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WO2022022364A1 - Modulateur de l'intégrine pyrrolidine et son utilisation - Google Patents

Modulateur de l'intégrine pyrrolidine et son utilisation Download PDF

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Publication number
WO2022022364A1
WO2022022364A1 PCT/CN2021/107688 CN2021107688W WO2022022364A1 WO 2022022364 A1 WO2022022364 A1 WO 2022022364A1 CN 2021107688 W CN2021107688 W CN 2021107688W WO 2022022364 A1 WO2022022364 A1 WO 2022022364A1
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formula
compound
butyl
cycloalkyl
fibrosis
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Chinese (zh)
Inventor
李小林
谢永华
石峰
李子忠
吴奕钦
马晓芸
张士猛
吴钎
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T2yc Co Ltd
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T2yc Co Ltd
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    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
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    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the invention belongs to the field of pharmaceutical compounds, and in particular relates to a pyrrolidine integrin regulator and use thereof.
  • the integrin family is a class of widely distributed transmembrane glycoproteins that link the extracellular matrix environment with intracellular signaling. Integrins are composed of ⁇ subunits and ⁇ subunits through non-covalent bonds to form heterodimers. At present, 18 kinds of ⁇ subunits and 8 kinds of ⁇ subunits have been found, which can be combined into at least 24 kinds of integrin dimers.
  • the integrin family of cell adhesion molecules is the main connecting substance between extracellular matrix, inflammatory cells, fibroblasts and parenchymal cells, and is closely related to the occurrence, maintenance and development of tissue fibrosis. Many key cell-cell and cell-extracellular matrix interactions are mediated during the process. (Manninen et al, Proteomics, 2017, 17(3-4):1600022.).
  • the ⁇ V family is mainly involved in the fibrosis process of body tissues.
  • the integrin ⁇ V family includes 5 isoforms ( ⁇ V ⁇ 1, ⁇ V ⁇ 3, ⁇ V ⁇ 5, ⁇ V ⁇ 6, ⁇ V ⁇ 8), which are lowly expressed in normal cells of various tissues and highly expressed in fibrotic tissue cells.
  • TGF- ⁇ is an important factor involved in the formation of tissue fibrosis, especially TGF- ⁇ 1.
  • TGF- ⁇ 1 is involved in physiological repair and collagen accumulation.
  • Integrin ⁇ V family proteins are involved in activating latent TGF- ⁇ molecules, which induce excessive autoimmune and inflammatory responses by activating TGF- ⁇ , and promote tissue fibrosis.
  • Integrin ⁇ v ⁇ 1 is a low-affinity fibronectin receptor that is highly expressed in basal epithelial cells and has the effect of promoting keratinocyte migration on the underlying fibronectin EDA. Blocking the interaction of integrin ⁇ v ⁇ 1 with TGF- ⁇ 1 helps to inhibit TGF- ⁇ 1 activity and block fibrosis.
  • integrin ⁇ v ⁇ 1 can also participate in the synthesis of gingival fibroblasts by activating latent TGF ⁇ 1 (Jakhu et al, Journal of oral biology and craniofacial research, 2018, 8(2): 122.).
  • TGF ⁇ 1 latent TGF ⁇ 1
  • ⁇ v family histones the research on ⁇ v ⁇ 6 is more in-depth. It has been reported that the expression of integrin ⁇ v ⁇ 6 is very low in normal lung tissue, but it is rapidly overexpressed when lung injury develops inflammation and fibrosis (Hatley et al, Angewandte Chemie International Edition, 2018, 57(13): 3298.).
  • integrin ⁇ V ⁇ 6 In patients with primary biliary cirrhosis (PBC), alcoholic fatty liver, hepatitis B, hepatitis C and other diseases, the mRNA expression of integrin ⁇ V ⁇ 6 is increased. The expression of integrin ⁇ V ⁇ 6 was significantly increased in kidney disease-related chronic inflammatory and fibrotic diseases compared with normal kidney tissue. In addition, integrin ⁇ V ⁇ 6 was significantly expressed in biopsy samples of patients with diabetes, pulmonary hemorrhagic nephritis syndrome, Alport syndrome, lupus nephritis and other patients (Koivisto et al, The international journal of biochemistry & cell biology, 2018, 99: 186.).
  • Tissue fibrosis can occur in a variety of organs, and is a relatively common fibrotic disease including idiopathic pulmonary fibrosis (IPF), nonalcoholic fatty liver (NASH), liver cirrhosis, renal fibrosis, scleroderma, Myocardial fibrosis, etc. Tissue damage and inflammation are important triggers of fibrosis. Inflammation leads to necrosis of parenchymal cells of the organ, local immune cells are activated, and various blood cells enter the injury site.
  • IPF idiopathic pulmonary fibrosis
  • NASH nonalcoholic fatty liver
  • liver cirrhosis liver cirrhosis
  • renal fibrosis scleroderma
  • Myocardial fibrosis etc.
  • Tissue damage and inflammation are important triggers of fibrosis. Inflammation leads to necrosis of parenchymal cells of the organ, local immune cells are activated, and various blood cells enter the injury site.
  • Activated immune cells produce large amounts of highly biologically active cytokines and chemokines, leading to local activation of mesenchymal cells that produce extracellular matrix (ECM), disrupt the extracellular microenvironment, and further increase pro-inflammatory cells Production of factors, chemokines and angiogenic factors.
  • ECM extracellular matrix
  • the abnormal increase and excessive deposition of extracellular matrix lead to pathological changes leading to tissue fibrosis (Ricard-Blum et al, Matrix Biology, 2018, 68: 122.).
  • the main feature of fibrosis is the formation and deposition of excess fibrous connective tissue. Chronic fibrotic injury can lead to tissue damage, organ dysfunction, and ultimately organ failure.
