CH 3 ) 3-methyl-2-butoxy (-OCH (CH) 3 )CH(CH 3 ) 2 ) 3-methyl-1-butoxy (-OCH) 2 CH 2 CH(CH 3 ) 2 ) 2-methyl-1-butoxyRadical (-OCH) 2 CH(CH 3 )CH 2 CH 3 ) And so on.
The term "alkylamino" or "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 embodiments, alkylamino is one or two C 1-6 An alkylamino group in which the alkyl group is attached to the nitrogen atom. In some embodiments, alkylamino is one or two C 1-4 An alkylamino group in which the alkyl group is attached to the nitrogen atom. In some embodiments, alkylamino is one or two C 1-3 An alkylamino group in which the alkyl group is attached to the nitrogen atom. In some embodiments, alkylamino is one or two C 1-2 An alkylamino group in which the alkyl group is attached to the nitrogen atom. Suitable alkylamino groups can be monoalkylamino or dialkylamino, and such examples include, but are not limited to, methylamino (N-methylamino), ethylamino (N-ethylamino), N-dimethylamino, N-diethylamino, and the like.
The terms "haloalkyl", "haloalkenyl" or "haloalkoxy" respectively denote alkyl, alkenyl or alkoxy groups substituted with one or more halogen atoms. Examples include, but are not limited to, fluoromethyl (-CH) 2 F) Difluoromethyl (-CHF) 2 ) Trifluoromethyl (-CF) 3 ) Fluoroethyl (-CHFCH) 3 ，-CH 2 CH 2 F) Difluoroethyl (-CF) 2 CH 3 ，-CHFCH 2 F，-CH 2 CHF 2 ) Perfluoroethyl, fluoropropyl (-CHFCH) 2 CH 3 ，-CH 2 CHFCH 3 ，-CH 2 CH 2 CH 2 F) Difluoropropyl (-CF) 2 CH 2 CH 3 ，-CFHCFHCH 3 ，-CH 2 CH 2 CHF 2 ，-CH 2 CF 2 CH 3 ，-CH 2 CHFCH 2 F) Trifluoroethyl (-CH) 2 CF 3 ，-CHFCHF 2 ，-CF 2 CH 2 F) Trifluoropropyl, 1,1-dichloroethyl, 1,2-dichloropropyl, trifluoromethoxy (-OCF) 3 ) Difluoromethoxy (-OCHF) 2 ) 2,2,2 trifluoroethoxy (-OCH) 2 CF 3 ) And the like.
The term "carbocyclyl" or "carbocycle" refers to a monovalent or multivalent non-aromatic, saturated or partially unsaturated monocyclic, bicyclic or tricyclic carbocyclic ring system containing from 3 to 14 ring atoms. The carbobicyclic group includes a spiro carbobicyclic group, a fused carbobicyclic group and a bridged carbobicyclic group. In some embodiments, the number of carbon atoms is 3 to 12, i.e., C 3-12 A carbocyclic ring; in other embodiments, the number of carbon atoms is from 3 to 10, i.e., C 3-10 A carbocyclic ring; in other embodiments, the number of carbon atoms is from 3 to 8, i.e., C 3-8 A carbocyclic ring; in other embodiments, the number of carbon atoms is 3 to 6, i.e., C 3-6 A carbocyclic ring; in other embodiments, the number of carbon atoms is from 5 to 6, i.e., C 5-6 A carbocyclic ring; in other embodiments, the number of carbon atoms is from 5 to 8, i.e., C 5-8 A carbocyclic ring. Examples of carbocyclyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopentyl-1-enyl, 1-cyclopentyl-2-enyl, 1-cyclopentyl-3-enyl, cyclohexyl, 1-cyclohexyl-1-enyl, 1-cyclohexyl-2-enyl, 1-cyclohexyl-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, and the like.
The term "cycloalkyl" denotes a monovalent or polyvalent, non-aromatic, saturated monocyclic, bicyclic or tricyclic carbocyclic ring system containing 3 to 14 ring atoms. In some embodiments, cycloalkyl contains 3 to 12 carbon atoms, i.e., C 3-12 A cycloalkyl group; in some embodiments, cycloalkyl contains 3 to 8 carbon atoms, i.e., C 3-8 A cycloalkyl group; in some embodiments, cycloalkyl contains 3 to 6 carbon atoms, i.e., C 3-6 A cycloalkyl group. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like. The cycloalkyl group is optionally substituted with one or more substituents described herein.
The terms "aryl" or "aromatic ring" are used interchangeably herein and refer to monocyclic, bicyclic, and tricyclic carbon ring systems containing 6 to 14 ring atoms, or 6 to 12 ring atoms, or 6 to 10 ring atoms, wherein at least one ring system is aromatic, wherein each ring system contains a 3 to 7 atom-forming carbocyclic ring with one or more attachment points to the remainder of the molecule. Examples of the aryl group may include phenyl, naphthyl and anthracenyl. The aryl group may be optionally substituted with one or more substituents described herein.
The term "heteroatom" refers to O, S, N, P and Si, including any oxidation state form of N, S and P; primary, secondary, tertiary amines and quaternary ammonium salt forms; or a form in which a hydrogen on a nitrogen atom in the heterocycle is substituted, e.g., N (like N in 3,4-dihydro-2H-pyrrolyl), NH (like NH in pyrrolidinyl) or NR (like NR in N-substituted pyrrolidinyl, R being a substituent as described herein).
The term "heterocyclyl" refers to a mono-, bi-or tricyclic ring system containing 3 to 14 ring atoms, wherein at least one ring atom is selected from the group consisting of heteroatoms, said heteroatoms having the meaning according to the invention. "Heterocyclyl" may be fully saturated or contain one or more unsaturations, but not one aromatic ring. The terms "heterocyclyl", "heterocyclic" and "heterocycle" are used interchangeably herein. In some embodiments, heterocyclyl groups are ring systems of 5-14 ring atoms, i.e., heterocyclyl groups of 5-14 atoms; in some embodiments, heterocyclyl groups are ring systems of 3-8 ring atoms, i.e., heterocyclyl groups of 3-8 atoms; in some embodiments, heterocyclyl groups are ring systems of 3-6 ring atoms, i.e., heterocyclyl groups of 3-6 atoms; in some embodiments, heterocyclyl is a ring system of 5-6 ring atoms, i.e., heterocyclyl of 5-6 atoms; in some embodiments, a heterocyclyl group is a ring system of 4 ring atoms, i.e., a heterocyclyl group of 4 atoms; in some embodiments, a heterocyclyl group is a ring system of 5 ring atoms, i.e., a heterocyclyl group of 5 atoms; in some embodiments, a heterocyclyl group is a ring system of 6 ring atoms, i.e., a heterocyclyl group of 6 atoms; in some embodiments, a heterocyclyl group is a 7-atom ring system, i.e., a 7-atom heterocyclyl group. In some embodiments, heterocyclyl groups are monocyclic (2-7 carbon atoms and 1-3 heteroatoms selected from N, O, P, S) consisting of 3-8 atoms, or bicyclic (4-12 carbon atoms and 1-3 heteroatoms selected from N, O, P, S) consisting of 7-13 atoms. In some embodiments, heterocyclyl is a monocyclic heterocyclyl consisting of 5-6 atoms. In some embodiments, heterocyclyl is a bridged heterocyclyl consisting of 7-9 atoms. In some embodiments, heterocyclyl is a spirobicyclic heterocyclyl consisting of 9-13 atoms; in still other embodiments, the heterocyclyl is a spirobicyclic heterocyclyl of 9-10 atoms. In some embodiments, heterocyclyl is a fused bicyclic heterocyclyl consisting of 7-11 atoms. The heterocyclyl group is optionally substituted with one or more substituents described herein.
Unless otherwise specified, a heterocyclyl group may be carbon-or nitrogen-based, and a-CH 2-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 heterocyclyl groups include, but are not limited to: <xnotran> , , , , ,2- ,3- , , , , , , , , , 5363 zxft 5363- , , , ,2H- ,4H- , , , , , , , , , , , , , , , </xnotran>
Figure GPA0000302900140000143
Base, diaza
Figure GPA0000302900140000144
Radical, S-N-aza
Figure GPA0000302900140000145
Aryl, 2-oxa-5-azabicyclo [2.2.1]Hept-5-yl, and the like. In heterocyclic radicals of-CH 2 Examples of-groups substituted with-C (= O) -include, but are not limited to, 2-oxopyrrolidinyl, oxo-1,3-thiazolidinyl, 2-piperidinonyl, 3,5-dioxopiperidinyl, and the like. Examples of heterocyclic sulfur atoms that are oxidized include, but are not limited to, sulfolane, thiomorpholinyl 1,1-dioxide, and the like. The following bicyclic or tricyclic groups are also included, but are in no way limited to
Figure GPA0000302900140000141
Figure GPA0000302900140000142
And so on. The heterocyclyl group may be optionally substituted with one or more substituents as described herein.
The term "heteroaryl" denotes a mono-or polyvalent mono-, bi-or tricyclic ring system containing 5 to 14 ring atoms, or 5 to 10 ring atoms, or 5 to 6 ring atoms, wherein at least one ring system is aromatic and at least one ring contains one or more heteroatoms, said heteroatoms having the definitions described herein. The terms "heteroaryl", "heteroaryl ring" or "heteroaromatic" are used interchangeably herein. When a heteroaryl group is present-CH 2 When said radical is-CH 2 -the group is optionally replaced by-C (= O) -. In some embodiments, heteroaryl is 5-14 ring atoms containing 1,2,3 or 4 heteroatoms independently selected from O, S and N, i.e., 5-14 atoms. In some embodiments, heteroaryl is heteroaryl consisting of 5 to 10 ring atoms containing 1,2,3 or 4 heteroatoms independently selected from O, S and N, i.e., 5 to 10 atoms. In some embodiments, heteroaryl is heteroaryl consisting of 5 to 6 ring atoms containing 1,2,3 or 4 heteroatoms independently selected from O, S and N, i.e., 5 to 6 atoms. In other embodiments, heteroaryl is heteroaryl consisting of 5 ring atoms containing 1,2,3 or 4 heteroatoms independently selected from O, S and N, i.e., 5A heteroaryl group consisting of atoms. In some embodiments, heteroaryl is a 6 ring atom heteroaryl comprising 1,2,3 or 4 heteroatoms independently selected from O, S and N, i.e., a 6 atom heteroaryl. In some embodiments, heteroaryl is monocyclic 5-6 atom heteroaryl. In some embodiments, heteroaryl is a spirobicyclic heteroaryl of 9-13 atoms. In some embodiments, heteroaryl is a fused bicyclic heteroaryl of 7-11 atoms; in still other embodiments, heteroaryl is a fused bicyclic heteroaryl of 8-10 atoms. The heteroaryl group is optionally substituted with one or more substituents described herein.
Examples of heteroaryl groups include, but are not limited to, furyl (e.g., 2-furyl, 3-furyl), imidazolyl (e.g., N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl), isoxazolyl (e.g., 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl), oxazolyl (e.g., 2-oxazolyl, 4-oxazolyl, 5-oxazolyl), pyrrolyl (e.g., N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), pyridyl (e.g., 2-pyridyl, 3-pyridyl, 4-pyridyl), pyrimidinyl (e.g., 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl), pyridazinyl (e.g., 3-pyridazinyl), thiazolyl (e.g., 2-thiazolyl, 4-ft, 5-thiazolyl), tetrazolyl (e.g., 5H-tetrazolyl, 2H-tetrazolyl), triazolyl (e.g., 2-triazolyl, 5-triazolyl, 4H-3245-triazolyl, 1H-3732-triazolyl, 3763-triazolyl), triazolyl (e.g., 3-pyrazolyl-thienyl, 3925, 3-thiazolyl (e.g., 3-pyrazolyl, 3-thiazolyl, 3,4-oxadiazolyl), thiadiazolyl (e.g., 1,2,3-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl), pyrazinyl, 1,3,5-triazinyl; the following bicyclic or tricyclic groups are also included, but are in no way limited to: benzimidazolyl, benzofuranyl, benzothienyl, indolyl (e.g., 2-indolyl), purinyl, quinolyl (e.g., 2-quinolyl, 3-quinolyl, 4-quinolyl), isoquinolyl (e.g., 1-isoquinolyl, 3-isoquinolyl, or 4-isoquinolyl), imidazo [1,2-a]Pyridyl, pyrazolo [1,5-a]Pyridyl, pyrazolo [1,5-a]Pyrimidinyl, imidazo [1,2-b]Pyridazinyl, [1,2,4]Triazolo [4,3-b]Pyridazinyl, [1,2,4]Triazolo [1,5-a]Pyrimidinyl, [1,2,4]Triazolo [1,5-a]Pyridyl, indolinyl, 1,2,3,4-tetrahydroisoquinolinyl, and pharmaceutically acceptable salts thereof,
Figure GPA0000302900140000151
Figure GPA0000302900140000152
And so on. The heteroaryl group is optionally substituted with one or more substituents described herein.
