Novel compounds as alpha4beta7 inhibitors

Abstract

Novel compounds that act as inhibitors of alpha4beta7 integrin are disclosed. Pharmaceutical compositions and methods of use of inhibitors of [alpha] 4 [beta] 7 integrin are disclosed. In particular, methods of using the [alpha] 4 [beta] 7 inhibitors in the treatment of diseases or conditions associated with inflammatory bowel diseases, including ulcerative colitis and Crohn's disease.

Description

Technical Field

[0001] This disclosure relates to novel compounds that act as inhibitors of integrins, particularly α4β7 integrins. Additionally, this disclosure relates to pharmaceutical compositions and methods for using α4β7 inhibitors in the treatment of diseases or conditions associated with inflammatory bowel diseases, including ulcerative colitis and Crohn's disease. Background Technology

[0002] Integrins are involved in many cellular processes, including cell-cell and cell-extracellular matrix interactions. Following extracellular ligand binding, integrins mediate intracellular signal transduction, leading to lymphocyte capture, adhesion, and infiltration into tissues. In fact, integrins are heterodimeric cell surface glycoprotein receptors composed of non-covalently bound α (alpha) and β (beta) subunits.

[0003] Twenty-four human integrins have been identified using molecular biology and protein chemistry, and they are known to act on a variety of human diseases, including platelet dysfunction, atherosclerosis, cancer, osteoporosis, fibrosis, diabetic nephropathy, macular degeneration, autoimmune diseases, and chronic inflammatory diseases.

[0004] α4-integrins α4β1 and α4β7 play important roles in lymphocyte migration on most leukocytes, including B and T lymphocytes. α4β1 and α4β7 integrins specifically adhere to VCAM-1 (vascular cell adhesion molecule 1) and MAdCAM-1 (mucosal addressin cell adhesion molecule 1), respectively. MAdCAM-1 is an immunoglobulin superfamily adhesion receptor for lymphocytes and a selective ligand for the α4β7 receptor. MAdCAM-1 is involved in the selective homing of lymphocytes to normal mucosal tissues. In humans, MAdCAM-1 expression is associated with lymphoid tissue and related lymphoid tissues in the gastrointestinal tract. Lymphocyte integrin α4β7 has been shown to mediate the adhesion of memory T cells to MAdCAM-1. During inflammation, MAdCAM-1 is upregulated in the gut and is thought to play an important role in inflammatory bowel disease (IBD) (a group of diseases such as ulcerative colitis (UC) and Crohn's disease (CD)). Inhibiting the interaction between integrins and their respective ligands has been proposed as an effective method for treating various autoimmune and inflammatory diseases, and blocking AdCAM-1 interaction has shown therapeutic benefits in inflammatory bowel diseases such as ulcerative colitis and Crohn's disease (Hao Li et al., α4β7integrin inhibitors: a patent review (2018), Vol. 28, No. 12, 903-917).

[0005] Currently, injectable monoclonal antibodies exist on the market as integrin inhibitors, such as natezumab (Tysabri®), approved for the treatment of highly active relapsing and remission-remitting multiple sclerosis, or vedolizumab (Entyvio®), approved for Crohn's disease and ulcerative colitis. However, orally bioavailable integrin inhibitors have not yet been approved.

[0006] Therefore, there is a need for integrin inhibitors, preferably α4β7 selective inhibitors, that can be used to prevent and / or treat diseases characterized by MAdCAM-1 upregulation, such as inflammatory bowel disease.

[0007] This invention relates to compounds of formula (I) or pharmaceutically acceptable salts thereof. Where R 1 To R 6 R x R y Y is defined below. Summary of the Invention

[0008] This invention relates to compounds of formula (I) or pharmaceutically acceptable salts thereof. in: R y It is -CH(CH3)2, -CF3, -CH2F, CHF2, -CH(CF3)2, cyclopropyl or cyclobutyl; R x It is hydrogen or methyl; R 1 It is -C(O)-R 7 ; Where R 7 It is a -C substituted with 0 or 1 pyridine, phenyl, or cyclopropyl groups. 1-6 alkyl; Or R 7 It is a phenyl or a 5-10 membered heterocyclic group, each independently of R 9 Replace with 0, 1, 2, 3, or 4 instances; Each R 9 Independently selected from halogens, =O, -C 1-6 Alkyl, -C(O)-R 10 -C 1-6 Halogenated groups, -SO2-C 1-6 Alkyl, -NH-C 1-4 Alkyl, -N(C) 1-4 Alkyl)2, -C 3-6 cycloalkyl, -OR 11, phenyl and 4-10 membered heterocycles; and each R 9 Independently selected from R by 0, 1, 2 or 3 independent selections. 17 Substitution of groups; R 17 Selected from halogens, -C 1-6 Alkyl, -OR 15 -C(O)-N(C) 1-4 Alkyl)2, -N(R 12 R 13 ), cyclopropyl and 4 to 10 membered heterocycles, when R 17 When it is a heterocyclic ring, it is further selected independently by 0, 1, 2, or 4 ions from halogens, -C 1-6 Alkyl, =O, -C(O)-R 14 -C 1-6 Halogenated groups, -SO2-C 1-6 Alkyl, -NH-C 1-4 Alkyl, -N(C) 1-4 Alkyl)2, -C 3-6 cycloalkyl, -OR 18 Substitution of groups; R 10 Independently selected from -C 1-6 Alkyl, -C 1-6 Alkyl-C 3-6 cycloalkyl and C 3-6 cycloalkyl; R 11 It is -C 1-6 Alkyl, -C 1-6 Halogenated groups, 4- to 10-membered heterocycles, or -C 1-6 Alkyl-N(C) 1-6 Alkyl)2, wherein the 4 to 10-membered heterocycle is separated by 0 or 1 -C 1-6 Alkyl substitution; R 12 and R 13 Independently selected from -C 1-6 Alkyl, -C 1-6 Halogenated, C 1-6 alkyl-cyclopropyl, C 1-6 Alkyl-(cyclopropyl)2, cyclobutyl, and cyclopropyl, wherein C 1-6 alkyl-cyclopropyl, C 1-6 Alkyl-(cyclopropyl)2, cyclobutyl, and cyclopropyl are substituted with 0, 1, 2, or 3 F atoms; R 14 Independently selected from -C 1-6 Alkyl and C 3-6 cycloalkyl; R 15 It is H, -C 1-6 Alkyl, -C 1-6Halogenated groups, 4- to 10-membered heterocycles, or -C 1-6 Alkyl-N(C) 1-6 Alkyl)2, when R 15 When it is a 4- to 10-membered heterocyclic ring, it is affected by 0 or 1 -C 1-6 Alkyl substitution; R 18 It is -C 1-6 Alkyl or -C 1-6 Halogenated groups; Among them, in each -N(C 1-6 alkyl)2 or -N(C 1-4 In alkyl)2, the two alkyl groups attached to N can be the same or different; R 2 The group consisting of Br, phenyl, naphthyl and 5-10 heteroaryl groups, each of which can be independently selected by 0, 1, 2, 3 or 4 independently selected from -CN, -C 1-6 Alkyl, halogen, -C 1-6 Halogenated, -OC 1-6 Alkyl, phenyl, 5- to 6-membered heteroaryl, -OC 3-6 Substitution with cycloalkyl, -O-phenyl, and -O- (5- to 6-membered heterocycloalkyl) groups; Y is -N= or -C(R) 3 = R 3 It is halogen, -C 1-6 Halogenated groups, -C 1-4 Alkyl or -C 3-6 cycloalkyl; R 4 It is either halogen or hydrogen; R 5 It is either halogen or hydrogen; R 6 It is -C(O)-OR 8 , Where R 8 Is it hydrogen or -C? 1-4 Alkyl, -C 1-4 Alkyl-R 16 -C 1-4 Alkyl-C(O)N(Me)-R 16 -C 1-4 Alkyl-R 16 -C 1-4 Alkyl-C(O)N(R) 16 ,R 16a - or -C 1-4 Alkyl-OC(O)-R 16 ; R 16 and R 16a Independently selected from -C 1-6Alkyl, 3- to 6-cycloalkyl, 4- to 6-membered heterocycles, 4- to 6-membered partially saturated heterocycles, wherein the partially saturated heterocycles are further selected by one or two independently from =O or -C. 1-4 Alkyl groups are substituted.

[0009] The present invention also relates to compounds of formula (I) or pharmaceutically acceptable salts thereof. in: R y It is -CH(CH3)2, cyclopropyl, or cyclobutyl; R x It is hydrogen or methyl; R 1 It is -C(O)-R 7 ; Where R 7 It is a -C substituted with 0 or 1 pyridine, phenyl, or cyclopropyl groups. 1-6 alkyl; Or R 7 It is a phenyl or a 5-10 membered heterocyclic group, each independently of R 9 Replace with 0, 1, 2, or 3 instances; Each R 9 Independently selected from halogens, =O, -C 1-6 Alkyl, -C(O)-R 10 -C 1-6 Halogenated groups, -SO2-C 1-6 Alkyl, -NH-C 1-4 Alkyl, -N(C) 1-4 Alkyl)2, -C 3-6 cycloalkyl, -OR 11 , phenyl and 4-10 membered heterocycles; and each R 9 Independently selected from R by 0, 1, 2 or 3 independent selections. 17 Substitution of groups; R 17 Selected from halogens, -C 1-6 Alkyl, -OR 15 -C(O)-N(C) 1-4 Alkyl)2, -N(R 12 R 13 ), 4 to 10-membered heterocyclic rings, when R 17 When it is a heterocyclic ring, it is further selected by 0, 1, or 2 independently selected from halogens, -C 1-6 Alkyl, =O, -C(O)-R 14 -C 1-6 Halogenated groups, -SO2-C 1-6 Alkyl, -NH-C 1-4 Alkyl, -N(C) 1-4Alkyl)2, -C 3-6 cycloalkyl, -OR 18 Substitution of groups; R 10 Independently selected from -C 1-6 Alkyl, -C 1-6 Alkyl-C 3-6 cycloalkyl and C 3-6 cycloalkyl; R 11 It is -C 1-6 Alkyl, -C 1-6 Halogenated groups, 4- to 10-membered heterocycles, or -C 1-6 Alkyl-N(C) 1-6 Alkyl)2, wherein the 4 to 10-membered heterocycle is separated by 0 or 1 -C 1-6 Alkyl substitution; R 12 and R 13 Independently selected from -C 1-6 Alkyl, -C 1-6 Halogenated alkyl groups and cyclopropyl groups; R 14 Independently selected from -C 1-6 Alkyl and C 3-6 cycloalkyl; R 15 It is -C 1-6 Alkyl, -C 1-6 Halogenated groups, 4- to 10-membered heterocycles, or -C 1-6 Alkyl-N(C) 1-6 Alkyl)2, when R 15 When it is a 4- to 7-membered heterocyclic ring, it is affected by 0 or 1 -C 1-6 Alkyl substitution; R 18 It is -C 1-6 Alkyl or -C 1-6 Halogenated groups; Among them, in each -N(C 1-6 alkyl)2 or -N(C 1-4 In alkyl)2, the two alkyl groups attached to N can be the same or different; R 2 The group consisting of Br, phenyl, naphthyl and 5-10 heteroaryl groups, each of which can be independently selected by 0, 1, 2 or 3 groups from -CN, -C 1-6 Alkyl, halogen, -C 1-6 Halogenated, -OC 1-6 Alkyl, phenyl, 5- to 6-membered heteroaryl, -OC 3-6 Substitution with cycloalkyl, -O-phenyl, and -O- (5- to 6-membered heterocycloalkyl) groups; Y is -N= or -C(R) 3 = R 3 It is halogen, -C 1-6 Halogenated groups, -C 1-4 Alkyl, -C 3-6 cycloalkyl; R 4 It is either halogen or hydrogen; R 5 It is either halogen or hydrogen; R 6 It is -C(O)-OR 8 , Where R 8 Is it hydrogen or -C? 1-4 Alkyl, -C 1-4 Alkyl-OC(O)-R 16 R 16 It is -C 1-6 Alkyl, 3- to 6-cycloalkyl, 4- to 6-membered partially saturated heterocycles, wherein the partially saturated heterocycles are further selected by one or two independently from =O or -C. 1-4 Alkyl groups are substituted.

[0010] In one embodiment, the present invention relates to a compound of formula (Ia) or a pharmaceutically acceptable salt thereof. Where R 1 To R 6 R x R y Y is as defined in this article.

[0011] In certain embodiments of the compounds of the present invention or pharmaceutically acceptable salts thereof, R x It is hydrogen.

[0012] In other embodiments of the compounds of the present invention or their pharmaceutically acceptable salts, R x It is a methyl group.

[0013] In certain embodiments of the compounds of the present invention or pharmaceutically acceptable salts thereof, R y It is -CH(CH3)2, -CF3, cyclopropyl or cyclobutyl.

[0014] In certain embodiments of the compounds of the present invention or pharmaceutically acceptable salts thereof, R y It is -CH(CH3)2, cyclopropyl or cyclobutyl.

[0015] In certain embodiments of the compounds of the present invention or pharmaceutically acceptable salts thereof, R y It is -CH(CH3)2.

[0016] In a further embodiment of the compound of the present invention or a pharmaceutically acceptable salt thereof, R y It is cyclopropyl.

[0017] In a further embodiment of the compound of the present invention or a pharmaceutically acceptable salt thereof, R y It is cyclobutyl.

[0018] In some embodiments of the compounds of the present invention or their pharmaceutically acceptable salts, wherein R 12 and R 13 Independently selected from -C 1-6 Alkyl, -C 1-6 Halogenated, C 1-6 alkyl-cyclopropyl, C 1-6 Alkyl-(cyclopropyl)2, cyclobutyl, and cyclopropyl, wherein C 1-6 alkyl-cyclopropyl, C 1-6 Alkyl-(cyclopropyl)2, cyclobutyl and cyclopropyl are substituted with 0, 1, 2 or 3 F.

[0019] In some embodiments of the compounds of the present invention or their pharmaceutically acceptable salts, wherein R 17 Selected from halogens, -C 1-6 Alkyl, -OR 15 -C(O)-N(C) 1-4 Alkyl)2, -N(R 12 R 13 ) and 4 to 10-membered heterocyclic rings, when R 17 When it is a heterocyclic ring, it is further selected by 0, 1, or 2 independently selected from halogens, -C 1-6 Alkyl, =O, -C(O)-R 14 -C 1-6 Halogenated groups, -SO2-C 1-6 Alkyl, -NH-C 1-4 Alkyl, -N(C) 1-4 Alkyl)2, -C 3-6 cycloalkyl and -OR 18 Substitution of groups.

[0020] In some embodiments of the compounds of the present invention or their pharmaceutically acceptable salts, wherein R 12 and R 13 Independently selected from -C 1-6 Alkyl, -C 1-6 Halogenated and cyclopropyl groups.

[0021] In some embodiments of the compounds of the present invention or their pharmaceutically acceptable salts, wherein R 15 It is -C 1-6 Alkyl, -C 1-6 Halogenated groups, 4- to 10-membered heterocycles, or -C1-6 Alkyl-N(C) 1-6 Alkyl)2, when R 15 When it is a 4- to 10-membered heterocyclic ring, it is affected by 0 or 1 -C 1-6 Alkyl substitution.

[0022] In some embodiments of the compounds of the present invention or their pharmaceutically acceptable salts, wherein R 8 Is it hydrogen or -C? 1-4 Alkyl or -C 1-4 Alkyl-OC(O)-R 16 .

[0023] In some embodiments of the compounds of the present invention or their pharmaceutically acceptable salts, wherein R 8 Is it hydrogen or -C? 1-4 Alkyl-C 1-4 Alkyl-R 16 -C 1-4 Alkyl-C(O)N(Me)-R 16 -or-C 1-4 Alkyl-OC(O)-R 16 And R 16 Independently selected from -C 1-6 Alkyl, 3- to 6-cycloalkyl, 4- to 6-membered partially saturated heterocycles, wherein the partially saturated heterocycles are further selected by one or two independently from =O or -C. 1-4 Alkyl groups are substituted.

