Amino acid integrin inhibitor, preparation method therefor, and use thereof

Abstract

An amino acid compound represented by formula (I), a preparation method therefor, and use thereof. The present invention further relates to a pharmaceutical composition containing the compound as an active ingredient, and use of the compound or pharmaceutical composition in the treatment and / or prevention of diseases related to αvβ1 / αvβ6 biological activity.

Description

A class of amino acid integrin inhibitors, preparation method and application thereof Technical Field

[0001] The present invention belongs to the field of medicinal chemistry, and in particular relates to a class of amino acid integrin inhibitors, a preparation method thereof and an application thereof. Background Art

[0002] TGF-β is a multifunctional cytokine belonging to the transforming growth factor superfamily. It regulates the migration, proliferation and differentiation of endothelial cells, epithelial cells and fibroblasts, and affects angiogenesis and wound healing. TGF-β produced by normal cells exists in an inactive state. Integrins are the main activators of TGF-β ligands, including integrins ανβ1, ανβ3, ανβ5, ανβ6 and ανβ8. [1] αν integrins (β1, β3, β5, β8) expressed on fibroblasts and ανβ6 expressed on epithelial cells activate TGFβ by interacting with the linear arginine-glycine-aspartate (RGD) binding motif on latency-associated peptide (LAP) in the extracellular matrix (ECM). [2] TGF-β released by damaged epithelial cells can directly signal to myofibroblasts, promoting ECM production. Furthermore, αv integrins on myofibroblasts can release active TGFβ from the ECM; TGF-β then signals in an autocrine manner, further driving myofibroblasts to produce ECM.

[0003] Inhibition of TGF-β provides a promising approach for anti-fibrosis. However, because TGF-β regulates many important physiological functions, systemic inhibition may lead to toxicity, and there is an urgent need for methods to specifically target and inhibit TGF-β. Studies have shown that inhibiting integrins ανβ3, ανβ5, or ανβ8 has no benefit in reducing fibrosis, and inhibition of ανβ3 / ανβ5 even aggravates liver fibrosis in mice. For example, the ανβ3 / ανβ5 inhibitor Cilengitide aggravates biliary tract (BDL) and diaphragm (TAA) fibrosis in rats. [3,4] Blocking αvβ8 integrin-mediated TGF-β activation in immune cells may also lead to side effects, such as the intestinal autoimmune phenotype observed in mice lacking αv or β8 integrin expression in immune cells. Integrin subunit β6 knockout mice are protected against bleomycin-induced pulmonary fibrosis. [5] Inhibition of ανβ1 has also been shown to alleviate bleomycin-induced pulmonary fibrosis in mice and CCL4-induced liver fibrosis in mice. [6] .

[0004] The above studies indicate that ανβ6 and ανβ1 can be used as the main targets for anti-fibrosis, and compared with the inhibition of ανβ6 or ανβ1 alone, the simultaneous inhibition of ανβ6 and ανβ1 showed stronger anti-fibrotic effects and safety. This suggests that inhibiting the main ligand activators of TGF-β, ανβ6 and ανβ1, is a potential anti-fibrotic treatment strategy, while avoiding the adverse reactions caused by global inhibition of TGF-β. Therefore, inhibiting ανβ6+ανβ1 is a very promising treatment strategy for fibrotic diseases. However, at present, there are no drugs that are dual inhibitors of ανβ1 / ανβ6 on the market, and further development of related drugs is needed.

[0005] Summary of the Invention

[0006] Problems to be solved by the invention:

[0007] Although several patent applications for αvβ1 / αvβ6 integrin inhibitors have been published, given the promising potential of αvβ6 / αvβ1 dual-specificity inhibitors in treating conditions related to fibrosis and the lack of currently marketed αvβ1 / αvβ6 dual-targeting drugs, new compounds remain under development. Through continuous effort, the inventors of the present application have designed compounds having the structure represented by general formula (I) and discovered that such compounds exhibit excellent αvβ1 / αvβ6 dual inhibitory effects and potential for treating and / or preventing diseases associated with the biological activity of αvβ1 / αvβ6.

[0008] Solutions used to solve the problem:

[0009] In order to solve the above problems, the inventors of the present application have attempted to conduct in-depth research and found that the amino acid compound represented by formula (I) can achieve the desired purpose, resulting in the completion of the present invention.

[0010] The present invention relates to the following amino acid compound integrin inhibitors.

[0011] The present invention protects the following specific embodiments:

[0012] A compound represented by formula (I), its stereoisomers, tautomers, polymorphs, cocrystals, solvates, metabolites, prodrugs, deuterated compounds or pharmaceutically acceptable salts:

[0013] in,

[0014] R 1 Selected from C 6-14 Aryl or 5-10 membered heteroaryl, wherein the 5-10 membered heteroaryl contains 1-4 heteroatoms selected from N, O or S; the C 6-14 The aryl or 5-10 membered heteroaryl group is unsubstituted or each independently substituted by one or more R1a replace;

[0015] R 2 Selected from hydrogen, deuterium, -OH, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 3-6 Cycloalkyloxy, 3-12 membered heterocyclic group or -S(O)2R 2d wherein the 3-12 membered heterocyclic group contains 1-4 heteroatoms selected from N, O or S, and the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 3-6 Cycloalkyloxy, 3-12 membered heterocyclic group are unsubstituted or each independently substituted by one or more R 2a Replacement; R 2d Selected from C 1-6 Alkyl, C 3-5 Cycloalkyl, R 2d Can be further represented by one or more R 2b replace;

[0016] R 1a Each occurrence is independently selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-8 Alkynyl, C 3-8 Cycloalkyl, C 4-8 Cycloalkenyl, 3-12 membered heterocyclic group, 5-10 membered heteroaryl, C 6-14 Aryl, deuterium, halogen, -CN, -OR 3 、-SR 3 、-NR 4 R 5 、-NO2、-C=NH(OR 3 ),-C(O)R 3 、-OC(O)R 3 、-C(O)OR 3 、-C(O)NR 4 R 5 、-NR 3 C(O)R 4 、-NR 3 C(O)OR 4 、-NR 3 C(O)NR 4 R 5 、-S(O)R 3 、-S(O)2R 3 、-NR 3 S(O)R 4 、 -NR 3 S(O)2R4 、-S(O)NR 4 R 5 、-S(O)2NR 4 R 5 OR-P(O)(OR 4 )(OR 5 ), wherein the 3-12 membered heterocyclyl and 5-10 membered heteroaryl each independently contain 1-4 heteroatoms selected from N, O or S;

[0017] R 1a Each occurrence may be further substituted, independently where possible, with one or more substituents selected from the group consisting of deuterium, halogen, oxo, -OR 6 、-NR 6 R 7 、-C(O)R 6 、-CN、-S(O)R 6 、-S(O)2R 6 、-P(O)(OR 6 )(OR 7 ), C 3-8 Cycloalkyl, 3-12 membered heterocyclic group, 5-10 membered heteroaryl, C 6-14 Aryl, or C optionally substituted by deuterium, oxo, -OH or halogen 1-6 Alkyl; wherein the 3-12 membered heterocyclic group and the 5-10 membered heteroaryl group each independently contain 1-4 heteroatoms selected from N, O or S;

[0018] R 2a and R 2b Each occurrence is independently selected from oxo or R la ;

[0019] R 3 Each occurrence is independently selected from hydrogen, deuterium, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 6-14 aryl, 5-10 membered heteroaryl or 3-12 membered heterocyclic group; wherein the 5-10 membered heteroaryl and 3-12 membered heterocyclic group each independently contain 1-4 heteroatoms selected from N, O or S, and the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 6-14 Aryl, 5-10 membered heteroaryl or 3-12 membered heterocyclyl is unsubstituted or each is independently substituted by one or more substituents selected from the group consisting of halogen, deuterium, oxo, -CN, -OR 8 , -NR8 R 9 ,-P(O)(OR 8 )(OR 9 ), C 1-6 Alkyl, C substituted by deuterium, halogen, -OH or oxo 1-6 alkyl;

[0020] R 4 and R 5 Each occurrence is independently selected from hydrogen, deuterium, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 6-14 aryl, 5-6 membered heteroaryl or 3-6 membered heterocyclic group; wherein the 5-6 membered heteroaryl and 3-6 membered heterocyclic group each independently contain 1-3 heteroatoms selected from N, O or S, and the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 6-14 Aryl, 5-6 membered heteroaryl or 3-6 membered heterocyclyl is unsubstituted or each independently substituted by one or more substituents selected from the group consisting of deuterium, halogen, oxo, -CN, -OR 8 , -NR 8 R 9 , C 1-6 Alkyl, C substituted by deuterium, halogen, -OH or oxo 1-6 alkyl;

[0021] or R 4 and R 5 Together with the atoms to which it is attached, it forms a 3-6 membered heterocyclic group containing 1-3 heteroatoms selected from N, O or S; the 3-6 membered heterocyclic group is unsubstituted or substituted by one or more substituents selected from the following groups: deuterium, halogen, oxo, -OR 8 , -NR 8 R 9 , C 1-6 Alkyl, C substituted by deuterium, halogen, oxo or -OH 1-6 alkyl;

[0022] R 6 and R 7 Each occurrence is independently selected from hydrogen, deuterium, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl; wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6Alkynyl groups are unsubstituted or each independently substituted with one or more substituents selected from deuterium, halogen or oxo;

[0023] or R 6 and R 7 Together with the atoms to which it is attached, it forms a 3-6 membered heterocyclic group containing 1-3 heteroatoms selected from N, O or S, wherein the 3-6 membered heterocyclic group is unsubstituted or substituted by one or more substituents selected from the following groups: deuterium, halogen, oxo, C 1-6 Alkyl, C substituted by deuterium, halogen or oxo 1-6 alkyl;

[0024] R 8 and R 9 Each occurrence is independently selected from hydrogen, deuterium, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl; wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl groups are unsubstituted or each independently substituted with one or more substituents selected from deuterium, halogen or oxo;

[0025] or R 8 and R 9 Together with the atoms to which it is attached, it forms a 3-6 membered heterocyclic group containing 1-3 heteroatoms selected from N, O or S, wherein the 3-6 membered heterocyclic group is unsubstituted or substituted by one or more substituents selected from the following groups: deuterium, halogen, oxo, C 1-6 Alkyl, C substituted by deuterium, oxo or halogen 1-6 alkyl;

[0026] R 10 、R l1 、R 12 and R 13 Each occurrence is independently selected from hydrogen or deuterium;

[0027] R 14 Each occurrence is independently selected from halogen, -CN, -OR 3 、-SR 3 、-NR 4 R 5 、-NO2、-NR 3 C(O)R 4 、-NR 3 C(O)OR 4 、-NR 3 C(O)NR 4 R 5 、-NR 3 S(O)R 4 、-NR3 S(O)2R 4 、C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 6-14 aryl, 5-10 membered heteroaryl or 3-12 membered heterocyclic group; wherein the 5-10 membered heteroaryl and 3-12 membered heterocyclic group each independently contain 1-4 heteroatoms selected from N, O or S, and the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 6-14 The aryl, 5-10 membered heteroaryl or 3-12 membered heterocyclyl is unsubstituted or each independently substituted by one or more substituents selected from the group consisting of deuterium, halogen, oxo, C 1-6 Alkyl, C substituted by deuterium or halogen 1-6 alkyl;

[0028] q is 1, 2, 3, 4, 5, 6, 7, or 8;

[0029] R 15 selected from hydrogen, deuterium or halogen;

[0030] R 16 is selected from hydrogen, deuterium or halogen; and

[0031] p is 3, 4, 5, 6, 7, 8 or 9.

[0032] In some specific embodiments, R 2 Any carbon atom directly bonded to a nitrogen atom in a group of 2a Partial replacement.

[0033] In some specific embodiments, R 1 is selected from phenyl, naphthyl or 5-10 membered heteroaryl, wherein the 5-10 membered heteroaryl contains 1-4 heteroatoms selected from N, O or S; the phenyl, naphthyl or 5-10 membered heteroaryl is unsubstituted or each independently substituted by one or more R 1a replace.

[0034] In some specific embodiments, R 1 is selected from 5-10 membered heteroaryl, wherein the 5-10 membered heteroaryl contains 1-4 heteroatoms selected from N, O or S; the 5-10 membered heteroaryl is unsubstituted or replaced by one or more R 1a replace.

[0035] In some specific embodiments, R 1is selected from a 5-6 membered monocyclic heteroaryl or a 9-10 membered bicyclic heteroaryl, wherein the 5-6 membered monocyclic heteroaryl contains 1-3 heteroatoms selected from N, O or S, and the 9-10 membered bicyclic heteroaryl contains 1-4 heteroatoms selected from N, O or S; the 5-6 membered monocyclic heteroaryl or the 9-10 membered bicyclic heteroaryl is unsubstituted or each independently substituted by one or more R 1a replace.

[0036] In some specific embodiments, R 1 is selected from a 5-6 membered monocyclic heteroaryl or a 9-10 membered bicyclic heteroaryl, wherein the 5-6 membered monocyclic heteroaryl contains 1-3 N heteroatoms, and the 9-10 membered bicyclic heteroaryl contains 1-4 heteroatoms selected from N or S; the 5-6 membered monocyclic heteroaryl or the 9-10 membered bicyclic heteroaryl is unsubstituted or each is independently substituted by 1, 2 or 3 R 1a replace.

[0037] In some specific embodiments, R 1 is selected from a 5-6 membered monocyclic heteroaryl or a 9-10 membered bicyclic heteroaryl, wherein the 5-6 membered monocyclic heteroaryl contains 2 N heteroatoms, and the 9-10 membered bicyclic heteroaryl contains 2-4 heteroatoms selected from N or S; the 5-6 membered monocyclic heteroaryl or the 9-10 membered bicyclic heteroaryl is unsubstituted or each is independently substituted by 1, 2 or 3 R 1a replace.

[0038] In some specific embodiments, R 1 is selected from pyrimidinyl, pyrazinyl, quinazolinyl, pyridopyrimidinyl, pyrazolopyrimidinyl, thienopyrimidinyl, benzothiazolyl, benzopyrazinyl; the pyrimidinyl, pyrazinyl, quinazolinyl, pyridopyrimidinyl, pyrazolopyrimidinyl, thienopyrimidinyl, benzothiazolyl, benzopyrazinyl is unsubstituted or each is independently substituted by 1, 2 or 3 R 1a replace.

[0039] In some specific embodiments, R 1 Selected from which are unsubstituted or each independently substituted with 1, 2 or 3 R 1a replace.

[0040] In some specific embodiments, R 1 is selected from pyrimidinyl, pyrazinyl, quinazolinyl, pyridopyrimidinyl, pyrazolopyrimidinyl, thienopyrimidinyl, benzothiazolyl, benzopyrazinyl, furopyrimidinyl; the pyrimidinyl, pyrazinyl, quinazolinyl, pyridopyrimidinyl, pyrazolopyrimidinyl, thienopyrimidinyl, benzothiazolyl, benzopyrazinyl, furopyrimidinyl is unsubstituted or each is independently substituted by 1, 2 or 3 R1a replace.

[0041] In some specific embodiments, R 1 Selected from which are unsubstituted or each independently substituted with 1, 2 or 3 R 1a replace.

[0042] In some specific embodiments, R 1a Each occurrence is independently selected from halogen, -CN, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, 5-10 membered heteroaryl, C 6-10 Aryl; wherein the 5-10 membered heteroaryl contains 1-4 heteroatoms selected from N, O or S, and the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, 5-10 membered heteroaryl, C 6-10 Aryl is unsubstituted or each independently substituted by one or more selected from deuterium, halogen, -CN, C 1-4 Alkyl, halogenated C 1-4 The alkyl group is substituted with a substituent.

[0043] In some specific embodiments, R 1a Each occurrence is independently selected from halogen, -CN, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, 5-6 membered heteroaryl, phenyl; wherein the 5-6 membered heteroaryl contains 1-3 heteroatoms selected from N, O or S, the C 1-4 Alkyl, C 1-4 The alkoxy groups are unsubstituted or independently substituted by one or more substituents selected from deuterium, F, Cl or Br; 3-6 Cycloalkyl, 5-6 membered heteroaryl, phenyl are unsubstituted or independently substituted by one or more groups selected from deuterium, halogen, -CN, C 1-4 Alkyl, halogenated C 1-4 The alkyl group is substituted with a substituent.

[0044] In some specific embodiments, R 1a Each occurrence is independently selected from halogen, -CN, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-4 Cycloalkyl, 5-6 membered heteroaryl, phenyl; wherein the 5-6 membered heteroaryl contains 1-3 N heteroatoms, the C 1-4 Alkyl, C 1-4The alkoxy groups are unsubstituted or independently substituted by one or more substituents selected from deuterium, F, Cl or Br; 3-4 The cycloalkyl, 5-6 membered heteroaryl and phenyl groups are unsubstituted or independently substituted with one or more substituents selected from deuterium, F, Cl, Br, methyl, halomethyl, ethyl or haloethyl.

[0045] In some specific embodiments, R 1a Each occurrence is independently selected from F, Cl, Br, -CN, methyl, ethyl, propyl, isopropyl, C4 alkyl, methoxy, ethoxy, propoxy, isopropyl, C4 alkoxy, cyclopropyl, cyclobutyl, C5 cycloalkyl, C6 cycloalkyl, phenyl, pyrazolyl, imidazolyl, pyrrolyl, triazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl; wherein the methyl, ethyl, propyl, isopropyl, C4 alkyl, methoxy, ethoxy, propoxy, isopropyl, C4 alkoxy, cyclopropyl, cyclobutyl, C5 cycloalkyl, C6 cycloalkyl, phenyl, pyrazolyl, imidazolyl, pyrrolyl, triazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl , isopropoxy, C4 alkoxy are unsubstituted or are each independently substituted by one or more substituents selected from deuterium, F, Cl or Br, and the cyclopropyl, cyclobutyl, C5 cycloalkyl, C6 cycloalkyl, phenyl, pyrazolyl, imidazolyl, pyrrolyl, triazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl are unsubstituted or are each independently substituted by one or more substituents selected from deuterium, F, Cl, Br, methyl, fluoromethyl, ethyl or fluoroethyl.

[0046] In some specific embodiments, R 1a Each occurrence is independently selected from F, Cl, Br, -CN, methyl, fluoromethyl, methoxy, cyclopropyl, phenyl, pyrazolyl.

[0047] In some specific embodiments, R 1a Each occurrence is independently selected from F, Cl, Br, -CN, methyl, -CF3, -CHF2, methoxy, cyclopropyl, phenyl,

[0048] In some specific embodiments, R 1a Each occurrence is independently selected from halogen, -CN, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, 5-10 membered heteroaryl, C 6-10 Aryl, -SR 3 wherein the 5-10 membered heteroaryl group contains 1-4 heteroatoms selected from N, O or S, and the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, 5-10 membered heteroaryl, C 6-10 Aryl is unsubstituted or each independently substituted by one or more selected from deuterium, halogen, -CN, C1-4 Alkyl, halogenated C 1-4 The alkyl group is substituted with a substituent.

[0049] In some specific embodiments, R 1a Each occurrence is independently selected from halogen, -CN, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, 5-6 membered heteroaryl, phenyl, -SR 3 wherein the 5-6 membered heteroaryl group contains 1-3 heteroatoms selected from N, O or S, and the C 1-4 Alkyl, C 1-4 The alkoxy groups are unsubstituted or independently substituted by one or more substituents selected from deuterium, F, Cl or Br; 3-6 Cycloalkyl, 5-6 membered heteroaryl, phenyl are unsubstituted or independently substituted by one or more groups selected from deuterium, halogen, -CN, C 1-4 Alkyl, halogenated C 1-4 The alkyl group is substituted with a substituent.

[0050] In some specific embodiments, R 1a Each occurrence is independently selected from F, Cl, Br, -CN, methyl, -CF3, -CHF2, methoxy, cyclopropyl, phenyl, -SR 3 .

[0051] In some specific embodiments, R 3 Selected from C 1-6 Alkyl, the C 1-6 Alkyl is unsubstituted or substituted by one or more radicals selected from halogen, cyano, deuterium, C 1-6 The substituents of the alkoxy group are substituted.

[0052] In some specific embodiments, R 3 Selected from C 1-4 Alkyl, the C 1-4 Alkyl is unsubstituted or substituted by one or more radicals selected from halogen, cyano, deuterium, C 1-4 The substituents of the alkoxy group are substituted.

[0053] In some specific embodiments, R 3 is selected from methyl, ethyl, propyl, isopropyl, wherein the methyl, ethyl, propyl, isopropyl is unsubstituted or substituted by one or more halogen, cyano, deuterium, C 1-4 The substituents of the alkoxy group are substituted.

[0054] In some specific embodiments, R 3 Selected from methyl.

[0055] In some specific embodiments, R 1 Selected from:

[0056] In some specific embodiments, R 1 Selected from:

[0057] In some specific embodiments, R 1 Selected from

[0058] In some specific embodiments, R 1 Selected from:

[0059] In some specific embodiments, R 1 Selected from

[0060] In some specific embodiments, R 2 Selected from C 1-6 Alkyl, the C 1-6 The alkyl group is replaced by one or more R 2a replace.

[0061] In some specific embodiments, R 2 Selected from C 1-4 Alkyl, the C 1-4 The alkyl group is replaced by one or more R 2a replace.

[0062] In some specific embodiments, R 2 Selected from methyl, ethyl, propyl, isopropyl, C4 alkyl, wherein the methyl, ethyl, propyl, isopropyl, C4 alkyl is replaced by 1, 2 or 3 R 2a replace.

[0063] In some specific embodiments, R 2 Selected from methyl, ethyl, said methyl, ethyl being 1, 2 or 3 R 2a replace.

[0064] In some specific embodiments, R 2a Each occurrence is independently selected from deuterium, halogen, -CN, C 1-6 Alkyl, 4-7 membered heterocyclic group, -OR 3 or -OC(O)R 3 The 4-7 membered heterocyclic group contains 1-4 heteroatoms selected from N, O or S, wherein at least one heteroatom is O, subject to the restriction that at least one R 2a Selected from 4-7 membered heterocyclic group, -OR 3 or -OC(O)R 3 ; the C1-6 Alkyl, 4-7 membered heterocyclic group is unsubstituted or substituted by one or more substituents selected from the following groups: deuterium, -OR 6 , halogen, C 1-6 Alkyl, hydroxyl C 1- 6-alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 alkyl.