  • the present invention provides a compound represented by formula I and its racemate, stereoisomer, tautomer, isotopic label, nitrogen oxide, solvate, polyamide, etc. Crystal forms, metabolites, esters, prodrugs or pharmaceutically acceptable salts thereof:
  • One R5 can be the same or different ;
  • the R 2 and R 3 are each independently selected from H, C 1 -C 12 aliphatic hydrocarbon group, C 3-12 cycloalkyl group, C 3-12 cycloalkyl group-C 1 -C 12 aliphatic hydrocarbon group, -L 4 - Ar, and at least one of R 2 and R 3 is selected from -L 4 -Ar;
  • the R 4 is independently selected from H, C 1 -C 12 aliphatic hydrocarbon groups
  • the X is selected from O, NH;
  • the n, m are each independently selected from 0-6;
  • L 2 is selected from the bond, -CH 2 -;
  • L 3 is selected from the bond, -CH 2 -, -(CH 2 ) 2 -;
  • L 4 is selected from the bond, -CH 2 -;
  • the "halogen” is selected from F, Cl, Br, and I;
  • the "aliphatic hydrocarbon group” is selected from alkyl, alkenyl, and alkynyl;
  • each of said R 1 and R 5 is independently selected from halogen, C 1 -C 6 aliphatic hydrocarbon group, for example, selected from F, Cl, Br, I, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl.
  • said R 2 is selected from H, C 1 -C 6 aliphatic hydrocarbon group or C 3-8 cycloalkyl-C 1 -C 6 aliphatic hydrocarbon group, and R 3 is selected from -L 4 -Ar or said R 2 is selected from -L 4 -Ar and R 3 is selected from H, C 1 -C 6 aliphatic hydrocarbon group or C 3-8 cycloalkyl-C 1 -C 6 aliphatic hydrocarbon group; more preferably, said The R 2 is selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, cyclopropyl ylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cyclopropyl ylmethyl,
  • the Ar is selected from the following groups optionally substituted with one, two or more R b : C 6 -C 14 aryl, 5-10 membered heterocyclyl, 5-6 A heteroaryl group, preferably, Ar is selected from phenyl, naphthyl, 2,3-dihydrobenzofuranyl, benzofuranyl, benzofuran optionally substituted with one, two or more R b Pyranyl, 3,4-dihydro-2H-1-benzopyranyl (chromanyl), 2,3-dihydrobenzo[b][1,4]dioxanyl, pyridyl, Pyrimidyl, indazolyl (1H-indazolyl, 2H-indazolyl), indolyl, isoindolyl, quinolinyl, isoquinolinyl, quinazolinyl, benzoxazolyl;
  • the R b is selected from H, halogen, CN, or the following groups optionally substituted by one, two or more R c : C 1 -C 6 aliphatic hydrocarbon group, C 1 -C 6 aliphatic hydrocarbyloxy, C 1 -C 6 aliphatic hydrocarbyl-SO 2 -, C 1 -C 6 aliphatic hydrocarbyl-NH-, bis(C 1 -C 6 aliphatic hydrocarbyl)N-, C 6-10 Aryl, C 6-10 Aryloxy, C 6-10 Aryl-SO 2 -, C 6-10 Aryl-NH-, 5-6 Member Heteroaryl, 5-6 Member Heteroaryloxy , 5-6-membered heteroaryl-SO 2 -, 5-6-membered heteroaryl-NH-, 5-6-membered heterocyclyl, 5-6-membered heterocyclyloxy, 5-6-membered heterocyclyl- SO 2 -,
  • the R 4 is independently selected from H, C 1 -C 6 aliphatic hydrocarbon groups, preferably, selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl base, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl;
  • the Ar is selected from the following groups:
  • R b is selected from the definitions described in formula I.
  • one of the R 2 or R 3 is selected from the following groups:
  • the structure of formula I is selected from the following formula Ia:
  • R 1 , R 2 , R 3 , R 4 , R 5 , L 1 , and L 2 are as defined in formula I above.
  • said formula I may be selected from compounds having a specific stereoconfiguration at one of said labels, or compounds having different specific stereoconfigurations at both said labels.
  • the structure of formula I may be selected from the following formulae IIa-IIj:
  • R 1 , R 2 , R 3 , R 4 , R 5 , L 1 , L 2 , L 3 and other chiral centers are as defined in formula I above.
  • the compound of formula I is further preferably the following formula III (formula IIIa, formula IIIb), formula IV (formula IVa, formula IVb):
  • R 1 , R 3 , R 4 , R 5 , L 1 , L 2 and others Chiral centers are as defined in formula I above.
  • the compound of formula I is further preferably of the following formulae V to XVII:
  • R 1 , R 3 , R 4 , R 5 , n, m and other chiral centers are as defined in Formula I above.
  • the compounds represented by Formula I (including Formula II to Formula VII) and their racemates, stereoisomers, tautomers, isotopic labels, nitrogen oxides, and solvates , polymorphs, metabolites, esters, prodrugs or pharmaceutically acceptable salts thereof, illustrative, non-limiting specific examples of compounds of formula I are shown below:
  • the stereoisomer of the compound of formula I may be further selected from, for example, the following structures:
  • the present invention also provides the compounds represented by the formula I (including formula II to VII) and their racemates, stereoisomers, tautomers, isotopic labels, nitrogen oxides, solvates, polymorphs
  • the compounds of the present invention can be synthesized using the methods described below in combination with synthetic methods known in the art of synthetic organic chemistry, or with relevant modifications recognized by those skilled in the art. Those skilled in the art know that, according to a specific target structure, one or more of the following schemes can be optionally combined, or any steps in one or more of the schemes can be combined to obtain a synthesis scheme.
  • the preparation method of the compound of the present invention comprises: under suitable conditions, reacting a raw material containing a naphthyridine ring structure with a raw material containing a nitrogen heterobicyclo[3.1.0]hexane structure in a suitable reagent, and optionally Yes, under suitable conditions, carry out the steps of protecting groups, deprotecting groups, substitution, condensation, reductive amination or hydrolysis. Specifically, the synthesis can be carried out with reference to the following scheme.
