WO2022022364A1 - Pyrrolidine integrin modulator and use thereof - Google Patents

Pyrrolidine integrin modulator and use thereof Download PDF

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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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PCT/CN2021/107688
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Chinese (zh)
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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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清药同创(北京)药物研发中心有限公司
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    • 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
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    • 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.

Abstract

Disclosed are a pyrrolidine integrin modulator compound as represented by formula (I), and a racemate, a stereoisomer, a tautomer, an isotopic label, a nitrogen oxide, a solvate, a polymorph, a metabolite, an ester, a prodrug or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition comprising same, a preparation method therefor, and the medical use thereof. The structure of formula (I) is as follows.

Description

一种吡咯烷类整合素调节剂及其用途A kind of pyrrolidine integrin regulator and use thereof
本申请要求2020年7月29日向中国国家知识产权局提交的，专利申请号为202010747225.9，发明名称为“一种吡咯烷类整合素调节剂及其用途”的在先申请的优先权。所述申请的全文通过引用的方式结合于本申请中。This application claims the priority of the prior application with the patent application number 202010747225.9 and the invention titled "A pyrrolidine-type integrin modulator and its use", which was submitted to the State Intellectual Property Office of China on July 29, 2020. The entirety of said application is incorporated herein by reference.
技术领域technical field
本发明属于药物化合物领域，具体涉及一种吡咯烷类整合素调节剂及其用途。The invention belongs to the field of pharmaceutical compounds, and in particular relates to a pyrrolidine integrin regulator and use thereof.
背景技术Background technique
整合素家族是一类分布广泛的跨膜糖蛋白，是连接细胞外基质环境与细胞内信号传导的纽带。整合素由α亚单位和β亚单位通过非共价键连接成异二聚体，目前已发现18种α亚基和8种β亚基，可组合成至少24种整合素二聚体。作为跨膜蛋白，细胞黏附分子整合素家族是细胞外基质、炎症细胞、成纤维细胞和实质细胞之间的主要连接物质，与组织纤维化的发生、维持和发展密切相关，在组织细胞纤维化过程中介导许多关键的细胞-细胞和细胞-细胞外基质相互作用。(Manninen et al,Proteomics,2017,17(3-4):1600022.)。The integrin family is a class of widely distributed transmembrane glycoproteins that link the extracellular matrix environment with intracellular signaling. Integrins are composed of α subunits and β subunits through non-covalent bonds to form heterodimers. At present, 18 kinds of α subunits and 8 kinds of β subunits have been found, which can be combined into at least 24 kinds of integrin dimers. As transmembrane proteins, 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.).
在整合素家族中，αV家族主要参与机体组织的纤维化进程。整合素αV家族包括5种亚型(αVβ1、αVβ3、αVβ5、αVβ6、αVβ8)，在多种组织的正常细胞中低表达，而在纤维性组织细胞中高表达。TGF-β是参与组织纤维化形成的重要因子，尤其是TGF-β1。在炎症和纤维化中，TGF-β1参与生理修复和胶原蛋白的积累。它可以促进上皮细胞和间质细胞的胶原和纤维连接素的生成，导致在创伤修复和纤维化过程中细胞外基质(ECM)积累(Weiskirchen et al,Molecular aspects of medicine,2019,65:2.)。整合素αV家族蛋白参与激活潜藏的TGF-β分子，通过活化TGF-β诱导过度的自身免疫反应和炎症反应，促进组织纤维化进程。In the integrin family, the αV family is mainly involved in the fibrosis process of body tissues. The integrin αV family includes 5 isoforms (αVβ1, αVβ3, αVβ5, αVβ6, αVβ8), which are lowly expressed in normal cells of various tissues and highly expressed in fibrotic tissue cells. TGF-β is an important factor involved in the formation of tissue fibrosis, especially TGF-β1. In inflammation and fibrosis, TGF-β1 is involved in physiological repair and collagen accumulation. It promotes collagen and fibronectin production in epithelial and mesenchymal cells, leading to extracellular matrix (ECM) accumulation during wound repair and fibrosis (Weiskirchen et al, Molecular aspects of medicine, 2019, 65:2. ). Integrin αV family proteins are involved in activating latent TGF-β molecules, which induce excessive autoimmune and inflammatory responses by activating TGF-β, and promote tissue fibrosis.
不同亚型的整合素参与机体不同部位的纤维化进展，在肾组织和肺组织纤维化中αvβ6及αvβ1发挥主要作用，在心脏纤维化中αvβ3/5较常见，而在肝纤维化中αvβ1占主导作用。整合素αvβ1是一种低亲和力的纤连蛋白受体，在基底上皮细胞中高表达，具有促进角化细胞在底层纤维连接蛋白EDA上迁移的作用。阻断整合素αvβ1与TGF-β1相互作用有助于抑制TGF-β1活性，阻断纤维化进程。此外整合素αvβ1通过激活潜伏的TGFβ1，还可参与牙龈成纤维细胞的合成(Jakhu et al,Journal of oral biology and craniofacial research,2018,8(2):122.)。在众多αv家组蛋白中，针对αvβ6的研究较为深入。有报道称，在正常的肺组织中整合素αvβ6表达量很低，但是当肺损伤发生炎症和纤维化时，αvβ6快速高表达(Hatley et al,Angewandte Chemie International Edition,2018,57(13):3298.)。在患有原发性胆汁性肝硬化(PBC)、酒精性脂肪肝、乙肝、丙肝等疾病的患者中，整合素αVβ6的mRNA表达量升高。在肾疾病相关的慢性炎症和纤维化疾病中整合素αVβ6的表达较于正常肾组织显著提高。此外，在糖尿病、肺出血肾炎综合症、Alport综合症、狼疮性肾炎等病人活检样品中整合素αVβ6都显著高表达(Koivisto et al,The international journal of biochemistry&cell biology,2018,99:186.)。Different subtypes of integrins are involved in the progression of fibrosis in different parts of the body. αvβ6 and αvβ1 play a major role in renal and lung fibrosis, αvβ3/5 are more common in cardiac fibrosis, and αvβ1 accounts for more leading role. Integrin αvβ1 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 αvβ1 with TGF-β1 helps to inhibit TGF-β1 activity and block fibrosis. In addition, integrin αvβ1 can also participate in the synthesis of gingival fibroblasts by activating latent TGFβ1 (Jakhu et al, Journal of oral biology and craniofacial research, 2018, 8(2): 122.). Among the many αv family histones, the research on αvβ6 is more in-depth. It has been reported that the expression of integrin αvβ6 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.). In patients with primary biliary cirrhosis (PBC), alcoholic fatty liver, hepatitis B, hepatitis C and other diseases, the mRNA expression of integrin αVβ6 is increased. The expression of integrin αVβ6 was significantly increased in kidney disease-related chronic inflammatory and fibrotic diseases compared with normal kidney tissue. In addition, integrin αVβ6 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.).
组织纤维化可发生于多种器官，是一种较为常见的纤维化疾病包括特发性肺纤维化(IPF)、非酒精性脂肪肝(NASH)、肝硬化、肾纤维化、硬皮症、心肌纤维化等。组织损伤和炎症是纤维化的重要诱因。由于炎症导致器官实质细胞发生坏死，局部免疫细胞被激活，多种血细胞 进入损伤部位。被激活的免疫细胞产生大量具有高度生物活性的细胞因子和趋化因子，导致间充质细胞的局部激活，这些细胞产生细胞外基质(ECM)，破坏细胞外微环境，并进一步增加促炎细胞因子、趋化因子和血管生成因子的产生。最终，细胞外基质异常增多和过度沉积而发生病变致使组织纤维化(Ricard-Blum et al,Matrix Biology,2018,68:122.)。纤维化的主要特征是形成和沉积过多的纤维结缔组织。慢性的伴纤维化损伤会使组织结构被破坏、器官功能发生障碍最终导致器官衰竭。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. 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. Ultimately, 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.
目前获批上市的整合素抑制剂尚为数不多，亟需开发一类结构新颖的，活性好且更加安全有效的整合素调节剂。At present, there are only a few integrin inhibitors approved for marketing, and there is an urgent need to develop a class of integrin modulators with novel structure, good activity, and more safety and effectiveness.
发明内容SUMMARY OF THE INVENTION
为解决现有技术中存在的问题，本发明提供一种式I所示的化合物及其消旋体、立体异构体、互变异构体、同位素标记物、氮氧化物、溶剂化物、多晶型物、代谢产物、酯、前药或其药学上可接受的盐：In order to solve the problems existing in the prior art, 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:
Figure PCTCN2021107688-appb-000001
Figure PCTCN2021107688-appb-000001
其中，所述R 1、R 5各自独立的选自H，OH，卤素，CN，SH，NH 2，COOH，任选被一个、两个或更多个R a取代的如下基团：C 1-C 12脂肪烃基，C 1-C 12脂肪烃基氧基；所述R a选自H，＝O，卤素，OH，CN，SH，NH 2，COOH；每一个R 1可以相同或不同；每一个R 5可以相同或不同； Wherein, the R 1 and R 5 are each independently selected from H, OH, halogen, CN, SH, NH 2 , COOH, the following groups optionally substituted by one, two or more R a : C 1 -C 12 aliphatic hydrocarbyl, C 1 -C 12 aliphatic hydrocarbyloxy; said R a is selected from H, =O, halogen, OH, CN, SH, NH 2 , COOH; each R 1 may be the same or different; each R 1 may be the same or different; One R5 can be the same or different ;
所述R 2、R 3各自独立的选自H，C 1-C 12脂肪烃基，C 3-12环烷基，C 3-12环烷基-C 1-C 12脂肪烃基，-L 4-Ar，并且R 2、R 3中至少一个选自-L 4-Ar； 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;
所述Ar选自任选被一个、两个或更多个R b取代的如下基团：C 3-12环烷基，3-12元杂环基，C 6-20芳基或5-14元杂芳基；所述R b选自H，＝O，卤素，OH，CN，SH，NH 2，COOH，或任选被一个、两个或更多个R c取代的如下基团：C 1-C 12脂肪烃基，C 1-C 12脂肪烃基氧基，C 1-C 12脂肪烃基-SO 2-，C 1-C 12脂肪烃基-NH-，二(C 1-C 12脂肪烃基)N-，C 3-12环烷基，C 3-12环烷基氧基，C 3-12环烷基-SO 2-，C 3-12环烷基-NH-，C 3-12环烷基-C 1-C 12脂肪烃基氧基，C 3-12环烷基-C 1-C 12脂肪烃基-SO 2-，C 3-12环烷基-C 1-C 12脂肪烃基-NH-，3-12元杂环基，3-12元杂环基氧基，3-12元杂环基-SO 2-，3-12元杂环基-NH-，C 6-20芳基，C 6-20芳基氧基，C 6-20芳基-SO 2-，C 6-20芳基-NH-，5-14元杂芳基，5-14元杂芳基氧基，5-14元杂芳基-SO 2-，5-14元杂芳基-NH-；所述R c选自H，＝O，卤素，OH，CN，SH，NH 2，COOH，C 1-C 12脂肪烃基，C 1-C 12脂肪烃基氧基，C 1-C 12脂肪烃基-SO 2-，C 1-C 12脂肪烃基-NH-，二(C 1-C 12脂肪烃基)N-； Said Ar is selected from the following groups optionally substituted by one, two or more R b : C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-20 aryl or 5-14 A membered heteroaryl; the R b is selected from H, =O, halogen, OH, CN, SH, NH 2 , COOH, or optionally substituted with one, two or more R c of the following groups: C 1 -C 12 aliphatic hydrocarbon group, C 1 -C 12 aliphatic hydrocarbon group, C 1 -C 12 aliphatic hydrocarbon group-SO 2 -, C 1 -C 12 aliphatic hydrocarbon group-NH-, bis(C 1 -C 12 aliphatic hydrocarbon group) N-, C 3-12 cycloalkyl, C 3-12 cycloalkyloxy, C 3-12 cycloalkyl-SO 2 -, C 3-12 cycloalkyl-NH-, C 3-12 cycloalkane Alkyl-C 1 -C 12 aliphatic alkyloxy, C 3-12 cycloalkyl-C 1 -C 12 aliphatic alkyl-SO 2 -, C 3-12 cycloalkyl-C 1 -C 12 aliphatic alkyl-NH- , 3-12-membered heterocyclyl, 3-12-membered heterocyclyloxy, 3-12-membered heterocyclyl-SO 2 -, 3-12-membered heterocyclyl-NH-, C 6-20 aryl, C 6-20 Aryloxy, C 6-20 Aryl-SO 2 -, C 6-20 Aryl-NH-, 5-14 Member Heteroaryl, 5-14 Member Heteroaryloxy, 5-14 Member Heteroaryl-SO 2 -, 5-14 Member Heteroaryl-NH-; The R c is selected from H, =O, halogen, OH, CN, SH, NH 2 , COOH, C 1 -C 12 aliphatic Hydrocarbyl, C 1 -C 12 aliphatic hydrocarbyloxy, C 1 -C 12 aliphatic hydrocarbyl-SO 2 -, C 1 -C 12 aliphatic hydrocarbyl-NH-, bis(C 1 -C 12 aliphatic hydrocarbyl)N-;
所述R 4独立的选自H，C 1-C 12脂肪烃基； The R 4 is independently selected from H, C 1 -C 12 aliphatic hydrocarbon groups;
所述L 1、L 2、L 3、L 4各自独立的选自-(CH 2) n-C(＝X)-或-C(＝X)-(CH 2) n-，-(CH 2) m-(当m＝0时，代表键)，-(CH 2) n-C(＝O)-NH-，-(CH 2) n-NH-C(＝O)-，-C(＝O)-NH-(CH 2) n-，-NH-C(＝O)-(CH 2) n-，-(CH 2) n-C(＝O)-NH-(CH 2) n-，-(CH 2) n-NH-C(＝O)-(CH 2) n-；所述X选自O，NH；所述n，m各自独立的选自0-6； The L 1 , L 2 , L 3 , and L 4 are each independently selected from -(CH 2 ) n -C(=X)- or -C(=X)-(CH 2 ) n -, -(CH 2 ) m -(when m=0, it represents a bond), -(CH 2 ) n -C(=O)-NH-, -(CH 2 ) n -NH-C(=O)-, -C(= O)-NH-(CH 2 ) n -, -NH-C(=O)-(CH 2 ) n -, -(CH 2 ) n -C(=O)-NH-(CH 2 ) n -, -(CH 2 ) n -NH-C(=O)-(CH 2 ) n -; the X is selected from O, NH; the n, m are each independently selected from 0-6;
根据本发明的实施方案，所述L 1、L 3各自独立的选自-(CH 2) n-C(＝X)-或-C(＝X)-(CH 2) n-，-(CH 2) m-(当m＝0时，代表键)，所述L 2选自-(CH 2) m-(当m＝0时，代表键)；所述L 4选自-NH-C(＝O)-,-C(＝O)-NH-，-(CH 2) m-(当m＝0时，代表键)；所述X选自O，NH；所述n，m各自独立的选自0，1，2，3，4，5，6； According to an embodiment of the present invention, the L 1 and L 3 are each independently selected from -(CH 2 ) n -C(=X)- or -C(=X)-(CH 2 ) n -, -(CH 2 ) m- (when m=0, it represents a bond), the L 2 is selected from -(CH 2 ) m- (when m=0, it represents a bond); the L 4 is selected from -NH-C ( =O)-,-C(=O)-NH-,-(CH 2 ) m- (when m=0, it represents a bond); the X is selected from O, NH; the n, m are each independent selected from 0, 1, 2, 3, 4, 5, 6;
根据本发明的实施方案，优选的，所述L 1选自-(CH 2) 2-，-(CH 2) 3-，-(CH 2) 4-，-(CH 2) 5-，-CH 2-C(＝O)-，-(CH 2) 2-C(＝O)-，-(CH 2) 3-C(＝O)-，-(CH 2) 4-C(＝O)-；L 2选自键，-CH 2-；L 3选自键，-CH 2-，-(CH 2) 2-；L 4选自键，-CH 2-； According to an embodiment of the present invention, preferably, the L 1 is selected from -(CH 2 ) 2 -, -(CH 2 ) 3 -, -(CH 2 ) 4 -, -(CH 2 ) 5 -, -CH 2 -C(=O)-, -(CH 2 ) 2 -C(=O)-, -(CH 2 ) 3 -C(=O)-, -(CH 2 ) 4 -C(=O)- ; 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 -;
根据本发明的实施方案，所述“卤素”选自F、Cl、Br、I；所述“脂肪烃基”选自烷基、烯基、炔基；According to an embodiment of the present invention, the "halogen" is selected from F, Cl, Br, and I; the "aliphatic hydrocarbon group" is selected from alkyl, alkenyl, and alkynyl;
根据本发明的实施方案，优选的，所述R 1、R 5各自独立的选自卤素，C 1-C 6脂肪烃基，例如，选自F、Cl、Br、I，甲基，乙基，正丙基，异丙基，正丁基，异丁基，叔丁基，正戊基，异戊基，新戊基，正己基。 According to an embodiment of the present invention, preferably, 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.
根据本发明的实施方案，优选的，所述R 2选自H，C 1-C 6脂肪烃基或C 3-8环烷基-C 1-C 6脂肪烃基，且R 3选自-L 4-Ar或所述R 2选自-L 4-Ar且R 3选自H，C 1-C 6脂肪烃基或C 3-8环烷基-C 1-C 6脂肪烃基；更优选的，所述R 2选自H，甲基，乙基，正丙基，异丙基，正丁基，异丁基，叔丁基，正戊基，异戊基，新戊基，正己基，环丙基甲基，环丁基甲基，环戊基甲基，环己基甲基，所述R 3选自Ar(L 4代表键时)。 According to an embodiment of the present invention, preferably, 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, the R 3 is selected from Ar (when L 4 represents a bond).
根据本发明的实施方案，所述Ar选自任选被一个、两个或更多个R b取代的如下基团：C 6-C 14芳基，5-10元杂环基，5-6元杂芳基，优选的，Ar选自任选被一个、两个或更多个R b取代的苯基，萘基，2,3-二氢苯并呋喃基，苯并呋喃基，苯并吡喃基，3,4-二氢-2H-1-苯并吡喃基(色烷基)，2,3-二氢苯并[b][1,4]二噁烷基，吡啶基，嘧啶基，吲唑基(1H-吲唑基，2H-吲唑基)，吲哚基，异吲哚基，喹啉基，异喹啉基，喹唑啉基，苯并噁唑基； According to an embodiment of the present invention, 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;
根据本发明的实施方案，优选的，所述R b选自H，卤素，CN，或任选被一个、两个或更多个R c取代的如下基团：C 1-C 6脂肪烃基，C 1-C 6脂肪烃基氧基，C 1-C 6脂肪烃基-SO 2-，C 1-C 6脂肪烃基-NH-，二(C 1-C 6脂肪烃基)N-，C 6-10芳基，C 6-10芳基氧基，C 6-10芳基-SO 2-，C 6-10芳基-NH-，5-6元杂芳基，5-6元杂芳基氧基，5-6元杂芳基-SO 2-，5-6元杂芳基-NH-，5-6元杂环基，5-6元杂环基氧基，5-6元杂环基-SO 2-，5-6元杂环基-NH-，C 3-8环烷基，C 3-8环烷基氧基，C 3-8环烷基-SO 2-，C 3-8环烷基-NH-，C 3-8环烷基-C 1-C 6脂肪烃基氧基，C 3-8环烷基-C 1-C 6脂肪烃基-SO 2-，C 3-8环烷基-C 1-C 6脂肪烃基-NH-；更优选的，所述R b选自H，卤素，CN或任选被一个、两个或更多个R c取代的C 1-C 6烷基，C 1-C 6烷氧基，C 1-C 6烷基-SO 2-，C 1-C 6烷基-NH-，二(C 1-C 6烷基)N-，5-6元杂芳基-SO 2-，5-6元杂芳基-NH-，5-6元杂环基，5-6元杂环基氧基，5-6元杂环基-SO 2-，5-6元杂环基-NH-，C 3-6环烷基，C 3-6环烷基氧基，C 3-6环烷基-SO 2-，C 3-6环烷基-NH-，C 3-6环烷基-C 1-C 6烷氧基，C 3-6环烷基-C 1-C 6烷基-SO 2-，C 3-6环烷基-C 1-C 6烷基-NH-；进一步优选的，所述R b选自H，卤素，CN或任选被一个、两个或更多个R c取代的甲基，乙基，正丙基，异丙基，正丁基，异丁基，叔丁基，正戊基，异戊基，新戊基，正己基，乙烯基，1-丙烯基，2-丙烯基，1-甲基乙烯基，1-丁烯基，1-乙基乙烯基，1-甲基-2-丙烯基，2-丁烯基，3-丁烯基、2-甲基-1-丙烯基，2-甲基-2-丙烯基，1-戊烯基、1-己烯基，乙炔基，1-丙炔基，2-丙炔基，1-丁炔基，1-甲基-2-丙炔基，3-丁炔基，1-戊炔基，1-己炔基，甲氧基，乙氧基，正丙氧基，异丙氧基，异丁氧基，正丁氧基，叔丁氧基，戊氧 基，己氧基，N,N-二甲基氨基，N,N-二乙基氨基，甲基-NH-，乙基-NH-，正丙基-NH-，异丙基-NH-，正丁基-NH-，异丁基-NH-，叔丁基-NH-，正戊基-NH-，异戊基-NH-，新戊基-NH-，正己基-NH-，甲基-SO 2-，乙基-SO 2-，正丙基-SO 2-，异丙基-SO 2-，正丁基-SO 2-，异丁基-SO 2-，叔丁基-SO 2-，正戊基-SO 2-，异戊基-SO 2-，新戊基-SO 2-，正己基-SO 2-，环丙基，环丁基，环戊基，环己基，环丙基氧基，环丁基氧基，环戊基氧基，环己基氧基，环丙基，环丁基，环戊基，环己基，环丙基-SO 2-，环丁基-SO 2-，环戊基-SO 2-，环己基-SO 2-，环丙基-NH-，环丁基-NH-，环戊基-NH-，环己基-NH-，环丙基甲基氧基，环丁基甲基氧基，环戊基甲基氧基，环己基甲基氧基，环丙基甲基-SO 2-，环丁基甲基-SO 2-，环戊基甲基-SO 2-，环己基甲基-SO 2-，环丙基甲基-NH-，环丁基甲基-NH-，环戊基甲基-NH-，环己基甲基-NH-，苯基，苯基-SO 2-，苯基-NH-，萘基，萘基-SO 2-，萘基-NH，氧杂环丁烷，吡喃基，四氢吡喃基，呋喃基，四氢呋喃基，四氢吡咯基，哌啶基，吡啶基，吡嗪基，吡咯基，咪唑基，吡唑基，三氮唑，噁唑基，异噁唑基，吗啉基；例如，R b选自F，Cl，Br，I，CN，甲基，乙基，正丙基，异丙基，正丁基，异丁基，叔丁基，新戊基，甲基-SO 2-，甲氧基，乙氧基，正丙氧基，异丙氧基，异丁氧基，N,N-二甲基氨基，异丙基-NH-，环丙基氧基，环丁基氧基，环戊基氧基，环丙基甲基氧基，环丙基氨基，CF 3，CHF 2，CH 2F，CF 3O，CHF 2O，CH 2FO，苯基，3,5-二甲基吡唑-1-基，咪唑基，吗啉基，1,2,4-三氮唑，氧杂环丁烷，四氢呋喃基，四氢吡喃基，四氢吡咯基； According to an embodiment of the present invention, preferably, 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 -, 5-6 membered heterocyclyl-NH-, C 3-8 cycloalkyl, C 3-8 cycloalkyloxy, C 3-8 cycloalkyl-SO 2 -, C 3-8 ring Alkyl-NH-, C 3-8 cycloalkyl-C 1 -C 6 aliphatic alkyloxy, C 3-8 cycloalkyl-C 1 -C 6 aliphatic alkyl-SO 2 -, C 3-8 cycloalkane base-C 1 -C 6 aliphatic alkyl-NH-; more preferably, the R b is selected from H, halogen, CN or C 1 -C 6 alkane optionally substituted with one, two or more R c base, C 1 -C 6 alkoxy, C 1 -C 6 alkyl-SO 2 -, C 1 -C 6 alkyl-NH-, bis(C 1 -C 6 alkyl) N-, 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 -, 5-6 membered heterocyclyl-NH-, C 3-6 cycloalkyl, C 3-6 cycloalkyloxy, C 3-6 cycloalkyl-SO 2 -, C 3-6 cycloalkyl-NH -, C 3-6 cycloalkyl-C 1 -C 6 alkoxy, C 3-6 cycloalkyl-C 1 -C 6 alkyl-SO 2 -, C 3-6 cycloalkyl-C 1 - C 6 alkyl-NH-; further preferably, the R b is selected from H, halogen, CN or methyl, ethyl, n-propyl, iso-methyl optionally substituted by one, two or more R c Propyl, 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-methyl- 2-propenyl, 1-pentenyl, 1-hexenyl, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 1-methyl-2-propynyl, 3 -butynyl, 1-pentynyl, 1-hexynyl, methoxy, ethoxy, n-propoxy, isopropoxy, isobutoxy, n-butoxy, tert-butoxy, Pentyloxy, Hexyloxy, N,N-Dimethylamino, N,N-Diethylamino, Methyl-N H-, ethyl-NH-, n-propyl-NH-, isopropyl-NH-, n-butyl-NH-, isobutyl-NH-, tert-butyl-NH-, n-pentyl-NH- , isopentyl-NH-, neopentyl-NH-, n-hexyl-NH-, methyl-SO 2 -, ethyl-SO 2 -, n-propyl-SO 2 -, isopropyl-SO 2 - , n-butyl-SO 2 -, isobutyl-SO 2 -, tert-butyl-SO 2 -, n-pentyl-SO 2 -, isopentyl-SO 2 -, neopentyl-SO 2 -, n-hexyl -SO 2 -, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cyclopropyl, cyclobutyl cyclopentyl, cyclopentyl, cyclohexyl, cyclopropyl-SO 2 -, cyclobutyl-SO 2 -, cyclopentyl-SO 2 -, cyclohexyl-SO 2 -, cyclopropyl-NH-, cyclobutyl -NH-, cyclopentyl-NH-, cyclohexyl-NH-, cyclopropylmethyloxy, cyclobutylmethyloxy, cyclopentylmethyloxy, cyclohexylmethyloxy, cyclopropylmethyloxy base-SO 2 -, cyclobutylmethyl-SO 2 -, cyclopentylmethyl-SO 2 -, cyclohexylmethyl-SO 2 -, cyclopropylmethyl-NH-, cyclobutylmethyl-NH-, cyclo Amylmethyl-NH-, cyclohexylmethyl-NH-, phenyl, phenyl- SO2- , phenyl-NH-, naphthyl, naphthyl- SO2- , naphthyl-NH, oxacycle Butane, pyranyl, tetrahydropyranyl, furanyl, tetrahydrofuranyl, tetrahydropyrrolyl, piperidinyl, pyridyl, pyrazinyl, pyrrolyl, imidazolyl, pyrazolyl, triazole, oxa oxazolyl, isoxazolyl, morpholinyl; for example, R b is selected from F, Cl, Br, I, CN, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, neopentyl, methyl-SO 2 -, methoxy, ethoxy, n-propoxy, isopropoxy, isobutoxy, N,N-dimethylamino, isopropyl -NH-, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclopropylmethyloxy, cyclopropylamino, CF3 , CHF2 , CH2F , CF3O , CHF 2 O, CH 2 FO, phenyl, 3,5-dimethylpyrazol-1-yl, imidazolyl, morpholinyl, 1,2,4-triazole, oxetane, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyrrolyl;
根据本发明的实施方案，优选的，所述R c选自H，＝O，卤素，OH，CN，SH，NH 2，COOH，C 1-C 6烷基，C 1-C 6烷氧基，C 1-C 6烷基-SO 2-，二(C 1-C 6烷基)N-，C 1-C 6烷基-NH-；例如选自H，＝O，F，Cl，Br，I，OH，CN，SH，NH 2，COOH，甲基，乙基，正丙基，异丙基，正丁基，异丁基，叔丁基，正戊基，异戊基，新戊基，正己基，甲氧基，乙氧基，正丙氧基，异丙氧基，异丁氧基，正丁氧基，叔丁氧基，戊氧基，己氧基，N,N-二甲基氨基，N,N-二乙基氨基，甲基-NH-，乙基-NH-，正丙基-NH-，异丙基-NH-，正丁基-NH-，异丁基-NH-，叔丁基-NH-，正戊基-NH-，异戊基-NH-，新戊基-NH-，正己基-NH-，甲基-SO 2-，乙基-SO 2-，正丙基-SO 2-，异丙基-SO 2-，正丁基-SO 2-，异丁基-SO 2-，叔丁基-SO 2-，正戊基-SO 2-，异戊基-SO 2-，新戊基-SO 2-，正己基-SO 2-； According to an embodiment of the present invention, preferably, the R c is selected from H, =O, halogen, OH, CN, SH, NH 2 , COOH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy , C 1 -C 6 alkyl-SO 2 -, di(C 1 -C 6 alkyl)N-, C 1 -C 6 alkyl-NH-; for example, selected from H, =O, F, Cl, Br , I, OH, CN, SH, NH 2 , COOH, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl base, n-hexyl, methoxy, ethoxy, n-propoxy, isopropoxy, isobutoxy, n-butoxy, tert-butoxy, pentyloxy, hexyloxy, N,N- Dimethylamino, N,N-diethylamino, methyl-NH-, ethyl-NH-, n-propyl-NH-, isopropyl-NH-, n-butyl-NH-, isobutyl -NH-, tert-butyl-NH-, n-pentyl-NH-, isopentyl-NH-, neopentyl-NH-, n-hexyl-NH-, methyl-SO 2 -, ethyl-SO 2 -, n-propyl-SO 2 -, isopropyl-SO 2 -, n-butyl-SO 2 -, isobutyl-SO 2 -, tert-butyl-SO 2 -, n-pentyl-SO 2 -, Isopentyl-SO 2 -, neopentyl-SO 2 -, n-hexyl-SO 2 -;
根据本发明的实施方案，所述R 4独立的选自H，C 1-C 6脂肪烃基，优选的，选自甲基，乙基，正丙基，异丙基，正丁基，异丁基，叔丁基，正戊基，异戊基，新戊基，正己基； According to an embodiment of the present invention, 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;
根据本发明的实施方案，优选的，所述Ar选自如下基团：According to an embodiment of the present invention, preferably, the Ar is selected from the following groups:
Figure PCTCN2021107688-appb-000002
Figure PCTCN2021107688-appb-000002
Figure PCTCN2021107688-appb-000003
Figure PCTCN2021107688-appb-000003
所述结构中，R b选自式I中所述定义。 In the structure, R b is selected from the definitions described in formula I.
根据本发明的实施方案，更优选的，所述R 2或R 3中的一个选自如下基团： According to an embodiment of the present invention, more preferably, one of the R 2 or R 3 is selected from the following groups:
Figure PCTCN2021107688-appb-000004
Figure PCTCN2021107688-appb-000004
Figure PCTCN2021107688-appb-000005
Figure PCTCN2021107688-appb-000005
Figure PCTCN2021107688-appb-000006
Figure PCTCN2021107688-appb-000006
根据本发明的实施方案，所述式I结构选自如下式Ia：According to an embodiment of the present invention, the structure of formula I is selected from the following formula Ia:
Figure PCTCN2021107688-appb-000007
Figure PCTCN2021107688-appb-000007
所述式Ia结构中，R 1、R 2、R 3、R 4、R 5、L 1、L 2如前述式I所定义。 In the structure of formula Ia, R 1 , R 2 , R 3 , R 4 , R 5 , L 1 , and L 2 are as defined in formula I above.
所述式Ia的*S 1标记处可存在Endo-和Exo-两种构型，示意如下： There can be two configurations of Endo- and Exo- at the *S 1 mark of the formula Ia, as shown below:
Figure PCTCN2021107688-appb-000008
Figure PCTCN2021107688-appb-000008
所述式Ia中，*S 2标记处存在两种构型，示意如下： In the formula Ia, there are two configurations at the *S mark, as shown below:
Figure PCTCN2021107688-appb-000009
Figure PCTCN2021107688-appb-000009
根据本发明的实施方案，所述式I可以选自在一个所述标记处具有特定立体构型的化合物，或在两个所述标记处均具有不同特定立体构型的化合物。According to an embodiment of the present invention, 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.
根据本发明的实施方案，所述式I结构可以选自如下式IIa-IIj：According to an embodiment of the present invention, the structure of formula I may be selected from the following formulae IIa-IIj:
Figure PCTCN2021107688-appb-000010
Figure PCTCN2021107688-appb-000010
Figure PCTCN2021107688-appb-000011
Figure PCTCN2021107688-appb-000011
所述式IIa-IIj结构中，R 1、R 2、R 3、R 4、R 5、L 1、L 2、L 3以及其他手性中心如前述式I所定义。 In the structures of formula 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.
根据本发明的实施方案，所述式I化合物进一步优选为如下式III(式IIIa、式IIIb)、式IV(式IVa、式IVb)：According to an embodiment of the present invention, the compound of formula I is further preferably the following formula III (formula IIIa, formula IIIb), formula IV (formula IVa, formula IVb):
Figure PCTCN2021107688-appb-000012
Figure PCTCN2021107688-appb-000012
根据本发明的实施方案，所述式III(式IIIa、式IIIb)、式IV(式IVa、式IVb)结构中，R 1、R 3、R 4、R 5、L 1、L 2以及其他手性中心如前述式I所定义。 According to an embodiment of the present invention, in the structures of formula III (formula IIIa, formula IIIb) and 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.
根据本发明的实施方案，所述式I化合物进一步优选为如下式V至式XVII：According to an embodiment of the present invention, the compound of formula I is further preferably of the following formulae V to XVII:
Figure PCTCN2021107688-appb-000013
Figure PCTCN2021107688-appb-000013
根据本发明的实施方案，所述式V至式VII结构中，R 1、R 3、R 4、R 5、n、m以及其他手性中心如前述式I所定义。 According to an embodiment of the present invention, in the structures of Formula V to Formula VII, R 1 , R 3 , R 4 , R 5 , n, m and other chiral centers are as defined in Formula I above.