The term "m-atomic" where m is an integer typically describes the number of ring-forming atoms in the molecule, which is m. For example, piperidinyl is a heterocyclyl consisting of 6 ring atoms, and naphthyl is an aryl group consisting of 10 atoms.
The term "halogen" refers to F, cl, br or I.
The term "D" refers to deuteration, i.e. 2 H。
The term "nitro" means-NO 2 。
The term "mercapto" refers to-SH.
The term "hydroxy" refers to-OH.
The term "amino" refers to the group-NH 2 。
The term "cyano" refers to — CN.
The term "carboxy", denotes — COOH, whether used alone or in combination with other terms, such as "carboxyalkyl".
The term "carbonyl", denotes- (C = O) -, whether used alone or in combination with other terms, such as "aminocarbonyl" or "acyloxy".
The term "protecting group" or "PG" refers to a substituent group that blocks or protects a particular functionality when other functional groups in a compound are reacted. For example, "amino protecting group" refers to a substituent attached to an amino group to block or protect the functionality of the amino group in a compound, suitably ammoniaThe group protecting groups include acetyl, trifluoroacetyl, t-butyloxycarbonyl (BOC ), benzyloxycarbonyl (CBZ ) and 9-fluorenylmethyloxycarbonyl (Fmoc). Similarly, "hydroxy protecting group" refers to the functionality of a substituent of a hydroxy group to block or protect the hydroxy group, and suitable protecting groups include, but are not limited to, acetyl, benzoyl, benzyl, p-methoxybenzyl, silyl, and the like. "carboxy protecting group" refers to the functionality of a substituent of a carboxy group to block or protect the carboxy group, and typical carboxy protecting groups include-CH 2 CH 2 SO 2 Ph, cyanoethyl, 2- (trimethylsilyl) ethyl, 2- (trimethylsilyl) ethoxymethyl, 2- (p-toluenesulfonyl) ethyl, 2- (p-nitrobenzenesulfonyl) ethyl, 2- (diphenylphosphino) ethyl, nitroethyl, and the like. General descriptions of protecting groups can be found in the literature: greene, protective Groups in Organic Synthesis, john Wiley&Sons，New York，1991；and P.J.Kocienski，Protecting Groups，Thieme，Stuttgart，2005.
The term "leaving group" or "LG" refers to an atom or functional group that is removed from a larger molecule in a chemical reaction and is the term used in nucleophilic substitution and elimination reactions. In nucleophilic substitution reactions, the reactant attacked by the nucleophile is called the substrate, and the atom or group of atoms cleaved away from the substrate molecule with a pair of electrons is called the leaving group. Common leaving groups are, for example, but not limited to, halogen atoms, ester groups, sulfonate groups, nitro groups, azide groups, hydroxyl groups, or the like.
The term "pharmaceutically acceptable" means that the substance or composition must be chemically and/or toxicologically compatible with the other ingredients comprising the formulation and/or the mammal being treated therewith. Preferably, the term "pharmaceutically acceptable" as used herein refers to those approved by a federal regulatory agency 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 any solvent, dispersion medium, coating, surfactant, antioxidant, preservative (e.g., antibacterial, antifungal), isotonic agent, salt, pharmaceutical stabilizer, binder, excipient, dispersant, lubricant, sweetener, flavoring agent, coloring agent, or combination thereof, which are known to those skilled in the art (e.g., described in Remington's Pharmaceutical Sciences,18th Ed. Mack Printing company,1990, pp. 1289-1329). Except insofar as any conventional carrier is incompatible with the active ingredient, its use in therapeutic or pharmaceutical compositions is contemplated.
The term "pharmaceutical composition" means a mixture of one or more compounds described herein or physiologically/pharmaceutically acceptable salts or prodrugs thereof with other chemical components such as physiologically/pharmaceutically acceptable carriers, excipients, diluents, binders, fillers and like excipients, and additional therapeutic agents such as anti-diabetic agents, anti-hyperglycemic agents, anti-obesity agents, anti-hypertensive agents, anti-platelet agents, anti-atherosclerotic agents or lipid-lowering agents. The purpose of the pharmaceutical composition is to facilitate the administration of the compound to an organism.
The term "syndrome X", also referred to as a disorder, disease of metabolic syndrome, the condition of which is described in detail in Johannsson et al, j.clin.endocrinol.metab.,1997, 82, 727-734.
As used herein, "inflammatory disease," "inflammatory disease," or "inflammatory disease" refers to any disease, disorder, or symptom of excessive inflammatory symptoms, host tissue damage, or loss of tissue function resulting from an excessive or uncontrolled inflammatory response. "inflammatory disease" also refers to a pathological condition mediated by leukocyte influx and/or neutrophil chemotaxis.
As used herein, "inflammation", "inflammatory" or "inflammatory" refers to a local protective response caused by tissue damage or destruction that serves to destroy, dilute, or separate (sequester) harmful substances from the damaged tissue. Inflammation is significantly linked to leukocyte influx and/or neutrophil chemotaxis. Inflammation can result from infection by pathogenic organisms and viruses, as well as from non-infectious means, such as trauma or reperfusion following myocardial infarction or stroke, immune and autoimmune responses to foreign antigens. Thus, inflammatory diseases that may be treated with the disclosed compounds include: diseases associated with specific defense system reactions as well as non-specific defense system reactions.
As used herein, "allergy" refers to any symptom of developing an allergy, tissue damage, or loss of tissue function. As used herein, "arthritic disease" refers to any disease characterized by inflammatory injury to the joints attributable to various etiologies. As used herein, "dermatitis" refers to any of a large family of skin diseases characterized by skin inflammation attributable to various etiologies. As used herein, "transplant rejection" refers to any immune response against a transplanted tissue, such as an organ or cell (e.g., bone marrow), characterized by loss of function of the transplanted or surrounding tissue, pain, swelling, leukocytosis, and thrombocytopenia. The therapeutic methods of the invention include methods for treating diseases associated with inflammatory cell activation.
In addition, unless otherwise indicated, the structural formulae of the compounds described herein include isotopically enriched concentrations of one or more different atoms.
The term "treating" or "treatment" as used herein refers, in some embodiments, to ameliorating a disease or disorder (i.e., slowing or arresting or reducing the development of the disease or at least one clinical symptom thereof). In other embodiments, "treating" or "treatment" refers to moderating or improving at least one physical parameter, including physical parameters that may not be perceived by the patient. In other embodiments, "treating" or "treatment" refers to modulating the disease or disorder, either physically (e.g., stabilizing a perceptible symptom) or physiologically (e.g., stabilizing a parameter of the body), or both. In other embodiments, "treating" or "treatment" refers to preventing or delaying the onset, occurrence, or worsening of a disease or disorder.
Description of the Compounds of the invention
The compound and the pharmaceutical composition thereof can be used for preparing medicines for treating inflammatory diseases and/or inflammation-related diseases, diabetes and/or diabetes-related diseases, ischemic diseases, vascular diseases, fibrosis or tissue transplant rejection, and particularly treating non-alcoholic fatty liver disease, diabetic retinopathy, diabetic nephropathy, diabetic neuropathy or diabetic macular edema. The invention also provides processes for preparing these compounds, pharmaceutical compositions comprising these compounds and methods of using these compounds and compositions in the manufacture of medicaments for the treatment of the above-mentioned diseases in mammals, especially humans. Compared with the existing similar compounds, the compound of the invention has good pharmacological activity and/or excellent in vivo metabolic kinetics property or in vivo pharmacodynamics property. Meanwhile, the preparation method is simple and feasible, the process method is stable, and the method is suitable for industrial production. Therefore, compared with the existing similar compounds, the compound provided by the invention has better drugability.
Specifically, the method comprises the following steps:
in one aspect, the invention relates to a compound that is a compound of formula (I) or a stereoisomer, a tautomer, a nitrogen oxide, a solvate, a metabolite, a pharmaceutically acceptable salt, or a prodrug thereof,
Figure GPA0000302900140000171
wherein A, R 1 、R 2 、R 3 、R 4 、R 5 、U 1 And U 2 Having the definitions as described in the present invention.
In some embodiments, U is 1 And U 2 Each independently is CH or N.
In some embodiments, R 1 、R 2 And R 3 Each independently is H, D, F, cl, br, I, CN, NO 2 、OH、NH 2 、C 1-6 Alkyl radical, C 1-6 Haloalkyl, C 1-6 Alkoxy radical, C 1-6 Alkylamino radical, C 1-6 Haloalkoxy or hydroxy C 1-6 An alkyl group.
In some embodiments, R 4 And R 5 Each independently H, D, F, cl、Br、I、CN、NO 2 、OH、NH 2 、C 1-6 Alkyl radical, C 1-6 Haloalkyl, C 1-6 Haloalkoxy or C 3-6 Cycloalkyl, wherein said C 1-6 Alkyl radical, C 1-6 Haloalkyl, C 1-6 Haloalkoxy and C 3-6 Cycloalkyl is each independently unsubstituted or substituted with 1,2,3 or 4 substituents independently selected from D, F, cl, br, I, CN, NO 2 、OH、NH 2 、-COOH、-SH、C 1-6 Alkyl radical, C 1-6 Haloalkyl, C 1-6 Alkoxy radical, C 1-6 Alkylamino or C 1-6 A haloalkoxy group;
or R 4 、R 5 Together with the carbon atom to which they are attached, form C 3-6 A carbocyclic ring or a heterocyclic ring of 3 to 6 atoms in which said C 3-6 The carbocycle and the heterocycle of 3-6 atoms are each independently unsubstituted or substituted with 1,2,3 or 4 substituents independently selected from D, F, cl, br, I, CN, NO 2 、OH、NH 2 、-COOH、-SH、C 1-6 Alkyl radical, C 1-6 Haloalkyl, C 1-6 Alkoxy radical, C 1-6 Alkylamino or C 1-6 A haloalkoxy group.
In some embodiments, A is heterocyclyl of 5-14 atoms or heteroaryl of 5-14 atoms, wherein A is unsubstituted or substituted with 1,2,3, or 4R 6 Substituted; wherein said R 6 Having the definitions set forth herein.
In some embodiments, each R is 6 Independently H, D, F, cl, br, I, CN, NO 2 、OH、-NR c R d 、＝O、-C(＝O)R a 、-C(＝O)OR b 、-C(＝O)NR c R d 、-S(＝O) q R e 、-NR f C(＝O)R a 、-NR f S(＝O) 2 R e 、C 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 1-6 Alkoxy radical, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, C 3-6 Cycloalkyl, 5-6 atom heterocyclic radical, C 6-10 Aryl or heteroaryl of 5 to 6 atoms, wherein said C 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 1-6 Alkoxy radical, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, C 3-6 Cycloalkyl, 5-6 atom heterocyclic radical, C 6-10 Aryl and heteroaryl of 5 to 6 atoms are each independently unsubstituted or substituted with 1,2,3 or 4 substituents independently selected from D, F, cl, br, I, CN, NO 2 、OH、NH 2 、-COOH、-SH、C 1-6 Alkyl radical, C 1-6 Haloalkyl, C 1-6 Alkoxy radical, C 1-6 Alkylamino or C 1-6 A haloalkoxy group; wherein said R a 、R b 、R c 、R d 、R e 、R f And q has the definitions stated in the present invention.
In some embodiments, q is 0, 1, or 2.