  • the preparation of the compounds of the present invention comprises one or more of the following steps:
  • the R 1 , R 3 , R 4 (R 4 ⁇ H), R 5 , L 1 , L 2 , L 3 are as defined in the aforementioned formula I;
  • the Lx is selected from L 1 -X 1 , wherein X 1 is a leaving group selected from, for example, OTs, OMs, OTf, halogens (Cl, Br, I), or the Lx is selected from L 1 groups (when a terminal -CH 2 - exists)
  • the terminal -CH2- is replaced by a group of CHO or COOH, for example selected from -( CH2 ) m-1- CHO or -( CH2 ) m-1- COOH, wherein m is as defined in formula I above;
  • the The PG 1 is a protecting group on N, selected from Boc- and the like; in the first scheme, compound A-3 is synthesized by using compounds A-1 and A-2, and the reaction conditions can be selected from (i) NaBH (OAc ) 3 , NaBH
  • the present invention further provides a pharmaceutical composition
  • a pharmaceutical composition comprising the compound of formula I described in the present invention and its racemates, stereoisomers, tautomers, isotopic labels, nitrogen oxides, solvates, polymorphs Forms, metabolites, esters, prodrugs or pharmaceutically acceptable salts thereof.
  • the pharmaceutical composition of the present invention further comprises a therapeutically effective amount of the compound of formula I of the present invention and its racemates, stereoisomers, tautomers, isotopic labels, nitrogen oxides compounds, solvates, polymorphs, metabolites, esters, prodrugs or pharmaceutically acceptable salts thereof and pharmaceutically acceptable carriers.
  • a carrier in the pharmaceutical composition is "acceptable" which is compatible with (and preferably, is capable of stabilizing) the active ingredient of the composition and which is not deleterious to the subject being treated.
  • One or more solubilizers can be used as pharmaceutical excipients for delivery of the active compounds.
  • the present invention further provides the compounds of formula I and their racemates, stereoisomers, tautomers, isotopic labels, nitrogen oxides, solvates, polymorphs, metabolites, esters, prodrugs or Use of a pharmaceutically acceptable salt thereof or the pharmaceutical composition in the preparation of an integrin modulator.
  • the present invention further provides the compounds of formula I and their racemates, stereoisomers, tautomers, isotopic labels, nitrogen oxides, solvates, polymorphs, metabolites, esters, prodrugs or Use of a pharmaceutically acceptable salt thereof or the pharmaceutical composition in the manufacture of a medicament for preventing, regulating or treating a disease or condition associated with integrin activity.
  • the present invention further provides the compounds of formula I and their racemates, stereoisomers, tautomers, isotopic labels, nitrogen oxides, solvates, polymorphs, metabolites, esters, prodrugs or Use of a pharmaceutically acceptable salt thereof or the pharmaceutical composition in the manufacture of a medicament for treating fibrotic diseases, inflammatory diseases or cell proliferative diseases.
  • the present invention further provides the compounds of formula I and their racemates, stereoisomers, tautomers, isotopic labels, nitrogen oxides, solvates, polymorphs, metabolites, esters, prodrugs or Use of a pharmaceutically acceptable salt thereof or the pharmaceutical composition in the manufacture of a medicament for inhibiting TGF- ⁇ activation in cells.
  • the present invention also provides a method of modulating the activity of at least one integrin in a subject, the method comprising administering a compound of the present invention as a therapeutic agent.
  • the modulation effect of the compound on integrin is any one of ⁇ V ⁇ 1, ⁇ V ⁇ 3, ⁇ V ⁇ 5, ⁇ V ⁇ 6, ⁇ V ⁇ 8, ⁇ 5 ⁇ 1 and ⁇ 8 ⁇ 1 or one or more of ⁇ V ⁇ 1, ⁇ V ⁇ 3, ⁇ V ⁇ 5, ⁇ V ⁇ 6, ⁇ V ⁇ 8, ⁇ 5 ⁇ 1 and ⁇ 8 ⁇ 1
  • the regulatory effect of a combination is manifested as an inhibitory effect.
  • the inhibitory effect may be the inhibition of ⁇ V ⁇ 1, ⁇ V ⁇ 3, ⁇ V ⁇ 5, ⁇ V ⁇ 6, and ⁇ V ⁇ 8, ⁇ 5 ⁇ 1, ⁇ 8 ⁇ 1; in other embodiments, the inhibitory effect is the inhibition of ⁇ V ⁇ 1, ⁇ V ⁇ 3, ⁇ V ⁇ 5, Inhibition of ⁇ V ⁇ 6, and one of ⁇ V ⁇ 8, ⁇ 5 ⁇ 1, ⁇ 8 ⁇ 1, for example, the inhibitory effect is the inhibition of ⁇ 8 ⁇ 1; in other embodiments, the inhibitory effect includes the inhibition of ⁇ 8 ⁇ 1 and ⁇ V ⁇ 1; in In other embodiments, the inhibitory effect includes the inhibition of ⁇ 8 ⁇ 1 and ⁇ 5 ⁇ 1; in other embodiments, the inhibitory effect includes the inhibition of ⁇ v ⁇ 3 and ⁇ v ⁇ 5; in some embodiments, the inhibitory effect includes Inhibition of ⁇ 8 ⁇ 1, ⁇ v ⁇ 3 and ⁇ v ⁇ 5; in some embodiments, the inhibition includes inhibition of ⁇ 8 ⁇ 1, ⁇ v ⁇ 1 and ⁇ 5 ⁇
  • the inhibitory effect includes inhibition of ⁇ V ⁇ 1, ⁇ V ⁇ 3, ⁇ V ⁇ 5, ⁇ 5 ⁇ 1, ⁇ 8 ⁇ 1.
  • the integrin comprises a combination of one or more of ⁇ V ⁇ 1, ⁇ V ⁇ 3, ⁇ V ⁇ 5, ⁇ V ⁇ 6, and ⁇ V ⁇ 8, ⁇ 5 ⁇ 1, ⁇ 8 ⁇ 1.