[0065] In some specific embodiments, R 2a Each occurrence is independently selected from deuterium, halogen, -CN, C 1-6 Alkyl, 4-7 membered heterocycloalkyl or -OR 3 The 4-7 membered heterocycloalkyl group contains 1-4 heteroatoms selected from N, O or S, wherein at least one heteroatom is O, subject to the restriction that at least one R 2a is a 4-7 membered heterocycloalkyl group or -OR 3 ; the C 1-6 Alkyl, 4-7 membered heterocycloalkyl is unsubstituted or substituted by one or more substituents selected from the following groups: deuterium, -OR 6 , halogen, C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, halogenated C 1- 6-alkyl, deuterated C 1-6 alkyl.

[0066] In some specific embodiments, R 2a Each occurrence is independently selected from deuterium, halogen, -CN, C 1-6 Alkyl, 4-7 membered heterocycloalkyl or -OR 3 The 4-7 membered heterocycloalkyl group contains 1-2 heteroatoms selected from N, O or S, wherein at least one heteroatom is O, subject to the restriction that at least one R 2a is a 4-7 membered heterocycloalkyl group or -OR 3 ; the C 1-6 Alkyl, 4-7 membered heterocycloalkyl is unsubstituted or substituted by one or more substituents selected from the following groups: deuterium, -OR 6 , halogen, C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, halogenated C 1- 6-alkyl, deuterated C 1-6 alkyl.

[0067] In some specific embodiments, R 6 For H.

[0068] In some specific embodiments, R 2a Each occurrence is independently selected from halogen, C 1-6 Alkyl, deuterated C1-6 Alkyl, halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, 4-7 membered heterocycloalkyl or -OR 3 The 4-7 membered heterocycloalkyl group contains 1-2 heteroatoms selected from N, O or S, wherein at least one heteroatom is O, subject to the restriction that at least one R 2a is a 4-7 membered heterocycloalkyl group or -OR 3 .

[0069] In some specific embodiments, R 2a Each occurrence is independently selected from halogen, C 1-6 Alkyl, deuterated C 1-6 Alkyl, fluorinated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, 4-6 membered heterocycloalkyl or -OR 3 The 4-6 membered heterocycloalkyl group contains 1-2 heteroatoms selected from N, O or S, wherein at least one heteroatom is O, subject to the restriction that at least one R 2a is a 4-6 membered heterocycloalkyl group or -OR 3 .

[0070] In some specific embodiments, R 2a Each occurrence is independently selected from halogen, C 1-4 Alkyl, deuterated C 1-4 Alkyl, fluorinated C 1-4 Alkyl, hydroxyl C 1-4 Alkyl, 4-6 membered heterocycloalkyl or -OR 3 , the 4-6 membered heterocycloalkyl group contains 1 oxygen heteroatom, subject to the restriction that at least one R 2a is a 4-6 membered heterocycloalkyl group or -OR 3 .

[0071] In some specific embodiments, R 2a Each occurrence is independently selected from F, Cl, Br, methyl, ethyl, propyl, isopropyl, fluoromethyl, fluoroethyl, fluoropropyl, fluoroisopropyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxyisopropyl, oxetanyl, oxolanyl, oxhexyl, or -OR 3 , the constraint is that there is at least one R 2a is oxetane, oxolane, oxhexyl or -OR 3 .

[0072] In some specific embodiments, R 2a Each occurrence is independently selected from F, methyl, -CH2OH, -CH2F, oxetanyl or -OR 3 , the constraint is that there is at least one R2a is oxetane or -OR 3 .

[0073] In some specific embodiments, R 3 Each occurrence is independently selected from hydrogen, deuterium, C 1-6 Alkyl, C 6- 14 Aryl, C 3-6 Cycloalkyl, 5-10 membered heteroaryl, wherein the 5-10 membered heteroaryl contains 1-4 heteroatoms selected from N, O or S; the C 1-6 Alkyl, C 6-14 Aryl, C 3-6 Cycloalkyl and 5-10 membered heteroaryl are unsubstituted or independently substituted by one or more substituents selected from the following groups: halogen, deuterium, C 1-6 Alkyl, C substituted by deuterium, halogen, -OH or oxo 1-6 alkyl.

[0074] In some specific embodiments, R 3 Each occurrence is independently selected from hydrogen, deuterium, C 1-6 Alkyl, C 6- 10 Aryl, C 3-6 Cycloalkyl, 5-10 membered heteroaryl, wherein the 5-10 membered heteroaryl contains 1-4 heteroatoms selected from N, O or S; the C 1-6 Alkyl, C 6-10 Aryl, C 3-6 Cycloalkyl and 5-10 membered heteroaryl are unsubstituted or independently substituted by one or more substituents selected from the following groups: halogen, deuterium, C 1-6 Alkyl, C substituted by deuterium, halogen, -OH 1-6 alkyl.

[0075] In some specific embodiments, R 3 Each occurrence is independently selected from hydrogen, deuterium, C 1-6 Alkyl, phenyl, C 3-6 Cycloalkyl, 5-6 membered heteroaryl, wherein the 5-6 membered heteroaryl contains 1-3 heteroatoms selected from N, O or S; the C 1-6 Alkyl, phenyl, C 3-6 Cycloalkyl and 5-6 membered heteroaryl are unsubstituted or independently substituted by one or more substituents selected from the following groups: halogen, deuterium, C 1-6 Alkyl, C substituted by deuterium, halogen, -OH 1-6 alkyl.

[0076] In some specific embodiments, R 3 Each occurrence is independently selected from H, halo1-6 Alkyl, deuterated C 1-6 Alkyl, phenyl, C 1-6 Alkyl, C 3-6 Cycloalkyl, 5-6 membered heteroaryl, wherein the 5-6 membered heteroaryl contains 1-3 heteroatoms selected from N, O or S; the phenyl, C 3-6 Cycloalkyl, 5-6 membered heteroaryl are unsubstituted or independently substituted by one or more substituents selected from the following groups: halogen, C 1-6 Alkyl, halogenated C 1-6 alkyl.

[0077] In some specific embodiments, R 3 Each occurrence is independently selected from H, halo 1-4 Alkyl, deuterated C 1-4 Alkyl, phenyl, C 1-4 Alkyl, C 3-6 Cycloalkyl, 5-6 membered heteroaryl, wherein the 5-6 membered heteroaryl contains 1-2 N heteroatoms; the phenyl, C 3-6 Cycloalkyl, 5-6 membered heteroaryl are unsubstituted or independently substituted by one or more substituents selected from the following groups: halogen, C 1-4 Alkyl, halogenated C 1-4 alkyl.

[0078] In some specific embodiments, R 3 Each occurrence is independently selected from H, fluoro C 1-4 Alkyl, deuterated C 1-4 Alkyl, phenyl, C 1-4 Alkyl, C 3-4 Cycloalkyl, 5-6 membered heteroaryl, wherein the 5-6 membered heteroaryl contains 1-2 N heteroatoms; the phenyl, C 3-4 The cycloalkyl and 5-6 membered heteroaryl groups are unsubstituted or independently substituted by one or more substituents selected from the group consisting of F, Cl, Br, methyl, ethyl, propyl and isopropyl.

[0079] In some specific embodiments, R 3 Each occurrence is independently selected from H, fluoromethyl, fluoroethyl, fluoropropyl, fluoroisopropyl, deuterated methyl, deuterated ethyl, deuterated propyl, deuterated isopropyl, phenyl, methyl or fluoro-substituted phenyl, methyl, ethyl, propyl, isopropyl, cyclopropyl, methyl or fluoro-substituted cyclopropyl, pyridyl, methyl or fluoro-substituted pyridyl.

[0080] In some specific embodiments, R 3 Each occurrence is independently selected from H, deuterated methyl, fluoromethyl, fluoroethyl, phenyl, methyl, ethyl, cyclopropyl, fluorocyclopropyl, pyridinyl, methyl or fluoro substituted pyridinyl, fluorophenyl.

[0081] In some specific embodiments, R 3 Each occurrence is independently selected from H, -CH2CHF2, -CHF2, -CH2CF3, phenyl, methyl, ethyl, -CF3, -CD3, cyclopropyl,

[0082] In some specific embodiments, R 2a Each occurrence is independently selected from F, -OH, -OCH2CHF2, -OCHF2, -OCH2CF3, phenoxy, methyl, methoxy, ethoxy, -CH2OH, -CH2F, -OCF3, -OCD3, The constraint is that there is at least one R 2a -OH, -OCH2CHF2, -OCHF2, -OCH2CF3, phenoxy, methoxy, ethoxy, -OCF3, -OCD3 or

[0083] In some specific embodiments, R 2 Selected from methoxyethyl, ethoxyethyl,

[0084] In some specific embodiments, R 14 Each occurrence is independently selected from halogen, -CN, -OR 3 、-SR 3 、-NR 4 R 5 、-NR 3 C(O)R 4 、-NR 3 S(O)2R 4 、C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 6-14 aryl, 5-10 membered heteroaryl or 3-12 membered heterocyclic group; wherein the 5-10 membered heteroaryl and 3-12 membered heterocyclic group each independently contain 1-4 heteroatoms selected from N, O or S, and the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 6-14 The aryl, 5-10 membered heteroaryl or 3-12 membered heterocyclic group is unsubstituted or each independently substituted by one or more substituents selected from the group consisting of deuterium, halogen, oxo, C 1-6 Alkyl, deuterated C 1-6 Alkyl, halogenated C 1-6 alkyl.

[0085] In some specific embodiments, R 14 Each occurrence is independently selected from halogen, -OR 3 、-SR 3 、-NR 4 R 5 、-NR 3 C(O)R 4 、-NR 3 S(O)2R 4 、C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 6-10 Aryl; wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 6-10 The aryl groups are unsubstituted or independently substituted by one or more substituents selected from the group consisting of deuterium, halogen, oxo, C 1-6 Alkyl, deuterated C 1-6 Alkyl, halogenated C 1-6 alkyl.

[0086] In some specific embodiments, R 14 Each occurrence is independently selected from halogen, -OR 3 、-SR 3 、-NR 4 R 5 、-NR 3 C(O)R 4 、-NR 3 S(O)2R 4 、C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, phenyl, naphthyl; wherein the C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, phenyl, naphthyl are unsubstituted or independently substituted by one or more substituents selected from the following groups: deuterium, halogen, oxo, C 1-4 Alkyl, deuterated C 1-4 Alkyl, halogenated C 1-4 alkyl.

[0087] In some specific embodiments, R 14 Each occurrence is independently selected from F, Cl, Br, -OR3 、-SR 3 、-NR 4 R 5 、-NR 3 C(O)R 4 、-NR 3 S(O)2R 4 , methyl, ethyl, vinyl, propenyl, ethynyl, propynyl, cyclopropyl, cyclobutyl, C5 cycloalkyl, C6 cycloalkyl, phenyl; wherein the methyl, ethyl, vinyl, propenyl, ethynyl, propynyl, cyclopropyl, cyclobutyl, C5 cycloalkyl, C6 cycloalkyl, phenyl is unsubstituted or is each independently substituted by one or more substituents selected from the following groups: deuterium, halogen, oxo, methyl, ethyl, deuterated methyl, deuterated ethyl, halomethyl, haloethyl.

[0088] In some specific embodiments, R 14 Each occurrence is independently selected from F, Cl, Br, -OR 3 、-SR 3 、-NR 4 R 5 、-NR 3 C(O)R 4 、-NR 3 S(O)2R 4 , methyl, ethyl, vinyl, propenyl, ethynyl, propynyl, cyclopropyl, cyclobutyl, C5 cycloalkyl, C6 cycloalkyl, phenyl; wherein the methyl, ethyl, vinyl, propenyl, ethynyl, propynyl, cyclopropyl, cyclobutyl, C5 cycloalkyl, C6 cycloalkyl, phenyl is unsubstituted or is each independently substituted by one or more substituents selected from the following groups: deuterium, F, Cl, Br, oxo, methyl, ethyl, deuterated methyl, deuterated ethyl, fluoromethyl, fluoroethyl.

[0089] In some specific embodiments, R 3 Each occurrence is independently selected from H, C 1-6 Alkyl, the C 1- 6 alkyl groups are unsubstituted or each independently substituted by one or more substituents selected from halogen, deuterium, -CN, and -OH.

[0090] In some specific embodiments, R 3 Each occurrence is independently selected from H, C 1-4 Alkyl, the C 1- 4-alkyl is unsubstituted or each independently substituted by one or more substituents selected from halogen, deuterium, -CN, -OH.

[0091] In some specific embodiments, R 3Each occurrence is independently selected from H, methyl, ethyl, propyl, isopropyl, C4 alkyl, said methyl, ethyl, propyl, isopropyl, C4 alkyl being unsubstituted or independently substituted with one or more substituents selected from halogen, deuterium, -CN, -OH.

[0092] In some specific embodiments, R 3 Each occurrence is independently selected from H, methyl, ethyl.

[0093] In some specific embodiments, R 3 Each occurrence is independently selected from H, methyl.

[0094] In some specific embodiments, R 4 and R 5 Each occurrence is independently selected from H, C 1-6 Alkyl, the C 1-6 The alkyl groups are unsubstituted or each independently substituted with one or more substituents selected from halogen, deuterium, -CN, -OH.

[0095] In some specific embodiments, R 4 and R 5 Each occurrence is independently selected from H, C 1-4 Alkyl, the C 1-4 The alkyl groups are unsubstituted or each independently substituted with one or more substituents selected from halogen, deuterium, -CN, -OH.

[0096] In some specific embodiments, R 4 and R 5 Each occurrence is independently selected from H, methyl, ethyl, propyl, isopropyl, C4 alkyl, said methyl, ethyl, propyl, isopropyl, C4 alkyl being unsubstituted or independently substituted with one or more substituents selected from halogen, deuterium, -CN, -OH.

[0097] In some specific embodiments, R 4 and R 5 Each occurrence is independently H, methyl.

[0098] In some specific embodiments, R 14 Each occurrence is independently selected from methyl, F, Cl, Br, amino, methoxy, cyclopropyl, vinyl, ethynyl, phenyl,

[0099] In some specific embodiments, R 14 Each occurrence is independently selected from methyl, Cl, cyclopropyl, vinyl.

[0100] In some specific embodiments, R 14Each occurrence is independently selected from methyl.

[0101] In some specific embodiments, R 15 、R 16 Each occurrence is independently H, deuterium, F, Cl, or Br.

[0102] In some specific embodiments, R 15 、R 16 Each occurrence is independently H or deuterium.

[0103] In some specific embodiments, R 15 、R 16 Each occurrence is independently H.

[0104] In some specific embodiments, R 10 、R l1 、R 12 and R 13 All are hydrogen.

[0105] In some specific embodiments, q is 1.

[0106] In some specific embodiments, p is 3.

[0107] In some specific embodiments, Formula (I) has the structure shown in Formula (IA):

[0108] Among them, R 1 、R 2 、R 14 , q are defined as described above.

[0109] In some specific embodiments, Formula (I) has the structure shown in Formula (IA-1):

[0110] Among them, R 1 、R 2 、R 14 Definitions are each as defined above.

[0111] In some specific embodiments, Formula (I) has the structure shown in Formula (IA'):

[0112] Among them, R 1 、R 2 、R 14 , q are defined as described above.

[0113] In some specific embodiments, formula (I) has the structure shown in formula (IA'-1):

[0114] Among them, R 1 、R 2 、R 14 The definitions are each as described for formula (I).

[0115] As exemplary compounds, the compounds represented by formula (I) of the present invention include:

[0116] The term "pharmaceutically acceptable salt" refers to salts of the compounds of the present invention, prepared by reacting the compounds discovered herein with the specified substituents with relatively nontoxic acids or bases. When the compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting the compounds with a sufficient amount of base in neat solution or in a suitable inert solvent. When the compounds of the present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting the compounds with a sufficient amount of acid in neat solution or in a suitable inert solvent.

[0117] The term "prodrug" refers to derivatives of the compound represented by formula (I) with specific substituents discovered in the present invention. They themselves may have weak activity or even no activity, but after administration, they are converted into the compound with specific substituents discovered in the present invention under physiological conditions (for example, by metabolism, solvent decomposition or other means) and produce corresponding biological activity in the body.

[0118] The term "metabolite" refers to a product obtained by in vivo metabolism of a compound of formula (I) having specific substituents discovered by the present invention. Metabolites of a compound can be identified by techniques known in the art, and their activity can be characterized by assays as described herein. Such products can be obtained by administering the compound through oxidation, reduction, hydrolysis, amidation, deamidation, esterification, defatting, enzymatic cleavage, and the like. Accordingly, the present invention includes metabolites of the compound, including metabolites produced by contacting the compound of the present invention with a mammal for a sufficient period of time.

[0119] The term "deuterated compound" refers to a compound of the present invention that includes at least one deuterium atom, specifically one or more hydrogen atoms in a compound of the present invention that can be replaced or substituted with a deuterium atom. In some embodiments, the compound includes two or more deuterium atoms. In some embodiments, the compound includes 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 deuterium atoms. Synthetic methods for incorporating isotopes into organic compounds are known in the art.

[0120] Preparation method:

[0121] The present invention also provides a method for preparing the compound. The preparation of the compound described in the general formula (I) of the present invention can be completed by the following illustrative methods and examples, but these methods and examples should not be considered in any way to limit the scope of the present invention. The compound described in the present invention can also be synthesized by synthetic techniques known to those skilled in the art, or a combination of synthetic methods known in the art and the method described in the present invention. The product obtained by each step of the reaction is obtained using separation techniques known in the art, including but not limited to extraction, filtration, distillation, crystallization, chromatographic separation, etc. The starting materials and chemical reagents required for the synthesis can be conventionally synthesized according to the literature (such as provided by Scifinder) or purchased.

[0122] The compound of the general formula (I) of the present invention can be synthesized according to the following method:

[0123] Route 1:

[0124] 1) Step 1: Raw materials A and B are dehydrated and cyclized to form intermediate C;

[0125] 2) Step 2: intermediate C is subjected to catalytic hydrogenation to obtain intermediate D;

[0126] 3) Step 3: Intermediate D is halogenated to obtain halogenated compound E;

[0127] 4) Step 4: hydrolyzing the ester group of the halide E to obtain the carboxylic acid F;

[0128] 5) Step 5: Carboxylic acid F and R 2 NH2 condenses to form amide G;

[0129] 6) Step 6: Amide G is reduced to obtain intermediate H;

[0130] 7) Step 7: Intermediate H is subjected to reductive amination to obtain intermediate I;

[0131] 8) Step 8: Removal of the protective group PG from intermediate I 1 Obtain primary amine J;

[0132] 9) Step 9: Primary amine J undergoes substitution reaction to obtain intermediate K;

[0133] 10) Step 10: The ester group of intermediate K is hydrolyzed to obtain a compound of formula (I-x1).

[0134] Among them, W, PG 2 is methyl, ethyl, benzyl or p-methoxybenzyl; X is F, Cl, Br or I; PG 1 is tert-butoxycarbonyl or benzyloxycarbonyl; R 1 、R 2 、R10 、R 11 、R 12 、R 13 、R 15 、R 16 , p are each defined as described herein.

[0135] Route 2:

[0136] 1) Step 1: Intermediate D is subjected to coupling reaction to obtain intermediate L;

[0137] 2) Step 2: hydrolyzing the ester group of intermediate L to obtain carboxylic acid M;

[0138] 3) Step 3: Carboxylic acid M and R 2 NH2 condenses to form amide N;

[0139] 4) Step 4: Amide N is reduced to obtain intermediate O;

[0140] 5) Step 5: Intermediate O is subjected to reductive amination to obtain intermediate P;

[0141] 6) Step 6: Removal of the protective group PG from the intermediate P 1 Obtain primary amine Q;

[0142] 7) Step 7: Primary amine Q undergoes substitution reaction to obtain intermediate R;

[0143] 8) Step 8: The ester group of the intermediate R is hydrolyzed to obtain a compound of formula (Ix).

[0144] Among them, W, PG 2 is methyl, ethyl, benzyl or p-methoxybenzyl; X is Cl, Br or I; PG 1 is tert-butoxycarbonyl or benzyloxycarbonyl; R 1 、R 2 、R 10 、R 11 、R 12 、R 13 、R 14 、R 15 、R 16 , p are each defined as described in formula (Ix).

[0145] Pharmaceutical composition

[0146] The present invention also provides a pharmaceutical composition comprising the aforementioned compound, its stereoisomers, tautomers, polymorphs, cocrystals, solvates, metabolites, prodrugs, deuterated compounds or pharmaceutically acceptable salts, and optional pharmaceutical adjuvants.

[0147] In some embodiments, the pharmaceutical composition may further comprise other drugs for treating and / or preventing diseases associated with the biological activity of αvβ1 and / or αvβ6.

[0148] Methods for preparing various pharmaceutical compositions containing a certain amount of active ingredient are known or will be apparent to those skilled in the art based on the disclosure of the present invention. As described in REMINGTON'S PHARMACEUTICAL SCIENCES, Martin, EW, ed., Mack Publishing Company, 19th ed. (1995), the method for preparing the pharmaceutical composition includes incorporating appropriate pharmaceutical excipients, carriers, diluents, etc.

[0149] Medical uses

[0150] The present invention also provides the aforementioned compounds, their stereoisomers, tautomers, polymorphs, cocrystals, solvates, metabolites, prodrugs, deuterated compounds or pharmaceutically acceptable salts, or the aforementioned pharmaceutical compositions, for use in treating and / or preventing diseases associated with the biological activity of αvβ1 or / and αvβ6.

[0151] The present invention also provides the use of the aforementioned compounds, their stereoisomers, tautomers, polymorphs, cocrystals, solvates, metabolites, prodrugs, deuterated compounds or pharmaceutically acceptable salts, or the aforementioned pharmaceutical compositions, in the preparation of medicaments for treating and / or preventing diseases associated with the biological activity of αvβ1 and / or αvβ6.

[0152] The present invention also provides the use of the aforementioned compounds, their stereoisomers, tautomers, polymorphs, cocrystals, solvates, metabolites, prodrugs, deuterated compounds or pharmaceutically acceptable salts, or the aforementioned pharmaceutical compositions, in the treatment and / or prevention of diseases associated with the biological activity of αvβ1 or / and αvβ6.

[0153] The present invention also provides a method for treating and / or preventing diseases associated with the biological activity of αvβ1 or / and αvβ6, comprising administering to an individual in need thereof a therapeutically / preventively effective amount of the aforementioned compound, its stereoisomers, tautomers, polymorphs, cocrystals, solvates, metabolites, prodrugs, deuterated compounds or pharmaceutically acceptable salts, or the aforementioned pharmaceutical composition.