[0024] In some embodiments of the compounds of the present invention or pharmaceutically acceptable salts thereof, R 2 It can be independently replaced by 0, 1, 2, 3 or 4 groups.

[0025] In a further embodiment of the compound of the present invention or a pharmaceutically acceptable salt thereof, R 2 It can be independently replaced by 0, 1, 2 or 3 groups.

[0026] In some embodiments of the compounds of the present invention or pharmaceutically acceptable salts thereof, R 2 It is a phenyl or a 5-10 membered heteroaryl group, each of which is independently selected from -CN, -C by 1, 2, 3 or 4 groups. 1-6 Alkyl, halogen, -C 1-6 Substitution of haloalkyl groups.

[0027] In a further embodiment of the compound of the present invention or a pharmaceutically acceptable salt thereof, R 2 It is a phenyl or a 5-10-membered heteroaryl group, each of which is surrounded by one, two, or three independently selected from -CN, -C 1-6 Alkyl, halogen, -C 1-6 Substitution of haloalkyl groups.

[0028] In some embodiments of the compounds of the present invention or pharmaceutically acceptable salts thereof, R 2 Selected independently by 1, 2, 3 or 4 from -CN, -C 1-6 Alkyl, halogen and -C 1-6 The alkyl group is substituted and selected from... .

[0029] In a further embodiment of the compound of the present invention or a pharmaceutically acceptable salt thereof, R 2 Selected independently by 1, 2, 3 or 4 from -CN, -C 1-6 Alkyl, halogen, -C 1-6 The alkyl group is substituted and selected from... .

[0030] In a further embodiment of the compound of the present invention or a pharmaceutically acceptable salt thereof, R 2 Selected independently by 1, 2 or 3 from -CN, -C 1-6 Alkyl, halogen, -C 1-6 The alkyl group is substituted and selected from... .

[0031] In a further embodiment of the compound of the present invention or a pharmaceutically acceptable salt thereof, R 2 It is substituted by 1, 2, 3 or 4 independently selected groups chosen from -CN, methyl, F, Cl and -CF3, and selected from .

[0032] In a further embodiment of the compound of the present invention or a pharmaceutically acceptable salt thereof, R 2 It is substituted by one, two, or three groups independently selected from -methyl, fluorine, or -CF3, and selected from... .

[0033] In some embodiments of the compounds of the present invention or pharmaceutically acceptable salts thereof, Y is -C(R) 3 = ).

[0034] In some embodiments of the compounds of the present invention or pharmaceutically acceptable salts thereof, R 3It is halogen, -CF3, methyl, ethyl, cyclopropyl.

[0035] In some embodiments of the compounds of the present invention or pharmaceutically acceptable salts thereof, Y is -N=.

[0036] In some embodiments of the compounds of the present invention or pharmaceutically acceptable salts thereof, Y is -C(R) 3 = and R 3 It is halogen, -CF3, methyl, ethyl, cyclopropyl.

[0037] In some embodiments of the compounds of the present invention or pharmaceutically acceptable salts thereof, R 4 It is either halogen or hydrogen.

[0038] In some embodiments of the compounds of the present invention or pharmaceutically acceptable salts thereof, R 4 It is halogen.

[0039] In some embodiments of the compounds of the present invention or pharmaceutically acceptable salts thereof, R 4 It's fluorine.

[0040] In some embodiments of the compounds of the present invention or pharmaceutically acceptable salts thereof, R 5 It is either fluorine or hydrogen.

[0041] In some embodiments of the compounds of the present invention or pharmaceutically acceptable salts thereof, R 5 It is hydrogen.

[0042] In some embodiments of the compounds of the present invention or pharmaceutically acceptable salts thereof, R 6 It is -C(O)-OR 8 , where R 8 It is hydrogen, methyl, CF3, ethyl, isopropyl, –CH2-(5-methyl-2-oxo-1,3-m-dioxacyclopenten-4-yl) or –CH2-C(O)N(Me)2.

[0043] In a further embodiment of the compound of the present invention or a pharmaceutically acceptable salt thereof, R 6 It is -C(O)-OR 8 , where R 8 It is hydrogen, methyl, ethyl or isopropyl, -O-CH2-OC(O)-R 16 or -OC(CH3)-OC(O)-R 16 , where R 16 It is methyl, ethyl, isopropyl, isobutyl, cyclobutyl, cyclopentyl, cyclohexane, neopentyl, or (5-methyl-2-oxo-1,3-m-dioxacyclopenten-4-yl)methyl.

[0044] In some embodiments of the compounds of the present invention or pharmaceutically acceptable salts thereof, R 6 It is -C(O)-OR 8 , where R 8 It is hydrogen, methyl, ethyl, or isopropyl.

[0045] In some embodiments of the compounds of the present invention or pharmaceutically acceptable salts thereof, R 6 It is -C(O)-OR 8 And R 8 It is hydrogen.

[0046] In some embodiments of the compounds of the present invention or pharmaceutically acceptable salts thereof, R 7 -C is replaced by 0 or 1 pyridine 1-6 Alkyl, or R 7 It is selected from 0, 1, 2 or 3 of -C 1-6 Alkyl, halogen or -OC 1-6 Alkyl groups substituted with phenyl groups, or R 7 It is selected independently from R by 0, 1, 2 or 3. 9 The group substituted with a 5-10 membered heterocyclic group, and each R 9 Independently selected from halogens, =O, -C 1-6 Alkyl, -C(O)-R 10 -C 1-6 Halogenated groups, -SO2-C 1-6 Alkyl, -NH-C 1-4 Alkyl, -N(C) 1-4 Alkyl)2, -C 3-6 Cycloalkyl, phenyl, 4- to 7-membered heterocycles, -OR 11 Each R 9 Independently selected from R by 0, 1, or 2 independent selections. 17 Substitution of groups; R 10 Independently selected from -C 1-6 Alkyl, C 3-6 cycloalkyl and -C 1-6 Alkyl-C 3-6 cycloalkyl; R 11 It is -C 1-6 Alkyl, -C 1-6 Alkyl-N(-C) 1-6 Alkyl)2, -C 1-6 Halogenated alkyl groups or 4- to 7-membered heterocyclic rings; R 17 Selected from halogens, -OR 15 -C(O)N(C 1-4 Alkyl)2, -N(R 12 R13 ) and 4 to 10-membered heterocyclic rings, when R 17 When it is a 4- to 10-membered heterocycle, it is selected by 0, 1, or 2 independently selected halogens and -C 1-6 Alkyl or -C 1-6 Halogenated alkylation; R 12 and R 13 Independently selected from -C 1-6 Alkyl, -C 1-6 Halogenated alkyl groups and cyclopropyl groups; R 15 It is -C 1-6 Alkyl, -C 1-6 Halogenated alkyl groups or 4- to 7-membered heterocycles, and when R 15 When it is a 4- to 7-membered heterocyclic ring, it is affected by 0 or 1 -C 1-6 Alkyl substitution; And in each -N(C 1-6 alkyl)2 or -N(C 1-4 In alkyl)2, the two alkyl groups attached to N can be the same or different.

[0047] In some embodiments of the compounds of the present invention or pharmaceutically acceptable salts thereof, R 7 -C is replaced by 0 or 1 pyridine 1-6 alkyl.

[0048] In some embodiments of the compounds of the present invention or pharmaceutically acceptable salts thereof, R 7 It is selected from 0, 1, 2, 3 or 4 of -C 1-6 Alkyl, halogen or -OC 1-6 Phenyl groups substituted with alkyl groups.

[0049] In some embodiments of the compounds of the present invention or pharmaceutically acceptable salts thereof, R 7 It is selected from 0, 1, 2 or 3 of -C 1-6 Alkyl, halogen or -OC 1-6 Phenyl groups substituted with alkyl groups.

[0050] In some embodiments of the compounds of the present invention or pharmaceutically acceptable salts thereof, R 7 It is selected independently from R by 0, 1, 2, 3 or 4. 9 The group substituted with a 5-10 membered heterocyclic group, and each R 9 Independently selected from halogens, =O, -C 1-6 Alkyl, -C(O)-R 10 -C 1-6 Halogenated groups, -SO2-C 1-6 Alkyl, -NH-C 1-4 Alkyl, -N(C)1-4 Alkyl)2, -C 3-6 Cycloalkyl, phenyl, 4- to 7-membered heterocycles, -OR 11 ; Each R 9 Independently selected from R by 0, 1, or 2 independent selections. 17 Substitution of groups; R 10 Independently selected from -C 1-6 Alkyl, C 3-6 cycloalkyl and -C 1-6 Alkyl-C 3-6 cycloalkyl; R 11 It is -C 1-6 Alkyl, -C 1-6 Alkyl-N(-C) 1-6 Alkyl)2, -C 1-6 Halogenated alkyl groups or 4- to 7-membered heterocyclic rings; R 17 Selected from halogens, -OR 15 -C(O)N(C 1-4 Alkyl)2, -N(R 12 R 13 ) and 4 to 10-membered heterocyclic rings, when R 17 When it is a 4- to 10-membered heterocycle, it is selected by 0, 1, 2, or 4 independently chosen halogens and -C. 1-6 Alkyl or -C 1-6 Halogenated alkylation; R 12 and R 13 Independently selected from -C 1-6 Alkyl, -C 1-6 Halogenated alkyl groups and cyclopropyl groups; R 15 It is -C 1-6 Alkyl, -C 1-6 Halogenated alkyl groups or 4- to 7-membered heterocycles, and when R 15 When it is a 4- to 7-membered heterocyclic ring, it is affected by 0 or 1 -C 1-6 Alkyl substitution; And in each -N(C 1-6 alkyl)2 or -N(C 1-4 In alkyl)2, the two alkyl groups attached to N can be the same or different.

[0051] In some embodiments of the compounds of the present invention or pharmaceutically acceptable salts thereof, R 7 It is a 5-10 membered heterocyclic group substituted with 0, 1, 2, or 3 groups, and R 17 It is a 4- to 10-membered heterocyclic ring, in which R 17 It can be replaced by 0, 1, or 2 groups.

[0052] In some embodiments of the compounds of the present invention or pharmaceutically acceptable salts thereof, R 7 It is selected independently from R by 0, 1, 2 or 3. 9 The group substituted with a 5-10 membered heterocyclic group, and each R 9 Independently selected from halogens, =O, -C 1-6 Alkyl, -C(O)-R 10 -C 1-6 Halogenated groups, -SO2-C 1-6 Alkyl, -NH-C 1-4 Alkyl, -N(C) 1-4 Alkyl)2, -C 3-6 Cycloalkyl, phenyl, 4- to 7-membered heterocycles, -OR 11 Each R 9 Independently controlled by 0, 1, or 2 R 17 replace; R 17 Selected from halogens, -OR 15 -C(O)N(C 1-4 Alkyl)2, -N(R 12 R 13 ) and 4 to 10-membered heterocyclic rings, when R 17 When it is a 4- to 10-membered heterocycle, it is affected by 0, 1, or 2 halogens, -C 1-6 Alkyl or -C 1-6 Halogenated alkylation; R 10 Independently selected from -C 1-6 Alkyl, -C 3-6 cycloalkyl and -C 1-6 Alkyl-C 3-6 cycloalkyl; R 11 It is -C 1-6 Alkyl, when R 11 It is -C 1-6 When alkyl, it is formed by 0 or 1 -N (C) 1-4 Alkyl)2-substituted, or R 11 It is -C 1-6 Halogenated alkyl groups or 4- to 7-membered heterocyclic rings; R 12 and R 13 Independently selected from -C 1-6 Alkyl, -C 1-6 Halogenated alkyl groups and cyclopropyl groups; R 15 It is -C 1-6 Alkyl, -C 1-6 Halogenated alkyl groups or 4- to 7-membered heterocycles, and when R 15 When it is a 4- to 7-membered heterocyclic ring, it is affected by 0 or 1 -C 1-6 Alkyl substitution.

[0053] In some embodiments of the compounds of the present invention or pharmaceutically acceptable salts thereof, R 9 It is -C 1-6 Alkyl groups, selected independently by 0, 1, 2 or 3 from -C(O)-N(C) 1-4 Alkyl)2, -OR 15 -N(R) 12 R 13 ), 4 to 10-membered heterocyclic alkyl groups, wherein the heterocyclic alkyl group is further replaced by 0, 1 or 2 groups independently selected from halogen or -C 1-6 Alkyl group substitution; R 12 and R 13 Independently selected from -C 1-6 Alkyl, -C 1-6 Halogenated alkyl groups and cyclopropyl groups; R 15 It is -C 1-6 Alkyl, -C 1-6 Halogenated alkyl groups or 4- to 7-membered heterocycles, and when R 15 When it is a 4- to 7-membered heterocyclic ring, it is affected by 0 or 1 -C 1-6 Alkyl substitution; And in each -N(C 1-6 alkyl)2 or -N(C 1-4 In alkyl)2, the two alkyl groups attached to N can be the same or different.

[0054] In some embodiments of the compounds of the present invention or pharmaceutically acceptable salts thereof, R 9 It is -C 1-6 Alkyl groups, selected independently by 0, 1, 2 or 3 from -C(O)-N(C) 1-4 Alkyl)2, -N(R 12 R 13 -OR 15 The heterocyclic alkyl group is substituted with a group consisting of a 4- to 7-membered heterocyclic alkyl group, wherein the heterocyclic alkyl group is further replaced by 0, 1, or 2 groups independently selected from halogens or -C. 1-6 Alkyl group substitution; R 12 and R 13 Independently selected from -C 1-6 Alkyl, -C 1-6 Halogenated alkyl groups and cyclopropyl groups; R 15 It is -C 1-6 Alkyl, -C 1-6 Halogenated alkyl groups or 4- to 7-membered heterocycles, and when R 15 When it is a 4- to 7-membered heterocyclic ring, it is affected by 0 or 1 -C 1-6 Alkyl substitution; And in each -N(C 1-6 alkyl)2 or -N(C1-4 In alkyl)2, the two alkyl groups attached to N can be the same or different.

[0055] In some embodiments of the compounds of the present invention or pharmaceutically acceptable salts thereof, R 9 It is -C 1-6 Alkyl groups, selected independently by 0, 1, 2 or 3 from -C(O)-N(C) 1-4 Alkyl)2, -OR 15 -N(R) 12 R 13 ), 4 to 10-membered heterocyclic alkyl groups, wherein the heterocyclic alkyl group is further replaced by 0, 1 or 2 groups independently selected from halogen or -C 1-6 Alkyl group substitution; R 12 and R 13 Independently selected from -C 1-6 Alkyl, -C 1-6 Halogenated alkyl groups and cyclopropyl groups; R 15 It is -C 1-6 Alkyl, -C 1-6 Halogenated alkyl groups or 4- to 7-membered heterocycles, and when R 15 When it is a 4- to 7-membered heterocyclic ring, it is affected by 0 or 1 -C 1-6 Alkyl substitution, and wherein in each -N(C) 1-6 alkyl)2 or -N(C 1-4 In alkyl)2, the two alkyl groups attached to N can be the same or different.

[0056] In some embodiments of the compounds of the present invention or their pharmaceutically acceptable salts, wherein R 7 Choose the group consisting of the following compounds, whether substituted or unsubstituted: .

[0057] In some embodiments of the compounds of the present invention or pharmaceutically acceptable salts thereof, R 7 Choose the group consisting of the following compounds, whether substituted or unsubstituted: .