根据本发明的实施方案，所述式I(包括式II至式VII)所示的化合物及其消旋体、立体异构体、互变异构体、同位素标记物、氮氧化物、溶剂化物、多晶型物、代谢产物、酯、前药或其药学上可接受的盐中，式I化合物的举例性的、非限制性的具体实例如下所示：According to an embodiment of the present invention, 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:
Figure PCTCN2021107688-appb-000014
Figure PCTCN2021107688-appb-000014
Figure PCTCN2021107688-appb-000015
Figure PCTCN2021107688-appb-000015
所述结构式中，以星号(“*”)标记表明所述结构在星号所示碳位具有手性，因而可以以所述标记位置具有相反构象的异构体混合物形式存在，并通过手性拆分得到具有所述结构的两种异构体。根据本发明的实施方案，所述式I化合物的立体异构体还可以进一步选自例如如下结构：In the formula, marked with an asterisk ("*") indicates that the structure has chirality at the carbon position indicated by the asterisk, so it can exist in the form of a mixture of isomers with the opposite conformation at the marked position, and can be obtained by hand. Sexual resolution gave two isomers with the stated structure. According to an embodiment of the present invention, the stereoisomer of the compound of formula I may be further selected from, for example, the following structures:
Figure PCTCN2021107688-appb-000016
Figure PCTCN2021107688-appb-000016
本发明还提供所述式I所示的化合物(包括式II至式VII)及其消旋体、立体异构体、互变异构体、同位素标记物、氮氧化物、溶剂化物、多晶型物、代谢产物、酯、前药或其药学上可接受的盐的制备方法，但不仅限于以下描述的方法。所有的原料都是根据符合通式规律的目标分子的基团特征，并通过这些路线中的方案、有机化学领域普通技术人员熟知的方法制备或者直接购买的。可将用下述方法和合成有机化学领域中已知的合成方法或本领域技术人员意识到的有关改变方法结合在一起，合成本发明化合物。本领域技术人员可知，根据特定的目标结构，可以任选采用下述一种或几种方案进行结合，或者一种或几种方案中的任意步骤进行组合得到合成方案。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 preparation method of the form, metabolite, ester, prodrug or its pharmaceutically acceptable salt, but not limited to the method described below. All starting materials are based on the group characteristics of the target molecule conforming to the general formula, and are prepared by the schemes in these routes, methods well known to those of ordinary skill in the field of organic chemistry, or purchased directly. 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.
本发明所述化合物的制备方法包括：在合适的条件下，将含萘啶环结构的原料与含氮杂双环[3.1.0]己烷结构的原料在合适的试剂中进行反应，并任选的，在合适的条件下，进行上保护基，脱保护基，取代，缩合，还原胺化或水解步骤。具体的，可以参照如下方案进行合成。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.
在第一种方案中，本发明的化合物的制备包括如下步骤中的一步或几步：In the first scheme, the preparation of the compounds of the present invention comprises one or more of the following steps:
Figure PCTCN2021107688-appb-000017
Figure PCTCN2021107688-appb-000017
所述方案中，所述R 1，R 3，R 4(R 4≠H)，R 5，L 1，L 2，L 3如前述式I所定义；所述Lx选自L 1-X 1，其中，X 1为离去基团，选自例如OTs，OMs，OTf，卤素(Cl，Br，I)，或者所述Lx选自L 1基团(当存在末端-CH 2-时)的末端-CH 2-替代为CHO或COOH的基团，例如选自 -(CH 2) m-1-CHO或-(CH 2) m-1-COOH，所述m如前述式I所定义；所述PG 1为N上保护基，选自Boc-等；所述第一种方案中，采用化合物A-1和A-2合成得到化合物A-3，反应条件可选自(i)NaBH(OAc) 3，NaBH 3CN，HOAc,甲醇；或(ii)HBTU，TEA，DMF和或任选的加入酸性试剂；或(iii)DIPEA，乙腈；(iv)K 2CO 3，NaI，乙腈；所述脱保护基条件包括在酸性试剂，第一种有机溶剂下进行，所述酸性试剂选自三氟乙酸(三氟乙酸)，盐酸，所述第一种有机溶剂选自二氯甲烷，1，4-二氧六环，醇类试剂中的一种或多种，所述醇类试剂选自甲醇，乙醇；所述水解条件包括在碱性条件，水+第二种有机溶剂条件下进行，所述碱性条件选自碱金属或碱土金属的氢氧化物，例如选自LiOH，NaOH，所述第二种有机溶剂选自醇类试剂，例如选自甲醇、乙醇。 In the scheme, 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 3 CN, HOAc, methanol; or (ii) HBTU, TEA, DMF and or optional addition of an acidic reagent; or (iii) DIPEA, acetonitrile; (iv) K 2 CO 3 , NaI, acetonitrile; Described deprotection group condition comprises in acid reagent, carry out under the first organic solvent, described acid reagent is selected from trifluoroacetic acid (trifluoroacetic acid), hydrochloric acid, described first organic solvent is selected from dichloromethane, 1, 4-dioxane, one or more of alcohol reagents, the alcohol reagents are selected from methanol, ethanol; the hydrolysis conditions include basic conditions, water+second organic solvent conditions, carry out, The basic conditions are selected from hydroxides of alkali metals or alkaline earth metals, such as LiOH and NaOH, and the second organic solvent is selected from alcohol reagents, such as methanol and ethanol.
本发明进一步提供一种药物组合物，其包含本发明所述的式I化合物及其消旋体、立体异构体、互变异构体、同位素标记物、氮氧化物、溶剂化物、多晶型物、代谢产物、酯、前药或其药学上可接受的盐。The present invention further provides 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.
在一些实施方案中，本发明所述的药物组合物进一步包含治疗有效量的本发明所述式I化合物及其消旋体、立体异构体、互变异构体、同位素标记物、氮氧化物、溶剂化物、多晶型物、代谢产物、酯、前药或其药学上可接受的盐和药学上可接受的载体。In some embodiments, 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.
所述药物组合物中的载体为“可接受的”，其可与组合物的活性成分相容(并且优选地，能够稳定活性成分)并且对被治疗的受试者不是有害的。可以使用一种或多种增溶剂作为药物赋形剂用于递送活性化合物。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.
本发明进一步提供所述式I化合物及其消旋体、立体异构体、互变异构体、同位素标记物、氮氧化物、溶剂化物、多晶型物、代谢产物、酯、前药或其药学上可接受的盐或所述药物组合物在制备整合素调节剂中的应用。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.
本发明进一步提供所述式I化合物及其消旋体、立体异构体、互变异构体、同位素标记物、氮氧化物、溶剂化物、多晶型物、代谢产物、酯、前药或其药学上可接受的盐或所述药物组合物在制备预防，调节或治疗与整合素活性有关的疾病或病症的药物中的用途。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.
本发明进一步提供所述式I化合物及其消旋体、立体异构体、互变异构体、同位素标记物、氮氧化物、溶剂化物、多晶型物、代谢产物、酯、前药或其药学上可接受的盐或所述药物组合物在制备用于治疗纤维化性疾病，炎性疾病或细胞增殖性疾病的药物中的用途。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.
本发明进一步提供所述式I化合物及其消旋体、立体异构体、互变异构体、同位素标记物、氮氧化物、溶剂化物、多晶型物、代谢产物、酯、前药或其药学上可接受的盐或所述药物组合物在制备用于抑制细胞中TGF-β活化的药物中的用途。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-β activation in cells.
本发明还提供了一种在受试者中调节至少一种整合素活性的方法，该方法包括给予本发明所述化合物作为治疗剂。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.
本发明中，化合物对整合素的调节作用是对αVβ1，αVβ3，αVβ5，αVβ6，αVβ8，α5β1和α8β1中的任一种或αVβ1，αVβ3，αVβ5，αVβ6，αVβ8，α5β1和α8β1中的一个或多个的组合的调节作用。在一些实施方式中，所述调节作用表现为抑制作用。在一些实施方式中，所述抑制作用可以是对αVβ1，αVβ3，αVβ5，αVβ6，和αVβ8，α5β1，α8β1的抑制作用；在另一些实施方式中，所述抑制作用是对αVβ1，αVβ3，αVβ5，αVβ6，和αVβ8，α5β1，α8β1中的一种的抑制作用，例如，所述抑制作用是对α8β1的抑制作用；在另一些实施方式中，所述抑制作用包括对α8β1和αVβ1的抑制作用；在另一些实施方式中，所述抑制作用包括对α8β1 和α5β1的抑制作用；在另一些实施方式中，所述抑制作用包括对αvβ3和αvβ5的抑制作用；在一些实施方式中，所述抑制作用包括对α8β1，αvβ3和αvβ5的抑制作用；在一些实施方式中，所述抑制作用包括对α8β1，αvβ1和α5β1的抑制作用；在一些实施方式中，所述抑制作用包括对α8β1，αvβ1，αvβ3和αvβ5的抑制作用。在一些实施方式中，所述抑制作用包括对αVβ1，αVβ3，αVβ5，α5β1，α8β1的抑制作用。根据本发明的实施方案，所述整合素包括αVβ1，αVβ3，αVβ5，αVβ6，和αVβ8，α5β1，α8β1中的一个或多个的组合。本发明还提供了一种用于治疗疾病或病症的方法，该方法包括向需要这种治疗的患者单独施用治疗有效量的至少一种本发明的化合物，或任选地，与本发明的另一种化合物和/或至少一种其他类型的治疗剂组合。In the present invention, the modulation effect of the compound on integrin is any one of αVβ1, αVβ3, αVβ5, αVβ6, αVβ8, α5β1 and α8β1 or one or more of αVβ1, αVβ3, αVβ5, αVβ6, αVβ8, α5β1 and α8β1 The regulatory effect of a combination. In some embodiments, the modulating effect is manifested as an inhibitory effect. In some embodiments, the inhibitory effect may be the inhibition of αVβ1, αVβ3, αVβ5, αVβ6, and αVβ8, α5β1, α8β1; in other embodiments, the inhibitory effect is the inhibition of αVβ1, αVβ3, αVβ5, Inhibition of αVβ6, and one of αVβ8, α5β1, α8β1, for example, the inhibitory effect is the inhibition of α8β1; in other embodiments, the inhibitory effect includes the inhibition of α8β1 and αVβ1; in In other embodiments, the inhibitory effect includes the inhibition of α8β1 and α5β1; in other embodiments, the inhibitory effect includes the inhibition of αvβ3 and αvβ5; in some embodiments, the inhibitory effect includes Inhibition of α8β1, αvβ3 and αvβ5; in some embodiments, the inhibition includes inhibition of α8β1, αvβ1 and α5β1; in some embodiments, the inhibition includes inhibition of α8β1, αvβ1, αvβ3 and αvβ5 inhibitory effect. In some embodiments, the inhibitory effect includes inhibition of αVβ1, αVβ3, αVβ5, α5β1, α8β1. According to an embodiment of the invention, the integrin comprises a combination of one or more of αVβ1, αVβ3, αVβ5, αVβ6, and αVβ8, α5β1, α8β1. 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.
本发明还提供了一种抑制细胞中TGF-β活化的方法，该方法包括向该细胞施用式I化合物及其消旋体、立体异构体、互变异构体、同位素标记物、氮氧化物、溶剂化物、多晶型物、代谢产物、酯、前药或其药学上可接受的盐或所述药物组合物。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.
在一些实施方案中，所述疾病或病症与纤维化有关，包括肺，肝，肾，心脏，皮肤，眼和胰腺纤维化。In some embodiments, the disease or disorder is associated with fibrosis, including fibrosis of the lung, liver, kidney, heart, skin, eye, and pancreas.
根据本发明的实施方案，所述疾病或病症与细胞增殖性病症例如癌症有关。在一些实施方案中，癌症包括实体瘤生长或瘤形成。在其他实施方案中，癌症包括肿瘤转移。在一些实施方案中，癌症是膀胱癌，血液癌，骨癌，脑癌，乳腺癌，中枢神经系统癌，子宫颈癌，结肠癌，子宫内膜癌，食道癌，胆囊癌，生殖器癌，泌尿生殖道癌，头癌，肾癌，喉癌，肝癌，肺癌，肌肉癌。组织，颈部，口腔或鼻粘膜，卵巢，胰腺，前列腺，皮肤，脾脏，小肠，大肠，胃，睾丸或甲状腺。在其他实施方案中，癌症是肉瘤，淋巴瘤，白血病，黑素瘤，间皮瘤，多发性骨髓瘤或精原细胞瘤。According to an embodiment of the invention, the disease or disorder is associated with a cell proliferative disorder such as cancer. In some embodiments, the cancer comprises solid tumor growth or neoplasia. In other embodiments, the cancer includes tumor metastasis. In some embodiments, 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. Tissue, neck, oral or nasal mucosa, ovary, pancreas, prostate, skin, spleen, small intestine, large intestine, stomach, testes or thyroid. In other embodiments, the cancer is sarcoma, lymphoma, leukemia, melanoma, mesothelioma, multiple myeloma, or seminoma.
根据本发明可以预防，调节或治疗的与αV整合素活性有关的疾病，病症或病状的实例包括但不限于移植注射，纤维化病症(例如特发性肺纤维化，间质性肺疾病，肝纤维化，非酒精性脂肪性肝，原发性硬化性胆管炎(PSC)，肾纤维化，皮肤纤维化，心肌纤维化，系统性硬化)，炎症性疾病(例如急性肝炎，慢性肝炎，，牛皮癣，肠易激综合征(IBS)，炎症性肠病(IBD))，骨质疏松症以及细胞增殖性疾病(例如癌症，骨髓瘤，纤维瘤，肝癌，白血病，卡波西氏肉瘤，实体瘤)。Examples of diseases, disorders or conditions associated with αV integrin activity that may be prevented, modulated or treated according to the present invention 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).
适用于通过本发明化合物预防或治疗的纤维化疾病，炎性疾病以及细胞增殖性疾病包括但不限于特发性肺纤维化(IPF)，间质性肺病，非特异性间质性肺炎(NSIP)，常规间质性肺炎(UIP)，辐射诱发性纤维化，家族性肺纤维化，气道纤维化，慢性阻塞性肺疾病(COPD)，糖尿病性肾病，局灶性节段性肾小球硬化，IgA肾病，药物或移植引起的肾病，自身免疫性肾病，狼疮性肾炎，肝纤维化，肾脏纤维化，慢性肾脏病(CKD)，糖尿病肾病(DKD)，皮肤纤维化，瘢痕，全身性硬化，硬皮病，病毒性纤维化，非酒精性脂肪肝病(NAFLD)，酒精性或非酒精性脂肪性肝炎(NASH)，急性肝炎，慢性肝炎，肝硬化，原发性硬化性胆管炎，药物性肝炎，胆汁性肝硬化，门脉高压，再生衰竭，肝功能不全，肝血流异常，肾病，肺炎，牛皮癣，肠易激综合征罗马(IBS)，炎性肠病(IBD)，胰腺分泌异常，前列腺增生，神经性膀胱疾病，脊髓肿瘤，椎间盘疝，椎管狭窄，心力衰竭，心脏纤维化，血管纤维化，血管周纤维化，足口疾病，癌症，骨髓瘤，纤维瘤，肝癌，白血病，慢性淋巴细胞性白血病，卡波济肉瘤，实体瘤，脑梗死，脑出血，神经性疼痛，周围神经病，年龄相关性黄斑变性(AMD)，青光眼，眼 纤维化，角膜瘢痕形成，糖尿病性视网膜病变，增生性玻璃体视网膜病变(PVR)，瘢痕性天疱疮性青光眼滤过手术瘢痕，克罗恩病或系统性红斑狼疮；伤口愈合异常导致瘢痕形成；器官移植后发生纤维化，骨髓纤维化和肌瘤。本发明还提供了一种用于治疗纤维化疾病，炎性疾病或细胞增殖性疾病的方法，包括向需要这种治疗的患者施用治疗有效量的至少一种化合物。单独地或任选地与本发明的另一种化合物和/或至少一种其他类型的治疗剂组合的本发明的“抗氧化剂”。在另一些实施方案中，本发明提供了用于治疗的本发明化合物。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 steatohepatitis (NASH), acute hepatitis, chronic hepatitis, cirrhosis, primary sclerosing cholangitis, drugs Hepatitis, biliary cirrhosis, portal hypertension, regenerative failure, hepatic insufficiency, abnormal hepatic blood flow, nephropathy, pneumonia, psoriasis, irritable bowel syndrome Rome (IBS), inflammatory bowel disease (IBD), pancreatic secretion Abnormalities, benign prostatic hyperplasia, neurogenic bladder disease, spinal cord tumor, intervertebral disc hernia, spinal stenosis, heart failure, cardiac fibrosis, vascular fibrosis, perivascular fibrosis, foot and mouth disease, cancer, myeloma, fibroma, liver cancer, Leukemia, Chronic Lymphocytic Leukemia, Kaposi's Sarcoma, Solid Tumors, Cerebral Infarction, Cerebral Hemorrhage, Neuropathic Pain, Peripheral Neuropathy, Age-Related Macular Degeneration (AMD), Glaucoma, Ocular Fibrosis, Corneal Scarring, Diabetic Retinopathy, proliferative vitreoretinopathy (PVR), cicatricial pemphigus glaucoma filtering surgical scars, Crohn's disease or systemic lupus erythematosus; abnormal wound healing leading to scarring; fibrosis after organ transplantation, bone marrow fibers fibroids and fibroids. 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. In other embodiments, the present invention provides compounds of the present invention for use in therapy.
本发明的化合物可以与另外的治疗剂例如一种或多种抗纤维化和/或抗炎治疗剂组合使用。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.
本发明进一步提供了一种用于治疗纤维化疾病，炎性疾病或细胞增殖性疾病的方法，所述方法包括向有需要的患者施用治疗有效量的第一和第二治疗剂，其中第一治疗剂是本发明的化合物。在一些实施方案中，本发明提供了本发明所述化合物与另外的治疗剂的组合制剂，用于在治疗中同时，分开或依次使用。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. In some embodiments, 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.
术语解释：Terminology Explanation:
除非另有说明，本申请说明书和权利要求书中记载的基团和术语定义，包括其作为实例的定义、示例性的定义、优选的定义、表格中记载的定义、实施例中具体化合物的定义等，可以彼此之间任意组合和结合。这样的组合和结合后的基团定义及化合物结构，应当属于本申请说明书记载的范围。Unless otherwise stated, definitions of groups and terms set forth in the specification and claims of this application, including their definitions as examples, exemplary definitions, preferred definitions, definitions set forth in tables, and definitions of specific compounds in the examples etc., can be arbitrarily combined and combined with each other. Such combinations, group definitions and compound structures after the combination should fall within the scope of the description of the present application.
本申请说明书和权利要求书记载的数值范围，当该数值范围被定义为“整数”时或按照本领域常规理解通常为“整数”时，应当理解为记载了该范围的两个端点以及该范围内的每一个整数。例如，“0～6”表示碳数时，应当理解为记载了0、1、2、3、4、5和6的每一个整数。“更多个”表示三个或三个以上。The numerical range described in the specification and claims of the present application, when the numerical range is defined as an "integer" or is generally understood as an "integer" according to the conventional understanding in the art, it should be understood that the two endpoints of the range and the range are described. each integer within. For example, when "0-6" represents a carbon number, it should be understood that each integer of 0, 1, 2, 3, 4, 5 and 6 is described. "More" means three or more.
术语“卤素”指F、Cl、Br和I。换言之，F、Cl、Br和I在本说明书中可描述为“卤素”。The term "halogen" refers to F, Cl, Br and I. In other words, F, Cl, Br and I may be described as "halogens" in this specification.
本文所述任选的被取代基所取代的情形涵盖了无取代以及被一个或多个取代基所取代的情形，例如“任选被一个、两个或更多个R取代”意味着可以不被R取代(无取代)或被一个、两个或更多个R取代。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.
术语“脂肪烃基”包括饱和或不饱和，直链或支链的链状或环状烃基，所述脂肪烃基的类型可选自烷基、烯基、炔基等，所述脂肪烃基的碳原子数优选为1-12，还可以为1-10，进一步的优选范围为1-6，具体可包括但不限于如下基团：甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、正戊基、异戊基、新戊基、正己基、乙烯基、1-丙烯基、2-丙烯基、1-甲基乙烯基、1-丁烯基、1-乙基乙烯基、1-甲基-2-丙烯基、2-丁烯基、3-丁烯基、2-甲基-1-丙烯基、2-甲基-2-丙烯基、1-戊烯基、1-己烯基、乙炔基，1-丙炔基，2-丙炔基，1-丁炔基，1-甲基-2-丙炔基，3-丁炔基，1-戊炔基、1-己炔基、环丙基、环丁基、环戊基和环己基；The term "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-methyl-2-propenyl, 1 -Pentenyl, 1-hexenyl, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 1-methyl-2-propynyl, 3-butynyl, 1 -pentynyl, 1-hexynyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl;
术语“C 3-12环烷基”应理解为表示饱和或不饱和的一价单环或双环，其具有3-12个碳原子，优选C 3-8环烷基，更优选的为C 3-6环烷基。例如C 3-8环烷基应理解为表示饱和或不饱和的一价单环或双环，其具有3、4、5、6、7或8个碳原子。所述C 3-12环烷基可以是单环烃基，如环丙基、环丁基、环戊基、环己基、环庚基、环辛基、环壬基或环癸基，或者是双环烃基如四氢化萘或十氢化萘。 The term "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. For example 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.
术语“3-12元杂环基”意指饱和或不饱和的一价单环或双环，其包含1-5个独立选自N、O 和S的杂原子，含杂原子的基团不具有芳香性，所述3-12元杂环基，优选3-10元杂环基。术语3-12元杂环基意指饱和的一价单环或双环，其包含1-5个，优选1-3个选自N、O和S的杂原子。所述杂环基可以通过所述碳原子中的任一个或氮原子(如果存在的话)与分子的其余部分连接。特别地，所述杂环基可以包括但不限于：4元环，如氮杂环丁烷基、氧杂环丁烷基；5元环，如四氢呋喃基、四氢噻吩基、二氧杂环戊烯基、吡咯烷基、咪唑烷基、吡唑烷基、吡咯啉基；或6元环，如四氢吡喃基、哌啶基、吗啉基、二噻烷基、硫代吗啉基、哌嗪基或三噻烷基；或7元环，如二氮杂环庚烷基。任选地，所述杂环基可以是苯并稠合的。所述杂环基可以是双环的，例如但不限于5,5元环，如六氢环戊并[c]吡咯-2(1H)-基环，或者5,6元双环，如六氢吡咯并[1,2-a]吡嗪-2(1H)-基环。含氮原子的环可以是部分不饱和的，即它可以包含一个或多个双键，例如但不限于2,5-二氢-1H-吡咯基、4H-[1,3,4]噻二嗪基、4,5-二氢噁唑基或4H-[1,4]噻嗪基，或者，它可以是苯并稠合的，例如但不限于二氢异喹啉基，2,3-二氢苯并呋喃基，3,4-二氢-2H-1-苯并吡喃基(色烷基)，2,3-二氢苯并[b][1,4]二噁烷基。所述3-12元杂环基还可以选自例如如下基团：The term "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. The term 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. In particular, 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. Optionally, 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. The nitrogen-containing ring may be partially unsaturated, i.e. it may contain one or more double bonds such as, but not limited to, 2,5-dihydro-1H-pyrrolyl, 4H-[1,3,4]thiadiene oxazinyl, 4,5-dihydrooxazolyl, or 4H-[1,4]thiazinyl, alternatively, it may be benzo-fused such as, but not limited to, dihydroisoquinolinyl, 2,3- Dihydrobenzofuranyl, 3,4-dihydro-2H-1-benzopyranyl (chromanyl), 2,3-dihydrobenzo[b][1,4]dioxanyl. The 3-12 membered heterocyclic group can also be selected from, for example, the following groups:
Figure PCTCN2021107688-appb-000018
Figure PCTCN2021107688-appb-000018
术语“C 6-20芳基”应理解为优选表示具有6-20个碳原子的一价芳香性或部分芳香性的单环、双环或三环烃环，优选“C 6-10芳基”。术语C 6-20芳基应理解为优选表示具有6、7、8、9、10、11、12、13、14、15、16、17、18、19、20个碳原子的一价芳香性或部分芳香性的单环、双环或三环烃环，特别是具有6个碳原子的环(“C 6芳基”)，例如苯基；或联苯基，或者是具有9个碳原子的环(“C 9芳基”)，例如茚满基或茚基，或者是具有10个碳原子的环(“C 10芳基”)，例如四氢化萘基、二氢萘基或萘基，或者是具有13个碳原子的环(“C 13芳基”)，例如芴基，或者是具有14个碳原子的环(“C 14芳基”)，例如蒽基。 The term "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 fluorenyl, or a ring with 14 carbon atoms (" C14 aryl"), such as anthracenyl.
术语“5-14元杂芳基”应理解为包括这样的一价单环、双环或三环芳族环系：其具有5、6、7、8、9、10、11、12、13或14个环原子，特别是5或6或9或10个碳原子，且其包含1-5个，优选1-3个独立选自N、O和S的杂原子，并且，另外在每一种情况下可为苯并稠合的。特别地，杂芳基选自噻吩基、呋喃基、吡咯基、噁唑基、噻唑基、咪唑基、吡唑基、异噁唑基、异噻唑基、噁二唑基、三唑基、噻二唑基、噻-4H-吡唑基等以及它们的苯并衍生物，例如苯并呋喃基、苯并噻吩基、苯并噁唑基、苯并异噁唑基、苯并咪唑基、苯并三唑基、吲唑基、吲哚基、异吲哚基等；或吡啶基、哒嗪基、嘧啶基、吡嗪基、三嗪基等，以及它们的苯并衍生物，例如喹啉基、喹唑啉基、异喹啉基等；或吖辛因基、吲嗪基、嘌呤基等以及它们的苯并衍生物；或噌啉基、酞嗪基、喹唑啉基、喹喔啉基、萘啶基、蝶啶基、咔唑基、吖啶基、吩嗪基、吩噻嗪基、吩噁嗪基等。The term "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. In particular, 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. and their benzo derivatives such as benzofuranyl, benzothienyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzene Triazolyl, indazolyl, indolyl, isoindolyl, etc.; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc., and their benzo derivatives, such as quinoline Or azinyl, indolizinyl, purinyl, etc. and their benzo derivatives; or cinnoline, phthalazinyl, quinazolinyl, quinoxaline olinyl, naphthyridinyl, pteridyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl and the like.
除非另有说明，杂环基或杂芳基包括其所有可能的异构形式，例如其位置异构体。因此，对于一些说明性的非限制性实例，吡啶基或亚吡啶基包括吡啶-2-基、亚吡啶-2-基、吡啶-3-基、亚吡啶-3-基、吡啶-4-基和亚吡啶-4-基；噻吩基或亚噻吩基包括噻吩-2-基、亚噻吩-2-基、噻吩-3-基和亚噻吩-3-基。Unless otherwise specified, a heterocyclyl or heteroaryl group includes all possible isomeric forms thereof, such as positional isomers thereof. Thus, for some illustrative non-limiting examples, 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.
根据其分子结构，本发明的化合物可以是手性的，因此可能存在各种对映异构体形式。因而这些化合物可以以消旋体形式或光学活性形式存在。本发明的化合物或其中间体可以通过本领域技术人员公知的化学或物理方法分离为对映异构体化合物，或者以此形式用于合成。在外消旋的胺的情况中，通过与光学活性的拆分试剂反应，从混合物制得非对映异构体。适当的拆分试剂的示例是光学活性的酸，例如R和S形式的酒石酸、二乙酰酒石酸、二苯甲酰酒石酸、扁桃酸、苹果酸、乳酸、适当的N-保护的氨基酸(例如N-苯甲酰脯氨酸或N-苯磺酰基脯氨酸)或各种光学活性的樟脑磺酸。借助光学活性的拆分试剂(例如固定在硅胶上的二硝基苯甲酰基苯基甘氨酸、三乙酸纤维素或其它碳水化合物的衍生物或手性衍生化的异丁烯酸酯聚合物)，也可有利地进行色谱对映体拆分。用于此目的的适当的洗脱剂是含水或含醇的溶剂混合物，例如，己烷/异丙醇/乙腈。Depending on their molecular structure, 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. Examples of 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.
本领域技术人员将理解，由于氮需要具有可用的孤对电子用于被氧化为氮氧化物，因此并非所有的含氮杂环都可以形成N-氧化物；本领域技术人员将识别能够形成N-氧化物的含氮杂环。本领域技术人员还将认识到叔胺能够形成N-氧化物。制备杂环和叔胺的N-氧化物的合成方法对于本领域技术人员而言是熟知的，所述合成方法包括用过氧酸如过氧乙酸和间氯过氧苯甲酸(MCPBA)、过氧化氢、烷基氢过氧化物如叔丁基氢过氧化物、过硼酸钠和双环氧乙烷(dioxirane)如二甲基双环氧乙烷氧化杂环和叔胺。这些制备N-氧化物的方法已在文献中广泛地描述和综述。Those skilled in the art will appreciate that not all nitrogen-containing heterocycles 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. Synthetic methods for the preparation of 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. These methods for preparing N-oxides have been extensively described and reviewed in the literature.
药学上可接受的盐可以是例如在链或环中具有氮原子的具有足够碱性的本发明的化合物的酸加成盐，例如与如下无机酸形成的酸加成盐：例如盐酸、氢氟酸、氢溴酸、氢碘酸、硫酸、焦硫酸、磷酸或硝酸，或硫酸氢盐、或者与如下有机酸形成的酸加成盐：例如甲酸、乙酸、乙酰乙酸、丙酮酸、三氟乙酸、丙酸、丁酸、己酸、庚酸、十一烷酸、月桂酸、苯甲酸、水杨酸、2-(4-羟基苯甲酰基)苯甲酸、樟脑酸、肉桂酸、环戊烷丙酸、二葡糖酸、3-羟基-2-萘甲酸、烟酸、扑酸、果胶酯酸、过硫酸、3-苯基丙酸、苦味酸、特戊酸、2-羟基乙磺酸、衣康酸、氨基磺酸、三氟甲磺酸、十二烷基硫酸、乙磺酸、苯磺酸、对甲苯磺酸、甲磺酸、2-萘磺酸、萘二磺酸、樟脑磺酸、柠檬酸、酒石酸、硬脂酸、乳酸、草酸、丙二酸、琥珀酸、苹果酸、己二酸、藻酸、马来酸、富马酸、D-葡糖酸、扁桃酸、抗坏血酸、葡庚酸、甘油磷酸、天冬氨酸、磺基水杨酸、半硫酸或硫氰酸。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 acid, pectic acid, persulfuric acid, 3-phenylpropionic acid, picric acid, pivalic acid, 2-hydroxyethanesulfonic acid acid, itaconic acid, sulfamic acid, trifluoromethanesulfonic acid, dodecyl sulfuric acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, 2-naphthalenesulfonic acid, naphthalenedisulfonic acid, Camphorsulfonic acid, citric acid, tartaric acid, stearic acid, lactic acid, oxalic acid, malonic acid, succinic acid, malic acid, adipic acid, alginic acid, maleic acid, fumaric acid, D-gluconic acid, mandelic acid , ascorbic acid, glucoheptanoic acid, glycerophosphoric acid, aspartic acid, sulfosalicylic acid, hemisulfuric acid or thiocyanic acid.
另外，具有足够酸性的本发明的化合物的另一种适合的药学上可接受的盐是碱金属盐(例如钠盐或钾盐)、碱土金属盐(例如钙盐或镁盐)、铵盐，或与提供生理学可接受的阳离子的有机碱形成的盐，例如与如下物质形成的盐：钠离子、钾离子、N-甲基葡糖胺、二甲基葡糖胺、乙基葡糖胺、赖氨酸、二环己基胺、1,6-己二胺、乙醇胺、葡糖胺、葡甲胺、肌氨酸、丝氨醇、三羟基甲基氨基甲烷、氨基丙二醇、1-氨基-2,3,4-丁三醇。作为实例，所述药学上可接受的盐包括基团-COOH与如下物质形成的盐：钠离子、钾离子、钙离子、镁离子、N-甲基葡糖胺、二甲基葡糖胺、乙基葡糖胺、赖氨酸、二环己基胺、1,6-己二胺、乙醇胺、葡糖胺、葡甲胺、肌氨酸、丝氨醇、三羟基甲基氨基甲烷、氨基丙二醇、1-氨基-2,3,4-丁三醇。In addition, another suitable pharmaceutically acceptable salt of the compounds of the present invention that is sufficiently acidic are 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. By way of example, 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.
另外，碱性含氮基团可用如下试剂季铵化：低级烷基卤化物，例如甲基、乙基、丙基和丁基氯化物、溴化物和碘化物；硫酸二烷基酯，例如硫酸二甲酯、硫酸二乙酯、硫酸二丁酯和硫酸二戊酯；长链卤化物，例如癸基、月桂基、肉豆蔻基和硬脂基氯化物、溴化物和碘化物；芳烷基卤化物如苄基和苯乙基溴化物等。作为实例，药学上可接受的盐包括盐酸盐、硫 酸盐、硝酸盐、硫酸氢盐、氢溴酸盐、醋酸盐、草酸盐、柠檬酸盐、甲磺酸盐、甲酸盐或葡甲胺盐等。In addition, 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. As examples, pharmaceutically acceptable salts include hydrochloride, sulfate, nitrate, bisulfate, hydrobromide, acetate, oxalate, citrate, mesylate, formate or Meglumine salts, etc.
由于本发明的化合物可存在多个成盐位点，所述药学上可接受的盐不仅包括本发明化合物其中1个成盐位点上形成的盐，而且还包括其中2、3或全部成盐位点上形成的盐。为此，所述药学上可接受的盐中式(I)化合物与成盐所需的酸的根离子(阴离子)或碱的阳离子摩尔比可以在较大的范围内变化，例如可以是4:1～1:4，如3:1、2:1、1:1、1:2、1:3等。Since the compounds of the present invention may have multiple salt-forming sites, 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. To this end, the molar ratio of the compound of formula (I) to the acid ion (anion) or base cation required for salt formation in the pharmaceutically acceptable salt 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.
根据不同取代基的位置和性质，本发明的化合物还可以包含一个或多个不对称中心。不对称碳原子可以(R)或(S)构型存在，仅有一个不对称中心时，产生外消旋混合物，含有多个不对称中心时，得到非对映异构体混合物。在某些情况下，由于围绕特定键的旋转受阻还可能存在不对称性，例如该中心键连接特定化合物的两个被取代的芳族环。并且，取代基还可以顺式或反式异构的形式存在。Depending on the position and nature of the various substituents, 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. In addition, the substituents may also exist in the form of cis or trans isomers.
本发明化合物还包括其各自所有可能的立体异构体，其是单一立体异构体或所述立体异构体(例如R-异构体或S-异构体，或者E-异构体或Z-异构体)的任意比例的任意混合物的形式。可通过任意适合的现有技术方法(例如色谱法，特别是例如手性色谱法)实现本发明的化合物的单一立体异构体(例如单一对映异构体或单一非对映异构体)的分离。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.
术语“互变异构体”是指因分子中某一原子在两个位置迅速移动而产生的官能团异构体。本发明化合物可表现出互变异构现象。互变异构的化合物可以存在两种或多种可相互转化的种类。质子移变互变异构体来自两个原子之间共价键合的氢原子的迁移。互变异构体一般以平衡形式存在，尝试分离单一互变异构体时通常产生一种混合物，其理化性质与化合物的混合物是一致的。平衡的位置取决于分子内的化学特性。例如，在很多脂族醛和酮如乙醛中，酮型占优势；而在酚中，烯醇型占优势。本发明包含化合物的所有互变异构形式。The term "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. For example, in many aliphatic aldehydes and ketones such as acetaldehyde, the ketone form predominates; in phenols, the enol form predominates. The present invention encompasses all tautomeric forms of the compounds.