In some embodiments, each R is a 、R b 、R c 、R d 、R e And R f Independently H, D, C 1-6 Haloalkyl, C 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 3-6 Cycloalkyl, heterocyclic group consisting of 3 to 6 atoms, C 6-10 Aryl or heteroaryl of 5 to 6 atoms, wherein said C 1-6 Haloalkyl, C 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 3-6 Cycloalkyl, heterocyclic group consisting of 3 to 6 atoms, C 6-10 Aryl and heteroaryl of 5 to 6 atoms are each independently unsubstituted or substituted with 1,2,3 or 4 substituents independently selected from D, F, cl, br, I, CN, -OH, NH 2 、C 1-6 Alkyl radical, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 An alkylamino group;
or R c 、R d And together with the nitrogen atom to which they are attached, form a 3-6 atom heterocyclic ring or a 5-6 atom heteroaromatic ring, wherein the 3-6 atom heterocyclic ring and the 5-6 atom heteroaromatic ring are each independently unsubstitutedOr by 1,2,3 or 4 substituents independently selected from D, F, cl, br, I, CN, -OH, NH 2 、C 1-6 Alkyl radical, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 An alkylamino group.
In other embodiments, A is a monocyclic heterocyclyl consisting of 5-6 atoms, a monocyclic heteroaryl consisting of 5-6 atoms, a bridged heterocyclyl consisting of 7-9 atoms, a spirobicyclic heterocyclyl consisting of 9-13 atoms, a spirobicyclic heteroaryl consisting of 9-13 atoms, a fused bicyclic heterocyclyl consisting of 7-11 atoms, or a fused bicyclic heteroaryl consisting of 7-11 atoms, wherein A is unsubstituted or substituted with 1,2,3, or 4R 6 Substituted; wherein said R 6 Having the definitions set forth herein.
In other embodiments, a is the following sub-structural formula:
Figure GPA0000302900140000181
wherein,
each E is independently N or CH;
each G is independently-CH 2 -, -NH-, -O-, or-S-, -S (= O) -or-S (= O) 2 -；
U is N, -C = or CH;
each T is independently- (CH) 2 ) x -；
Each y is independently 0, 1 or 2;
each w is independently 0, 1 or 2;
x is 1,2 or 3;
ring C being C 3-6 Carbocyclic ring, heterocyclic ring of 3-6 atoms, C 6-10 An aromatic ring or a heteroaromatic ring of 5 to 6 atoms;
each ring D is independently C 3-6 Carbocyclic ring, heterocyclic ring of 3-6 atoms, C 6-10 An aromatic ring or a heteroaromatic ring of 5 to 6 atoms;
wherein A is unsubstituted or substituted by 1,2,3 or 4R 6 And (4) substituting.
In yet other embodiments, ring C is cyclopropane, cyclobutane, cyclopentane, cyclohexane, oxirane, azetidine, oxetane, thietane, 1,3-dioxolane, tetrahydrofuran, tetrahydrothiophene, dihydrothiophene, tetrahydropyran, dihydropyran, pyrrolidine, piperidine, morpholine, thiomorpholine, piperazine, benzene, pyrrole, pyridine, pyrimidine, thiazole, thiophene, furan, pyrazole, imidazole, triazole, tetrazole, oxazole, isoxazole, oxadiazole, pyrazine, or pyridazine.
In still other embodiments, each ring D is independently cyclopropane, cyclobutane, cyclopentane, cyclohexane, oxirane, azetidine, oxetane, thietane, 1,3-dioxolane, tetrahydrofuran, tetrahydrothiophene, dihydrothiophene, tetrahydropyran, dihydropyran, pyrrolidine, piperidine, morpholine, thiomorpholine, piperazine, benzene, pyrrole, pyridine, pyrimidine, thiazole, thiophene, furan, pyrazole, imidazole, triazole, tetrazole, oxazole, isoxazole, oxadiazole, pyrazine, or pyridazine.
In still other embodiments, A is
Figure GPA0000302900140000191
Figure GPA0000302900140000192
Figure GPA0000302900140000193
Wherein A is unsubstituted or substituted by 1,2,3 or 4R 6 Is substituted, wherein R is 6 Having the definitions set out in the present invention.
In other embodiments, each R6 is independently H, D, F, cl, br, I, CN, NO 2 、OH、-NR c R d 、＝O、-C(＝O)R a 、-C(＝O)OR b 、-C(＝O)NR c R d 、-S(＝O) q R e 、-NR f C(＝O)R a 、-NR f S(＝O) 2 R e 、C 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, C 1-4 Alkoxy radical, C 1-4 Haloalkyl group、C 1-4 Haloalkoxy, C 3-6 Cycloalkyl, 5-6 atom heterocyclic radical, C 6-10 Aryl or heteroaryl of 5 to 6 atoms, wherein said C 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, C 1-4 Alkoxy radical, C 1-4 Haloalkyl, C 1-4 Haloalkoxy, C 3-6 Cycloalkyl, heterocyclic radical of 5-6 atoms, C 6-10 Aryl and heteroaryl of 5 to 6 atoms are each independently unsubstituted or substituted with 1,2,3 or 4 substituents independently selected from D, F, cl, br, I, CN, NO 2 、OH、NH 2 、-COOH、-SH、C 1-4 Alkyl radical, C 1-4 Haloalkyl, C 1-4 Alkoxy radical, C 1-4 Alkylamino or C 1-4 A haloalkoxy group; wherein said R a 、R b 、R c 、R d 、R e 、R f And q has the definitions stated in the present invention.
In other embodiments, each R a 、R b 、R c 、R d 、R e And R f Independently H, D, C 1-4 Haloalkyl, C 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 5-6 atom heterocyclic radical, C 6-10 Aryl or heteroaryl of 5 to 6 atoms, wherein said C 1-4 Haloalkyl, C 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, C 3-6 Cycloalkyl, heterocyclic radical of 5-6 atoms, C 6-10 Aryl and heteroaryl of 5 to 6 atoms are each independently unsubstituted or substituted with 1,2,3 or 4 substituents independently selected from D, F, cl, br, I, CN, -OH, NH 2 、C 1-4 Alkyl radical, C 1-4 Haloalkyl, C 1-4 Alkoxy or C 1-4 An alkylamino group;
or R c 、R d Together with the nitrogen atom to which they are attached, form a 5-6 atom heterocyclic ring or a 5-6 atom heteroaromatic ring, wherein the 5-6 atom heterocyclic ring and the 5-6 atom heteroaromatic ring are each independentlyIndependently unsubstituted or substituted with 1,2,3 or 4 substituents independently selected from D, F, cl, br, I, CN, -OH, NH 2 、C 1-4 Alkyl radical, C 1-4 Haloalkyl, C 1-4 Alkoxy or C 1-4 An alkylamino group.
In still other embodiments, each R is 6 Independently H, D, F, cl, br, I, CN, NO 2 、OH、NH 2 、-NHCH 3 、-N(CH 3 ) 2 、＝O、-C(＝O)OH、-C(＝O)OCH 3 、-C(＝O)OCH 2 CH 3 、-C(＝O)NH 2 、-C(＝O)N(CH 3 ) 2 、-S(＝O) 2 CH 3 、-S(＝O) 2 CH 2 CH 3 、-NHC(＝O)R a 、-NHS(＝O) 2 R e Methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, trifluoromethyl, trifluoroethyl, trifluoromethoxy, cyclopropyl, cyclobutyl, cyclopentyl, tetrahydrofuryl, tetrahydrothienyl, dihydrothienyl, tetrahydropyranyl, dihydropyranyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, phenyl, pyrrolyl, pyridinyl, pyrimidinyl, thiazolyl, thienyl, furyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, pyrazinyl, or pyridazinyl, wherein said methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, trifluoroethyl, cyclopropyl, cyclobutyl, cyclopentyl, tetrahydrofuryl, tetrahydrothienyl, dihydrothienyl, tetrahydropyranyl, dihydropyranyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, phenyl, pyrrolyl, pyridinyl, pyrimidinyl, thiazolyl, thienyl, furyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, pyrazinyl, and pyridazinyl are each independently unsubstituted or substituted with 1,2,3,4 or 4 substituents selected from said I, cl, br, CN, NO, cl, NO, and Br 2 、OH、NH 2 -COOH, -SH, methyl, ethyl, trifluoromethyl, methoxy or ethoxy, wherein R is e And R a Having the inventionThe definition is described.
In yet other embodiments, each R is a 、R b 、R c 、R d 、R e And R f Independently H, D, trifluoromethyl, methyl, ethyl, n-propyl, isopropyl, tert-butyl, cyclopropyl, cyclobutyl, 5-6 atom heterocyclyl, phenyl, or 5-6 atom heteroaryl, wherein said methyl, ethyl, n-propyl, isopropyl, tert-butyl, cyclopropyl, cyclobutyl, 5-6 atom heterocyclyl, phenyl, and 5-6 atom heteroaryl are each independently unsubstituted or substituted with 1,2,3, or 4 substituents independently selected from D, F, cl, br, I, -CN, -OH, -NH, and 2 methyl, ethyl, n-propyl, isopropyl, trifluoromethyl or methoxy;
or R c 、R d And the nitrogen atom to which they are attached, form a 5-6 atom heterocyclic ring or a 5-6 atom heteroaromatic ring, wherein the 5-6 atom heterocyclic ring and the 5-6 atom heteroaromatic ring are each independently unsubstituted or substituted with 1,2,3, or 4 substituents independently selected from D, F, cl, br, I, -CN, -OH, -NH 2 Methyl, ethyl, n-propyl, isopropyl, trifluoromethyl or methoxy.
In some embodiments, R 1 、R 2 And R 3 Each independently is H, D, F, cl, br, I, CN, NO 2 、OH、NH 2 、C 1-4 Alkyl radical, C 1-4 Haloalkyl, C 1-4 Alkoxy radical, C 1-4 Alkylamino radical, C 1-4 Haloalkoxy or hydroxy C 1-4 An alkyl group.
In still other embodiments, R 1 、R 2 And R 3 Each independently is H, D, F, cl, br, I, CN, NO 2 、OH、NH 2 Methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, trifluoroethyl, methoxy, ethoxy, methylamino, trifluoromethoxy, or hydroxymethyl.
In some embodiments, R 4 And R 5 Each independently H, D, F, cl、Br、I、CN、NO 2 、OH、NH 2 、C 1-4 Alkyl radical, C 1-4 Haloalkyl, C 1-4 Haloalkoxy or C 3-6 Cycloalkyl, wherein said C 1-4 Alkyl radical, C 1-4 Haloalkyl, C 1-4 Haloalkoxy and C 3-6 Cycloalkyl is each independently unsubstituted or substituted with 1,2,3 or 4 substituents independently selected from D, F, cl, br, I, CN, NO 2 、OH、NH 2 、-COOH、-SH、C 1-4 Alkyl radical, C 1-4 Haloalkyl, C 1-4 Alkoxy radical, C 1-4 Alkylamino or C 1-4 A haloalkoxy group;
or R 4 、R 5 Together with the carbon atom to which they are attached, form C 3-6 A carbocyclic ring or a heterocyclic ring of 3 to 6 atoms in which said C 3-6 The carbocycle and the heterocycle of 3-6 atoms are each independently unsubstituted or substituted with 1,2,3 or 4 substituents independently selected from D, F, cl, br, I, CN, NO 2 、OH、NH 2 、-COOH、-SH、C 1-4 Alkyl radical, C 1-4 Haloalkyl, C 1-4 Alkoxy radical, C 1-4 Alkylamino or C 1-4 A haloalkoxy group.
In still other embodiments, R 4 And R 5 Each independently is H, D, F, cl, br, I, CN, NO 2 、OH、NH 2 Methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, trifluoroethyl, trifluoromethoxy, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, wherein said methyl, ethyl, n-propyl, isopropyl, trifluoroethyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl are each independently unsubstituted or substituted with 1,2,3, or 4 substituents independently selected from D, F, cl, br, I, CN, NO 2 、OH、NH 2 -COOH, -SH, methyl, ethyl, trifluoromethyl, methoxy or ethoxy;
or R 4 、R 5 Together with the carbon atom to which they are attached, form cyclopropane, cyclobutane, cyclopentane, cyclohexane, oxirane, azetidine, oxetane, and,Thietane, 1,3-dioxolane, tetrahydrofuran, tetrahydrothiophene, dihydrothiophene, tetrahydropyran, dihydropyran, pyrrolidine, piperidine, morpholine, thiomorpholine, or piperazine, wherein said cyclopropane, cyclobutane, cyclopentane, cyclohexane, oxirane, azetidine, oxetane, thietane, 1,3-dioxolane, tetrahydrofuran, tetrahydrothiophene, dihydrothiophene, tetrahydropyran, dihydropyran, pyrrolidine, piperidine, morpholine, thiomorpholine, and piperazine are each independently unsubstituted or substituted with 1,2,3, or 4 substituents independently selected from D, F, cl, br, I, CN, NO 2 、OH、NH 2 -COOH, -SH, methyl, ethyl, trifluoromethyl, methoxy or ethoxy.