[0058] In some embodiments of the compounds of the present invention or pharmaceutically acceptable salts thereof, R 7 Choose from the following groups: Each of the following groups is substituted by 0, 1, or 2 independent substituents selected from the following: –F, –Cl, oxo, –Me, –isobutyl, –isopropyl, cyclobutyl, –CH2F, –CHF2, –CH2CF3, –CF3, –OMe, –OCF3, –O-azacyclobutane-3-yl, –N(Me)2, –C(O)Me, –C(O)cyclopropyl, 1-Me-azacyclobutane-3-yl, 3-F-azacyclobutane-1-yl, 3-N(Me)2-3-Me-azacyclobutane-1-yl, 3-N(Me)2-pyrrolidine-1-yl, 4-Me-piperidin-1-yl, 1-Me-piperidin-4-yl, 1-isopropyl-piperidin-4-yl, 4-N(Me)2-piperidin-1-yl, 4-cyclopropyl-piperazin-1-yl , 4-Isopropyl-piperazin-1-yl, 4-Me-1,4-diazacycloheptane-1-yl, 4-Isopropyl-1,4-diazacycloheptane-1-yl, 4-Cyclopropyl-1,4-diazacycloheptane-1-yl, 5-Methyl-2,4,6,7-tetrahydropyrazole[4,3-c]pyridin-2-yl, 2-Methyl-2,7-diazaspiro[3,5]nonane-7- 1-methyl-1,7-diazaspiro[3.5]nonane-2-yl, 1-methyl-1,7-diazaspiro[3.5]nonane-7-yl, 2-methyl-2,6-diazaspiro[3.3]heptane-6-yl, 3-(3-azabicyclo[3.1.1]heptane-3-yl)-azabicyclobutane-1-yl, 2-methyl-2,5-diazabicyclo[2.2].1] Heptane-5-yl, –C(O)CH2cyclopropyl, –CH2-CH2-azacyclobutane-1-yl, –CH2-CH2-(3-F-azacyclobutane-1-yl), –CH2-CH2-(3-OMe-azacyclobutane-1-yl), –CH2-CH2-CH2-(3-OMe-azacyclobutane-1-yl), –CH2-CH2-C(Me)2-(3-OMe-azacyclobutane-1-yl), –CH2-CH2-(3-CF3-azacyclobutane-1-yl), –CH2-CH2-(3-OCF3-azacyclobutane-1-yl), –CH2-CH2-(3-CHF2-azacyclobutane-1-yl), –C H2-CH2-(3-OCHF2-azacyclobutane-1-yl), –CH2-CH2-(3,3-diF-azacyclobutane-1-yl), –CH2-CH2-(2,2-diMe-azacyclobutane-1-yl), –CH2-CH2-(3,3-diMe-azacyclobutane-1-yl), –CH2-CH2-(3-MeO-3-Me-azacyclobutane-1-yl), –CH2-CH2-(3-CHF2-3-Me-azacyclobutane-1-yl), –CH2-CH2-(3-F-3-Me-azacyclobutane-1-yl), –CH2-CH2-CH2-(3-F-3-Me-azacyclobutane-1-yl), –C H2-azacyclobutane-1-yl, –CH2-(3-F-azacyclobutane-1-yl), –CH2-(1-Me-azacyclobutane-3-yl), –CH2-azacyclobutane-3-yl, –CH2CH2-(3-F-pyrrolidine-1-yl), –CH2CH2-(3-CF3-pyrrolidine-1-yl), –CH2CH2-(3,3-diF-pyrrolidine-1-yl), oxacyclobutane-3yl, –CH2CH2OCH3, –CH2CH2OH, –CH2C(O)N(Me)2, –CH2N(Me)2, –CH2CH2N(Me)2, –CH2CH2N(Me)CH(cyclopropyl)2, –CH2CH2N( Me)CH2(cyclopropyl), –CH2CH2CH2N(Me)2, –C(Me)2CH2N(Me)2, –CH2C(Me)2N(Me)2, –CH2CH2C(Me)2N(Me)2, –CH2CH2N(Me)CH2CF3, –CH2CH2N(Me)CH(Me)2, –CH2CH2N(Me)C(Me)3, –CH2CH2N(Me)cyclopropyl, 4-F-phenyl, –CH2CH2-(2-azaspiro[3.4]octane-2-yl), –CH2CH2CH2-(2-azaspiro[3.4]octane-2-yl), –CH2CH2CH2CH2-(2-azaspiro[3.4]octane-2-yl), –CH2CH2CH2CH2-(2-azaspiro[3.4]octane-2-yl).4] Octane-2-yl), –CH2CH2-(6-azaspiro[3.4]octan-6-yl), –CH2CH2CH2-(6-azaspiro[3.4]octan-6-yl), –CH2CH2-(2,2-diF-6-azaspiro[3.4]octan-6-yl), –CH2CH2-(2-azaspiro[3.3]heptane-2-yl), –CH2CH2-(6-MeO-2-azaspiro[3.3]heptane-2-yl), –CH2CH2-(2-azaspiro[4.5]decane-2-yl), –CH2C H2-(7-azaspiro[3.5]nonane-7-yl), –CH2CH2-(6-azaspiro[3.5]nonane-6-yl), –CH2CH2-(2-azaspiro[3.5]nonane-2-yl), –CH2CH2-(5-oxa-8-azaspiro[3.5]nonane-8-yl), –CH2CH2-(7-oxa-2-azaspiro[3.5]nonane-2-yl), –CH2CH2CH2CH2-(7-oxa-2-azaspiro[3.5]nonane-2-yl), –CH2CH2(6,6-diF- 2-azaspiro[3.3]heptane-2-yl), –CH2CH2-(8-azabicyclo[3.2.1]octane-8-yl), –CH2CH2-(8-oxa-3-azabicyclo[3.2.1]octane-3-yl), CH2CH2CH2-(2-azabicyclo[2.2.2]octane-2-yl), –CH2CH2CH2-(6-oxa-3-azabicyclo[3.1.1]heptane-3-yl), –CH2CH2-(7,7-diF-1,6-diMe-3-azabicyclo[4.1.0]heptane- 3-yl), –CH2CH2-(3-azabicyclo[3.1.1]heptane-3-yl), –CH2CH2CH2-(2-azabicyclo[2.2.1]heptane-2-yl), CH2CH2CH2-(3-azabicyclo[3.1.1]heptane-3-yl), –CH2CH2CH2CH2-(3-azabicyclo[3.1.1]heptane-3-yl), –CH2CH2-(2-azabicyclo[2.1.1]hexane-2-yl), –CH2CH2-(6,6-diMe-3-azabicyclo[3.1.1]heptane-3-yl).0] hexane-3-yl), –CH2CH2N(Me)cyclobutyl), –CH2CH2N(Me)(3,3-diF)cyclobutyl-1-yl), –CH2-CH2-(4-CF3-piperidin-1-yl), –CH2-CH2-(4,4-diMe-piperidin-1-yl), –CH2-CH2-(morpholin-4-yl), –CH2-CH2-CH2-(morpholin-4-yl), –CH2-CH2-CH2-(2,6- (2,2,6,6-tetra-Me-morpholin-4-yl), –CH2-CH2-CH2-(2,2-diMe-morpholin-4-yl), –CH2-CH2-CH2-(2,6-diMe-morpholin-4-yl), –CH2-CH2-(1,4-oxazaza-4-yl), –CH2CH2-CH2-(1,4-oxazaza-4-yl), and –S(O)2Me.

[0059] In some embodiments of the compounds of the present invention or pharmaceutically acceptable salts thereof, R 7 Choose from the following groups: Each of the following groups is substituted by 0, 1, or 2 independent substituents selected from the following: –F, –Cl, oxo, –Me, isobutyl, isopropyl, cyclobutyl, –CH2F, –CHF2, –CH2CF3, –OMe, –O-CF3, –O-azacyclobutane-3-yl, –N(Me)2, –C(O)Me, –C(O)cyclopropyl, 1-Me-azacyclobutane-3-yl, 3-F-azacyclobutane-1-yl, –C(O)CH2cyclopropyl, –CH2-CH2-azacyclobutane-1-yl, –CH2-CH2-(3-F-azacyclobutane-1-yl), –CH2-CH2-(3-CF3-azacyclobutane-1-yl), –CH2-CH2-(3,3- (diF-azircyclobutane-1-yl), –CH2-CH2-(3,3-diMe-azircyclobutane-1-yl), –CH2-azircyclobutane-1-yl, –CH2-(3-F-azircyclobutane-1-yl), –CH2-(1-Me-azircyclobutane-3-yl), –CH2-azircyclobutane-3-yl, –CH2CH2-(3-F-pyrrolidine-1-yl), –CH2CH2OCH3, –CH2C(O)N(Me)2, –CH2CH2N(Me)2, –CH2CH2CH2N(Me)2, –CH2CH2N(Me)CH2CF3, –CH2CH2N(Me)cyclopropyl, 4-F-phenyl and –S(O)2Me.

[0060] In some embodiments of the compounds of the present invention or pharmaceutically acceptable salts thereof, R 7 Choose from the following groups: Each of the following groups is substituted by 0, 1, or 2 independent substituents selected from the following: –F, –Cl, oxo, –Me, isobutyl, isopropyl, cyclobutyl, –CH2F, –CHF2, –CH2CF3, –OMe, –O-CF3, –O-azacyclobutane-3-yl, –N(Me)2, –C(O)Me, –C(O)cyclopropyl, 1-Me-azacyclobutane-3-yl, 3-F-azacyclobutane-1-yl, –C(O)CH2cyclopropyl, –CH2-CH2-azacyclobutane-1-yl, –CH2-CH2-(3-F-azacyclobutane-1-yl), –CH2-CH2-(3-CF3-azacyclobutane-1-yl), –CH2-CH2-(3,3- (diF-azircyclobutane-1-yl), –CH2-CH2-(3,3-diMe-azircyclobutane-1-yl), –CH2-azircyclobutane-1-yl, –CH2-(3-F-azircyclobutane-1-yl), –CH2-(1-Me-azircyclobutane-3-yl), –CH2-azircyclobutane-3-yl, –CH2CH2-(3-F-pyrrolidine-1-yl), –CH2CH2OCH3, –CH2C(O)N(Me)2, –CH2CH2N(Me)2, –CH2CH2CH2N(Me)2, –CH2CH2N(Me)CH2CF3, –CH2CH2N(Me)cyclopropyl, 4-F-phenyl and –S(O)2Me.

[0061] In some embodiments of the compounds of the present invention or pharmaceutically acceptable salts thereof, R 7 Choose from the following groups: Each of the following groups is substituted by 0, 1, or 2 independent substituents selected from the following: –F, –Cl, oxo, –Me, –isobutyl, –isopropyl, cyclobutyl, –CH2F, –CHF2, –CH2CF3, –CF3, –OMe, –OCF3, –O-azacyclobutane-3-yl, –N(Me)2, –C(O)Me, –C(O)cyclopropyl, 1-Me-azacyclobutane-3-yl, 3-F-azacyclobutane-1-yl, 3-N(Me)2-3-Me-azacyclobutane-1-yl, 3-N(Me)2-pyrrolidine-1-yl, 4-Me-piperidin-1-yl, 1-Me-piperidin-4-yl, 1-isopropyl-piperidin-4-yl, 4-N(Me)2-piperidin-1-yl, 4-cyclopropyl-piperazin-1-yl , 4-Isopropyl-piperazin-1-yl, 4-Me-1,4-diazacycloheptane-1-yl, 4-Isopropyl-1,4-diazacycloheptane-1-yl, 4-Cyclopropyl-1,4-diazacycloheptane-1-yl, 5-Methyl-2,4,6,7-tetrahydropyrazole[4,3-c]pyridin-2-yl, 2-Methyl-2,7-diazaspiro[3,5]nonane-7- 1-methyl-1,7-diazaspiro[3.5]nonane-2-yl, 1-methyl-1,7-diazaspiro[3.5]nonane-7-yl, 2-methyl-2,6-diazaspiro[3.3]heptane-6-yl, 3-(3-azabicyclo[3.1.1]heptane-3-yl)-azabicyclobutane-1-yl, 2-methyl-2,5-diazabicyclo[2.2].1] Heptane-5-yl, –C(O)CH2cyclopropyl, –CH2-CH2-azacyclobutane-1-yl, –CH2-CH2-(3-F-azacyclobutane-1-yl), –CH2-CH2-(3-OMe-azacyclobutane-1-yl), –CH2-CH2-CH2-(3-OMe-azacyclobutane-1-yl), –CH2-CH2-C(Me)2-(3-OMe-azacyclobutane-1-yl), –CH2-CH2-(3-CF3-azacyclobutane-1-yl), –CH2-CH2-(3-OCF3-azacyclobutane-1-yl), –CH2-CH2-(3-CHF2-azacyclobutane-1-yl), –C H2-CH2-(3-OCHF2-azacyclobutane-1-yl), –CH2-CH2-(3,3-diF-azacyclobutane-1-yl), –CH2-CH2-(2,2-diMe-azacyclobutane-1-yl), –CH2-CH2-(3,3-diMe-azacyclobutane-1-yl), –CH2-CH2-(3-MeO-3-Me-azacyclobutane-1-yl), –CH2-CH2-(3-CHF2-3-Me-azacyclobutane-1-yl), –CH2-CH2-(3-F-3-Me-azacyclobutane-1-yl), –CH2-CH2-CH2-(3-F-3-Me-azacyclobutane-1-yl), –C H2-azacyclobutane-1-yl, –CH2-(3-F-azacyclobutane-1-yl), –CH2-(1-Me-azacyclobutane-3-yl), –CH2-azacyclobutane-3-yl, –CH2CH2-(3-F-pyrrolidine-1-yl), –CH2CH2-(3-CF3-pyrrolidine-1-yl), –CH2CH2-(3,3-diF-pyrrolidine-1-yl), oxacyclobutane-3yl, –CH2CH2OCH3, –CH2CH2OH, –CH2C(O)N(Me)2, –CH2N(Me)2, –CH2CH2N(Me)2, –CH2CH2N(Me)CH(cyclopropyl)2, –CH2CH2N( Me)CH2(cyclopropyl), –CH2CH2CH2N(Me)2, –C(Me)2CH2N(Me)2, –CH2C(Me)2N(Me)2, –CH2CH2C(Me)2N(Me)2, –CH2CH2N(Me)CH2CF3, –CH2CH2N(Me)CH(Me)2, –CH2CH2N(Me)C(Me)3, –CH2CH2N(Me)cyclopropyl, 4-F-phenyl, –CH2CH2-(2-azaspiro[3.4]octane-2-yl), –CH2CH2CH2-(2-azaspiro[3.4]octane-2-yl), –CH2CH2CH2CH2-(2-azaspiro[3.4]octane-2-yl), –CH2CH2CH2CH2-(2-azaspiro[3.4]octane-2-yl).4] Octane-2-yl), –CH2CH2-(6-azaspiro[3.4]octan-6-yl), –CH2CH2CH2-(6-azaspiro[3.4]octan-6-yl), –CH2CH2-(2,2-diF-6-azaspiro[3.4]octan-6-yl), –CH2CH2-(2-azaspiro[3.3]heptane-2-yl), –CH2CH2-(6-MeO-2-azaspiro[3.3]heptane-2-yl), –CH2CH2-(2-azaspiro[4.5]decane-2-yl), –CH2C H2-(7-azaspiro[3.5]nonane-7-yl), –CH2CH2-(6-azaspiro[3.5]nonane-6-yl), –CH2CH2-(2-azaspiro[3.5]nonane-2-yl), –CH2CH2-(5-oxa-8-azaspiro[3.5]nonane-8-yl), –CH2CH2-(7-oxa-2-azaspiro[3.5]nonane-2-yl), –CH2CH2CH2CH2-(7-oxa-2-azaspiro[3.5]nonane-2-yl), –CH2CH2(6,6-diF- 2-azaspiro[3.3]heptane-2-yl), –CH2CH2-(8-azabicyclo[3.2.1]octane-8-yl), –CH2CH2-(8-oxa-3-azabicyclo[3.2.1]octane-3-yl), CH2CH2CH2-(2-azabicyclo[2.2.2]octane-2-yl), –CH2CH2CH2-(6-oxa-3-azabicyclo[3.1.1]heptane-3-yl), –CH2CH2-(7,7-diF-1,6-diMe-3-azabicyclo[4.1.0]heptane- 3-yl), –CH2CH2-(3-azabicyclo[3.1.1]heptane-3-yl), –CH2CH2CH2-(2-azabicyclo[2.2.1]heptane-2-yl), CH2CH2CH2-(3-azabicyclo[3.1.1]heptane-3-yl), –CH2CH2CH2CH2-(3-azabicyclo[3.1.1]heptane-3-yl), –CH2CH2-(2-azabicyclo[2.1.1]hexane-2-yl), –CH2CH2-(6,6-diMe-3-azabicyclo[3.1.1]heptane-3-yl).0] hexane-3-yl), –CH2CH2N(Me)cyclobutyl), –CH2CH2N(Me)(3,3-diF)cyclobutyl-1-yl), –CH2-CH2-(4-CF3-piperidin-1-yl), –CH2-CH2-(4,4-diMe-piperidin-1-yl), –CH2-CH2-(morpholin-4-yl), –CH2-CH2-CH2-(morpholin-4-yl), –CH2-CH2-CH2-(2,6- (2,2,6,6-tetra-Me-morpholin-4-yl), –CH2-CH2-CH2-(2,2-diMe-morpholin-4-yl), –CH2-CH2-CH2-(2,6-diMe-morpholin-4-yl), –CH2-CH2-(1,4-oxazaza-4-yl), –CH2CH2-CH2-(1,4-oxazaza-4-yl), and –S(O)2Me.