  • the present invention also provides a method for treating a disease or disorder comprising administering to a patient in need of such treatment a therapeutically effective amount of at least one compound of the present invention alone, or optionally, in combination with another of the present invention A compound and/or at least one other type of therapeutic agent in combination.
  • the present invention also provides a method of inhibiting TGF-beta activation in a cell, the method comprising administering to the cell a compound of formula I and its racemates, stereoisomers, tautomers, isotopic labels, nitrogen oxides compound, solvate, polymorph, metabolite, ester, prodrug or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition.
  • the disease or disorder is associated with fibrosis, including fibrosis of the lung, liver, kidney, heart, skin, eye, and pancreas.
  • the disease or disorder is associated with a cell proliferative disorder such as cancer.
  • the cancer comprises solid tumor growth or neoplasia.
  • the cancer includes tumor metastasis.
  • the cancer is bladder cancer, blood cancer, bone cancer, brain cancer, breast cancer, central nervous system cancer, cervical cancer, colon cancer, endometrial cancer, esophageal cancer, gallbladder cancer, genital cancer, urinary Reproductive tract cancer, head cancer, kidney cancer, throat cancer, liver cancer, lung cancer, muscle cancer.
  • the cancer is sarcoma, lymphoma, leukemia, melanoma, mesothelioma, multiple myeloma, or seminoma.
  • diseases, disorders or conditions associated with ⁇ V integrin activity include, but are not limited to, transplantation injections, fibrotic disorders (eg idiopathic pulmonary fibrosis, interstitial lung disease, liver Fibrosis, nonalcoholic fatty liver disease, primary sclerosing cholangitis (PSC), renal fibrosis, skin fibrosis, myocardial fibrosis, systemic sclerosis), inflammatory diseases (eg acute hepatitis, chronic hepatitis, Psoriasis, Irritable Bowel Syndrome (IBS), Inflammatory Bowel Disease (IBD)), Osteoporosis, and Cell Proliferative Disorders (e.g. Cancer, Myeloma, Fibroma, Liver Cancer, Leukemia, Kaposi's Sarcoma, Solid tumor).
  • fibrotic disorders eg idiopathic pulmonary fibrosis, interstitial lung disease, liver Fibrosis, nonalcoholic fatty liver disease, primary s
  • Fibrotic diseases, inflammatory diseases, and cell proliferative diseases suitable for prevention or treatment by the compounds of the present invention include, but are not limited to, idiopathic pulmonary fibrosis (IPF), interstitial lung disease, nonspecific interstitial pneumonia (NSIP) , conventional interstitial pneumonia (UIP), radiation-induced fibrosis, familial pulmonary fibrosis, airway fibrosis, chronic obstructive pulmonary disease (COPD), diabetic nephropathy, focal segmental glomerulosclerosis , IgA nephropathy, drug- or transplant-induced nephropathy, autoimmune nephropathy, lupus nephritis, liver fibrosis, renal fibrosis, chronic kidney disease (CKD), diabetic nephropathy (DKD), skin fibrosis, scarring, systemic sclerosis , scleroderma, viral fibrosis, nonalcoholic fatty liver disease (NAFLD), alcoholic or nonalcoholic stea
  • the present invention also provides a method for treating a fibrotic, inflammatory or cell proliferative disease comprising administering to a patient in need of such treatment a therapeutically effective amount of at least one compound.
  • An "antioxidant" of the present invention alone or optionally in combination with another compound of the present invention and/or at least one other type of therapeutic agent.
  • the present invention provides compounds of the present invention for use in therapy.
  • the compounds of the present invention may be used in combination with additional therapeutic agents such as one or more anti-fibrotic and/or anti-inflammatory therapeutic agents.
  • the present invention further provides a method for treating a fibrotic disease, an inflammatory disease or a cell proliferative disease, the method comprising administering to a patient in need thereof a therapeutically effective amount of a first and a second therapeutic agent, wherein the first Therapeutic agents are compounds of the present invention.
  • the present invention provides a combined formulation of a compound of the present invention and an additional therapeutic agent for simultaneous, separate or sequential use in therapy.
  • halogen refers to F, Cl, Br and I.
  • F, Cl, Br and I may be described as “halogens" in this specification.
  • Optionally substituted with substituents described herein encompasses both unsubstituted as well as substituted with one or more substituents, eg "optionally substituted with one, two or more R" means that there may be no substitution Substituted with R (unsubstituted) or substituted with one, two or more Rs.
  • aliphatic hydrocarbon group includes saturated or unsaturated, straight or branched chain or cyclic hydrocarbon groups, the type of the aliphatic hydrocarbon group can be selected from alkyl, alkenyl, alkynyl, etc., the carbon atoms of the aliphatic hydrocarbon group
  • the number is preferably 1-12, can also be 1-10, and a further preferred range is 1-6, which may specifically include but not be limited to the following groups: methyl, ethyl, n-propyl, isopropyl, n-butyl , isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, vinyl, 1-propenyl, 2-propenyl, 1-methylvinyl, 1-butenyl, 1-ethylvinyl, 1-methyl-2-propenyl, 2-butenyl, 3-butenyl, 2-methyl-1-propenyl, 2-
  • C 3-12 cycloalkyl should be understood to mean a saturated or unsaturated monovalent mono- or bicyclic ring having 3-12 carbon atoms, preferably C 3-8 cycloalkyl, more preferably C 3 -6 cycloalkyl.
  • C3-8cycloalkyl is understood to mean a saturated or unsaturated monovalent monocyclic or bicyclic ring having 3, 4, 5, 6, 7 or 8 carbon atoms.
  • the C 3-12 cycloalkyl group may be a monocyclic hydrocarbon group, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl or cyclodecyl, or a bicyclic Hydrocarbyl such as tetralin or decalin.