In still other embodiments, the invention relates to the structure of one of the following, or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof,
Figure GPA0000302900140000211
Figure GPA0000302900140000221
Figure GPA0000302900140000231
in another aspect, the invention relates to a pharmaceutical composition comprising a compound of the invention.
In some embodiments, the pharmaceutical composition of the present invention further comprises a pharmaceutically acceptable carrier, excipient, adjuvant, vehicle, or combination thereof.
In some embodiments, the pharmaceutical composition of the present invention further comprises one or more additional therapeutic agents.
In other embodiments, the additional therapeutic agent of the present invention is selected from a VAP-1 inhibitor.
In other embodiments, the additional therapeutic agent of the invention is Vapaliximab, PRX-167700, BTT-1023, ASP-8232, PXS-4728A, or RTU-1096.
In other embodiments, the pharmaceutical compositions of the present invention may be in liquid, solid, semi-solid, gel, or spray form.
In another aspect, the invention relates to the use of a compound or pharmaceutical composition of the invention in the manufacture of a medicament, wherein the medicament is for inhibiting VAP-1.
In another aspect, the invention relates to the use of a compound or pharmaceutical composition according to the invention for inhibiting the activity of VAP-1.
In another aspect, the invention relates to a method of inhibiting VAP-1 activity using a compound or pharmaceutical composition described herein by administering to a patient a therapeutically effective amount of the compound or pharmaceutical composition.
In another aspect, the invention relates to the use of a compound of the invention or a pharmaceutical composition of the invention in the manufacture of a medicament for the prevention, treatment or amelioration of diseases associated with the VAP-1 protein or modulated by VAP-1.
In another aspect, the invention relates to the use of a compound or pharmaceutical composition according to the invention for the prevention, treatment or alleviation of diseases related to the VAP-1 protein or modulated by VAP-1.
In another aspect, the invention relates to a method of preventing, treating or ameliorating a disease associated with or modulated by VAP-1 protein using a compound or pharmaceutical composition of the invention by administering to a patient a therapeutically effective amount of the compound or pharmaceutical composition of the invention. Also, the present invention provides the above-mentioned compounds or pharmaceutical compositions thereof can be co-administered with other therapies or therapeutic agents. The administration may be simultaneous, sequential or at intervals.
In some embodiments, the diseases related to VAP-1 protein or modulated by VAP-1 according to the present invention are inflammatory diseases and/or inflammation-related diseases, diabetes and/or diabetes-related diseases, ischemic diseases, vascular diseases, fibrosis or tissue transplant rejection.
In other embodiments, the inflammatory disease and/or inflammation-related disorder of the invention is arthritis, systemic inflammatory syndrome, sepsis, synovitis, crohn's disease, ulcerative colitis, inflammatory bowel disease, liver disease, respiratory disease, eye disease, skin disease, or neuroinflammatory disease.
In still other embodiments, the arthritis of the invention is osteoarthritis, rheumatoid arthritis, or juvenile rheumatoid arthritis.
In still other embodiments, the systemic inflammatory syndrome of the invention is systemic inflammatory sepsis.
In still other embodiments, the inflammatory bowel disease of the present invention is irritable bowel disease.
In still other embodiments, the liver disease of the present invention is liver autoimmune disease, autoimmune hepatitis, primary biliary cirrhosis, sclerosing cholangitis, autoimmune cholangitis, alcoholic liver disease, or non-alcoholic fatty liver disease.
In some embodiments, the non-alcoholic fatty liver disease of the invention is non-alcoholic simple fatty liver, non-alcoholic steatohepatitis, non-alcoholic fatty liver disease phase Guan Yin-derived cirrhosis, or primary liver cancer.
In still other embodiments, the respiratory disease of the invention is asthma, acute lung injury, acute respiratory distress syndrome, pulmonary inflammation, chronic obstructive pulmonary disease, bronchitis, or bronchiectasis.
In still other embodiments, the ocular disease of the present invention is uveitis, iritis, retinitis, autoimmune ocular inflammation, inflammation due to angiogenesis and/or lymphangiogenesis, or macular degeneration.
In still other embodiments, the skin disease of the present invention is contact dermatitis, skin inflammation, psoriasis, or eczema.
In still other embodiments, the neuroinflammatory disorder of the invention is parkinson's disease, alzheimer's disease, vascular dementia, multiple sclerosis or chronic multiple sclerosis.
In other embodiments, the diabetes and/or diabetes related disorders of the present invention are type I diabetes, type II diabetes, syndrome X, diabetic retinopathy, diabetic nephropathy, diabetic neuropathy, or diabetic macular edema.
In other embodiments, the ischemic disease of the invention is stroke and/or its complications, myocardial infarction and/or its complications, or destruction of tissue by inflammatory cells after stroke.
In other embodiments, the fibrosis of the invention is liver fibrosis, cystic fibrosis, kidney fibrosis, idiopathic pulmonary fibrosis, or radiation-induced fibrosis.
In other embodiments, the vascular disease of the present invention is atherosclerosis, chronic heart failure, or congestive heart failure.
In some embodiments, the disease of the invention is cancer.
In other embodiments, the cancer of the invention is melanoma and lymphoma.
The dosage of a compound or pharmaceutical composition required to effect a therapeutic, prophylactic or delay-acting effect, etc., will generally depend on the particular compound being administered, the patient, the particular disease or condition and its severity, route and frequency of administration, etc., and will need to be determined on a case-by-case basis by the attending physician. For example, when a compound or pharmaceutical composition provided by the present invention is administered by intravenous route, administration may be performed once per week or at even longer intervals.
Unless otherwise indicated, all stereoisomers, tautomers, nitrogen oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts and pharmaceutically acceptable prodrugs of the compounds of the present invention are within the scope of the present invention.
In particular, the salts are pharmaceutically acceptable salts. The term "pharmaceutically acceptable" includes materials or compositions which must be compatible chemically or toxicologically, with the other components comprising the formulation, and with the mammal being treated.
Salts of the compounds of the present invention also include, but are not necessarily pharmaceutically acceptable salts of intermediates used in the preparation or purification of the compounds of formula (I) or isolated enantiomers of the compounds of formula (I).
Compositions, formulations and administration of the compounds of the invention
The invention relates to a pharmaceutical composition which comprises a compound of the invention or a compound of the structure shown in the examples, or a stereoisomer, a tautomer, a nitrogen oxide, a solvate, a metabolite and a pharmaceutically acceptable salt thereof or a prodrug thereof. The pharmaceutical composition further comprises at least one pharmaceutically acceptable carrier, excipient, adjuvant, vehicle, or combination thereof, and optionally, other therapeutic and/or prophylactic ingredients. In some embodiments, the pharmaceutical composition comprises an effective amount of at least one pharmaceutically acceptable carrier, excipient, adjuvant, or vehicle. The amount of compound in the pharmaceutical composition of the invention is effective to detectably inhibit VAP-1 activity in a biological sample or patient.
The compounds of the invention exist in free form or, where appropriate, as pharmaceutically acceptable derivatives. According to the present invention, pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable prodrugs, salts, esters, salts of esters, or any other adduct or derivative that can be administered directly or indirectly in accordance with the needs of the patient, compounds described in other aspects of the invention, metabolites thereof, or residues thereof.
As described herein, the pharmaceutically acceptable compositions of the present invention further comprise a pharmaceutically acceptable carrier, adjuvant, vehicle or combination thereof, as applicable herein, including any solvent, diluent, or other liquid excipient, dispersant or suspending agent, surfactant, isotonic agent, thickening agent, emulsifier, preservative, solid binder or lubricant, and the like, as appropriate for the particular target dosage form. As described in the following documents: in Remington: the Science and Practice of Pharmacy,21st edition,2005, ed.D.B.Troy, lippincott Williams and Wilkins, philadelphia, and Encyclopedia of Pharmaceutical technology, eds.J.Swarbrick and J.C.Boylan,1988-1999, marcel Dekker, new York, taken together with The disclosure of The literature herein, indicate that different carriers can be used in The formulation of pharmaceutically acceptable compositions and their well known methods of preparation. Except insofar as any conventional carrier vehicle is incompatible with the compounds of the invention, e.g., any adverse biological effect produced or interaction in a deleterious manner with any other component of a pharmaceutically acceptable composition, its use is contemplated by the present invention.
Some examples of substances that can be used as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (e.g., human serum albumin), buffer substances (e.g., tween 80, phosphate, glycine, sorbic acid, or potassium sorbate), partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes (e.g., protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, or zinc salts), silica gel, magnesium trisilicate, polyvinyl pyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-block copolymers, methyl cellulose, hydroxypropyl methyl cellulose, lanolin, sugars (e.g., lactose, glucose, and sucrose), starches (e.g., corn starch and potato starch) cellulose and its derivatives (e.g., sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate), powdered tragacanth, malt, gelatin, talc, excipients (e.g., cocoa butter and suppository waxes), oils (e.g., peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil), glycols (e.g., propylene glycol or polyethylene glycol), esters (e.g., ethyl oleate and ethyl laurate), agar, buffers (e.g., magnesium hydroxide and aluminum hydroxide), alginic acid, pyrogen-free water, isotonic saline, ringer's solution, ethanol and phosphate buffers, and other non-toxic compatible lubricants (e.g., sodium lauryl sulfate and magnesium stearate), as well as coloring agents, detackifying agents, gelling agents, and the like, as judged by the formulator, coating agents, sweeteners and flavoring agents, preservatives and antioxidants may also be present in the composition.
The compounds or compositions of the present invention may be administered by any suitable means, and the above-described compounds and pharmaceutically acceptable compositions may be administered to humans or other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments or drops), or by nasal spray, etc., depending on the severity of the disease.
Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. In addition to inert diluents, oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
Injectable preparations may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents, for example sterile injectable aqueous or oily suspensions. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, ringer's solution and isotonic sodium chloride solution. In addition, sterile fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono-or diglycerides. In addition, fatty acids, such as octadecenoic acid, are used in the preparation of injections. For example, injectable formulations can be sterilized by filtration through a bacterial-retaining filter or by the addition of a sterilizing agent in the form of a sterile solid composition which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.
To prolong the effect of the compounds or compositions of the present invention, it is often desirable to slow the absorption of the compounds from subcutaneous or intramuscular injection. This can be achieved by using a liquid suspension of crystalline or amorphous material which is poorly water soluble, since the rate of absorption of the compound depends on its rate of dissolution, which in turn depends on crystal size and crystal form. Alternatively, delayed absorption of the parenterally administered compound is achieved by dissolving or suspending the compound in an oil vehicle. Alternatively, injectable depot forms are made by forming microcapsule matrices of the compounds in biodegradable polymers such as polylactide-polyglycolic acid, the rate of release of the compounds being controlled depending on the ratio of compound to polymer and the nature of the particular polymer employed. Examples of other biodegradable polymers include polyorthoesters and polyanhydrides. Depot injectable formulations can also be prepared by entrapping the compound in liposomes or microemulsions which are compatible with body tissues.
Compositions for rectal or vaginal administration are in particular suppositories which can be prepared by mixing the compounds of the invention with suitable non-irritating excipients or carriers, for example cocoa butter, polyethylene glycol or a suppository wax, which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
Oral solid dosage forms include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as carboxymethylcellulose, alginates, gels, polyvinylpyrrolidone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar- -agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as cetyl alcohol and glyceryl monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents.
Solid compositions of a similar type may also be employed as fillers in soft and hard gel capsules using excipients such as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. Solid dosage forms of tablets, dragees, capsules, pills and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical art. They may optionally contain opacifying agents and may also have the properties of a composition such that the active ingredient is released only, optionally in a delayed manner, or preferably, in a certain part of the intestinal tract. Examples of embedding compositions that can be used include polymers and waxes.
The active compound may also be in the form of a microencapsulated form with one or more of the above-mentioned excipients. In such solid dosage forms, the active compound may be mixed with at least one inert diluent, for example sucrose, lactose or starch. In general, such dosage forms may also contain additional substances in addition to the inert diluents, such as tableting lubricants and other tableting aids, for example magnesium stearate and microcrystalline cellulose. They may optionally contain opacifying agents and may also have the properties of a composition such that the active ingredient is released only, optionally in a delayed manner, or preferably, in a certain part of the intestinal tract. Examples of embedding compositions that can be used include polymers and waxes.