在本发明中，所涉及的化合物亦包括经同位素标记的化合物，所述经同位素标记的化合物与式I中所示的那些相同，但是其中一或多个原子被原子质量或质量数不同于通常天然存在的原子质量或质量数的原子替代。可掺入本发明的化合物的同位素的实例包括H、C、N、O、S、F及Cl的同位素，分别诸如 2H、 3H、 13C、 11C、 14C、 15N、 18O、 17O、 32P、 35S、 18F及 36Cl。含有上述同位素和/或其他原子的其他同位素的本发明的化合物、其前药、或者所述化合物或所述前药的药学上可接受的盐在本发明的范围内。本发明的某些经同位素标记的化合物，例如掺入放射性同位素(诸如 3H和 14C)的化合物可用于药物和/或底物组织分布测定。氚(即 3H)和碳14(即 14C)同位素因易于制备和可检测性而成为特别优选的。再者，以较重的同位素(诸如氘，即 2H)替代可提供源自更高的代谢稳定性的某些治疗优势(例如增加的体内半衰期或减少的剂量需求)，并因此可在某些情况下是优选的。如权利要求所请求保护的本发明化合物可特别地限定以氘或氚替代。此外，取代基中出现的氢未单独列明术语氘或氚并不表示排除氘或氚，而是同样也可以包含氘或氚。 In the present invention, 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. Examples of 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. Furthermore, substitution with heavier isotopes (such as deuterium, i.e., 2H) 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. Furthermore, the presence of hydrogen in a substituent group is not individually listed. The term deuterium or tritium does not imply the exclusion of deuterium or tritium, but may equally well include deuterium or tritium.
术语“有效量”或者“治疗有效量”是指足以实现预期应用(包括但不限于如下定义的疾病治疗)的本发明所述化合物的量。治疗有效量可以取决于以下因素而改变：预期应用(体外或者体内)，或者所治疗的受试者和疾病病症如受试者的重量和年龄、疾病病症的严重性和给药方式等，其可以由本领域普通技术人员容易地确定。具体剂量将取决于以下因素而改变：所选择的特定化合物、所依据的给药方案、是否与其它化合物组合给药、给药的时间安排、所给药的组织和所承载的物理递送系统。The term "effective amount" or "therapeutically 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.
术语“溶剂化物”是本发明的化合物的那些形式，其以固体或液体的状态通过与溶剂分子的配位作用形成配合物。水合物是溶剂化物的特定形式，其中配位作用是与水进行。在本发明中，优选的溶剂化物是水合物。进一步的，本发明通式I化合物的药学上可接受的溶剂化物(水合物)是指化合物I与化学计量学的一个或多个分子的水或其他溶剂形成的共晶和包合物。可用于溶剂化物的溶剂包括但不限于：水、甲醇、乙醇、乙二醇和醋酸。The term "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.
术语“前药”或称为“药物前体”，代表化合物在体内转化为前述通式或具体化合物所示的化合物。这样的转化受前体药物在血液中水解或在血液或组织中经酶转化为母体结构的影响。本发明前药可以是酯，在本发明中酯可以作为前药的有苯酯类，脂肪族酯类，酰氧基甲基酯类，碳酸酯，氨基甲酸酯类和氨基酸酯类。例如本发明里的一个化合物包含羟基/羧基，即可以将其酰化得到前体药物形式的化合物。其他的前药形式包括磷酸酯，如这些磷酸酯类化合物是经母体上的羟基磷酸化得到的。The term "prodrug" or "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. In the present invention, esters can be used as prodrugs including phenyl esters, aliphatic esters, acyloxymethyl esters, carbonates, carbamates and amino acid esters. For example, 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.
有益效果beneficial effect
1)本发明提供了新颖的通式I化合物，具有对整合素的良好抑制作用；1) The present invention provides a novel compound of general formula I, which has a good inhibitory effect on integrins;
2)本发明化合物对多种整合素亚型均具有抑制作用，其中一些化合物对所有亚型都有良好的抑制作用，一些化合物对αVβ1，αVβ3，αVβ5，αVβ6αVβ8，α5β1和α8β1中的一种或几种具有明显的抑制作用。2) 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 αVβ1, αVβ3, αVβ5, αVβ6, αVβ8, α5β1 and α8β1. Several have significant inhibitory effects.
具体实施方式detailed description
下文将结合具体实施例对本发明的技术方案做更进一步的详细说明。应当理解，下列实施例仅为示例性地说明和解释本发明，而不应被解释为对本发明保护范围的限制。凡基于本发明上述内容所实现的技术均涵盖在本发明旨在保护的范围内。The technical solutions of the present invention will be described in further detail below with reference to specific embodiments. It should be understood that the following examples are only for illustrating and explaining the present invention, and should not be construed as limiting the protection scope of the present invention. All technologies implemented based on the above content of the present invention are covered within the intended protection scope of the present invention.
除非另有说明，以下实施例中使用的原料和试剂均为市售商品，或者可以通过已知方法制备。Unless otherwise stated, the starting materials and reagents used in the following examples are commercially available or can be prepared by known methods.
仪器仪表和一般方法Instrumentation and General Methods
采用氘代试剂(DMSO-d 6、CDCl 3、CD 3OD)在Bruker Ascend 400光谱仪上记录 1H和 19F NMR。氘代溶剂或TMS作为内标。化学位移以ppm表示，耦合常数(J)以Hz表示，裂分方式有s(单峰)，d(双峰)，t(三重峰)，q(四重峰)，m(多重峰)，br(宽峰)。LC-MS采用安捷伦1260-6120系统配备Waters Cortecs C18，2.7μm,4.6×30mm柱子；HPLC采用Waters Acquity UPLC H-class仪器配备Acquity BEH C18,1.7μm,50×2.1mm柱子。采用制备型HPLC(Kromasil-C18(100×21.2mm，5μm)柱子、Xtimate-C18(250×30mm)柱子或者Xbridge-C18(150×19mm，5μm)柱子)、手性制备型SFC(Daicel ChiralPak IG(250mm×30mm,10μm)柱子、Daicel Chiralpak OZ-H(250mm×20mm,5μm)柱子、Daicel Chiralpak AD-H(250×4.6mm)柱子)纯化或者拆分最终化合物。 1 H and 19 F NMR were recorded on a Bruker Ascend 400 spectrometer using deuterated reagents (DMSO-d 6 , CDCl 3 , CD 3 OD). Deuterated solvent or TMS was used as internal standard. The chemical shift is expressed in ppm, the coupling constant (J) is expressed in Hz, and the splitting modes are s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br (broad peak). LC-MS adopts Agilent 1260-6120 system equipped with Waters Cortecs C18, 2.7 μm, 4.6 × 30 mm column; HPLC adopts Waters Acquity UPLC H-class instrument equipped with Acquity BEH C18, 1.7 μm, 50 × 2.1 mm column. Preparative HPLC (Kromasil-C18 (100×21.2mm, 5μm) column, Xtimate-C18 (250×30mm) column or Xbridge-C18 (150×19mm, 5μm) column), chiral preparative SFC (Daicel ChiralPak IG) (250 mm x 30 mm, 10 μm) column, Daicel Chiralpak OZ-H (250 mm x 20 mm, 5 μm) column, Daicel Chiralpak AD-H (250 x 4.6 mm) column) to purify or resolve the final compound.
实施例Example
通用中间体的合成步骤示例：Examples of synthetic steps for generic intermediates:
中间体A的合成：Synthesis of Intermediate A:
Figure PCTCN2021107688-appb-000019
Figure PCTCN2021107688-appb-000019
步骤1：(1R,5S,6s)-6-((2-甲氧基-2-氧代-1-苯基乙基)氨基)-3-氮杂双环[3.1.0]己烷-3-羧酸叔丁酯Step 1: (1R,5S,6s)-6-((2-methoxy-2-oxo-1-phenylethyl)amino)-3-azabicyclo[3.1.0]hexane-3 - tert-butyl carboxylate
Figure PCTCN2021107688-appb-000020
Figure PCTCN2021107688-appb-000020
在N 2气氛下，向(1R,5S,6s)-6-氨基-3-氮杂双环[3.1.0]己烷-3-羧酸叔丁酯(1.01g,5.09mmol)，2-溴-2-苯乙酸甲酯(1.40g,6.1mmol)，碘甲烷(76mg,0.51mmol)的无水乙腈(20mL)溶液中加入碳酸钾(1.41mg,10.2mmol)。反应混合液在60℃搅拌14小时后，在真空下除去溶剂，残留物用柱层析(0～60％乙酸乙酯的石油醚溶液)纯化得到标题化合物(1.34g,76％)，为黄色油状物。 1H NMR(400MHz,CDCl 3)δ7.42–7.27(m,5H),4.40(s,1H),3.72(s,3H),3.50–3.27(m,4H),1.88–1.84(m,1H),1.62–1.60(m,1H),1.55–1.51(m,1H),1.41(s,9H).LC-MS:ESI m/z347.14[M+H] +,C 19H 26N 2O 4计算值346.19. To (1R,5S,6s)-6-amino- 3 -azabicyclo[3.1.0]hexane-3-carboxylate tert-butyl ester (1.01 g, 5.09 mmol), 2-bromo To a solution of methyl-2-phenylacetate (1.40 g, 6.1 mmol), iodomethane (76 mg, 0.51 mmol) in dry acetonitrile (20 mL) was added potassium carbonate (1.41 mg, 10.2 mmol). After the reaction mixture was stirred at 60°C for 14 hours, the solvent was removed in vacuo and the residue was purified by column chromatography (0-60% ethyl acetate in petroleum ether) to give the title compound (1.34 g, 76%) as yellow Oil. 1 H NMR (400MHz, CDCl 3 )δ7.42-7.27(m,5H), 4.40(s,1H), 3.72(s,3H), 3.50-3.27(m,4H), 1.88-1.84(m,1H) ), 1.62–1.60 (m, 1H), 1.55–1.51 (m, 1H), 1.41 (s, 9H). LC-MS: ESI m/z347.14[M+H] + , C 19 H 26 N 2 O 4 computed 346.19.
步骤2：(1R,5S,6s)-6-((2-甲氧基-2-氧代-1-苯基乙基)(甲基)氨基)-3-氮杂双环[3.1.0]己烷-3-羧酸叔丁酯Step 2: (1R,5S,6s)-6-((2-methoxy-2-oxo-1-phenylethyl)(methyl)amino)-3-azabicyclo[3.1.0] Hexane-3-carboxylate tert-butyl ester
Figure PCTCN2021107688-appb-000021
Figure PCTCN2021107688-appb-000021
在N 2气氛下，向(1R,5S,6s)-6-((2-甲氧基-2-氧代-1-苯基乙基)氨基)-3-氮杂双环[3.1.0]己烷-3-羧酸叔丁酯(793mg，2.29mmol)和多聚甲醛(344mg，11.45mmol)的甲醇(10mL)溶液中加入三乙酰氧基硼氢化钠(1.46g，6.87mmol)，反应液于25℃搅拌18小时。然后再分批次加入氰基硼氢化钠(216mg，3.43mmol)，反应液于25℃继续搅拌14小时。浓缩至干后，将残余物溶在饱和碳酸氢钠(20mL)中，以乙酸乙酯(30mL)萃取。有机相用盐水洗涤，经硫酸钠干燥，过滤并浓缩至干。残余物通过快速柱色谱法纯化(0～60％乙酸乙酯的石油醚溶液)，得到标题化合物(661mg，80％)，为黄色油状物。 1H NMR(400MHz,CDCl 3)δ7.38–7.31(m,5H),4.34–4.31(m,1H),3.72(s,3H),3.38–3.20(m,4H),2.34(s,3H),2.27–2.26(m,1H),1.68–1.63(m,1H),1.59–1.52(m,1H),1.43(s,9H).LC-MS:ESI m/z 361.16[M+H] +,C 20H 28N 2O 4计算值360.20. Under a N atmosphere, transfer to (1R,5S,6s)-6-(( 2 -methoxy-2-oxo-1-phenylethyl)amino)-3-azabicyclo[3.1.0] To a solution of tert-butyl hexane-3-carboxylate (793 mg, 2.29 mmol) and paraformaldehyde (344 mg, 11.45 mmol) in methanol (10 mL) was added sodium triacetoxyborohydride (1.46 g, 6.87 mmol) to react The solution was stirred at 25°C for 18 hours. Then sodium cyanoborohydride (216 mg, 3.43 mmol) was added in batches, and the reaction solution was stirred at 25° C. for 14 hours. After concentration to dryness, the residue was dissolved in saturated sodium bicarbonate (20 mL) and extracted with ethyl acetate (30 mL). The organic phase was 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 (661 mg, 80%) as a yellow oil. 1 H NMR (400MHz, CDCl 3 )δ7.38-7.31(m,5H), 4.34-4.31(m,1H), 3.72(s,3H), 3.38-3.20(m,4H), 2.34(s,3H) ), 2.27–2.26 (m, 1H), 1.68–1.63 (m, 1H), 1.59–1.52 (m, 1H), 1.43 (s, 9H). LC-MS: ESI m/z 361.16[M+H] + , calcd for C 20 H 28 N 2 O 4 360.20.
步骤3：2-(((1R,5S,6s)-3-氮杂双环[3.1.0]己-6-基)(甲基)氨基)-2-苯基乙酸甲酯Step 3: Methyl 2-(((1R,5S,6s)-3-azabicyclo[3.1.0]hex-6-yl)(methyl)amino)-2-phenylacetate
Figure PCTCN2021107688-appb-000022
Figure PCTCN2021107688-appb-000022
向(1R,5S,6s)-6-(((2-甲氧基-2-氧代-1-苯基乙基)(甲基)氨基)-3-氮杂双环[3.1.0]己烷-3-羧酸酯叔丁酯(661mg，1.83mmol)的二氯甲烷(10mL)溶液中加入三氟乙酸(3mL)，将所得混合物在25℃下搅拌16小时。真空除去溶剂，得到呈黄色油状的标题化合物(477mg，粗品)。LC-MS: ESI m/z 261.12[M+H] +,C 15H 20N 2O 2计算值260.15. To (1R,5S,6s)-6-(((2-methoxy-2-oxo-1-phenylethyl)(methyl)amino)-3-azabicyclo[3.1.0]hexane To a solution of tert-butyl alkane-3-carboxylate (661 mg, 1.83 mmol) in dichloromethane (10 mL) was added trifluoroacetic acid (3 mL) and the resulting mixture was stirred at 25° C. for 16 h. The solvent was removed in vacuo to give The title compound (477 mg, crude) as a yellow oil. LC-MS: ESI m/z 261.12 [ M + H] + , calcd for C15H20N2O2 260.15.
中间体B的合成：Synthesis of Intermediate B:
Figure PCTCN2021107688-appb-000023
Figure PCTCN2021107688-appb-000023
步骤1：(1R,5S,6s)-6-((3-乙氧基-3-氧代-1-苯基丙基)氨基)-3-氮杂双环[3.1.0]己烷-3-羧酸叔丁酯Step 1: (1R,5S,6s)-6-((3-ethoxy-3-oxo-1-phenylpropyl)amino)-3-azabicyclo[3.1.0]hexane-3 - tert-butyl carboxylate
Figure PCTCN2021107688-appb-000024
Figure PCTCN2021107688-appb-000024
在N 2气氛下，向(1R,5S,6s)-6-氨基-3-氮杂双环[3.1.0]己烷-3-羧酸叔丁酯(1.02g，5.14mmol)和3-氧代-3-苯基丙酸乙酯(1.19g，6.17mmol)的无水甲醇(20mL)溶液中，依次加入三乙酰氧基硼氢化钠(2.73g，12.86mmol)和氰基硼氢化钠(485mg，7.72mmol)，将所得混合物于60℃搅拌18小时。然后将反应液浓缩至干，将残余物溶解在饱和碳酸氢钠(30mL)中，乙酸乙酯(30mL×3)萃取。合并的有机相用盐水洗涤，经硫酸钠干燥，过滤并浓缩至干。残余物通过快速柱色谱法纯化(0～60％乙酸乙酯的石油醚溶液)，得到标题化合物(1.66g，86％)，为浅色胶状物。 1H NMR(400MHz,DMSO-d 6)δ7.38–7.29(m,4H),7.24(t,J＝6.9Hz,1H),4.09–3.90(m,3H),3.19(d,J＝16.2Hz,4H),2.77–2.65(m,1H),2.61–2.51(m,1H),1.91(s,2H),1.48–1.45(m,1H),1.43–1.37(m,1H),1.31(s,9H),1.08(t,J＝7.1Hz,3H).LC-MS:ESI m/z 375.21[M+H] +,C 21H 30N 2O 4.计算值374.22. To (1R,5S,6s)-6-amino-3-azabicyclo[3.1.0]hexane-3-carboxylate tert-butyl ester (1.02 g, 5.14 mmol) and 3 -oxocarboxylate under N atmosphere To a solution of ethyl 3-phenylpropionate (1.19 g, 6.17 mmol) in anhydrous methanol (20 mL), sodium triacetoxyborohydride (2.73 g, 12.86 mmol) and sodium cyanoborohydride ( 485 mg, 7.72 mmol) and the resulting mixture was stirred at 60 °C for 18 h. The 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. 1 H NMR (400MHz, DMSO-d 6 ) δ 7.38-7.29 (m, 4H), 7.24 (t, J=6.9Hz, 1H), 4.09-3.90 (m, 3H), 3.19 (d, J=16.2 Hz, 4H), 2.77–2.65 (m, 1H), 2.61–2.51 (m, 1H), 1.91 (s, 2H), 1.48–1.45 (m, 1H), 1.43–1.37 (m, 1H), 1.31 ( s, 9H), 1.08 (t, J=7.1 Hz, 3H). LC-MS: ESI m/z 375.21 [M+H] + , C 21 H 30 N 2 O 4 . Calculated 374.22.
步骤2：3-(((1R,5S,6s)-3-氮杂双环[3.1.0]己-6-基)氨基)-3-苯基丙酸乙酯Step 2: Ethyl 3-(((1R,5S,6s)-3-azabicyclo[3.1.0]hex-6-yl)amino)-3-phenylpropanoate
Figure PCTCN2021107688-appb-000025
Figure PCTCN2021107688-appb-000025
在N 2气氛下，向(1R,5S,6s)-6-((3-乙氧基-3-氧代-1-苯基丙基)氨基)-3-氮杂双环[3.1.0]己烷-3-羧酸叔丁酯(468mg 1.25mmol)的二氯甲烷(5mL)溶液中滴加三氟乙酸(2mL)，并将得到的混合物在25℃搅拌16小时。真空除去溶剂，得到标题化合物的三氟乙酸盐(352mg，粗品)，为黄色油状物。LC-MS:ESI m/z 275.18[M+H] +,C 16H 22N 2O 2.计算值274.17. Under a N atmosphere, transfer to (1R,5S,6s)-6-(( 3 -ethoxy-3-oxo-1-phenylpropyl)amino)-3-azabicyclo[3.1.0] To a solution of tert-butyl hexane-3-carboxylate (468 mg 1.25 mmol) in dichloromethane (5 mL) was added dropwise trifluoroacetic acid (2 mL), and the resulting mixture was stirred at 25°C for 16 hours. The solvent was removed in vacuo to give the title compound as a trifluoroacetate salt (352 mg, crude) as a yellow oil. LC-MS: ESI m/z 275.18 [M+H] + , calcd for C 16 H 22 N 2 O 2 . 274.17.
中间体C的合成：Synthesis of Intermediate C:
Figure PCTCN2021107688-appb-000026
Figure PCTCN2021107688-appb-000026
步骤1. (1R,5S,6s)-6-(((苄氧基)羰基)氨基)-3-氮杂双环[3.1.0]己烷-3-羧酸叔丁酯Step 1. (1R,5S,6s)-6-(((benzyloxy)carbonyl)amino)-3-azabicyclo[3.1.0]hexane-3-carboxylate tert-butyl ester
Figure PCTCN2021107688-appb-000027
Figure PCTCN2021107688-appb-000027
在N 2气氛下，于0℃向(1R,5S,6s)-6-氨基-3-氮杂双环[3.1.0]己烷-3-羧酸叔丁酯(8.0g，40.35mmol)的无水二氯甲烷(120mL)溶液中，加入三乙胺(17mL，121mmol)，氯甲酸苄酯(8.26g，48.42mmol)，将所得混合物于25℃搅拌4天。然后用饱和碳酸氢钠(100mL)淬灭，乙酸乙酯(100mL×3)萃取有机相用盐水洗涤，经硫酸钠干燥，过滤并浓缩至干。残余物通过快速柱色谱法纯化(0～50％乙酸乙酯的石油醚溶液)，得到标题化合物(8.82g，66％)，为黄色油状物。 1H NMR(400MHz,CDCl 3)δ7.42–7.27(m,5H),5.09(s,2H),4.93(s,1H),3.67(d,J＝10.6Hz,2H),3.37(td,J＝10.6,3.7Hz,2H),2.35(d,J＝1.8Hz,1H),1.68(s,2H),1.43(s,9H).LC-MS:ESI m/z355.06[M+Na] +,C 18H 24N 2O 4.计算值332.17. To a solution of (1R,5S,6s)-6-amino-3-azabicyclo[3.1.0]hexane-3-carboxylate tert-butyl ester (8.0 g, 40.35 mmol) at 0 °C under N atmosphere To anhydrous dichloromethane (120 mL) solution, triethylamine (17 mL, 121 mmol) and benzyl chloroformate (8.26 g, 48.42 mmol) were added, and the resulting mixture was stirred at 25°C for 4 days. It was then quenched with saturated sodium bicarbonate (100 mL) and extracted with ethyl acetate (100 mL x 3). The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by flash column chromatography (0-50% ethyl acetate in petroleum ether) to give the title compound (8.82 g, 66%) as a yellow oil. 1 H NMR (400 MHz, CDCl 3 ) δ 7.42-7.27 (m, 5H), 5.09 (s, 2H), 4.93 (s, 1H), 3.67 (d, J=10.6 Hz, 2H), 3.37 (td, J=10.6, 3.7Hz, 2H), 2.35(d, J=1.8Hz, 1H), 1.68(s, 2H), 1.43(s, 9H). LC-MS: ESI m/z355.06[M+Na ] + , C 18 H 24 N 2 O 4 . Calculated 332.17.
步骤2. ((1R,5S,6s)-3-氮杂双环[3.1.0]己-6-基)氨基甲酸苄酯Step 2. Benzyl ((1R,5S,6s)-3-azabicyclo[3.1.0]hex-6-yl)carbamate
Figure PCTCN2021107688-appb-000028
Figure PCTCN2021107688-appb-000028
在N 2气氛下，向(1R,5S,6s)-6-(((苄氧基)羰基)氨基)-3-氮杂双环[3.1.0]己烷-3-羧酸叔丁酯(4.0g，12.0mmol)的二氯甲烷(40mL)溶液中加入三氟乙酸(10mL)，将所得混合物在25℃下搅拌16小时。真空除去溶剂，得到标题化合物的三氟乙酸盐(2.8g，粗品)，为黄色油状物。LC-MS:ESI m/z 233.05[M+H] +,C 13H 16N 2O 2.计算值232.12. Under N atmosphere, tert - butyl (1R,5S,6s)-6-(((benzyloxy)carbonyl)amino)-3-azabicyclo[3.1.0]hexane-3-carboxylate ( To a solution of 4.0 g, 12.0 mmol) in dichloromethane (40 mL) was added trifluoroacetic acid (10 mL) and the resulting mixture was stirred at 25°C for 16 hours. The solvent was removed in vacuo to give the title compound as a trifluoroacetate salt (2.8 g, crude) as a yellow oil. LC-MS: ESI m/z 233.05 [M+H] + , calcd for C 13 H 16 N 2 O 2 . 232.12.
步骤3. 7-(3-((1R,5S,6s)-6-(((苄氧基)羰基)氨基)-3-氮杂双环[3.1.0]己-3-基)丙基)-3,4-二氢-1,8-萘啶-1(2H)-羧酸叔丁酯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
Figure PCTCN2021107688-appb-000029
Figure PCTCN2021107688-appb-000029
在N 2气氛下，向((1R,5S,6s)-3-氮杂双环[3.1.0]己-6-基)氨基甲酸苄酯(2.8g，12mmol)和7-(3-氧代丙基)-3，4-二氢-1,8-萘啶-1(2H)-羧酸叔丁酯(4.2g，14.47mmol)的甲醇(100mL)溶液中，加入三乙酰氧基硼氢化钠(7.63g，36mmol)，得到的混合物在25℃搅拌18小时。然后分批次加入氰基硼氢化钠(1.13g，18mmol)，所得混合物于25℃继续搅拌14小时。浓缩至干后，将 残余物溶解在饱和碳酸氢钠(80mL)中，以乙酸乙酯(100mL×3)萃取。合并的有机相用盐水洗涤，经硫酸钠干燥，过滤并浓缩至干。残余物通过快速柱色谱法纯化(0-8％甲醇的二氯甲烷溶液)，得到标题化合物(2.62g，43％)，为黄色固体。 1H NMR(400MHz,CDCl 3)δ7.37–7.27(m,6H),6.79(d,J＝7.6Hz,1H),5.08(s,2H),4.89–4.76(m,1H),3.78–3.70(m,3H),3.07–2.89(m,2H),2.78–2.64(m,6H),2.62–2.48(m,2H),1.94–1.87(m,4H),1.51(s,9H),1.49–1.48(m,2H).LC-MS:ESI m/z 507.20[M+H] +,C 29H 38N 4O 4.计算值506.29. To benzyl ((1R,5S,6s)-3-azabicyclo[3.1.0]hex-6-yl)carbamate (2.8 g, 12 mmol) and 7-( 3 -oxo) under N atmosphere Propyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate tert-butyl ester (4.2 g, 14.47 mmol) in methanol (100 mL) was added triacetoxyhydroboration Sodium (7.63 g, 36 mmol) and the resulting mixture was stirred at 25°C for 18 hours. Sodium cyanoborohydride (1.13 g, 18 mmol) was then added in portions and the resulting mixture was stirred for a further 14 hours at 25°C. After concentration to dryness, the residue was dissolved in saturated sodium bicarbonate (80 mL) and extracted with ethyl acetate (100 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 (0-8% methanol in dichloromethane) to give the title compound (2.62 g, 43%) as a yellow solid. 1 H NMR (400MHz, CDCl 3 )δ7.37-7.27(m,6H),6.79(d,J=7.6Hz,1H),5.08(s,2H),4.89-4.76(m,1H),3.78- 3.70(m,3H), 3.07–2.89(m,2H), 2.78–2.64(m,6H), 2.62–2.48(m,2H), 1.94–1.87(m,4H), 1.51(s,9H), 1.49–1.48 (m, 2H). LC-MS: ESI m/z 507.20 [M+H] + , C 29 H 38 N 4 O 4 . Calculated 506.29.
步骤4. 7-(3-((1R,5S,6s)-6-氨基-3-氮杂双环[3.1.0]己-3-基)丙基)-3,4-二氢-1,8-萘啶-1(2H)-羧酸叔丁酯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
Figure PCTCN2021107688-appb-000030
Figure PCTCN2021107688-appb-000030
向7-(3-((1R,5S,6s)-6-(((苄氧基)羰基)氨基)-3-氮杂双环[3.1.0]己-3-基)丙基)-3,4-二氢-1,8-萘啶-1(2H)-羧酸叔丁酯(2.62g，5.17mmol)的甲醇(40mL)溶液加入10％钯碳(460mg)，得到的混合物在25℃，H 2气氛下搅拌16小时。然后在硅藻土上过滤并用甲醇(300mL)洗脱，将滤液浓缩，得到呈黄色油状的标题化合物(1.88g，粗品)。LC-MS:ESI m/z 373.19[M+H] +,C 21H 32N 4O 2.计算值372.25. To 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 (2.62 g, 5.17 mmol) in methanol (40 mL) was added 10% palladium on carbon (460 mg), the resulting mixture was heated at 25 °C, stirring under H2 atmosphere for 16 h. It was then filtered on celite and eluted with methanol (300 mL) and the filtrate was concentrated to give the title compound (1.88 g, crude) as a yellow oil. LC-MS: ESI m/z 373.19 [M+H] + , calcd for C 21 H 32 N 4 O 2 . 372.25.
具体化合物的合成如下：The specific compounds were synthesized as follows:
实施例1.化合物1的合成Example 1. Synthesis of Compound 1
Figure PCTCN2021107688-appb-000031
Figure PCTCN2021107688-appb-000031
步骤1. 7-(3-((1R,5S,6s)-6)-((2-甲氧基-2-氧代-1-苯基乙基)(甲基)氨基)-3-氮杂双环[3.1.0]己-3-基)丙基)-3,4-二氢-1,8-萘啶-1(2H)-羧酸叔丁酯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
Figure PCTCN2021107688-appb-000032
Figure PCTCN2021107688-appb-000032
在N 2气氛下，向2-(((1R,5S,6s)-3-氮杂双环[3.1.0]己-6-基)(甲基)氨基)-2-苯基乙酸甲酯(238mg，0.92mmol)和7-(3-氧代丙基)-3,4-二氢-1,8-萘啶-1(2H)-羧酸叔丁酯(320mg，1.10mmol)的甲醇(10mL)溶液中加入三乙酰氧基硼氢化钠(583mg，2.75mmol)，将所得混合物于25℃搅拌18小时。然后分批次加入氰基硼氢化钠(86mg，1.38mmol)，将所得混合物于25℃继续搅拌14小时。浓缩至干后，将残余物溶在饱和碳酸氢钠(20mL)溶液中，以乙酸乙酯(20mL×3)萃取。合并有机相并用盐水洗涤，经硫酸钠干燥，过滤并浓缩至干。残余物通过快速柱色谱法纯化(0-40％甲醇的二氯甲烷溶液)，得到标题化合物(190mg，39％)，为黄色油状物。LC-MS:ESI m/z 535.23[M+H] +,C 32H 44N 4O 4.计算值534.32. Under a N atmosphere, methyl 2 -(((1R,5S,6s)-3-azabicyclo[3.1.0]hex-6-yl)(methyl)amino)-2-phenylacetate ( 238 mg, 0.92 mmol) and 7-(3-oxopropyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate tert-butyl ester (320 mg, 1.10 mmol) in methanol ( 10 mL) solution was added with sodium triacetoxyborohydride (583 mg, 2.75 mmol), and the resulting mixture was stirred at 25° C. for 18 hours. Sodium cyanoborohydride (86 mg, 1.38 mmol) was then added in portions and the resulting mixture was stirred for a further 14 hours at 25°C. After concentration to dryness, the residue was dissolved in saturated sodium bicarbonate (20 mL) solution and extracted with ethyl acetate (20 mL×3). The organic phases were combined and washed with brine, dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by flash column chromatography (0-40% methanol in dichloromethane) to give the title compound (190 mg, 39%) as a yellow oil. LC-MS: ESI m/z 535.23 [M+H] + , calcd for C 32 H 44 N 4 O 4 . 534.32.
步骤2. 2-(甲基((1R,5S,6s)-3-(3-(5,6,7,8-四氢-1,8-萘啶-2-基)丙基)-3-氮杂双环[3.1.0]己-6-基) 氨基)-2-苯基乙酸Step 2. 2-(methyl((1R,5S,6s)-3-(3-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)propyl)-3 -azabicyclo[3.1.0]hex-6-yl)amino)-2-phenylacetic acid
Figure PCTCN2021107688-appb-000033
Figure PCTCN2021107688-appb-000033
在N 2气氛下，向7-(3-((1R,5S,6s)-6-((2-甲氧基-2-氧代-1-苯基乙基)(甲基)氨基)-3-氮杂双环[3.1.0]己-3-基)丙基)-3,4-二氢-1,8-萘啶-1(2H)-羧酸叔丁酯(190mg，0.36mmol)的二氯甲烷(5mL)溶液中滴加三氟乙酸(2mL)，将得到的混合物在25℃下搅拌16小时。真空除去溶剂，得到2-(甲基((1R,5S,6s)-3-(3-(5,6,7,8-四氢-1,8-萘啶-2-基)丙基)-3-氮杂双环[3.1.0]己-6-基)氨基)-2-苯基乙酸甲酯的三氟乙酸盐(154mg，粗品)，为黄色油状物。LC-MS:ESI m/z 435.21[M+H] +,C 27H 36N 4O 2.计算值434.27.将得到的粗品(154mg)溶在甲醇(4mL)和水(1mL)的混合溶剂中，然后加入NaOH(57mg，1.42mmol)，将所得混合物在25℃下搅拌16小时。用1N HCl(1.5mL)中和后，将混合物浓缩，并通过制备HPLC在以下条件下纯化[柱：Kromasil 100-5-C18，30×150mm；流动相：1-35％MeCN的水溶液(含0.1％甲酸)；时间：14分钟]，得到标题化合物(29.73mg，20％)，为白色固体。 1H NMR(400MHz,CD 3OD)δ7.51–7.42(m,2H),7.40–7.27(m,4H),6.46(d,J＝7.3Hz,1H),4.31(s,1H),3.47–3.40(m,2H),3.36–3.32(m,1H),3.15–2.98(m,3H),2.96–2.85(m,2H),2.76(t,J＝6.1Hz,2H),2.63(t,J＝7.5Hz,2H),2.49(s,3H),2.33(s,1H),1.99–1.82(m,5H),1.72–1.64(m,1H).LC-MS:ESI m/z 421.12[M+H] +,C 25H 32N 4O 2计算值420.25. Under N2 atmosphere, to 7-(3-((1R,5S,6s)-6-((2-methoxy-2-oxo-1-phenylethyl)(methyl)amino)- 3-Azabicyclo[3.1.0]hex-3-yl)propyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate tert-butyl ester (190 mg, 0.36 mmol) To a solution of dichloromethane (5 mL) was added dropwise trifluoroacetic acid (2 mL), and the resulting mixture was stirred at 25° C. for 16 hours. The solvent was removed in vacuo to give 2-(methyl((1R,5S,6s)-3-(3-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)propyl) - The trifluoroacetate salt of methyl 3-azabicyclo[3.1.0]hex-6-yl)amino)-2-phenylacetate (154 mg, crude) as a yellow oil. LC-MS: ESI m/z 435.21 [M+H] + , C 27 H 36 N 4 O 2 . Calculated 434.27. The obtained crude product (154 mg) was dissolved in a mixed solvent of methanol (4 mL) and water (1 mL) Then NaOH (57 mg, 1.42 mmol) was added and the resulting mixture was stirred at 25 °C for 16 h. After neutralization with 1N HCl (1.5 mL), the mixture was concentrated and purified by preparative HPLC under the following conditions [column: Kromasil 100-5-C18, 30 x 150 mm; mobile phase: 1-35% MeCN in water (containing 0.1% formic acid); time: 14 min] to give the title compound (29.73 mg, 20%) as a white solid. 1 H NMR (400 MHz, CD 3 OD) δ 7.51–7.42 (m, 2H), 7.40–7.27 (m, 4H), 6.46 (d, J=7.3 Hz, 1H), 4.31 (s, 1H), 3.47 –3.40(m,2H),3.36-3.32(m,1H),3.15-2.98(m,3H),2.96-2.85(m,2H),2.76(t,J=6.1Hz,2H),2.63(t , J=7.5Hz, 2H), 2.49(s, 3H), 2.33(s, 1H), 1.99–1.82(m, 5H), 1.72–1.64(m, 1H). LC-MS: ESI m/z 421.12 [M+H] + , calcd for C 25 H 32 N 4 O 2 420.25.