[0062] In some embodiments of the compounds of the present invention or pharmaceutically acceptable salts thereof, R 1 Selected from: -C(O)-CH3, .

[0063] In some embodiments of the compounds of the present invention or pharmaceutically acceptable salts thereof, R 1 Selected from: -C(O)-CH3, .

[0064] In some embodiments of the compounds of the present invention or pharmaceutically acceptable salts thereof, R 1 Selected from: .

[0065] In some embodiments of the compounds of the present invention or pharmaceutically acceptable salts thereof, R 1Selected from: -C(O)-CH3, .

[0066] In some embodiments of the compounds of the present invention or pharmaceutically acceptable salts thereof, R 2 Independently select from the following groups: -Br, -CF3, .

[0067] In some embodiments of the compounds of the present invention or pharmaceutically acceptable salts thereof, R 2 Choose independently from the following groups: .

[0068] In some embodiments of the compounds of the present invention or pharmaceutically acceptable salts thereof, R 2 Independently select from the following groups: -Br, -CF3, .

[0069] In some embodiments of the compounds of the present invention or pharmaceutically acceptable salts thereof, R 2 Independently select from the following groups: -Br, -CF3, .

[0070] In some embodiments of the compounds of the present invention or pharmaceutically acceptable salts thereof, R 2 Choose independently from the following groups: .

[0071] In some embodiments of the compounds of the present invention or their pharmaceutically acceptable salts, wherein R 3 Choose independently the group consisting of -F, -CF3, and -CH3.

[0072] In another embodiment, the present invention relates to a compound selected from any one of Examples 1 to 122 described herein, or a pharmaceutically acceptable salt thereof.

[0073] In a further embodiment, the present invention relates to a compound or a pharmaceutically acceptable salt thereof selected from any one of Examples 200 to 359, 359A, 360 to 402, 404, 405, 407, 410, 411 described herein.

[0074] In one embodiment, the present invention relates to a pharmaceutical composition comprising a pharmaceutically effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

[0075] In one embodiment, the present invention relates to the use of the compounds of the present invention or pharmaceutically acceptable salts thereof in the preparation of pharmaceutical preparations.

[0076] In one embodiment, the present invention relates to the compounds of the present invention or pharmaceutically acceptable salts thereof, which are used as pharmaceutical agents.

[0077] In some embodiments, the present invention relates to compounds that inhibit α4β7-integrin.

[0078] In some embodiments, the present invention relates to a prodrug of a compound that inhibits α4β7-integrin (i.e., a compound that is converted into an α4β7-integrin inhibitor under physiological conditions or by enzyme activity in a mammalian host).

[0079] This compound can be used to treat inflammatory bowel disease, ulcerative colitis, Crohn's disease, small intestinal bacterial overgrowth (SIBO), eosinophilic gastrointestinal disease (EGID), enteritis, enteropathy associated with seronegative arthropathy, intestinal flora imbalance, microscopic or collagenous colitis, cholecystitis, cholangitis, pericholangitis, inflammatory gastrointestinal cancer associated with familial adenomatous polyposis (FAP), intestinal graft-versus-host disease (GVHD), celiac disease, chronic pouchitis, and checkpoint inhibitor-associated colitis.

[0080] In one embodiment, the present invention relates to a method for inhibiting the interaction between α4β7 integrin and MAdCAM-1 protein in a subject, the method comprising administering to a subject in need a pharmaceutically effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof.

[0081] In another embodiment, the present invention relates to a method for treating inflammatory bowel disease in a person in need, the method comprising administering to the person a pharmaceutically effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof.

[0082] In another embodiment, the present invention relates to the compounds of the present invention or pharmaceutically acceptable salts of any of the foregoing, for the treatment of inflammatory bowel disease.

[0083] In another embodiment, the present invention relates to a pharmaceutically acceptable salt of the compound of the present invention or any of the foregoing, for the treatment of inflammatory bowel disease, wherein the inflammatory bowel disease is ulcerative colitis.

[0084] In another embodiment, the present invention relates to a pharmaceutically acceptable salt of the compound of the present invention or any of the foregoing, for the treatment of inflammatory bowel disease, wherein the inflammatory bowel disease is Crohn's disease.

[0085] In another embodiment, the present invention relates to a method for treating ulcerative colitis in humans, the method comprising administering to a person in need a pharmaceutically effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof.

[0086] In another embodiment, the present invention relates to the compounds of the present invention or pharmaceutically acceptable salts of any of the foregoing, for the treatment of ulcerative colitis.

[0087] In another embodiment, the present invention relates to the compounds of the present invention, or pharmaceutically acceptable salts of any of the foregoing, for the treatment of ulcerative colitis, wherein the ulcerative colitis is ulcerative colitis.

[0088] In another embodiment, the present invention relates to the compounds of the present invention, or pharmaceutically acceptable salts of any of the foregoing, for the treatment of ulcerative colitis, wherein the ulcerative colitis is Crohn's disease.

[0089] In another embodiment, the present invention relates to a pillbox comprising: a) One or more compositions, each composition comprising a pharmaceutically effective amount of a pharmaceutically acceptable salt of the compound of the present invention or any of the present invention, and a pharmaceutically acceptable carrier or excipient; and b) Instructions for use on one or more of the compositions in need.

[0090] The terminology used in the specification, description, embodiments, and claims is compiled herein. These definitions should be interpreted in accordance with the remainder of this disclosure and as will be understood by those skilled in the art. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art.

[0091] Unless otherwise stated, terms and phrases are defined below and apply throughout the specification.

[0092] Unless the context clearly indicates otherwise, the articles “a,” “a,” and “the” include plural objects and are used in this document to refer to one or more (i.e., at least one) grammatical object of the article. For example, “an element” means one element or more elements.

[0093] The phrase “and / or” as used in the specification and claims should be understood to mean “any one or both” of the elements so connected.

[0094] In the claims and the foregoing description, all conjunctions such as “comprising,” “including,” “with,” “having,” “containing,” “involving,” “owning,” and “composed of” are understood to be open-ended, meaning including but not limited to. As stated in the United States Patent Office Manual of Patent Examining Procedures, Section 2111.03, only the conjunctions “consisting of” and “consisting substantially of” should be closed or semi-closed conjunctions, respectively.

[0095] Certain compounds contained in the compositions of the present invention may exist in specific geometric or stereoisomer forms. The present invention contemplates all such compounds falling within the scope of the invention, including cis- and trans-isomers. R -and S - Enantiomers, diastereomers, (D)-isomers, (L)-isomers, racemic mixtures thereof, and other mixtures thereof. Additional asymmetric carbon atoms may be present in the substituents, such as alkyl groups. All such isomers and mixtures thereof are intended to be included in this invention. Unless the stereochemistry is explicitly specified in the structure, the structure is intended to include all possible stereoisomers of the depicted compound. If the stereochemistry is explicitly specified for one or more portions of the molecule but not for another one or more portions of the molecule, the structure is intended to include all possible stereoisomers for one or more portions for which the stereochemistry is not explicitly specified. If, for example, a specific enantiomer of the compound of this invention is required, the desired enantiomer can be separated from the racemic mixture using chiral separation methods known in the art, such as chiral chromatography. Alternatively, it can be prepared by asymmetric synthesis or by derivatization with a chiral auxiliary, wherein the resulting diastereomer mixture is separated and the auxiliary group is cleaved to provide the pure desired enantiomer. Alternatively, if the molecule contains a basic functional group, such as an amino group, or an acidic functional group, such as a carboxyl group, it can form a diastereomer salt with a suitable optically active acid or base, and then the resulting diastereomer can be resolved by fractional crystallization or chromatographic means known in the art, followed by recovery of the pure enantiomer.

[0096] Stereochemistry / solvates / hydrates: Unless otherwise stated, the structural formulas or chemical names given in the specification or claims refer to the corresponding compounds themselves, mixtures of the forms mentioned above (if such forms exist), and their salts, particularly pharmaceutically acceptable salts. Compounds and salts according to the invention may exist in a solvated form (e.g., with pharmaceutically acceptable solvents such as water, ethanol, etc.) or a non-solvated form. Generally, for the purposes of this invention, solvated forms, such as hydrates, are considered to be of equal value to non-solvated forms.

[0097] Aliphatic chains include the alkyl, alkenyl, and alkynyl categories as defined below. As used herein, the term "aliphatic group" refers to an unbranched or straight-chain, branched or cyclic aliphatic hydrocarbon group, and includes saturated and unsaturated aliphatic groups such as alkyl, alkenyl, or alkynyl groups.

[0098] The term "alkyl" refers to a straight-chain or branched hydrocarbon. For example, an alkyl group can have a specified number of carbon atoms, such as 1 to 6 carbon atoms (i.e., C1-C6 alkyl or C6 alkyl). 1-6Alkyl groups). Examples of suitable alkyl groups include, but are not limited to, methyl (Me, -CH3), ethyl (Et, -CH2CH3), 1-propyl (n-Pr, n-propyl, -CH2CH2CH3), 2-propyl (i-Pr, i-propyl, -CH(CH3)2), 1-butyl (n-Bu, n-butyl, -CH2CH2CH2CH3), 2-methyl-1-propyl (i-Bu, isobutyl, -CH2CH(CH3)2), 2-butyl (s-Bu, sec-butyl, - CH(CH3)CH2CH3), 2-methyl-2-propyl (t-Bu, tert-butyl, --C(CH3)3), 1-pentyl (n-pentyl, --CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 2-methyl-2-butyl (-C(CH3)2CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH(CH3)2), 3-methyl 1-Methyl-1-butyl (-CH2CH2CH(CH3)2), 2-methyl-1-butyl (-CH2CH(CH3)CH2CH3), 1-hexyl (-CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH2CH3), 3-hexyl (-CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl (-C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl (-CH(CH3)CH(CH3)CH2CH3), 4-methyl-2-pentyl (-CH(CH3)CH2CH(CH3)2), 3-methyl-3-pentyl (--C(CH3)(CH2CH3)2), 2-methyl-3-pentyl (-CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl (--C(CH3)2CH(CH3)2) and 3,3-dimethyl-2-butyl (-CH(CH3)C(CH3)3).

[0099] As used herein, the term "alkylene" refers to an alkyl group having a specified number of carbon atoms, such as 2 to 12, on its longest carbon chain, where it has two connection points with the remainder of the compound. Non-limiting examples of alkylenes include methylene-(CH2)-, ethylene-(CH2CH2)-, n-propylene-(CH2CH2CH2)-, isopropylene-(CH2CH(CH3))-, etc. Alkylenes can be cyclic or acyclic, branched or straight-chain carbon chain portions, and may optionally be substituted with one or more substituents.

[0100] "Alkenyl" refers to any cyclic or acyclic, branched or straight-chain unsaturated carbon chain portion having a specified number of carbon atoms, or, if no limit is specified, a maximum of 26 carbon atoms; and having one or more double bonds in the portion. Examples of alkenyl groups with 6 to 26 carbon atoms are hexenyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, dodecaenyl, tridecenyl, tetradecenyl, pentadecenyl, hexadecenyl, heptadecenyl, octadecenyl, nonadecenyl, icosyl, icosyl, icosyl, tridecenyl, and tetradecenyl, in their various isomers, wherein the unsaturated bonds may be located anywhere in the portion and may have (Z) or (E) configurations surrounding the double bonds.

[0101] "Alkyne" refers to the hydrocarbon group in the alkenyl range, but with one or more triple bonds in that group.

[0102] The term "alkoxy" refers to a group having the formula "-O-alkyl", wherein the alkyl group, as defined above, is attached to the parent molecule via an oxygen atom. The alkyl portion of an alkoxy group may have a specified number of carbon atoms, such as 1 to 6 carbon atoms (i.e., C1-C6 alkoxy or C...). 1-6 Alkoxy groups. Examples of suitable alkoxy groups include, but are not limited to, methoxy (-O-CH3 or --OMe), ethoxy (-OCH2CH3 or --OEt), tert-butoxy (-O--C(CH3)3 or --OtBu), etc.

[0103] The term "haloalkyl" refers to a group in which one or more hydrogen atoms of an alkyl group, as defined above, are replaced by halogen atoms. The alkyl portion of a haloalkyl group may have a specified number of carbon atoms, such as 1 to 6 carbon atoms (i.e., -C1-C6 haloalkyl or -C...). 1-6 (Halogenated compounds). Examples include: -CFH2, -CF2H, -CF3, -CF2CF3, -CHFCF3, -CH2CF3, -CF2CH3, -CHFCH3, -CF2CF2CF3, -CF2CH2CH3, etc.

[0104] The term "carbonyl" refers to C=O, where a carbon atom is bonded to oxygen via a double bond and further to two other atoms. It is represented herein as -CO- or -C(O)-.

[0105] The term “carbocyclic” or “carbocyclic group” refers to a chemical ring containing only carbon atoms, including saturated, unsaturated, partially saturated, and aromatic rings. For clarity, “carbocyclic” includes “cycloalkyl” and “aryl” as defined herein.

[0106] "Cycloalkyl" refers to a monocyclic, bicyclic, bridged, spirocyclic, or polycyclic saturated carbon ring, each having 3 to 12 carbon atoms. Similarly, and unless otherwise stated, preferred cycloalkyl groups have 3 to 10 carbon atoms in their ring structure, more preferably 3 to 6 carbon atoms. Cycloalkyl groups can be substituted or unsubstituted. In some embodiments, preferred cycloalkyl groups are monocyclic rings having 3 to 6 carbon atoms.

[0107] As used herein, the term "aryl" includes a 6- to 12-membered substituted or unsubstituted monocyclic aromatic group, wherein each atom of the ring is a carbon. Preferably, the aryl group comprises a 5- to 12-membered ring, more preferably a 6- to 10-membered ring. The term "aryl" also includes polycyclic systems having two or more cyclic rings, wherein two or more carbons are common to two adjacent rings, and wherein at least one ring is aromatic; for example, the other cyclic rings may be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, and / or heterocyclic groups, wherein the linking point is on the aromatic ring. Aryl groups include benzene, naphthalene, phenanthrene, phenol, aniline, etc. Aryl groups also include dihydrobenzofuran, indoline, isoindoline, quinoline, isoquinoline, etc., wherein the linking point is on the phenyl ring.

[0108] The terms "heterocyclic group," "heterocyclic ring," or "heterocyclic radical" refer to a 3- to 12-membered ring structure, more preferably a 4- to 12-membered ring, and even more preferably a 5- to 10-membered ring, whose ring structure includes 1 to 4 heteroatoms selected from N, O, S, and their oxidized forms. Heterocyclic groups can be saturated, partially saturated, unsaturated, and / or aromatic. Heterocyclic rings can be monocyclic, bicyclic, spirocyclic, or polycyclic. Heterocyclic groups include, for example, aziridine, thiophene, thiathrone, furan, pyran, isobenzofuran, benzopyran, xanthan, phenoxthia, pyrrole, imidazole, pyrazole, isothiazol, isoxazole, pyridine, pyrazine, pyrimidine, pyridazine, indazine, isoindole, indole, indazole, purine, quinazine, isoquinoline, quinoline, phthalazine, naphthidine, quinoxaline, quinazoline, cyclophosphine, pteridine, carbazole, caroline, phenanthridine, acridine, pyrimidine, phenanthroxaline, phenazine, phenpyrazine, phenothiazine, furazan, phenothiazine, pyrrole, oxolane, thiolane, oxazole, piperidine, piperazine, morpholine, lactone, lactam such as aziridine, pyridinone and pyrrolidone, sulfonamide, sulfonyl lactone, etc.