Formulations for topical or transdermal administration of the compounds of the present invention include ointments, salves, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. Under sterile conditions, the active compound is combined with a pharmaceutically acceptable carrier and any required preservatives or buffers that may be required. Ophthalmic formulations, ear drops and eye drops are also contemplated within the scope of the present invention. In addition, the present invention contemplates the use of dermal patches with the added advantage of providing controlled delivery of compounds to the body. Such dosage forms may be made by dissolving or dispersing the compound in the appropriate medium. Absorption enhancers may also be used to increase the flux of the compound through the skin. The rate can be controlled by providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.
The compositions of the present invention may also be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted kit. The term "parenteral" as used herein includes, but is not limited to, subcutaneous, intravenous, intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques. In particular, the compositions are administered orally, intraperitoneally, or intravenously.
The sterile injectable form of the composition of the invention may be an aqueous or oily suspension. These suspensions may be prepared using suitable dispersing or wetting agents and suspending agents following techniques known in the art. In addition, sterile fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono-or diglycerides. In addition, as natural pharmaceutically acceptable oils, such as olive oil or castor oil, especially in polyoxyethylated form, fatty acids, such as octadecenoic acid and its glyceride derivatives are used for the preparation of injections. These oil solutions or suspensions may also contain a long chain alcohol diluent or dispersant, such as carboxymethyl cellulose or similar dispersing agents commonly used in formulating pharmaceutically acceptable dosage forms, including emulsions and suspensions. Other commonly used surfactants such as Tweens, spans, and other emulsifiers or bioavailability enhancers commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for formulation purposes.
The pharmaceutical compositions of the present invention may be administered orally in any orally acceptable dosage form, including, but not limited to, capsules, tablets, aqueous suspensions or solutions. In the case of tablets for oral administration, carriers which are commonly used include, but are not limited to, lactose and starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in capsule form, useful diluents include lactose and dried corn starch. When aqueous suspensions are required for oral administration, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added.
Alternatively, the pharmaceutical compositions of the present invention may be administered in the form of suppositories for rectal use. These pharmaceutical compositions can be prepared by mixing the agent and the non-irritating excipient. Such materials include, but are not limited to, cocoa butter, beeswax and polyethylene glycols.
The pharmaceutical compositions of the present invention may also be administered topically, particularly when the target of treatment includes topical application to an easily accessible area or organ, including the eye, skin, or lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.
Local instillation to the lower intestinal tract may be achieved with rectal suppository formulations (see above) or suitable enema formulations. Topical skin patches may also be used.
For topical application, the pharmaceutical compositions may be formulated as a suitable ointment containing the active ingredient suspended or dissolved in one or more carriers. Suitable carriers for topical application of the compounds of the present invention include, but are not limited to, mineral oil, petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water. Alternatively, the pharmaceutical compositions may be formulated as a suitable lotion or cream containing the active ingredient suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.
For ophthalmic use, the pharmaceutical compositions may be formulated as micronized suspensions in isotonic pH adjusted sterile saline, or solutions in isotonic pH adjusted sterile saline in particular, with or without preservatives such as benzalkonium chloride. Alternatively, for ophthalmic use, the pharmaceutical composition may be formulated as an ointment, such as petrolatum.
The pharmaceutical compositions may also be administered by nasal aerosol spray or inhalation. Such compositions are prepared according to techniques well known in the pharmaceutical art and are prepared as solutions in saline using benzyl alcohol and other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons and/or other conventional solubilizing or dispersing agents.
The compounds for use in the methods of the invention may be formulated in unit dosage form. The term "unit dosage form" refers to physically discrete units suitable as unitary dosages for subjects, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, optionally in association with a suitable pharmaceutical carrier. The unit dosage form can be administered in a single daily dose or in multiple daily doses (e.g., about 1-4 or more times per day). When multiple daily doses are used, the unit dosage form for each dose may be the same or different.
Use of the Compounds and compositions of the invention
The invention relates to the use of a compound according to the invention or a pharmaceutical composition according to the invention for the preparation of a medicament for inhibiting VAP-1 or for the prevention, treatment or alleviation of a disease associated with a VAP-1 protein or modulated by VAP-1.
The present invention relates to a method of inhibiting VAP-1 activity, or a method of preventing, treating or ameliorating a disease associated with VAP-1 protein or modulated by VAP-1, using a compound or a pharmaceutical composition of the present invention; the method is administering to an individual in need thereof a therapeutically effective amount of the compound or the pharmaceutical composition. Also, the above-described compounds or pharmaceutical compositions thereof provided by the present invention may be co-administered with other therapies or therapeutic agents. The administration may be simultaneous, sequential or at intervals.
The invention relates to a method for using the compound or the pharmaceutical composition for inhibiting VAP-1 activity or preventing, treating or alleviating diseases related to VAP-1 protein or regulated by VAP-1.
The diseases related to VAP-1 protein or modulated by VAP-1 in the invention are inflammatory diseases and/or inflammation-related diseases, diabetes and/or diabetes-related diseases, ischemic diseases, vascular diseases, fibrosis or tissue transplant rejection.
In addition to being beneficial for human therapy, the compounds of the present invention may also find use in veterinary therapy for pets, animals of the introduced species and animals in farms, including mammals, rodents, and the like. Examples of other animals include horses, dogs, and cats. Herein, the compound of the present invention includes pharmaceutically acceptable derivatives thereof.
An "effective amount", "therapeutically effective amount" or "effective dose" of a compound or pharmaceutically acceptable pharmaceutical composition of the invention refers to an amount effective to treat or reduce the severity of one or more of the conditions mentioned herein. The compounds or pharmaceutically acceptable pharmaceutical compositions of the present invention are effective over a relatively wide dosage range. For example, the daily dosage may be in the range of about 0.1mg to about 1000mg per person, divided into one or more administrations. The methods, compounds and pharmaceutical compositions according to the present invention can be of any amount administered and any route of administration effective to treat or reduce the severity of the disease. The exact amount necessary will vary depending on the patient, depending on the race, age, general condition of the patient, severity of infection, particular factors, mode of administration, and the like. The compounds or pharmaceutical compositions of the present invention may be administered in combination with one or more other therapeutic agents, as discussed herein.
General Synthesis and detection methods
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 this specification, a structure is dominant if there is any difference between the chemical name and the chemical structure.
In general, the compounds of the present invention may be prepared by the methods described herein, wherein the substituents are as defined in formula (I), unless otherwise indicated. 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 drugs other than 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 structure of the compound is determined by nuclear magnetic resonance 1 H-NMR、 13 C-NMR or/and 19 F-NMR). 1 H-NMR、 13 C-NMR、 19 F-NMR chemical shifts (δ) are given in parts per million (ppm). 1 H-NMR、 13 C-NMR、 19 F-NMR was measured using a Bruker Ultrashield-400 NMR spectrometer and a Bruker Avance III HD 600 NMR spectrometer in deuterated chloroform (CDCl) 3 ) Deuterated methanol (CD) 3 OD or MeOH-d 4 ) Or deuterated dimethyl sulfoxide (DMSO-d) 6 ). TMS (0 ppm) or chloroform (7.25 ppm) was used as reference standard. When multiple peaks occur, the following abbreviations will be used: s (singlets, singlet), d (doublets ), t (triplets, triplets), m (multiplets ), br (broadcasters, broad), dd (doublets of doublets), dt (doublets of triplets, doublets), td (triplets of doublets, triplet), brs (broad singlets). Coupling constant J, in Hertz (Hz).
Preparative purification or preparative resolution generally uses a Novasep pump 250 high performance liquid chromatograph.
The LC-MS was determined using an Agilen-6120 Quadrupole LC/MS mass spectrometer.
The column chromatography generally uses 300-400 mesh silica gel in Qingdao ocean chemical industry as a carrier.
The starting materials of the present invention are known and commercially available, are available from Shanghai Acccla Company, an Naiji Company, energy Company, bailingwei Company (J & K), tianjin Afaha Angsa Company (Alfa Company), etc., or may be synthesized using or according to methods known in the art.
The nitrogen atmosphere refers to a reaction flask connected with a nitrogen balloon or steel kettle with the volume of about 1L.
The hydrogen atmosphere refers to a reaction bottle connected with a hydrogen balloon with the volume of about 1L or a stainless steel high-pressure reaction kettle with the volume of about 1L.
In the examples, unless otherwise specified, the solution refers to an aqueous solution.
In the examples, the reaction temperature is room temperature unless otherwise specified; in the examples, the room temperature is 20 ℃ to 40 ℃ unless otherwise specified.
The progress of the reaction in the examples was monitored by Thin Layer Chromatography (TLC) using a system of developing solvents: dichloromethane and methanol system, dichloromethane and ethyl acetate system, petroleum ether and ethyl acetate system, and the volume ratio of the solvent is adjusted according to the polarity of the compound.
The system of eluent for column chromatography comprises: a: petroleum ether and ethyl acetate system, B: dichloromethane and ethyl acetate system, C: dichloromethane and methanol system. The volume ratio of the solvent is adjusted according to the polarity of the compound, and a small amount of ammonia water, acetic acid and the like can be added for adjustment.
HPLC refers to high performance liquid chromatography;
HPLC was carried out using Agilent 1260 high pressure liquid chromatograph (Eclipse Plus C18.6X 150mm 3.5um column);
HPLC test conditions: column temperature: 30 ℃ PDA:210nm,254nm
Mobile phase: phase A: 0.1% potassium phosphate phase B: flow rate of acetonitrile: 1.0mL/min
Mobile phase gradients are shown in table a:
TABLE A
Time (min) Gradient of mobile phase A Gradient of mobile phase B
0 90％ 10％
5-8 70％ 30％
12-18 80％ 20％
18.1-22 90％ 10％
The analytical LC/MS/MS system in the biological test experiment includes Agilent 1200 series vacuum degassing furnace, binary injection pump, orifice plate automatic sampler, column thermostat, agilent G6430 three-stage quadrupole mass spectrometer with electric spray ionization source (ESI). The quantitative analysis was performed in MRM mode, with the parameters of the MRM transition as shown in table B:
TABLE B
Full scan 50→1400
Fragmentation voltage 230V
Capillary voltage 55V
Dryer temperature 350℃
Atomizer 0.28MPa
Flow rate of dryer 10L/min
Analysis 5. Mu.L of sample was injected using AgilentXDB-C18, 2.1X 30mm, 3.5. Mu.M column. Analysis conditions were as follows: the mobile phase was 0.1% aqueous formic acid (A) and 0.1% methanolic formic acid (B). The flow rate was 0.4mL/min. Mobile phase gradients are shown in table C:
watch C
Figure GPA0000302900140000291
Figure GPA0000302900140000301
Also used for the analysis was an Agilent 6330 series LC/MS spectrometer equipped with a G1312A binary syringe pump, a G1367A auto sampler and a G1314C UV detector; the LC/MS/MS spectrometer uses an ESI radiation source. The appropriate cation model treatment and MRM conversion for each analyte was performed using standard solutions for optimal analysis. During the analysis a Capcell MP-C18 column was used, with the specifications: 100X 4.6mm I.D., 5. Mu.M (Phenomenex, torrance, california, USA). The mobile phase was 5mM ammonium acetate, 0.1% aqueous methanol (a): 5mM ammonium acetate, 0.1% methanolic acetonitrile solution (B) (70/30, v/v); the flow rate is 0.6mL/min; the column temperature was kept at room temperature; 20 μ L of sample was injected.
The following acronyms are used throughout the invention:
DMSO-d 6 : deuterated dimethyl sulfoxide; TBS: tertiary amineButyl dimethyl silicon base;
CDCl 3 : deuterated chloroform; % wt,% mass: weight percentage;
CD 3 OD: deuterated methanol; mL, mL: ml;
μ L, μ L: microliter; mol/L: moles per liter;
mol: molar ratio; mmol: millimole;
g: g; h: hours;
H 2 : hydrogen gas; min: the method comprises the following steps of (1) taking minutes;
N 2 : nitrogen gas; MPa: megapascals;
atm: standard atmospheric pressure.
General synthetic methods
A typical synthetic procedure for the preparation of the disclosed compounds is shown in scheme 1 below. Unless otherwise specified, a has the definition as described herein, X is halogen; PG is a hydroxyl protecting group.