实施例2 参照化合物1的合成方法，可以得到以下化合物：Embodiment 2 With reference to the synthetic method of compound 1, the following compounds can be obtained:
化合物2(甲酸盐)： 1H NMR(400MHz,CD 3OD)δ7.50–7.41(m,2H),7.41–7.28(m,4H),6.48(d,J＝7.3Hz,1H),4.26(s,1H),3.46–3.41(m,2H),3.35–3.32(m,1H),3.21–3.01(m,3H),3.00–2.86(m,2H),2.76(t,J＝6.2Hz,2H),2.61(t,J＝7.2Hz,2H),2.45(s,3H),2.30(d,J＝1.8Hz,1H),1.94–1.84(m,3H),1.73–1.54(m,5H).LC-MS:ESI m/z 435.2[M+H] +,C 26H 34N 4O 2.计算值434.27. Compound 2 (formate salt): 1 H NMR (400 MHz, CD 3 OD) δ 7.50-7.41 (m, 2H), 7.41-7.28 (m, 4H), 6.48 (d, J=7.3 Hz, 1H), 4.26(s, 1H), 3.46-3.41(m, 2H), 3.35-3.32(m, 1H), 3.21-3.01(m, 3H), 3.00-2.86(m, 2H), 2.76(t, J=6.2 Hz, 2H), 2.61 (t, J=7.2Hz, 2H), 2.45 (s, 3H), 2.30 (d, J=1.8Hz, 1H), 1.94–1.84 (m, 3H), 1.73–1.54 (m , 5H). LC-MS: ESI m/z 435.2 [M+H] + , C 26 H 34 N 4 O 2 . Calculated 434.27.
化合物3(甲酸盐)： 1H NMR(400MHz,CD 3OD)δ7.45(d,J＝8.1Hz,3H),7.38–7.29(m,3H),6.39(d,J＝7.3Hz,1H),4.49(s,1H),3.54(dd,J＝10.8,4.3Hz,2H),3.49–3.44(m,2H),3.11(dd,J＝10.7,3.8Hz,2H),2.91(t,J＝6.6Hz,2H),2.79(dd,J＝13.0,6.8Hz,3H),2.57(t,J＝7.7Hz,2H),2.06–2.02(m,1H),1.98–1.82(m,5H).LC-MS:ESI m/z 407.12[M+H] +,C 24H 30N 4O 2计算值406.24. Compound 3 (formate salt): 1 H NMR (400 MHz, CD 3 OD) δ 7.45 (d, J=8.1 Hz, 3H), 7.38-7.29 (m, 3H), 6.39 (d, J=7.3 Hz, 1H), 4.49(s, 1H), 3.54(dd, J=10.8, 4.3Hz, 2H), 3.49–3.44(m, 2H), 3.11(dd, J=10.7, 3.8Hz, 2H), 2.91(t , J=6.6Hz, 2H), 2.79 (dd, J=13.0, 6.8Hz, 3H), 2.57 (t, J=7.7Hz, 2H), 2.06–2.02 (m, 1H), 1.98–1.82 (m, 5H).LC-MS: ESI m/z 407.12 [ M + H] + , calcd for C24H30N4O2 406.24.
化合物4(甲酸盐)： 1H NMR(400MHz,CD 3OD)δ7.53–7.40(m,3H),7.40–7.25(m,3H),6.47(dd,J＝7.3,2.0Hz,1H),4.40(s,1H),3.57–3.40(m,4H),3.16–3.03(m,2H),2.94–2.83(m,2H),2.78(t,J＝6.2Hz,2H),2.75–2.69(m,1H),2.60–2.46(m,2H),2.04–1.84(m,4H),1.69–1.44(m,4H).LC-MS:ESI m/z 421.1[M+H] +,C 25H 32N 4O 2计算值420.25. Compound 4 (formate salt): 1 H NMR (400 MHz, CD 3 OD) δ 7.53-7.40 (m, 3H), 7.40-7.25 (m, 3H), 6.47 (dd, J=7.3, 2.0 Hz, 1H ), 4.40 (s, 1H), 3.57–3.40 (m, 4H), 3.16–3.03 (m, 2H), 2.94–2.83 (m, 2H), 2.78 (t, J=6.2Hz, 2H), 2.75– 2.69(m,1H),2.60–2.46(m,2H),2.04–1.84(m,4H),1.69–1.44(m,4H).LC-MS:ESI m/z 421.1[M+H] + , Calcd for C25H32N4O2 420.25 .
将中间体A的起始原料替换成(1R,5S,6r)-6-氨基-3-氮杂双环[3.1.0]己烷-3-羧酸叔丁酯，按照相似的方法，可以得到：Substituting the starting material of Intermediate A with (1R,5S,6r)-6-amino-3-azabicyclo[3.1.0]hexane-3-carboxylate tert-butyl ester, according to a similar method, can be obtained :
化合物5(甲酸盐)： 1H NMR(400MHz,DMSO-d 6)δ8.17(brs,1H),7.40–7.35(m,2H),7.32–7.21(m,3H),7.18–7.14(m,1H),6.33–6.29(d,J＝4.0Hz,1H),4.21(s,1H),3.29–3.20(m,4H),3.03–2.97(m,1H),2.76–2.62(m,4H),2.57–2.51(t,J＝4.4Hz,2H),2.47–2.42(m,1H),2.27– 2.20(t,J＝4.8Hz 1H),1.82–1.60(m,4H),1.57–1.44(m,4H).LC-MS:(ESI)m/z 421.4[M+H] +,C 25H 32N 4O 2计算值420.25.纯度:96.9％(214nm),93.6％(254nm). Compound 5 (formate salt): 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.17 (brs, 1H), 7.40-7.35 (m, 2H), 7.32-7.21 (m, 3H), 7.18-7.14 ( m, 1H), 6.33–6.29 (d, J=4.0Hz, 1H), 4.21 (s, 1H), 3.29–3.20 (m, 4H), 3.03–2.97 (m, 1H), 2.76–2.62 (m, 4H), 2.57–2.51 (t, J=4.4Hz, 2H), 2.47–2.42 (m, 1H), 2.27– 2.20 (t, J=4.8Hz 1H), 1.82–1.60 (m, 4H), 1.57– 1.44 (m, 4H). LC-MS: (ESI) m/z 421.4 [M+H] + , calcd for C 25 H 32 N 4 O 2 420.25. Purity: 96.9% (214 nm), 93.6% (254 nm) .
化合物6(甲酸盐)： 1H NMR(400MHz,DMSO-d 6)δ8.19(brs,1H),7.33–7.27(m,4H),7.26–7.21(m,1H),7.09(d,J＝7.2Hz,1H),6.31(d,J＝7.2Hz,1H),4.30(s,1H),3.51(d,J＝11.2Hz,1H),3.34(d,J＝11.2Hz,1H),3.30–3.24(m,2H),3.18(dd,J＝11.2,4.4Hz,1H),3.09(dd,J＝11.2,4.4Hz,1H),2.94–2.79(m,2H),2.62(t,J＝6.4Hz,2H),2.53–2.49(m,2H),2.20(t,J＝6.4Hz,1H),2.09(s,3H),1.89–1.83(m,1H),1.81–1.73(m,2H),1.71–1.60(m,5H).LC-MS:(ESI)m/z 435.3[M+H] +；C 26H 34N 4O 2计算值434.27.纯度:98.8％(214nm),98.1％(254nm). Compound 6 (formate salt): 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.19 (brs, 1H), 7.33-7.27 (m, 4H), 7.26-7.21 (m, 1H), 7.09 (d, J=7.2Hz, 1H), 6.31(d, J=7.2Hz, 1H), 4.30(s, 1H), 3.51(d, J=11.2Hz, 1H), 3.34(d, J=11.2Hz, 1H) ,3.30–3.24(m,2H),3.18(dd,J=11.2,4.4Hz,1H),3.09(dd,J=11.2,4.4Hz,1H),2.94–2.79(m,2H),2.62(t , J=6.4Hz, 2H), 2.53–2.49 (m, 2H), 2.20 (t, J=6.4Hz, 1H), 2.09 (s, 3H), 1.89–1.83 (m, 1H), 1.81–1.73 ( m, 2H), 1.71–1.60 (m, 5H). LC-MS: (ESI) m/z 435.3 [M+H] + ; calcd for C 26 H 34 N 4 O 2 434.27. Purity: 98.8% (214 nm ), 98.1% (254nm).
实施例3化合物7的合成Example 3 Synthesis of Compound 7
Figure PCTCN2021107688-appb-000034
Figure PCTCN2021107688-appb-000034
步骤1. 7-(3-((1R,5S,6s)-6-((3-乙氧基-3-氧代-1-苯基丙基)氨基)-3-氮杂双环[3.1.0]己-3-基)丙基)-3，4-二氢-1，8-萘啶-1(2H)-羧酸叔丁酯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
Figure PCTCN2021107688-appb-000035
Figure PCTCN2021107688-appb-000035
在N 2气氛下，向3-(((1R,5S,6s)-3-氮杂双环[3.1.0]己-6-基)氨基)-3-苯基丙酸乙酯(174mg，0.63mmol)和7-(3-氧丙基)-3,4-二氢-1,8-萘啶-1(2H)-羧酸叔丁酯(221mg，0.76mmol)的甲醇(10mL)溶液中加入三乙酰氧基硼氢化钠(336mg，1.59mmol)，将所得混合物于25℃搅拌18小时。然后分批次加入氰基硼氢化钠(60mg，0.95mmol)，将所得混合物于25℃搅拌14小时。浓缩至干后，将残余物溶在饱和碳酸氢钠(20mL)中，以乙酸乙酯(20mL×3)萃取。合并有机相并用盐水洗涤，经硫酸钠干燥，过滤并浓缩至干。残余物通过快速柱色谱法纯化(0-8％甲醇的二氯甲烷溶液)，得到标题化合物(94mg，27％)，为黄色油状物。LC-MS:ESI m/z 549.31[M+H] +,C 32H 44N 4O 4.计算值548.34. Under N atmosphere, ethyl 3 -(((1R,5S,6s)-3-azabicyclo[3.1.0]hex-6-yl)amino)-3-phenylpropanoate (174 mg, 0.63 mmol) and 7-(3-oxopropyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate tert-butyl ester (221 mg, 0.76 mmol) in methanol (10 mL) Sodium triacetoxyborohydride (336 mg, 1.59 mmol) was added and the resulting mixture was stirred at 25°C for 18 hours. Then sodium cyanoborohydride (60 mg, 0.95 mmol) was added in portions and the resulting mixture was stirred at 25°C for 14 hours. After concentration to dryness, the residue was dissolved in saturated sodium bicarbonate (20 mL) and extracted with ethyl acetate (20 mL×3). The organic phases were combined and washed with brine, dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by flash column chromatography (0-8% methanol in dichloromethane) to give the title compound (94 mg, 27%) as a yellow oil. LC-MS: ESI m/z 549.31 [M+H] + , calcd for C 32 H 44 N 4 O 4 . 548.34.
步骤2. 3-苯基-3-(((1R,5S,6s)-3-(3-(5,6,7,8-四氢-1,8-萘啶-2-基)丙基)-3-氮杂双环[3.1.0]己-6-基)氨基)丙酸Step 2. 3-Phenyl-3-(((1R,5S,6s)-3-(3-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)propyl )-3-azabicyclo[3.1.0]hex-6-yl)amino)propionic acid
Figure PCTCN2021107688-appb-000036
Figure PCTCN2021107688-appb-000036
向7-(3-((1R,5S,6s)-6-((3-乙氧基-3-氧代-1-苯基丙基)氨基)-3-氮杂双环[3.1.0]己-3-基)丙基)-3，4-二氢-1，8-萘啶-1(2H)-羧酸叔丁酯(94mg，0.17mmol)的二氯甲烷(5mL)溶液中，滴加三氟乙酸(2mL)，在25℃下搅拌16小时。真空除去溶剂，得到3-苯基-3-(((1R,5S,6s)-3-(3-(5,6,7,8-四氢-1,8-萘吡啶-2-基)丙基)-3-氮杂双环[3.1.0]己-6-基)氨基)丙酸乙酯的三氟乙酸盐(77mg，粗品)，为黄色油状物。LC-MS：ESI m/z 449.28[M+H] +，C 27H 36N 4O 2.计算值448.28.将粗品(77mg)溶在甲醇(4mL)和水(1mL)中，加入NaOH(27mg，0.69mmol)，将所得混合物在25℃ 下搅拌16小时。用1N HCl(0.8mL)中和后，将混合物浓缩并将残余物通过制备HPLC在以下条件下纯化[柱：Kromasil 100-5-C18，30×150mm；流动相：1-35％MeCN的水溶液(含0.1％甲酸)；时间：14分钟]，得到白色固体状的标题化合物(12.1mg，17％)。 1H NMR(400MHz,CD 3OD)δ7.55–7.20(m,6H),6.44(d,J＝7.3Hz,1H),4.30(dd,J＝9.0,5.0Hz,1H),3.45–3.40(m,2H),3.33–3.31(m,1H),3.25(d,J＝10.7Hz,1H),3.14(d,J＝10.3Hz,1H),3.03(dd,J＝10.7,4.6Hz,1H),2.95(dd,J＝10.7,4.6Hz,1H),2.80–2.73(m,4H),2.68–2.54(m,3H),2.44(t,J＝2.1Hz,1H),1.96–1.79(m,5H),1.76–1.66(m,1H).LC-MS:ESI m/z 421.0[M+H] +,C 25H 32N 4O 2.计算值420.25. To 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 (94 mg, 0.17 mmol) in dichloromethane (5 mL), Trifluoroacetic acid (2 mL) was added dropwise, and the mixture was stirred at 25°C for 16 hours. The solvent was removed in vacuo to give 3-phenyl-3-(((1R,5S,6s)-3-(3-(5,6,7,8-tetrahydro-1,8-naphthypyridin-2-yl) Propyl)-3-azabicyclo[3.1.0]hex-6-yl)amino)propionic acid ethyl ester trifluoroacetate (77 mg, crude) as a yellow oil. LC-MS: ESI m/z 449.28 [M+H] + , calculated for C 27 H 36 N 4 O 2. 448.28. The crude product (77 mg) was dissolved in methanol (4 mL) and water (1 mL) and NaOH ( 27 mg, 0.69 mmol) and the resulting mixture was stirred at 25 °C for 16 h. After neutralization with 1N HCl (0.8 mL), the mixture was concentrated and the residue was purified by preparative HPLC under the following conditions [column: Kromasil 100-5-C18, 30 x 150 mm; mobile phase: 1-35% MeCN in water (with 0.1% formic acid); time: 14 min] to give the title compound (12.1 mg, 17%) as a white solid. 1 H NMR (400MHz, CD 3 OD) δ 7.55-7.20 (m, 6H), 6.44 (d, J=7.3Hz, 1H), 4.30 (dd, J=9.0, 5.0Hz, 1H), 3.45-3.40 (m, 2H), 3.33–3.31 (m, 1H), 3.25 (d, J=10.7Hz, 1H), 3.14 (d, J=10.3Hz, 1H), 3.03 (dd, J=10.7, 4.6Hz, 1H), 2.95 (dd, J=10.7, 4.6Hz, 1H), 2.80–2.73 (m, 4H), 2.68–2.54 (m, 3H), 2.44 (t, J=2.1Hz, 1H), 1.96–1.79 (m, 5H), 1.76–1.66 (m, 1H). LC-MS: ESI m/z 421.0 [M+H] + , C 25 H 32 N 4 O 2 . Calculated 420.25.
得到的化合物7，通过制备手性SFC，在以下条件下分离粗残余物：[柱：Daicel ChiralPak IG(250×30mm，10μm)；流动相：60％甲醇的二氧化碳溶液(含0.1％NH 3.H 2O)；流速：70g/min]，分别得到化合物7a和化合物7b，为黄色固体。 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 μm); 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.
化合物7a(胺盐)： 1H NMR(400MHz,CD 3OD)δ7.45–7.26(m,5H),7.17(d,J＝7.3Hz,1H),6.35(d,J＝7.3Hz,1H),4.24(dd,J＝9.2,4.6Hz,1H),3.41–3.36(m,2H),3.36(s,1H),3.19(d,J＝10.5Hz,1H),3.05(d,J＝10.4Hz,1H),2.94–2.88(m,1H),2.84–2.79(m,1H),2.77–2.63(m,5H),2.58–2.47(m,3H),2.35(s,1H),1.92–1.77(m,5H). Compound 7a (amine salt): 1 H NMR (400 MHz, CD 3 OD) δ 7.45-7.26 (m, 5H), 7.17 (d, J=7.3 Hz, 1H), 6.35 (d, J=7.3 Hz, 1H) ), 4.24(dd, J=9.2, 4.6Hz, 1H), 3.41–3.36(m, 2H), 3.36(s, 1H), 3.19(d, J=10.5Hz, 1H), 3.05(d, J= 10.4Hz, 1H), 2.94–2.88 (m, 1H), 2.84–2.79 (m, 1H), 2.77–2.63 (m, 5H), 2.58–2.47 (m, 3H), 2.35 (s, 1H), 1.92 –1.77(m,5H).
化合物7b(胺盐)： 1H NMR(400MHz,CD 3OD)δ7.47–7.25(m,5H),7.17(d,J＝7.3Hz,1H),6.35(d,J＝7.3Hz,1H),4.23(s,1H),3.42–3.36(m,2H),3.34–3.33(m,1H),3.18(d,J＝10.4Hz,1H),3.07–3.00(m,1H),2.92–2.85(m,1H),2.82–2.76(m,1H),2.75–2.60(m,5H),2.52(t,J＝7.3Hz,3H),2.33(s,1H),1.94–1.74(m,5H). Compound 7b (amine salt): 1 H NMR (400 MHz, CD 3 OD) δ 7.47-7.25 (m, 5H), 7.17 (d, J=7.3 Hz, 1H), 6.35 (d, J=7.3 Hz, 1H) ), 4.23 (s, 1H), 3.42–3.36 (m, 2H), 3.34–3.33 (m, 1H), 3.18 (d, J=10.4Hz, 1H), 3.07–3.00 (m, 1H), 2.92– 2.85(m,1H),2.82-2.76(m,1H),2.75-2.60(m,5H),2.52(t,J=7.3Hz,3H),2.33(s,1H),1.94-1.74(m, 5H).
实施例4 参照化合物7的合成方法，可以得到以下化合物：Embodiment 4 With reference to the synthetic method of compound 7, the following compounds can be obtained:
化合物8(甲酸盐)： 1H NMR(400MHz,CD 3OD)δ7.47–7.26(m,6H),6.48(d,J＝7.3Hz,1H),4.22(dd,J＝8.6,5.5Hz,1H),3.47–3.40(m,2H),3.34–3.31(m,1H),3.26–3.17(m,2H),3.16–3.10(m,1H),2.97–2.87(m,2H),2.78–2.69(m,3H),2.67–2.53(m,3H),2.29(s,1H),1.95–1.87(m,3H),1.76–1.52(m,5H).LC-MS:ESI m/z 435.22[M+H] +,C 26H 34N 4O 2计算值434.27. Compound 8 (formate salt): 1 H NMR (400 MHz, CD 3 OD) δ 7.47-7.26 (m, 6H), 6.48 (d, J=7.3 Hz, 1 H), 4.22 (dd, J=8.6, 5.5 Hz, 1H), 3.47–3.40 (m, 2H), 3.34–3.31 (m, 1H), 3.26–3.17 (m, 2H), 3.16–3.10 (m, 1H), 2.97–2.87 (m, 2H), 2.78–2.69 (m, 3H), 2.67–2.53 (m, 3H), 2.29 (s, 1H), 1.95–1.87 (m, 3H), 1.76–1.52 (m, 5H). LC-MS: ESI m/ z 435.22 [M+H] + , calcd for C 26 H 34 N 4 O 2 434.27.
化合物9(甲酸盐)： 1H NMR(400MHz,CD 3OD)δ7.47–7.30(m,6H),6.46(d,J＝7.3Hz,1H),4.33(dd,J＝8.4,5.8Hz,1H),3.45–3.39(m,2H),3.33–3.31(m,1H),3.20(d,J＝10.6Hz,1H),3.18–3.08(m,3H),3.05(dd,J＝10.7,4.6Hz,1H),2.88–2.78(m,3H),2.77–2.66(m,3H),2.31(t,J＝2.2Hz,1H),1.97–1.87(m,3H),1.80–1.74(m,1H).LC-MS:ESI m/z 407.1[M+H] +,C 24H 30N 4O 2.计算值406.24. Compound 9 (formate salt): 1 H NMR (400 MHz, CD 3 OD) δ 7.47-7.30 (m, 6H), 6.46 (d, J=7.3 Hz, 1 H), 4.33 (dd, J=8.4, 5.8 Hz, 1H), 3.45–3.39 (m, 2H), 3.33–3.31 (m, 1H), 3.20 (d, J=10.6Hz, 1H), 3.18–3.08 (m, 3H), 3.05 (dd, J= 10.7, 4.6Hz, 1H), 2.88–2.78 (m, 3H), 2.77–2.66 (m, 3H), 2.31 (t, J=2.2Hz, 1H), 1.97–1.87 (m, 3H), 1.80–1.74 (m, 1H). LC-MS: ESI m/z 407.1 [M+H] + , C 24 H 30 N 4 O 2 . Calculated 406.24.
化合物10(甲酸盐)： 1H NMR(400MHz,CD 3OD)δ7.56–7.32(m,5H),7.28(d,J＝7.3Hz,1H),6.41(d,J＝7.3Hz,1H),3.98–3.90(m,1H),3.43–3.36(m,2H),3.28(d,J＝11.1Hz,1H),3.21–3.03(m,5H),2.79(t,J＝6.9Hz,2H),2.73(t,J＝6.2Hz,2H),2.27–2.13(m,4H),2.02–1.86(m,4H),1.79-1.76(m,1H).LC-MS:ESI m/z:421.2[M+H] +,C 25H 32N 4O 2.计算值420.25. Compound 10 (formate salt): 1 H NMR (400 MHz, CD 3 OD) δ 7.56-7.32 (m, 5H), 7.28 (d, J=7.3 Hz, 1 H), 6.41 (d, J=7.3 Hz, 1H), 3.98–3.90 (m, 1H), 3.43–3.36 (m, 2H), 3.28 (d, J=11.1Hz, 1H), 3.21–3.03 (m, 5H), 2.79 (t, J=6.9Hz) ,2H),2.73(t,J＝6.2Hz,2H),2.27-2.13(m,4H),2.02-1.86(m,4H),1.79-1.76(m,1H).LC-MS:ESI m/ z: 421.2 [M+H] + , calcd for C 25 H 32 N 4 O 2. 420.25.
化合物11(甲酸盐)： 1H NMR(400MHz,CD 3OD)δ7 7.52(d,J＝7.2Hz,1H),7.44–7.18(m,5H),6.56(d,J＝7.3Hz,1H),3.8–3.76(m,1H),3.50-3.43(m,5H),3.18–3.07(m,3H),2.96–2.87(m,2H),2.82–2.69(m,5H),1.99–1.93(m,6H).LC-MS:ESI m/z:421.2[M+H] +,C 25H 32N 4O 2.计算值420.25. Compound 11 (formate salt): 1 H NMR (400 MHz, CD 3 OD) δ7 7.52 (d, J=7.2 Hz, 1H), 7.44-7.18 (m, 5H), 6.56 (d, J=7.3 Hz, 1H) ), 3.8–3.76 (m, 1H), 3.50–3.43 (m, 5H), 3.18–3.07 (m, 3H), 2.96–2.87 (m, 2H), 2.82–2.69 (m, 5H), 1.99–1.93 (m, 6H). LC-MS: ESI m/z: 421.2 [M+H] + , calcd for C 25 H 32 N 4 O 2. 420.25.
按照中间体A的N-甲基化方法，结合化合物7的合成方法，可以得到化合物12：According to the N-methylation method of intermediate A, combined with the synthesis method of compound 7, compound 12 can be obtained:
1HNMR(400MHz,CD 3OD)δ7.39–7.22(m,6H),6.42(d,J＝7.3Hz,1H),4.28(dd,J＝8.9,6.0Hz,1H),3.44–3.37(m,3H),3.29–3.19(m,3H),3.00–2.92(m,3H),2.72(t,J＝6.2Hz,2H),2.64–2.57(m,3H),2.23(s,3H),2.06–1.99(m,2H),1.95–1. 85(m,5H).LC-MS:ESI m/z 435.20[M+H] +,C 26H 34N 4O 2计算值434.27. 1 HNMR (400MHz, CD 3 OD) δ 7.39–7.22 (m, 6H), 6.42 (d, J=7.3Hz, 1H), 4.28 (dd, J=8.9, 6.0Hz, 1H), 3.44–3.37 ( m, 3H), 3.29–3.19 (m, 3H), 3.00–2.92 (m, 3H), 2.72 (t, J=6.2Hz, 2H), 2.64–2.57 (m, 3H), 2.23 (s, 3H) , 2.06–1.99 (m, 2H), 1.95–1.85 (m, 5H). LC-MS: ESI m/z 435.20[M+H] + , calcd. for C 26 H 34 N 4 O 2 434.27.
将中间体B的原料替换成(1R,5S,6r)-6-氨基-3-氮杂双环[3.1.0]己烷-3-羧酸叔丁酯，按照与化合物7相似的合成方法，可以得到The raw material of intermediate B was replaced with (1R,5S,6r)-6-amino-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester, and according to the synthetic method similar to compound 7, can get
化合物13(甲酸盐)： 1HNMR(400MHz,DMSO-d 6)δ8.30(brs,1H),7.27–7.19(m,4H),7.09(d,J＝7.2Hz,1H),6.72–6.56(m,1H),6.34(d,J＝7.2Hz,1H),5.34(t,J＝4.8Hz,1H),3.91–3.86(m,1H),3.37–3.36(m,1H),3.29–3.27(m,1H),2.90–2.83(m,2H),2.76–2.22(m,1H),2.70–2.60(m,4H),2.49–2.26(m,3H),2.07–1.97(m,3H),1.84–1.70(m,2H),1.53–1.42(m,2H).LC-MS:(ESI)m/z 407.3[M+H] +,C 24H 30N 4O 2计算值406.24.纯度:97.9％(254nm),98.6％(214nm). Compound 13 (formate salt): 1 HNMR (400 MHz, DMSO-d 6 ) δ 8.30 (brs, 1H), 7.27-7.19 (m, 4H), 7.09 (d, J=7.2Hz, 1H), 6.72- 6.56(m,1H),6.34(d,J=7.2Hz,1H),5.34(t,J=4.8Hz,1H),3.91-3.86(m,1H),3.37-3.36(m,1H),3.29 –3.27 (m, 1H), 2.90–2.83 (m, 2H), 2.76–2.22 (m, 1H), 2.70–2.60 (m, 4H), 2.49–2.26 (m, 3H), 2.07–1.97 (m, 3H), 1.84–1.70 (m, 2H), 1.53–1.42 (m, 2H). LC-MS: (ESI) m/z 407.3 [M+H] + , calcd for C 24 H 30 N 4 O 2 406.24 .Purity: 97.9% (254nm), 98.6% (214nm).
化合物14(甲酸盐)： 1H NMR(400MHz,DMSO-d 6)δ7.35(d,J＝7.2Hz,2H),7.26(t,J＝7.6Hz,2H),7.22–7.15(m,1H),7.07(d,J＝7.2Hz,1H),6.26(d,J＝7.2Hz,1H),4.00(dd,J＝8.5,5.4Hz,1H),3.31–3.23(m,2H),3.05(d,J＝9.2Hz,1H),2.73(d,J＝9.2Hz,1H),2.62(t,J＝6.3Hz,2H),2.58–2.50(m,3H),2.46–2.30(m,5H),2.00(t,J＝7.1Hz,1H),1.83–1.73(m,2H),1.67-1.62(m,2H),1.32(m,2H).LC-MS:(ESI)m/z 421.3[M+H] +,C 25H 32N 4O 2计算值420.25.纯度:96.0％(214nm),95.0％(254nm). Compound 14 (formate salt): 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.35 (d, J=7.2 Hz, 2H), 7.26 (t, J=7.6 Hz, 2H), 7.22-7.15 (m ,1H),7.07(d,J＝7.2Hz,1H),6.26(d,J＝7.2Hz,1H),4.00(dd,J＝8.5,5.4Hz,1H),3.31–3.23(m,2H) ,3.05(d,J＝9.2Hz,1H),2.73(d,J＝9.2Hz,1H),2.62(t,J＝6.3Hz,2H),2.58–2.50(m,3H),2.46–2.30( m, 5H), 2.00 (t, J=7.1Hz, 1H), 1.83–1.73 (m, 2H), 1.67–1.62 (m, 2H), 1.32 (m, 2H). LC-MS: (ESI)m /z 421.3 [M+H] + , calcd for C 25 H 32 N 4 O 2 420.25. Purity: 96.0% (214nm), 95.0% (254nm).
化合物15(甲酸盐)： 1H NMR(400MHz,DMSO-d 6)δ8.21(s,1H),7.60-7.21(m,5H),7.11(d,J＝7.2Hz,1H),6.33(d,J＝7.2Hz,1H),4.05-4.01(m,1H),3.35-3.27(m,3H),2.94(d,J＝10.0Hz,2H),2.88-2.81(m,1H),2.77-2.59(m,5H),2.53-2.49(m,3H),2.15-2.06(m,1H),1.89-1.77(m,2H),1.73-1.61(m,2H),1.60-1.47(m,4H).LC-MS:(ESI)m/z 435.3[M+H] +；C 26H 34N 4O 2计算值434.27.纯度:90.1％(214nm),93.8％(254nm). Compound 15 (formate salt): 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.21 (s, 1H), 7.60-7.21 (m, 5H), 7.11 (d, J=7.2Hz, 1H), 6.33 (d, J＝7.2Hz, 1H), 4.05-4.01(m, 1H), 3.35-3.27(m, 3H), 2.94(d, J＝10.0Hz, 2H), 2.88-2.81(m, 1H), 2.77-2.59(m, 5H), 2.53-2.49(m, 3H), 2.15-2.06(m, 1H), 1.89-1.77(m, 2H), 1.73-1.61(m, 2H), 1.60-1.47(m , 4H). LC-MS: (ESI) m/z 435.3 [M+H] + ; calcd for C 26 H 34 N 4 O 2 434.27. Purity: 90.1% (214 nm), 93.8% (254 nm).
化合物16(甲酸盐)： 1H NMR(400MHz,DMSO-d 6)δ8.27(brs,2H)(H of formic acid),7.38–7.31(m,2H),7.28–7.26(m,3H),7.08(d,J＝7.2Hz,1H),6.32(d,J＝7.2Hz,1H),4.02–4.00(m,1H),3.75–3.72(m,1H),3.39–3.37(m,2H),3.26–3.23(m,3H),3.05–2.90(m,4H),2.63–2.58(m,2H),2.36–2.22(m,2H),2.05(s,3H),1.97-1.72(m,3H),1.77–1.74(m,3H),1.61–1.53(m,1H).LC-MS:(ESI)m/z 435.4[M+H] +,C 26H 34N 4O 2计算值434.27.纯度:96.0％(214nm),95.0％(254nm). Compound 16 (formic acid salt): 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.27 (brs, 2H) (H of formic acid), 7.38–7.31 (m, 2H), 7.28–7.26 (m, 3H) ),7.08(d,J=7.2Hz,1H),6.32(d,J=7.2Hz,1H),4.02–4.00(m,1H),3.75–3.72(m,1H),3.39–3.37(m, 2H), 3.26–3.23 (m, 3H), 3.05–2.90 (m, 4H), 2.63–2.58 (m, 2H), 2.36–2.22 (m, 2H), 2.05 (s, 3H), 1.97–1.72 ( m, 3H), 1.77–1.74 (m, 3H), 1.61–1.53 (m, 1H). LC-MS: (ESI) m/z 435.4[M+H] + , calculated for C 26 H 34 N 4 O 2 Value 434.27. Purity: 96.0% (214nm), 95.0% (254nm).
实施例5 化合物17的合成Example 5 Synthesis of compound 17
Figure PCTCN2021107688-appb-000037
Figure PCTCN2021107688-appb-000037
步骤1. 7-(3-((1R,5S,6s)-6-((3-乙氧基-3-氧代-1-苯基丙基)氨基)-3-氮杂双环[3.1.0]己-3-基)-3-氧代丙基)-3,4-二氢-1,8-萘啶-1(2H)-羧酸叔丁酯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
Figure PCTCN2021107688-appb-000038
Figure PCTCN2021107688-appb-000038
在N 2气氛下，向3-((1R,5S,6s)-3-氮杂双环[3.1.0]己-6-基)氨基)-3-苯基丙酸乙酯(96mg，0.35mmol)和3-(8-(叔丁氧羰基)-5,6,7,8-四氢-1,8-萘啶-2-基)丙酸(128mg，0.42mmol)的二氯甲烷(3mL)溶液中加入HBTU(170mg，0.45mmol)和三乙胺(0.15mL，0.5mmol)。在25℃下搅拌16小时后，反应混合物在真空下旋干，残余物溶在饱和碳酸氢钠(10mL)中，用乙酸乙酯(10mL× 3)萃取。合并有机相并用盐水洗涤，经硫酸钠干燥，过滤并浓缩至干。残余物通过快速柱色谱法纯化(0-8％甲醇的二氯甲烷溶液)，得到标题化合物(166mg，84％)，为浅黄色油状物。LC-MS:ESI m/z 563.33[M+H] +,C 32H 42N 4O 5计算值562.32. To ethyl 3-((1R,5S,6s)-3-azabicyclo[3.1.0]hex-6-yl)amino)-3-phenylpropanoate (96 mg, 0.35 mmol ) under N atmosphere ) and 3-(8-(tert-butoxycarbonyl)-5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)propanoic acid (128 mg, 0.42 mmol) in dichloromethane (3 mL) ) solution was added HBTU (170 mg, 0.45 mmol) and triethylamine (0.15 mL, 0.5 mmol). After stirring at 25°C for 16 hours, the reaction mixture was spun dry in vacuo and the residue was dissolved in saturated sodium bicarbonate (10 mL) and extracted with ethyl acetate (10 mL x 3). The organic phases were combined and washed with brine, dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by flash column chromatography (0-8% methanol in dichloromethane) to give the title compound (166 mg, 84%) as a pale yellow oil. LC-MS: ESI m/z 563.33 [M+H] + , calcd for C 32 H 42 N 4 O 5 562.32.