[0154] In some embodiments, herein, the disease associated with the biological activity of αvβ1 or / and αvβ6 is selected from fibrotic diseases.

[0155] As used herein, "treat" generally refers to obtaining a desired pharmacological and / or physiological effect. This effect can be prophylactic, in terms of completely or partially preventing a disease or its symptoms; and / or therapeutic, in terms of partially or completely stabilizing or curing a disease and / or causing side effects due to the disease. As used herein, "treat" encompasses any treatment of a disease in a patient, including: (a) preventing the onset of a disease or symptom in a patient who is susceptible to the disease or symptom but has not yet been diagnosed with the disease; (b) suppressing the symptoms of a disease, i.e., arresting its development; or (c) alleviating the symptoms of a disease, i.e., causing the disease or symptom to regress.

[0156] In the present invention, "subject" / "individual in need thereof" refers to a vertebrate. In certain embodiments, a vertebrate refers to a mammal. Mammals include, but are not limited to, livestock (such as cattle), pets (such as cats, dogs, and horses), primates, mice, and rats. In certain embodiments, a mammal refers to a human.

[0157] In the present invention, an "effective amount" refers to an amount that is effective at the necessary dosage and time to achieve the desired therapeutic or preventive effect. The "therapeutically effective amount" of a substance / molecule of the present invention may vary according to factors such as the disease state, age, sex, and weight of the individual and the ability of the substance / molecule to elicit the desired response in the individual. A therapeutically effective amount also encompasses an amount in which the therapeutically beneficial effects of the substance / molecule outweigh any toxic or deleterious consequences. A "prophylactically effective amount" refers to an amount that is effective at the necessary dosage and time to achieve the desired preventive effect. Typically, but not necessarily, a prophylactic effective amount will be lower than a therapeutically effective amount because a prophylactic dose is administered to a subject prior to the onset of disease or in the early stages of the disease.

[0158] Definition of terms:

[0159] According to the common practice in this field, The bonds used in the formulae herein to describe the points of attachment of the moiety or substituent to the parent core or structure.

[0160] A dash "-" that does not appear between two letters or symbols is used to indicate the point of attachment of a substituent. For example, C3-C6 cycloalkyl-(C1-C6 alkyl) r - means (C1-C6 alkyl) r - connected to the rest of the molecule.

[0161] As used herein, the term "substituted" means that any one or more hydrogens on a designated atom or group are replaced with the selection of a designated group, provided that the normal valence of the designated atom is not exceeded.

[0162] In various parts of this specification, substituents of compounds disclosed herein are disclosed in terms of group types or ranges. It is specifically noted that the present invention includes every independent subcombination of the individual members of these group types and ranges. For example, the term "C 1-6 "Alkyl" specifically refers to methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl and C6 alkyl disclosed independently, or "C 1-4 Alkyl", or independently disclosed "C 1-3 alkyl".

[0163] The term "alkyl" is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. For example, "C 1-6 "Alkyl" refers to C1, C2, C3, C4, C5 and C6. In addition, for example, "C 1-6 "Alkyl" refers to an alkyl group having 1 to 6 carbon atoms. An alkyl group can be unsubstituted or substituted such that one or more of its hydrogen atoms are replaced by another chemical group. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, tert-butyl), pentyl (e.g., n-pentyl, isopentyl, neopentyl), and the like.

[0164] The term "alkoxy" refers to any of the above alkyl groups (e.g., C 1-6 Alkyl, C 1-4 Alkyl, C 1-3 alkyl, etc.), which is attached to the rest of the molecule through an oxygen atom (—O—).

[0165] The term "halogenated C 1-6 Alkyl" or "halogenated C 1-6 "Alkoxy" refers to an alkyl or alkoxy group in which one or more (such as 2 or 3) hydrogen atoms are replaced by halogen atoms, such as fluorine, chlorine, or bromine. The alkyl or alkoxy group is defined as above. In some embodiments, the term "halogenated C 1-6 "Alkyl" is preferably fluorinated, for example, -CF3, -CHF2, -CH2F, -CH2CH2F, -CH2CHF2, -CH2CF3, etc. In some embodiments, the term "halogenated C 1-6 The "alkoxy" is preferably fluorinated, for example, it can be -OCF3, -OCHF2, -OCH2F, -OCH2CH2F, -OCH2CHF2, -OCH2CF3, etc.

[0166] The term "hydroxy substituted C 1-6 "C alkyl" means that one of the hydrogen atoms in the alkyl group is replaced by a hydroxyl group, and the definition of the alkyl group is as described above. As an example, the "C alkyl group substituted by a hydroxyl group" 1-6 The "alkyl" may be a hydroxymethyl group.

[0167] The term "alkenyl" refers to a hydrocarbon group including straight or branched configurations and having one or more carbon-carbon double bonds which may be present at any stable point along the chain. For example, "C 2-6 The term "alkenyl" is intended to include C2, C3, C4, C5 and C6. Examples of alkenyl groups include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-methyl-2-propenyl, 4-methyl-3-pentenyl, and the like.

[0168] The term "alkynyl" refers to hydrocarbon groups including straight or branched configurations and having one or more carbon-carbon triple bonds that may be present at any stable point along the chain. For example, "C 2-6 The term "alkynyl" is intended to include C2, C3, C4, C5 and C6 alkynyl groups. Examples of alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like.

[0169] The term "cycloalkyl" refers to a cyclized alkyl group, including monocyclic, bicyclic or polycyclic ring systems. When the cycloalkyl group is bicyclic or polycyclic, each ring should be a saturated carbocyclic ring or a carbocyclic ring residue. The two rings of the bicyclic or polycyclic cycloalkyl group can be connected in a manner including bridging, fusion or spiro connection. For example, C 3-10 Cycloalkyl refers to C3, C4, C5, C6, C7, C8, C9 and C 10 Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, wait.

[0170] The term "cycloalkyloxy" refers to any of the above cycloalkyl groups (e.g., C 3-6 cycloalkyl, cyclopropyl, cyclobutyl, cyclopentyl, etc.), which is attached to the rest of the molecule through an oxygen atom (—O—).

[0171] The term "cycloalkenyl" refers to a cyclized alkenyl group, including monocyclic, bicyclic, or polycyclic ring systems. When the cycloalkenyl group is bicyclic or polycyclic, the fused rings completing the bicyclic and tricyclic groups may be saturated, partially saturated, or fully unsaturated, aromatic or non-aromatic carbocyclic rings or carbocyclic residues. The two rings of the bicyclic or polycyclic cycloalkenyl group may be connected in various ways, including bridged, fused, or spiro-connected.

[0172] The term "carbocycle" or "carbocycle residue" refers to any stable 3-, 4-, 5-, 6- or 7-membered monocyclic ring or 5-, 6-, 7-, 8-, 9-, 10-, 11-, 12-, 13- or 14-membered bicyclic or polycyclic ring, any one of which may be saturated, partially saturated, unsaturated or aromatic. The bicyclic or polycyclic carbocycles may be connected in a manner such as bridging, fusion or spiro. Examples of these carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptenyl, cycloheptyl, adamantyl, cyclooctyl, phenyl, naphthyl, [2,2,2]bicyclooctane, wait.

[0173] The term "aryl" refers to a monocyclic, bicyclic, or tricyclic aromatic hydrocarbon group having 5 to 14 carbon atoms in the ring portion. When the "aryl" group is bicyclic or tricyclic, each ring is aromatic. The two rings of the bicyclic or tricyclic aryl group can be connected in a manner including bridging, fusion, and spiro connection. Examples include phenyl and naphthyl, each of which can be substituted.

[0174] The terms "heterocycle," "heterocyclic," or "heterocyclyl" are used interchangeably and refer to substituted and unsubstituted 4-14 membered monocyclic, bicyclic, tricyclic, or polycyclic groups, wherein at least one ring has at least one heteroatom (O, S, or N), preferably 1, 2, or 3 heteroatoms selected from O, S, and N. Each heteroatom-containing ring in the group may contain 1 or 2 oxygen or sulfur atoms and / or 1 to 4 nitrogen atoms, provided that the total number of heteroatoms in each ring is 4 or less, and further provided that the ring contains at least one carbon atom. In some embodiments herein, the heteroatom is exclusively N or O, and the total number does not exceed 3, preferably only 1-2 heteroatoms. The carbon and sulfur atoms may be optionally oxidized, the nitrogen atoms may be optionally quaternized, and when valence permits, the ring atoms in the heterocycle may be optionally substituted with =O (oxo) (e.g., ). The fused rings completing the bicyclic and tricyclic groups may contain only carbon atoms and may be saturated, partially saturated or fully unsaturated, aromatic or non-aromatic; the limitation being that in the bicyclic or polycyclic heterocyclic group, at least one ring is non-aromatic and at least one ring has at least one heteroatom (O, S or N). The heterocyclic group may be attached on any available nitrogen or carbon atom. In some embodiments herein, the fused rings completing the bicyclic and tricyclic groups are non-aromatic, i.e., all rings in the bicyclic or polycyclic heterocyclic group are non-aromatic, such as 5-6-membered heterocycloalkyl and 5-6-membered heterocycloalkyl, 5-6-membered heterocycloalkyl and 5-6-membered heterocycloalkenyl, 5-6-membered heterocycloalkyl and 5-6-membered heterocycloalkynyl, 5-6-membered heterocycloalkyl and C 5-6In some specific embodiments of the present invention, the fused ring of the heterocyclic group to complete the bicyclic and tricyclic groups is an aromatic ring, that is, there are 1 or 2 aromatic rings in the bicyclic or polycyclic heterocyclic group; such as 5-6 membered heteroaryl and 5-6 membered heterocyclic group, phenyl and 5-6 membered heterocyclic group, 5-6 membered heteroaryl and C 5-6 cycloalkyl;Herein, the 5-6 membered heterocyclyl can be a 5-6 membered heterocyclyl, a 5-6 membered heterocyclyl or a 5-6 membered heterocyclylalkynyl. As previously described, heterocyclyl includes "spiroheterocycloalkyl", "heterobridged cycloalkyl" and "heterocycloalkenyl" as described below. Exemplary heterocyclyls include, but are not limited to, azetidinyl, oxetanyl, pyrrolidinyl, imidazolinyl, oxazolidinyl, isoxazolinyl, thiazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxazacycloheptatrienyl, 1-pyridonyl, 4-piperidonyl, tetrahydropyranyl, morpholinyl, 1,3-dioxolane, quinuclidine, wait.

[0175] The term "saturated heterocyclic group" or "heterocycloalkyl" refers to the above-mentioned "heterocyclic group" in which the monocyclic group, bicyclic group, or tricyclic group is completely saturated. The "heterocyclic group" is defined as above. As an example, the saturated heterocyclic group can be morpholinyl (such as ), piperidinyl (such as ), piperazinyl etc.

[0176] The term "heterocycloalkenyl" refers to a monocyclic, bicyclic or polycyclic ring system in which at least one ring of the "cycloalkenyl" group as defined above has at least one heteroatom (O, S or N), and the heteroatom-containing ring preferably has 1, 2, 3 or 4 heteroatoms selected from O, S and N. Each heteroatom-containing ring in the group may contain 1 or 2 oxygen or sulfur atoms and / or 1 to 4 nitrogen atoms, provided that the total number of heteroatoms in each ring is 4 or less, and further provided that the ring contains at least one carbon atom. In some preferred embodiments, the heteroatom refers only to N or O, and the total number does not exceed 3, preferably only 1-2 heteroatoms, for example

[0177] The term "heteroaryl" refers to substituted and unsubstituted aryl groups described above having at least one heteroatom (O, N, or S) in at least one ring, including aromatic 5-6 membered monocyclic groups, 8-10 membered bicyclic groups, and 11-14 membered tricyclic groups, wherein the heteroatom-containing ring preferably has 1, 2, or 3 heteroatoms selected from O, N, or S. Each heteroatom-containing ring of the heteroaryl group may contain 1 or 2 oxygen or sulfur atoms and / or 1 to 4 nitrogen atoms, provided that the total number of heteroatoms in each ring is 4 or less and each ring has at least one carbon atom. Each ring of the heteroaryl group that is bicyclic or tricyclic herein is an aromatic ring.

[0178] The term "spirocyclyl" refers to a bicyclic structure having one common ring atom, wherein each monocyclic ring is a saturated or unsaturated, aromatic or non-aromatic carbocyclic ring having 3-7 carbon atoms. Exemplary spiroalkyl groups include, but are not limited to, spiro[4.5]decane, spiro[3.4]octane, spiro[2.3]hexane, Herein, the spirocyclic group does not include the aryl group defined above.

[0179] The term "spiroalkyl" refers to a "spirocyclyl" as defined above in which each single ring is fully saturated. Exemplary spiroalkyls include, but are not limited to, spiro[4.5]decane, spiro[3.4]octane, and spiro[2.3]hexane.

[0180] The term "spiroheterocyclyl" refers to a bicyclic structure having one common ring atom, wherein each monocyclic ring is a saturated or unsaturated monocyclic group having 3 to 8 ring atoms, wherein at least one ring has 1 or 2 ring atoms selected from N, O or S(O) n wherein n is an integer from 0 to 2 and the remaining ring atoms are C. In addition, one or two ring carbon atoms in the heterocyclyl ring may optionally be replaced by a -CO- group. Exemplary spiroheterocyclyls include, but are not limited to, 5-azaspiro[2.3]hexane and 6-oxaspiro[3.4]-7-octanone. As used herein, the spiroheterocyclyl group does not include heteroaryl groups as defined above.

[0181] The term "spiroheterocycloalkyl" refers to a "spiroheterocyclyl" as defined above in which each monocyclic ring is fully saturated. Exemplary spiroheterocycloalkyls include, but are not limited to:

[0182] The term "bridged ring group" refers to a saturated or unsaturated, aromatic or non-aromatic 3- to 8-membered monocyclic carbocyclic group in which two non-adjacent ring atoms are connected by (CRR) n group, C2-C6 alkenyl, C2-C6 alkynyl or bond connection, wherein n is an integer from 1 to 3, and each R is independently H or methyl (wherein, (CRR) nA bridged cyclic group is optionally substituted with one or two substituents independently selected from alkyl, halogen, alkoxy, hydroxyl or cyano, wherein each of alkyl, alkoxy, alkenyl and alkynyl is defined as above. Examples of bridged cyclic groups include, but are not limited to, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane and the like. It should be understood that when two non-adjacent ring atoms of a monocyclic 4 to 7 membered hydrocarbon group are connected by a bond, the "bridged cyclic alkyl" may be referred to as a "bicycloalkyl" or "fused cycloalkyl". As used herein, the bridged cyclic group does not include an aryl group as defined above.

[0183] The term "bridged cycloalkyl" refers to a "bridged cycloalkyl" as defined above wherein each ring is saturated, where saturated means that each ring carbon atom in the bridged cycloalkyl is saturated (including the carbon atoms in the bridging group).

[0184] The term "heterobridged cyclic group" refers to a "bridged cyclic group" as defined above, wherein one, two, three or four ring carbon atoms (including the carbon atoms in the bridging group) are replaced by heteroatoms selected from N, O or S(O)n, wherein n is an integer from 0 to 2. Examples of "heterobridged cyclic groups" include, but are not limited to, 2-azabicyclo[2.2.2]octane, quinuclidine, 7-oxabicyclo[2.2.1]heptane, and the like. Herein, the heterobridged cyclic group does not include heteroaryl groups as defined above.

[0185] The term "heterobridged cycloalkyl" refers to a "heterobridged cyclic group" as defined above in which each ring is saturated, where saturation is understood to mean that each ring carbon atom in the bridged cyclic group is saturated (including the carbon atoms in the bridging group).

[0186] Unless otherwise indicated, when referring to a specifically named aryl (e.g., phenyl), cycloalkyl (e.g., cyclohexyl), heterocycle (e.g., pyrrolidinyl, piperidinyl, morpholinyl) or heteroaryl (e.g., imidazolyl, pyrazolyl, triazolyl) group, the reference is meant to include the ring having 0 to 3, preferably 0 to 2, substituents optionally selected from the substituents described above for aryl, cycloalkyl, heterocycle and / or heteroaryl groups.

[0187] The term "heteroatom" shall include oxygen, sulfur and nitrogen.

[0188] The term "oxo" refers to =0;

[0189] The term "halogen" shall include "F, Cl, Br, I".

[0190] When the term "unsaturated" is used herein to refer to a ring or group, the ring or group may be fully unsaturated or partially unsaturated.

[0191] When the term "saturated" is used herein to refer to a ring or group, unless otherwise specified, the ring or group shall be fully saturated.

[0192] From all the above descriptions, it is obvious to those skilled in the art that any group whose name is a composite name, such as "C 3-10 Cycloalkyl-C(O)-" shall mean a moiety conventionally derived therefrom, e.g., from a C 3-10 The cycloalkyl group is constructed by a carbonyl group substituted by a cycloalkyl group, wherein the cycloalkyl group is as defined above. Other similar compound names can be understood by referring to the above content.

[0193] From all the above descriptions, it is obvious to those skilled in the art that any group whose name is a composite name, such as "C 3-10 Cycloalkyl-C(O)-" shall mean a moiety conventionally derived therefrom, e.g., from a C 3-10 The cycloalkyl group is constructed by a carbonyl group substituted by a cycloalkyl group, wherein the cycloalkyl group is as defined above. Other similar compound names can be understood by referring to the above content.

[0194] The term "optionally" means that it can be selected or not. For example, "optionally 1 to 3 R d Substituted C 1- 6 alkyl", which means that the C 1-6 The alkyl group may be substituted with 1 to 3 R d It may be replaced by 1 to 3 R d Other similar definitions can be understood with reference to the above content.

[0195] The term "the ring atoms of the heterocyclic group may be optionally substituted with oxo" means that the ring atoms of the heterocyclic ring may be optionally substituted with =O(oxo) (for example: The ring atom CH2 undergoes oxygenation to obtain the group ).

[0196] Throughout the specification, groups and substituents thereof may be selected by one skilled in the art to provide stable structural units and / or compounds, as well as compounds useful as pharmaceutically acceptable compounds and / or intermediates useful in preparing pharmaceutically acceptable compounds.

[0197] Herein, unless otherwise expressly stated, the description “…are independently selected from” used throughout this document may mean that in different groups, the specific options expressed by the same or different symbols do not affect each other, or that in the same group, the specific options expressed by the same or different symbols do not affect each other.

[0198] Effects of the invention:

[0199] The compound of the present invention has excellent αvβ1 / αvβ6 dual inhibitory activity and has weaker αvβ3, αvβ5, and αvβ8 inhibitory effects than PLN-74809.

[0200] Furthermore, the compound of the present invention has better exposure in mouse plasma, liver, kidney, lung and other tissues than Yangshen PLN-74809, and has potential application value in diseases related to fibrosis of organs such as liver, kidney and lung.

[0201] Furthermore, the present invention also demonstrates through in vivo animal experiments that the compound of the present invention has a more excellent effect of reducing the expression of fibrosis-related genes than Yangshen PLN-74809, showing a more excellent anti-fibrosis effect. DETAILED DESCRIPTION

[0202] It should be understood that the terminology used herein is intended to describe specific embodiments and is not intended to be limiting. In addition, although any method, device, and material similar or equivalent to those described herein may be used for implementing or testing the present invention, preferred methods, devices, and materials are now described.

[0203] The structures of the compounds were determined by nuclear magnetic resonance (NMR) or mass spectrometry (MS). NMR measurements were performed using a Bruker ASCENA-400 NMR spectrometer. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD). The internal standard was tetramethylsilane (TMS). Chemical shifts were calculated based on a 10 - 6 The units are given in ppm.

[0204] Reaction monitoring and MS measurements were performed using a Thermofisher ESQ (ESI) mass spectrometer.

[0205] HPLC determination was performed using a Thermo Fisher U3000 DAD high pressure liquid chromatograph (GL Sciences ODS-HL HP 3 μm 3.0*100 mm column).

[0206] Qingdao Ocean GF254 silica gel plates were used for thin-layer chromatography (TLC). Silica gel plates with a size of 0.15-0.2 mm were used for thin-layer chromatography (TLC). High-performance thin-layer chromatography (HPLC) preparative plates with a size of 0.9-1.0 mm were used for TLC separation and purification. Column chromatography used Qingdao Ocean 200-300 mesh silica gel as the carrier. The developing solvents used were A: dichloromethane and methanol; B: petroleum ether and ethyl acetate. The solvent volume ratio was adjusted according to the polarity of the compound. A Biotage Isera One preparative liquid phase was used for medium-pressure preparative liquid chromatography (HPLC). An Agilent 1290 Infinity II preparative liquid chromatograph was used.

[0207] In the following examples, unless otherwise specified, all reaction raw materials can be purchased from manufacturers such as San Chemical Technology (Shanghai) Co., Ltd., Shanghai Shaoyuan Reagent Co., Ltd., Nanjing Yaoshi Technology Co., Ltd., Jiangsu Aikon Biopharmaceutical R&D Co., Ltd., and Shanghai Bid Pharmaceutical Technology Co., Ltd.

[0208] Abbreviated description

[0209] int-1(S)-2-((tert-Butoxycarbonyl)amino)-4-oxobutanoic acid methyl ester

[0210] Step 1: Compound int-1a (5 g, 22.81 mmol) was placed in a 250 mL eggplant-shaped flask. 30 mL of tetrahydrofuran solution was added, followed by iodomethane (1.69 mL, 27.31 mmol), and then tetrabutylammonium fluoride hydrate (7.1 g, 27.31 mmol). The mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated and purified by column chromatography (PE:EA = 1:1) to obtain compound int-1b (3.4 g, 14.57 mmol, 64% yield). 1 H NMR (400MHz, DMSO-d6) δ7.15(s,1H),4.57(s,1H),4.14-4.08(m,1H),3.63(s,3H),1.85–1.67(m,2H),1.39(s,9H).

[0211] Step 2: Oxalyl chloride (0.79 mL, 9.43 mmol) was added to DCM (10 mL), cooled to -78°C, and then DMSO (1.34 mL, 18.86 mmol) was added. The mixture was stirred at this temperature for 20 minutes, followed by the addition of a DCM solution of int-1b (1.1 g, 4.71 mmol). The mixture was stirred at this temperature for 1 hour, followed by the addition of triethylamine (1.48 mL, 10.72 mmol). The mixture was stirred at this temperature for 20 minutes, and then slowly returned to room temperature and stirred for 3 hours. The reaction system was washed with aqueous hydrochloric acid (1N), and the organic layer was dried and concentrated to give the crude product of int-1 (740 mg, 3.20 mmol, 67.9% yield), which was directly reacted in the next step without further purification.