Synthesis scheme 1:
Figure GPA0000302900140000302
the compounds having the structure shown in general formula (I-A) can be prepared by general synthetic methods described in scheme 1, and specific procedures can be referred to examples. Carrying out nucleophilic reaction on the compound (I-a) and the compound (I-b) under alkaline conditions to obtain a compound (I-c); carrying out nucleophilic reaction on the compound (I-c) and the compound (I-d) under the alkaline condition and the action of a palladium catalyst to obtain a compound (I-e); removing a hydroxyl protecting group from the compound (I-e) to obtain a compound (I-f); or the compound (I-c) and the compound (I-g) are subjected to nucleophilic reaction under the alkaline condition and the action of a palladium catalyst to directly obtain a compound (I-f); the compound (I-f) is firstly reacted with 1,1' -dicarbonyl imidazole and then reacted with a proper guanidine salt (such as guanidine carbonate) to obtain the target compound shown in the general formula (I-A).
Detailed Description
The following examples are intended to illustrate the invention but are not intended to limit the scope of the invention.
Preparation examples
In the following preparation examples, the inventors described in detail the preparation of the compounds of the present invention by taking some of the compounds of the present invention as examples.
Example 1 [ 3-fluoro-2- (2-morpholinylpyrimidin-5-yl) -4-pyridyl ] methyl N-carbamimidoyl carbamate (Compound 1)
Figure GPA0000302900140000311
Step 1) 4- [5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyrimidin-2-yl]Morpholine
Figure GPA0000302900140000312
2-fluoro-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyrimidine (2.00g, 8.93mmol) was dissolved in tetrahydrofuran (50 mL), morpholine (0.80mL, 9.20mmol) and N, N-diisopropylethylamine (2.00g, 12.00mmol) were added, and the reaction was refluxed at 80 ℃ for 24 hours. The reaction was cooled to room temperature, a solid precipitated, filtered, and the filter cake was collected to give the title compound (2.00 g, yield 77%) as a white solid.
MS(ESI，pos.ion)m/z：292.2[M+H] + 。
Step 2) tert-butyl- [ [ 3-fluoro-2- (2-morpholinylpyrimidin-5-yl) -4-pyridinyl]Methoxy radical]-dimethyl-silicon Alkane (I) and its preparation method
Figure GPA0000302900140000313
4- [5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyrimidin-2-yl ] morpholine (1.85g, 6.35mmol) was dissolved in tetrahydrofuran (40 mL), t-butyl- [ (2-chloro-3-fluoro-4-pyridinyl) methoxy ] -dimethyl-silane (1.50g, 5.44mmol), tetrakis (triphenylphosphine) palladium (0.30g, 0.26mmol) and saturated sodium carbonate solution (30 mL) were added and reacted at 90 ℃ for 25 hours. The reaction solution was cooled, the organic phase was separated, dried over anhydrous sodium sulfate, filtered and concentrated, and the obtained residue was purified by silica gel column chromatography [ petroleum ether/ethyl acetate (v/v) =2/1] to give the title compound (1.80 g, yield 82%) as a colorless oil.
MS(ESI，pos.ion)m/z：405.3[M+H] + 。
Step 3) [ 3-fluoro-2- (2-morpholinylpyrimidin-5-yl) -4-pyridyl group]Methanol
Figure GPA0000302900140000321
Tert-butyl- [ [ 3-fluoro-2- (2-morpholinylpyrimidin-5-yl) -4-pyridinyl ] methoxy ] -dimethyl-silane (1.80g, 4.45mmol) was dissolved in tetrahydrofuran (30 mL), and a solution of tetrabutylammonium fluoride in tetrahydrofuran (8mL, 1mol/L) was slowly added dropwise at 0 ℃ to react for 0.5 hour. The reaction was quenched by addition of water (30 mL), extracted with ethyl acetate (30 mL), washed with saturated sodium chloride solution (30 mL × 2) with a camera, dried over anhydrous sodium sulfate, concentrated by suction filtration, and the resulting residue was purified by silica gel column chromatography [ petroleum ether/ethyl acetate (v/v) =2/1] to give the title compound (0.60 g, yield 46%) as a white solid.
MS(ESI，pos.ion)m/z：291.1[M+H] + 。
Step 4) [ 3-fluoro-2- (2-morpholinylpyrimidin-5-yl) -4-pyridinyl]Methyl N-amidinocarbamate
Figure GPA0000302900140000322
[ 3-fluoro-2- (2-morpholinylpyrimidin-5-yl) -4-pyridyl ] methanol (0.45g, 1.56mmol) was dissolved in NN-dimethylformamide (20 mL), 1,1' -dicarbonylimidazole (0.60g, 3.60mmol) was added, the reaction was carried out at room temperature for 0.5 hour, guanidine carbonate (0.70g, 3.80mmol) was added, and the reaction was continued for 3 hours. The reaction was quenched by addition of water (20 mL), extracted with ethyl acetate (30 mL), washed with saturated sodium chloride solution (30 mL × 2) with a camera, dried over anhydrous sodium sulfate, concentrated by suction filtration, and the resulting residue was purified by silica gel column chromatography [ dichloromethane/methanol (v/v) =20/1] to give the title compound (0.23 g, yield 40%, HPLC purity: 99.13%) as a white solid.
MS(ESI，pos.ion)m/z：376.1[M+H] + ；
1 H NMR(400MHz，DMSO-d 6 )δ(ppm)12.02(s，1H)，8.91(s，2H)，8.47(d，J＝4.7Hz，1H)，7.64(s，1H)，7.33(t，J＝4.9Hz，1H)，7.02(s，2H)，5.13(s，2H)，3.89-3.74(m，4H)，3.75-3.60(m，4H)。
Example 2[3-fluoro-2- [2- [3- (trifluoromethyl) -6,8-dihydro-5H- [1,2,4] triazole [4,3-a ] pyrazin-7-yl ] pyrimidin-5-yl ] -4-pyridyl ] methyl N-carbamimidoyl ester (Compound 2)
Figure GPA0000302900140000323
Step 1) 7- [5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyrimidin-2-yl]-3- (III) Fluoromethyl) -6,8-dihydro-5H- [1,2,4]Triazole [4,3-a]Pyrazine esters
Figure GPA0000302900140000331
3- (trifluoromethyl) -5,6,7,8-tetrahydro- [1,2,4] triazolo [4,3-a ] pyrazine hydrochloride (1.05g, 4.6 mmol) was dissolved in ethanol (10 mL), triethylamine (1.5mL, 7.7 mmol) was added, and after 5 minutes of reaction, 2-chloro-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyrimidine (1.0g, 4.2 mmol) was added and heated to 80 ℃ for 4 hours. The reaction solution was cooled to room temperature, a solid precipitated, filtered, and the filter cake was washed with a small amount of anhydrous ethanol, collected and dried to obtain the title compound (1.0 g, yield 61%) as a white solid.
MS(ESI，pos.ion)m/z：397.1[M+H] + 。
Step 2) tert-butyl- [ [ 3-fluoro-2- [2- [3- (trifluoromethyl) -6,8-dihydro-5H- [1,2,4]The triazole-o (4) compound is a compound of the formula, 3-a]pyrazin-7-yl]Pyrimidin-5-yl]-4-pyridinyl]Methoxy radical]-dimethyl-silane
Figure GPA0000302900140000332
7- [5- (4,4,5,5-tetramethyl-1,3,2-dioxolan-2-yl) pyrimidin-2-yl ] -3- (trifluoromethyl) -6,8-dihydro-5H- [1,2,4] triazolo [4,3-a ] pyrazine (1.0g, 2.5mmol) and tert-butyl- [ (2-chloro-3-fluoro-4-pyridyl) methoxy ] -dimethyl-silane (0.65g, 2.4mmol) were dissolved in ethylene glycol dimethyl ether (20 mL), a sodium carbonate solution (7mL, 7mmol, 1mol/L) was added, nitrogen protection was replaced, and [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride (0.18g, 0.24mmol) was added and reacted at 90 ℃ for 12 hours. The reaction solution was cooled and filtered, the aqueous phase was separated from the filtrate, the organic phase was concentrated, and the obtained residue was purified by silica gel column chromatography [ petroleum ether/ethyl acetate (v/v) =1/1] to obtain the title compound (0.95 g, yield 79%) as an off-white solid.
MS(ESI，pos.ion)m/z：510.3[M+H] + 。
Step 3) [ 3-fluoro-2- [2- [3- (trifluoromethyl) -6,8-dihydro-5H- [1,2,4]Triazole [4,3-a]Pyridine (II) Oxazin-7-yl]Pyrimidin-5-yl]-4-pyridinyl]Methanol
Figure GPA0000302900140000333
Tert-butyl- [ [ 3-fluoro-2- [2- [3- (trifluoromethyl) -6,8-dihydro-5H- [1,2,4] triazolo [4,3-a ] pyrazin-7-yl ] pyrimidin-5-yl ] -4-pyridyl ] methoxy ] -dimethyl-silane (1.0g, 2.0mmol) was dissolved in tetrahydrofuran (4 mL), and a solution of tetrabutylammonium fluoride in tetrahydrofuran (4 mL,4mmol,1 mol/L) was added dropwise at 0 ℃ and reacted at room temperature for 1.5 hours. The reaction was quenched with water (10 mL), extracted with ethyl acetate (20 mL), the organic phase was washed with saturated aqueous sodium chloride (8 mL × 2), dried over anhydrous sodium sulfate, concentrated by suction filtration, and the resulting residue was recrystallized from ethanol/ethyl acetate/petroleum ether (v/v/v =1/1/3, 15 mL) to give the title compound (0.56 g, yield 72%) as a white solid.
Step 4) [ 3-fluoro-2- [2- [3- (trifluoromethyl) -6,8-dihydro-5H- [1,2,4]Triazole [4,3-a]Pyrazine- 7-yl]Pyrimidin-5-yl]-4-pyridinyl]Methyl N-amidinocarbamate
Figure GPA0000302900140000341
[ 3-fluoro-2- [2- [3- (trifluoromethyl) -6,8-dihydro-5H- [1,2,4] triazolo [4,3-a ] pyrazin-7-yl ] pyrimidin-5-yl ] -4-pyridyl ] methanol (0.10g, 0.25mmol) was dissolved in N, N-dimethylformamide (6 mL), N' -carbonyldiimidazole (0.111g, 0.66mmol) was added, and the reaction was continued for 8 hours at room temperature under nitrogen protection, after which guanidine carbonate (0.12g, 0.99mmol) was added. The reaction liquid was purified by direct column chromatography [ dichloromethane/methanol (v/v) =10/1] to give the title compound (86 mg, yield 71%, HPLC purity: 98.73%) as a white solid.
MS(ESI，pos.ion)m/z：418.3[M+H] + ；
1 H NMR(400MHz，DMSO-d 6 )δ(ppm)9.00(s，2H)，8.51(s，1H)，7.37(s，1H)，5.26(s，2H)，5.14(s，2H)，4.34(d，J＝31.2Hz，4H)。
Example 3[3-fluoro-2- [2- (2-oxo-3,8-diazaspiro [4,5] decan-8-yl) pyrimidin-5-yl ] -4-pyridyl ] methyl N-carbamimidoyl ester (Compound 3)
Figure GPA0000302900140000342
Step 1) 8- [5- (4,4,5,5-tetramethyl-1,3,2-dioxoborolan-2-yl) pyrimidin-2-yl]-3，8-two Azaspiro [4,5]Decan-2-ones
Figure GPA0000302900140000343
Diisopropylethylamine (2.1mL, 13mmol), 2,8-diazaspiro [4,5] decan-3-one (0.77g, 5.0 mmol) was added to a solution of 2-chloro-5- (4,4,5,5-tetramethyl-1,3,2-dioxazapentaborane-2-yl) pyrimidine (1.0 g,4.2 mmol) in absolute ethanol (30 mL) and reacted at 80 ℃ for 15 hours. The reaction was cooled to room temperature, concentrated, ethanol (5 mL) was added, stirred for 10 minutes, filtered, the filter cake was washed with ethanol (1 mL), the filter cake was collected and dried to give the title compound (0.86 g, 58% yield) as an off-white solid.