步骤2. 3-苯基-3-(((1R,5S,6s)-3-(3-(5,6,7,8-四氢-1,8-萘吡啶-2-基)丙酰基)-3-氮杂双环[3.1.0]己-6-基)氨基)丙酸Step 2. 3-Phenyl-3-(((1R,5S,6s)-3-(3-(5,6,7,8-tetrahydro-1,8-naphthyridine-2-yl)propionyl )-3-azabicyclo[3.1.0]hex-6-yl)amino)propionic acid
Figure PCTCN2021107688-appb-000039
Figure PCTCN2021107688-appb-000039
向7-(3-((1R,5S,6s)-6-((3-乙氧基-3-氧代-1-苯基丙基)氨基)-3-氮杂双环[3.1.0]己-3-基)-3-氧代丙基)-3,4-二氢-1,8-萘啶-1(2H)-羧酸叔丁酯(166mg，0.3mmol)的二氯甲烷(3mL)加入三氟乙酸(2mL)将得到的混合物在25℃下搅拌16小时。真空除去溶剂，得到3-苯基-3-(((1R,5S,6s)-3-(3-(5,6,7,8-四氢-1,8-萘吡啶-2-基)丙酰基)-3-氮杂双环[3.1.0]己-6-基)氨基)丙酸乙酯的三氟乙酸盐(138mg，粗品)，为浅黄色油状物。LC-MS:ESI m/z 463.28[M+H] +,C 27H 34N 4O 3.计算值462.26。将得到的粗品(138mg)溶解在甲醇(2mL)和水(0.5mL)的混合溶剂中，加入NaOH(24mg，0.6mmol)，所得混合物在25℃下搅拌16小时。用1N HCl(0.6mL)中和后，将混合物浓缩，并通过制备HPLC在以下条件下纯化残余物[柱：Kromasil 100-5-C18，30×150mm；[M+H] +。流动相：1-35％MeCN的水溶液(含0.1％甲酸)；时间：14分钟]，得到标题化合物(66.6mg，51％)，为白色固体。 1H NMR(400MHz,CD 3OD)δ7.48–7.26(m,6H),6.49(dd,J＝7.3,5.5Hz,1H),4.30(dd,J＝14.3,6.7Hz,1H),3.64–3.48(m,2H),3.48–3.41(m,3H),3.38(dd,J＝12.2,4.9Hz,0.5H),3.26(dd,J＝12.2,4.9Hz,0.5H),2.91–2.70(m,5H),2.69–2.51(m,3H),1.96–1.80(m,4H),1.71–1.65(m,0.5H),1.60–1.54(m,0.5H).LC-MS:ESI m/z 435.19[M+H] +,C 25H 30N 4O 3计算值434.23. To 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 (166 mg, 0.3 mmol) in dichloromethane ( 3 mL) trifluoroacetic acid (2 mL) was added and the resulting mixture was stirred at 25°C for 16 hours. The solvent was removed in vacuo to give 3-phenyl-3-(((1R,5S,6s)-3-(3-(5,6,7,8-tetrahydro-1,8-naphthypyridin-2-yl) Propionyl)-3-azabicyclo[3.1.0]hex-6-yl)amino)propionic acid ethyl ester trifluoroacetate (138 mg, crude) as a pale yellow oil. LC-MS: ESI m/z 463.28 [M + H] + , C27H34N4O3 . Calculated 462.26 . The obtained crude product (138 mg) was dissolved in a mixed solvent of methanol (2 mL) and water (0.5 mL), NaOH (24 mg, 0.6 mmol) was added, and the resulting mixture was stirred at 25° C. for 16 hours. After neutralization with 1N HCl (0.6 mL), the mixture was concentrated and the residue was purified by preparative HPLC under the following conditions [column: Kromasil 100-5-C18, 30×150 mm; [M+H] + . Mobile phase: 1-35% MeCN in water (with 0.1% formic acid); time: 14 min] to give the title compound (66.6 mg, 51%) as a white solid. 1 H NMR (400 MHz, CD 3 OD) δ 7.48-7.26 (m, 6H), 6.49 (dd, J=7.3, 5.5 Hz, 1H), 4.30 (dd, J=14.3, 6.7 Hz, 1H), 3.64 –3.48 (m, 2H), 3.48–3.41 (m, 3H), 3.38 (dd, J=12.2, 4.9Hz, 0.5H), 3.26 (dd, J=12.2, 4.9Hz, 0.5H), 2.91–2.70 (m, 5H), 2.69–2.51 (m, 3H), 1.96–1.80 (m, 4H), 1.71–1.65 (m, 0.5H), 1.60–1.54 (m, 0.5H). LC-MS: ESI m /z 435.19[M+H] + , calcd for C 25 H 30 N 4 O 3 434.23.
得到的化合物17，通过制备手性SFC，在以下条件下分离粗残余物：[柱：Daicel ChiralPak IG(250×30mm，10μm)；流动相：60％甲醇的二氧化碳溶液(含0.1％NH 3.H 2O)；流速：70g/min]，分别得到化合物17a和化合物17b，为白色固体。 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 μm); 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.
化合物17a(胺盐)： 1H NMR(400MHz,CD 3OD)δ7.36–7.23(m,4H),7.22–7.05(m,2H),6.29(dd,J＝11.0,7.3Hz,1H),4.18–4.09(m,1H),3.52–3.40(m,2H),3.35–3.24(m,3H),3.16–3.09(m,1H),2.71–2.58(m,5H),2.54–2.37(m,3H),1.84–1.74(m,2H),1.72–1.63(m,2H),1.43(d,J＝41.0Hz,1H).LC-MS:ESI m/z 435.19[M+H] +C 25H 30N 4O 3计算值434.23,RT＝1.439min. Compound 17a (amine salt): 1 H NMR (400 MHz, CD 3 OD) δ 7.36-7.23 (m, 4H), 7.22-7.05 (m, 2H), 6.29 (dd, J=11.0, 7.3 Hz, 1H) ,4.18–4.09(m,1H),3.52–3.40(m,2H),3.35–3.24(m,3H),3.16–3.09(m,1H),2.71–2.58(m,5H),2.54–2.37( m, 3H), 1.84–1.74 (m, 2H), 1.72–1.63 (m, 2H), 1.43 (d, J=41.0Hz, 1H). LC-MS: ESI m/z 435.19[M+H] + Calcd for C25H30N4O3 434.23 , RT = 1.439 min.
化合物17b(胺盐)： 1H NMR(400MHz,CD 3OD)δ7.34–7.24(m,4H),7.22–7.12(m,2H),6.31(dd,J＝9.8,7.4Hz,1H),4.20–4.10(m,1H),3.54–3.41(m,2H),3.38–3.27(m,3H),3.17–3.09(m,1H),2.73–2.59(m,5H),2.54–2.39(m,3H),1.85–1.65(m,4H),1.45(d,J＝41.5Hz,1H).LC-MS:ESI m/z 435.19[M+H] +C 25H 30N 4O 3计算值434.23. Compound 17b (amine salt): 1 H NMR (400 MHz, CD 3 OD) δ 7.34-7.24 (m, 4H), 7.22-7.12 (m, 2H), 6.31 (dd, J=9.8, 7.4 Hz, 1H) ,4.20–4.10(m,1H),3.54–3.41(m,2H),3.38–3.27(m,3H),3.17–3.09(m,1H),2.73–2.59(m,5H),2.54–2.39( m, 3H), 1.85–1.65 (m, 4H), 1.45 (d, J=41.5Hz, 1H). LC-MS: ESI calculated for m/z 435.19[M+H] + C 25 H 30 N 4 O 3 value 434.23.
实施例6 参照化合物17的合成方法，可以得到以下化合物：Example 6 With reference to the synthetic method of compound 17, the following compounds can be obtained:
化合物18(甲酸盐): 1H NMR(400MHz,DMSO-d 6)δ8.17(brs,1H),7.49-7.23(m,5H),7.15–7.08(m,1H),6.53–6.18(m,2H),4.08–4.00(m,1H),3.69–3.39(m,4H),3.34–3.29(m,2H),2.79–2.61(m,5H),2.52–2.31(m,3H),2.11–1.96(m,1H),1.87–1.77(m,2H),1.71–1.54(m, 2H).LC-MS:(ESI)m/z 435.3[M+H] +,C 25H 30N 4O 3计算值434.23.纯度:97.1％(214nm),98.4％(254nm). Compound 18 (formate salt): 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.17 (brs, 1H), 7.49-7.23 (m, 5H), 7.15-7.08 (m, 1H), 6.53-6.18 ( m, 2H), 4.08–4.00 (m, 1H), 3.69–3.39 (m, 4H), 3.34–3.29 (m, 2H), 2.79–2.61 (m, 5H), 2.52–2.31 (m, 3H), 2.11–1.96 (m, 1H), 1.87–1.77 (m, 2H), 1.71–1.54 (m, 2H). LC-MS: (ESI) m/z 435.3[M+H] + , C 25 H 30 N Calcd for 4 O 434.23 . Purity: 97.1% (214nm), 98.4% (254nm).
化合物18通过制备手性SFC，在以下条件下分离粗残余物：[柱：Daicel ChiralPak AD(250×30mm，10μm)；流动相：60％甲醇的二氧化碳溶液(含0.1％DEA)；流速：70g/min]，分别得到化合物18a和化合物18b，为白色固体。Compound 18 was isolated from the crude residue by preparative chiral SFC under the following conditions: [column: Daicel ChiralPak AD (250 x 30 mm, 10 μm); mobile phase: 60% methanol in carbon dioxide (with 0.1% DEA); flow rate: 70 g /min], compound 18a and compound 18b were obtained as white solids, respectively.
化合物18a(胺盐)： 1H NMR(400MHz,CD 3OD)δ7.47–7.39(m,3H),7.34(t,J＝7.2Hz,2H),7.26(dd,J＝7.2,3.6Hz,1H),6.56(d,J＝7.2Hz,1H),4.38–4.28(m,1H),4.19–4.03(m,2H),3.71–3.61(m,2H),3.47–3.41(m,2H),3.08–2.92(m,2H),2.83–2.74(m,2H),2.62–2.39(m,3H),2.33(t,J＝7.2Hz,1H),2.00(d,J＝10.0Hz,2H),1.91–1.79(m,2H),1.69–1.60(m,2H)；LC-MS:ESI m/z 435.5[M+H] +,C 25H 30N 4O 3计算值434.23.纯度:99.2％(214nm),99.1％(254nm). Compound 18a (amine salt): 1 H NMR (400 MHz, CD 3 OD) δ 7.47-7.39 (m, 3H), 7.34 (t, J=7.2 Hz, 2H), 7.26 (dd, J=7.2, 3.6 Hz) ,1H),6.56(d,J＝7.2Hz,1H),4.38-4.28(m,1H),4.19-4.03(m,2H),3.71-3.61(m,2H),3.47-3.41(m,2H) ), 3.08–2.92 (m, 2H), 2.83–2.74 (m, 2H), 2.62–2.39 (m, 3H), 2.33 (t, J=7.2Hz, 1H), 2.00 (d, J=10.0Hz, 2H), 1.91–1.79 (m, 2H), 1.69–1.60 (m, 2H); LC-MS: ESI m/z 435.5 [M+H] + , calcd for C 25 H 30 N 4 O 3 434.23. Purity : 99.2% (214nm), 99.1% (254nm).
化合物18b(胺盐)： 1H NMR(400MHz,CD 3OD)δ7.47–7.38(m,3H),7.34(t,J＝7.2Hz,2H),7.28–7.22(m,1H),6.55(dd,J＝7.2,3.6Hz,1H),4.09(dd,J＝10.9,2.9Hz,1H),3.91(d,J＝10.6Hz,1H),3.71–3.52(m,3H),3.42(dd,J＝11.6,6.6Hz,2H),3.15–2.80(m,3H),2.81–2.74(m,2H),2.62–2.39(m,3H),2.22–2.05(m,1H),2.04–1.98(m,1H),1.95–1.87(m,2H),1.78–1.61(m,2H).LC-MS:ESI m/z 435.5[M+H] +,C 25H 30N 4O 3计算值434.23.纯度:99.0％(214nm),98.7％(254nm). Compound 18b (amine salt): 1 H NMR (400 MHz, CD 3 OD) δ 7.47-7.38 (m, 3H), 7.34 (t, J=7.2 Hz, 2H), 7.28-7.22 (m, 1 H), 6.55 (dd, J＝7.2, 3.6Hz, 1H), 4.09 (dd, J＝10.9, 2.9Hz, 1H), 3.91 (d, J＝10.6Hz, 1H), 3.71–3.52 (m, 3H), 3.42 ( dd, J=11.6, 6.6Hz, 2H), 3.15–2.80 (m, 3H), 2.81–2.74 (m, 2H), 2.62–2.39 (m, 3H), 2.22–2.05 (m, 1H), 2.04– 1.98 (m, 1H), 1.95–1.87 (m, 2H), 1.78–1.61 (m, 2H). LC-MS: ESI m/z 435.5[M+H] + , calculated for C 25 H 30 N 4 O 3 Value 434.23. Purity: 99.0% (214nm), 98.7% (254nm).
实施例7 化合物19的合成方法Example 7 Synthetic method of compound 19
Figure PCTCN2021107688-appb-000040
Figure PCTCN2021107688-appb-000040
步骤1. 3-(4-异丙氧基苯基)-3-氧代丙酸甲酯Step 1. Methyl 3-(4-isopropoxyphenyl)-3-oxopropanoate
Figure PCTCN2021107688-appb-000041
Figure PCTCN2021107688-appb-000041
在N 2气氛下，将1-(4-异丙氧基苯基)乙酮(3.0g，17mmol)和NaH(2.0g，50mmol)溶解在碳酸二甲酯(30mL)中。反应混合物在70℃下搅拌3小时后，将混合物用饱和氯化铵(20mL)淬灭，并用乙酸乙酯(30mL×2)萃取。合并的有机层用盐水(20mL)洗涤，经硫酸钠干燥并浓缩至干。粗产物通过硅胶柱色谱法纯化(石油醚/乙酸乙酯＝20∶1-10∶1)，得到标题化合物(3.2g，73％)，为黄色油状物。 1H NMR(400MHz,CDCl 3)δ7.45(d,J＝7.6Hz,2H),7.35(t,J＝7.6Hz,1H),7.10(d,J＝9.2Hz,1H),4.65–4.55(m,1H),3.97(s,2H),3.74(s,3H),1.33(d,J＝6.0Hz,6H).LC-MS:(ESI)m/z 237.1[M+H] +,C 13H 16O 4计算值236.10. 1-(4-Isopropoxyphenyl)ethanone (3.0 g, 17 mmol) and NaH (2.0 g, 50 mmol) were dissolved in dimethyl carbonate (30 mL) under N2 atmosphere. After the reaction mixture was stirred at 70°C for 3 hours, the mixture was quenched with saturated ammonium chloride (20 mL) and extracted with ethyl acetate (30 mL x 2). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate and concentrated to dryness. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate=20:1-10:1) to give the title compound (3.2 g, 73%) as a yellow oil. 1 H NMR (400 MHz, CDCl 3 ) δ 7.45 (d, J=7.6 Hz, 2H), 7.35 (t, J=7.6 Hz, 1H), 7.10 (d, J=9.2 Hz, 1H), 4.65-4.55 (m,1H),3.97(s,2H),3.74(s,3H),1.33(d,J=6.0Hz,6H).LC-MS:(ESI)m/z 237.1[M+H] + , Calcd for C13H16O4 236.10 .
步骤2. (1R,5S,6s)-6-((1-(4-异丙氧基苯基)-3-甲氧基-3-氧丙基)氨基)-3-氮杂双环[3.1.0]己烷- 3-羧酸叔丁酯Step 2. (1R,5S,6s)-6-((1-(4-isopropoxyphenyl)-3-methoxy-3-oxopropyl)amino)-3-azabicyclo[3.1 .0] Hexane-3-carboxylate tert-butyl ester
Figure PCTCN2021107688-appb-000042
Figure PCTCN2021107688-appb-000042
在N 2气氛下，(1R,5S,6s)-6-氨基-3-氮杂双环[3.1.0]己烷-3-羧酸叔丁酯(0.50g，2.5mmol)，3-(4-异丙氧基苯基)-3-氧代丙酸甲酯(0.59g，2.5mmol)溶解在甲醇(10mL)溶液中，然后加入HOAc(15mg，0.25mmol)和氰基硼氢化钠(0.31mg，5.1mmol)，反应液60℃下搅拌14小时。然后用水(50mL)淬灭反应液，并用二氯甲烷(30mL×2)萃取。合并的有机层用盐水(50mL)洗涤，经硫酸钠干燥并浓缩至干。粗产物通过硅胶柱色谱法纯化(石油醚/乙酸乙酯＝10：1-3：1)，得到标题化合物(0.67g，60％)，为红色油状物。LC-MS:(ESI)m/z 419.3[M+H] +；C 23H 34N 2O 5计算值418.25. Under N atmosphere, (1R,5S,6s)-6-amino- 3 -azabicyclo[3.1.0]hexane-3-carboxylate tert-butyl ester (0.50 g, 2.5 mmol), 3-(4 Methyl isopropoxyphenyl)-3-oxopropionate (0.59 g, 2.5 mmol) was dissolved in methanol (10 mL), then HOAc (15 mg, 0.25 mmol) and sodium cyanoborohydride (0.31 mmol) were added mg, 5.1 mmol), and the reaction solution was stirred at 60° C. for 14 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 crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate=10:1-3:1) to give the title compound (0.67 g, 60%) as a red oil. LC-MS: (ESI) m/z 419.3 [M+H] + ; calcd for C23H34N2O5 418.25 .
步骤3. 3-(((1R,5S,6s)-3-氮杂双环[3.1.0]己-6-基)氨基)-3-(4-异丙氧基苯基)丙酸甲酯Step 3. Methyl 3-(((1R,5S,6s)-3-azabicyclo[3.1.0]hex-6-yl)amino)-3-(4-isopropoxyphenyl)propanoate
Figure PCTCN2021107688-appb-000043
Figure PCTCN2021107688-appb-000043
在N 2气氛下，向(1R,5S,6s)-6-((1-(4-异丙氧基苯基)-3-甲氧基-3-氧丙基)氨基)-3-氮杂双环[3.1.0]己-3-羧酸叔丁酯(0.61g，1.5mmol)的甲醇(10mL)溶液中，加入HCl/二氧六环(3.6mL，4.0mmol)。将混合物在25℃搅拌18小时。然后浓缩反应液，得到标题化合物的三氟乙酸盐(0.80g，粗品)，为红色油状物，其无需进一步纯化直接用于下一步。LC-MS:(ESI)m/z 319.1[M+H] +；C 18H 26N 2O 3计算值318.19. Under a N atmosphere, the addition of (1R,5S,6s)-6-((1-( 4 -isopropoxyphenyl)-3-methoxy-3-oxopropyl)amino)-3-nitrogen To a solution of tert-butyl heterobicyclo[3.1.0]hexan-3-carboxylate (0.61 g, 1.5 mmol) in methanol (10 mL) was added HCl/dioxane (3.6 mL, 4.0 mmol). The mixture was stirred at 25°C for 18 hours. The reaction was then concentrated to give the title compound as trifluoroacetate salt (0.80 g, crude) as a red oil, which was used in the next step without further purification. LC-MS: (ESI) m/z 319.1 [ M +H] + ; calcd for C18H26N2O3 318.19 .
步骤4. 7-(3-((1R,5S,6s)-6-((1-(4-异丙氧基苯基)-3-甲氧基-3-氧丙基)氨基)-3-氮杂双环[3.1.0]己-3-基)丙基)-3,4-二氢-1,8-萘啶-1(2H)-羧酸叔丁酯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
Figure PCTCN2021107688-appb-000044
Figure PCTCN2021107688-appb-000044
在N 2气氛下，向7-(3-氧丙基)-3,4-二氢-2H-1,8-萘啶-1-羧酸叔丁酯(0.40g，1.4mmol)，3-(((1R,5S,6s)-3-氮杂双环[3.1.0]己-6-基)氨基)-3-(4-异丙氧基苯基)丙酸甲酯(0.44g，1.4mmol)和N，N-二异丙基乙胺(0.53g，4.1mmol)的1，2-二氯乙烷(20mL)溶液中加入三乙酰氧基硼氢化钠(0.58g，2.7mmol)。将反应液在25℃搅拌18小时。然后用水(50mL)淬灭反应液，并用二氯甲烷(30mL×2)萃取。合并的有机层用盐水洗涤(50mL)，经硫酸钠干燥并浓缩至干。粗产物通过硅胶柱色谱法纯化(二氯甲烷/甲醇＝50：1–10：1)，得到7-(3-(((1R,5S,6s))-6-((1-(4- 异丙氧基苯基)-3-甲氧基-3-氧丙基)氨基)-3-氮杂双环[3.1.0]己-3-基)丙基)-3,4-二氢-1,8-萘啶-1(2H)-羧酸盐(0.51g，50％)，为红色油。LC-MS:(ESI)m/z 593.3[M+H] +；C 34H 48N 4O 5计算值592.36. To 7-(3 - oxopropyl)-3,4-dihydro-2H-1,8-naphthyridine-1-carboxylic acid tert-butyl ester (0.40 g, 1.4 mmol), 3- Methyl (((1R,5S,6s)-3-azabicyclo[3.1.0]hex-6-yl)amino)-3-(4-isopropoxyphenyl)propanoate (0.44 g, 1.4 mmol) and N,N-diisopropylethylamine (0.53 g, 4.1 mmol) in 1,2-dichloroethane (20 mL) was added sodium triacetoxyborohydride (0.58 g, 2.7 mmol). The 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 crude product was purified by silica gel column chromatography (dichloromethane/methanol=50:1-10:1) to give 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 (0.51 g, 50%) as a red oil. LC-MS: (ESI) m/z 593.3 [M + H] + ; calcd for C34H48N4O5 592.36 .
步骤5. 3-(4-异丙氧基苯基)-3-(((1R,5S,6s)-3-(3-(5,6,7,8-四氢-1,8-萘啶-2-基)丙基)-3-氮杂双环[3.1.0]己-6-基)氨基)丙酸Step 5. 3-(4-Isopropoxyphenyl)-3-(((1R,5S,6s)-3-(3-(5,6,7,8-tetrahydro-1,8-naphthalene) Perid-2-yl)propyl)-3-azabicyclo[3.1.0]hex-6-yl)amino)propionic acid
Figure PCTCN2021107688-appb-000045
Figure PCTCN2021107688-appb-000045
向7-(3-((1R,5S,6s)-6-((1-(4-异丙氧基苯基)-3-甲氧基-3-氧丙基)氨基)-3-氮杂双环[3.1.0]己-3-基)丙基)-3,4-二氢-1,8-萘啶-1(2H)-羧酸叔丁酯(0.40g，0.67mmol)的甲醇(10mL)溶液中加入HCl/dioxane(1.7mL,6.7mmol)。将混合物在25℃下搅拌18小时。将混合物浓缩至干，得到3-(4-异丙氧基苯基)-3-(((1R,5S,6s)-3-(3-(5,6,7,8-四氢-1,8-萘啶)-2-基)丙基)-3-氮杂双环[3.1.0]己基-6-基)氨基)丙酸甲酯的三氟乙酸盐(0.50g，粗品)，呈红色油状，其无需进一步纯化直接用于下一步。LC-MS：(ESI)m/z 493.3[M+H] +，C 29H 40N 4O 3计算值492.31。将得到的粗品(0.50g，粗品)溶解到甲醇/水(8mL，10：1)，一次性加入LiOH.H 2O(0.17g，4.0mmol)。将混合物在25℃下搅拌18小时。将混合物用HCl(1M)酸化至pH＝4-5，并浓缩至干。残余物通过制备型HPLC(柱：Xbridge 5u C18 150×19mm；流动相：ACN-H 2O(0.05％NH 3.H 2O)；梯度：5-15％ACN，流速：20mL/min)纯化得到标题化合物(0.11g，21％)，为黄色固体。 1H NMR(400MHz,DMSO-d 6)δ7.22(d,J＝8.8Hz,2H),6.97(d,J＝7.2Hz,1H),6.83(d,J＝8.8Hz,2H),6.17(d,J＝7.2Hz,1H),5.91(brs,1H),4.53(dt,J＝12.0,6.0Hz,1H),3.92(dd,J＝8.4,6.0Hz,1H),3.28–3.19(m,2H),2.81(d,J＝8.6Hz,1H),2.74(d,J＝8.6Hz,1H),2.63–2.51(m,3H),2.39–2.30(m,3H),2.29–2.19(m,3H),2.15(dd,J＝8.8,4.0Hz,1H),2.06(s,1H),1.80–1.71(m,2H),1.65–1.55(m,2H),1.31–1.29(m,1H),1.25(d,J＝6.0Hz,6H),1.22–1.19(m,1H).LC-MS:(ESI)m/z 479.1[M+H] +；C 28H 38N 4O 3计算值478.2. To 7-(3-((1R,5S,6s)-6-((1-(4-isopropoxyphenyl)-3-methoxy-3-oxopropyl)amino)-3-nitrogen Heterobicyclo[3.1.0]hex-3-yl)propyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate tert-butyl ester (0.40 g, 0.67 mmol) in methanol (10 mL) was added HCl/dioxane (1.7 mL, 6.7 mmol). The mixture was stirred at 25°C for 18 hours. The mixture was concentrated to dryness to give 3-(4-isopropoxyphenyl)-3-(((1R,5S,6s)-3-(3-(5,6,7,8-tetrahydro-1 , 8-Naphthyridinyl)-2-yl)propyl)-3-azabicyclo[3.1.0]hexyl-6-yl)amino)propionic acid methyl ester trifluoroacetate (0.50 g, crude), As a red oil, it was used in the next step without further purification. LC-MS: (ESI) m/z 493.3 [ M + H] + , calcd for C29H40N4O3 492.31 . The resulting crude product (0.50 g, crude product) was dissolved in methanol/water (8 mL, 10: 1 ) and LiOH.H2O (0.17 g, 4.0 mmol) was added in one portion. The mixture was stirred at 25°C for 18 hours. The mixture was acidified with HCl (1 M) to pH=4-5 and concentrated to dryness. The residue was purified by preparative HPLC (column: Xbridge 5u C18 150 x 19 mm; mobile phase: ACN - H2O (0.05% NH3.H2O); gradient: 5-15% ACN, flow rate: 20 mL/min) The title compound (0.11 g, 21%) was obtained as a yellow solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.22 (d, J=8.8 Hz, 2H), 6.97 (d, J=7.2 Hz, 1H), 6.83 (d, J=8.8 Hz, 2H), 6.17 (d, J=7.2Hz, 1H), 5.91 (brs, 1H), 4.53 (dt, J=12.0, 6.0Hz, 1H), 3.92 (dd, J=8.4, 6.0Hz, 1H), 3.28–3.19 ( m, 2H), 2.81 (d, J=8.6Hz, 1H), 2.74 (d, J=8.6Hz, 1H), 2.63–2.51 (m, 3H), 2.39–2.30 (m, 3H), 2.29–2.19 (m, 3H), 2.15 (dd, J=8.8, 4.0Hz, 1H), 2.06 (s, 1H), 1.80–1.71 (m, 2H), 1.65–1.55 (m, 2H), 1.31–1.29 (m , 1H), 1.25 (d, J=6.0Hz, 6H), 1.22–1.19 (m, 1H). LC-MS: (ESI) m/z 479.1 [M+H] + ; C 28 H 38 N 4 O 3 Calculated value 478.2.
实施例8 参考化合物19的合成方法，可以得到如下化合物：Example 8 With reference to the synthetic method of compound 19, the following compounds can be obtained:
化合物20(甲酸盐)： 1H NMR(400MHz,DMSO-d 6)δ8.18(brs,2H)(H of formic acid),7.20(t,J＝7.6Hz,1H),7.00(d,J＝7.6Hz,1H),6.91(s,1H),6.87(d,J＝7.6Hz,1H),6.77(d,J＝8.0Hz,1H),6.34(brs,1H),6.17(d,J＝7.2Hz,1H),4.62–4.58(m,1H),3.90(d,J＝8.0Hz,1H),3.22(s,2H),2.92–2.80(m,2H),2.63–2.52(m,3H),2.49–2.36(m,7H),2.04(s,1H),1.78–1.68(m,2H),1.67–1.60(m,2H),1.37(s,2H),1.25(d,J＝6.0Hz,6H).LC-MS:(ESI)m/z 479.3[M+H] +,C 28H 38N 4O 3计算值478.64.纯度:99.6％(214nm),99.1％(254nm). Compound 20 (formic acid salt): 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.18 (brs, 2H) (H of formic acid), 7.20 (t, J=7.6 Hz, 1H), 7.00 (d, J=7.6Hz, 1H), 6.91(s, 1H), 6.87(d, J=7.6Hz, 1H), 6.77(d, J=8.0Hz, 1H), 6.34(brs, 1H), 6.17(d, J=7.2Hz, 1H), 4.62–4.58 (m, 1H), 3.90 (d, J=8.0Hz, 1H), 3.22 (s, 2H), 2.92–2.80 (m, 2H), 2.63–2.52 (m ,3H),2.49–2.36(m,7H),2.04(s,1H),1.78–1.68(m,2H),1.67–1.60(m,2H),1.37(s,2H),1.25(d,J = 6.0 Hz, 6H). LC-MS: (ESI) m/z 479.3 [M+H] + , calcd for C 28 H 38 N 4 O 3 478.64. Purity: 99.6% (214 nm), 99.1% (254 nm) .
化合物21(甲酸盐)： 1H NMR(400MHz,DMSO-d 6)δ8.18(brs,2H)(H of formic acid),7.34(d,J＝7.6Hz,1H),7.20(t,J＝7.6Hz,1H),7.00(d,J＝7.6Hz,2H),6.91(t,J＝7.2Hz,1H),6.35(bs,1H),6.17(d,J＝7.2Hz,1H),4.63(dd,J＝12.0,6.0Hz,1H),4.32(dd,J＝8.8,5.6Hz,1H),3.21(d,J＝4.8Hz,2H),2.91–2.86(m,2H),2.67–2.50(m,2H),2.45–2.28(m,8H),2.08(s,1H),1.77– 1.68(m,2H),1.66–1.58(m,2H),1.40(s,2H),1.28(d,J＝6.0Hz,6H).LC-MS:(ESI)m/z 479.3[M+H] +,C 28H 38N 4O 3计算值478.29.纯度:97.8％(214nm),98.5％(254nm). Compound 21 (formic acid salt): 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.18 (brs, 2H) (H of formic acid), 7.34 (d, J=7.6 Hz, 1H), 7.20 (t, J=7.6Hz, 1H), 7.00 (d, J=7.6Hz, 2H), 6.91 (t, J=7.2Hz, 1H), 6.35 (bs, 1H), 6.17 (d, J=7.2Hz, 1H) ,4.63(dd,J＝12.0,6.0Hz,1H),4.32(dd,J＝8.8,5.6Hz,1H),3.21(d,J＝4.8Hz,2H),2.91–2.86(m,2H), 2.67–2.50(m,2H), 2.45–2.28(m,8H), 2.08(s,1H), 1.77–1.68(m,2H), 1.66–1.58(m,2H), 1.40(s,2H), 1.28 (d, J=6.0 Hz, 6H). LC-MS: (ESI) m/z 479.3 [M+H] + , calcd for C 28 H 38 N 4 O 3 478.29. Purity: 97.8% (214 nm), 98.5% (254nm).
化合物22(甲酸盐)： 1H NMR(400MHz,DMSO-d 6)δ7.44–7.40(m,2H),7.37–7.30(m,2H),6.97(d,J＝7.2Hz,1H),6.16(d,J＝7.3Hz,1H),6.03(s,1H),5.90(s,1H),4.06(t,J＝7.1Hz,1H),3.26–3.22(m,2H),2.81(d,J＝8.4Hz,1H),2.76(d,J＝8.4Hz,1H),2.68–2.58(m,3H),2.46(d,J＝6.4Hz,1H),2.33(t,J＝7.2Hz,2H),2.29–2.21(m,6H),2.18–2.15(m,4H),2.10(s,1H),1.80–1.73(m,2H),1.64–1.55(m,2H),1.33(s,1H),1.25(s,1H).LC-MS:(ESI)m/z 515.1[M+H] +；C 30H 38N 6O 2计算值514.31.纯度:93.0％(214nm),97.0％(254nm). Compound 22 (formate salt): 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.44-7.40 (m, 2H), 7.37-7.30 (m, 2H), 6.97 (d, J=7.2 Hz, 1H) ,6.16(d,J＝7.3Hz,1H),6.03(s,1H),5.90(s,1H),4.06(t,J＝7.1Hz,1H),3.26–3.22(m,2H),2.81( d, J=8.4Hz, 1H), 2.76 (d, J=8.4Hz, 1H), 2.68–2.58 (m, 3H), 2.46 (d, J=6.4Hz, 1H), 2.33 (t, J=7.2 Hz, 2H), 2.29–2.21 (m, 6H), 2.18–2.15 (m, 4H), 2.10 (s, 1H), 1.80–1.73 (m, 2H), 1.64–1.55 (m, 2H), 1.33 ( s, 1H), 1.25 (s, 1H). LC-MS: (ESI) m/z 515.1 [M+H] + ; calcd for C 30 H 38 N 6 O 2 514.31. Purity: 93.0% (214 nm), 97.0% (254nm).
化合物23(甲酸盐)： 1H NMR(400MHz,DMSO-d 6)δ7.14(t,J＝7.6Hz,1H),6.96(d,J＝7.2Hz,1H),6.90(s,1H),6.77(d,J＝7.6Hz,2H),6.16(d,J＝7.2Hz,1H),5.89(brs,1H),3.91(dd,J＝8.4,5.6Hz,1H),3.74–3.69(m,4H),3.25–3.20(m,2H),3.11–3.06(m,4H),2.80(d,J＝8.6Hz,1H),2.74(d,J＝8.6Hz,1H),2.62–2.51(m,3H),2.39–2.30(m,3H),2.24–2.07(m,4H),2.07(s,1H),1.78–1.71(m,2H),1.62–1.57(m,2H),1.29(s,1H),1.24(s,1H).LC-MS:(ESI)m/z 506.3[M+H] +；C 29H 39N 5O 3计算值505.31.纯度:100％(214nm),100％(254nm). Compound 23 (formate salt): 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.14 (t, J=7.6 Hz, 1H), 6.96 (d, J=7.2 Hz, 1H), 6.90 (s, 1H) ),6.77(d,J=7.6Hz,2H),6.16(d,J=7.2Hz,1H),5.89(brs,1H),3.91(dd,J=8.4,5.6Hz,1H),3.74–3.69 (m, 4H), 3.25–3.20 (m, 2H), 3.11–3.06 (m, 4H), 2.80 (d, J=8.6Hz, 1H), 2.74 (d, J=8.6Hz, 1H), 2.62– 2.51 (m, 3H), 2.39–2.30 (m, 3H), 2.24–2.07 (m, 4H), 2.07 (s, 1H), 1.78–1.71 (m, 2H), 1.62–1.57 (m, 2H), 1.29(s, 1H), 1.24(s, 1H). LC-MS: (ESI) m/z 506.3 [M+H] + ; calcd for C 29 H 39 N 5 O 3 505.31. Purity: 100% (214 nm ), 100% (254nm).