[0212] int-2 4-(3-chloro-5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)-N-(2-methoxyethyl)butan-1-amine

[0213] Step 1: Add compound int-2a (5 g, 31.61 mmol), 2-aminopyridine-3-carboxaldehyde (3.9 g, 31.61 mmol), L-proline (1.8 g, 15.80 mmol), and ethanol (50 mL) to a 250 mL reaction flask and reflux with stirring at 80°C overnight. The reaction solution was concentrated, and the residue was purified by flash column chromatography (PE:EA = 1:1) to obtain compound int-2b (5.3 g, 21.69 mmol, 68.6%). MS Calcd: 244.12; MS Found: 245.13 ([M+H] + ).

[0214] Step 2: Add compound int-2b (4.5 g, 18.42 mmol), methanol (50 mL), and 10% palladium / C (0.45 g, 4.23 mmol) to a 250 mL eggplant flask and stir overnight at room temperature under a hydrogen atmosphere. Filter through celite while hot and concentrate the filtrate to obtain crude int-2c (4.5 g, 18.12 mmol, 98.4%) for use in the next reaction. MS Calcd: 248.15; MS Found: 249.19 ([M+H] + )

[0215] Step 3: Int-2c (1.0 g, 4.03 mmol), acetonitrile (20 mL), and NCS (806.5 mg, 6.04 mmol) were added to a 50 mL eggplant flask and stirred overnight at room temperature. The reaction mixture was concentrated, and the residue was purified by flash column chromatography (DCM:CH3OH = 50:1) to obtain int-2d (764.6 mg, 2.70 mmol, 67.1%). MS Calcd: 282.11; MS Found: 283.10 ([M+H] + ).

[0216] Step 4: At room temperature, add a solution of lithium hydroxide (594.1 mg, 14.14 mmol) in water (4 mL) to a solution of int-2d (800 mg, 2.83 mmol) in tetrahydrofuran (20 mL) and stir overnight. Concentrate the reaction mixture, adjust the remaining aqueous phase to pH 6 with dilute hydrochloric acid, concentrate, and use in the next reaction. This yields compound int-2e (612.6 mg, 2.41 mmol, 85.0%). MS Calcd: 254.08; MS Found: 255.04 ([M+H] + ).

[0217] Step 5: Compound int-2e (600 mg, 2.36 mmol), DMF (10 mL), 2-methoxyethane-1-amine (0.31 mL, 3.53 mmol), DIPEA (1.17 mL, 7.07 mmol), and HATU (1342.8 mg, 3.53 mmol) were added to a 50 mL eggplant flask and stirred at room temperature for 2 hours. The reaction solution was poured into 100 mL of water, extracted with EA (3*100 mL), concentrated, and the residue was washed with sodium chloride aqueous solution (2*100 mL). The organic phase was concentrated and flash column chromatography (PE:EA=6:1) was performed to obtain compound int-2f (396.2 mg, 1.27 mmol, 53.9%). MS Calcd: 311.14; MS Found: 312.10 ([M+H] + ).

[0218] Step 6: Add compound int-2f (400 mg, 1.28 mmol) and dioxane (5 mL) to a 50 mL eggplant-shaped flask. Slowly add LiAlH4 (97.5 mg, 2.57 mmol) in portions at 0°C. After addition, heat to 100°C and stir overnight. Add 2 mL of water to quench the mixture. Then add 2 mL of 15% aqueous sodium hydroxide solution and 4 mL of water. Stir for half an hour, filter, and dry the filtrate through a column (DCM:CH3OH = 50:1). The title compound int-2 (62.7 mg, 0.21 mmol, 32.8%) was obtained. MS Calcd: 297.16; MS Found: 298.23 ([M+H] + ).

[0219] Example 1 (S)-4-((4-(3-chloro-5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)(2-methoxyethyl)amino)-2-((2-methylquinazolin-4-yl)amino)butanoic acid (Compound 1)

[0220] Step 1: Compound int-2 (230 mg, 0.77 mmol) and compound int-1 (268 mg, 1.16 mmol) were added to methanol (3 ml), followed by sodium acetate borohydride (490 mg, 2.3 mmol). The mixture was stirred at room temperature for 3 hours and concentrated under reduced pressure. The pH of the residue was adjusted to 7 with saturated aqueous sodium bicarbonate solution, followed by extraction with DCM (5 ml x 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (DCM:MeOH = 20:1) to obtain compound 1-a (190 mg, 0.37 mmol, 48% yield). MS Calcd: 512.28; MS Found: 513.31.

[0221] Step 2: Compound 1-a (190 mg, 0.37 mmol) was added to DCM (3 ml), followed by a solution of hydrogen chloride in dioxane (3 ml). The mixture was stirred at room temperature for 2 hours and concentrated under reduced pressure. The residue was adjusted to pH 7 with saturated aqueous sodium bicarbonate solution and extracted with DCM (5 ml x 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to afford compound 1-b (140 mg, 0.34 mmol, 91% yield). MS Calcd: 412.22; MS Found: 413.24.

[0222] Step 3: Compound 1-b (70 mg, 0.17 mmol), 4-chloro-2-methylquinazoline (60 mg, 0.34 mmol), and DIPEA (88 mg, 0.68 mmol) were added to isopropanol (2 ml). The temperature was raised to 70°C and the mixture was stirred overnight. The mixture was concentrated under reduced pressure. The residue was purified by column chromatography (DCM:MeOH = 20:1) to obtain compound 1-c (51 mg, 0.09 mmol, 54% yield). MS Calcd: 554.28; MS Found: 555.31.

[0223] Step 4: Compound 1-c (51 mg, 0.09 mmol) was added to methanol (2 ml), followed by an aqueous solution of lithium hydroxide (7 mg, 0.27 mmol). The mixture was stirred for 2 hours, the pH adjusted to 7 with acetic acid, and concentrated under reduced pressure. The residue was purified by Prep-HPLC to afford compound 1 (9 mg, 0.017 mmol, 18% yield). MS Calcd: 540.26; MS Found: 541.28. 1 H NMR (400 MHz, DMSO-d6, heavy water exchange) δ 8.11 (dd, J = 8.4, 1.2 Hz, 1H), 7.74 (ddd, J = 8.2, 6.8, 1.2 Hz, 1H), 7.61 (dd, J = 8.4, 1.2 Hz, 1H), 7.46 (ddd, J = 8.4, 6.8, 1.2 Hz, 1H), 7.11 (s, 1H), 4.56 (dd, J = 6.8, 5.2 Hz, 1H), 3.54 (t,J=5.2Hz,2H),3.22-3.19(m,5H),3.14–3.02(m,2H),2.99–2.93(m,3H),2.83-2.78(m,1H),2.61-2 .54(m,4H),2.43(s,3H),2.19-2.10(m,1H),2.05–2.00(m,1H),1.73–1.67(m,2H),1.60-1.54(m,4H).

[0224] Example 2 (S)-4-((4-(3-chloro-5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)(2-methoxyethyl)amino)-2-(quinazolin-4-ylamino)butanoic acid (Compound 2)

[0225] Step 1: Compound 1-b (70 mg, 0.17 mmol), 4-chloroquinazoline (56 mg, 0.34 mmol), and DIPEA (114 mg, 0.88 mmol) were added to isopropanol (2 ml). The temperature was raised to 70°C and the mixture was stirred overnight. The mixture was concentrated under reduced pressure. The residue was purified by column chromatography (DCM:MeOH = 20:1) to obtain compound 2-a (42 mg, 0.078 mmol, 46% yield). MS Calcd: 540.26; MS Found: 541.28.

[0226] Step 2: Compound 2-a (42 mg, 0.078 mmol) was added to methanol (2 ml), followed by an aqueous solution of lithium hydroxide (8 mg, 0.3 mmol). The mixture was stirred for 2 hours, the pH adjusted to 7 with acetic acid, and concentrated under reduced pressure. The residue was purified by Prep-HPLC to afford compound 2 (7 mg, 0.013 mmol, 17% yield). MS Calcd: 526.25; MS Found: 527.28. 1 H NMR (400 MHz, DMSO-d6, heavy water exchange) δ 8.41 (s, 1H), 8.16 (dd, J = 8.4, 1.2 Hz, 1H), 7.79 (ddd, J = 8.4, 6.8, 1.2 Hz, 1H), 7.69 (dd, J = 8.4, 1.2 Hz, 1H), 7.53 (ddd, J = 8.4, 6.8, 1.2 Hz, 1H), 7.11 (s, 1H), 4.52 (t, J =6.0Hz,1H),3.51(t,J=5.6Hz,2H),3.22–3.18(m,6H),3.05–2.67(m,6H),2.59(t,J=6.4Hz,2H) ,2.54-2.51(m,1H),2.19-2.10(m,1H),2.04-1.99(m,1H),1.73–1.67(m,2H),1.57-1.53(m,4H).

[0227] Example 3 (S)-4-((2-methoxyethyl)(4-(3-methyl-5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid (Compound 3)

[0228] Step 1: Add intermediate int-2c (2 g, 8.1 mmol) to acetonitrile (20 ml), followed by NBS (1.7 g, 9.7 mmol), and stir at room temperature for 3 hours. Add saturated aqueous sodium bicarbonate solution to the reaction system, stir thoroughly, and extract with ethyl acetate (20 ml x 3). The organic layers are combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue is purified by column chromatography (EA:PE = 1:3) to obtain compound 3-a (2.1 g, 6.4 mmol, 79% yield). MS Calcd: 326.06; MS Found: 327.09

[0229] Step 2: Compound 3-a (2.1 g, 6.4 mmol), methylboronic acid (1.2 g, 19.2 mmol), Pd(dppf)Cl2 (468 mg, 0.64 mmol), and cesium carbonate (4.2 g, 12.8 mmol) were added to a mixed solvent of dioxane (20 ml) and water (6 ml). The atmosphere was replaced with nitrogen for 3 minutes, the temperature was raised to 120°C, and the mixture was stirred for 3 hours. After the reaction was complete, the mixture was concentrated under reduced pressure. The residue was purified by column chromatography (EA:PE = 1:2) to obtain compound 3-b (1.2 g, 4.6 mmol, 72% yield). MS Calcd: 262.17; MS Found: 263.19

[0230] Step 3: Compound 3-b (1.2 g, 4.6 mmol) was added to ethanol (15 ml), followed by a 4 ml solution of lithium hydroxide (331 mg, 13.8 mmol). The mixture was stirred at room temperature for 3 hours, then the pH was adjusted to 5 with citric acid, followed by a saturated aqueous sodium bicarbonate solution to pH 7. The mixture was concentrated under reduced pressure, and the residue was washed with a mixed solvent of methanol and dichloromethane (1:20), filtered, and the filtrate was concentrated under reduced pressure to give compound 3-c (910 mg, 3.9 mmol, 85% yield). MS Calcd: 234.14; MS Found: 235.16

[0231] Step 4: Compound 3-c (910 mg, 3.9 mmol), 2-methoxyethane-1-amine (439 mg, 5.9 mmol), DIPEA (1 g, 7.8 mmol), and HATU (1.5 g, 3.9 mmol) were added to DMF (10 ml) and stirred at room temperature for 3 hours. The mixture was then poured into water and extracted with EA (10 ml x 5). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (DCM:MeOH = 40:1) to give compound 3-d (810 mg, 2.8 mmol, 72% yield). MS Calcd: 291.19; MS Found: 292.21

[0232] Step 5: Compound 3-d (810 mg, 2.8 mmol) was added to dioxane (10 ml), followed by a solution of LiAlH4 in THF (8 ml, 1 N), heated to 90°C, and stirred overnight. The reaction system was cooled to 0°C, and water (0.5 ml) and an aqueous NaOH solution (0.5 ml, 1 N) were added dropwise. Then, 10 ml of methanol was added. After thorough stirring, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (DCM:MeOH = 20:1) to give compound 3-e (420 mg, 1.5 mmol, 54% yield). MS Calcd: 277.22; MS Found: 278.24

[0233] Step 6: Compound 3-e (420 mg, 1.5 mmol) and methyl (S)-2-((tert-butoxycarbonyl)amino)-4-oxobutanoate (536 mg, 2.3 mmol) were added to methanol (10 ml), followed by sodium acetate borohydride (950 mg, 4.5 mmol). The mixture was stirred at room temperature for 3 hours and concentrated under reduced pressure. The pH of the residue was adjusted to 7 with saturated aqueous sodium bicarbonate solution, followed by extraction with DCM (20 ml x 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (DCM:MeOH = 20:1) to obtain compound 3-f (410 mg, 0.83 mmol, 55% yield). MS Calcd: 492.33; MS Found: 493.35

[0234] Step 7: Compound 3-f (410 mg, 0.83 mmol) was added to DCM (3 ml), followed by a solution of hydrogen chloride in dioxane (3 ml). The mixture was stirred at room temperature for 2 hours and concentrated under reduced pressure. The residue was adjusted to pH 7 with a saturated aqueous sodium bicarbonate solution and then extracted with DCM (5 ml x 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to afford compound 3-g (310 mg, 0.79 mmol, 95% yield). MS Calcd: 392.28; MS Found: 393.31

[0235] Step 8: Compound 3-g (90 mg, 0.23 mmol), 4-chloroquinazoline (75 mg, 0.46 mmol), and DIPEA (148 mg, 1.15 mmol) were added to isopropanol (2 ml), the temperature was raised to 70°C, and the mixture was stirred overnight. The mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (DCM:MeOH = 20:1) to obtain compound 3-h (95 mg, 0.18 mmol, 79% yield). MS Calcd: 520.32; MS Found: 521.34

[0236] Step 9: Compound 3-h (95 mg, 0.18 mmol) was added to methanol (2 ml), followed by an aqueous solution of lithium hydroxide (13 mg, 0.54 mmol). The mixture was stirred for 2 hours, the pH adjusted to 7 with acetic acid, and concentrated under reduced pressure. The residue was purified by Prep-HPLC to afford compound 3 (16 mg, 0.032 mmol, 18% yield). MS Calcd: 506.30; MS Found: 507.32. 1 H NMR (400 MHz, DMSO-d6, heavy water exchange) δ 8.41 (s, 1H), 8.17 (dd, J = 8.4, 1.2 Hz, 1H), 7.81 (ddd, J = 8.4, 7.2, 1.2 Hz, 1H), 7.72–7.69 (m, 1H), 7.55 (ddd, J = 8.4, 7.2, 1.2 Hz, 1H), 7.09 (s, 1H), 4.59 (dd, J = 7.2, 4.4 Hz, 1H), 3.60 (t, J = 5.2 Hz, 2H), 3.29–2.95 (m, 13H), 2.59 (t, J = 6.0 Hz, 2H), 2.29–2.24 (m, 1H), 2.09–2.03 (m, 4H), 1.75–1.53 (m, 6H).

[0237] Example 4 (S)-4-((2-methoxyethyl)(4-(3-methyl-5-[6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(((2-methylquinazolin-4-yl)amino)butanoic acid (Compound 4)

[0238] Step 1: Compound 3-g (90 mg, 0.23 mmol), 4-chloro-2-methylquinazoline (82 mg, 0.46 mmol), and DIPEA (148 mg, 1.15 mmol) were added to isopropanol (2 ml), the temperature was raised to 70°C, and the mixture was stirred overnight. The mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (DCM:MeOH=20:1) to obtain compound 4-a (86 mg, 0.16 mmol, 70% yield). MS Calcd: 534.33; MS Found: 535.35

[0239] Step 2: Compound 4-a (86 mg, 0.16 mmol) was added to methanol (2 ml), followed by an aqueous solution of lithium hydroxide (12 mg, 0.48 mmol). The mixture was stirred for 2 hours, the pH adjusted to 7 with acetic acid, and concentrated under reduced pressure. The residue was purified by Prep-HPLC to afford compound 4 (20 mg, 0.038 mmol, 24% yield). MS Calcd: 520.32; MS Found: 521.35.1 H NMR (400 MHz, DMSO-d6, heavy water exchange) δ 8.12 (d, J = 8.4 Hz, 1H), 7.72 (ddd, J = 8.4, 6.8, 1.2 Hz, 1H), 7.60 (dd, J = 8.4, 1.2 Hz, 1H), 7.43 (ddd, J = 8.4, 6.8, 1.2 Hz, 1H), 6.93 (s, 1H), 4.59 (t, J = 6.0 Hz, 1 H),3.48(t,J=5.6Hz,2H),3.22–3.17(m,5H),2.99–2.65(m,6H),2.57(t,J=6.0Hz,2H),2.4 5-2.40(m,5H),2.16-2.09(m,1H),2.05-2.00(m,4H),1.75-1.69(m,2H),1.55-1.50(m,4H).

[0240] Example 5 (S)-4-((2-methoxyethyl)(4-(3-methyl-5-(6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(((5-(trifluoromethyl)pyrimidin-2-yl)amino)butanoic acid (Compound 5)

[0241] Step 1: Compound 3-g (90 mg, 0.23 mmol), 2-chloro-5-(trifluoromethyl)pyrimidine (84 mg, 0.46 mmol), and DIPEA (148 mg, 1.15 mmol) were added to isopropanol (2 ml). The temperature was raised to 70°C and the mixture was stirred overnight. The mixture was concentrated under reduced pressure. The residue was purified by column chromatography (DCM:MeOH = 20:1) to give compound 5-a (95 mg, 0.17 mmol, 77% yield). MS Calcd: 538.29; MS Found: 539.31.

[0242] Step 2: Compound 5-a (95 mg, 0.17 mmol) was added to methanol (2 ml), followed by an aqueous solution of lithium hydroxide (12 mg, 0.51 mmol). The mixture was stirred for 2 hours, the pH adjusted to 7 with acetic acid, and concentrated under reduced pressure. The residue was purified by Prep-HPLC to afford the title compound 5 (24 mg, 0.046 mmol, 27% yield). MS Calcd: 524.27; MS Found: 525.30. 1H NMR (400 MHz, DMSO-d6, heavy water exchange) δ 8.58 (s, 2H), 7.00 (s, 1H), 4.20 (dd, J = 6.8, 4.8 Hz, 1H), 3.53 (t, J = 5.2 Hz, 2H), 3.23-3.20 (m, 5H), 3.06-2.82 (m, 6H), 2.58 (t, J = 6.0 Hz, 2H), 2.47 (t, J = 7.2 Hz, 2H), 2.10-2.04 (m, 4H), 1.98-1.93 (m, 1H), 1.76-1.70 (m, 2H), 1.56-1.50 (m, 4H).

[0243] Example 6 (S)-4-((4-(3-cyclopropyl-5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)(2-methoxyethyl)amino)-2-(quinazolin-4-ylamino)butanoic acid (Compound 14)

[0244] Step 1: To a 100 mL eggplant-shaped flask, compound 3-a (4.2 g, 12.84 mmol) and the solvents 1,4-dioxane (30 mL) and water (6 mL) were added. 2-cyclopropyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (3.2 g, 19.25 mmol), Pd(dppf)Cl2 (0.94 g, 1.28 mmol), and potassium carbonate (5.3 g, 38.51 mmol) were then added. The atmosphere was purged with nitrogen three times and stirred at 100°C overnight. The mixture was diluted with water (30 mL) and extracted with ethyl acetate (50 mL x 3). The organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (PE:EA = 1:1) to obtain compound 14-a (2.0 g, 6.93 mmol, 54.0% yield). MS Calcd:288.18.;MS Found:289.21([M+H] + ).

[0245] Step 2: Compound 14-a (2000 mg, 6.93 mmol) and THF (20 mL) and water (4 mL) were added to a 100 mL eggplant flask. Lithium hydroxide monohydrate (1.5 g, 34.67 mmol) was then added and stirred at room temperature overnight. Dilute hydrochloric acid was added to adjust the pH to acidic. The crude product was dried under reduced pressure and then lyophilized. The crude product was washed with a mixed solution of DCM:MeOH = 20:1. The organic phase was concentrated to give compound 14-b (1.7 g, 5.22 mmol, 75.3% yield). MS Calcd: 260.15.; MS Found: 261.21 ([M+H] + ).

[0246] Step 3: Compound 14-b (1600 mg, 6.15 mmol), 2-methoxyethane-1-amine (923.2 mg, 12.29 mmol), and DMF (30 mL) were added to a 100 mL eggplant-shaped flask. HATU (3503.6 mg, 9.22 mmol) and DIPEA (3.05 mL, 18.44 mmol) were then added and stirred at room temperature for 2 hours. Water (100 mL) was added and the mixture was extracted with ethyl acetate (50 mL x 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and dried under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (DCM:MeOH = 25:1) to obtain compound 14-c (1400 mg, 4.41 mmol, 71.8% yield). MS Calcd: 317.21.; MS Found: 318.14 ([M+H] + ).

[0247] Step 4: Compound 14-c (1200 mg, 3.78 mmol) and dioxane (20 mL) were added to a 100 mL eggplant-shaped flask. A 1N solution of LiAlH4 in THF (9.45 mL, 9.45 mmol) was then added and stirred at 90°C for 5 hours. Sodium sulfate decahydrate was slowly added and stirred for 1 hour. The mixture was filtered and the solid was washed with a mixture of DCM:MeOH = 10:1. The organic phase was concentrated under reduced pressure to remove the solvent to afford compound 14-d (1050 mg, 3.47 mmol, 91.7% yield). MS Calcd: 303.23.; MS Found: 304.33 ([M+H] + ).

[0248] Step 5: Compound 14-d (1000 mg, 3.03 mmol) and methanol (20 mL) were added to a 100 mL eggplant flask, followed by the addition of intermediate int-1 (1524.1 mg, 6.59 mmol) and sodium acetate borohydride (2086.4 mg, 9.89 mmol), and the mixture was stirred at room temperature for 2 hours. Water (50 mL) was added, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and dried under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (DCM:MeOH = 20:1) to obtain compound 14-e (300 mg, 0.58 mmol, 17.5% yield). MS Calcd: 518.35.; MS Found: 519.38 ([M+H] + ).

[0249] Step 6: Compound 14-e (250 mg, 0.48 mmol) and DCM (3 mL) were added to a 50 mL eggplant flask. 4N dioxane hydrochloride solution (2 mL) was then added and stirred at room temperature for 3 hours. The solvent was evaporated to dryness under reduced pressure to give compound 14-f (190 mg, 0.45 mmol, 94.2% yield). MS Calcd: 418.29; MS Found: 419.21 ([M+H] + ).