1 H NMR(600MHz，DMSO-d 6 )δ(ppm)8.47(s，2H)，7.56(s，1H)，3.94(dt，J＝10.9，5.0Hz，2H)，3.72-3.63(m，2H)，3.09(s，2H)，2.13(s，2H)，1.62-1.49(m，4H)，1.27(s，12H)。
Step 2) 8- [5- [4- [ tert-butyl (dimethyl) silyl]Oxymethyl radical]-3-fluoro-2-pyridinyl]Pyrimidin-2-yl]-3， 8-diazaspiro [4,5]Decan-2-ones
Figure GPA0000302900140000351
[1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (0.11g, 0.15mmol), aqueous sodium carbonate solution (4.4 mL,0.76mmol, 1mol/L), 8- [5- (4,4,5,5-tetramethyl-1,3,2-dioxoborolan-2-yl) pyrimidin-2-yl ] -3,8-diazaspiro [4,5] decan-3-one (0.58g, 1.59mmol) were added to a solution of [ (2-chloro-3-fluoro-4-pyridyl) methoxy ] -tert-butyldimethylsilane (0.40g, 1.45mmol) in ethylene glycol dimethyl ether (13 mL) and reacted at 90 ℃ for 23 hours. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography [ dichloromethane/methanol (v/v) =9/1] to give the title compound (0.43 g, yield 63%) as a pale yellow solid.
MS(ESI，pos.ion)m/z：472.3[M+1] + 。
Step 3) 8- [5- [ 3-fluoro-4- (hydroxymethyl) -2-pyridinyl]Pyrimidin-2-yl]-3,8-diazaspiro [4,5]Hair removing device Alk-2-ones
Figure GPA0000302900140000352
Tetrabutylammonium fluoride (1.1mL, 1mol/L in tetrahydrofuran) was added dropwise to a solution of 8- [5- [4- [ tert-butyl (dimethyl) silicon ] oxymethyl ] -3-fluoro-2-pyridyl ] pyrimidin-2-yl ] -3,8-diazaspiro [4,5] decan-2-one (0.43g, 0.91mmol) in tetrahydrofuran (5 mL) at 0 ℃ and reacted at room temperature for 3 hours. The reaction solution was concentrated, and the resulting residue was purified by silica gel column chromatography [ dichloromethane/methanol (v/v) =9/1] to obtain the title compound (0.18 g, yield 55%) as a pale yellow solid.
1 H NMR(400MHz，DMSO-d 6 )δ(ppm)8.87(s，2H)，8.47(d，J＝4.6Hz，1H)，7.57(s，1H)，7.46(t，J＝4.9Hz，1H)，5.60(t，J＝5.6Hz，1H)，4.67(d，J＝5.4Hz，2H)，4.07-3.92(m，2H)，3.81-3.65(m，2H)，3.11(s，2H)，2.15(s，2H)，1.60(t，J＝5.1Hz，4H)。
Step 4) [ 3-fluoro-2- (2-oxo-3,8-diazaspiro [4,5]Decan-8-yl) pyrimidin-5-yl]-4-pyridinyl] Methyl N-amidinocarbamate
Figure GPA0000302900140000353
N, N' -carbonyldiimidazole (0.21g, 1.31mmol) was added to a solution of 8- [5- [ 3-fluoro-4- (hydroxymethyl) -2-pyridyl ] pyrimidin-2-yl ] -3,8-diazaspiro [4,5] decan-2-one (0.18g, 0.50mmol) in N, N-dimethylformamide (10 mL) and reacted at room temperature for 2 hours. Guanidine carbonate (0.25g, 2.01mmol) was added and the reaction was continued for 8 hours. The reaction solution was concentrated, and the obtained residue was purified by silica gel column chromatography [ dichloromethane/methanol (v/v) =10/1] to obtain the title compound (0.11 g, yield 49%, HPLC purity: 98.35%) as a white solid.
MS(ESI，pos.ion)m/z：443.1[M+H] + ；
1 H NMR(400MHz，DMSO-d 6 )δ(ppm)8.88(s，2H)，8.46(d，J＝4.8Hz，1H)，7.57(s，1H)，7.32(t，J＝4.8Hz，1H)，5.13(s，2H)，4.03-3.94(m，2H)，3.78-3.68(m，2H)，3.29(s，1H)，3.12(s，1H)，2.15(s，2H)，1.60(t，J＝5.5Hz，4H)。
Example 4[3-fluoro-2- [2- (2-oxo-3,8-diazaspiro [4,5] decan-8-yl) pyrimidin-5-yl ] -4-pyridinyl ] methyl N-amidinocarbamate (Compound 4)
Figure GPA0000302900140000361
Step 1) 8- [5- [4- [ [ tert-butyl (dimethyl) silyl ] silicon]Oxymethyl radical]-3-fluoro-2-pyridinyl]Pyrimidin-2-yl]- 3-methyl-3,8-diazaspiro [4,5]Decan-2-ones
Figure GPA0000302900140000362
Sodium hydride (30mg, 0.75mmol) was added to a solution of 8- [5- [4- [ [ tert-butyl (dimethyl) silyl ] oxymethyl ] -3-fluoro-2-pyridinyl ] pyrimidin-2-yl ] -3,8-diazaspiro [4,5] decan-2-one (0.23g, 0.49mmol) in N, N-dimethylformamide (6 mL) at 0 deg.C, and the reaction was allowed to proceed for 30 minutes at room temperature, iodomethane (89mg, 0.58mmol) was added and the reaction was continued for 4 hours. The reaction solution was quenched by pouring into ice water (10 mL), a saturated ammonium chloride solution (10 mL) was added, extraction was performed with ethyl acetate (15 mL × 2), the combined organic phases were washed with a saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, concentrated by suction filtration, and the resulting residue was purified by silica gel column chromatography [ dichloromethane/methanol (v/v) =20/1] to obtain the title compound (0.19 g, yield 80%) as a yellow solid.
MS(ESI，pos.ion)m/z：486.15[M+1] + 。
Step 2) 8-, [2 ]5- [ 3-fluoro-4- (hydroxymethyl) -2-pyridinyl]Pyrimidin-2-yl]-3-methyl-3,8-diazaspiro [4，5]Decan-2-ones
Figure GPA0000302900140000363
Tetrabutylammonium fluoride (0.5 mL,1mol/L tetrahydrofuran solution) was added dropwise to a solution of 8- [5- [4- [ [ tert-butyl (dimethyl) silyl ] oxymethyl ] -3-fluoro-2-pyridyl ] pyrimidin-2-yl ] -3-methyl-3,8-diazaspiro [4,5] decan-2-one (0.20g, 0.41mmol) in tetrahydrofuran (5 mL) at 0 ℃ and reacted at room temperature for 1 hour. The reaction was quenched by addition of water (15 mL), extracted with ethyl acetate (20 mL × 2), the combined organic phases were washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, concentrated by suction filtration, and the resulting residue was purified by silica gel column chromatography [ dichloromethane/methanol (v/v) =25/1] to give the title compound (0.10 g, yield 65%) as a white solid.
Step 3) [ 3-fluoro-2- [2- (3-methyl-2-oxo-3,8-diazaspiro [4,5]Decan-8-yl) pyrimidine-5- Base of]-4-pyridinyl]Methyl N-amidinocarbamate
Figure GPA0000302900140000371
N, N' -carbonyldiimidazole (0.10g, 0.59mmol) was added to a solution of 8- [5- [ 3-fluoro-4- (hydroxymethyl) -2-pyridyl ] pyrimidin-2-yl ] -3-methyl-3,8-diazaspiro [4,5] decan-2-one (85mg, 0.23mmol) in N, N-dimethylformamide (6 mL) and reacted at room temperature for 3 hours, followed by addition of guanidine carbonate (0.25g, 2.01mmol) and continued reaction for 12 hours. The reaction solution was concentrated, and the obtained residue was purified by silica gel column chromatography [ dichloromethane/methanol (v/v) =10/1] to obtain the title compound (48 mg, yield 46%, HPLC purity: 98.98%) as a white solid.
MS(ESI，pos.ion)m/z：457.1[M+H] + ；
1 H NMR(400MHz，DMSO-d 6 )δ(ppm)8.88(s，2H)，8.47(d，J＝4.8Hz，1H)，7.32(t，J＝4.8Hz，1H)，5.13(s，2H)，4.03-3.92(m，2H)，3.82-3.71(m，2H)，3.23(s，2H)，2.73(s，3H)，2.25(s，2H)，1.60(t，J＝5.2Hz，4H)。
Example 5[3-fluoro-2- [2- (1-piperidinyl) pyrimidin-5-yl ] -4-pyridinyl ] methyl N-carbamimidoyl (compound 5)
Figure GPA0000302900140000372
Step 1) 2- (1-piperidinyl) -5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyrimidine
Figure GPA0000302900140000373
2-chloro-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyrimidine (3.00g, 12.5 mmol) was dissolved in absolute ethanol (30 mL), piperidine (1.50mL, 15.0mmol) and N, N-diisopropylethylamine (4.20mL, 25.0mmol) were added, and the reaction was refluxed at 80 ℃ for 14 hours. The reaction was cooled to room temperature, concentrated, ethanol (6 mL) was added, stirred for 10 minutes, filtered, the filter cake was washed with ethanol (2 mL), the filter cake was collected and dried to give the title compound (2.00 g, 77% yield) as an off-white solid.
MS(ESI，pos.ion)m/z：290.2[M+H] + 。
1 H NMR(400MHz，DMSO-d 6 )δ(ppm)8.45(s，2H)，3.82-3.74(m，4H)，1.64(d，J＝4.8Hz，2H)，1.50(s，4H)，1.27(s，12H)。
Step 2) tert-butyl- [ [ 3-fluoro-2- [2- (1-piperidinyl) pyrimidin-5-yl]-4-pyridinyl]Methoxy radical]-dimethyl Radical-silanes
Figure GPA0000302900140000374
2- (1-piperidinyl) -5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyrimidine (0.50g, 1.81mmol) was dissolved in ethylene glycol dimethyl ether (15 mL), and tert-butyl- [ (2-chloro-3-fluoro-4-pyridinyl) methoxy ] -dimethyl-silane (580ng, 1.99mmol), [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (0.14g, 0.18mmol) and aqueous sodium carbonate solution (5.4mL, 1mol/L) were added and reacted at 90 ℃ for 23 hours. The reaction solution was cooled to room temperature, concentrated, and the resulting residue was purified by silica gel column chromatography [ petroleum ether/ethyl acetate (v/v) =4/1] to give the title compound (0.47 g, yield 64%) as a colorless oil.
MS(ESI，pos.ion)m/z：403.3[M+H] + 。
Step 3) [ 3-fluoro-2- [2- (1-piperidinyl) pyrimidin-5-yl group]-4-pyridinyl]Methanol
Figure GPA0000302900140000381
Tert-butyl- [ [ 3-fluoro-2- [2- (1-piperidinyl) pyrimidin-5-yl ] -4-pyridinyl ] methoxy ] -dimethyl-silane (0.47g, 1.16mmol) was dissolved in tetrahydrofuran (5 mL), and a solution of tetrabutylammonium fluoride in tetrahydrofuran (1.4 mL, 1mol/L) was added dropwise at 0 ℃ and reacted at room temperature for 3.5 hours. The reaction solution was concentrated, and the resulting residue was purified by silica gel column chromatography [ dichloromethane/methanol (v/v) =19/1] to obtain the title compound (0.33 g, yield 99%) as a white solid.
1 H NMR(400MHz，DMSO-d 6 )δ(ppm)8.86(s，2H)，8.46(d，J＝4.6Hz，1H)，7.45(t，J＝5.0Hz，1H)，5.60(t，J＝5.7Hz，1H)，4.67(d，J＝5.7Hz，2H)，3.90-3.72(m，4H)，1.71-1.62(m，2H)，1.59-1.47(m，4H)。
Step 4) [ 3-fluoro-2- [2- (1-piperidinyl) pyrimidin-5-yl group]-4-pyridinyl]Methyl N-ureido carbamates
Figure GPA0000302900140000382
[ 3-fluoro-2- [2- (1-piperidinyl) pyrimidin-5-yl ] -4-pyridinyl ] methanol (0.40g, 1.39mmol) was dissolved in N, N-dimethylformamide (10 mL), 1,1' -dicarbonylimidazole (0.58g, 3.61mmol) was added, and the reaction was carried out at room temperature for 3 hours, followed by addition of guanidine carbonate (0.70g, 3.80mmol) and at room temperature for 12 hours. The reaction was quenched by the addition of water (20 mL), extracted with ethyl acetate (30 mL. Times.3), the combined organic layers were washed with saturated sodium chloride solution (60 mL), dried over anhydrous sodium sulfate, concentrated by suction filtration, and the resulting residue was purified by silica gel column chromatography [ ethyl acetate/methanol (v/v) =12/1] to give the title compound (0.23 g, yield 44%, HPLC purity: 99.20%) as a white solid.