得到的化合物23，通过制备手性SFC，在以下条件下分离粗残余物：[柱：Daicel ChiralPak OZ-H(250×20mm，5μm)；流动相：50％甲醇的二氧化碳溶液(含0.2％的DEA)；流速：40g/min]，分别得到化合物23a和化合物23b。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 μm); mobile phase: 50% methanol in carbon dioxide (containing 0.2% DEA); flow rate: 40 g/min] to obtain compound 23a and compound 23b, respectively.
化合物23a(胺盐): 1H NMR(400MHz,CD 3OD)δ7.20(t,J＝7.9Hz,1H),7.10(d,J＝7.3Hz,1H),7.00(s,1H),6.90-6.83(m,2H),6.29(d,J＝7.3Hz,1H),4.09-4.06(m,1H),3.81(t,J＝4.7Hz,4H),3.37-3.34(m,2H),3.13(t,J＝4.8Hz,4H),3.00-2.99(m,1H),2.84(d,J＝9.6Hz,1H),2.68(t,J＝6.2Hz,2H),2.63-2.57(m,1H),2.53-2.39(m,7H),2.22-2.21(m,1H),1.89-1.83(m,2H),1.74-1.66(m,2H),1.62-1.60(m,1H),1.38-1.36(m,1H).LC-MS:(ESI)m/z 506.3[M+H] +；C 29H 39N 5O 3计算值505.31. Compound 23a (amine salt): 1 H NMR (400 MHz, CD 3 OD) δ 7.20 (t, J=7.9 Hz, 1H), 7.10 (d, J=7.3 Hz, 1H), 7.00 (s, 1H), 6.90-6.83(m, 2H), 6.29(d, J=7.3Hz, 1H), 4.09-4.06(m, 1H), 3.81(t, J=4.7Hz, 4H), 3.37-3.34(m, 2H) ,3.13(t,J＝4.8Hz,4H),3.00-2.99(m,1H),2.84(d,J＝9.6Hz,1H),2.68(t,J＝6.2Hz,2H),2.63-2.57( m,1H),2.53-2.39(m,7H),2.22-2.21(m,1H),1.89-1.83(m,2H),1.74-1.66(m,2H),1.62-1.60(m,1H), 1.38-1.36 (m, 1H). LC-MS: (ESI) m/z 506.3 [ M +H] + ; calcd for C29H39N5O3 505.31 .
化合物23b(胺盐): 1H NMR(400MHz,CD 3OD)δ7.21(t,J＝7.9Hz,1H),7.11(d,J＝7.3Hz,1H),7.00(s,1H),6.90-6.85(m,2H),6.29(d,J＝7.3Hz,1H),4.13-4.09(m,1H),3.81(t,J＝4.7Hz,4H),3.37-3.34(m,2H),3.13(t,J＝4.8Hz,4H),3.05-3.04(m,1H),2.90(d,J＝9.7Hz,1H),2.68(t,J＝6.2Hz,2H),2.63-2.58(m,1H),2.53-2.43(m,7H),2.27-2.26(m,1H),1.87-1.83(m,2H),1.76-1.70(m,2H),1.68-1.65(m,1H),1.44-1.42(m,1H).LC-MS:(ESI)m/z 506.3[M+H] +；C 29H 39N 5O 3计算值505.31. Compound 23b (amine salt): 1 H NMR (400 MHz, CD 3 OD) δ 7.21 (t, J=7.9 Hz, 1H), 7.11 (d, J=7.3 Hz, 1H), 7.00 (s, 1H), 6.90-6.85(m, 2H), 6.29(d, J=7.3Hz, 1H), 4.13-4.09(m, 1H), 3.81(t, J=4.7Hz, 4H), 3.37-3.34(m, 2H) ,3.13(t,J＝4.8Hz,4H),3.05-3.04(m,1H),2.90(d,J＝9.7Hz,1H),2.68(t,J＝6.2Hz,2H),2.63-2.58( m,1H),2.53-2.43(m,7H),2.27-2.26(m,1H),1.87-1.83(m,2H),1.76-1.70(m,2H),1.68-1.65(m,1H), 1.44-1.42 (m, 1H). LC-MS: (ESI) m/z 506.3 [ M +H] + ; calcd for C29H39N5O3 505.31 .
化合物24(甲酸盐)： 1H NMR(400MHz,DMSO-d 6)δ8.21(brs,1H)(H of formic acid),7.82(s,1H),7.75–7.66(m,2H),7.54(t,J＝7.6Hz,1H),7.01(d,J＝7.2Hz,1H),6.43(brs,1H),6.18(d,J＝7.2Hz,1H),4.03–3.99(s,1H),3.26–3.20(m,2H),2.89(dd,J＝20.8,9.2Hz,2H),2.64–2.56(m,3H),2.49–2.27(m,7H),1.97(s,1H),1.75–1.67(m,2H),1.66–1.58(m,2H),1.38(d,J＝2.0Hz,1H),1.30(d,J＝2.0Hz,1H).LC-MS:(ESI)m/z 446.3[M+H] +,C 26H 31N 5O 2计算值445.25.纯度:96.8％(214nm),91.4％(254nm). Compound 24 (formic acid salt): 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.21 (brs, 1H) (H of formic acid), 7.82 (s, 1H), 7.75–7.66 (m, 2H), 7.54(t,J＝7.6Hz,1H),7.01(d,J＝7.2Hz,1H),6.43(brs,1H),6.18(d,J＝7.2Hz,1H),4.03–3.99(s,1H) ), 3.26–3.20(m, 2H), 2.89(dd, J=20.8, 9.2Hz, 2H), 2.64–2.56(m, 3H), 2.49–2.27(m, 7H), 1.97(s, 1H), 1.75–1.67(m,2H),1.66–1.58(m,2H),1.38(d,J=2.0Hz,1H),1.30(d,J=2.0Hz,1H).LC-MS:(ESI)m /z 446.3 [M+H] + , calcd for C 26 H 31 N 5 O 2 445.25. Purity: 96.8% (214nm), 91.4% (254nm).
得到的化合物24，通过制备手性SFC，在以下条件下分离粗残余物：[柱：Daicel ChiralPak OZ-H(250×20mm，5μm)；流动相：50％甲醇的二氧化碳溶液(含0.2％的DEA)；流速：40g/min]，分别得到化合物24a和化合物24b。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 μm); mobile phase: 50% methanol in carbon dioxide (containing 0.2% DEA); flow rate: 40 g/min] to obtain compound 24a and compound 24b, respectively.
化合物24a(胺盐): 1H NMR(400MHz,CD 3OD)δ7.76(s,1H),7.70(d,J＝7.8Hz,1H),7.59(d,J＝7.7Hz,1H),7.51-7.47(m,1H),7.12(d,J＝7.3Hz,1H),6.31(d,J＝7.3Hz,1H),4.15(t,J＝6.2Hz,1H),3.38-3.34(m,2H),3.07-3.04(m,1H),2.97-2.94(m,1H),2.76-2.41(m,10H), 2.17-2.15(m,1H),1.89-1.83(m,2H),1.79-1.72(m,2H),1.68-1.64(m,1H),1.43-1.39(m,1H).LC-MS:(ESI)m/z 446.3[M+H] +,C 26H 31N 5O 2计算值445.25. Compound 24a (amine salt): 1 H NMR (400 MHz, CD 3 OD) δ 7.76 (s, 1H), 7.70 (d, J=7.8 Hz, 1H), 7.59 (d, J=7.7 Hz, 1H), 7.51-7.47(m, 1H), 7.12(d, J=7.3Hz, 1H), 6.31(d, J=7.3Hz, 1H), 4.15(t, J=6.2Hz, 1H), 3.38-3.34(m ,2H),3.07-3.04(m,1H),2.97-2.94(m,1H),2.76-2.41(m,10H), 2.17-2.15(m,1H),1.89-1.83(m,2H),1.79 -1.72(m,2H),1.68-1.64(m,1H),1.43-1.39(m,1H).LC-MS:(ESI)m/z 446.3[M+H] + ,C 26 H 31 N 5 Calculated for O 445.25 .
化合物24b(胺盐): 1H NMR(400MHz,CD 3OD)δ7.76(s,1H),7.70(d,J＝7.8Hz,1H),7.59(d,J＝7.7Hz,1H),7.51-7.47(m,1H),7.12(d,J＝7.3Hz,1H),6.33(d,J＝7.3Hz,1H),4.15(t,J＝6.2Hz,1H),3.38-3.34(m,2H),3.17-3.15(m,1H),3.07-3.05(m,1H),2.95-2.91(m,1H),2.86-2.82(m,1H),2.72-2.67(m,4H),2.64-2.43(m,4H),2.19-2.17(m,1H),1.91-1.76(m,4H),1.68-1.64(m,1H),1.49-1.44(m,1H).LC-MS:(ESI)m/z 446.3[M+H] +,C 26H 31N 5O 2计算值445.25. Compound 24b (amine salt): 1 H NMR (400 MHz, CD 3 OD) δ 7.76 (s, 1H), 7.70 (d, J=7.8 Hz, 1H), 7.59 (d, J=7.7 Hz, 1H), 7.51-7.47(m,1H),7.12(d,J=7.3Hz,1H),6.33(d,J=7.3Hz,1H),4.15(t,J=6.2Hz,1H),3.38-3.34(m ,2H),3.17-3.15(m,1H),3.07-3.05(m,1H),2.95-2.91(m,1H),2.86-2.82(m,1H),2.72-2.67(m,4H),2.64 -2.43(m,4H),2.19-2.17(m,1H),1.91-1.76(m,4H),1.68-1.64(m,1H),1.49-1.44(m,1H).LC-MS:(ESI) ) m/z 446.3 [M+H] + , calcd for C 26 H 31 N 5 O 2 445.25.
化合物25(甲酸盐)： 1H NMR(400MHz,DMSO-d 6)δ7.19(t,J＝7.6Hz,1H),6.97(d,J＝7.2Hz,1H),6.93–6.87(m,2H),6.76(d,J＝8.0Hz,1H),6.24(s,1H),6.15(d,J＝6.8Hz,1H),4.06(s,2H),3.87(d,J＝6.4Hz,1H),3.64(s,2H),3.29(d,J＝1.2Hz,3H),3.21(s,2H),2.79(d,J＝8.4Hz,1H),2.73(d,J＝8.4Hz,1H),2.56(t,J＝5.6Hz,2H),2.54(d,J＝1.6Hz,1H),2.46–2.38(m,1H),2.33–2.24(m,3H),2.19–2.11(m,2H),2.08(d,J＝6.0Hz,1H),2.00(s,1H),1.76–1.70(m,2H),1.61–1.51(m,2H),1.27–1.20(m,2H).LC-MS:(ESI)m/z 495.3[M+H] +；C 28H 38N 4O 4计算值494.29.纯度:91.8％(214nm),91.0％(254nm). Compound 25 (formate salt): 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.19 (t, J=7.6 Hz, 1H), 6.97 (d, J=7.2 Hz, 1H), 6.93-6.87 (m ,2H),6.76(d,J＝8.0Hz,1H),6.24(s,1H),6.15(d,J＝6.8Hz,1H),4.06(s,2H),3.87(d,J＝6.4Hz ,1H),3.64(s,2H),3.29(d,J＝1.2Hz,3H),3.21(s,2H),2.79(d,J＝8.4Hz,1H),2.73(d,J＝8.4Hz ,1H),2.56(t,J=5.6Hz,2H),2.54(d,J=1.6Hz,1H),2.46–2.38(m,1H),2.33–2.24(m,3H),2.19–2.11( m, 2H), 2.08 (d, J=6.0Hz, 1H), 2.00 (s, 1H), 1.76–1.70 (m, 2H), 1.61–1.51 (m, 2H), 1.27–1.20 (m, 2H) .LC-MS: (ESI) m/z 495.3 [M + H] + ; calcd for C28H38N4O4 494.29 . Purity: 91.8% (214 nm), 91.0% (254 nm).
化合物26(甲酸盐)： 1H NMR(400MHz,DMSO-d 6)δ8.51(s,1H),7.86(d,J＝7.4Hz,1H),7.77(s,1H),7.50(d,J＝7.2Hz,1H),7.32(d,J＝8.0Hz,1H),6.55(d,J＝7.2Hz,1H),4.21(s,1H),3.32–3.30(m,2H),3.26–3.20(m,2H),2.99–2.93(m,3H),2.84–2.52(m,8H),2.48(s,3H),2.00–1.91(m,3H),1.85–1.75(m,3H).LC-MS:(ESI)m/z 436.2[M+H] +,C 25H 33N 5O 2计算值435.26.纯度:100％(214nm),100％(254nm). Compound 26 (formate salt): 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.51 (s, 1H), 7.86 (d, J=7.4 Hz, 1H), 7.77 (s, 1H), 7.50 (d , J＝7.2Hz, 1H), 7.32(d, J＝8.0Hz, 1H), 6.55(d, J＝7.2Hz, 1H), 4.21(s, 1H), 3.32–3.30(m, 2H), 3.26 –3.20 (m, 2H), 2.99–2.93 (m, 3H), 2.84–2.52 (m, 8H), 2.48 (s, 3H), 2.00–1.91 (m, 3H), 1.85–1.75 (m, 3H) .LC-MS: (ESI) m/z 436.2 [M+H] + , calcd for C 25 H 33 N 5 O 2 435.26. Purity: 100% (214 nm), 100% (254 nm).
化合物27(甲酸盐)： 1H NMR(400MHz,DMSO-d 6)δ8.06(d,J＝2.4Hz,1H),7.69(dd,J＝8.8,2.4Hz,1H),6.98(d,J＝7.2Hz,1H),6.77(d,J＝8.4Hz,1H),6.25(brs,1H),6.16(d,J＝7.2Hz,1H),3.91(t,J＝7.2Hz,1H),3.82(s,3H),3.21(s,2H),2.81(d,J＝8.8Hz,1H),2.73(d,J＝8.8Hz,1H),2.63–2.52(m,3H),2.38–2.28(m,3H),2.25–2.13(m,3H),2.12–2.06(m,1H),1.96(s,1H),1.76–1.69(m,2H),1.62–1.51(m,2H),1.30–1.26(m,1H),1.20–1.15(m,1H).LC-MS:(ESI)m/z 452.3[M+H] +；C 25H 33N 5O 3计算值451.26.纯度:98.17％(214nm),97.95％(254nm). Compound 27 (formate salt): 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.06 (d, J=2.4 Hz, 1H), 7.69 (dd, J=8.8, 2.4 Hz, 1H), 6.98 (d ,J=7.2Hz,1H),6.77(d,J=8.4Hz,1H),6.25(brs,1H),6.16(d,J=7.2Hz,1H),3.91(t,J=7.2Hz,1H) ),3.82(s,3H),3.21(s,2H),2.81(d,J=8.8Hz,1H),2.73(d,J=8.8Hz,1H),2.63–2.52(m,3H),2.38 –2.28(m,3H), 2.25–2.13(m,3H), 2.12–2.06(m,1H), 1.96(s,1H), 1.76–1.69(m,2H), 1.62–1.51(m,2H) , 1.30–1.26 (m, 1H), 1.20–1.15 (m, 1H). LC-MS: (ESI) m/z 452.3 [M+H] + ; calcd for C 25 H 33 N 5 O 3 451.26. Purity : 98.17% (214nm), 97.95% (254nm).
得到的化合物27，通过制备手性SFC，在以下条件下分离粗残余物：[柱：Daicel ChiralPak OZ-H(250×20mm，5μm)；流动相：50％甲醇的二氧化碳溶液(含0.2％的DEA)；流速：40g/min]，分别得到化合物27a和化合物27b。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 μm); mobile phase: 50% methanol in carbon dioxide (containing 0.2% DEA); flow rate: 40 g/min] to obtain compound 27a and compound 27b, respectively.
化合物27a(胺盐): 1H NMR(400MHz,CD 3OD)δ8.09(d,J＝2.1Hz,1H),7.72(dd,J＝2.3,8.6Hz,1H),7.13(d,J＝7.3Hz,1H),6.77(d,J＝7.5Hz,1H),6.31(d,J＝7.3Hz,1H),4.11-4.08(m,1H),3.87(s,3H),3.38-3.35(m,2H),3.06-2.97(m,2H),2.70-2.41(m,10H),2.18-2.17(m,1H),1.89-1.83(m,2H),1.78-1.71(m,2H),1.64-1.60(m,1H),1.38-1.35(m,1H).LC-MS:(ESI)m/z 452.3[M+H] +；C 25H 33N 5O 3计算值451.26. Compound 27a (amine salt): 1 H NMR (400 MHz, CD 3 OD) δ 8.09 (d, J=2.1 Hz, 1H), 7.72 (dd, J=2.3, 8.6 Hz, 1H), 7.13 (d, J =7.3Hz,1H),6.77(d,J=7.5Hz,1H),6.31(d,J=7.3Hz,1H),4.11-4.08(m,1H),3.87(s,3H),3.38-3.35 (m,2H),3.06-2.97(m,2H),2.70-2.41(m,10H),2.18-2.17(m,1H),1.89-1.83(m,2H),1.78-1.71(m,2H) , 1.64-1.60 (m, 1H), 1.38-1.35 (m, 1H). LC-MS: (ESI) m/z 452.3 [M+H] + ; calcd for C 25 H 33 N 5 O 3 451.26.
化合物27b(胺盐): 1H NMR(400MHz,CD 3OD)8.09(d,J＝2.1Hz,1H),7.72(dd,J＝2.3,8.5Hz,1H),7.11(d,J＝7.3Hz,1H),6.77(d,J＝8.5Hz,1H),6.31(d,J＝7.3Hz,1H),4.11-4.08(m,1H),3.87(s,3H),3.38-3.35(m,2H),3.04-2.97(m,1H),2.90(d,J＝9.8Hz,1H),2.70-2.41(m,10H),2.17-2.15(m,1H),1.89-1.83(m,2H),1.78-1.71(m,2H),1.64-1.60(m,1H),1.37-1.34(m,1H).LC-MS:(ESI)m/z 452.3[M+H] +；C 25H 33N 5O 3计算值451.26. Compound 27b (amine salt): 1 H NMR (400 MHz, CD 3 OD) 8.09 (d, J=2.1 Hz, 1H), 7.72 (dd, J=2.3, 8.5 Hz, 1H), 7.11 (d, J=7.3 Hz, 1H), 6.77(d, J=8.5Hz, 1H), 6.31(d, J=7.3Hz, 1H), 4.11-4.08(m, 1H), 3.87(s, 3H), 3.38-3.35(m ,2H),3.04-2.97(m,1H),2.90(d,J=9.8Hz,1H),2.70-2.41(m,10H),2.17-2.15(m,1H),1.89-1.83(m,2H ), 1.78-1.71 (m, 2H), 1.64-1.60 (m, 1H), 1.37-1.34 (m, 1H). LC-MS: (ESI) m/z 452.3 [M+H] + ; C 25 H Calcd for 33N5O3 451.26 .
化合物28(甲酸盐)： 1H NMR(400MHz,DMSO-d 6)δ9.04(s,1H),8.74(s,2H),6.96(d,J＝7.2Hz,1H),6.26(s,1H),6.14(d,J＝7.2Hz,1H),3.97(t,J＝7.2Hz,1H),3.19(s,2H),2.81(d,J＝8.8Hz,1H),2.74–2.63(m,2H),2.59–2.50(m,3H),2.29(t,J＝7.6Hz,2H),2.24–2.13(m,3H),2.08(dd,J＝8.6,3.6Hz,1H),1.96(s,1H),1.75–1.67(m,2H),1.59–1.51(m,2H),1.31–1.25(m,1H),1.13–1.07(m,1H).LC-MS:(ESI)m/z 423.1[M+H] +；C 23H 30N 6O 2计算值422.24.纯度:91.3％(214nm),95.6％(254nm). Compound 28 (formate salt): 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.04 (s, 1H), 8.74 (s, 2H), 6.96 (d, J=7.2 Hz, 1H), 6.26 (s ,1H),6.14(d,J＝7.2Hz,1H),3.97(t,J＝7.2Hz,1H),3.19(s,2H),2.81(d,J＝8.8Hz,1H),2.74–2.63 (m, 2H), 2.59–2.50 (m, 3H), 2.29 (t, J=7.6Hz, 2H), 2.24–2.13 (m, 3H), 2.08 (dd, J=8.6, 3.6Hz, 1H), 1.96(s,1H),1.75–1.67(m,2H),1.59–1.51(m,2H),1.31–1.25(m,1H),1.13–1.07(m,1H).LC-MS:(ESI) m/z 423.1 [M+H] + ; calcd for C 23 H 30 N 6 O 2 422.24. Purity: 91.3% (214 nm), 95.6% (254 nm).
化合物29(甲酸盐)： 1H NMR(400MHz,DMSO-d 6)δ8.53(s,1H),8.45(d,J＝4.8Hz,1H),8.19(brs,2H)(H of fomic acid),7.77(d,J＝7.6Hz,1H),7.36(dd,J＝7.6,4.8Hz,1H),7.01(d,J＝7.2Hz,1H),6.41(brs,1H),6.18(d,J＝7.2Hz,1H),3.99(t,J＝7.2Hz,1H),3.26–3.18(m,2H),2.93(d,J＝9.2Hz,1H),2.87(d,J＝9.2Hz,1H),2.66(dd,J＝15.6,7.6Hz,1H),2.59(t,J＝6.0Hz,2H),2.49–2.28(m,7H),1.99(s,1H),1.78–1.69(m,2H),1.66–1.58(m,2H),1.39–1.30(m,2H).LC-MS:(ESI)m/z 422.3[M+H] +,C 24H 31N 5O 2计算值421.25.纯度:100％(214nm),100％(254nm). Compound 29 (formate salt): 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.53 (s, 1H), 8.45 (d, J=4.8 Hz, 1H), 8.19 (brs, 2H) (H of fomic acid), 7.77(d, J=7.6Hz, 1H), 7.36(dd, J=7.6, 4.8Hz, 1H), 7.01(d, J=7.2Hz, 1H), 6.41(brs, 1H), 6.18( d, J=7.2Hz, 1H), 3.99 (t, J=7.2Hz, 1H), 3.26–3.18 (m, 2H), 2.93 (d, J=9.2Hz, 1H), 2.87 (d, J=9.2 Hz, 1H), 2.66 (dd, J=15.6, 7.6 Hz, 1H), 2.59 (t, J=6.0 Hz, 2H), 2.49–2.28 (m, 7H), 1.99 (s, 1H), 1.78–1.69 (m, 2H), 1.66–1.58 (m, 2H), 1.39–1.30 (m, 2H). LC-MS: (ESI) m/z 422.3 [M+H] + , C 24 H 31 N 5 O 2 Calculated 421.25. Purity: 100% (214nm), 100% (254nm).
实施例9 化合物30的合成Example 9 Synthesis of compound 30
Figure PCTCN2021107688-appb-000046
Figure PCTCN2021107688-appb-000046
步骤1:7-(3-((1R,5S,6s)-6-((1-(4-氯苯基)-3-乙氧基-3-氧丙基)氨基)-3-氮杂双环[3.1.0]己-3-基)丙基)-3,4-二氢-1,8-萘啶-1(2H)-羧酸叔丁酯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
Figure PCTCN2021107688-appb-000047
Figure PCTCN2021107688-appb-000047
在N 2气氛下，向7-(3-((1R,5S,6s)-6-氨基-3-氮杂双环[3.1.0]己-3-基)丙基)-3,4-二氢-1，8-萘啶-1(2H)-羧酸叔丁酯(中间体C，290mg，0.78mmol)和3-(4-氯苯基)-3-氧代丙酸乙酯(212mg，0.93mmol)的甲醇(10mL)溶液中依次加入三乙酰氧基硼氢化钠(494mg，2.33mmol)和氰基硼氢化钠(73mg，1.17mmol)，将得到的混合物于60℃搅拌14小时。浓缩至干后，将残余物溶在饱和碳酸氢钠(20mL)中，以乙酸乙酯(20mL×3)萃取。合并的有机相用盐水洗涤，经硫酸钠干燥，过滤并浓缩至干。残余物通过快速柱色谱法纯化(0-8％甲醇的二氯甲烷溶液)，得到标题化合物(107mg，24％)，为黄色油状物。LC-MS：ESI m/z 583.2，585.2[M+H，Cl] +，C 32H 43ClN 4O 4。计算值582.30。 Under a N atmosphere, 7-( 3 -((1R,5S,6s)-6-amino-3-azabicyclo[3.1.0]hex-3-yl)propyl)-3,4-di Hydro-1,8-naphthyridine-1(2H)-carboxylate tert-butyl ester (Intermediate C, 290 mg, 0.78 mmol) and ethyl 3-(4-chlorophenyl)-3-oxopropanoate (212 mg , 0.93 mmol) in methanol (10 mL) were sequentially added sodium triacetoxyborohydride (494 mg, 2.33 mmol) and sodium cyanoborohydride (73 mg, 1.17 mmol), and the resulting mixture was stirred at 60 °C for 14 hours. After concentration to dryness, the residue was dissolved in saturated sodium bicarbonate (20 mL) and extracted with ethyl acetate (20 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 (0-8% methanol in dichloromethane) to give the title compound (107 mg, 24%) as a yellow oil. LC-MS: ESI m/z 583.2, 585.2 [M + H, Cl] + , C32H43ClN4O4 . Calculated 582.30.
步骤2：3-(4-氯苯基)-3-(((1R,5S,6s)-3-(3-(5,6,7,8-四氢-1,8-萘啶-2-基)丙基)-3-氮杂双环[3.1.0]己-6-基)氨基)丙酸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
Figure PCTCN2021107688-appb-000048
Figure PCTCN2021107688-appb-000048
向7-(3-((1R,5S,6s)-6-((1-(4-氯苯基)-3-乙氧基-3-氧丙基)氨基)-3-氮杂双环[3.1.0]己-3-基)丙基)-3,4-二氢-1,8-萘啶-1(2H)-羧酸叔丁酯(107mg，0.18mmol)的二氯甲烷(5mL)溶液中加入三氟乙酸(2mL)，将得到的混合物在25℃下搅拌16小时。真空除去溶剂，得到3-(4-氯苯基)-3-(((1R,5S,6s)-3-(3-(5,6,7,8-四氢-1,8-萘啶-2-基)丙基)-3-氮杂双环[3.1.0]己-6-基)氨基)丙酸甲酯的三氟乙酸盐(89mg，粗品)，呈黄色油状。LC-MS:ESI m/z 483.20,485.17[M+H] +,C 27H 35ClN 4O 2.计算值482.24.将粗品(89mg)溶在甲醇(4mL)和水(1mL)的混合溶液中，加入NaOH(29mg，0.73mmol)，反应液在25℃下搅拌16小时。用1N HCl(0.8mL)中和后，将混合物浓缩并将残余物通过制备HPLC在以下条件下纯化[柱：Kromasil 100-5-C18，30×150mm；流动相：1-35％MeCN的水溶液(含0.1％甲酸)；时间：14分钟]，得到标题化合物(37.67mg，45％)，为黄色固体。 To 7-(3-((1R,5S,6s)-6-((1-(4-chlorophenyl)-3-ethoxy-3-oxopropyl)amino)-3-azabicyclo[ 3.1.0] Hex-3-yl)propyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate tert-butyl ester (107 mg, 0.18 mmol) in dichloromethane (5 mL) ) solution was added trifluoroacetic acid (2 mL), and the resulting mixture was stirred at 25°C for 16 hours. The solvent was removed in vacuo to give 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 methyl ester trifluoroacetate (89 mg, crude) as a yellow oil. LC-MS: ESI m/z 483.20, 485.17 [M+H] + , C 27 H 35 ClN 4 O 2 . Calculated 482.24. The crude product (89 mg) was dissolved in a mixed solution of methanol (4 mL) and water (1 mL) To this, NaOH (29 mg, 0.73 mmol) was added, and the reaction solution was stirred at 25°C for 16 hours. After neutralization with 1N HCl (0.8 mL), the mixture was concentrated and the residue was purified by preparative HPLC under the following conditions [column: Kromasil 100-5-C18, 30 x 150 mm; mobile phase: 1-35% MeCN in water (with 0.1% formic acid); time: 14 min] to give the title compound (37.67 mg, 45%) as a yellow solid.
1H NMR(400MHz,CD 3OD)δ7.46–7.29(m,5H),6.47–6.41(m,1H),4.25–4.17(m,1H),3.44–3.39(m,2H),3.27–3.09(m,4H),2.89(d,J＝6.8Hz,2H),2.76–2.68(m,3H),2.64–2.54(m,3H),2.31–2.24(m,1H),1.89–1.88(m,5H),1.75–1.69(m,1H).LC-MS:ESI m/z 455.24,457.37[M+H,Cl] +,C 25H 31ClN 4O 2计算值454.21. 1 H NMR (400MHz, CD 3 OD) δ 7.46–7.29(m, 5H), 6.47–6.41 (m, 1H), 4.25–4.17 (m, 1H), 3.44–3.39 (m, 2H), 3.27– 3.09(m, 4H), 2.89(d, J=6.8Hz, 2H), 2.76-2.68(m, 3H), 2.64-2.54(m, 3H), 2.31-2.24(m, 1H), 1.89-1.88( m, 5H), 1.75–1.69 (m, 1H). LC-MS: ESI m/z 455.24, 457.37 [M+H, Cl] + , calcd for C 25 H 31 ClN 4 O 2 454.21.
实施例10参考化合物30及化合物17的合成方法，可以合成如下化合物，Example 10 With reference to the synthetic methods of compound 30 and compound 17, the following compounds can be synthesized,
化合物31(甲酸盐)： 1H NMR(400MHz,CD 3OD)δ7.65(d,J＝8.1Hz,2H),7.59(d,J＝8.1Hz,2H),7.26(d,J＝7.2Hz,1H),6.40(d,J＝7.3Hz,1H),4.29–4.20(m,1H),3.42–3.36(m,2H),3.27–3.15(m,3H),2.96–2.86(m,2H),2.80–2.63(m,4H),2.61–2.53(m,3H),2.25–2.18(m,1H),1.93–1.83(m,5H),1.71(s,1H).LC-MS:ESI m/z 489.3[M+H] +,C 26H 31F 3N 4O 2计算值488.24. Compound 31 (formate salt): 1 H NMR (400 MHz, CD 3 OD) δ 7.65 (d, J=8.1 Hz, 2H), 7.59 (d, J=8.1 Hz, 2H), 7.26 (d, J= 7.2Hz, 1H), 6.40 (d, J=7.3Hz, 1H), 4.29–4.20 (m, 1H), 3.42–3.36 (m, 2H), 3.27–3.15 (m, 3H), 2.96–2.86 (m ,2H),2.80–2.63(m,4H),2.61–2.53(m,3H),2.25–2.18(m,1H),1.93–1.83(m,5H),1.71(s,1H).LC-MS : ESI m/z 489.3 [M+H] + , calcd for C 26 H 31 F 3 N 4 O 2 488.24.
化合物32(甲酸盐)： 1H NMR(400MHz,CD 3OD)δ7.64(d,J＝8.2Hz,2H),7.57(d,J＝8.1Hz,2H),7.34(dd,J＝12.8,7.3Hz,1H),6.45(dd,J＝7.2,5.6Hz,1H),4.25(d,J＝6.4Hz,1H),3.58–3.39(m,5H),3.38–3.34(m,0.5H),3.27–3.23(m,0.5H),2.82(t,J＝7.1Hz,2H),2.78–2.68(m,3H),2.65–2.50(m,3H),1.93–1.86(m,2H),1.77–1.66(m,2H),1.56(s,0.5H),1.46(s,0.5H).LC-MS:ESI m/z 503.2[M+H] +,C 26H 29F 3N 4O 3计算值502.22. Compound 32 (formate salt): 1 H NMR (400 MHz, CD 3 OD) δ 7.64 (d, J=8.2 Hz, 2H), 7.57 (d, J=8.1 Hz, 2H), 7.34 (dd, J= 12.8, 7.3Hz, 1H), 6.45 (dd, J=7.2, 5.6Hz, 1H), 4.25 (d, J=6.4Hz, 1H), 3.58–3.39 (m, 5H), 3.38–3.34 (m, 0.5 H), 3.27–3.23 (m, 0.5H), 2.82 (t, J=7.1Hz, 2H), 2.78–2.68 (m, 3H), 2.65–2.50 (m, 3H), 1.93–1.86 (m, 2H) ), 1.77–1.66(m, 2H), 1.56(s, 0.5H), 1.46(s, 0.5H). LC-MS: ESI m/z 503.2[M+H] + , C 26 H 29 F 3 N 4 O 3 calcd 502.22.
化合物33(甲酸盐)： 1H NMR(400MHz,CD 3OD)δ7.37-7.35(m,1H),7.31-7.27(m,1H),6.99-6.97(m,2H),6.89-6.86(m,1H),6.45-6.43(m,1H),4.27-4.24(m,1H),3.79(s,3H),3.43-3.41(m,2H),3.25-3.15(m,2H),3.07-2.95(m,2H),2.82-2.79(m,2H),2.76-2.71(m,3H),2.63-2.57(m,3H),2.45-2.43(m,1H),1.93-1.82(m,5H),1.75-1.73(m,1H).LC-MS:ESI m/z 451.3[M+H] +,C 26H 34N 4O 3.计算值450.26. Compound 33 (formate salt): 1 H NMR (400 MHz, CD 3 OD) δ 7.37-7.35 (m, 1H), 7.31-7.27 (m, 1H), 6.99-6.97 (m, 2H), 6.89-6.86 (m,1H),6.45-6.43(m,1H),4.27-4.24(m,1H),3.79(s,3H),3.43-3.41(m,2H),3.25-3.15(m,2H),3.07 -2.95(m, 2H), 2.82-2.79(m, 2H), 2.76-2.71(m, 3H), 2.63-2.57(m, 3H), 2.45-2.43(m, 1H), 1.93-1.82(m, 5H), 1.75-1.73 (m, 1H). LC-MS: ESI m/z 451.3 [M+H] + , C 26 H 34 N 4 O 3 . Calculated 450.26.
化合物34(甲酸盐)： 1H NMR(400MHz,CD 3OD)δ7.41-7.36(m,1H),7.30-7.26(m,1H),6.98-6.97(m,2H),6.89-6.86(m,1H),6.48-6.45(m,1H),4.29-4.24(m,1H),3.79(s,3H),3.62-3.57(m,1H),3.55-3.36(m,4H),3.38-3.32(m,0.5H),3.29-3.25(m,0.5H),2.86-2.81(m,2H),2.80-2.75(m,3H),2.67-2.54(m,3H),1.92-1.82(m,4H),1.75-1.59(m,1H).LC-MS:ESI m/z 465.3[M+H] +,C 26H 32N 4O 4计算值464.24. Compound 34 (formate salt): 1 H NMR (400 MHz, CD 3 OD) δ 7.41-7.36 (m, 1H), 7.30-7.26 (m, 1H), 6.98-6.97 (m, 2H), 6.89-6.86 (m,1H),6.48-6.45(m,1H),4.29-4.24(m,1H),3.79(s,3H),3.62-3.57(m,1H),3.55-3.36(m,4H),3.38 -3.32(m, 0.5H), 3.29-3.25(m, 0.5H), 2.86-2.81(m, 2H), 2.80-2.75(m, 3H), 2.67-2.54(m, 3H), 1.92-1.82( m, 4H), 1.75-1.59 (m, 1H). LC-MS: ESI m/z 465.3 [M+H] + , calcd for C 26 H 32 N 4 O 4 464.24.