[0109] For clarity, "heterocyclic" includes "heteroaryl" and "heterocyclic alkyl".

[0110] The heterocyclic ring can be substituted at one or more positions with substituents as described above, such as halogens, alkyl groups, aralkyl groups, alkenyl groups, alkynyl groups, cycloalkyl groups, hydroxyl groups, amino groups, nitro groups, mercapto groups, imino groups, amide groups, phosphate groups, phosphonates, phosphonites, carbonyl groups, carboxyl groups, silyl groups, aminosulfonyl groups, sulfinyl groups, ethers, alkylthio groups, sulfonyl groups, ketones, aldehydes, esters, heterocyclic groups, aromatic or heteroaromatic moieties, -CF3, -CN, etc.

[0111] It is to be understood that the general term for heterocycles used herein includes every isomer of the heterocycle, such as the term “dithiaalkyl” including 1,2-dithiaalkyl, 1,3-dithiaalkyl and 1,4-dithiaalkyl, the term “thiadiazinyl” including 1,2,5-thiadiazinyl and 1,3,4-thiadiazinyl, the term “azaindolyl” including 4-azaindolyl, 5-azaindolyl, 6-azaindolyl and 7-azaindolyl, and “benzothiophenyl” including benzo[b]thiophenyl and benzo[c]thiophenyl.

[0112] Similarly, generic heterocyclic names include each variation of one or more unsaturation points. For example, the term "dihydropyrrole" refers to both the "2,3-dihydro-1H-pyrrole" and "2,5-dihydro-1H-pyrrole" groups.

[0113] "Heterocyclic alkyl" refers to a saturated heterocyclic ring having 3 to 12 ring member atoms, more preferably 4 to 10 members, and even more preferably 4 to 7 members, wherein the ring structure includes 1 to 4 heteroatoms selected from N, O, S, and their oxidized forms. The heterocycle can be monocyclic, bicyclic, spirocyclic, or polycyclic. Heterocyclic groups include, for example, aziridine, oxadiazine, tetrahydrofuran, pyrrolidine, piperidine, morpholine, tetrahydropyran, dioxadiazine, azirheptan, etc.

[0114] Heterocyclic alkyl groups can be substituted or unsubstituted. In some embodiments, preferred heterocyclic alkyl groups are monocyclic rings having 4 to 6 ring members, including 1 or 2 heteroatoms.

[0115] A partially saturated heterocycle refers to a heterocyclic ring having at least one carbon-carbon double bond, preferably one, two, or three carbon-carbon double bonds, preferably one or two carbon-carbon double bonds, and preferably one carbon-carbon double bond.

[0116] Heteroaryl groups include substituted or unsubstituted aromatic 5- to 12-membered ring structures, more preferably 5- to 10-membered rings, whose ring structure includes 1 to 4 heteroatoms selected from N, O, S, and their oxidized forms. The term "heteroaryl" also includes polycyclic systems having two or more cyclic rings, wherein two or more atoms are common to two adjacent rings, and at least one ring is aromatic; for example, other cyclic rings may be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or heterocyclic groups, wherein the connecting point is on an aromatic ring. Heteroaryl groups include, for example, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, triazole, pyrazole, pyridine, pyrazine, pyridazine, and pyrimidine. Heteroaryl groups also include benzofuran, benzothiophene, indole, benzothiazole, etc., regardless of the position of the connecting point. Aryl and heteroaryl groups can be monocyclic, bicyclic, or polycyclic.

[0117] The term "halogen" refers to an atom selected from the elements chlorine, fluorine, bromine, and iodine, namely -F, -Cl, -Br, or -I.

[0118] The term "oxo" refers to the double bond oxygen "=O".

[0119] As used herein, the term "nitro" refers to -NO2; the term "mercapto" refers to -SH; the term "hydroxyl" refers to -OH; the term "sulfonyl" refers to -SO2-; the term "azido" refers to -N3; ​​the term "cyano" refers to -CN; the term "isocyanate" refers to -NCO; the term "thiocyanate" refers to -SCN; the term "isothiocyanate" refers to -NCS; and the term "cyanoxy" refers to -OCN.

[0120] As used herein, the term "substituted" is intended to include all permissible substituents of an organic compound. In a broad sense, permissible substituents include acyclic and cyclic, branched and linear, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of an organic compound. Exemplary substituents include, for example, those described above. For a suitable organic compound, permissible substituents may be one or more and may be the same or different. For the purposes of this invention, heteroatoms such as nitrogen may have hydrogen substituents satisfying the valence of the heteroatom and / or any permissible substituents of the organic compound described herein. This invention is not intended to be limited in any way to the permissible substituents of an organic compound. It is to be understood that "substituted" or "replaced" includes the implicit premise that such substitution conforms to the permissible valence of the substituted atom and the substituent, and that the substitution yields a stable compound, for example, which does not spontaneously transform, such as through rearrangement, cyclization, elimination, etc.

[0121] As used herein, the term "prodrug" encompasses compounds that are converted into a therapeutically active agent under physiological conditions. A common method for manufacturing prodrugs involves hydrolysis under physiological conditions to present a selected moiety of the desired molecule. In other embodiments, the prodrug is converted via enzymatic activity of a mammalian host. Examples of hydrolysis under physiological conditions to present a moiety of the desired molecule include functionalized carboxyl groups and carboxylic acid esters, which can be converted into the corresponding active molecule under physiological conditions. Examples of hydrolysis under physiological conditions to present a moiety of the desired molecule are shown below. .

[0122] For the purposes of this invention, chemical elements are identified according to the periodic table, CAS version, Handbook of Chemistry and Physics, 67th edition, 1986-87, inner cover.

[0123] The terms “therapeutic effective amount” and “pharmaceutical effective amount” refer to amounts sufficient to achieve the treatment as defined below when administered to a subject requiring such treatment (e.g., a mammal, such as a human). Therapeutic or pharmaceutically effective amounts will vary depending on the subject being treated and the disease condition, the subject's weight and age, the severity of the disease condition, the method of administration, etc., which can be readily determined by one of ordinary skill in the art. For example, a “therapeutic effective amount” or “pharmaceutical effective amount” of a compound of formula (I) or a pharmaceutically acceptable salt or eutectic thereof is an amount sufficient to inhibit and thereby treat a subject (e.g., a human) with the indication or to improve or alleviate existing symptoms of the indication.

[0124] "Treatment" or "treating" is a method used to achieve a beneficial or desired outcome, including clinical outcomes. Beneficial or desired clinical outcomes may include one or more of the following: (i) suppressing a disease or condition (e.g., reducing one or more symptoms caused by the disease or condition, and / or reducing the severity of the disease or condition); (ii) slowing or halting the development of one or more clinical symptoms associated with the disease or condition (e.g., stabilizing the disease or condition, preventing or delaying the worsening or progression of the disease or condition, and / or preventing or delaying the spread of the disease or condition (e.g., metastasis)); and / or (iii) alleviating the disease, i.e. causing the disappearance of clinical symptoms (e.g., improving the disease state, providing partial or complete remission of the disease or condition, enhancing the effect of another agent, delaying disease progression, improving quality of life, and / or prolonging survival).

[0125] The term "inhibitor" refers to compounds of the present invention that selectively bind to α4β7 integrin to prevent the interaction between α4β7 integrin and the MAdCAM-1 protein. Therefore, "inhibiting" or "inhibition" indicates a reduction in the baseline activity of a biological activity or process regulated by the interaction between α4β7 integrin and the MAdCAM-1 protein. In some embodiments, the inhibition of α4β7 integrin activity can be compared in the same pre-treatment subjects or in other untreated subjects. The term "inhibitor" is understood to mean a compound or agent that provides the desired inhibitory activity after administration to a person in need at a pharmaceutically or therapeutically effective dose.

[0126] The numerical values ​​in the specification and claims of this application should be understood to include the same numerical values ​​when simplified to the same number of significant digits, and numerical values ​​that differ from the specified numerical values ​​by less than the experimental error of conventional measurement techniques used to determine the type of numerical value described in this application.

[0127] All scopes disclosed and / or claimed herein include the listed endpoints and can be combined independently (e.g., the scopes “2 to 10” and “2-10” include endpoints 2 and 10, as well as all intermediate values ​​3, 4, 5, 6, 7, 8 and 9).

[0128] "Significant" means any detectable change that is statistically significant in a standard parameter test of statistical significance, such as the Student's t-test, where p < 0.05.

[0129] Salt: The term "pharmaceutically acceptable" is used herein to mean a compound, material, composition, and / or formulation that, according to generally accepted medical opinion, is suitable for use in combination with human and / or animal tissues and does not have or produce any excessive toxicity, irritation, or immune response or cause other problems or complications, i.e., corresponds to an acceptable risk / benefit ratio overall. The term "pharmaceutically acceptable salt" refers to derivatives of the disclosed chemical compounds in which the parent compound is modified by the addition of an acid or base. Examples of pharmaceutically acceptable salts include (but are not limited to): salts of inorganic or organic acids with a basic functional group, such as amines, or salts of alkali metals or organic salts with an acidic functional group, such as carboxylic acids. These salts specifically include acetates, ascorbic acid salts, benzenesulfonates, benzoates, benzenesulfonates, bicarbonates, tartrates, bromides / hydrobromides, calcium EDTA / EDTA, camphorsulfonates, carbonates, chlorides / hydrochlorides, citrates, ethanedisulfonates, ethanedisulfonates, propionate, estolate, esylate, fumarate, glucono-p-oxophosphate, gluconate, glutamate, glycolate, glycolyllarsnilate, hexylresorcinate, hydrabamine, hydroxymaleate, hydroxynaphthylcarboxylate, iodides, isothionates, and lactates. Lacturonate, malate, maleate, mandelate, methanesulphonate, mesylate, methyl bromide, methyl nitrate, methyl sulfate, mucilage, naphthalene sulfonate, nitrate, oxalate, dihydroxynaphthalate, pantothenate, phenylacetate, phosphate / hydrogen phosphate, polygalacturonate, propionate, salicylate, stearate, subacetate, succinate, sulfonamide, sulfate, tannin, tartrate, teoclate, toluene sulfonate, triethiodide, ammonium, benzathine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine, and procaine. Other pharmaceutically acceptable salts can be formed from cations of metals such as aluminum, calcium, lithium, magnesium, potassium, sodium, zinc, etc. (see also Pharmaceuticalsalts, Birge, SM et al., J. Pharm.Sci., (1977), 66, 1-19).

[0130] As used herein, the terms “isotope” and “isotopic” with respect to the compounds disclosed herein refer to the substitution of one or more atoms of the compound by an isotope of one or more such atoms. “Isotope” refers to any two or more forms of a chemical element having the same number of protons in its nucleus but different numbers of neutrons. For example, an isotopic compound includes a compound in which one or more hydrogen atoms (H) have been substituted by one or more deuterium atoms (D). In this example, deuterium is an isotope of hydrogen, and substituting hydrogen atoms (at one or more positions) with deuterium makes the resulting compound an isotopic compound. For example, and referring to formula (I), replacing the two methyl groups of the isopropyl moiety (-CH(CH3)2) with a fully deuterated methyl group (-CH(CD3)2) would result in an isotopic compound of formula (I). Besides replacing hydrogen with deuterium, other stable (non-radioactive) isotopic substitutions include replacing carbon-12 with carbon-13, while unstable (radioactive) isotopes include replacing hydrogen with tritium, replacing carbon-12 with carbon-14, and replacing iodine-127 with iodine-123 or iodine-125, etc. Therefore, all references herein to isotopic compounds of formula (I) and to all embodiments thereof relate to compounds having one or more isotopic substitutions, including (but not limited to) one or more hydrogen atoms being replaced by one or more deuterium atoms, and any occurrence thereof in the compound. For this purpose, the isotopic compounds disclosed herein offer advantages relative to their non-isotopic forms. Isotopic modification thus provides a means to improve existing drugs and / or serves as a tool in new drug design. For example, isotopic drug design has already proven successful in the case of deuterium (D) kinetic isotope effects. Because D has twice the mass of H, the CD bond is much more resistant to oxidation processes (such as its ability to be catalyzed by CYP450 or other enzymes involved in metabolism), while maintaining very similar spatial properties. Therefore, HD electron isosteric substitution typically preserves the pharmacodynamics of a compound while improving its pharmacokinetics, thereby affecting half-life and / or area under the curve (AUC), and ultimately influencing dosage and / or dosing regimens. For example, drug exposure can be enhanced by isotopic modification and / or reduced clearance. These benefits are provided to the compounds disclosed herein through their isotopic derivatization.

[0131] Terms such as “subject” and “patient” refer to animals, such as mammals, that are already or will be the subject of treatment, observation, or experimentation. The methods described herein are applicable to human treatment and veterinary applications. In some embodiments, the subject is a mammal; in some embodiments, the subject is a human; and in some embodiments, the subject is selected from cats and dogs. “Subject in need” or “person in need” refers to a subject, such as a human, who may have or is suspected of having a disease or condition that would benefit from a particular treatment (e.g., treatment with a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or cocrystal thereof). This includes subjects who may be identified as being at risk or susceptible to such a disease or condition so that treatment will prevent the development of the disease or condition.

[0132] Pharmaceutically acceptable salts of the present invention can be prepared from parent compounds carrying basic or acidic functional groups by conventional chemical methods. Typically, such salts can be synthesized by reacting the free acidic or basic form of these compounds with a sufficient amount of the corresponding base or acid in water or an organic solvent, such as ether, ethyl acetate, ethanol, isopropanol, acetonitrile (or mixtures thereof). Salts of acids other than those described above (e.g., trifluoroacetates) that can be used, for example, to purify or isolate the compound from the reaction mixture are also considered part of the present invention.

[0133] As used herein, the phrase "pharmaceutically acceptable excipient" or "pharmaceutically acceptable carrier" refers to a pharmaceutically acceptable material, composition, or medium, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material, which participates in carrying or transporting the chemicals involved from one organ or site of the body to another. Each carrier must be "acceptable" in the sense of compatibility with other components of the formulation, harmlessness to the patient, and substantially pyrogen-free. Some examples of materials that can serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose, and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; (4) powdered tragacanth gum; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerol, sorbitol, mannitol, and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffers, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) (18) Isotonic saline; (19) Ringer's solution; (20) ethanol; (21) phosphate buffer solution; and (22) other non-toxic and compatible substances used in pharmaceutical preparations. In some embodiments, the pharmaceutical compositions of the present invention are pyrogen-free, i.e., do not induce a significant increase in temperature when administered to a patient.

[0134] The compounds of the present invention may optionally exist as racemic derivatives, but may also be obtained as pure enantiomers, i.e., in (R) or (S) form. Preferably, compounds having a specific stereochemistry of formula Ia are preferred.

[0135] The present invention relates to the compounds discussed, optionally in the form of individual optical isomers, diastereomers, mixtures of diastereomers, mixtures of individual enantiomers, or racemic compounds, tautomers, and free bases or corresponding acid addition salts with pharmacologically acceptable acids, such as acid addition salts with hydrohalic acids (e.g., hydrochloric acid or hydrobromic acid) or organic acids (e.g., oxalic acid, fumaric acid, diethylene glycol, or methanesulfonic acid).

[0136] This invention relates to compounds of formula I in their pharmacologically acceptable salt form. These pharmacologically acceptable salts of the compounds of formulas I and Ia may also exist as their respective hydrates (e.g., monohydrates, dihydrates, etc.) and as their respective solvates.

[0137] For the purposes of this invention, a hydrate of a compound according to Formula I refers to a crystalline salt of a compound according to Formula I containing water of crystallization.

[0138] For the purposes of this invention, a solvate of a compound according to Formula I refers to a crystalline salt of a compound according to Formula I that contains solvent molecules (e.g., ethanol, methanol, etc.) in a crystal lattice.