[0250] Step 7: Compound 14-f (100 mg, 0.24 mmol) and isopropanol (2 mL) were added to a 50 mL eggplant-shaped flask. 4-Chloroquinazoline (60 mg, 0.36 mmol) and DIPEA (0.12 mL, 0.72 mmol) were then added. The mixture was stirred at 70°C overnight. Water (20 mL) was added and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and dried under reduced pressure to give a crude product. The crude product was purified by column chromatography to give compound 14-g (70 mg, 0.13 mmol, 53.6% yield). MS Calcd: 546.33; MS Found: 547.11 ([M+H] + ).

[0251] Step 8: Compound 14-g (70 mg, 0.13 mmol) and methanol (1 mL) were added to a 50 mL eggplant-shaped flask. A solution of lithium hydroxide monohydrate (26.9 mg, 0.64 mmol) in water (0.3 mL) was then added and stirred at room temperature for 2 hours. The pH was adjusted to acidic and purified by Prep-HPLC to afford the title compound 14 (11 mg, 0.02 mmol, 16.0% yield). MS Calcd: 532.32; MS Found: 533.08 ([M+H] + ). 1H NMR (400 MHz, DMSO-d6, heavy water exchange) δ 8.42 (s, 1H), 8.18 (d, J = 8.4 Hz, 1H), 7.79 (t, J = 8.0 Hz, 1H), 7.70 (d, J = 8.4 Hz, 1H), 7.53 (t, J = 8.0 Hz, 1H), 6.75 (s, 1H), 4.59-4.55 (m, 1H), 3.47 (t, J = 5.6 Hz, 2H), 3.20 (t, J = 5.6 Hz, 2H ), 3.17 (s, 3H), 2.96–2.56 (m, 11H), 2.16–1.91 (m, 2H), 1.75–1.50 (m, 6H), 0.77–0.72 (m, 2H), 0.42-0.40 (m, 2H). Example 7 (S)-4-((2-methoxyethyl)(4-(3-vinyl-5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid (Compound 43)

[0252] Step 1: Compound 3-a (3 g, 9.2 mmol), vinylboronic acid pinacol ester (2.8 g, 18.4 mmol), Pd(dppf)Cl2 (656 mg, 0.92 mmol), and potassium carbonate (3.8 g, 27.6 mmol) were added to a mixed solvent of dioxane (20 ml) and water (6 ml). The atmosphere was replaced with nitrogen for 3 minutes, the temperature was raised to 100°C, and the mixture was stirred for 3 hours. After the reaction was complete, the mixture was concentrated under reduced pressure. The residue was purified by column chromatography (EA:PE = 1:2) to obtain compound 43-a (1.4 g, 5.1 mmol, 55% yield). MS Calcd: 274.17; MS Found: 275.19.

[0253] Step 2: Compound 43-a (1.4 g, 5.1 mmol) was added to ethanol (15 ml), followed by an aqueous solution (5 ml) of lithium hydroxide monohydrate (642 mg, 15.3 mmol). The mixture was stirred at room temperature for 3 hours, then the pH was adjusted to 6 with acetic acid, followed by a saturated aqueous sodium bicarbonate solution to 7. The mixture was concentrated under reduced pressure, and the residue was washed with a mixture of methanol and dichloromethane (1:20), filtered, and the filtrate was concentrated under reduced pressure to give compound 43-b (950 mg, 3.9 mmol, 76% yield). MS Calcd: 246.14; MS Found: 247.16.

[0254] Step 3: Compound 43-b (439 mg, 5.9 mmol), 2-methoxyethyl-1-amine (886 mg, 11.8 mmol), DIPEA (1 g, 7.8 mmol), and HATU (1.5 g, 3.9 mmol) were added to DMF (10 ml) and stirred at room temperature for 3 hours. The mixture was then poured into water and extracted with EA (10 ml x 5). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (DCM:MeOH = 40:1) to give compound 43-c (860 mg, 2.8 mmol, 72% yield). MS Calcd: 303.19; MS Found: 304.21.

[0255] Step 4: Compound 43-c (860 mg, 2.8 mmol) was added to dioxane (10 ml), followed by the addition of a solution of LiAlH4 in THF (8 ml, 1 N). The temperature was raised to 100°C and stirred for 2 hours. The reaction system was cooled to 0°C, and water (0.5 ml), a 15% aqueous NaOH solution (0.5 ml), and water (1.5 ml) were added dropwise. Then, 20 ml of methanol was added. After thorough stirring, the mixture was filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (DCM:MeOH = 20:1) to afford compound 43-d (510 mg, 1.8 mmol, 63% yield). MS Calcd: 289.22; MS Found: 290.24. Step 5: Compound 43-d (510 mg, 1.8 mmol) and intermediate int-1 (416 mg, 1.8 mmol) were added to 1,2-dichloroethane (10 ml), followed by sodium acetate borohydride (1.1 g, 5.4 mmol). The mixture was stirred at room temperature for 3 hours and concentrated under reduced pressure. The pH of the residue was adjusted to 7 with saturated aqueous sodium bicarbonate solution, followed by extraction with DCM (20 ml x 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (DCM:MeOH = 20:1) to obtain compound 43-e (520 mg, 1.03 mmol, 57% yield). MS Calcd: 504.33; MS Found: 505.35.

[0256] Step 6: Compound 43-e (520 mg, 1.03 mmol) was added to DCM (5 ml), followed by a solution of hydrogen chloride in dioxane (5 ml). The mixture was stirred at room temperature for 2 hours and concentrated under reduced pressure. The pH of the residue was adjusted to 7 with saturated aqueous sodium bicarbonate solution, followed by extraction with DCM (5 ml x 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to afford compound 43-f (350 mg, 0.87 mmol, 84% yield). MS Calcd: 404.28; MS Found: 405.31.

[0257] Step 7: Compound 43-f (350 mg, 0.87 mmol) was added to methanol (5 ml), followed by an aqueous solution of lithium hydroxide monohydrate (110 mg, 2.61 mmol). The mixture was stirred for 2 hours, the pH was adjusted to 7 with acetic acid, and the mixture was concentrated under reduced pressure to obtain compound 43-g (280 mg, 0.72 mmol, 83% yield). MS Calcd: 390.26; MS Found: 391.28.

[0258] Step 8: Compound 43-g (100 mg, 0.26 mmol), 4-chloroquinazoline (85 mg, 0.52 mmol), and sodium bicarbonate (109 mg, 1.3 mmol) were added to a mixed solvent of tetrahydrofuran (2 ml) and water (0.5 ml). The temperature was raised to 70°C, and the mixture was stirred for 3 hours. The mixture was concentrated under reduced pressure, and the residue was purified by prep-HPLC to obtain the title compound 43 (13 mg, 0.025 mmol, 10% yield). MS Calcd: 518.30; MS Found: 519.32. 1 H NMR (400 MHz, DMSO-d6, heavy water exchange) δ 8.44 (s, 1H), 8.20 (dd, J = 8.2, 1.6 Hz, 1H), 7.80 (ddd, J = 8.4, 6.8, 1.6 Hz, 1H), 7.71 (d, J = 8.4 Hz, 1H), 7.54 (ddd, J = 8.4, 6.6, 1.6 Hz, 1H), 7.34 (s, 1H), 6.73 (dd, J = 16.8, 11.2 Hz, 1H), 5.41 (dd, J = 16 .8,1.6Hz,1H),4.98(dd,J=11.2,1.2Hz,1H),4.61(t,J=6.4Hz,1H),3.49(t,J=5.6Hz,2H),3.24(t,J=5.6Hz,2H ),3.18(s,3H),3.02–2.74(m,6H),2.69–2.62(m,3H),2.17–2.01(m,2H),1.78-1.72(m,2H),1.55-1.48(m,4H).

[0259] Example 8 (S)-4-((4-(3-chloro-5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)(2-methoxyethyl)amino)-2-((6-fluoro-2-methylquinazolin-4-yl)amino)butanoic acid (Compound 108)

[0260] Step 1: Compound 1-b (80 mg, 0.19 mmol) and 4-chloro-6-fluoro-2-methylquinazoline (76 mg, 0.39 mmol) were placed in a 50 mL eggplant flask and 2 mL of isopropanol was added. DIPEA (0.1 mL, 0.58 mmol) was then added and the temperature was raised to 80°C and stirred for 3 hours. The reaction solution was concentrated and purified by column chromatography (DCM:MeOH = 20:1) to give compound 108-a (68 mg, 0.12 mmol, 61% yield). MS Calcd: 572.27; MS Found: 573.02 ([M+H] + ).

[0261] Step 2: Compound 108-a (68 mg, 0.12 mmol) was added to methanol (3 mL), followed by a solution of lithium hydroxide (18.6 mg, 0.45 mmol) in water (1 mL). The mixture was stirred at room temperature for 1 hour. Glacial acetic acid was slowly added dropwise to the reaction mixture to adjust the pH to neutral. The reaction mixture was concentrated and purified by Prep-HPLC to give the title compound 108 (30 mg, 0.05 mmol, 47% yield). MS Calcd: 558.25; MS Found: 559.28 ([M+H] + ). 1 H NMR (400 MHz, DMSO-d6, heavy water exchange) δ 8.03 (dd, J = 9.6, 2.8 Hz, 1H), 7.89-7.60 (m, 2H), 7.09 (s, 1H), 4.66 (t, J = 6.0 Hz, 1H), 3.49 (t, J = 5.6 Hz, 2H), 3.23-3.19 (m, 6H), 3.00-2.90 (m, 6H), 2.89-2.58 (m, 3H), 2.42 (s, 3H), 2.17-2.08 (m, 1H), 2.00-1.95 (m, 1H), 1.74-1.68 (m, 2H), 1.54-1.49 (m, 4H).

[0262] Example 9 (S)-4-((4-(3-chloro-5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)(2-methoxyethyl)amino)-2-((7-fluoroquinazolin-4-yl)amino)butanoic acid (Compound 109)

[0263] Step 1: Compound 1-b (80 mg, 0.19 mmol) and 4-chloro-7-fluoroquinazoline (70 mg, 0.39 mmol) were placed in a 50 mL eggplant flask and 2 mL of isopropanol was added. DIPEA (0.1 mL, 0.58 mmol) was then added and the temperature was raised to 80°C and stirred for 3 hours. The reaction solution was concentrated and purified by column chromatography (DCM:MeOH = 20:1) to give compound 109-a (65 mg, 0.12 mmol, 60% yield). MS Calcd: 558.25; MS Found: 559.24 ([M+H] + ).

[0264] Step 2: Compound 109-a (65 mg, 0.12 mmol) was added to methanol (3 mL), followed by a solution of lithium hydroxide (18.6 mg, 0.45 mmol) in water (1 mL). The mixture was stirred at room temperature for 1 hour. Glacial acetic acid was slowly added dropwise to the reaction mixture to adjust the pH to neutral. The reaction mixture was concentrated and purified by Prep-HPLC to give the title compound 109 (15 mg, 0.03 mmol, 23% yield). MS Calcd: 544.24; MS Found: 545.02 ([M+H] + ). 1 H NMR (400 MHz, DMSO-d6, heavy water exchange) δ 8.42 (s, 1H), 8.33–8.29 (m, 1H), 7.43–7.38 (m, 2H), 7.10 (s, 1H), 4.60 (t, J = 6.0 Hz, 1H), 3.49 (t, J = 5.6 Hz, 2H), 3.23–3.17 (m, 6H), 3.01–2.78 (m, 6H), 2.71–2.66 (m, 1H), 2.60 (t, J = 6.0 Hz, 2H), 2.17–2.07 (m, 1H), 2.02–1.97 (m, 1H), 1.74–1.68 (m, 2H), 1.57–1.48 (m, 4H).

[0265] Example 10 (S)-2-((8-Fluoroquinazolin-4-yl)amino)-4-((2-methoxyethyl)(4-(3-methyl-5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid (Compound 110)

[0266] Step 1: Compound 3-g (1 g, 2.55 mmol) was added to methanol (10 ml), followed by the addition of an aqueous solution (5 mL) of lithium hydroxide (321 mg, 7.65 mmol). The mixture was stirred for 2 hours, the pH was adjusted to 7 with acetic acid, and the mixture was concentrated under reduced pressure to afford compound 110-a (820 mg, 2.17 mmol, 85% yield). MS Calcd: 378.26; MS Found: 379.28.

[0267] Step 2: Compound 110-a (100 mg, 0.26 mmol), 4-chloro-8-fluoroquinazoline (71 mg, 0.39 mmol), and sodium bicarbonate (97 mg, 1.2 mmol) were added to a mixed solvent of THF (2 ml) and water (0.4 ml). The temperature was raised to 70°C, and the mixture was stirred overnight. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC to obtain the title compound 110 (15 mg, 0.029 mmol, 11% yield). MS Calcd: 524.29; MS Found: 525.31. 1 H NMR (400 MHz, DMSO-d6, heavy water exchange) δ8.47 (s, 1H), 8.02 (d, J = 8.4 Hz, 1H), 7.64-7.59 (m, 1H), 7.52-7.56 (m, 1H), 6.95 (s, 1H), 4.61 (t, J = 6.0 Hz, 1H), 3.50 (t, J = 5.6 Hz, 2H), 3.22 (t, J = 5.6 Hz, 2H), 3.18 (s, 3 H),3.03-2.91(m,2H),2.88-2.79(m,3H),2.72–2.69(m,1H),2.58(t,J=6.4Hz,2H),2.45(t,J=3.2 Hz,2H),2.20-2.11(m,1H),2.08-2.03(m,1H),2.00(s,3H),1.76-1.70(m,2H),1.56-1.48(m,4H).

[0268] Example 11 (S)-2-((5-fluoroquinazolin-4-yl)amino)-4-((2-methoxyethyl)(4-(3-methyl-5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid (Compound 111)

[0269] Step 1: Compound 110-a (100 mg, 0.26 mmol), 4-chloro-5-fluoroquinazoline (71 mg, 0.39 mmol), and sodium bicarbonate (97 mg, 1.2 mmol) were added to a mixed solvent of THF (2 ml) and water (0.4 ml). The temperature was raised to 70°C, and the mixture was stirred overnight. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC to obtain the title compound 111 (13 mg, 0.025 mmol, 9.5% yield). MS Calcd: 524.29; MS Found: 525.31. 1 H NMR (400 MHz, DMSO-d6, heavy water exchange) δ 8.46 (s, 1H), 7.80-7.75 (m, 1H), 7.55 (dd, J = 8.4, 1.2 Hz, 1H), 7.37-7.32 (m, 1H), 6.99 (s, 1H), 4.33-4.30 (m, 1H), 3.55 (t, J = 5.6 Hz, 2H), 3.23 (t, J = 5.6Hz,2H),3.20(s,3H),3.15–2.95(m,4H),2.89-2.85(m,2H),2.59(t,J=6.4Hz,2H),2 .50-2.46(m,2H),2.20-2.11(m,2H),2.04(s,3H),1.77–1.72(m,2H),1.63-1.50(m,4H).

[0270] Example 12 (S)-4-((2-methoxyethyl)(4-(3-methyl-5-[6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(((5-phenylpyrimidin-4-yl)amino)butanoic acid (Compound 112)

[0271] Step 1: Compound 110-a (100 mg, 0.26 mmol), 4-chloro-5-phenylpyrimidine (74 mg, 0.39 mmol), and sodium bicarbonate (97 mg, 1.2 mmol) were added to a mixed solvent of THF (2 ml) and water (0.4 ml). The temperature was raised to 70°C, stirred overnight, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by Prep-HPLC to obtain the title compound 112 (16 mg, 0.030 mmol, 12% yield). MS Calcd: 532.32; MS Found: 533.34. 1H NMR (400 MHz, DMSO-d6, heavy water exchange) δ 8.46 (s, 1H), 8.00 (s, 1H), 7.55–7.44 (m, 5H), 6.98 (s, 1H), 4.21 (dd, J = 7.6, 3.6 Hz, 1H), 3.46 (t, J = 5.6 Hz, 2H), 3.22–3.19 (m, 5H), 3.07–2.72 (m, 6H), 2.59 (t, J = 6.4 Hz, 2H), 2.48–2.45 (m, 2H), 2.07–1.98 (m, 5H), 1.76–1.70 (m, 2H), 1.53–1.46 (m, 4H).

[0272] Example 13 (S)-2-(Furo[2,3-d]pyrimidin-4-ylamino)-4-((2-methoxyethyl)(4-(3-methyl-5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid (Compound 113)

[0273] Step 1: Compound 110-a (100 mg, 0.26 mmol), 4-chlorofuro[2,3-d]pyrimidine (60 mg, 0.39 mmol), and sodium bicarbonate (97 mg, 1.2 mmol) were added to a mixed solvent of THF (2 ml) and water (0.4 ml). The temperature was raised to 70°C, and the mixture was stirred overnight. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC to obtain the title compound 113 (12 mg, 0.024 mmol, 9.3% yield). MS Calcd: 496.28; MS Found: 497.30. 1 H NMR (400 MHz, DMSO-d6, heavy water exchange) δ 8.21 (s, 1H), 7.78 (d, J = 2.4 Hz, 1H), 7.11 (d, J = 2.4 Hz, 1H), 6.95 (s, 1H), 4.58 (s, 1H), 3.46 (t, J = 5.6 Hz, 2H), 3.22 (t, J = 5.6 Hz, 2H), 3.19 (s, 3H), 2.94–2.64 (m, 6H), 2.59 (t, J = 6.4 Hz, 2H), 2.43 (d, J = 7.2 Hz, 2H), 2.09–2.02 (m, 4H), 1.98–1.89 (m, 1H), 1.78–1.72 (m, 2H), and 1.53–1.46 (m, 4H).

[0274] Example 14 (S)-4-((2-methoxyethyl)(4-(3-methyl-5-[6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(thieno[2,3-d]pyrimidin-4-ylamino)butanoic acid (Compound 114)

[0275] Step 1: Compound 110-a (100 mg, 0.26 mmol), 4-chlorothienyl[2,3-d]pyrimidine (66 mg, 0.39 mmol), and sodium bicarbonate (97 mg, 1.2 mmol) were added to a mixed solvent of THF (2 ml) and water (0.4 ml). The temperature was raised to 70°C, and the mixture was stirred overnight. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC to obtain the title compound 114 (17 mg, 0.033 mmol, 13% yield). MS Calcd: 512.26; MS Found: 513.28. 1 H NMR (400 MHz, DMSO-d6, heavy water exchange) δ 8.31 (s, 1H), 7.65 (d, J = 6.0 Hz, 1H), 7.57 (d, J = 6.0 Hz, 1H), 6.95 (s, 1H), 4.61 (t, J = 6.4 Hz, 1H), 3.47 (t, J = 5.6 Hz, 2H), 3.22 (t, J = 5.6 Hz, 2H) ,3.18(s,3H),2.98–2.64(m,6H),2.59(d,J=6.4Hz,2H),2.43(d,J=7.2Hz,2H),2.14 -2.05(m,1H),2.02(s,3H),2.00–1.92(m,1H),1.77–1.71(m,2H),1.53-1.46(m,4H).

[0276] Example 15 (S)-4-((2-methoxyethyl)(4-(3-methyl-5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(((2-(methylthio)quinazolin-4-yl)amino)butanoic acid (Compound 115)

[0277] Step 1: To a 50 mL eggplant-shaped flask, compound 110-a (100 mg, 0.24 mmol), 4-chloro-2-(methylsulfanyl)quinazoline (76 mg, 0.36 mmol), and THF (4 mL) and H2O (0.8 mL) were added. NaHCO3 (100 mg, 1.19 mmol) was then added and stirred at 70°C for 1 hour. The solvent was dried and purified by prep-HPLC to afford the title compound 115 (28.3 mg, 0.05 mmol, 21.1% yield). MS Calcd: 552.29; MS Found: 553.15 ([M+H] + ). 1 H NMR (400 MHz, DMSO-d6, heavy water exchange) δ 8.06 (dd, J = 8.4, 1.2 Hz, 1H), 7.70 (ddd, J = 8.4, 6.8, 1.2 Hz, 1H), 7.52 (dd, J = 8.4, 1.2 Hz, 1H), 7.37(ddd,J=8.4,6.8,1.2Hz,1H),6.97(s,1H),4.51(dd,J=6.8,5.2Hz,1H),3.52(t,J=5.6Hz,2H),3.22-3.19(m,2H),3.18(s,3H),3.11–2.7 4(m,6H),2.56(t,J=6.4Hz,2H),2.46-2.41(m,5H),2.22-2.14(m,1H), 2.07-2.05(m,1H),2.00(s,3H),1.74-1.68(m,2H),1.58-1.49(m,4H).

[0278] Example 16 (S)-2-((2-chloroquinazolin-4-yl)amino)-4-((2-methoxyethyl)(4-(3-methyl-5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid (Compound 116)

[0279] Step 1: To a 50 mL eggplant-shaped flask, compound 110-a (100 mg, 0.24 mmol), 2,4-dichloroquinazoline (72 mg, 0.36 mmol), and THF (4 mL) and H2O (0.8 mL) were added. NaHCO3 (100 mg, 1.19 mmol) was then added and stirred at 70°C for 1 hour. The solvent was evaporated and the residue was purified by prep-HPLC to afford the title compound 116 (43.2 mg, 0.07 mmol, 31.0% yield). MS Calcd: 540.26; MS Found: 541.23 ([M+H] + ). 1H NMR (400 MHz, DMSO-d6, heavy water exchange) δ 8.25 (dd, J = 8.4, 1.2 Hz, 1H), 7.81 (ddd, J = 8.4, 7.2, 1.2 Hz, 1H), 7.64–7.61 (m, 1H), 7.53 (ddd, J = 8.4, 7.2, 1.2 Hz, 1H), 6.96 (s, 1H), 4.63 (t, J = 6.0 Hz, 1H), 3.48 (t, J = 5.6 Hz, 1H). z,2H),3.23(t,J=6.4Hz,2H),3.18(s,3H),2.96-2.86(m,2H),2.82-2.72(m,3H),2.68–2.57(m,3H) ,2.44(d,J=7.2Hz,2H),2.20–2.16(m,1H),2.06-1.99(m,4H),1.77–1.71(m,2H),1.55-1.48(m,4H).