  • 3-12 membered heterocyclyl means a saturated or unsaturated monovalent monocyclic or bicyclic ring containing 1-5 heteroatoms independently selected from N, O and S, and the heteroatom-containing group does not have For aromaticity, the 3-12-membered heterocyclic group is preferably a 3-10-membered heterocyclic group.
  • 3-12 membered heterocyclyl means a saturated monovalent monocyclic or bicyclic ring containing 1-5, preferably 1-3 heteroatoms selected from N, O and S.
  • the heterocyclyl group can be attached to the remainder of the molecule through any of the carbon atoms or a nitrogen atom, if present.
  • the heterocyclic group may include, but is not limited to: 4-membered ring, such as azetidinyl, oxetanyl; 5-membered ring, such as tetrahydrofuranyl, tetrahydrothienyl, dioxane Pentenyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl; or 6-membered ring, such as tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholine group, piperazinyl, or trithianyl; or a 7-membered ring such as diazepanyl.
  • 4-membered ring such as azetidinyl, oxetanyl
  • 5-membered ring such as tetrahydrofuranyl, tetrahydrothienyl, dioxane Pentenyl,
  • the heterocyclyl group can be benzo-fused.
  • the heterocyclyl group may be bicyclic, such as, but not limited to, a 5,5 membered ring, such as a hexahydrocyclopento[c]pyrrole-2(1H)-yl ring, or a 5,6 membered bicyclic ring, such as a hexahydropyrrole
  • the [1,2-a]pyrazin-2(1H)-yl ring may be partially unsaturated, i.e.
  • the 3-12 membered heterocyclic group can also be selected from, for example, the following groups:
  • C 6-20 aryl is to be understood to mean preferably a monovalent aromatic or partially aromatic monocyclic, bicyclic or tricyclic hydrocarbon ring having 6-20 carbon atoms, preferably a "C 6-10 aryl” .
  • the term C 6-20 aryl is understood to preferably mean a monovalent aromaticity having 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 carbon atoms or partially aromatic monocyclic, bicyclic or tricyclic hydrocarbon rings, especially those having 6 carbon atoms ("C 6 aryl”), such as phenyl; or biphenyl, or those having 9 carbon atoms a ring (“C 9 aryl”) such as indanyl or indenyl, or a ring having 10 carbon atoms (“C 10 aryl”) such as tetrahydronaphthyl, dihydronaphthyl or naphthyl, Either a ring with 13 carbon atoms (" C13 aryl”), such as fluoren
  • 5-14 membered heteroaryl is understood to include monovalent monocyclic, bicyclic or tricyclic aromatic ring systems having 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms, especially 5 or 6 or 9 or 10 carbon atoms, and which contain 1-5, preferably 1-3 heteroatoms independently selected from N, O and S, and, in addition, in each may be benzo-fused.
  • heteroaryl is selected from the group consisting of thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiazolyl oxazolyl, thi-4H-pyrazolyl, etc.
  • a heterocyclyl or heteroaryl group includes all possible isomeric forms thereof, such as positional isomers thereof.
  • pyridyl or pyridylene includes pyridin-2-yl, pyridin-2-yl, pyridin-3-yl, pyridin-3-yl, pyridin-4-yl and pyridin-4-yl;
  • thienyl or thienylene includes thien-2-yl, thien-2-yl, thien-3-yl and thien-3-yl.
  • the compounds of the present invention may be chiral and thus may exist in various enantiomeric forms. Thus these compounds may exist in racemic or optically active forms.
  • the compounds of the present invention or their intermediates can be separated into enantiomeric compounds by chemical or physical methods well known to those skilled in the art, or used in this form for synthesis. In the case of racemic amines, diastereomers are prepared from the mixture by reaction with an optically active resolving agent.
  • suitable resolving agents are optically active acids such as the R and S forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, suitable N-protected amino acids such as N- Benzoylproline or N-benzenesulfonylproline) or various optically active camphorsulfonic acids. It is also possible to use optically active resolving agents such as dinitrobenzoylphenylglycine, cellulose triacetate or other carbohydrate derivatives or chiral derivatized methacrylate polymers immobilized on silica gel. Chromatographic enantiomeric resolution is advantageously performed. Suitable eluents for this purpose are aqueous or alcoholic solvent mixtures, eg hexane/isopropanol/acetonitrile.
  • N-oxides can form N-oxides since nitrogen needs to have available lone pairs of electrons for oxidation to nitrogen oxides; those skilled in the art will recognize that N-oxides can be formed - Nitrogen-containing heterocycles of oxides. Those skilled in the art will also recognize that tertiary amines are capable of forming N-oxides.
  • N-oxides of heterocycles and tertiary amines are well known to those skilled in the art and include the use of peroxyacids such as peracetic acid and m-chloroperoxybenzoic acid (MCPBA), peroxyacids Hydrogen oxide, alkyl hydroperoxides such as t-butyl hydroperoxide, sodium perborate, and dioxiranes such as dimethyldioxirane oxidize heterocycles and tertiary amines.
  • MCPBA m-chloroperoxybenzoic acid
  • Hydrogen oxide alkyl hydroperoxides such as t-butyl hydroperoxide
  • sodium perborate sodium perborate
  • dioxiranes such as dimethyldioxirane oxidize heterocycles and tertiary amines.