[0139] combination Compounds of Formula I can be used alone or in combination with other active substances of Formula I according to the invention. Compounds of Formula I can also optionally be used in combination with other pharmacologically active substances. Preferably, the active substances used herein can be selected from, for example, anti-IL17, bispecific antibody IL23p19 / TNF, fecal grafts, aminosalicylate (5-ASA), Cox-2 inhibitors, corticosteroids, azathioprine, cyclosporine, tacrolimus, 6-mercaptopurine, and / or antibiotics (such as ciprofloxacin, metronidazole, ampicillin).

[0140] preparation The compounds of Formula I according to the invention also possess properties necessary for the manufacture of suitable pharmaceutical dosage forms. These properties include, for example, those related to sufficient bioavailability of the active ingredient, particularly its sufficiently high solubility, such as >2 µg / ml solubility measured in an aqueous solution at pH 6.8.

[0141] Suitable forms for administration include, for example, tablets, capsules, solutions, syrups, emulsions, or inhalable powders or aerosols. In each case, the amount of the pharmaceutically effective compound should be in the range of 0.1 to 90% by weight of the total composition, preferably 0.5 to 50% by weight, sufficient to achieve the dosage range specified below.

[0142] This formulation can be administered orally in the form of tablets, powder, powder in capsules (e.g., hard gelatin capsules), solution, or suspension. When administered by inhalation, the active ingredient combination can be administered as a powder, as an aqueous solution or water-ethanol solution, or as a propellant gas formulation.

[0143] Therefore, preferably, the pharmaceutical preparation is characterized by the content of one or more compounds of Formula I according to the above preferred embodiments.

[0144] Particularly preferred are the compounds of Formula I administered orally, and equally preferred are they administered once or twice daily. Suitable tablets can be obtained, for example, by mixing the active substance with known excipients, such as inert diluents like calcium carbonate, calcium phosphate, or lactose, disintegrants like corn starch or alginate, binders like starch or gelatin, lubricants like magnesium stearate or talc, and / or delayed-release agents like carboxymethyl cellulose, cellulose phthalate acetate, or polyvinyl acetate. Tablets may also comprise several layers.

[0145] Accordingly, coated tablets can be prepared by coating a core similar to that used in tablet coatings, using substances commonly used for tablet coatings, such as collidone or shellac, gum arabic, talc, titanium dioxide, or sugar. To achieve delayed release or prevent incompatibility, the core can also consist of multiple layers. Similarly, tablet coatings can consist of multiple layers to achieve delayed release, possibly using the excipients mentioned above for tablets.

[0146] Syrups containing the active substances or combinations thereof according to the invention may additionally contain sweeteners such as saccharin, cyclamate, glycerin or sugar, and flavor enhancers such as flavoring agents like vanillin or orange extract. They may also contain suspending agents or thickeners such as sodium carboxymethyl cellulose, wetting agents such as condensation products of fatty alcohols and ethylene oxide, or preservatives such as parabens.

[0147] Capsules containing one or more active substances or combinations thereof can be prepared, for example, by mixing the active substances with an inert carrier such as lactose or sorbitol and encapsulating them in a gelatin capsule. Suitable suppositories can be manufactured, for example, by mixing with a carrier provided for this purpose, such as neutral fats or polyethylene glycol or derivatives thereof.

[0148] Excipients that may be used include, for example, water, pharmaceutically acceptable organic solvents such as paraffin (e.g., petroleum fractions), vegetable oils (e.g., peanut oil or sesame oil), monofunctional or polyfunctional alcohols (e.g., ethanol or glycerol), carriers such as natural mineral powders (e.g., kaolin, clay, talc, chalk), synthetic mineral powders (e.g., highly dispersed silica and silicates), sugars (e.g., sucrose, lactose, and glucose), emulsifiers (e.g., lignin, sulfite waste, methylcellulose, starch, and polyvinylpyrrolidone), and lubricants (e.g., magnesium stearate, talc, stearic acid, and sodium dodecyl sulfate).

[0149] For oral administration, in addition to the carriers mentioned above, tablets may also contain additives such as sodium citrate, calcium carbonate, and dicalcium phosphate, as well as various additives such as starch, preferably potato starch, gelatin, etc. Furthermore, lubricants such as magnesium stearate, sodium dodecyl sulfate, and talc can be used simultaneously in the tableting process. In the case of aqueous suspensions, in addition to the excipients mentioned above, the active ingredient can also be combined with various flavor enhancers or colorants.

[0150] It is also preferred that the compounds of Formula I be administered by inhalation, particularly preferably once or twice daily. For this purpose, the compounds of Formula I must be supplied in a form suitable for inhalation. Inhalable formulations include inhalable powders, propellant-containing metered aerosols, or propellant-free inhalable solutions, optionally mixed with excipients that are generally physiologically acceptable.

[0151] Within the scope of this invention, the term "propellant-free inhalable solution" also includes concentrates or sterile, ready-to-use inhalable solutions. Formulations usable according to the invention are described in more detail in the next section of this specification.

[0152] Exemplary methods – indications In some embodiments, the present invention relates to a method for treating a disease or condition selected from the group consisting of inflammatory bowel disease, small intestinal bacterial overgrowth (SIBO), eosinophilic gastrointestinal disease (EGID), enteritis, enteropathy associated with seronegative arthropathy, intestinal flora imbalance, microscopic or collagenous colitis, cholecystitis, cholangitis, pericholangitis, inflammatory gastrointestinal cancer associated with familial adenomatous polyposis (FAP), intestinal graft-versus-host disease (GVHD), celiac disease, chronic pouchitis, and checkpoint inhibitor-associated colitis, comprising the step of administering a therapeutically effective amount of any of the above compounds to a subject in need.

[0153] In some implementations, the disease or condition is inflammatory bowel disease. In some implementations, the inflammatory bowel disease is colitis, Crohn's disease, ileitis, celiac disease, nontropical stomatitis, enteropathy associated with seronegative arthropathy, gastroenteritis, or pouchitis.

[0154] In some implementations, the disease or condition is Crohn's disease.

[0155] In some implementations, the disease or condition is colitis.

[0156] In some implementations, the disease or condition is ulcerative colitis.

[0157] In some embodiments, the present invention relates to any of the aforementioned methods, wherein the subject is a mammal. In some embodiments, the present invention relates to any of the aforementioned methods, wherein the subject is a human.

[0158] synthesis The compounds described herein can be prepared by methods known in the art, and are illustrated by the following non-limiting description.

[0159] Unless otherwise stated, all reactions are generally carried out under an inert atmosphere (e.g., nitrogen). The following abbreviations are used in this document: ss = saturated solution ON = overnight List of abbreviations ACN or MeCN CH3CN, acetonitrile AcOH (acetic acid) aq. water-based 9-BBN 9-Borobicyclo[3.3.1]nonane BINAP (2,2'-bis(diphenylphosphino)-1,1'-binaphthyl) Boc tert-butoxycarbonyl nBuLi n-Butyllithium CDCl3 (deuterated chloroform) C6H5N pyridine CO2 (carbon dioxide) Cs2CO3 (cesium carbonate) CuCl cuprous chloride CuI cuprous iodide CV column volume DCM dichloromethane DCE 1,2-Dichloroethane DIPEA (Diisopropylethylamine) DMAP (Dimethylpyridin-4-ylamine) DMF N,N-dimethylformamide DMSO (dimethyl sulfoxide) EDTA (ethylenediaminetetraacetic acid) EtOAc or EA (ethyl acetate) EtOH (ethanol) Et2O diethyl ether FA Formic acid FC or FCC rapid chromatography h or hr hours H2 hydrogen gas H2O2 Hydrogen peroxide HATU 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide HCl (hydrogen chloride) HPLC (High Performance Liquid Chromatography) KF potassium fluoride KOAc potassium acetate K2CO3 (potassium carbonate) K3PO4 Potassium phosphate LCMS (Liquid Chromatography-Mass Spectrometry) LiHMDS (Lithium Hexamethyldisilamide) LiOH (Lithium hydroxide) M Moore MgSO4 Magnesium sulfate MnO2 Manganese dioxide Min minutes mL MS mass spectrometry MW microwave N Standard (Concentration) N2 nitrogen gas NaBH3CN Sodium cyanoborohydride NaBH4 sodium borohydride Sodium hydride (NaH) NaOH (sodium hydroxide) Na2SO3 Sodium sulfite Na2SO4 Sodium sulfate NH3 ammonia NH4Cl ammonium chloride NH4OH ammonium hydroxide NaHCO3 (Sodium bicarbonate) Na2CO3 (Sodium carbonate) NMR nuclear resonance spectroscopy ON or on overnight PD / C Palladium / Carbon Pd(dppf)Cl2 cyclopentyl(diphenylphosphine) dichloromethane dichloropalladium iron Pd(OAc)2 Palladium acetate PE petroleum ether pin pineol PPh3 triphenylphosphine MeOH (methanol) IPA isopropanol Int. intermediate THF Tetrahydrofuran DIBAL (Diisobutylaluminum hydride) rac racemic RP inversion RPM (revolutions per minute) RT or rt room temperature RTP at room temperature and atmospheric pressure SFC Supercritical Fluid Chromatography SCX strong cation exchange resin STAB sodium triacetoxyborohydride TBAB Tetrabutylammonium bromide TBME tert-butyl methyl ether TEA Triethylamine T3P propionic anhydride tert Uncle TFA (trifluoroacetic acid) THF Tetrahydrofuran Ti(OEt)4 Tetraethoxytitanium Rt Retention time [min] TRIS Tris(hydroxymethyl)aminomethane tBuXPhos 2-Di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl wt% Weight percentage sat. Saturated uPLC Ultra performance liquid chromatography uL Microliter Ar Aromatic

[0160] From the following more detailed examples, other features and advantages of the present invention will become apparent, which exemplify the principles of the present invention without limiting its scope.

[0161] General rules Unless otherwise stated, all reactions were carried out in commercially available equipment using methods commonly used in chemical laboratories. Starting materials sensitive to air and / or moisture were stored under a protective gas, and their corresponding reactions and operations were carried out under a protective gas (nitrogen or argon).

[0162] Analysis methods The LCMS conditions were as follows: System 1 (S1): Acidic IPC method Analytical (MET / uPLC / 1704) uHPLC-MS was performed on a Waters Acquity uPLC system using a Waters UPLC® BEH C18 column (2.1 mm × 50 mm, 1.7 µm; temperature 40 °C) and a gradient of 5 - 100% B over 1.1 minutes (A = 0.1% formic acid / H2O2-H: B = 0.1% formic acid / MeCN), then 100% B for 0.25 minutes. Then a second gradient of 100 - 5% B was applied over 0.05 minutes and held for 0.1 minutes, the injection volume was 1 µL, and the flow rate was 0.9 mL / min. The UV spectrum was recorded at 215 nm on a Waters Acquity PDA with a spectral range of 200 - 400 nm. The mass spectrum was obtained using a Waters QDa. The data was integrated and reported using Waters MassLynx and OpenLynx software, and the retention time (Rt) was reported in minutes.

[0163] System 2 (S2): Basic IPC method Analytical (MET / uPLC / AB2010) (M15) UHPLC-MS was performed using a Waters UPLC™ BEH™ C18 column (2.1 mm × 30 mm, 1.7 μm; temperature 55 °C) reversed-phase. The injection volume was 1 µL, the flow rate was 1.0 mL / min, and a gradient of 1–100% B was applied for 1.10 min, followed by 100% B for 0.25 min, where A = 2 mM ammonium bicarbonate / water, buffered to pH 10, and B = acetonitrile. A second gradient of 100–1% B was then applied for 0.05 min and held for 0.40 min. UV spectra were recorded at 215 nm; spectral range: 200–400 nm. Mass spectra were obtained using a Waters QuattroPremier XE or SQD2; ionization mode: electrospray ionization positive or negative. The data was integrated and reported using Waters MassLynx and OpenLynx software, with retention time (Rt) reported in minutes.

[0164] System 3 (S3): Acidic Final Method A Phenomenex Kinetex-XB C18 column (2.1 mm × 100 mm, 1.7 µM; 40 °C) was used on a Waters Acquity uPLC system with a 5-100% B gradient (A = 0.1% formic acid / H₂O; B = 0.1% formic acid / MeCN) for 5.3 min, followed by 0.25 min of 100% B for analytical (MET / uPLC / AB101) uHPLC-MS. A second gradient of 100-5% B was then applied for 0.02 min and held for 1.18 min, with an injection volume of 1 µL and a flow rate of 0.6 mL / min. UV spectra were recorded at 215 nm using a Waters Acquity PDA detector, with a spectral range of 200-400 nm. Mass spectra were obtained using a Waters SQD or Waters Acquity QDA detector. The data was integrated and reported using Waters MassLynx and OpenLynx software, with retention time (Rt) reported in minutes.

[0165] System 4 (S4): Alkaline Final Method A Waters UPLC® BEH™ C18 column (2.1 mm × 100 mm, 1.7 µm column; temperature 40 °C) was used on a Waters Acquity uPLC system with a 5-100% gradient (A = 2 mM ammonium bicarbonate, buffered to pH 10; B = MeCN) for 5.3 min, followed by 0.5 min of 100% B for analytical (MET / uHPLC / AB105) uPLC-MS. A second gradient of 100-5% B was then applied for 0.02 min and held for 1.18 min, with an injection volume of 1 µL and a flow rate of 0.6 mL / min. UV spectra were recorded at 215 nm using a Waters Acquity photodiode array detector, with a spectral range of 200-400 nm. Mass spectra were obtained using a Waters Quattro Premier XE mass detector. Data were integrated and reported using Waters MassLynx and OpenLynx software, with retention times (Rt) reported in minutes.

[0166] System 5 (S5): Neutral Final Method Analytical UHPLC-MS was performed on an Agilent 1260 system using an Agilent Poroshell 120 EC-C18 column (2.1 mm × 50 mm, 1.9 µm; temperature 50 °C) in binary gradient mode (A = 10 mM NH4OAc / H2O: B = ACN) at 0.8 mL / min for 4.5 min (1% B 0.25 min, then linearly increased to 100% B over 2.25 min, then 100% B 0.40 min, then back to initial conditions over 0.1 min). The default injection volume was 0.2 µL. UV spectra were recorded at 220 and 254 nm on an Agilent PDA, with a spectral range of 190–400 nm. Mass spectra were obtained using an Agilent 6490A QQQ (Agilent Jet Stream source) with positive or negative electrospray ionization. The data is utilized using the Agilent MassHunter software suite, and the retention time (Rt) is reported in minutes.

[0167] System 6 (S6): Neutral IPC Method 1 Analytical UHPLC-MS was performed on an Agilent 1260 system using an Agilent Poroshell 120 EC-C18 column (2.1 mm × 50 mm, 1.9 µm; temperature 50 °C) in binary gradient mode (A = 10 mM NH4OAc / H2O: B = ACN) at 0.8 mL / min for 4.2 min (1% B 0.25 min, then linearly increased to 100% B over 2.25 min, then 100% B 0.40 min, then back to initial conditions over 0.1 min). The default injection volume was 1 µL. UV spectra were recorded at 220 and 254 nm on an Agilent PDA, with a spectral range of 190–400 nm. Mass spectra were obtained using an Agilent 6120B SQ with simultaneous positive and negative electrospray ionization. Data were utilized using Agilent OpenLab software, with retention times (Rt) reported in minutes.

[0168] System 7 (S7): Neutral IPC Method 2 Analytical UHPLC-MS was performed on an Agilent 1260 system using an Agilent Poroshell 120 EC-C18 column (2.1 mm × 50 mm, 2.7 µm; temperature 50 °C) in binary gradient mode (A = 10 mM NH4OAc / H2O: B = ACN) at 1.0 mL / min for 3.8 min (0.5% B 0.10 min, then linearly increased to 100% B over 1.6 min, then 100% B 0.40 min, then back to initial conditions over 0.1 min). The default injection volume was 1 µL. UV spectra were recorded at 220 and 254 nm on an Agilent PDA, with a spectral range of 190–400 nm. Mass spectra were obtained using an Agilent 6120B SQ with simultaneous positive and negative electrospray ionization. Data were utilized using Agilent OpenLab software, with retention times (Rt) reported in minutes.