[0280] Example 17 (S)-2-((6,7-dimethoxyquinazolin-4-yl)amino)-4-((2-methoxyethyl)(4-(3-methyl-5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid (Compound 118)

[0281] Step 1: To a 50 mL eggplant-shaped flask, compound 110-a (100 mg, 0.24 mmol), 4-chloro-6,7-dimethoxyquinazoline (81 mg, 0.36 mmol), and THF (4 mL) and H2O (0.8 mL) were added. NaHCO3 (100 mg, 1.19 mmol) was then added and stirred at 70°C for 1 hour. The solvent was evaporated and the residue was purified by prep-HPLC to afford the title compound 118 (30.8 mg, 0.05 mmol, 22% yield). MS Calcd: 566.32; MS Found: 567.03 ([M+H] + ). 1H NMR (400 MHz, DMSO-d6, heavy water exchange) δ 8.30 (s, 1H), 7.55(s,1H),7.09(s,1H),6.90(s,1H),4.69(t,J=6.4Hz,1H),3.90(s, 3H),3.88(s,3H),3.44(t,J=5.6Hz,2H),3.20(t,J=5.6Hz,2H),3.16(s, 3H),2.88-2.78(m,2H),2.75–2.55(m,6H),2.41(t,J=2.8Hz,2H),2.16 –2.08(m,1H),2.02-1.97(m,4H),1.76-1.70(m,2H),1.55-1.45(m,4H).

[0282] Example 18 (S)-4-((2-methoxyethyl)(4-(3-methyl-5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((2-methylthieno[2,3-d]pyrimidin-4-yl)amino)butanoic acid (Compound 119)

[0283] Step 1: To a 50 mL eggplant-shaped flask, compound 110-a (100 mg, 0.24 mmol), 4-chloro-2-methylthiophene[2,3-d]pyrimidine (67 mg, 0.36 mmol), and THF (4 mL) and H2O (0.8 mL) were added. NaHCO3 (100 mg, 1.19 mmol) was then added and stirred at 70°C for 1 hour. The solvent was dried and purified by prep-HPLC to afford the title compound 119 (29.6 mg, 0.06 mmol, 23.2% yield). MS Calcd: 526.27; MS Found: 527.21 ([M+H] + ). 1 H NMR (400 MHz, DMSO-d6, heavy water exchange) δ 7.56 (d, J = 6.0 Hz, 1H), 7.41 (d, J = 6.0 Hz, 1H), 6.96 (s, 1H), 4.60 (t, J = 6.0 Hz, 1H), 3.47 (t, J = 5.6 Hz, 2H), 3.21 (t, J = 5.6 Hz, 2H), 3.18 (s, 3H) ,3.98–2.65(m,6H),2.58(t,J=6.0Hz,2H),2.44(t,J=6.8Hz,2H),2.40(s,3H),2.14 -2.05(m,1H),2.01(s,3H),1.98–1.92(m,1H),1.76–1.69(m,2H),1.55-1.49(m,4H).

[0284] Example 19 (S)-4-((2-methoxyethyl)(4-(3-methyl-5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(((6-(trifluoromethyl)quinazolin-4-yl)amino)butanoic acid (Compound 122)

[0285] Step 1: Intermediate 110-a (100 mg, 0.26 mmol), 4-chloro-6-(trifluoromethyl)quinazoline (91 mg, 0.39 mmol), and sodium bicarbonate (97 mg, 1.2 mmol) were added to a mixture of THF (2 ml) and water (0.4 ml). The mixture was heated to 70°C and stirred overnight. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by prep-HPLC to afford the title compound 122 (21 mg, 0.037 mmol, 14% yield). MS Calcd: 574.29; MS Found: 575.31.

[0286] Example 20 (S)-4-((2-methoxyethyl)(4-(3-methyl-5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(((7-(trifluoromethyl)quinazolin-4-yl)amino)butanoic acid (Compound 123)

[0287] Step 1: Intermediate 110-a (100 mg, 0.26 mmol), 4-chloro-7-(trifluoromethyl)quinazoline (91 mg, 0.39 mmol), and sodium bicarbonate (97 mg, 1.2 mmol) were added to a mixed solvent of THF (2 ml) and water (0.4 ml). The temperature was raised to 70°C, and the mixture was stirred overnight. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by prep-HPLC to obtain the title compound 123 (18 mg, 0.031 mmol, 12% yield). MS Calcd: 574.29; MS Found: 575.31. 1H NMR (400 MHz, DMSO-d6, heavy water exchange) δ8.54 (s, 1H), 8.47 (d, J = 8.8 Hz, 1H), 8.01 (d, J = 2.0 Hz, 1H), 7.82 (dd, J = 8.8, 2.0 Hz, 1H), 6.96 (s, 1H), 4.67 (t, J = 6.0 Hz, 1H), 3.51 (t, J = 5.6 Hz, 2H), 3.23–3.1 8(m,6H),3.01–2.94(m,1H),2.87-2.80(m,2H),2.73–2.69(m,1H),2.58(t,J=6.0Hz,3H),2. 46-2.42(m,2H),2.18-2.16(m,1H),2.07-2.00(m,4H),1.77-1.71(m,2H),1.57-1.50(m,4H).

[0288] Example 21 (S)-2-((5-fluoroquinazolin-4-yl)amino)-4-((2-methoxyethyl)(4-(3-vinyl-5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid (Compound 121)

[0289] Step 1: Intermediate 43-g (100 mg, 0.25 mmol), 4-chloro-5-fluoroquinazoline (69 mg, 0.38 mmol), and sodium bicarbonate (97 mg, 1.2 mmol) were added to a mixture of THF (2 ml) and water (0.4 ml). The temperature was raised to 70°C and the mixture was stirred overnight. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by prep-HPLC to obtain the title compound 121 (21 mg, 0.039 mmol, 16% yield). MS Calcd: 536.29; MS Found: 537.31. 1 H NMR (400 MHz, DMSO-d6, heavy water exchange) δ8.44 (s, 1H), 7.81-7.75 (m, 1H), 7.55 (dd, J = 8.4, 1.2 Hz, 1H), 7.38–7.32 (m, 2H), 6.76 (dd, J = 17.2, 11.2 Hz, 1H), 5.43 (dd, J = 17.2, 1.2 Hz, 1 H),5.01(dd,J=11.2,1.2Hz,1H),4.28(brs,1H),3.60(t,J=5.2Hz,2H),3.29–2.94( m,11H),2.64-2.54(m,4H),2.15-2.10(m,2H),1.76-1.73(m,2H),1.62–1.52(m,4H).

[0290] Example 22 (S)-4-((2-methoxyethyl)(4-(3-vinyl-5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(thieno[2,3-d]pyrimidin-4-ylamino)butanoic acid (Compound 124)

[0291] Step 1: Intermediate 43-g (100 mg, 0.25 mmol), 4-chlorothienyl[2,3-d]pyrimidine (65 mg, 0.38 mmol), and sodium bicarbonate (97 mg, 1.2 mmol) were added to a mixture of THF (2 ml) and water (0.4 ml). The temperature was raised to 70°C and the mixture was stirred overnight. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by prep-HPLC to afford the title compound 124 (25 mg, 0.048 mmol, 19% yield). MS Calcd: 524.26; MS Found: 525.28. 1 H NMR (400 MHz, DMSO-d6, heavy water exchange) δ 8.30 (s, 1H), 7.62 (d, J = 6.0 Hz, 1H), 7.55 (d, J = 6.0 Hz, 1H), 7.35 (s, 1H), 6.74 (dd, J = 17.2, 11.2 Hz, 1H), 5.42 (dd, J = 17.2, 1.6 Hz, 1H), 5.00 (dd, J = 11.2, 1.6 Hz, 1 H),4.54(t,J=6.0Hz,1H),3.52(t,J=5.6Hz,2H),3.26–3.22(m,6H),3.10–2.74(m,7H),2.63(t ,J=6.0Hz,2H),2.17-2.07(m,1H),2.00–1.95(m,1H),1.74(t,J=6.0Hz,2H),1.57-1.47(m,4H).

[0292] Example 23 (S)-2-((5-chloroquinazolin-4-yl)amino)-4-((2-methoxyethyl)(4-(3-methyl-5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid (Compound 125)

[0293] Step 1: Intermediate 110-a (100 mg, 0.26 mmol), 4,5-dichloroquinazoline (78 mg, 0.39 mmol), and sodium bicarbonate (97 mg, 1.2 mmol) were added to a mixture of THF (2 ml) and water (0.4 ml). The mixture was heated to 70°C and stirred overnight. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by prep-HPLC to afford the title compound 125 (16 mg, 0.030 mmol, 11% yield). MS Calcd: 540.26; MS Found: 541.28. 1 H NMR (400 MHz, DMSO-d6, heavy water exchange) δ 8.44 (s, 1H), 7.74–7.60 (m, 3H), 6.99 (s, 1H), 4.31 (dd, J = 8.0, 2.8 Hz, 1H), 3.61–3.56 (m, 2H), 3.25–3.15 (m, 6H), 3.09–3.01 (m, 3H), 2.97–2.89 (m, 2H), 2.59 (t, J = 6.4 Hz, 3H), 2.21–2.01 (m, 6H), 1.78–1.71 (m, 2H), 1.63–1.53 (m, 4H).

[0294] Example 24 (S)-4-((2-methoxyethyl)(4-(3-vinyl-5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((2-methylquinazolin-4-yl)amino)butanoic acid (Compound 44)

[0295] Step 1: Intermediate 43-g (100 mg, 0.25 mmol), 4-chloro-2-methylquinazoline (68 mg, 0.38 mmol), and sodium bicarbonate (97 mg, 1.2 mmol) were added to a mixed solvent of THF (2 ml) and water (0.4 ml). The temperature was raised to 70°C, and the mixture was stirred overnight. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by prep-HPLC to give the title compound 44 (21 mg, 0.039 mmol, 16% yield). MS Calcd: 532.32; MS Found: 533.34. 1H NMR (400 MHz, DMSO-d6, heavy water exchange) δ 8.15 (dd, J = 8.4, 1.6 Hz, 1H), 7.76-7.72 (m, 1H), 7.62 (dd, J = 8.4, 1.6 Hz, 1H), 7.48-4.43 (m, 1H), 7.33 (s, 1H), 6.73 (dd, J = 17.2, 11.2 Hz, 1H), 5.41 (dd, J = 17.2, 1.6 Hz, 1H) ,4.97(dd,J=11.2,1.6Hz,1H),4.63(t,J=6.4Hz,1H),3.50(t,J=5.6Hz,2H),3.33–3.21(m,2H),3.1 9(s,3H),3.01–2.62(m,10H),2.43(s,3H),2.16–1.99(m,2H),1.78–1.72(m,2H),1.55–1.48(m,4H).

[0296] Example 25 (S)-4-((2-methoxyethyl)(4-(3-vinyl-5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((7-(trifluoromethyl)quinazolin-4-yl)amino)butanoic acid (Compound 126)

[0297] Step 1: Intermediate 43-g (100 mg, 0.25 mmol), 4-chloro-7-(trifluoromethyl)quinazoline (88 mg, 0.38 mmol), and sodium bicarbonate (97 mg, 1.2 mmol) were added to a mixed solvent of THF (2 ml) and water (0.4 ml). The temperature was raised to 70°C, and the mixture was stirred overnight. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by prep-HPLC to give the title compound 126 (26 mg, 0.044 mmol, 18% yield). MS Calcd: 586.29; MS Found: 587.31. 1H NMR (400 MHz, DMSO-d6, heavy water exchange) δ 8.52 (s, 1H), 8.44 (d, J = 8.8 Hz, 1H), 7.99 (s, 1H), 7.78 (dd, J = 8.8, 2.0 Hz, 1H), 7.34 (s, 1H), 6.71 (dd, J = 17.2, 11.2 Hz, 1H), 5.41 (dd, J = 17.2, 1.6 Hz, 1H), 4.98 (dd, J = 11. 2,1.6Hz,1H),4.61(t,J=6.0Hz,1H),3.53(t,J=5.6Hz,2H),3.25-3.19(m,5H),3.10–2.79(m,6H), 2.62(t,J=6.4Hz,2H),2.20-2.15(m,1H),2.06-2.01(m,1H),1.75-1.73(m,2H),1.58-1.48(m,4H).

[0298] Experimental Example 1: Evaluation of integrin binding activity in vitro:

[0299] By determining the IC 50 The inhibitory activity of the compound on the binding of human integrins αvβ6 and αvβ1 to their ligands was evaluated using the β-value. PLN-74809 was prepared according to patent CN114173803A. The structure of PLN-74809 is as follows:

[0300] IC of compounds that inhibit integrin αvβ1 binding to ligands 50 Determination method:

[0301] The compound was diluted 4× in series with DMSO (Sigma, Catalog No. D5879) (starting concentration 10.0 μM, 4× dilution, a total of 10 concentration points) and the mixture was diluted with a non-contact acoustic pipetting system. SYSTEM (LABCYTE) was used to add 0.2 μL of DMSO to each well of a 384-well assay plate (Perkin Elmer, Cat. No. 6007279) to a final DMSO concentration of 1%. 1× assay buffer (Tris 20 mM, NaCl 150 mM, MnCl2 2.00 mM, CaCl2 0.10 mM, Triton X-100 0.01%, pH = 7.4) was then prepared to dilute αvβ1 (Acrobiosystems, Cat. IT1-H52E1) to a 20 nM αvβ1 protein solution and the tracer Cyclo[-RGDy-K(5-FAM)] (Anaspec, Cat. AS-65160) to a 10 nM tracer solution. 10 μL of the αvβ1 protein solution was added to each gradient well, and 10 μL of 1× assay buffer was added to the DMSO well. Buffer was used as a control and incubated at room temperature for 20 minutes. Then, 10 μL of tracer solution was added to each well and incubated at room temperature for 60 minutes. Finally, fluorescence polarization readings were read on an EnVision (PerkinElmer) reader with an excitation wavelength of 480 nm and emission wavelengths of 535 P nm and 535 S nm (FP program). The percent inhibition (%) of each compound concentration was calculated based on the minimum and maximum fluorescence polarization signals in each assay plate. The minimum fluorescence polarization group had no protein or compound added, and all other groups were identical to the compound group. The fluorescence polarization signal was minimized and was set to 100% inhibition. The maximum fluorescence signal group had no compound added, and all other groups were identical to the compound group. The polarization signal was maximized and was set to 0% inhibition.

[0302] The inhibition rate of each compound concentration was calculated as follows:

[0303] Inhibition rate % = [(maximum polarization signal group - compound group luminescence signal) / (maximum positive polarization signal group - minimum polarization signal group)] * 100%, and finally the four-parameter logistic dose-response equation was used, Y = Bottom + (Top-Bottom) / (1 + (IC 50 =X)*HillSlope), and determine the compound concentration required for 50% inhibition, i.e. IC 50 The results are shown in Table 1. Where Y is the inhibition rate, X is the logarithm of the compound concentration, Top refers to the maximum response (inhibition rate when the compound concentration is the maximum), Bottom refers to the baseline response (inhibition rate when the compound concentration is 0), HillSlope refers to the IC 50 The slope of the curve, IC 50 is the concentration of compound that results in half inhibition.

[0304] IC of compounds that inhibit integrin αvβ6 binding to ligands 50 Determination method:

[0305] The compound was diluted 4× in series with DMSO (Sigma, Catalog No. D5879) (starting concentration 10.0 μM, 4× dilution, a total of 10 concentration points) and the mixture was diluted with a non-contact acoustic pipetting system. SYSTEM (LABCYTE) was used to add 0.1 μL of DMSO to each well of a 384-well assay plate (Perkin Elmer, Cat. No. 6007279) to a final DMSO concentration of 0.5%. 1× assay buffer (Tris 20 mM, NaCl 150 mM, MnCl 2 2.00 mM, CaCl 2 0.10 mM, Triton X-100 0.01%, pH = 7.4) was then prepared to dilute αvβ6 (Acrobiosystems, Cat. IT6-H52E1) to a 20 nM αvβ6 protein solution, dilute LAP (TGF-β) (Acrobiosystems, Cat. LAP-H82F8) to a 10 nM ligand solution, and add Anti-His to the 1× assay buffer. Tb (PerkinElmer, Cat. 61HI2TLB, dilution ratio 1:150) and SA-XL665 (Cat. 610SAXLF, dilution ratio 1:850) antibodies were prepared into a detection solution. 5 μL of αvβ6 protein solution was added to each gradient well, and 5 μL of 1× assay buffer was added to the DMSO well as a control. The mixture was incubated at room temperature for 20 minutes. 5 μL of ligand solution and 10 μL of detection solution were then added to each well, and the reaction was incubated at room temperature for 60 minutes. Finally, the plate fluorescence was read on an EnVision (PerkinElmer) with an excitation wavelength of 340 nm and emission wavelengths of 615 nm and 665 nm (HTRF program). The percentage inhibition (%) of each compound concentration was calculated based on the signals of the minimum and maximum luminescence signal groups included in each assay plate. The minimum luminescence signal group had no added protein and compound, and the others were consistent with the compound group, with the minimum luminescence signal, set to 100% inhibition. The maximum luminescence signal group had no added compound, and the others were consistent with the compound group, with the maximum luminescence signal, set to 0% inhibition.

[0306] The inhibition rate of each compound concentration was calculated as follows:

[0307] Inhibition rate % = [(maximum luminescence signal group - compound group luminescence signal) / (maximum luminescence signal group - minimum luminescence signal group)] * 100%, and finally the four-parameter logistic dose-response equation was used, Y = Bottom + (Top-Bottom) / (1 + (IC 50 =X)*HillSlope), and determine the compound concentration required for 50% inhibition, i.e. IC 50 The results are shown in Table 2. Where Y is the inhibition rate, X is the logarithmic value of the compound concentration, Top refers to the maximum response (inhibition rate when the compound concentration is the maximum), Bottom refers to the baseline response (inhibition rate when the compound concentration is 0), HillSlope refers to the IC 50 The slope of the curve, IC 50 is the concentration of compound that results in half inhibition.

[0308] IC of compounds that inhibit integrin αvβ3 binding to ligands 50 Determination method:

[0309] The compound was dissolved and diluted with DMSO (Sigma, catalog number: D5879) (initial concentration 30.0 μM, 3X dilution, a total of 10 concentration points), and then the mixture was diluted with DMSO (Sigma, catalog number: D5879) and ... SYSTEM (LABCYTE) was used to add 0.2 μL of DMSO to each well of a 384-well assay plate (Perkin Elmer, Cat. No. 6007279) to a final DMSO concentration of 1%. 1× assay buffer (Tris 20 mM, NaCl 150 mM, MnCl2 2.00 mM, CaCl2 0.10 mM, Triton X-100 0.01%, pH 7.4) was then prepared to dilute αvβ3 (Acrobiosystems, Cat. IT3-H52E3) to a 10 nM αvβ3 protein solution and the tracer Cyclo[-RGDy-K(5-FAM)] (Anaspec, Cat. AS-65160) to a 10 nM tracer solution. 10 μL of the αvβ3 protein solution was added to each gradient well, and 10 μL of 1× assay buffer was added to the DMSO well. Buffer was used as a control and incubated at room temperature for 20 minutes. Then, 10 μL of tracer solution was added to each well and incubated at room temperature for 60 minutes. Finally, fluorescence polarization readings were read on an EnVision assay with an excitation wavelength of 480 nm and emission wavelengths of 535 P nm and 535 S nm (FP program). The percent inhibition (%) of each compound concentration was calculated based on the minimum and maximum fluorescence polarization signals in each assay plate. The minimum fluorescence polarization group had no protein or compound added, and all other groups were identical to the compound group. The fluorescence polarization signal was minimized and was set to 100% inhibition. The maximum fluorescence signal group had no compound added, and all other groups were identical to the compound group. The polarization signal was maximized and was set to 0% inhibition.

[0310] The inhibition rate of each compound concentration was calculated as follows:

[0311] Inhibition rate % = [(maximum luminescence signal group - compound group luminescence signal) / (maximum luminescence signal group - minimum luminescence signal group)] * 100%, and finally the four-parameter logistic dose-response equation was used, Y = Bottom + (Top-Bottom) / (1 + (IC 50 =X)*HillSlope), and determine the compound concentration required for 50% inhibition, i.e. IC 50 The results are shown in Table 1. Where Y is the inhibition rate, X is the logarithm of the compound concentration, Top refers to the maximum response (inhibition rate when the compound concentration is the maximum), Bottom refers to the baseline response (inhibition rate when the compound concentration is 0), HillSlope refers to the IC 50 The slope of the curve, IC 50 is the concentration of compound that results in half inhibition.

[0312] Inhibits integrin α vIC of β5-binding ligand compounds 50 Determination method:

[0313] The compound was diluted 3× in a series with DMSO (Sigma, Cat. No. D5879) using a BioTek Precision automated pipetting system (starting at 3000.0 μM, 3× dilution, for a total of 8 concentration points). The compound was then diluted 20× in an assay buffer (20.0 mM Tris-HCl, pH 7.4, 150.0 mM NaCl, 2.0 mM MnCl2, 0.1 mM CaCl2, 0.01% Triton X-100) using a multichannel pipette (starting at 150.0 μM, 3× dilution, for a total of 8 concentration points). α was prepared in assay buffer. v β5 (Acrobiosystems, IT5-H52W5) and Cyclo[-RGDy-K(5-FAM)] (AnaSpec, AS-65160) solution. v The final concentrations of β5 and Cyclo[-RGDy-K(5-FAM)] were 20.0 nM and 10.0 nM, respectively. 2.0 μL of compound at different concentrations (starting at 30.0 μM, 3× dilution, 8 concentration points in total) was added to each well of a 384-well assay plate (Coring, 3575) using a 12-channel pipettor (Rainin: Pipet-Lite XLS+). The same volume of assay buffer containing 1.0% DMSO was added to the signal and background groups. 5.0 μL of α v The β5 protein solution was added to the compound test wells and signal group wells in the 384 reaction plate. The same volume of assay buffer was added to each well of the background group, and then centrifuged at 1000 rpm for 1 minute and incubated at 25°C for 20.0 minutes. 3.0 μL of Cyclo[-RGDy-K(5-FAM)] protein solution was transferred to all wells of the 384 reaction plate, centrifuged at 1000 rpm for 1 minute, and incubated at 25°C for 60.0 minutes. Finally, a high-throughput drug screening multifunctional microplate reader (TECAN Spark) was used to read the luminescence signal of the reaction system in the Fluorescence polarization mode to read the FP signal (Ex480 / Em535S&535P nm). IC was obtained using GraphPad Prism software. 50 Values ​​and nonlinear regression curve fitting.