  • Pharmaceutically acceptable salts may be, for example, acid addition salts of sufficiently basic compounds of the invention having nitrogen atoms in the chain or ring, such as acid addition salts with inorganic acids such as hydrochloric acid, hydrofluoric acid acid, hydrobromic acid, hydroiodic acid, sulfuric acid, pyrosulfuric acid, phosphoric acid or nitric acid, or hydrogen sulfate, or acid addition salts with organic acids such as formic acid, acetic acid, acetoacetic acid, pyruvic acid, trifluoroacetic acid , propionic acid, butyric acid, caproic acid, heptanoic acid, undecanoic acid, lauric acid, benzoic acid, salicylic acid, 2-(4-hydroxybenzoyl)benzoic acid, camphoric acid, cinnamic acid, cyclopentane Propionic acid, digluconic acid, 3-hydroxy-2-naphthoic acid, niacin, pamoic
  • alkali metal salts eg sodium or potassium salts
  • alkaline earth metal salts eg calcium or magnesium salts
  • ammonium salts or salts with organic bases that provide physiologically acceptable cations, such as salts with sodium ions, potassium ions, N-methylglucamine, dimethylglucamine, ethylglucamine, Lysine, Dicyclohexylamine, 1,6-Hexanediamine, Ethanolamine, Glucosamine, Meglumine, Sarcosine, Serinol, Trishydroxymethylaminomethane, Aminopropanediol, 1-Amino-2 , 3,4-Butanetriol.
  • such pharmaceutically acceptable salts include salts of the group -COOH with sodium ions, potassium ions, calcium ions, magnesium ions, N-methylglucamine, dimethylglucamine, Ethylglucosamine, lysine, dicyclohexylamine, 1,6-hexanediamine, ethanolamine, glucosamine, meglumine, sarcosine, serinol, trihydroxymethylaminomethane, aminopropylene glycol , 1-amino-2,3,4-butanetriol.
  • basic nitrogen-containing groups can be quaternized with the following reagents: lower alkyl halides such as methyl, ethyl, propyl and butyl chlorides, bromides and iodides; dialkyl sulfates such as sulfuric acid Dimethyl, diethyl, dibutyl, and dipentyl sulfates; long-chain halides such as decyl, lauryl, myristyl, and stearyl chlorides, bromides, and iodides; aralkyl groups Halides such as benzyl and phenethyl bromide etc.
  • lower alkyl halides such as methyl, ethyl, propyl and butyl chlorides, bromides and iodides
  • dialkyl sulfates such as sulfuric acid Dimethyl, diethyl, dibutyl, and dipentyl sulfates
  • long-chain halides such as decyl,
  • pharmaceutically acceptable salts include hydrochloride, sulfate, nitrate, bisulfate, hydrobromide, acetate, oxalate, citrate, mesylate, formate or Meglumine salts, etc.
  • the pharmaceutically acceptable salts include not only the salts formed on one of the salt-forming sites of the compounds of the present invention, but also 2, 3 or all of them.
  • the salt formed on the site can vary within a wide range, for example, it can be 4:1 ⁇ 1:4, such as 3:1, 2:1, 1:1, 1:2, 1:3, etc.
  • the compounds of the present invention may also contain one or more asymmetric centers.
  • Asymmetric carbon atoms can exist in (R) or (S) configuration. When there is only one asymmetric center, a racemic mixture is produced, and when multiple asymmetric centers are contained, a diastereoisomeric mixture is obtained. In some cases, asymmetry may also exist due to hindered rotation about a particular bond, such as the central bond connecting two substituted aromatic rings of a particular compound.
  • the substituents may also exist in the form of cis or trans isomers.
  • the compounds of the present invention also include all possible stereoisomers of each, either a single stereoisomer or said stereoisomer (eg, R-isomer or S-isomer, or E-isomer or Z-isomers) in any ratio in the form of any mixture.
  • Single stereoisomers eg single enantiomers or single diastereomers
  • of the compounds of the invention can be achieved by any suitable prior art method (eg chromatography, particularly eg chiral chromatography) separation.
  • tautomer refers to an isomer of a functional group resulting from the rapid movement of an atom in two positions in a molecule.
  • the compounds of the present invention may exhibit tautomerism.
  • Tautomeric compounds can exist as two or more interconvertible species.
  • Proton tautomers arise from the migration of covalently bonded hydrogen atoms between two atoms.
  • Tautomers generally exist in equilibrium, and attempts to separate individual tautomers usually result in a mixture whose physicochemical properties are consistent with a mixture of compounds. The position of equilibrium depends on the chemical properties within the molecule.
  • the ketone form predominates; in phenols, the enol form predominates.
  • the present invention encompasses all tautomeric forms of the compounds.
  • the compounds referred to also include isotopically-labeled compounds that are the same as those shown in formula I, but in which one or more atoms are assigned an atomic mass or mass number different from the usual Atomic substitution for naturally occurring atomic mass or mass number.
  • isotopes that may be incorporated into the compounds of the present invention include isotopes of H, C, N, O, S, F, and Cl, such as 2 H, 3 H, 13 C, 11 C, 14 C, 15 N, 18 O, respectively , 17 O, 32 P, 35 S, 18 F and 36 Cl.
  • Compounds of the invention, prodrugs thereof, or pharmaceutically acceptable salts of said compounds or said prodrugs containing the above isotopes and/or other isotopes of other atoms are within the scope of the invention.
  • Certain isotopically-labeled compounds of the invention, eg, compounds incorporating radioactive isotopes such as3H and14C are useful in drug and/or substrate tissue distribution assays. Tritium (ie 3 H) and carbon 14 (ie 14 C) isotopes are particularly preferred for ease of preparation and detectability.
  • substitution with heavier isotopes may provide certain therapeutic advantages (eg, increased in vivo half - life or reduced dosage requirements) derived from greater metabolic stability, and may therefore be is preferred in some cases.
  • the compounds of the invention as claimed in the claims may in particular be substituted with deuterium or tritium.
  • the presence of hydrogen in a substituent group is not individually listed.
  • deuterium or tritium does not imply the exclusion of deuterium or tritium, but may equally well include deuterium or tritium.
  • an effective amount refers to an amount of a compound of the present invention sufficient to achieve the intended application, including but not limited to disease treatment as defined below.
  • a therapeutically effective amount may vary depending on the intended application (in vitro or in vivo), or the subject and disease condition being treated such as the weight and age of the subject, the severity of the disease condition and the mode of administration, etc., which It can be easily determined by one of ordinary skill in the art.