[0169] System 8 (S8): Acidic Delayed Elution IPC Method Analytical (MET / uPLC / 1906) (M12) UHPLC-MS was performed using a Waters UPLC™ CORTECS™ C8 column (2.1 mm × 50 mm, 1.6 µm; temperature 40 °C) at a flow rate of 0.9 mL / min with an injection volume of 1 μL and a gradient of 5% to 100% B over 1.10 min, followed by 100% B over 0.30 min, where A = 0.1% formic acid aqueous solution and B = 0.1% formic acid acetonitrile solution. A second gradient of 100% to 5% B was then applied over 0.02 min and held for 0.28 min. UV spectra were recorded at 215 nm; spectral range: 200–400 nm. ELS data were collected using a Waters ELS detector for reporting. Mass spectra were obtained using a Waters SQD2 or QDa; ionization mode: electrospray positive or negative ion. The data was integrated and reported using Waters MassLynx and OpenLynx software, with retention time (Rt) reported in minutes.

[0170] The purification method is as follows: Purify the compound using one of the following methods: normal-phase or reversed-phase automated rapid column chromatography on silica gel or C-18 silica gel (e.g., Biotage™ Isolera or Selekt instruments); open-access reversed-phase preparative HPLC (methods detailed below, pp. 1-4); and custom-developed reversed-phase preparative HPLC methods.

[0171] Method 1: Early acidic elution method (P1) Purification was performed on a Gilson LC system using a Waters Sunfire C18 column (30 mm × 100 mm, 10 μM; temperature: RT) with a 10-95% B gradient (A = 0.1% formic acid / H₂O; B = 0.1% formic acid / MeCN) for 14.44 min, followed by 2.11 min of 95% B (P1) LC. A second gradient of 95-10% B was then applied over 0.2 min at an injection volume of 1500 μL and a flow rate of 40 mL / min. UV spectra were recorded at 215 nm using a Gilson detector.

[0172] Method 2: Acidic Standard Method (P2) Purification was performed on a Gilson LC system using a Waters Sunfire C18 column (30 mm × 100 mm, 10 μM; temperature: RT) with a gradient of 30–95% B for 11.00 min (A = 0.1% formic acid / water; B = 0.1% formic acid / MeCN), followed by 2.00 min of 95% B for (P2) LC. A second gradient of 95–30% B was then applied for 0.2 min at an injection volume of 1500 μL and a flow rate of 40 mL / min. UV spectra were recorded at 215 nm using a Gilson detector.

[0173] Method 3: Early alkaline elution method (P3) Purification was performed using reverse-phase (P3) LC on a Waters XBridge™ C18 column (30 mm × 100 mm, 5 μm; temperature: room temperature) at an injection volume of 1500 μL and a flow rate of 40 mL / min. The solution was incubated at 10% B for 2.00 min, followed by a 10–95% B gradient for 14.00 min and a hold for 2.00 min, where A = 0.2% NH4OH / water and B = MeCN. A second gradient of 95–10% B was then applied for 0.20 min and held for 1.25 min. UV spectra were recorded at 215 nm.

[0174] Method 4: Alkaline Standard Method (P4) Purification was performed using a Waters XBridge™ C18 column (30 mm × 100 mm, 5 μm; temperature: room temperature) via reverse-phase (P4) LC at an injection volume of 1500 μL and a flow rate of 40 mL / min. The incubation was carried out at 30% B for 2.00 min, followed by a gradient of 30–95% B for 9.50 min and a hold for 1.97 min, where A = 0.2% NH4OH / water and B = MeCN. A second gradient of 95–30% B was then applied over 0.33 min and held for 1.65 min. UV spectra were recorded at 215 nm.

[0175] Chiral separation methods: LC method: Chiral separation was performed on a Gilson LC column at room temperature; isocratic eluent; flow rate: 18 mL / min; detector wavelength: 215 / 254 nm; dilution solvent: IPA; injection volume: 100-1000 µL. SFC method: Chiral separation was performed on a Waters Thar SFC column at 40°C; isocratic eluent; back pressure: 120 bar; flow rate: 15 mL / min; dilution solvent: MeOH / acetonitrile; injection volume: 250 µL. The NMR method is as follows: Method 1, NMR (N1) Unless otherwise specified, records were taken at 500 MHz, 400 MHz, or 250 MHz on a Bruker Avance III HD 500 MHz spectrometer, a Bruker Avance III HD 400 MHz spectrometer, or a Bruker Avance III HD 250 MHz spectrometer, respectively. 1 1H NMR spectra. Chemical shifts δ are expressed in parts per million (ppm) and referenced to residual solvent peaks. The following abbreviations are used to denote multiplicity and general assignments: s (singlet), d (doublet), t (triplet), q (quartet), dd (doublet), ddd (doublet of doublets), dt (doublet of doublets), dq (doublet of quartets), hep (septet), m (multiplet), pent (quintet), td (triple doublet), qd (quartet), app. (apparent), and br. (broad). The coupling constant J is given accurate to 0.1 Hz.

[0176] Method 2, NMR: (N2) Unless otherwise stated, in cases with dual z-grad 1 Recordings were taken at 300 K on a Bruker 300 MHz Fourier transform spectrometer with an H / 13C probe, or at 298 K on a Bruker 500 MHz AVIIIHD spectrometer with a N2-cooled z-grad broadband CPP BBO probe, at 300 MHz or 500 MHz. 1 1H NMR spectra. Chemical shifts δ are expressed in parts per million (ppm) and referenced to residual solvent peaks. The following abbreviations are used to denote multiplicity and general assignments: s (singlet), d (doublet), t (triplet), q (quartet), dd (doublet), ddd (doublet of doublets), dt (doublet of doublets), dq (doublet of quartets), hep (septet), m (multiplet), pent (quintet), td (triple doublet), qd (quartet), app. (apparent), and br. (broad). The coupling constant J is given accurate to 0.1 Hz.

[0177] General Synthesis Unless otherwise stated, all compounds were synthesized with a purity greater than 95%.

[0178] Diagram of General Route 1a Synthesis of intermediate A1 (R)-N-[(E)-(5-bromo-2,3-difluorophenyl)methylidene]-2-methylpropane-2-sulfonamide (Step B) Titanium ethoxide (IV) (35 mL, 0.170 mol) was added dropwise to a stirred solution of 5-bromo-2,3-difluorobenzaldehyde (25.00 g, 0.113 mol) and (R)-2-methylpropane-2-sulfinamide (15.08 g, 0.124 mol) in anhydrous THF (300 mL) at room temperature. The reaction mixture was stirred at room temperature for 1 hour, followed by stirring at 40 °C for 1.5 hours. The reaction mixture was poured into a mixture of water (300 mL) and EtOAc (200 mL) and stirred vigorously for 10 minutes. The suspension was then sonicated and filtered, and washed with EtOAc (200 mL). The organic layer was separated, and the aqueous phase was extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (2 × 100 mL), dried over MgSO4 and concentrated under vacuum to give the title product as a white solid (33.74 g, 87% yield).

[0179] LCMS m / z: 323.9 / 325.9 [M+H]+, (ESI+), Rt = 1.08 (S1) 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 8.61 (s, 1H), 8.09 (ddd, J = 9.8,7.1, 2.5 Hz,1H), 7.95 (dt, J = 5.3, 2.2 Hz, 1H), 1.20 (s, 9H).

[0180] Synthesis of intermediate A2 (3S)-3-(5-bromo-2,3-difluorophenyl)-3-{[(R)-2-methylpropane-2-sulfinyl]amino}propionic acid ethyl ester (Step C) (3S)-3-{4,5-difluoro-2',6'-dimethyl-[1,1'-biphenyl]-3-yl}-3-{[(R)-2-methylpropane-2- sulfinyl]amino}propionic acid ethyl ester (Step D) Condition A A stirred suspension of activated zinc powder (26.91 g, 0.411 mol) in anhydrous THF (350 mL) was treated dropwise over 20 minutes at 65 °C under N2 with ethyl 2-bromoacetic acid (29 mL, 0.257 mol). The solution was stirred at 65 °C for 1.5 hours, then cooled to room temperature and allowed to settle for 30 minutes. This organozinc solution was added over 5 minutes at 65 °C under N2 to a stirred solution of (R)-N-[(E)-(5-bromo-2,3-difluorophenyl)methylene]-2-methylpropane-2-sulfinamide (35.10 g, 0.103 mol) in anhydrous THF (350 mL). The reaction was stirred at 65 °C for 1.5 hours, then cooled and poured into a mixture of TBME (400 mL) and 10% citric acid (600 mL). The organic layer was separated, and the aqueous layer was extracted with TBME (3 × 150 mL). The combined organic layers were washed with brine (2 × 150 mL), dried over MgSO4, and concentrated under vacuum to give the crude product. Purification was performed by column chromatography (approximately 300 g silica, 0–70% EtOAc / heptane) to give the title product as orange oil (29.40 g, 55% yield).

[0181] Condition B A stirred suspension of activated zinc powder (39.87 g, 0.610 mol) in THF (400 mL) was added at room temperature under N2 at 65 °C with copper chloride (1+) (7.54 g, 76.2 mmol). The suspension was heated at 65 °C for 30 min. Heating was stopped, and ethyl 2-bromoacetate (34 mL, 0.305 mol) was added dropwise over 15 min to achieve reflux (note: highly exothermic). After the addition was complete, the reaction mixture was stirred at 65 °C for another 1 h. The reaction was cooled to -5 °C, and a solution of (R)-N-[(E)-(5-bromo-2,3-difluorophenyl)methylene]-2-methylpropane-2-sulfinamide (95%, 52.00 g, 0.152 mol) in THF (200 mL) was added dropwise over 10 min. The reaction was stirred at -5 °C for 30 min, and then at 0 °C for 45 min. The reaction was performed by filtration through diatomaceous earth and washing with TBME (~200 mL). The filtrate was poured into 10% citric acid (300 mL) to separate the organic layer. The aqueous layer was extracted with TBME (2 × 150 mL). The combined organic layers were washed with brine (150 mL), dried over MgSO4, and concentrated under vacuum. Purification was performed by column chromatography (340 g silica, 20-35% acetone / heptane) to give the title product as a yellow oil (63.26 g, 84% pure, 55% yield).

[0182] LCMS m / z: 412.4 / 414.2 [M+H]+, (ESI+), Rt = 0.98 (S1) 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 7.74 (ddd, J = 9.6, 6.9, 2.4 Hz, 1H), 7.57 (dt, J = 5.4, 2.1 Hz, 1H), 5.85 (d, J = 7.0 Hz, 1H), 4.95 (d, J =7.2 Hz, 1H), 4.07 – 3.97 (m, 2H), 3.02 (dd, J = 15.8, 7.2Hz, 1H), 2.90 (dd, J= 15.8, 7.5 Hz, 1H), 1.13 (t, J = 7.1 Hz, 3H), 1.06 (s, 9H).

[0183] Synthesis of intermediate A3 Step E: (3S)-3-amino-3-{4,5-difluoro-2',6'-dimethyl-[1,1'-biphenyl]-3-yl}propionic acid ethyl ester hydrochloride salt (Step E) 5-bromo-2-fluoro-3-(trifluoromethyl)benzaldehyde (Step A) Ethyl (3S)-3-(5-bromo-2,3-difluorophenyl)-3-{[(R)-2-methylpropane-2-sulfinyl]amino}propionate (20.00 g, 38.3 mmol), (2,6-dimethylphenyl)boronic acid (11.50 g, 76.6 mmol), and K₂CO₃ (15.89 g, 0.115 mol) in 1,4-dioxane (110 mL) and water (8 mL) were degassed for 10 min. Pd(dppf)Cl₂ (1.57 g, 1.92 mmol) was added, and the reaction was stirred at 100 °C under N₂ for 4 h. The reaction was cooled, poured into water (400 mL), and extracted with EtOAc (4 × 150 mL). The combined organic layers were washed with brine (2 × 100 mL), dried over MgSO₄, and concentrated to give the crude product. Purification by column chromatography (350 g silica; 10%-100% EtOAc / heptane, then 0-20% MeOH / EtOAc) yielded the title product as brown oil (8.25 g, 44% yield).

[0184] LCMS m / z: 438.4 [M+H]+, (ESI+), Rt = 1.14 (S1).

[0185] Synthesis of intermediate A4 (R)-N-[(E)-(5-bromo-2-fluoro-3-methylphenyl)methylidene]-2-methylpropane-2-sulfonamide (Step A) (3S)-3-(5-bromo-2-fluoro-3-methylphenyl)-3-{[(R)-2-methylpropane-2-sulfinyl]amino}propionic acid ethyl ester (Step B) Ethyl (3S)-3-{4,5-difluoro-2',6'-dimethyl-[1,1'-biphenyl]-3-yl}-3-{[(R)-2-methylpropane-2-sulfinyl]amino}propionate (9.63 g, 18.3 mmol) in a stirred solution in DCM (100 mL) was treated with HCl (4 M in dioxane, 9.1 mL, 36.5 mmol) at room temperature. The reaction mixture was stirred at room temperature for 2 hours and then concentrated under vacuum. Purification by column chromatography on silica gel (50 g silica, 0%–40% MeOH / EtOAc) gave the title product (7.38 g, 94% yield) as an orange solid.

[0186] LCMS m / z: 334.1 [M+H]+, (ESI+), Rt = 0.71 (S1) 1 H NMR (500 MHz, DMSO-d6) δ [ppm]: 8.80 (s, 3H), 7.42 – 7.35 (m, 1H), 7.35 – 7.27 (m, 1H), 7.22 – 7.17 (m, 1H), 7.17 – 7.09 (m, 2H), 4.95 – 4.81(m, 1H), 4.08 –3.94 (m, 2H), 3.25 – 3.17 (m, 1H), 3.17 – 3.03 (m, 1H), 2.03(s, 3H), 1.95 (s,3H), 1.08 (t, J = 7.1 Hz, 3H). (N1).

[0187] Synthesis of intermediate A5 (3S)-3-amino-3-(5-bromo-2-fluoro-3-methylphenyl)propionic acid ethyl ester hydrochloride salt (Step C) At -78 °C, LDA (1 M in THF, 31 mL, 30.9 mmol) was added dropwise over 1 hour to a solution of 4-bromo-1-fluoro-2-(trifluoromethyl)benzene (5.00 g, 20.6 mmol) in THF (39 mL). After 1 hour at -78 °C, DMF (1.6 mL, 20.6 mmol) was added dropwise, and the reaction mixture was stirred at -78 °C for another 2 hours. The reaction was quenched with NH4Cl (50 mL saturated aqueous solution) at 0 °C and extracted with EtOAc (3 × 60 mL). The combined organic layers were washed with brine (80 mL), dried over MgSO4, and concentrated under vacuum to give a crude residue. Purification by column chromatography (25 g silica, 0–25% EtOAc / heptane) gave the title product (2.40 g, 38% yield) as a yellow oil.

[0188] LCMS m / z: No mass-charged ions observed, Rt = 0.87, S8 1 H NMR (400 MHz, CDCl3) δ [ppm]: 10.34 (s, 1H), 8.18 (dd, J = 5.6, 2.6 Hz, 1H), 7.97 (dd, J = 6.1, 2.6 Hz, 1H). (N1).

[0189] The intermediates in Table 1 were synthesized according to General Scheme 1, taking intermediate A4 (step BD) as an example, using the corresponding starting materials. Diastereomers were isolated during final purification, or, if necessary, by chiral separation methods. The intermediates were obtained as the title compound or its salts.

[0190] Table 1 .

[0191] Diagram of General Route 1b Synthesis of intermediate A11 (3S)-3-[(2S)-2-{[(tert-butoxy)carbonyl]amino}-4-methylpentanamido]-3-{4,5-difluoro-2',6'- dimethyl-[1,1'-biphenyl]-3-yl}propionic acid ethyl ester (Step A) It was prepared using 5-bromo-2-fluoro-3-methylbenzaldehyde as a starting material in a manner similar to intermediate A1.