[0314] The percent inhibition (%) for each compound concentration was calculated based on the signals from the background and signal groups included in each assay plate. The background group, with no protein or compound added and identical to the compound group, had the lowest fluorescence polarization signal and was set to 100% inhibition. The signal group, with no compound added and identical to the compound group, had the highest fluorescence polarization signal and was set to 0% inhibition.

[0315] The inhibition rate of each compound concentration was calculated as follows:

[0316] Inhibition rate %=[(maximum polarization signal group-polarization signal of compound group) / (maximum polarization signal group-minimum polarization signal group)]*100%.

[0317] Inhibits integrin α v IC of β8-binding ligand compounds 50 Determination method:

[0318] The compound was diluted 4× in a series with DMSO (Sigma, Cat. No. D5879) using a BioTek Precision automated pipetting system (starting at 2000.0 μM, 4× dilution, for a total of 8 concentration points). The compound was then diluted 40× in an assay buffer (50.0 mM Tris-HCl, pH 7.5, 150.0 mM NaCl, 1.0 mM CaCl2, 0.01% Tween-20, 0.01% BSA) using a multichannel pipette (starting at 50.0 μM, 4× dilution, for a total of 8 concentration points). α was prepared in assay buffer. v β8 (Acrobiosystems, IT8-H52W4) and LAP (Acrobiosystems, LAP-H82F8) solutions, the final reaction mixture contained α v The final concentrations of β8 and LAP were 5.0 nM and 10.0 nM, respectively. Anti-His Tb (PerkinEler, Cat. 61HI2TLB, dilution ratio 1:150) and SA-XL665 (Cat. 610SAXLF, dilution ratio 1:850) antibodies were added to the assay buffer to prepare the detection solution.

[0319] In a 384-well plate with assay buffer, add 2.0 μL of compounds diluted with assay buffer to each well of a 384-well test plate (Coring, 3824) using a 12-channel pipette (Rainin: Pipet-Lite XLS+). Add the same volume of assay buffer containing 0.5% DMSO to the signal group and background group. Add 5.0 μL of α diluted with assay buffer. v The β8 protein solution was transferred to the compound test wells and signal group wells in a 384-well reaction plate. The same volume of assay buffer was added to each well of the background group. The plates were then centrifuged at 1000 rpm for 1 minute and incubated at 25°C for 20 minutes. 3.0 μL of LAP protein solution diluted in assay buffer was transferred to all wells of the 384-well reaction plate. The plates were centrifuged at 1000 rpm for 1 minute and incubated at 25°C for 60 minutes. Anti-His Tb and SA-XL665 antibody detection solutions diluted in assay buffer were added to each well. The plates were centrifuged at 1000 rpm for 1 minute and incubated at 25°C for 120 minutes.

[0320] Finally, the luminescence signal of the reaction system in TR-FRET mode was read using a high-throughput drug screening multifunctional microplate reader (TECAN Spark) (Ex320 / Em620, Ex320 / Em665). IC was obtained using GraphPad Prism software. 50 The inhibition percentage (%) of each compound concentration was calculated based on the signal of the background and signal groups included in each assay plate. The background group had no protein or compound added, and the signal was the same as the compound group. The signal was minimized and was set to 100% inhibition. The signal group had no compound added, and the signal was the same as the compound group. The signal was maximized and was set to 0% inhibition.

[0321] The inhibition rate of each compound concentration was calculated as follows:

[0322] Inhibition rate %=[(maximum signal group-compound group signal) / (maximum signal group-minimum signal group)]*100%.

[0323] Table 1 The activity of the compounds of the present invention in inhibiting the binding of various integrin subtypes to ligands

[0324] Summarize:

[0325] According to the IC of compound in Table 1 50 The results show that the compounds of the present invention have good dual inhibitory effects on αvβ6 and αvβ1. The IC values ​​of compounds 1 to 126 for αvβ6 and αvβ1 are50 The values ​​are all less than 20nM, and the compounds can be used as drugs for the prevention and / or improvement and / or treatment of diseases related to the target. v β5, α v β8 has a weaker inhibitory effect than PLN-74809, which can reduce potential safety risks.

[0326] Experimental Example 2: Tissue Distribution in Mice

[0327] Experimental materials, methods and results analysis:

[0328] The experimental animals were healthy adult Balb / c female mice (provided by Beijing Weitonglihua Laboratory Animal Technology Co., Ltd.);

[0329] Mouse medication and sample collection:

[0330] BALB / c female mice were orally gavaged with 30 mg / kg of the drug (vehicle: 5% DMSO + 95% 0.2% Tween 80 / 0.5% CMC-Na (DMSO, Chengdu Kelong Chemical Co., Ltd.; CMC-Na, Cat. No. 419273-100G, Sigma). Plasma, liver, lung, and kidney samples were collected 1 and 4 hours after administration. 60 μL of whole blood was collected from the fundus venous plexus and centrifuged at 4000 rpm for 10 minutes to obtain plasma. The peritoneal cavity was opened and the heart was perfused with normal saline. Liver, lung, and kidney samples were then collected and wiped clean of moisture with filter paper. The samples were weighed and a proportional amount of normal saline was added. The homogenized samples were then placed in EP tubes.

[0331] Sample analysis:

[0332] 10 μL of mouse plasma and 30 μL of each tissue sample were collected and protein precipitated with 120 μL of acetonitrile containing an internal standard. The samples were vortexed for 10 minutes and then centrifuged at 4000 rpm for 10 minutes. The supernatant was collected and transferred to a 96-well plate for analysis using a LC-MS / MS (mass spectrometer, TQ4500, liquid chromatograph, Shimadzu 30AD).

[0333] The LC-MS / MS method was used to determine the drug concentrations in plasma and various tissues at different times after oral administration of the example compounds to mice, and the relevant pharmacokinetic parameters were calculated to study the pharmacokinetic behavior of the compounds in mice and evaluate their pharmacokinetic characteristics.

[0334] Table 2 Tissue distribution of the compounds of the present invention in mice

[0335] Summarize:

[0336] According to Table 2, it can be seen that the compound provided by the present invention has a better exposure amount in mouse plasma, liver, kidney, lung and other tissues than Yangshen PLN-74809.

[0337] Experimental Example 3: In vivo efficacy evaluation in a mouse model of unilateral ureteral ligation and obstruction

[0338] Test materials:

[0339] PLN-74809 and compound 4 were prepared into clear solutions using 5% DMSO-containing physiological saline (containing 20% ​​HP-β-CD (Zibo Qianhui Biotechnology Co., Ltd.)) and then administered.

[0340] Transcriptor First Strand cDNA Synthesis Kit (Roche, Cat. No.: 04897030001)

[0341] FastStart Universal SYBR Green Master (Rox) (Roche, Catalog No.: 4913914001)

[0342] PCR instrument (Biometra TOne 96)

[0343] Fluorescence quantitative PCR instrument (Applied Biosystems QuantStudio™ 3 Real-Time PCR Instrument 96-well 0.1ml Block A28131)

[0344] The primer sequences are shown in the table below (Suzhou Jinweizhi Biotechnology Co., Ltd.):

[0345] Test method:

[0346] Seven-week-old male C57 BL / 6J mice (Guangdong Weitong Lihua Laboratory Animal Technology Co., Ltd.) were randomly divided into four groups, with 6-8 animals in each group. PLN-74809 and compound 4 were administered orally at a dose of 100 mg / kg twice daily for 12 consecutive days. Body weights were measured every other day.

[0347] On the second day after group administration, all mice underwent skin preparation and disinfection after anesthesia. An incision was made on the left side of the back to expose the left kidney and ureter. The left ureter was then freed, ligated, and cut, and sutured layer by layer to complete the surgery. Mice in the sham-operated group only underwent ureteral freeing without ligation or cutting.

[0348] On the 12th day after group administration, all mice were gavage-administered, anesthetized, and euthanized by bleeding. After bleeding, the heart was perfused with normal saline until the outflowing fluid was clear.

[0349] The left and right kidneys of the mice were removed, and RNA was extracted and the expression of different genes (Fibronectin, COL1A1, α-SMA, COL3A1) was detected using real-time quantitative PCR.

[0350] The gene expression of each group was calculated according to the formula:

[0351] The formula for calculating relative gene expression is as follows: gene expression = 2^(–ΔCt). Where ΔCt = Ct (target gene) – Ct (reference gene);

[0352] Data were statistically analyzed using GraphPad Prism 9.0 software and expressed as Mean ± SEM (standard error). Pairwise comparisons between the treatment groups and the control group were analyzed using one-way analysis of variance (ANOVA), with homogeneity of variance tested using the Brown-Forsythe method and unequal variance tested using the Dunnett's T3 method.

[0353] Table 3 Pharmacodynamics of unilateral ureteral ligation and obstruction model in mice

[0354] Summarize:

[0355] The experimental results are shown in Table 3: Compared with the model group, PLN-74809 administration for 12 days failed to reduce the expression of fibrosis-related genes Fibronectin, COL1A1, and α-SMA; while compound 4 could significantly reduce the expression of fibrosis-related genes Fibronectin and COL3A1, and the expression of fibrosis genes COL1A1 and α-SMA was reduced by about 50%.

[0356] In summary, in the mouse unilateral ureteral ligation obstruction model, the compound of the present invention has a good anti-fibrosis effect and is superior to PLN-74809 in efficacy.

[0357] Industrial applicability

[0358] The compounds of the present invention exhibit excellent dual αvβ1 / αvβ6 inhibitory activity and can be used to prepare drugs for treating or preventing diseases associated with this activity. Compared to PLN-74809, they exhibit weaker αvβ3, αvβ5, and αvβ8 inhibitory activity and stronger reduction of fibrosis-related gene expression, resulting in lower potential medication risks and better therapeutic efficacy. Furthermore, compared to PLN-74809, the compounds of the present invention exhibit better exposure in mouse plasma, liver, kidney, lung, and other tissues, particularly for the treatment of fibrosis-related diseases in the liver, kidney, and lung.

[0359] The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principles of the present invention. These improvements and modifications should also be regarded as within the scope of protection of the present invention.

[0360] References:

[0361] [1]Pang, Xiaocong et al. "Targeting integrin pathways: mechanisms and advances in therapy." Signal transduction and targeted therapy vol.8,1 1.2 Jan.2023.

[0362] [2]Henderson, Neil C, and Dean Sheppard. "Integrin-mediated regulation of TGFβin fibrosis." Biochimica et biophysica acta vol.1832,7(2013):891-6.

[0363] [3]Decaris ML,Schaub JR,Chen C,et al.Dual inhibition ofαvβ6andαvβ1reduces fibrogenesis in lung tissue explants from patients with IPF.[J].Respiratory Research,2021(1).

[0364] [4]Patsenker E,Popov Y,Stickel F,et al.Pharmacological inhibition of integrin alphavbeta3 aggravates experimental liver fibrosis and suppresses hepatic angiogenesis.Hepatology.2009;50(5):1501-1511.

[0365] [5]Reed NI et al.The alphavbeta1 integrin plays a critical in vivo role in tissue fibrosis.Sci Transl Med 7,288ra279.

[0366] [6]Reed NI,Jo H,Chen C,et al.Theανβ1integrin plays a critical in vivo role in tissue fibrosis.Sci Transl Med.2015;7(288):288ra79.

Claims

1. A compound represented by formula (I), its stereoisomers, tautomers, polymorphs, cocrystals, solvates, metabolites, prodrugs, deuterated compounds or pharmaceutically acceptable salts: in, R 1 Selected from C 6-14 Aryl or 5-10 membered heteroaryl, wherein the 5-10 membered heteroaryl contains 1-4 heteroatoms selected from N, O or S; the C 6-14 The aryl or 5-10 membered heteroaryl is unsubstituted or each independently substituted by one or more R 1a replace; R 2 Selected from hydrogen, deuterium, -OH, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 3-6 Cycloalkyloxy, 3-12 membered heterocyclic group or -S(O)2R 2d wherein the 3-12 membered heterocyclic group contains 1-4 heteroatoms selected from N, O or S, and the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 3-6 The cycloalkyloxy and 3-12 membered heterocyclic groups are unsubstituted or each independently substituted with one or more R 2a Replacement; R 2d Selected from C 1-6 Alkyl, C 3-5 Cycloalkyl, R 2d can be further represented by one or more R 2b replace; R 1a Each occurrence is independently selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-8 Alkynyl, C 3-8 Cycloalkyl, C 4-8 Cycloalkenyl, 3-12 membered heterocyclic group, 5-10 membered heteroaryl, C 6-14 Aryl, deuterium, halogen, -CN, -OR 3 、-SR 3 、-NR 4 R 5 、-NO2、-C=NH(OR 3 )、-C(O)R 3 、-OC(O)R 3 、-C(O)OR 3 、-C(O)NR 4 R 5 、-NR 3 C(O)R 4 、-NR 3 C(O)OR 4 、-NR 3 C(O)NR 4 R 5 、-S(O)R 3 、-S(O)2R 3 、-NR 3 S(O)R 4 、-NR 3 S(O)2R 4 、-S(O)NR 4 R 5 、-S(O)2NR 4 R 5 OR-P(O)(OR 4 )(OR 5 ), wherein the 3-12 membered heterocyclyl and the 5-10 membered heteroaryl each independently contain 1-4 heteroatoms selected from N, O or S; R 1a Each occurrence independently, where possible, may be further substituted with one or more substituents selected from the group consisting of deuterium, halogen, oxo, -OR 6 、-NR 6 R 7 、-C(O)R 6 、-CN、-S(O)R 6 、-S(O)2R 6 、-P(O)(OR 6 )(OR 7 ), C 3-8 Cycloalkyl, 3-12 membered heterocyclyl, 5-10 membered heteroaryl, C 6-14 Aryl, or C optionally substituted by deuterium, oxo, -OH or halogen 1-6 Alkyl; wherein the 3-12 membered heterocyclic group and the 5-10 membered heteroaryl group each independently contain 1-4 heteroatoms selected from N, O or S; R 2a and R 2b Each occurrence is independently selected from oxo or R la ; R 3 Each occurrence is independently selected from hydrogen, deuterium, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 6-14 aryl, 5-10 membered heteroaryl or 3-12 membered heterocyclic group; wherein the 5-10 membered heteroaryl and 3-12 membered heterocyclic group each independently contain 1-4 heteroatoms selected from N, O or S, and the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 6-14 Aryl, 5-10 membered heteroaryl or 3-12 membered heterocyclic group is unsubstituted or independently substituted by one or more substituents selected from the group consisting of halogen, deuterium, oxo, -CN, -OR 8 , -NR 8 R 9 , -P(O)(OR 8 )(OR 9 ), C 1-6 Alkyl, C substituted by deuterium, halogen, -OH or oxo 1-6 alkyl; R 4 and R 5 Each occurrence is independently selected from hydrogen, deuterium, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 6-14 aryl, 5-6 membered heteroaryl or 3-6 membered heterocyclic group; wherein the 5-6 membered heteroaryl and 3-6 membered heterocyclic group each independently contain 1-3 heteroatoms selected from N, O or S, and the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 6-14 The aryl, 5-6 membered heteroaryl or 3-6 membered heterocyclyl is unsubstituted or each independently substituted by one or more substituents selected from the group consisting of deuterium, halogen, oxo, -CN, -OR 8 , -NR 8 R 9 , C 1-6 Alkyl, C substituted by deuterium, halogen, -OH or oxo 1-6 alkyl; or R 4 and R 5 Together with the atoms to which it is attached, it forms a 3-6 membered heterocyclic group containing 1-3 heteroatoms selected from N, O or S; the 3-6 membered heterocyclic group is unsubstituted or substituted by one or more substituents selected from the following groups: deuterium, halogen, oxo, -OR 8 , -NR 8 R 9 , C 1-6 Alkyl, C substituted by deuterium, halogen, oxo or -OH 1-6 alkyl; R 6 and R 7 Each occurrence is independently selected from hydrogen, deuterium, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl; wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl groups are unsubstituted or each independently substituted with one or more substituents selected from deuterium, halogen or oxo; or R 6 and R 7 Together with the atoms to which it is attached, it forms a 3-6 membered heterocyclic group containing 1-3 heteroatoms selected from N, O or S, wherein the 3-6 membered heterocyclic group is unsubstituted or substituted by one or more substituents selected from the following groups: deuterium, halogen, oxo, C 1-6 Alkyl, C substituted by deuterium, halogen or oxo 1-6 alkyl; R 8 and R 9 Each occurrence is independently selected from hydrogen, deuterium, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl; wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl groups are unsubstituted or each independently substituted with one or more substituents selected from deuterium, halogen or oxo; or R 8 and R 9 Together with the atoms to which it is attached, it forms a 3-6 membered heterocyclic group containing 1-3 heteroatoms selected from N, O or S, wherein the 3-6 membered heterocyclic group is unsubstituted or substituted by one or more substituents selected from the following groups: deuterium, halogen, oxo, C 1-6 Alkyl, C substituted by deuterium, oxo or halogen 1-6 alkyl; R 10 , R l1 , R 12 and R 13 Each occurrence is independently selected from hydrogen or deuterium; R 14 Each occurrence is independently selected from halogen, -CN, -OR 3 、-SR 3 、-NR 4 R 5 、-NO2、-NR 3 C(O)R 4 、-NR 3 C(O)OR 4 、-NR 3 C(O)NR 4 R 5 、-NR 3 S(O)R 4 、-NR 3 S(O)2R 4 , C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 6-14 Aryl, 5-10 membered heteroaryl or 3-12 membered heterocyclic wherein the 5-10 membered heteroaryl and the 3-12 membered heterocyclic group each independently contain 1-4 heteroatoms selected from N, O or S, and the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 6-14 The aryl, 5-10 membered heteroaryl or 3-12 membered heterocyclyl is unsubstituted or each independently substituted by one or more substituents selected from the group consisting of deuterium, halogen, oxo, C 1-6 Alkyl, C substituted by deuterium or halogen 1-6 alkyl; q is 1, 2, 3, 4, 5, 6, 7 or 8; R 15 is selected from hydrogen, deuterium or halogen; R 16 is selected from hydrogen, deuterium or halogen; and p is 3, 4, 5, 6, 7, 8 or 9.