  • the specific dose will vary depending on the particular compound chosen, the dosing regimen followed, whether it is administered in combination with other compounds, the timing of administration, the tissue to which it is administered, and the physical delivery system on which it is carried.
  • solvates are those forms of the compounds of the present invention which, in solid or liquid state, form complexes by coordination with solvent molecules. Hydrates are a specific form of solvates in which the coordination is with water. In the present invention, preferred solvates are hydrates. Further, the pharmaceutically acceptable solvates (hydrates) of the compounds of the general formula I of the present invention refer to co-crystals and clathrates formed by the compound I with stoichiometric one or more molecules of water or other solvents.
  • Useful solvents for solvates include, but are not limited to, water, methanol, ethanol, ethylene glycol, and acetic acid.
  • prodrug refers to the in vivo conversion of a compound to a compound of the aforementioned general formula or specific compound. Such conversion is effected by hydrolysis of the prodrug in blood or enzymatic conversion to the parent structure in blood or tissue.
  • the prodrugs of the present invention can be esters.
  • esters can be used as prodrugs including phenyl esters, aliphatic esters, acyloxymethyl esters, carbonates, carbamates and amino acid esters.
  • a compound of the present invention contains a hydroxyl/carboxyl group, which can be acylated to give the compound in the form of a prodrug.
  • Other prodrug forms include phosphates, such as these phosphates are phosphorylated by the hydroxyl group on the parent.
  • the present invention provides a novel compound of general formula I, which has a good inhibitory effect on integrins;
  • the compounds of the present invention have inhibitory effects on a variety of integrin subtypes, some of which have good inhibitory effects on all subtypes, and some compounds have inhibitory effects on one of ⁇ V ⁇ 1, ⁇ V ⁇ 3, ⁇ V ⁇ 5, ⁇ V ⁇ 6, ⁇ V ⁇ 8, ⁇ 5 ⁇ 1 and ⁇ 8 ⁇ 1.
  • Several have significant inhibitory effects.
  • LC-MS adopts Agilent 1260-6120 system equipped with Waters Cortecs C18, 2.7 ⁇ m, 4.6 ⁇ 30 mm column; HPLC adopts Waters Acquity UPLC H-class instrument equipped with Acquity BEH C18, 1.7 ⁇ m, 50 ⁇ 2.1 mm column.
  • Step 1 (1R,5S,6s)-6-((2-methoxy-2-oxo-1-phenylethyl)amino)-3-azabicyclo[3.1.0]hexane-3 - tert-butyl carboxylate
  • Step 3 Methyl 2-(((1R,5S,6s)-3-azabicyclo[3.1.0]hex-6-yl)(methyl)amino)-2-phenylacetate
  • Step 1 (1R,5S,6s)-6-((3-ethoxy-3-oxo-1-phenylpropyl)amino)-3-azabicyclo[3.1.0]hexane-3 - tert-butyl carboxylate
  • reaction solution was then concentrated to dryness, the residue was dissolved in saturated sodium bicarbonate (30 mL), and extracted with ethyl acetate (30 mL ⁇ 3). The combined organic phases were washed with brine, dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by flash column chromatography (0-60% ethyl acetate in petroleum ether) to give the title compound (1.66 g, 86%) as a pale gum.
  • Step 2 Ethyl 3-(((1R,5S,6s)-3-azabicyclo[3.1.0]hex-6-yl)amino)-3-phenylpropanoate
  • Step 3 7-(3-((1R,5S,6s)-6-(((benzyloxy)carbonyl)amino)-3-azabicyclo[3.1.0]hex-3-yl)propyl) -3,4-Dihydro-1,8-naphthyridine-1(2H)-carboxylate tert-butyl ester
  • Step 4 7-(3-((1R,5S,6s)-6-amino-3-azabicyclo[3.1.0]hex-3-yl)propyl)-3,4-dihydro-1, 8-Naphthyridine-1(2H)-carboxylate tert-butyl ester
  • Step 1 7-(3-((1R,5S,6s)-6)-((2-methoxy-2-oxo-1-phenylethyl)(methyl)amino)-3-nitrogen Heterobicyclo[3.1.0]hex-3-yl)propyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate tert-butyl ester
  • Embodiment 2 With reference to the synthetic method of compound 1, the following compounds can be obtained:
  • Step 1 7-(3-((1R,5S,6s)-6-((3-ethoxy-3-oxo-1-phenylpropyl)amino)-3-azabicyclo[3.1. 0] Hex-3-yl)propyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate tert-butyl ester
  • the resulting compound 7 was isolated from the crude residue by preparative chiral SFC under the following conditions: [column: Daicel ChiralPak IG (250 x 30 mm, 10 ⁇ m); mobile phase: 60% methanol in carbon dioxide (containing 0.1% NH3 . H 2 O); flow rate: 70 g/min] to obtain compound 7a and compound 7b, respectively, as yellow solids.
  • Step 1 7-(3-((1R,5S,6s)-6-((3-ethoxy-3-oxo-1-phenylpropyl)amino)-3-azabicyclo[3.1. 0] Hex-3-yl)-3-oxopropyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate tert-butyl ester
  • the resulting compound 17 was isolated from the crude residue by preparative chiral SFC under the following conditions: [column: Daicel ChiralPak IG (250 ⁇ 30 mm, 10 ⁇ m); mobile phase: 60% methanol in carbon dioxide (containing 0.1% NH 3 . H 2 O); flow rate: 70 g/min] to obtain compound 17a and compound 17b, respectively, as white solids.
  • Step 4 7-(3-((1R,5S,6s)-6-((1-(4-isopropoxyphenyl)-3-methoxy-3-oxopropyl)amino)-3 - Azabicyclo[3.1.0]hex-3-yl)propyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate tert-butyl ester
  • reaction solution was stirred at 25°C for 18 hours.
  • the reaction solution was then quenched with water (50 mL) and extracted with dichloromethane (30 mL x 2).
  • the combined organic layers were washed with brine (50 mL), dried over sodium sulfate and concentrated to dryness.