得到的化合物34，通过制备手性SFC，在以下条件下分离粗残余物：[柱：Daicel ChiralPak IG (250×30mm，10μm)；流动相：60％甲醇的二氧化碳溶液(含0.1％NH 3.H 2O)；流速：70g/min]，分别得到化合物34a和化合物34b，为白色固体。 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 μm); 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.
化合物34a(胺盐)： 1H NMR(400MHz,CD 3OD)δ7.55-7.52(m,1H),7.34-7.30(m,1H),7.01-6.99(m,2H),6.93-6.91(m,1H),6.59-6.57(m,1H),4.35-4.30(m,1H),3.84(s,3H),3.64-3.62(m,1H),3.56-3.48(m,4H),3.46-3.42(m,1H),2.93-2.90(m,2H),2.83-2.80(m,3H),2.71-2.65(m,3H),1.97-1.94(m,4H),1.82-1.68(m,1H)LC-MS:ESI m/z 465.2[M+H] +,C 26H 32N 4O 4计算值464.24. Compound 34a (amine salt): 1 H NMR (400 MHz, CD 3 OD) δ 7.55-7.52 (m, 1H), 7.34-7.30 (m, 1H), 7.01-6.99 (m, 2H), 6.93-6.91 ( m,1H),6.59-6.57(m,1H),4.35-4.30(m,1H),3.84(s,3H),3.64-3.62(m,1H),3.56-3.48(m,4H),3.46- 3.42(m, 1H), 2.93-2.90(m, 2H), 2.83-2.80(m, 3H), 2.71-2.65(m, 3H), 1.97-1.94(m, 4H), 1.82-1.68(m, 1H ) LC-MS: ESI m/z 465.2 [M+H] + , calcd for C 26 H 32 N 4 O 464.24 .
化合物34b(胺盐)： 1H NMR(400MHz,CD 3OD)δ7.55-7.52(m,1H),7.33-7.31(m,1H),7.01-6.99(m,2H),6.94-6.92(m,1H),6.61-6.57(m,1H),4.34-4.33(m,1H),3.83(s,3H),3.64-3.59(m,1H),3.51-3.48(m,4H),3.45-3.42(m,1H),2.93-2.90(m,2H),2.82-2.80(m,3H),2.71-2.66(m,3H),1.97-1.94(m,4H),1.84-1.68(m,1H).LC-MS:ESI m/z 465.2[M+H] +,C 26H 32N 4O 4计算值464.24. Compound 34b (amine salt): 1 H NMR (400 MHz, CD 3 OD) δ 7.55-7.52 (m, 1H), 7.33-7.31 (m, 1H), 7.01-6.99 (m, 2H), 6.94-6.92 ( m,1H),6.61-6.57(m,1H),4.34-4.33(m,1H),3.83(s,3H),3.64-3.59(m,1H),3.51-3.48(m,4H),3.45- 3.42(m, 1H), 2.93-2.90(m, 2H), 2.82-2.80(m, 3H), 2.71-2.66(m, 3H), 1.97-1.94(m, 4H), 1.84-1.68(m, 1H ).LC-MS: ESI m/z 465.2 [M+H] + , calcd for C 26 H 32 N 4 O 4 464.24.
化合物35(甲酸盐)： 1H NMR(400MHz,CD 3OD)δ7.35(dd,J＝11.5,7.3Hz,3H),7.06(d,J＝8.3Hz,1H),6.99(t,J＝7.5Hz,1H),6.45(dd,J＝7.3,3.9Hz,1H),4.75–4.67(m,1H),3.89(d,J＝1.8Hz,3H),3.65–3.50(m,3H),3.45–3.40(m,2H),3.40–3.36(m,0.5H),3.30–3.26(m,0.5H),2.94–2.85(m,1H),2.83(t,J＝7.1Hz,2H),2.74(dd,J＝12.1,6.0Hz,2H),2.69–2.52(m,3H),2.04–1.86(m,4.5H),1.77–1.71(m,0.5H).LC-MS:ESI m/z 465.3[M+H] +,C 26H 32N 4O 4计算值464.24. Compound 35 (formate salt): 1 H NMR (400 MHz, CD 3 OD) δ 7.35 (dd, J=11.5, 7.3 Hz, 3H), 7.06 (d, J=8.3 Hz, 1H), 6.99 (t, J=7.5Hz, 1H), 6.45 (dd, J=7.3, 3.9Hz, 1H), 4.75–4.67 (m, 1H), 3.89 (d, J=1.8Hz, 3H), 3.65–3.50 (m, 3H) ), 3.45–3.40 (m, 2H), 3.40–3.36 (m, 0.5H), 3.30–3.26 (m, 0.5H), 2.94–2.85 (m, 1H), 2.83 (t, J=7.1Hz, 2H ), 2.74 (dd, J=12.1, 6.0 Hz, 2H), 2.69–2.52 (m, 3H), 2.04–1.86 (m, 4.5H), 1.77–1.71 (m, 0.5H). LC-MS: ESI m/z 465.3 [M+H] + , calcd for C 26 H 32 N 4 O 4 464.24.
化合物36(甲酸盐): 1H NMR(400MHz,CD 3OD)δ7.38-7.32(m,3H),6.95-6.93(m,2H),6.47-6.44(m,1H),4.30-4.27(m,1H),3.79-3.78(m,3H),3.65-3.58(m,1H),3.57-3.43(m,4H),3.40-3.34(m,0.5H),3.29-3.25(m,0.5H),2.85-2.80(m,2H),2.78-2.73(m,3H),2.68-2.53(m,3H),1.90-1.86(m,4H),1.71-1.60(m,1H).LC-MS:ESI m/z 465.3[M+H] +,C 26H 32N 4O 4.计算值464.24. Compound 36 (formate salt): 1 H NMR (400 MHz, CD 3 OD) δ 7.38-7.32 (m, 3H), 6.95-6.93 (m, 2H), 6.47-6.44 (m, 1H), 4.30-4.27 (m,1H),3.79-3.78(m,3H),3.65-3.58(m,1H),3.57-3.43(m,4H),3.40-3.34(m,0.5H),3.29-3.25(m,0.5 LC- MS: ESI m/z 465.3 [M+H] + , C 26 H 32 N 4 O 4 . Calculated 464.24.
化合物37(甲酸盐)： 1H NMR(400MHz,CD 3OD)δ7.73(s,1H),7.67-7.65(m,1H),7.59-7.52(m,2H),7.35-7.34(m,1H),6.44-6.42(m,1H),4.28-4.24(m,1H),3.44-3.40(m,2H),3.34-3.31(m,1H),3.27-3.14(m,3H),2.95-2.91(m,2H),2.76-2.68(m,3H),2.62-2.54(m,3H),2.27-2.22(m,1H),1.92-1.88(m,5H),1.68-1.66(m,1H).LC-MS:ESI m/z 489.3[M+H] +,C 26H 31F 3N 4O 2计算值488.24. Compound 37 (formate salt): 1 H NMR (400 MHz, CD 3 OD) δ 7.73 (s, 1H), 7.67-7.65 (m, 1H), 7.59-7.52 (m, 2H), 7.35-7.34 (m ,1H),6.44-6.42(m,1H),4.28-4.24(m,1H),3.44-3.40(m,2H),3.34-3.31(m,1H),3.27-3.14(m,3H),2.95 -2.91(m, 2H), 2.76-2.68(m, 3H), 2.62-2.54(m, 3H), 2.27-2.22(m, 1H), 1.92-1.88(m, 5H), 1.68-1.66(m, 1H).LC-MS: ESI m/z 489.3 [M+H] + , calcd for C 26 H 31 F 3 N 4 O 2 488.24.
化合物38(甲酸盐): 1H NMR(400MHz,CD 3OD)δ7.42–7.33(m,5H),6.49(dd,J＝7.3,3.0Hz,1H),4.22(dd,J＝14.1,7.0Hz,1H),3.60–3.50(m,2H),3.50–3.34(m,4H),2.86(t,J＝6.9Hz,2H),2.79–2.71(m,3H),2.67–2.54(m,3H),1.93–1.89(m,2H),1.82–1.74(m,2H),1.66–1.62(m,0.5H),1.56–1.51(m,0.5H).LC-MS:ESI m/z 469.3,471.1[M+H,Cl] +,C 25H 29ClN 4O 3计算值468.19. Compound 38 (formate salt): 1 H NMR (400 MHz, CD 3 OD) δ 7.42-7.33 (m, 5H), 6.49 (dd, J=7.3, 3.0 Hz, 1H), 4.22 (dd, J=14.1 ,7.0Hz,1H),3.60–3.50(m,2H),3.50–3.34(m,4H),2.86(t,J=6.9Hz,2H),2.79–2.71(m,3H),2.67–2.54( m, 3H), 1.93–1.89 (m, 2H), 1.82–1.74 (m, 2H), 1.66–1.62 (m, 0.5H), 1.56–1.51 (m, 0.5H). LC-MS: ESI m/ z 469.3,471.1 [M+H, Cl ] + , calcd for C25H29ClN4O3 468.19 .
得到的化合物38，通过制备手性SFC，在以下条件下分离粗残余物：[柱：Daicel ChiralPak OZ-H(250×20mm，5μm)；流动相：50％甲醇的二氧化碳溶液(含0.2％的DEA)；流速：40g/min]，分别得到化合物38a和化合物38b。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 μm); mobile phase: 50% methanol in carbon dioxide (containing 0.2% DEA); flow rate: 40 g/min] to obtain compound 38a and compound 38b, respectively.
化合物38a(胺盐): 1H NMR(400MHz,CD 3OD)δ7.36-7.29(m,4H),7.12-7.05(m,1H),6.32-6.27(m,1H),4.07(m,1H),3.49–3.48(m,1H),3.39–3.35(m,4H),3.20–3.16(m,1H),2.73–2.67(m,4H),2.63–2.43(m,4H),1.88–1.86(m,2H),1.67–1.64(m,1H),1.57–1.54(m,1H),1.40–1.37(m,1H).LC-MS:ESI m/z 469.2[M+H] +,C 25H 29ClN 4O 3计算值468.19. Compound 38a (amine salt): 1 H NMR (400 MHz, CD 3 OD) δ 7.36-7.29 (m, 4H), 7.12-7.05 (m, 1H), 6.32-6.27 (m, 1H), 4.07 (m, 1H), 3.49–3.48 (m, 1H), 3.39–3.35 (m, 4H), 3.20–3.16 (m, 1H), 2.73–2.67 (m, 4H), 2.63–2.43 (m, 4H), 1.88– 1.86(m,2H),1.67–1.64(m,1H),1.57–1.54(m,1H),1.40–1.37(m,1H).LC-MS:ESI m/z 469.2[M+H] + , Calcd for C25H29ClN4O3 468.19 .
化合物38b(胺盐): 1H NMR(400MHz,CD 3OD)δ7.36-7.30(m,4H),7.16-7.09(m,1H),6.34-6.30(m,1H),4.09(m,1H),3.53–3.50(m,1H),3.41–3.36(m,4H),3.22–3.17(m,1H),2.73– 2.69(m,4H),2.63–2.45(m,4H),1.88–1.85(m,2H),1.69–1.64(m,1H),1.60–1.58(m,1H),1.43–1.41(m,1H).LC-MS:ESI m/z 469.2[M+H] +,C 25H 29ClN 4O 3计算值468.19. Compound 38b (amine salt): 1 H NMR (400 MHz, CD 3 OD) δ 7.36-7.30 (m, 4H), 7.16-7.09 (m, 1H), 6.34-6.30 (m, 1H), 4.09 (m, 1H), 3.53–3.50 (m, 1H), 3.41–3.36 (m, 4H), 3.22–3.17 (m, 1H), 2.73– 2.69 (m, 4H), 2.63–2.45 (m, 4H), 1.88– 1.85(m,2H),1.69–1.64(m,1H),1.60–1.58(m,1H),1.43–1.41(m,1H).LC-MS:ESI m/z 469.2[M+H] + , Calcd for C25H29ClN4O3 468.19 .
化合物39(甲酸盐)： 1H NMR(400MHz,CD 3OD)δ7.35(dd,J＝11.4,8.0Hz,3H),6.94(d,J＝8.5Hz,2H),6.45(d,J＝7.3Hz,1H),4.37–4.28(m,1H),3.79(s,3H),3.46–3.39(m,2H),3.23(d,J＝10.3Hz,1H),3.12(d,J＝10.2Hz,1H),2.92–2.86(m,1H),2.86–2.77(m,2H),2.77–2.67(m,4H),2.66–2.57(m,3H),2.54(s,1H),1.95–1.78(m,5H),1.71(s,1H).LC-MS:ESI m/z451.2[M+H] +,C 26H 34N 4O 3计算值450.26. Compound 39 (formate salt): 1 H NMR (400 MHz, CD 3 OD) δ 7.35 (dd, J=11.4, 8.0 Hz, 3H), 6.94 (d, J=8.5 Hz, 2H), 6.45 (d, J=7.3Hz, 1H), 4.37–4.28 (m, 1H), 3.79 (s, 3H), 3.46–3.39 (m, 2H), 3.23 (d, J=10.3Hz, 1H), 3.12 (d, J = 10.2Hz, 1H), 2.92–2.86 (m, 1H), 2.86–2.77 (m, 2H), 2.77–2.67 (m, 4H), 2.66–2.57 (m, 3H), 2.54 (s, 1H), 1.95–1.78 (m, 5H), 1.71 (s, 1H). LC-MS: ESI m/z 451.2 [M+H] + , calcd for C 26 H 34 N 4 O 3 450.26.
化合物40(甲酸盐): 1H NMR(400MHz,CD 3OD)δ7.44(s,1H),7.35-7.27(m,4H),6.44-6.42(m,1H),4.20-4.17(m,1H),3.43-3.41(m,2H),3.29-3.27(m,1H),3.24-3.18(m,2H),3.16-3.12(m,1H),2.93-2.89(m,2H),2.75-2.72(m,2H),2.68-2.66(m,1H),2.61-2.53(m,3H),2.30-2.28(m,1H),1.92-1.86(m,5H),1.73-1.67(m,1H)LC-MS:ESI m/z 455.2[M+H] +,C 25H 31ClN 4O 2.计算值454.21. Compound 40 (formate salt): 1 H NMR (400 MHz, CD 3 OD) δ 7.44 (s, 1H), 7.35-7.27 (m, 4H), 6.44-6.42 (m, 1H), 4.20-4.17 (m ,1H),3.43-3.41(m,2H),3.29-3.27(m,1H),3.24-3.18(m,2H),3.16-3.12(m,1H),2.93-2.89(m,2H),2.75 -2.72(m, 2H), 2.68-2.66(m, 1H), 2.61-2.53(m, 3H), 2.30-2.28(m, 1H), 1.92-1.86(m, 5H), 1.73-1.67(m, 1H) LC-MS: ESI m/z 455.2 [M+H] + , C 25 H 31 ClN 4 O 2 . Calculated 454.21.
化合物41(甲酸盐)： 1H NMR(400MHz,CD 3OD)δ7.43-7.42(m,1H),7.41-7.34(m,1H),7.34-7.26(m,3H),6.49-6.46(m,1H),4.22-4.17(m,1H),3.58-3.55(m,1H),3.51-3.38(m,4H),3.37-3.33(m,0.5H),3.29-3.25(m,0.5H),2.87-2.83(m,2H),2.782.70(m,3H),2.67-2.54(m,3H),1.92-1.89(m,2H),1.82-1.72(m,2H),1.63-1.50(m,1H).LC-MS:ESI m/z 469.2,471.2[M+H,Cl] +,C 25H 29ClN 4O 3.计算值468.19. Compound 41 (formate salt): 1 H NMR (400 MHz, CD 3 OD) δ 7.43-7.42 (m, 1H), 7.41-7.34 (m, 1H), 7.34-7.26 (m, 3H), 6.49-6.46 (m,1H),4.22-4.17(m,1H),3.58-3.55(m,1H),3.51-3.38(m,4H),3.37-3.33(m,0.5H),3.29-3.25(m,0.5 H), 2.87-2.83(m, 2H), 2.782.70(m, 3H), 2.67-2.54(m, 3H), 1.92-1.89(m, 2H), 1.82-1.72(m, 2H), 1.63- 1.50 (m, 1H). LC-MS: ESI m/z 469.2, 471.2 [M + H, Cl ] + , C25H29ClN4O3 . calcd. 468.19 .
化合物42(甲酸盐): 1H NMR(400MHz,CD 3OD)δ7.53(d,J＝7.7Hz,1H),7.41–7.31(m,3H),7.25(t,J＝7.5Hz,1H),6.46(dd,J＝7.3,3.7Hz,1H),4.80–4.74(m,1H),3.60–3.46(m,3H),3.45–3.41(m,2H),3.36(dd,J＝12.0,4.5Hz,0.5H),3.28–3.24(m,0.5H),2.83(t,J＝7.1Hz,2H),2.75(dd,J＝10.9,5.6Hz,2H),2.70–2.53(m,4H),1.93–1.87(m,2H),1.80–1.69(m,2H),1.64–1.60(m,0.5H),1.52–1.48(m,0.5H).LC-MS:ESI m/z 469.31,471.36[M+H,Cl] +,C 25H 29ClN 4O 3.计算值468.19. Compound 42 (formate salt): 1 H NMR (400 MHz, CD 3 OD) δ 7.53 (d, J=7.7 Hz, 1H), 7.41-7.31 (m, 3H), 7.25 (t, J=7.5 Hz, 1H), 6.46 (dd, J=7.3, 3.7Hz, 1H), 4.80–4.74 (m, 1H), 3.60–3.46 (m, 3H), 3.45–3.41 (m, 2H), 3.36 (dd, J= 12.0, 4.5Hz, 0.5H), 3.28–3.24 (m, 0.5H), 2.83 (t, J=7.1Hz, 2H), 2.75 (dd, J=10.9, 5.6Hz, 2H), 2.70–2.53 (m ,4H),1.93–1.87(m,2H),1.80–1.69(m,2H),1.64–1.60(m,0.5H),1.52–1.48(m,0.5H).LC-MS:ESI m/z 469.31, 471.36 [M+H,Cl] + , C 25 H 29 ClN 4 O 3 . Calculated 468.19.
化合物43(甲酸盐)： 1H NMR(400MHz,CD 3OD)δ7.70(s,1H),7.67-7.63(m,1H),7.57-7.51(m,2H),7.38-7.34(m,1H),6.47-6.44(m,1H),4.29-4.24(m,1H),3.58-3.53(m,1H),3.53-3.37(m,4H),3.37-3.30(m,0.5H),3.26-3.22(m,0.5H),2.84-2.81(m,2H),2.75-2.70(m,3H),2.64-2.52(m,3H),1.93-1.87(m,2H),1.77-1.69(m,2H),1.55-1.42(m,1H).LC-MS:ESI m/z 503.3[M+H] +,C 26H 29F 3N 4O 3计算值502.22. Compound 43 (formate salt): 1 H NMR (400 MHz, CD 3 OD) δ 7.70 (s, 1H), 7.67-7.63 (m, 1H), 7.57-7.51 (m, 2H), 7.38-7.34 (m ,1H),6.47-6.44(m,1H),4.29-4.24(m,1H),3.58-3.53(m,1H),3.53-3.37(m,4H),3.37-3.30(m,0.5H), 3.26-3.22(m, 0.5H), 2.84-2.81(m, 2H), 2.75-2.70(m, 3H), 2.64-2.52(m, 3H), 1.93-1.87(m, 2H), 1.77-1.69( m, 2H), 1.55-1.42 (m, 1H). LC-MS: ESI m/z 503.3 [M+H] + , calcd for C 26 H 29 F 3 N 4 O 3 502.22.
化合物44(甲酸盐): 1H NMR(400MHz,CD 3OD)δ7.55-7.53(m,1H),7.49-7.37(m,1H),7.36-7.31(m,1H),7.30-7.24(m,1H),7.20-7.18(m,1H),6.38-6.36(m,1H),4.77-4.73(m,1H),3.39-3.37(m,2H),3.25-3.05(m,5H),2.89-2.85(m,2H),2.72-2.69(m,2H),2.61-2.52(m,4H),2.33-2.26(m,1H),1.87-1.84(m,5H),1.67-1.60(m,1H).LC-MS:ESI m/z 455.4[M+H] +,C 25H 31ClN 4O 2计算值454.21. Compound 44 (formate salt): 1 H NMR (400 MHz, CD 3 OD) δ 7.55-7.53 (m, 1H), 7.49-7.37 (m, 1H), 7.36-7.31 (m, 1H), 7.30-7.24 (m,1H),7.20-7.18(m,1H),6.38-6.36(m,1H),4.77-4.73(m,1H),3.39-3.37(m,2H),3.25-3.05(m,5H) ,2.89-2.85(m,2H),2.72-2.69(m,2H),2.61-2.52(m,4H),2.33-2.26(m,1H),1.87-1.84(m,5H),1.67-1.60( m,1H).LC-MS: ESI m/z 455.4 [M+H] + , calcd for C 25 H 31 ClN 4 O 2 454.21.
化合物45(甲酸盐)： 1H NMR(400MHz,CD 3OD)δ7.39-7.34(m,3H),7.08-6.98(m,2H),6.46-6.44(m,1H),4.75-4.72(m,1H),3.90(s,3H),3.44-3.41(m,2H),3.18-3.10(m,2H),2.91-2.80(m,2H),2.79-2.74(m,4H),2.70-2.61(m,5H),1.93-1.88(m,3H),1.82-1.81(m,3H).LC-MS:ESI m/z 451.3[M+H] +,C 26H 34N 4O 3.计算值450.26. Compound 45 (formate salt): 1 H NMR (400 MHz, CD 3 OD) δ 7.39-7.34 (m, 3H), 7.08-6.98 (m, 2H), 6.46-6.44 (m, 1H), 4.75-4.72 (m,1H),3.90(s,3H),3.44-3.41(m,2H),3.18-3.10(m,2H),2.91-2.80(m,2H),2.79-2.74(m,4H),2.70 -2.61(m,5H),1.93-1.88(m,3H),1.82-1.81(m,3H).LC-MS: ESI m/z 451.3[M+H] + ,C 26 H 34 N 4 O 3 .calculated 450.26.
生物活性评价实验Biological Activity Evaluation Experiment
实验材料：带有His标签的人类整合素蛋白购自Acro Biosystems公司，包括α5β1(IT1-H52W5)，α8β1(IT1-H52W9)，αvβ1(IT1-H52E1)，αvβ3(IT3-H52E3)，αvβ5(IT8-H52W5)，αvβ6(IT6-H52E1)，αvβ8(IT8-H52W4)。蛋白用无菌水溶解，分装后储存于-80 ℃。生物素标记的多肽由GenScript合成，DMSO溶解后分装存于-20℃。
Figure PCTCN2021107688-appb-000049
Hisdidine Detection Kit(Nickel Chelate)(6760619M)购自于PerkinElmer公司。Source板(PP-0200)购自于Labcyte公司，Proxiplate-384plus目标板购自于Perkin Elmer公司。反应缓冲液自行配制：25mM Tris pH7.4，150mM NaCl，0.1％BSA，1mM MgCl 2，1mM CaCl 2。 Experimental materials: His-tagged human integrin proteins were purchased from Acro Biosystems, including α5β1 (IT1-H52W5), α8β1 (IT1-H52W9), αvβ1 (IT1-H52E1), αvβ3 (IT3-H52E3), αvβ5 (IT8) -H52W5), αvβ6 (IT6-H52E1), αvβ8 (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.
Figure PCTCN2021107688-appb-000049
Hisdidine Detection Kit (Nickel Chelate) (6760619M) was purchased from PerkinElmer. Source plate (PP-0200) was purchased from Labcyte, and Proxiplate-384plus target plate was purchased from Perkin Elmer. 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 .
实验方法：将备选化合物用DMSO溶解，按一定浓度梯度加到Source板上，然后用ECHO550将化合物转移到目标板，使之形成11个浓度。按下表所示的整合素对应RGD多肽以及工作浓度，用反应缓冲液稀释，轻柔混匀，并用Multidrop以每孔10μl加到目标板中，室温孵育1个小时。每孔加入10μl Donor/Acceptor beads(终浓度15μg/mL)，室温孵育一个小时。最后用Envision Plate Reader读数。每个化合物的IC 50用XLfit拟合后获得。下表1为本发明化合物对不同整合素亚型抑制活性的效果。 Experimental method: 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 μl per well to the target plate with Multidrop, and incubate at room temperature for 1 hour. Add 10 μl Donor/Acceptor beads (final concentration 15 μg/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.
Figure PCTCN2021107688-appb-000050
Figure PCTCN2021107688-appb-000050
表1：本发明化合物对不同整合素亚型抑制活性的效果评价Table 1: Evaluation of the effect of the compounds of the present invention on the inhibitory activity of different integrin subtypes
注：A：<100nM；B：100-1000nM；C：>1000nMNote: A: <100nM; B: 100-1000nM; C: >1000nM
   α5β1α5β1 α8β1α8β1 αvβ1αvβ1 αvβ3αvβ3 αvβ5αvβ5 αvβ6αvβ6 αvβ8αvβ8
化合物1Compound 1    CC CC CC CC CC CC
化合物1Compound 1    CC CC CC CC CC CC
化合物2Compound 2    CC CC BB BB CC CC
化合物3Compound 3    CC CC CC CC CC CC
化合物4Compound 4 CC CC CC CC CC CC CC
化合物5Compound 5    CC CC CC CC CC CC
化合物6Compound 6    CC CC CC CC CC CC
化合物7Compound 7    AA AA AA AA BB BB
化合物7aCompound 7a AA AA AA AA AA BB BB
化合物7bCompound 7b AA AA AA BB AA CC BB
化合物8Compound 8 CC AA BB CC CC CC CC
化合物9Compound 9    AA AA BB BB CC CC
化合物10Compound 10    AA CC CC CC CC CC
化合物11Compound 11    AA CC BB BB CC CC
化合物12Compound 12    AA BB BB BB CC CC
化合物13Compound 13    BB CC BB CC CC CC
化合物14Compound 14    AA BB CC BB CC CC
化合物15Compound 15    BB CC CC CC CC CC
化合物16Compound 16    CC CC CC CC CC CC
化合物17Compound 17 AA AA AA BB AA CC CC
化合物17aCompound 17a AA AA AA AA AA CC CC
化合物17bCompound 17b CC AA CC CC BB CC CC
化合物18Compound 18    AA BB BB AA CC CC
化合物18aCompound 18a BB AA AA BB AA CC CC
化合物18bCompound 18b CC BB CC CC CC CC CC
化合物19Compound 19 AA AA AA AA AA BB AA
化合物20Compound 20 AA AA AA AA AA AA AA
化合物21Compound 21 BB AA AA CC BB BB AA
化合物22Compound 22 AA AA AA AA AA AA AA
化合物23Compound 23 AA AA AA AA AA AA AA
化合物23aCompound 23a BB AA BB CC BB BB BB
化合物23bCompound 23b AA AA AA AA AA AA AA
化合物24Compound 24 AA AA AA AA AA AA AA
化合物24aCompound 24a AA AA BB BB BB CC BB
化合物24bCompound 24b AA AA AA AA AA AA AA
化合物25Compound 25 AA AA AA AA AA BB BB
化合物26Compound 26 AA AA AA AA AA BB AA
化合物27Compound 27 AA AA AA AA AA BB AA
化合物27aCompound 27a BB AA BB BB BB CC BB
化合物27bCompound 27b AA AA AA AA AA AA AA
化合物28Compound 28 AA AA AA AA AA BB BB
化合物29Compound 29 AA AA AA AA AA BB BB
化合物30Compound 30 AA AA AA AA AA BB BB
化合物31Compound 31 AA AA AA AA AA BB AA
化合物32Compound 32 AA AA AA BB AA CC BB
化合物33Compound 33 AA AA AA AA AA BB BB
化合物34Compound 34    AA AA AA AA CC BB
化合物34aCompound 34a AA AA AA AA AA CC BB
化合物34bCompound 34b BB AA BB BB BB CC CC
化合物35Compound 35 AA AA AA BB AA CC BB
化合物36Compound 36 AA AA AA AA AA CC BB
化合物37Compound 37 AA AA AA AA AA AA AA
化合物38Compound 38 AA AA AA AA AA CC BB
化合物38aCompound 38a AA AA AA AA AA CC CC
化合物38bCompound 38b BB AA BB BB BB CC CC
化合物39Compound 39 AA AA AA AA AA BB AA
化合物40Compound 40 CC AA AA AA AA AA AA
化合物41Compound 41 AA AA AA AA AA CC BB
化合物42Compound 42 AA AA AA BB AA CC CC
化合物43Compound 43 AA AA AA AA AA BB BB
化合物44Compound 44 AA AA AA BB AA CC CC
化合物45Compound 45 AA AA AA AA AA BB BB
上述实验结果表明：本发明化合物对不同整合素亚型均具有良好抑制作用。The above experimental results show that the compounds of the present invention have a good inhibitory effect on different integrin subtypes.
以上对本发明的实施方式进行了说明。但是，本发明不限定于上述实施方式。凡在本发明的精神和原则之内，所做的任何修改、等同替换、改进等，均应包含在本发明的保护范围之内。The embodiments of the present invention have been described above. However, the present invention is not limited to the above-described embodiments. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included within the protection scope of the present invention.

Claims (16)

  1. 一种式I所示的化合物及其消旋体、立体异构体、互变异构体、同位素标记物、氮氧化物、溶剂化物、多晶型物、代谢产物、酯、前药或其药学上可接受的盐：A compound of formula I and its racemate, stereoisomer, tautomer, isotope label, nitrogen oxide, solvate, polymorph, metabolite, ester, prodrug or its Pharmaceutically acceptable salts:
    Figure PCTCN2021107688-appb-100001
    Figure PCTCN2021107688-appb-100001
    其中，所述R 1、R 5各自独立的选自H，OH，卤素，CN，SH，NH 2，COOH，任选被一个、两个或更多个R a取代的如下基团：C 1-C 12脂肪烃基，C 1-C 12脂肪烃基氧基；所述R a选自H，＝O，卤素，OH，CN，SH，NH 2，COOH；每一个R 1可以相同或不同；每一个R 5可以相同或不同； Wherein, the R 1 and R 5 are each independently selected from H, OH, halogen, CN, SH, NH 2 , COOH, the following groups optionally substituted by one, two or more R a : C 1 -C 12 aliphatic hydrocarbyl, C 1 -C 12 aliphatic hydrocarbyloxy; said R a is selected from H, =O, halogen, OH, CN, SH, NH 2 , COOH; each R 1 may be the same or different; each R 1 may be the same or different; One R5 can be the same or different ;
    所述R 2、R 3各自独立的选自H，C 1-C 12脂肪烃基，C 3-12环烷基，C 3-12环烷基-C 1-C 12脂肪烃基，-L 4-Ar，并且R 2、R 3中至少一个选自-L 4-Ar； 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;
    所述Ar选自任选被一个、两个或更多个R b取代的如下基团：C 3-12环烷基，3-12元杂环基，C 6-20芳基或5-14元杂芳基；所述R b选自H，＝O，卤素，OH，CN，SH，NH 2，COOH，或任选被一个、两个或更多个R c取代的如下基团：C 1-C 12脂肪烃基，C 1-C 12脂肪烃基氧基，C 1-C 12脂肪烃基-SO 2-，C 1-C 12脂肪烃基-NH-，二(C 1-C 12脂肪烃基)N-，C 3-12环烷基，C 3-12环烷基氧基，C 3-12环烷基-SO 2-，C 3-12环烷基-NH-，C 3-12环烷基-C 1-C 12脂肪烃基氧基，C 3-12环烷基-C 1-C 12脂肪烃基-SO 2-，C 3-12环烷基-C 1-C 12脂肪烃基-NH-，3-12元杂环基，3-12元杂环基氧基，3-12元杂环基-SO 2-，3-12元杂环基-NH-，C 6-20芳基，C 6-20芳基氧基，C 6-20芳基-SO 2-，C 6-20芳基-NH-，5-14元杂芳基，5-14元杂芳基氧基，5-14元杂芳基-SO 2-，5-14元杂芳基-NH-；所述R c选自H，＝O，卤素，OH，CN，SH，NH 2，COOH，C 1-C 12脂肪烃基，C 1-C 12脂肪烃基氧基，C 1-C 12脂肪烃基-SO 2-，C 1-C 12脂肪烃基-NH-，二(C 1-C 12脂肪烃基)N-； Said Ar is selected from the following groups optionally substituted by one, two or more R b : C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-20 aryl or 5-14 A membered heteroaryl; the R b is selected from H, =O, halogen, OH, CN, SH, NH 2 , COOH, or optionally substituted with one, two or more R c of the following groups: C 1 -C 12 aliphatic hydrocarbon group, C 1 -C 12 aliphatic hydrocarbon group, C 1 -C 12 aliphatic hydrocarbon group-SO 2 -, C 1 -C 12 aliphatic hydrocarbon group-NH-, bis(C 1 -C 12 aliphatic hydrocarbon group) N-, C 3-12 cycloalkyl, C 3-12 cycloalkyloxy, C 3-12 cycloalkyl-SO 2 -, C 3-12 cycloalkyl-NH-, C 3-12 cycloalkane Alkyl-C 1 -C 12 aliphatic alkyloxy, C 3-12 cycloalkyl-C 1 -C 12 aliphatic alkyl-SO 2 -, C 3-12 cycloalkyl-C 1 -C 12 aliphatic alkyl-NH- , 3-12-membered heterocyclyl, 3-12-membered heterocyclyloxy, 3-12-membered heterocyclyl-SO 2 -, 3-12-membered heterocyclyl-NH-, C 6-20 aryl, C 6-20 Aryloxy, C 6-20 Aryl-SO 2 -, C 6-20 Aryl-NH-, 5-14 Member Heteroaryl, 5-14 Member Heteroaryloxy, 5-14 Member Heteroaryl-SO 2 -, 5-14 Member Heteroaryl-NH-; The R c is selected from H, =O, halogen, OH, CN, SH, NH 2 , COOH, C 1 -C 12 aliphatic Hydrocarbyl, C 1 -C 12 aliphatic hydrocarbyloxy, C 1 -C 12 aliphatic hydrocarbyl-SO 2 -, C 1 -C 12 aliphatic hydrocarbyl-NH-, bis(C 1 -C 12 aliphatic hydrocarbyl)N-;
    所述R 4独立的选自H，C 1-C 12脂肪烃基； The R 4 is independently selected from H, C 1 -C 12 aliphatic hydrocarbon groups;
    所述L 1、L 2、L 3、L 4各自独立的选自-(CH 2) n-C(＝X)-或-C(＝X)-(CH 2) n-，-(CH 2) m-(当m＝0时，代表键)，-(CH 2) n-C(＝O)-NH-，-(CH 2) n-NH-C(＝O)-，-C(＝O)-NH-(CH 2) n-，-NH-C(＝O)-(CH 2) n-，-(CH 2) n-C(＝O)-NH-(CH 2) n-，-(CH 2) n-NH-C(＝O)-(CH 2) n-；所述X选自O，NH；所述n，m各自独立的选自0-6。 The L 1 , L 2 , L 3 , and L 4 are each independently selected from -(CH 2 ) n -C(=X)- or -C(=X)-(CH 2 ) n -, -(CH 2 ) m -(when m=0, it represents a bond), -(CH 2 ) n -C(=O)-NH-, -(CH 2 ) n -NH-C(=O)-, -C(= O)-NH-(CH 2 ) n -, -NH-C(=O)-(CH 2 ) n -, -(CH 2 ) n -C(=O)-NH-(CH 2 ) n -, -(CH 2 ) n -NH-C(=O)-(CH 2 ) n -; the X is selected from O, NH; the n, m are each independently selected from 0-6.