2. The compound of formula (I) according to claim 1, its stereoisomer, tautomer, polymorph, cocrystal, solvate, metabolite, prodrug, deuterated compound or pharmaceutically acceptable salt, characterized in that: R 1 is selected from phenyl, naphthyl or 5-10 membered heteroaryl, wherein the 5-10 membered heteroaryl contains 1-4 heteroatoms selected from N, O or S; the phenyl, naphthyl or 5-10 membered heteroaryl is unsubstituted or each independently substituted by one or more R 1a replace; Preferably, R 1 is selected from 5-10 membered heteroaryl, wherein the 5-10 membered heteroaryl contains 1-4 heteroatoms selected from N, O or S; the 5-10 membered heteroaryl is unsubstituted or substituted by one or more R 1a replace; Preferably, R 1 is selected from a 5-6 membered monocyclic heteroaryl or a 9-10 membered bicyclic heteroaryl, wherein the 5-6 membered monocyclic heteroaryl contains 1-3 heteroatoms selected from N, O or S, and the 9-10 membered bicyclic heteroaryl contains 1-4 heteroatoms selected from N, O or S; the 5-6 membered monocyclic heteroaryl or the 9-10 membered bicyclic heteroaryl is unsubstituted or each independently substituted by one or more R 1a replace; Preferably, R 1 is selected from a 5-6 membered monocyclic heteroaryl or a 9-10 membered bicyclic heteroaryl, wherein the 5-6 membered monocyclic heteroaryl contains 1-3 N heteroatoms, and the 9-10 membered bicyclic heteroaryl contains 1-4 heteroatoms selected from N or S; the 5-6 membered monocyclic heteroaryl or the 9-10 membered bicyclic heteroaryl is unsubstituted or each independently substituted by 1, 2 or 3 R 1a replace; Preferably, R 1 is selected from a 5-6 membered monocyclic heteroaryl or a 9-10 membered bicyclic heteroaryl, wherein the 5-6 membered monocyclic heteroaryl contains 2 N heteroatoms, and the 9-10 membered bicyclic heteroaryl contains 2-4 heteroatoms selected from N or S; the 5-6 membered monocyclic heteroaryl or the 9-10 membered bicyclic heteroaryl is unsubstituted or each independently substituted by 1, 2 or 3 R 1a replace; Preferably, R 1 is selected from the group consisting of pyrimidinyl, pyrazinyl, quinazolinyl, pyridopyrimidinyl, pyrazolopyrimidinyl, thienopyrimidinyl, benzothiazolyl, and benzopyrazinyl; The pyrimidinyl, pyrazolopyrimidinyl, thienopyrimidinyl, benzothiazolyl and benzopyrazinyl groups are unsubstituted or each of them is independently substituted with 1, 2 or 3 R 1a replace; Preferably, R 1 Selected from which are unsubstituted or each independently substituted with 1, 2 or 3 R 1a replace; Or preferably, R 1 is selected from pyrimidinyl, pyrazinyl, quinazolinyl, pyridopyrimidinyl, pyrazolopyrimidinyl, thienopyrimidinyl, benzothiazolyl, benzopyrazinyl, furanopyrimidinyl; the pyrimidinyl, pyrazinyl, quinazolinyl, pyridopyrimidinyl, pyrazolopyrimidinyl, thienopyrimidinyl, benzothiazolyl, benzopyrazinyl, furanopyrimidinyl is unsubstituted or each is independently substituted by 1, 2 or 3 R 1a replace; Preferably, R 1 Selected from which are unsubstituted or each independently substituted with 1, 2 or 3 R 1a replace; Preferably, R 1a Each occurrence is independently selected from halogen, -CN, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, 5-10 membered heteroaryl, C 6-10 Aryl; wherein the 5-10 membered heteroaryl contains 1-4 heteroatoms selected from N, O or S, and the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, 5-10 membered heteroaryl, C 6-10 The aryl group is unsubstituted or each independently substituted by one or more selected from deuterium, halogen, -CN, C 1-4 Alkyl, halogenated C 1-4 Substitution of alkyl groups; Preferably, R 1a Each occurrence is independently selected from halogen, -CN, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, 5-6 membered heteroaryl, phenyl; wherein the 5-6 membered heteroaryl contains 1-3 heteroatoms selected from N, O or S, and the C 1-4 Alkyl, C 1-4 The alkoxy groups are unsubstituted or independently substituted by one or more substituents selected from deuterium, F, Cl or Br; 3-6 The cycloalkyl, 5-6 membered heteroaryl, and phenyl groups are unsubstituted or are each independently substituted with one or more groups selected from deuterium, halogen, -CN, C 1-4 Alkyl, halogenated C 1- 4 Alkyl substituent substitution; Preferably, R 1a Each occurrence is independently selected from halogen, -CN, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-4 Cycloalkyl, 5-6 membered heteroaryl, phenyl; wherein the 5-6 membered heteroaryl contains 1-3 N heteroatoms, the C 1-4 Alkyl, C 1-4 The alkoxy groups are unsubstituted or independently substituted by one or more substituents selected from deuterium, F, Cl or Br; 3-4 Cycloalkyl, 5-6 membered heteroaryl, phenyl are unsubstituted or each independently substituted by one or more substituents selected from deuterium, F, Cl, Br, methyl, halomethyl, ethyl or haloethyl; Preferably, R 1a Each occurrence is independently selected from F, Cl, Br, -CN, methyl, ethyl, propyl, isopropyl, C4 alkyl, methoxy, ethoxy, propoxy, isopropyl, C4 alkoxy, cyclopropyl, cyclobutyl, C5 cycloalkyl, C6 cycloalkyl, phenyl, pyrazolyl, imidazolyl, pyrrolyl, triazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl; wherein the methyl, ethyl, propyl, isopropyl, C4 alkyl, methoxy, ethoxy, propoxy, isopropyl, C4 alkoxy, cyclopropyl, cyclobutyl, C5 cycloalkyl, C6 cycloalkyl, phenyl, pyrazolyl, imidazolyl, pyrrolyl, triazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl , isopropoxy, C4 alkoxy are unsubstituted or are each independently substituted by one or more substituents selected from deuterium, F, Cl or Br, and the cyclopropyl, cyclobutyl, C5 cycloalkyl, C6 cycloalkyl, phenyl, pyrazolyl, imidazolyl, pyrrolyl, triazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl are unsubstituted or are each independently substituted by one or more substituents selected from deuterium, F, Cl, Br, methyl, fluoromethyl, ethyl or fluoroethyl; Preferably, R 1a Each occurrence is independently selected from F, Cl, Br, -CN, methyl, fluoromethyl, methoxy, cyclopropyl, phenyl, pyrazolyl; Preferably, R 1a Each occurrence is independently selected from F, Cl, Br, -CN, methyl, -CF3, -CHF2, methoxy, cyclopropyl, phenyl, Or preferably, R 1a Each occurrence is independently selected from halogen, -CN, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, 5-10 membered heteroaryl, C 6-10 Aryl, -SR 3 wherein the 5-10 membered heteroaryl group contains 1-4 heteroatoms selected from N, O or S, and the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, 5-10 membered heteroaryl, C 6-10 The aryl group is unsubstituted or each independently substituted by one or more selected from deuterium, halogen, -CN, C 1-4 Alkyl, halogenated C 1-4 Substitution of alkyl groups; Preferably, R 1a Each occurrence is independently selected from halogen, -CN, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, 5-6 membered heteroaryl, phenyl, -SR 3 wherein the 5-6 membered heteroaryl group contains 1-3 heteroatoms selected from N, O or S, and the C 1-4 Alkyl, C 1-4 The alkoxy groups are unsubstituted or independently substituted by one or more substituents selected from deuterium, F, Cl or Br; 3-6 The cycloalkyl, 5-6 membered heteroaryl, and phenyl groups are unsubstituted or are each independently substituted with one or more groups selected from deuterium, halogen, -CN, C 1-4 Alkyl, halogenated C 1-4 Substitution of alkyl groups; Preferably, R 1a Each occurrence is independently selected from F, Cl, Br, -CN, methyl, -CF3, -CHF2, methoxy, cyclopropyl, phenyl, -SR 3 ; Preferably, R 3 Selected from C 1-6 Alkyl, the C 1-6 The alkyl group is unsubstituted or substituted by one or more radicals selected from halogen, cyano, deuterium, C 1-6 Substitution of alkoxy groups; Preferably, R 3 Selected from C 1-4 Alkyl, the C 1-4 The alkyl group is unsubstituted or substituted by one or more radicals selected from halogen, cyano, deuterium, C 1-4 Substitution of alkoxy groups; Preferably, R 3 is selected from methyl, ethyl, propyl, isopropyl, wherein the methyl, ethyl, propyl, isopropyl is unsubstituted or substituted by one or more selected from halogen, cyano, deuterium, C 1-4 Substitution of alkoxy groups; Preferably, R 3 Selected from methyl; Preferably, R 1 Selected from: Preferably, R 1 Selected from: Preferably, R 1 Selected from Preferably, R 1 Selected from Preferably, R 1 Selected from 3. The compound of formula (I) according to claim 1, its stereoisomer, tautomer, polymorph, cocrystal, solvate, metabolite, prodrug, deuterated compound or pharmaceutically acceptable salt, characterized in that: R 2 Selected from C 1-6 Alkyl, the C 1-6 The alkyl group is replaced by one or more R 2a replace; Preferably, R 2 Selected from C 1-4 Alkyl, the C 1-4 The alkyl group is replaced by one or more R 2a replace; Preferably, R 2 is selected from methyl, ethyl, propyl, isopropyl, C4 alkyl, wherein the methyl, ethyl, propyl, isopropyl, C4 alkyl is replaced by 1, 2 or 3 R 2a replace; Preferably, R 2 is selected from methyl and ethyl, wherein the methyl and ethyl are substituted by 1, 2 or 3 R 2a replace; Preferably, R 2a Each occurrence is independently selected from deuterium, halogen, -CN, C 1-6 Alkyl, 4-7 membered heterocyclic group, -OR 3 or -OC(O)R 3 The 4-7 membered heterocyclic group contains 1-4 heteroatoms selected from N, O or S, wherein at least one heteroatom is O, subject to the restriction that at least one R 2a Selected from 4-7 membered heterocyclic group, -OR 3 or -OC(O)R 3 ; said C 1-6 The alkyl group and the 4-7 membered heterocyclic group are unsubstituted or substituted by one or more substituents selected from the following groups: deuterium, -OR 6 , halogen, C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, halogenated C 1- 6-alkyl, deuterated C 1-6 alkyl; Preferably, R 2a Each occurrence is independently selected from deuterium, halogen, -CN, C 1-6 Alkyl, 4-7 membered heterocycloalkyl or -OR 3 The 4-7 membered heterocycloalkyl contains 1-4 heteroatoms selected from N, O or S, wherein at least one heteroatom is O, subject to the restriction that at least one R 2a is a 4-7 membered heterocycloalkyl group or -OR 3 ; said C 1-6 Alkyl, 4-7 membered heterocycloalkyl is unsubstituted or substituted by one or more substituents selected from the following groups: deuterium, -OR 6 , halogen, C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated C 1- 6 alkyl; Preferably, R 2a Each occurrence is independently selected from deuterium, halogen, -CN, C 1-6 Alkyl, 4-7 membered heterocycloalkyl or -OR 3 The 4-7 membered heterocycloalkyl contains 1-2 heteroatoms selected from N, O or S, wherein at least one heteroatom is O, subject to the restriction that at least one R 2a is a 4-7 membered heterocycloalkyl group or -OR 3 ; said C 1-6 Alkyl, 4-7 membered heterocycloalkyl is unsubstituted or substituted by one or more substituents selected from the following groups: deuterium, -OR 6 , halogen, C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated C 1- 6 alkyl; Preferably, R 6 is H; Preferably, R 2a Each occurrence is independently selected from halogen, C 1-6 Alkyl, deuterated C 1-6 Alkyl, halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, 4-7 membered heterocycloalkyl or -OR 3 The 4-7 membered heterocycloalkyl contains 1-2 heteroatoms selected from N, O or S, wherein at least one heteroatom is O, subject to the restriction that at least one R 2a is a 4-7 membered heterocycloalkyl group or -OR 3 ; Preferably, R 2a Each occurrence is independently selected from halogen, C 1-6 Alkyl, deuterated C 1-6 Alkyl, fluorinated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, 4-6 membered heterocycloalkyl or -OR 3 The 4-6 membered heterocycloalkyl contains 1-2 heteroatoms selected from N, O or S, wherein at least one heteroatom is O, subject to the restriction that at least one R 2a is a 4-6 membered heterocycloalkyl group or -OR 3 ; Preferably, R 2a Each occurrence is independently selected from halogen, C 1-4 Alkyl, deuterated C 1-4 Alkyl, fluorinated C 1-4 Alkyl, hydroxyl C 1-4 Alkyl, 4-6 membered heterocycloalkyl or -OR 3 , the 4-6 membered heterocycloalkyl group contains 1 Oxygen heteroatom, with the restriction that at least one R 2a is a 4-6 membered heterocycloalkyl group or -OR 3 ; Preferably, R 2a Each occurrence is independently selected from F, Cl, Br, methyl, ethyl, propyl, isopropyl, fluoromethyl, fluoroethyl, fluoropropyl, fluoroisopropyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxyisopropyl, oxetanyl, oxolanyl, oxhexyl, or -OR 3 , the constraint is that there is at least one R 2a is oxetane, oxopentyl, oxhexyl or -OR 3 ; Preferably, R 2a Each occurrence is independently selected from F, methyl, -CH2OH, -CH2F, oxetanyl or -OR 3 , the constraint is that there is at least one R 2a is oxetane or -OR 3 ; Preferably, R 3 Each occurrence is independently selected from hydrogen, deuterium, C 1-6 Alkyl, C 6-14 Aryl, C 3-6 Cycloalkyl, 5-10 membered heteroaryl, wherein the 5-10 membered heteroaryl contains 1-4 heteroatoms selected from N, O or S; the C 1-6 Alkyl, C 6-14 Aryl, C 3-6 Cycloalkyl and 5-10 membered heteroaryl are unsubstituted or each independently substituted by one or more substituents selected from the following groups: halogen, deuterium, C 1-6 Alkyl, C substituted by deuterium, halogen, -OH or oxo 1-6 alkyl; Preferably, R 3 Each occurrence is independently selected from hydrogen, deuterium, C 1-6 Alkyl, C 6-10 Aryl, C 3-6 Cycloalkyl, 5-10 membered heteroaryl, wherein the 5-10 membered heteroaryl contains 1-4 heteroatoms selected from N, O or S; the C 1-6 Alkyl, C 6-10 Aryl, C 3-6 Cycloalkyl and 5-10 membered heteroaryl are unsubstituted or each independently substituted by one or more substituents selected from the following groups: halogen, deuterium, C 1-6 Alkyl, C substituted by deuterium, halogen, -OH 1-6 alkyl; Preferably, R 3 Each occurrence is independently selected from hydrogen, deuterium, C 1-6 Alkyl, phenyl, C 3-6 Cycloalkyl, 5-6 membered heteroaryl, wherein the 5-6 membered heteroaryl contains 1-3 heteroatoms selected from N, O or S; 1- 6 alkyl, phenyl, C 3-6 Cycloalkyl and 5-6 membered heteroaryl are unsubstituted or each independently substituted by one or more substituents selected from the following groups: halogen, deuterium, C 1-6 Alkyl, C substituted by deuterium, halogen, -OH 1- 6 alkyl; Preferably, R 3 Each occurrence is independently selected from H, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, phenyl, C 1-6 Alkyl, C 3-6 Cycloalkyl, 5-6 membered heteroaryl, wherein the 5-6 membered heteroaryl contains 1-3 heteroatoms selected from N, O or S; the phenyl, C 3-6 The cycloalkyl and 5-6 membered heteroaryl groups are unsubstituted or independently substituted by one or more substituents selected from the following groups: halogen, C 1-6 Alkyl, halogenated C 1-6 alkyl; Preferably, R 3 Each occurrence is independently selected from H, halogenated C 1-4 Alkyl, deuterated C 1-4 Alkyl, phenyl, C 1-4 Alkyl, C 3-6 Cycloalkyl, 5-6 membered heteroaryl, the 5-6 membered heteroaryl contains 1-2 N heteroatoms; the phenyl, C 3-6 The cycloalkyl and 5-6 membered heteroaryl groups are unsubstituted or independently substituted by one or more substituents selected from the following groups: halogen, C 1-4 Alkyl, halogenated C 1-4 alkyl; Preferably, R 3 Each occurrence is independently selected from H, fluoro- 1-4 Alkyl, deuterated C 1-4 Alkyl, phenyl, C 1-4 Alkyl, C 3-4 Cycloalkyl, 5-6 membered heteroaryl, the 5-6 membered heteroaryl contains 1-2 N heteroatoms; the phenyl, C 3-4 Cycloalkyl and 5-6 membered heteroaryl are unsubstituted or each independently substituted by one or more substituents selected from the following groups: F, Cl, Br, methyl, ethyl, propyl, isopropyl; Preferably, R 3 each occurrence is independently selected from H, fluoromethyl, fluoroethyl, fluoropropyl, fluoroisopropyl, deuterated methyl, deuterated ethyl, deuterated propyl, deuterated isopropyl, phenyl, methyl or fluoro substituted phenyl, methyl, ethyl, propyl, isopropyl, cyclopropyl, methyl or fluoro substituted cyclopropyl, pyridyl, methyl or fluoro substituted pyridyl; Preferably, R 3 Each occurrence is independently selected from H, deuterated methyl, fluoromethyl, fluoroethyl, phenyl, methyl, ethyl, cyclopropyl, fluorocyclopropyl, pyridinyl, methyl or fluorine-substituted pyridinyl, fluorophenyl; Preferably, R 3 Each occurrence is independently selected from H, -CH2CHF2, -CHF2, -CH2CF3, phenyl, methyl, ethyl, -CF3, -CD3, cyclopropyl, Preferably, R 2a Each occurrence is independently selected from F, -OH, -OCH2CHF2, -OCHF2, -OCH2CF3, phenoxy, methyl, methoxy, ethoxy, -CH2OH, -CH2F, -OCF3, -OCD3, The constraint is that there is at least one R 2a is -OH, -OCH2CHF2, -OCHF2, -OCH2CF3, phenoxy, methoxy, ethoxy, -OCF3, -OCD3 or Preferably, R 2 Selected from methoxyethyl, ethoxyethyl, 4. The compound of formula (I) according to claim 1, its stereoisomer, tautomer, polymorph, cocrystal, solvate, metabolite, prodrug, deuterated compound or pharmaceutically acceptable salt, characterized in that: R 14 Each occurrence is independently selected from halogen, -CN, -OR 3 、-SR 3 、-NR 4 R 5 、-NR 3 C(O)R 4 、-NR 3 S(O)2R 4 , C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 6-14 aryl, 5-10 membered heteroaryl or 3-12 membered heterocyclic group; wherein the 5-10 membered heteroaryl and 3-12 membered heterocyclic group each independently contain 1-4 heteroatoms selected from N, O or S, and the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 6-14 The aryl, 5-10 membered heteroaryl or 3-12 membered heterocyclyl is unsubstituted or each is independently substituted by one or more substituents selected from the group consisting of deuterium, halogen, oxo, C 1-6 Alkyl, deuterated C 1- 6 Alkyl, halogenated C 1-6 alkyl; Preferably, R 14 Each occurrence is independently selected from halogen, -OR 3 、-SR 3 、-NR 4 R 5 、-NR 3 C(O)R 4 、-NR 3 S(O)2R 4 , C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 6-10 Aryl; wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 6-10 The aryl groups are unsubstituted or each independently substituted by one or more substituents selected from the group consisting of deuterium, halogen, oxo, C 1-6 Alkyl, deuterated C 1-6 Alkyl, halogenated C 1-6 alkyl; Preferably, R 14 Each occurrence is independently selected from halogen, -OR 3 、-SR 3 、-NR 4 R 5 、-NR 3 C(O)R 4 、-NR 3 S(O)2R 4 , C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, phenyl, naphthyl; wherein the C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, phenyl, naphthyl are unsubstituted or independently substituted by one or more substituents selected from the following groups: deuterium, halogen, oxo, C 1-4 Alkyl, deuterated C 1-4 Alkyl, halogenated C 1-4 alkyl; Preferably, R 14 Each occurrence is independently selected from F, Cl, Br, -OR 3 、-SR 3 、-NR 4 R 5 、-NR 3 C(O)R 4 、-NR 3 S(O)2R 4 , methyl, ethyl, vinyl, propenyl, ethynyl, propynyl, cyclopropyl, cyclobutyl, C5 cycloalkyl, C6 cycloalkyl, phenyl; wherein the methyl, ethyl, vinyl, propenyl, ethynyl, propynyl, cyclopropyl, cyclobutyl, C5 cycloalkyl, C6 cycloalkyl, phenyl is unsubstituted or each independently substituted by one or more substituents selected from the following groups: deuterium, halogen, oxo, methyl, ethyl, deuterated methyl, deuterated ethyl, halomethyl, haloethyl; Preferably, R 14 Each occurrence is independently selected from F, Cl, Br, -OR 3 、-SR 3 、-NR 4 R 5 、-NR 3 C(O)R 4 、-NR 3 S(O)2R 4 , methyl, ethyl, vinyl, propenyl, ethynyl, propynyl, cyclopropyl, cyclobutyl, C5 cycloalkyl, C6 cycloalkyl, phenyl; wherein the methyl, ethyl, vinyl, propenyl, ethynyl, propynyl, cyclopropyl, cyclobutyl, C5 cycloalkyl, C6 cycloalkyl, phenyl is unsubstituted or are each independently substituted by one or more substituents selected from the following groups: deuterium, F, Cl, Br, oxo, methyl, ethyl, deuterated methyl, deuterated ethyl, fluoromethyl, fluoroethyl; Preferably, R 3 Each occurrence is independently selected from H, C 1-6 Alkyl, the C 1-6 The alkyl groups are unsubstituted or each independently substituted by one or more substituents selected from halogen, deuterium, -CN, -OH; Preferably, R 3 Each occurrence is independently selected from H, C 1-4 Alkyl, the C 1-4 The alkyl groups are unsubstituted or each independently substituted by one or more substituents selected from halogen, deuterium, -CN, -OH; Preferably, R 3 Each occurrence is independently selected from H, methyl, ethyl, propyl, isopropyl, C4 alkyl, said methyl, ethyl, propyl, isopropyl, C4 alkyl being unsubstituted or independently substituted with one or more substituents selected from halogen, deuterium, -CN, -OH; Preferably, R 3 Each occurrence is independently selected from H, methyl, ethyl; Preferably, R 3 Each occurrence is independently selected from H, methyl; Preferably, R 4 and R 5 Each occurrence is independently selected from H, C 1-6 Alkyl, the C 1-6 The alkyl groups are unsubstituted or each independently substituted by one or more substituents selected from halogen, deuterium, -CN, -OH; Preferably, R 4 and R 5 Each occurrence is independently selected from H, C 1-4 Alkyl, the C 1-4 The alkyl groups are unsubstituted or each independently substituted by one or more substituents selected from halogen, deuterium, -CN, -OH; Preferably, R 4 and R 5 Each occurrence is independently selected from H, methyl, ethyl, propyl, isopropyl, C4 alkyl, said methyl, ethyl, propyl, isopropyl, C4 alkyl being unsubstituted or independently substituted with one or more substituents selected from halogen, deuterium, -CN, -OH; Preferably, R 4 and R 5 Each occurrence is independently H, methyl; Preferably, R 14 Each occurrence is independently selected from methyl, F, Cl, Br, amino, methoxy, cyclopropyl, vinyl, ethynyl, phenyl, Preferably, R 14 Each occurrence is independently selected from methyl, Cl, cyclopropyl, vinyl; Preferably, R 14 Each occurrence is independently selected from methyl.

5. The compound of formula (I) according to claim 1, its stereoisomer, tautomer, polymorph, cocrystal, solvate, metabolite, prodrug, deuterated compound or pharmaceutically acceptable salt, characterized in that: R 15 , R 16 Each occurrence is independently H, deuterium, F, Cl or Br; Preferably, R 15 , R 16 Each occurrence is independently H or deuterium; Preferably, R 15 , R 16 Each occurrence is independently H; Preferably, R 10 , R l1 , R 12 and R 13 All are hydrogen.

6. The compound of formula (I) according to claim 1, its stereoisomer, tautomer, polymorph, cocrystal, solvate, metabolite, prodrug, deuterated compound or pharmaceutically acceptable salt, characterized in that: q is 1; Preferably, p is 3; Preferably, formula (I) has the structure shown in formula (IA): Among them, R 1 , R 2 , R 14 , q are each defined as described in formula (I); Preferably, formula (I) has the structure shown in formula (IA-1): Among them, R 1 , R 2 , R 14 Definitions are each as defined in formula (I); Preferably, formula (I) has the structure shown in formula (IA'): Among them, R 1 , R 2 , R 14 , q are each defined as described in formula (I); Preferably, formula (I) has the structure shown in formula (IA'-1): Among them, R 1 , R 2 , R 14 Definitions are each as defined in formula (I).

7. The compound of formula (I) according to claim 1, its stereoisomer, tautomer, polymorph, cocrystal, solvate, metabolite, prodrug, deuterated compound or pharmaceutically acceptable salt, which is selected from any of the following specific compounds: Compounds: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69 9, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126.

8. A pharmaceutical composition, characterized in that It includes the compound according to any one of claims 1 to 7, its stereoisomers, tautomers, polymorphs, cocrystals, solvates, metabolites, prodrugs, deuterated compounds or pharmaceutically acceptable salts, and pharmaceutical adjuvants; the pharmaceutical adjuvants are preferably pharmaceutically acceptable carriers, diluents, excipients or combinations thereof.

9. The compound of any one of claims 1 to 7, its stereoisomer, tautomer, polymorph, cocrystal, solvate, metabolite, prodrug, deuterated compound or pharmaceutically acceptable salt, or the composition of claim 8, for use in treating and / or preventing diseases associated with the biological activity of αvβ1 or / and αvβ6; Preferably, the disease associated with the biological activity of αvβ1 and / or αvβ6 is selected from fibrotic diseases.

10. Use of the compound of any one of claims 1 to 7, its stereoisomers, tautomers, polymorphs, cocrystals, solvates, metabolites, prodrugs, deuterated compounds or pharmaceutically acceptable salts, or the pharmaceutical composition of claim 8, in the preparation of a medicament for treating and / or preventing a disease associated with the biological activity of αvβ1 or / and αvβ6, and / or in treating and / or preventing a disease associated with the biological activity of αvβ1 or / and αvβ6; Preferably, the disease associated with the biological activity of αvβ1 and / or αvβ6 is selected from fibrotic diseases.

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