MS(ESI，pos.ion)m/z：374.1[M+H] + ；
1 H NMR(400MHz，DMSO-d 6 )δ(ppm)8.87(s，2H)，8.46(d，J＝4.7Hz，1H)，7.31(t，J＝4.9Hz，1H)，5.14(s，2H)，3.91-3.76(m，4H)，1.66(d，J＝4.6Hz，2H)，1.56(d，J＝4.1Hz，4H)。
Activity test examples
1. VAP-1 inhibitory Activity assay
The test purpose is as follows: the following method was used to determine the inhibitory activity of the compounds of the present invention against VAP-1.
Test materials:
human recombinant VAP-1 (VAP-1, human) was purchased from Sigma, cat.no. srp6241;
Figure GPA0000302900140000383
red Monoamine oxide Assay Kit available from Invitrogen, cat.No. A12214;
384 well plates purchased from Corning, cat.no.6005174;
benzylamine hydrochloride (Benzylamine hydrochloride) from Sigma, cat. No. B5136-25G;
DMSO (Dimethyl Sulfoxide ) was purchased from Sigma, cat. No. D2650-100ML;
the test method comprises the following steps:
test compounds were dissolved in DMSO and diluted 4-fold for a total of 10 concentrations. In 384-well plates, 25. Mu.L of human recombinant VAP-1 (1.6. Mu.g/mL) was added to each well. Will be 100nLThe same concentration of test compound was added to each well containing human recombinant VAP-1 and incubated at room temperature for 30min. After 30min incubation, 25. Mu.L of 1mM benzylamine hydrochloride
Figure GPA0000302900140000394
Red Monoamine oxide Assay Kit (reaction mixture containing 200. Mu.M Amplex Red reagent,1U/mL HRP) was added to the corresponding well and incubated at room temperature in the dark for 60min. After 60min, fluorescence values (RFU) were read using an Envision of Perkinelmer at excitation 530-560nm and emission 590 nm. The IC was calculated using Graph Pad Prism 5 software to plot curves 50 The value is obtained. The results are shown in table 1:
table 1: the compounds provided in the examples of the present invention have inhibitory activity against human recombinant VAP-1
Example numbering VAP-1(IC 50 /nM)
Example 1 1.5
Example 3 1.18
The test results show that: the compound of the invention has obvious inhibition effect on human recombinant VAP-1.
2. DAO Selective inhibition assay
The test purpose is as follows: the following method was used to determine the selective inhibitory activity of the compounds of the present invention against DAO.
Test materials:
human Recombinant DAO (Recombinant Human ABP-1/DAO) purchased from R & D, cat.No.8298-AO;
Figure GPA0000302900140000391
red Hydrogen Peroxepixooxidases assay Kit available from Invitrogen, cat.No. A22188;
1,4-butanediamine dihydrochloride (1,4-Diaminobutane dihydride) available from Aladdin, cat. No. D106194-25G;
the test method comprises the following steps:
test compounds were dissolved in DMSO and diluted 5-fold for a total of 6 concentrations. In 384-well plates, 24. Mu.L of human recombinant DAO (1. Mu.g/ml) was added to each well. mu.L of test compound at different concentrations was added to each well containing human recombinant DAO and incubated at 37 ℃ for 30min. After 30min incubation, 25. Mu.L of 1, 4-butanediamine dihydrochloride in water was added
Figure GPA0000302900140000392
Red Hydrogen peroxidisepoxidase Assay Kit (containing 100. Mu.M)
Figure GPA0000302900140000393
Reaction mixture of Red and 0.2U/ml HRP) was added to the corresponding wells and incubated for 30min at 37 ℃ in the dark. After 30min, fluorescence values (RFU) were read at excitation 540nm and emission 580nm using a PHERAStar FSX microplate reader from BMG LABTECH. The IC was calculated using Graph Pad Prism 5 software to plot curves 50 The value is obtained.
The test result shows that the compound of the invention has high selectivity to VAP-1.
3. Pharmacokinetic determination of Compounds of the invention
The purpose of measurement is as follows: the following methods were used to determine the pharmacokinetics of the compounds of the present invention.
Test materials:
the used experimental reagents and test articles are as follows: propranolol (internal standard)), methanol, ammonium acetate, K2EDTA (potassium ethylenediaminetetraacetate), formic acid, acetonitrile, MTBE (methyl tert-butyl ether), kolliphorHS15 (polyethylene glycol 12 hydroxystearate), DMSO (dimethyl sulfoxide) are all commercially available;
SD rat: male, 180-220g,7-8 weeks old, purchased from Schleik laboratory animals, inc., hunan.
The test method comprises the following steps:
1. preparation of test article
The test solution was prepared as 5% DMSO +5% KolliphorHS15+90% saline, specifically adjusted for the dissolution of each compound, to allow complete dissolution of the compound.
2. Design of animal experiments
Figure GPA0000302900140000401
3. Animal administration dose meter
Group of Sex Number of animals Dosage to be administered Concentration of drug administration Volume of administration
I.v. intravenous injection. Male sex 3 1mg/kg 1mg/mL 1mL/kg
P.O is administered orally. Male sex 3 5mg/kg 1mg/mL 5mL/kg
4. Solution preparation
(1) Preparing a stock solution of a test sample: accurately weighing a proper amount of a test sample, dissolving the test sample in DMSO, diluting the test sample to 1mg/mL by using acetonitrile, and shaking up the test sample to obtain the test sample. Storing at-20 deg.C for use.
(2) Preparing an internal standard substance solution: a certain amount of 1mg/mL Propranol stock solution was precisely aspirated and diluted to 100ng/mL with water.
5. Sample analysis
Processing a sample by adopting a liquid-liquid extraction method, carrying out chromatographic separation, carrying out quantitative analysis on the sample by a triple quadrupole tandem mass spectrometer in a multiple reactive ion monitoring (MRM) mode, and calculating the concentration of the result by using instrument quantitative software.
6. Plasma sample pretreatment
Accurately sucking 30 μ L of plasma sample, adding 250 μ L of internal standard, and mixing by vortex. Extract once with 1mL MTBE, centrifuge at 13000rpm for 2min at 4 ℃, aspirate supernatant 800 μ L, evaporate in a 96-well nitrogen blower, redissolve the residue with 150 μ L methanol/water =50/50, vortex mix, sample injection 8 μ L.
7. Preparation of Standard samples
Accurately sucking a proper amount of compound stock solution, and adding acetonitrile to dilute to prepare a standard series solution. Accurately sucking 20 mu L of each standard series solution, adding 180 mu L of blank plasma, uniformly mixing by vortex, preparing plasma samples with the plasma concentrations of 3,5, 10, 30, 100, 300, 1000, 3000, 5000 and 10000ng/mL, performing double-sample analysis on each concentration according to the operation of plasma sample pretreatment, and establishing a standard curve.
8. Analytical method
The LC/MS method was used to determine the amount of test compound in rat plasma after administration of the different compounds.
9. Data processing
Pharmacokinetic parameters were calculated using WinNonlin 6.1 software, a non-compartmental model method.
The test results show that: the compounds of the invention have good pharmacokinetic properties.
In the description herein, references to the description of the term "one embodiment," "some embodiments," "an example," "a specific example," or "some examples," etc., mean that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the invention. In this specification, the schematic representations of the terms used above are not necessarily intended to refer to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples. Furthermore, various embodiments or examples and features of different embodiments or examples described in this specification can be combined and combined by one skilled in the art without contradiction.
Although embodiments of the present invention have been shown and described above, it is understood that the above embodiments are exemplary and should not be construed as limiting the present invention, and that variations, modifications, substitutions and alterations can be made to the above embodiments by those of ordinary skill in the art within the scope of the present invention.

Claims (8)

1. A compound which is a compound represented by formula (I) or a pharmaceutically acceptable salt of the compound represented by formula (I),
Figure FDA0003734049510000011
wherein,
U 1 and U 2 Each independently is N;
R 1 、R 2 and R 3 Each independently is H, D, F, cl, br, I, CN、NO 2 、OH、NH 2 Or C 1-6 An alkyl group;
R 4 and R 5 Each independently is H;
a is
Figure FDA0003734049510000012
Wherein said A is unsubstituted or substituted by 1,2,3 or 4R 6 Substituted;
each R 6 Independently H, D, F, cl, br, I, CN, NO 2 、OH、＝O、C 1-6 Alkyl or C 1-6 A haloalkyl group.
2. The compound of claim 1, wherein each R is 6 Independently H, D, F, cl, br, I, CN, NO 2 、OH、＝O、C 1-4 Alkyl or C 1-4 A haloalkyl group.
3. A compound according to claim 1 or 2, wherein each R is 6 Independently H, D, F, cl, br, I, CN, NO 2 OH, = O, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl or trifluoroethyl.
4. The compound of claim 1, wherein R is 1 、R 2 And R 3 Each independently is H, D, F, cl, br, I, CN, NO 2 、OH、NH 2 Methyl, ethyl, n-propyl or isopropyl.
5. The compound of claim 1, having the structure of one of:
Figure FDA0003734049510000013
Figure FDA0003734049510000014
or a pharmaceutically acceptable salt thereof.
6. A pharmaceutical composition comprising a compound of any one of claims 1-5, optionally further comprising a pharmaceutically acceptable carrier.
7. Use of a compound according to any one of claims 1 to 5 or a pharmaceutical composition according to claim 6 for the manufacture of a medicament for inhibiting VAP-1; or a medicament for preventing, treating or alleviating a disease associated with a VAP-1 protein or modulated by VAP-1, wherein the disease associated with a VAP-1 protein or modulated by VAP-1 is an inflammatory disease and/or an inflammation-related disease, diabetes and/or a diabetes-related disease, an ischemic disease, a vascular disease, fibrosis or tissue transplant rejection;
the inflammatory disease and/or inflammation-related disease is arthritis, systemic inflammatory syndrome, sepsis, synovitis, crohn's disease, ulcerative colitis, inflammatory bowel disease, liver disease, respiratory disease, eye disease, skin disease or neuroinflammatory disease; wherein the arthritis is osteoarthritis, rheumatoid arthritis, or juvenile rheumatoid arthritis; systemic inflammatory syndrome is systemic inflammatory sepsis; inflammatory bowel disease is irritable bowel disease; the liver disease is liver autoimmune disease, autoimmune hepatitis, primary biliary cirrhosis, sclerosing cholangitis, autoimmune cholangitis, alcoholic liver disease or non-alcoholic fatty liver disease; the respiratory disease is asthma, acute lung injury, acute respiratory distress syndrome, pulmonary inflammation, chronic obstructive pulmonary disease, bronchitis or bronchiectasis; the eye disease is uveitis, iritis, retinitis, autoimmune ocular inflammation, inflammation caused by angiogenesis and/or lymphangiogenesis, or macular degeneration; the skin diseases are contact dermatitis, skin inflammation, psoriasis or eczema; the neuroinflammatory disease is Parkinson disease, alzheimer disease, vascular dementia, multiple sclerosis or chronic multiple sclerosis;
the diabetes and/or diabetes-related diseases are type I diabetes, type II diabetes, syndrome X, diabetic retinopathy, diabetic nephropathy, diabetic neuropathy or diabetic macular edema;
the ischemic disease is stroke and/or complications thereof, myocardial infarction and/or complications thereof, or destruction of tissue by inflammatory cells after stroke;
the fibrosis is liver fibrosis, cystic fibrosis, kidney fibrosis, idiopathic pulmonary fibrosis or radioactivity-induced fibrosis;
the vascular disease is atherosclerosis, chronic heart failure or congestive heart failure.
8. The use of claim 7, wherein the non-alcoholic fatty liver disease is non-alcoholic simple fatty liver, non-alcoholic steatohepatitis, non-alcoholic fatty liver disease phase Guan Yin-derived cirrhosis, or primary liver cancer.
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Patentee after: Guangdong Dongyangguang Pharmaceutical Co.,Ltd.

Address before: 523808 Songshan Lake Science and Technology Industrial Park, Dongguan City, Guangdong Province

Patentee before: SUNSHINE LAKE PHARMA Co.,Ltd.