  • the resulting compound 23 was isolated from the crude residue by preparative chiral SFC under the following conditions: [column: Daicel ChiralPak OZ-H (250 x 20 mm, 5 ⁇ m); mobile phase: 50% methanol in carbon dioxide (containing 0.2% DEA); flow rate: 40 g/min] to obtain compound 23a and compound 23b, respectively.
  • the resulting compound 24 was isolated from the crude residue by preparative chiral SFC under the following conditions: [column: Daicel ChiralPak OZ-H (250 x 20 mm, 5 ⁇ m); mobile phase: 50% methanol in carbon dioxide (containing 0.2% DEA); flow rate: 40 g/min] to obtain compound 24a and compound 24b, respectively.
  • the resulting compound 27 was isolated from the crude residue by preparative chiral SFC under the following conditions: [column: Daicel ChiralPak OZ-H (250 x 20 mm, 5 ⁇ m); mobile phase: 50% methanol in carbon dioxide (containing 0.2% DEA); flow rate: 40 g/min] to obtain compound 27a and compound 27b, respectively.
  • Step 1 7-(3-((1R,5S,6s)-6-((1-(4-chlorophenyl)-3-ethoxy-3-oxopropyl)amino)-3-aza Bicyclo[3.1.0]hex-3-yl)propyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate tert-butyl ester
  • Step 2 3-(4-Chlorophenyl)-3-(((1R,5S,6s)-3-(3-(5,6,7,8-tetrahydro-1,8-naphthyridine-2 -yl)propyl)-3-azabicyclo[3.1.0]hex-6-yl)amino)propionic acid
  • the resulting compound 34 was isolated from the crude residue by preparative chiral SFC under the following conditions: [column: Daicel ChiralPak IG (250 x 30 mm, 10 ⁇ m); mobile phase: 60% methanol in carbon dioxide (with 0.1% NH 3 . H 2 O); flow rate: 70 g/min] to obtain compound 34a and compound 34b, respectively, as white solids.
  • the resulting compound 38 was isolated from the crude residue by preparative chiral SFC under the following conditions: [column: Daicel ChiralPak OZ-H (250 x 20 mm, 5 ⁇ m); mobile phase: 50% methanol in carbon dioxide (containing 0.2% DEA); flow rate: 40 g/min] to obtain compound 38a and compound 38b, respectively.
  • His-tagged human integrin proteins were purchased from Acro Biosystems, including ⁇ 5 ⁇ 1 (IT1-H52W5), ⁇ 8 ⁇ 1 (IT1-H52W9), ⁇ v ⁇ 1 (IT1-H52E1), ⁇ v ⁇ 3 (IT3-H52E3), ⁇ v ⁇ 5 (IT8) -H52W5), ⁇ v ⁇ 6 (IT6-H52E1), ⁇ v ⁇ 8 (IT8-H52W4). Proteins were dissolved in sterile water and stored at -80°C after aliquoting. Biotin-labeled peptides were synthesized by GenScript, dissolved in DMSO and stored in aliquots at -20°C.
  • the reaction buffer was prepared in-house: 25 mM Tris pH 7.4, 150 mM NaCl, 0.1% BSA, 1 mM MgCl 2 , 1 mM CaCl 2 .
  • the candidate compound was dissolved in DMSO, added to the source plate according to a certain concentration gradient, and then the compound was transferred to the target plate with ECHO550 to form 11 concentrations.
  • the integrins correspond to RGD polypeptides and working concentrations shown in the table below, dilute with reaction buffer, mix gently, and add 10 ⁇ l per well to the target plate with Multidrop, and incubate at room temperature for 1 hour. Add 10 ⁇ l Donor/Acceptor beads (final concentration 15 ⁇ g/mL) to each well, and incubate at room temperature for one hour. Finally read with Envision Plate Reader. The IC50 for each compound was obtained after fitting with XLfit. Table 1 below shows the effect of the compounds of the present invention on the inhibitory activity of different integrin subtypes.

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Abstract

L'invention concerne un composé modulateur de l'intégrine pyrrolidine tel que représenté par la formule (I), et un racémate, un stéréoisomère, un tautomère, une étiquette isotopique, un oxyde d'azote, un solvate, un polymorphe, un métabolite, un ester, un promédicament ou un sel pharmaceutiquement acceptable de celui-ci, et une composition pharmaceutique le comprenant, son procédé de préparation et son utilisation médicale. La structure de formule (I) est la suivante.
PCT/CN2021/107688 2020-07-29 2021-07-21 Modulateur de l'intégrine pyrrolidine et son utilisation Ceased WO2022022364A1 (fr)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001024797A1 (fr) * 1999-10-04 2001-04-12 Merck & Co., Inc. Antagonistes des recepteurs d'integrine
CN101035784A (zh) * 2004-09-24 2007-09-12 埃科特莱茵药品有限公司 新的二环抗菌素
WO2018160522A1 (fr) * 2017-02-28 2018-09-07 Lazuli, Inc. Inhibiteurs de l'intégrine (alpha-v) (bêta-6)
CN110167934A (zh) * 2016-11-08 2019-08-23 百时美施贵宝公司 作为αV整联蛋白抑制剂的含有环丁烷和含有氮杂环丁烷的单环和螺环化合物

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001024797A1 (fr) * 1999-10-04 2001-04-12 Merck & Co., Inc. Antagonistes des recepteurs d'integrine
CN101035784A (zh) * 2004-09-24 2007-09-12 埃科特莱茵药品有限公司 新的二环抗菌素
CN110167934A (zh) * 2016-11-08 2019-08-23 百时美施贵宝公司 作为αV整联蛋白抑制剂的含有环丁烷和含有氮杂环丁烷的单环和螺环化合物
WO2018160522A1 (fr) * 2017-02-28 2018-09-07 Lazuli, Inc. Inhibiteurs de l'intégrine (alpha-v) (bêta-6)

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