  2. 根据权利要求1所述的一种式I所示的化合物及其消旋体、立体异构体、互变异构体、同位素标记物、氮氧化物、溶剂化物、多晶型物、代谢产物、酯、前药或其药学上可接受的盐，其特征在于：A compound of formula I according to claim 1 and its racemates, stereoisomers, tautomers, isotopic labels, nitrogen oxides, solvates, polymorphs, metabolites , ester, prodrug or a pharmaceutically acceptable salt thereof, characterized in that:
    所述L 1、L 3各自独立的选自-(CH 2) n-C(＝X)-或-C(＝X)-(CH 2) n-，-(CH 2) m-(当m＝0时，代表键)，所述L 2选自-(CH 2) m-(当m＝0时，代表键)；所述L 4选自-NH-C(＝O)-,-C(＝O)-NH-，-(CH 2) m-(当m＝0时，代表键)；所述X选自O，NH；所述n，m各自独立的选自0，1，2，3，4，5，6； The L 1 and L 3 are independently selected from -(CH 2 ) n -C(=X)- or -C(=X)-(CH 2 ) n -, -(CH 2 ) m - (when m =0, represents a bond), the L 2 is selected from -(CH 2 ) m - (when m=0, represents a bond); the L 4 is selected from -NH-C(=O)-,-C (=O)-NH-, -(CH 2 ) m - (when m=0, it represents a bond); the X is selected from O, NH; the n, m are independently selected from 0, 1, 2 , 3, 4, 5, 6;
    优选的，所述L 1选自-(CH 2) 2-，-(CH 2) 3-，-(CH 2) 4-，-(CH 2) 5-，-CH 2-C(＝O)-，-(CH 2) 2-C(＝O)-，-(CH 2) 3-C(＝O)-，-(CH 2) 4-C(＝O)-；L 2选自键，-CH 2-；L 3选自键，-CH 2-，-(CH 2) 2-；L 4选自 键，-CH 2-。 Preferably, the L 1 is selected from -(CH 2 ) 2 -, -(CH 2 ) 3 -, -(CH 2 ) 4 -, -(CH 2 ) 5 -, -CH 2 -C(=O) -, -(CH 2 ) 2 -C(=O)-, -(CH 2 ) 3 -C(=O)-, -(CH 2 ) 4 -C(=O)-; L 2 is selected from a bond, -CH 2 -; L 3 is selected from a bond, -CH 2 -, -(CH 2 ) 2 -; L 4 is selected from a bond, -CH 2 -.
  3. 根据权利要求1-2任一项所述的一种式I所示的化合物及其消旋体、立体异构体、互变异构体、同位素标记物、氮氧化物、溶剂化物、多晶型物、代谢产物、酯、前药或其药学上可接受的盐，其特征在于：A compound of formula I according to any one of claims 1-2 and its racemates, stereoisomers, tautomers, isotopic labels, nitrogen oxides, solvates, polymorphs Forms, metabolites, esters, prodrugs or pharmaceutically acceptable salts thereof, characterized by:
    所述“卤素”选自F、Cl、Br、I；所述“脂肪烃基”选自烷基、烯基、炔基；The "halogen" is selected from F, Cl, Br, and I; the "aliphatic hydrocarbon group" is selected from alkyl, alkenyl, and alkynyl;
    优选的，优选的，所述R 1、R 5各自独立的选自卤素，C 1-C 6脂肪烃基，例如，选自F、Cl、Br、I，甲基，乙基，正丙基，异丙基，正丁基，异丁基，叔丁基，正戊基，异戊基，新戊基，正己基； Preferably, preferably, the R 1 and R 5 are each 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;
    优选的，所述R 2选自H，C 1-C 6脂肪烃基或C 3-8环烷基-C 1-C 6脂肪烃基，且R 3选自-L 4-Ar或所述R 2选自-L 4-Ar且R 3选自H，C 1-C 6脂肪烃基或C 3-8环烷基-C 1-C 6脂肪烃基；更优选的，所述R 2选自H，甲基，乙基，正丙基，异丙基，正丁基，异丁基，叔丁基，正戊基，异戊基，新戊基，正己基，环丙基甲基，环丁基甲基，环戊基甲基，环己基甲基，所述R 3选自Ar(L 4代表键时)； Preferably, the 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 the 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 R 2 is selected from H, Methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, cyclopropylmethyl, cyclobutylmethyl , cyclopentylmethyl, cyclohexylmethyl, the R 3 is selected from Ar (when L 4 represents a bond);
    优选的，所述Ar选自任选被一个、两个或更多个R b取代的如下基团：C 6-C 14芳基，5-10元杂环基，5-6元杂芳基，优选的，Ar选自任选被一个、两个或更多个R b取代的苯基，萘基，2,3-二氢苯并呋喃基，苯并呋喃基，苯并吡喃基，3,4-二氢-2H-1-苯并吡喃基(色烷基)，2,3-二氢苯并[b][1,4]二噁烷基，吡啶基，嘧啶基，吲唑基(1H-吲唑基，2H-吲唑基)，吲哚基，异吲哚基，喹啉基，异喹啉基，喹唑啉基，苯并噁唑基； Preferably, the Ar is selected from the following groups optionally substituted by one, two or more R b : C 6 -C 14 aryl, 5-10 membered heterocyclyl, 5-6 membered heteroaryl , preferably, Ar is selected from phenyl optionally substituted by one, two or more R b , naphthyl, 2,3-dihydrobenzofuranyl, benzofuranyl, benzopyranyl, 3,4-Dihydro-2H-1-benzopyranyl (chromanyl), 2,3-dihydrobenzo[b][1,4]dioxanyl, pyridyl, pyrimidinyl, indium azolyl (1H-indazolyl, 2H-indazolyl), indolyl, isoindolyl, quinolinyl, isoquinolinyl, quinazolinyl, benzoxazolyl;
    优选的，所述R b选自H，卤素，CN，或任选被一个、两个或更多个R c取代的如下基团：C 1-C 6脂肪烃基，C 1-C 6脂肪烃基氧基，C 1-C 6脂肪烃基-SO 2-，C 1-C 6脂肪烃基-NH-，二(C 1-C 6脂肪烃基)N-，C 6-10芳基，C 6-10芳基氧基，C 6-10芳基-SO 2-，C 6-10芳基-NH-，5-6元杂芳基，5-6元杂芳基氧基，5-6元杂芳基-SO 2-，5-6元杂芳基-NH-，5-6元杂环基，5-6元杂环基氧基，5-6元杂环基-SO 2-，5-6元杂环基-NH-，C 3-8环烷基，C 3-8环烷基氧基，C 3-8环烷基-SO 2-，C 3-8环烷基-NH-，C 3-8环烷基-C 1-C 6脂肪烃基氧基，C 3-8环烷基-C 1-C 6脂肪烃基-SO 2-，C 3-8环烷基-C 1-C 6脂肪烃基-NH-；更优选的，所述R b选自H，卤素，CN或任选被一个、两个或更多个R c取代的C 1-C 6烷基，C 1-C 6烷氧基，C 1-C 6烷基-SO 2-，C 1-C 6烷基-NH-，二(C 1-C 6烷基)N-，5-6元杂芳基-SO 2-，5-6元杂芳基-NH-，5-6元杂环基，5-6元杂环基氧基，5-6元杂环基-SO 2-，5-6元杂环基-NH-，C 3-6环烷基，C 3-6环烷基氧基，C 3-6环烷基-SO 2-，C 3-6环烷基-NH-，C 3-6环烷基-C 1-C 6烷氧基，C 3-6环烷基-C 1-C 6烷基-SO 2-，C 3-6环烷基-C 1-C 6烷基-NH-；进一步优选的，所述R b选自H，卤素，CN或任选被一个、两个或更多个R c取代的甲基，乙基，正丙基，异丙基，正丁基，异丁基，叔丁基，正戊基，异戊基，新戊基，正己基，乙烯基，1-丙烯基，2-丙烯基，1-甲基乙烯基，1-丁烯基，1-乙基乙烯基，1-甲基-2-丙烯基，2-丁烯基，3-丁烯基、2-甲基-1-丙烯基，2-甲基-2-丙烯基，1-戊烯基、1-己烯基，乙炔基，1-丙炔基，2-丙炔基，1-丁炔基，1-甲基-2-丙炔基，3-丁炔基，1-戊炔基，1-己炔基，甲氧基，乙氧基，正丙氧基，异丙氧基，异丁氧基，正丁氧基，叔丁氧基，戊氧基，己氧基，N,N-二甲基氨基，N,N-二乙基氨基，甲基-NH-，乙基-NH-，正丙基-NH-，异丙基-NH-，正丁基-NH-，异丁基-NH-，叔丁基-NH-，正戊基-NH-，异戊基-NH-，新戊基-NH-，正己基-NH-，甲基-SO 2-，乙基-SO 2-，正丙基-SO 2-，异丙基-SO 2-，正丁基-SO 2-，异丁基-SO 2-，叔丁基-SO 2-，正戊基-SO 2-，异戊基-SO 2-，新戊基-SO 2-，正己基-SO 2-，环丙基，环丁基，环戊基，环己 基，环丙基氧基，环丁基氧基，环戊基氧基，环己基氧基，环丙基，环丁基，环戊基，环己基，环丙基-SO 2-，环丁基-SO 2-，环戊基-SO 2-，环己基-SO 2-，环丙基-NH-，环丁基-NH-，环戊基-NH-，环己基-NH-，环丙基甲基氧基，环丁基甲基氧基，环戊基甲基氧基，环己基甲基氧基，环丙基甲基-SO 2-，环丁基甲基-SO 2-，环戊基甲基-SO 2-，环己基甲基-SO 2-，环丙基甲基-NH-，环丁基甲基-NH-，环戊基甲基-NH-，环己基甲基-NH-，苯基，苯基-SO 2-，苯基-NH-，萘基，萘基-SO 2-，萘基-NH，氧杂环丁烷，吡喃基，四氢吡喃基，呋喃基，四氢呋喃基，四氢吡咯基，哌啶基，吡啶基，吡嗪基，吡咯基，咪唑基，吡唑基，三氮唑，噁唑基，异噁唑基，吗啉基；例如，R b选自F，Cl，Br，I，CN，甲基，乙基，正丙基，异丙基，正丁基，异丁基，叔丁基，新戊基，甲基-SO 2-，甲氧基，乙氧基，正丙氧基，异丙氧基，异丁氧基，N,N-二甲基氨基，异丙基-NH-，环丙基氧基，环丁基氧基，环戊基氧基，环丙基甲基氧基，环丙基氨基，CF 3，CHF 2，CH 2F，CF 3O，CHF 2O，CH 2FO，苯基，3,5-二甲基吡唑-1-基，咪唑基，吗啉基，1,2,4-三氮唑，氧杂环丁烷，四氢呋喃基，四氢吡喃基，四氢吡咯基； Preferably, 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 hydrocarbon group Oxygen, C 1 -C 6 aliphatic hydrocarbon group-SO 2 -, C 1 -C 6 aliphatic hydrocarbon group -NH-, bis(C 1 -C 6 aliphatic hydrocarbon group) N-, C 6-10 aryl group, C 6-10 Aryloxy, C 6-10 aryl-SO 2 -, C 6-10 aryl-NH-, 5-6 membered heteroaryl, 5-6 membered heteroaryloxy, 5-6 membered heteroaryl base-SO 2 -, 5-6 membered heteroaryl-NH-, 5-6 membered heterocyclyl, 5-6 membered heterocyclyloxy, 5-6 membered heterocyclyl-SO 2 -, 5-6 Member Heterocyclyl-NH-, C 3-8 Cycloalkyl, C 3-8 Cycloalkyloxy, C 3-8 Cycloalkyl-SO 2 -, C 3-8 Cycloalkyl-NH-, C 3-8 cycloalkyl-C 1 -C 6 aliphatic hydrocarbyloxy, C 3-8 cycloalkyl-C 1 -C 6 aliphatic hydrocarbyl-SO 2 -, C 3-8 cycloalkyl-C 1 -C 6 Aliphatic -NH-; more preferably, said R b is selected from H, halogen, CN or C 1 -C 6 alkyl optionally substituted with one, two or more R c , C 1 -C 6 Alkoxy, C 1 -C 6 alkyl-SO 2 -, C 1 -C 6 alkyl-NH-, di(C 1 -C 6 alkyl) N-, 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 -, 5-6 membered heterocyclyl -NH-, C 3-6 cycloalkyl, C 3-6 cycloalkyloxy, C 3-6 cycloalkyl-SO 2 -, C 3-6 cycloalkyl-NH-, C 3-6 cyclo Alkyl-C1-C6alkoxy, C3-6cycloalkyl - C1 - C6alkyl - SO2- , C3-6cycloalkyl - C1 - C6alkyl -NH- ; Further preferably, the R b is selected from H, halogen, CN or methyl, ethyl, n-propyl, isopropyl, n-butyl optionally substituted by one, two or more R c , 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-methyl-2-propenyl, 1- Pentenyl, 1-hexenyl, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 1-methyl-2-propynyl, 3-butynyl, 1- Pentynyl, 1-hexynyl, methoxy, ethoxy, n-propoxy, isopropoxy, isobutoxy, n-butoxy, tert-butoxy, pentyloxy, hexyloxy , N,N-dimethylamino, N,N-diethylamino, methyl-NH-, ethyl-NH-, n- Propyl-NH-, isopropyl-NH-, n-butyl-NH-, isobutyl-NH-, tert-butyl-NH-, n-pentyl-NH-, isopentyl-NH-, neopentyl Base-NH-, n-hexyl-NH-, methyl- SO2- , ethyl- SO2- , n-propyl- SO2- , isopropyl- SO2- , n-butyl- SO2- , isopropyl Butyl- SO2- , tert-butyl- SO2- , n-pentyl- SO2- , isopentyl- SO2- , neopentyl- SO2- , n-hexyl- SO2- , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclo Propyl- SO2- , cyclobutyl- SO2- , cyclopentyl- SO2- , cyclohexyl- SO2- , cyclopropyl-NH-, cyclobutyl-NH-, cyclopentyl-NH- , cyclohexyl-NH-, cyclopropylmethyloxy, cyclobutylmethyloxy, cyclopentylmethyloxy, cyclohexylmethyloxy, cyclopropylmethyl-SO 2 -, cyclobutylmethyl- SO 2 -, cyclopentylmethyl-SO 2 -, cyclohexylmethyl-SO 2 -, cyclopropylmethyl-NH-, cyclobutylmethyl-NH-, cyclopentylmethyl-NH-, cyclohexyl Methyl-NH-, Phenyl, Phenyl-SO 2 -, Phenyl-NH-, Naphthyl, Naphthyl-SO 2 -, Naphthyl-NH, Oxetane, Pyranyl, Tetrahydropyridine Alanyl, Furanyl, Tetrahydrofuranyl, Tetrahydropyrrolyl, Piperidinyl, Pyridyl, Pyrazinyl, Pyrrolyl, Imidazolyl, Pyrazolyl, Triazole, Oxazolyl, Isoxazolyl, Morpholine group; for example, R b is selected from F, Cl, Br, I, CN, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, neopentyl, methyl -SO 2 -, methoxy, ethoxy, n-propoxy, isopropoxy, isobutoxy, N,N-dimethylamino, isopropyl-NH-, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclopropylmethyloxy, cyclopropylamino, CF3 , CHF2 , CH2F , CF3O , CHF2O , CH2FO , phenyl, 3,5-Dimethylpyrazol-1-yl, imidazolyl, morpholinyl, 1,2,4-triazole, oxetane, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyrrolyl ;
    优选的，所述R c选自H，＝O，卤素，OH，CN，SH，NH 2，COOH，C 1-C 6烷基，C 1-C 6烷氧基，C 1-C 6烷基-SO 2-，二(C 1-C 6烷基)N-，C 1-C 6烷基-NH-；例如选自H，＝O，F，Cl，Br，I，OH，CN，SH，NH 2，COOH，甲基，乙基，正丙基，异丙基，正丁基，异丁基，叔丁基，正戊基，异戊基，新戊基，正己基，甲氧基，乙氧基，正丙氧基，异丙氧基，异丁氧基，正丁氧基，叔丁氧基，戊氧基，己氧基，N,N-二甲基氨基，N,N-二乙基氨基，甲基-NH-，乙基-NH-，正丙基-NH-，异丙基-NH-，正丁基-NH-，异丁基-NH-，叔丁基-NH-，正戊基-NH-，异戊基-NH-，新戊基-NH-，正己基-NH-，甲基-SO 2-，乙基-SO 2-，正丙基-SO 2-，异丙基-SO 2-，正丁基-SO 2-，异丁基-SO 2-，叔丁基-SO 2-，正戊基-SO 2-，异戊基-SO 2-，新戊基-SO 2-，正己基-SO 2-； Preferably, the R c is selected from H, =O, halogen, OH, CN, SH, NH 2 , COOH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkane radical-SO 2 -, di(C 1 -C 6 alkyl)N-, C 1 -C 6 alkyl -NH-; for example selected from H, =O, F, Cl, Br, I, OH, CN, SH, NH 2 , COOH, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, methoxy base, ethoxy, n-propoxy, isopropoxy, isobutoxy, n-butoxy, tert-butoxy, pentoxy, hexyloxy, N,N-dimethylamino, N, N-diethylamino, methyl-NH-, ethyl-NH-, n-propyl-NH-, isopropyl-NH-, n-butyl-NH-, isobutyl-NH-, tert-butyl -NH-, n-pentyl-NH-, isopentyl-NH-, neopentyl-NH-, n-hexyl-NH-, methyl- SO2- , ethyl- SO2- , n-propyl-SO 2 -, isopropyl-SO 2 -, n-butyl-SO 2 -, isobutyl-SO 2 -, tert-butyl-SO 2 -, n-pentyl-SO 2 -, isopentyl-SO 2 - , neopentyl-SO 2 -, n-hexyl-SO 2 -;
    优选的，所述R 4独立的选自H，C 1-C 6脂肪烃基，优选的，选自甲基，乙基，正丙基，异丙基，正丁基，异丁基，叔丁基，正戊基，异戊基，新戊基，正己基。 Preferably, 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, tert-butyl base, n-pentyl, isopentyl, neopentyl, n-hexyl.
  4. 根据权利要求1-3任一项所述的一种式I所示的化合物及其消旋体、立体异构体、互变异构体、同位素标记物、氮氧化物、溶剂化物、多晶型物、代谢产物、酯、前药或其药学上可接受的盐，其特征在于，所述Ar选自如下基团：A compound of formula I according to any one of claims 1-3 and its racemates, stereoisomers, tautomers, isotopic labels, nitrogen oxides, solvates, polymorphs Forms, metabolites, esters, prodrugs or pharmaceutically acceptable salts thereof, characterized in that the Ar is selected from the following groups:
    Figure PCTCN2021107688-appb-100002
    Figure PCTCN2021107688-appb-100002
    Figure PCTCN2021107688-appb-100003
    Figure PCTCN2021107688-appb-100003
    所述结构中，R b选自式I中所述定义。 In the structure, R b is selected from the definitions described in formula I.
  5. 根据权利要求1-4任一项所述的一种式I所示的化合物及其消旋体、立体异构体、互变异构体、同位素标记物、氮氧化物、溶剂化物、多晶型物、代谢产物、酯、前药或其药学上可接受的盐，其特征在于，所述R 2或R 3中的一个选自如下基团： A compound of formula I according to any one of claims 1-4 and its racemates, stereoisomers, tautomers, isotopic labels, nitrogen oxides, solvates, polymorphs Forms, metabolites, esters, prodrugs or pharmaceutically acceptable salts thereof, wherein one of the R 2 or R 3 is selected from the following groups:
    Figure PCTCN2021107688-appb-100004
    Figure PCTCN2021107688-appb-100004
    Figure PCTCN2021107688-appb-100005
    Figure PCTCN2021107688-appb-100005
    Figure PCTCN2021107688-appb-100006
    Figure PCTCN2021107688-appb-100006
  6. 根据权利要求1-5任一项所述的一种式I所示的化合物及其消旋体、立体异构体、互变异构体、同位素标记物、氮氧化物、溶剂化物、多晶型物、代谢产物、酯、前药或其药学上可接受的盐，其特征在于，所述式I结构可以选自式Ia：A compound of formula I according to any one of claims 1-5 and its racemates, stereoisomers, tautomers, isotopic labels, nitrogen oxides, solvates, polymorphs Forms, metabolites, esters, prodrugs or pharmaceutically acceptable salts thereof, wherein the structure of formula I can be selected from formula Ia:
    Figure PCTCN2021107688-appb-100007
    Figure PCTCN2021107688-appb-100007
    所述式Ia结构中，R 1、R 2、R 3、R 4、R 5、L 1、L 2如前述式I所定义； In the structure of the formula Ia, R 1 , R 2 , R 3 , R 4 , R 5 , L 1 , and L 2 are as defined in the aforementioned formula I;
    优选的，所述式II结构进一步如下式IIa-IIj：Preferably, the structure of the formula II is further as follows: formula IIa-IIj:
    Figure PCTCN2021107688-appb-100008
    Figure PCTCN2021107688-appb-100008
    Figure PCTCN2021107688-appb-100009
    Figure PCTCN2021107688-appb-100009
    所述式IIa-IIj结构中，R 1、R 2、R 3、R 4、R 5、L 1、L 2、L 3以及其他手性中心如前述式I所定义。 In the structures of formula 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.
  7. 根据权利要求1-6任一项所述的一种式I所示的化合物及其消旋体、立体异构体、互变异构体、同位素标记物、氮氧化物、溶剂化物、多晶型物、代谢产物、酯、前药或其药学上可接受的盐，其特征在于，所述式I结构可以选自如下式III(式IIIa、式IIIb)、式IV(式IVa、式IVb)：A compound of formula I according to any one of claims 1-6 and its racemates, stereoisomers, tautomers, isotopic labels, nitrogen oxides, solvates, polymorphs Forms, metabolites, esters, prodrugs or pharmaceutically acceptable salts thereof, wherein the structure of formula I can be selected from the following formula III (formula IIIa, formula IIIb), formula IV (formula IVa, formula IVb) ):
    Figure PCTCN2021107688-appb-100010
    Figure PCTCN2021107688-appb-100010
    所述式III(式IIIa、式IIIb)、式IV(式IVa、式IVb)结构中，R 1、R 3、R 4、R 5、L 1、L 2以及其他手性中心如前述式I所定义。 In the structures of the formula III (formula IIIa, formula IIIb) and formula IV (formula IVa, formula IVb), R 1 , R 3 , R 4 , R 5 , L 1 , L 2 and other chiral centers are as in the aforementioned formula I defined.
  8. 根据权利要求1-7任一项所述的一种式I所示的化合物及其消旋体、立体异构体、互变异构体、同位素标记物、氮氧化物、溶剂化物、多晶型物、代谢产物、酯、前药或其药学上可接受的盐，其特征在于，式I选自如下具体化合物：A compound of formula I according to any one of claims 1-7 and its racemates, stereoisomers, tautomers, isotopic labels, nitrogen oxides, solvates, polymorphs Forms, metabolites, esters, prodrugs or pharmaceutically acceptable salts thereof, characterized in that Formula I is selected from the following specific compounds:
    Figure PCTCN2021107688-appb-100011
    Figure PCTCN2021107688-appb-100011
    Figure PCTCN2021107688-appb-100012
    Figure PCTCN2021107688-appb-100012
  9. 根据权利要求1-7任一项所述的一种式I所示的化合物及其消旋体、立体异构体、互变异构体、同位素标记物、氮氧化物、溶剂化物、多晶型物、代谢产物、酯、前药或其药学上可接受的盐，其特征在于，式I选自如下具体化合物：A compound of formula I according to any one of claims 1-7 and its racemates, stereoisomers, tautomers, isotopic labels, nitrogen oxides, solvates, polymorphs Forms, metabolites, esters, prodrugs or pharmaceutically acceptable salts thereof, characterized in that Formula I is selected from the following specific compounds:
    Figure PCTCN2021107688-appb-100013
    Figure PCTCN2021107688-appb-100013
  10. 根据权利要求1-9任一项所述化合物的制备方法，其特征在于，包括如下步骤：在合适的条件下，将含萘啶环结构的原料与含氮杂双环[3.1.0]己烷结构的原料在合适的试剂中进行反应，并任选的，在合适的条件下，进行上保护基，脱保护基，还原，胺化，缩合或水解步骤。The method for preparing the compound according to any one of claims 1-9, characterized in that it comprises the steps of: under suitable conditions, mixing the raw material containing a naphthyridine ring structure with a nitrogen-containing heterobicyclo[3.1.0]hexane The starting materials of the structure are reacted in suitable reagents and, optionally, under suitable conditions, subjected to a protecting group, deprotecting group, reduction, amination, condensation or hydrolysis step.
  11. 一种药物组合物，其包含权利要求1-9任一项所述的式I化合物及其消旋体、立体异构体、互变异构体、同位素标记物、氮氧化物、溶剂化物、多晶型物、代谢产物、酯、前药或其药学上可接受的盐；优选的，所述药物组合物包含治疗有效量的式I化合物及其消旋体、立体异构体、互变异构体、同位素标记物、氮氧化物、溶剂化物、多晶型物、代谢产物、酯、前药或其药学上可接受的盐和药学上可接受的载体。A pharmaceutical composition comprising the compound of formula I according to any one of claims 1-9 and its racemate, stereoisomer, tautomer, isotopic label, nitrogen oxide, solvate, Polymorphs, metabolites, esters, prodrugs or pharmaceutically acceptable salts thereof; preferably, the pharmaceutical composition comprises a therapeutically effective amount of a compound of formula I and its racemates, stereoisomers, interconversions Isomers, isotopic labels, nitrogen oxides, solvates, polymorphs, metabolites, esters, prodrugs or pharmaceutically acceptable salts thereof and pharmaceutically acceptable carriers.
  12. 根据权利要求1-9任一项所述的式I化合物及其消旋体、立体异构体、互变异构体、同位素标记物、氮氧化物、溶剂化物、多晶型物、代谢产物、酯、前药或其药学上可接受的盐或所述药物组合物在制备预防，调节或治疗与整合素活性有关的疾病或病症的药物中的用途。The compound of formula I according to any one of claims 1-9 and its racemates, stereoisomers, tautomers, isotopic labels, nitrogen oxides, solvates, polymorphs, metabolites , ester, prodrug or a pharmaceutically acceptable salt thereof or the use of said pharmaceutical composition in the manufacture of a medicament for the prevention, modulation or treatment of a disease or condition associated with integrin activity.
  13. 根据权利要求12所述的用途，其特征在于，所述整合素选自αVβ1，αVβ3，αVβ5，αVβ6，和αVβ8，α5β1，α8β1中的任一种或αVβ1，αVβ3，αVβ5，αVβ6，和αVβ8，α5β1，α8β1中的一个或多个的组合。The use according to claim 12, wherein the integrin is selected from any one of αVβ1, αVβ3, αVβ5, αVβ6, and αVβ8, α5β1, α8β1 or αVβ1, αVβ3, αVβ5, αVβ6, and αVβ8, A combination of one or more of α5β1, α8β1.
  14. 根据权利要求1-9任一项所述式I化合物及其消旋体、立体异构体、互变异构体、同位素标记物、氮氧化物、溶剂化物、多晶型物、代谢产物、酯、前药或其药学上可接受的盐或所述药物组合物在用于抑制细胞中TGF-β活化的药物中的用途。Compounds of formula I according to any one of claims 1-9 and their racemates, stereoisomers, tautomers, isotopic labels, nitrogen oxides, solvates, polymorphs, metabolites, Use of an ester, a prodrug or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in a medicament for inhibiting TGF-beta activation in a cell.
  15. 根据权利要求1-9任一项所述的式I化合物及其消旋体、立体异构体、互变异构体、同位素标记物、氮氧化物、溶剂化物、多晶型物、代谢产物、酯、前药或其药学上可接受的盐或所述药物组合物在制备用于治疗纤维化性疾病，炎性疾病或细胞增殖性疾病的药物中的用途。The compound of formula I according to any one of claims 1-9 and its racemates, stereoisomers, tautomers, isotopic labels, nitrogen oxides, solvates, polymorphs, metabolites , ester, prodrug or a pharmaceutically acceptable salt thereof or the use of the pharmaceutical composition in the manufacture of a medicament for the treatment of fibrotic diseases, inflammatory diseases or cell proliferative diseases.
  16. 根据权利要求12或13所述的用途，所述疾病或病症选自移植注射，纤维化病症(例如特发性肺纤维化，间质性肺疾病，肝纤维化，非酒精性脂肪性肝，原发性硬化性胆管炎(PSC)，肾纤维化，皮肤纤维化，心肌纤维化，系统性硬化)，炎症性疾病(例如急性肝炎，慢性肝炎，牛皮癣，肠易激综合征(IBS)，炎症性肠病(IBD)，骨质疏松症以及细胞增殖性疾病(例如癌症，骨髓瘤，纤维瘤，肝癌，白血病，卡波西氏肉瘤，实体瘤)；Use according to claim 12 or 13, wherein the disease or condition is selected from transplantation injection, fibrotic conditions (eg idiopathic pulmonary fibrosis, interstitial lung disease, liver fibrosis, nonalcoholic fatty liver, 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 diseases (eg, cancer, myeloma, fibroma, liver cancer, leukemia, Kaposi's sarcoma, solid tumors);
    所述疾病或病症进一步选自特发性肺纤维化(IPF)，间质性肺病，非特异性间质性肺炎(NSIP)，常规间质性肺炎(UIP)，辐射诱发性纤维化，家族性肺纤维化，气道纤维化，慢性阻 塞性肺疾病(COPD)，糖尿病性肾病，局灶性节段性肾小球硬化，IgA肾病，药物或移植引起的肾病，自身免疫性肾病，狼疮性肾炎，肝纤维化，肾脏纤维化，慢性肾脏病(CKD)，糖尿病肾病(DKD)，皮肤纤维化，瘢痕，全身性硬化，硬皮病，病毒性纤维化，非酒精性脂肪肝病(NAFLD)，酒精性或非酒精性脂肪性肝炎(NASH)，急性肝炎，慢性肝炎，肝硬化，原发性硬化性胆管炎，药物性肝炎，胆汁性肝硬化，门脉高压，再生衰竭，肝功能不全，肝血流异常，肾病，肺炎，牛皮癣，肠易激综合征罗马(IBS)，炎性肠病(IBD)，胰腺分泌异常，前列腺增生，神经性膀胱疾病，脊髓肿瘤，椎间盘疝，椎管狭窄，心力衰竭，心脏纤维化，血管纤维化，血管周纤维化，足口疾病，癌症，骨髓瘤，纤维瘤，肝癌，白血病，慢性淋巴细胞性白血病，卡波济肉瘤，实体瘤，脑梗死，脑出血，神经性疼痛，周围神经病，年龄相关性黄斑变性(AMD)，青光眼，眼纤维化，角膜瘢痕形成，糖尿病性视网膜病变，增生性玻璃体视网膜病变(PVR)，瘢痕性天疱疮性青光眼滤过手术瘢痕，克罗恩病或系统性红斑狼疮；伤口愈合异常导致瘢痕形成；器官移植后发生纤维化，骨髓纤维化和肌瘤。The disease or disorder is further selected from 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, Kidney Fibrosis, Chronic Kidney Disease (CKD), Diabetic Nephropathy (DKD), Skin Fibrosis, Scarring, Systemic Sclerosis, Scleroderma, Viral Fibrosis, Non-Alcoholic Fatty Liver Disease (NAFLD) , alcoholic or nonalcoholic steatohepatitis (NASH), acute hepatitis, chronic hepatitis, cirrhosis, primary sclerosing cholangitis, drug-induced hepatitis, biliary cirrhosis, portal hypertension, regenerative failure, hepatic insufficiency , abnormal liver blood flow, kidney disease, pneumonia, psoriasis, irritable bowel syndrome Rome (IBS), inflammatory bowel disease (IBD), abnormal pancreatic secretion, benign prostatic hyperplasia, neurogenic bladder disease, spinal cord tumor, intervertebral disc hernia, spinal canal Stenosis, heart failure, cardiac fibrosis, vascular fibrosis, perivascular fibrosis, foot and mouth disease, cancer, myeloma, fibroma, liver cancer, leukemia, chronic lymphocytic leukemia, Kaposi's sarcoma, solid tumor, cerebral infarction , cerebral hemorrhage, neuropathic pain, peripheral neuropathy, age-related macular degeneration (AMD), glaucoma, ocular fibrosis, corneal scarring, diabetic retinopathy, proliferative vitreoretinopathy (PVR), cicatricial pemphigus Glaucoma filtering surgical scars, Crohn's disease or systemic lupus erythematosus; abnormal wound healing leading to scarring; fibrosis, myelofibrosis, and fibroids after organ transplantation.
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Citations (4)

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WO2001024797A1 (en) * 1999-10-04 2001-04-12 Merck & Co., Inc. Integrin receptor antagonists
CN101035784A (en) * 2004-09-24 2007-09-12 埃科特莱茵药品有限公司 New bicyclic antibiotics
WO2018160522A1 (en) * 2017-02-28 2018-09-07 Lazuli, Inc. Inhibitors of (alpha-v)(beta-6) integrin
CN110167934A (en) * 2016-11-08 2019-08-23 百时美施贵宝公司 Monocycle and spiro-compound containing cyclobutane and containing azetidine as α V integrin inhibitor

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001024797A1 (en) * 1999-10-04 2001-04-12 Merck & Co., Inc. Integrin receptor antagonists
CN101035784A (en) * 2004-09-24 2007-09-12 埃科特莱茵药品有限公司 New bicyclic antibiotics
CN110167934A (en) * 2016-11-08 2019-08-23 百时美施贵宝公司 Monocycle and spiro-compound containing cyclobutane and containing azetidine as α V integrin inhibitor
WO2018160522A1 (en) * 2017-02-28 2018-09-07 Lazuli, Inc. Inhibitors of (alpha-v)(beta-6) integrin

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