[0192] LCMS m / z: 320.1 / 322.1 [M+H]+, (ESI+), Rt = 1.12 (S1) 1H NMR (400 MHz, CDCl3) δ [ppm]: 8.85 (s, 1H), 7.94 (dd, J = 5.6, 2.5Hz, 1H), 7.49 (dd, J = 6.5, 1.9 Hz, 1H), 2.33 (d, J = 2.2 Hz, 3H), 1.30 (s,9H).

[0193] Synthesis of intermediate A12 (1R,2S,5S)-3-{imidazo[1,2-a]pyrazine-2-carbonyl}-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2- carboxylic acid (2R)-2-{[(1S)-1-{[(1S)-1-{4,5-difluoro-2',6'-dimethyl-[1,1'-biphenyl]-3-yl]amino}formyl}-3- methoxy-3-oxopropyl]carbamoyl}-3-methylbutyl}piperidine-1-carboxylic acid tert-butyl ester It was prepared using intermediate A11 as the starting material in a manner similar to intermediate A2 and condition B.

[0194] LCMS m / z: 408.0 / 410.0 [M+H]+, (ESI+), Rt = 1.02 (S1) 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 7.55 –7.47 (m, 1H), 7.43 (d, J =6.1 Hz, 1H), 5.74 (d, J = 7.0 Hz, 1H), 4.92 (q, J = 7.2 Hz, 1H), 4.02 (q, J =7.1 Hz, 2H), 2.98 (dd, J = 15.5, 7.2 Hz, 1H), 2.82(dd, J = 15.5, 7.4 Hz, 1H), 2.21 (s, 3H), 1.18 – 1.07 (m, 3H), 1.06 (s, 9H).

[0195] Synthesis of intermediate A13 (3S)-3-{4,5-difluoro-2',6'-dimethyl-1,1'-biphenyl-3-yl}-3-[(2S)-4-methyl-2-{[(2R)- piperidin-2-yl]formamidyl}pentanamido]propionic acid methyl ester hydrochloride salt It was prepared using intermediate A12 as the starting material in a manner similar to intermediate A4, under condition B.

[0196] LCMS m / z: 304.1 / 306.1 [M+H]+, (ESI+), Rt = 0.57 (S1) 1H NMR (400 MHz, DMSO-d6) δ [ppm]: 8.69 (s, 3H), 7.82 – 7.71 (m, 1H), 7.63 – 7.54 (m, 1H), 4.87 – 4.74 (m, 1H), 4.10 – 3.94 (m, 2H), 3.16 (dd, J =15.9, 6.4 Hz, 1H), 3.05 (dd, J = 16.3, 8.8 Hz, 1H), 2.25 (d, J = 1.5 Hz, 3H), 1.16 – 1.05 (m, 3H).

[0197] The intermediates in Table 2 were synthesized according to general diagram 1B, taking intermediate A13 (step AC) as an example, using the corresponding starting materials. Diastereomers were isolated in the final purification or, if necessary, by chiral separation methods. The intermediates were obtained as the title compound or its salts.

[0198] Table 2 .

[0199] Diagram of General Route 2 Synthesis of intermediate B1 (3S)-3-[(2S)-2-[[(2R)-1-acetylpiperidin-2-yl]formamidyl]-4-methylpentanamido]-3-{4,5- difluoro-2',6'-dimethyl-[1,1'-biphenyl]-3-yl}propionic acid methyl ester 1-fluoro-4-iodo-2,3,5-trimethylbenzene (Step A) DIPEA (2.3 mL, 13.0 mmol) was added to a solution of ethyl intermediate A4 (1.85 g, 4.50 mmol) and (2S)-2-{[(tert-butoxy)carbonyl]amino}-4-methylpentanoic acid (1.30 g, 5.63 mmol) in DCM (40 mL) under stirring, followed by HATU (2.31 g, 6.08 mmol). The reaction mixture was stirred at room temperature for 72 hours. The reactants were treated again with (2S)-2-{[(tert-butoxy)carbonyl]amino}-4-methylpentanoic acid (1.30 g, 5.63 mmol) and HATU (2.31 g, 6.08 mmol) and stirred for 1 hour before dilution with water (30 mL). The organic layer was separated, and the aqueous layer was extracted with DCM (2 × 30 mL). The combined organic layers were washed with brine (30 mL), dried (MgSO4), and concentrated under vacuum to give crude oil. The title product (1.85 g, 70% yield) was purified by column chromatography (50 g silica, 5-60% EtOAc / heptane) to obtain a colorless solid.

[0200] LCMS m / z: 547.8 [M+H]+, (ESI+), Rt = 0.71 (S2) 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 8.57 – 8.33 (m, 1H), 7.22 – 7.14(m, 2H), 7.15 – 7.08 (m, 2H), 7.02 – 6.93 (m, 1H), 6.83 (d, J = 8.2 Hz, 1H),5.53 (q, J = 7.6 Hz, 1H), 4.02 (qd, J = 7.1, 4.3 Hz, 2H), 3.91 (td, J = 8.7,6.1 Hz, 1H),2.83 (d, J = 7.6 Hz, 2H), 1.95 (d, J = 7.7 Hz, 6H), 1.69 – 1.56(m, 3H), 1.31 (s, 9H), 1.12 (t, J = 6.8 Hz, 3H), 0.88 – 0.83 (m, 6H).

[0201] Synthesis of intermediate B2 2-(4-fluoro-2,3,6-trimethylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Step B) 4,4,5,5-tetramethyl-2-(2,3,6-trimethylphenyl)-1,3,2-dioxaborolane HCl (4 M in dioxane, 3.0 mL, 12.0 mmol) was added to a stirred solution of (3S)-3-[(2S)-2-{[(tert-butoxy)carbonyl]amino}-4-methylpentamido]-3-{4,5-difluoro-2',6'-dimethyl-[1,1'-biphenyl]-3-yl}propionate (1.85 g, 3.38 mmol) in DCM (15 mL). The reaction was stirred at room temperature for 18 hours. The reaction was concentrated under vacuum, and the residue was dried in a vacuum oven at 40 °C for 2 hours to give the title product (1.73 g, 97% yield) as a white solid.

[0202] LCMS m / z: 447.6 [M+H]+, (ESI+), Rt = 0.80 (S1) 1H NMR (400 MHz, DMSO-d6) δ [ppm]: 9.32 – 9.10 (m, 1H), 8.21 (s,3H), 7.29 –7.09 (m, 4H), 7.04 – 6.97 (m, 1H), 5.56 (q, J = 7.6 Hz, 1H), 4.03(qd, J = 7.1, 2.0 Hz, 2H), 3.75 (d, J = 8.4 Hz, 1H), 2.93 (d, J = 7.6 Hz,2H), 1.96 (d, J =2.4 Hz, 6H), 1.47 – 1.38 (m, 2H), 1.12 (t, J = 7.1 Hz, 3H),0.93 – 0.87 (m, 1H), 0.75 (dd, J = 13.0, 5.7 Hz, 6H). (N1).

[0203] The intermediates in Table 3 were synthesized using the corresponding starting materials according to General Scheme 2, taking intermediate B2 (step AB) as an example. Diastereomers were isolated during final purification or, if necessary, by chiral separation methods. The intermediates were obtained as the title compound or its salts.

[0204] Table 3 .

[0205] Synthesis of intermediate B17 ​ ​ ​ A solution of intermediate B4 (200 mg, 0.43 mmol) in pyridine (10 mL) was added to (2R)-1-[(tert-butoxy)carbonyl]piperidine-2-carboxylic acid (100 mg, 0.43 mmol), followed by EDC.HCl (129 mg, 0.64 mmol). The reaction mixture was stirred at room temperature for 12 hours. The solvent was removed under vacuum to obtain the residue. The residue was redissolved in EtOAc (25 mL), washed successively with NaHCO3 (saturated aqueous solution, 25 mL), water (25 mL), dried over MgSO4, and concentrated under vacuum to give the title product (200 mg, 73% yield) as a pale yellow solid.

[0206] LCMS m / z: 544.2 [M−Boc+H]+, (ESI+), Rt = 3.14 (S6).

[0207] Synthesis of intermediate B18 ​ ​ HCl (4 M in dioxane, 0.78 mL, 3.11 mmol) was added to a solution of (2R)-2-{[(1S)-1-{[(1S)-1-{4,5-difluoro-2',6'-dimethyl-[1,1'-biphenyl]-3-yl}-3-methoxy-3-oxopropyl]carbamoyl}-3-methylbutyl]carbamoyl}piperidine-1-carboxylate (intermediate B17, 200 mg, 0.311 mmol) in 1,4-dioxane (10 mL). The reaction mixture was stirred at room temperature for 4 hours. HCl (4 M in dioxane, 0.78 mL, 3.11 mmol) was added again, and the reaction mixture was stirred at room temperature for another 2 hours. The solvent was removed under vacuum to give the title product (180 mg, 100% yield) as a yellow solid.

[0208] LCMS m / z: 544.2 [M+H]+, (ESI+), Rt = 2.63 (S6) Synthesis of intermediate B19 ​ ​ Acetyl chloride (0.024 mL, 0.341 mmol) was added to a solution of methyl(3S)-3-{4,5-difluoro-2',6'-dimethyl-[1,1'-biphenyl]-3-yl}-3-[(2S)-4-methyl-2-{[(2R)-piperidin-2-yl]formamido}pentamido](intermediate B18, 180 mg, 0.310 mmol) and DIPEA (0.24 mL, 1.55 mmol) in DCM (5 mL) at room temperature, and the reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was then concentrated under vacuum to give a crude residue, which was purified by column chromatography (12 g silica, 0–50% EtOAc / heptane, followed by 0–5% MeOH / DCM, followed by 0–2% MeOH / DCM) to give the title compound as a white solid (122 mg, 61% yield).

[0209] LCMS m / z: 586.2 [M+H]+, (ESI+), Rt = 2.85 (S6).

[0210] Diagram of general route 3a Synthesis of intermediate C1 ​ CuI (10.6 g, 55.66 mmol) and tert-butyl nitrite (10.0 mL, 84.08 mmol) were added to a stirred solution of 4-fluoro-2,3,6-trimethylaniline (7.27 g, 42.71 mmol) in MeCN (120 mL). The solution was stirred at 60 °C for 18 h, then at room temperature for 48 h. The reaction mixture was concentrated under vacuum, and the residue was suspended in EtOAc (100 mL) and filtered. The filtrate was concentrated under vacuum, and the residue was purified by column chromatography (350 g silica, 0-100% EtOAc / heptane) to give the title product as an oil (4.07 g, 33% yield).

[0211] LCMS m / z: non-ionized, (ESI+), Rt = 1.23 (S1) 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 7.09 (d, J = 10.5 Hz, 1H), 2.45 (s, 3H), 2.39 (s, 3H), 2.25 – 2.19 (m, 3H).

[0212] Synthesis of intermediate C2 (intermediate 555a) ​ To a degassed suspension of 1-fluoro-4-iodo-2,3,5-trimethylbenzene (200.0 mg, 0.72 mmol), triethylamine (0.3 mL, 2.15 mmol), and pinacolborane (0.31 mL, 2.14 mmol) in anhydrous 1,4-dioxane (3.5 mL), palladium acetate (16.0 mg, 0.07 mmol) and dicyclohexyl-(2-phenylphenyl)phosphine (50.0 mg, 0.14 mmol) were added. The reaction mixture was heated at 80 °C for 18 hours. The reaction mixture was concentrated under vacuum, and the residue was suspended in EtOAc (15 mL). The mixture was filtered, and the filtrate was concentrated under vacuum. Purification by column chromatography (10 g silica, 0-100% EtOAc / heptane) gave the title product as a yellow solid (181 mg, 86% yield).

[0213] LCMS m / z: non-ionized, (ESI+), Rt = 1.25 (S1) 1 H NMR (400 MHz, CDCl3) δ [ppm]: 6.66 (d, J = 10.7 Hz, 1H), 2.34 (s,3H), 2.31 (s, 3H), 2.13 – 2.08 (m, 3H), 1.39 (s, 12H).

[0214] Diagram of General Route 3b Synthesis of intermediate C3 ​ Pd(dppf)Cl2 (59 mg, 0.0813 mmol) was added to a degassed suspension of 2-iodo-1,3,4-trimethylbenzene (0.20 g, 0.813 mmol), B2(pin)2 (310 mg, 1.22 mmol), and potassium acetate (239 mg, 2.44 mmol) in anhydrous 1,4-dioxane (7 mL). The reaction mixture was heated at 100 °C for 3 hours. After cooling, the mixture was purged with nitrogen for 2 minutes, and then Cs2CO3 (397 mg, 1.22 mmol), tris(4-methoxyphenyl)phosphine (3.2 mg, 8.94 μmol), and Pd(OAc)2 (18 mg, 0.0813 mmol) were added. The reaction mixture was heated at 100 °C for another 3 hours. After cooling, the mixture was diluted with EtOAc (40 mL) and filtered. The filtrate was concentrated under vacuum, and the crude product was purified by column chromatography (25 g silica, 0–20% EtOAc / heptane) to obtain 4,4,5,5-tetramethyl-2-(2,3,6-trimethylphenyl)-1,3,2-dioxane (86 mg, 0.346 mmol, yield 43%) as a colorless oil.

[0215] LCMS m / z: No mass observed, (ESI+), Rt = 1.18 (S1) 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 7.01 (d, J = 7.6 Hz, 1H), 6.84 (d,J = 7.6 Hz, 1H), 2.24 (s, 3H), 2.19 (s, 3H), 2.14 (s, 3H), 1.33 (s, 12H). (N1).

[0216] The following intermediates are prepared using the corresponding starting materials in a manner similar to intermediate C3, as outlined in general route 3b.

[0217] Table 4 .

[0218] Diagram of General Route 4 Synthesis of intermediate D1 Step A: (3S)-3-[(2S)-2-{[(tert-butoxy)carbonyl]amino}-4-methylpentamido]-3-{4,4'- Ethyl difluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl propionate (Step A) K₃PO₄ (9.25 g, 42.97 mmol) was added to a stirred solution of (3S)-3-(5-bromo-2-fluoro-3-methylphenyl)-3-[(2S)-2-{[(tert-butoxy)carbonyl]amino}-4-methylpentamido]propionate (5.5 g, 10.6 mmol) and 2-(4-fluoro-2,6-dimethylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane (3.07 g, 12.15 mmol) in 1,4-dioxacyclohexane (90 mL) and water (9 mL). The mixture was degassed with N₂ for 5 min, and then Pd(dppf)Cl₂·DCM (0.83 g, 1.01 mmol) was added. The reaction mixture was stirred at 100 °C for 3.5 h. The mixture was concentrated under vacuum, and the residue was dissolved in EtOAc (100 mL) and washed with water (50 mL) and brine (30 mL). The aqueous phase was then extracted with EtOAc (2 x 50 mL), and the combined organic phases were dried over MgSO4 and concentrated under vacuum. Purification was performed by column chromatography (100 g silica, 0-100% gradient EtOAc / heptane) to give the title product (5.29 g, 88% yield) as a grayish-white solid.

[0219] LCMS m / z: 583.4 [M+Na]+, (ESI+), Rt = 1.23 (S1) 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 8.39 (d, J = 8.4 Hz, 1H), 6.99 –6.91 (m, 4H), 6.82 (d, J = 8.2 Hz, 1H), 5.52 (q, J = 7.6 Hz, 1H),4.08 – 3.97(m, 2H), 3.96 – 3.86 (m, 1H), 2.76 (d, J = 7.4 Hz, 2H), 2.28 – 2.20 (m, 3H), 2.04 – 1.91 (m, 6H), 1.49 – 1.40 (m, 1H), 1.33 – 1.24 (m, 11H), 1.11(t, J =7.1 Hz, 3H), 0.79 – 0.73 (m, 6H).

[0220] Synthesis of intermediate D2 (3S)-3-[(2S)-2-amino-4-methylpentamido]-3-{4,4'-difluoro-2',5,6'-trimethyl-[1, 1'-Biphenyl]-3-yl}Ethyl propionate hydrochloride (Step B) Ethyl (3S)-3-[(2S)-2-{[(tert-butoxy)carbonyl]amino}-4-methylpentamido]-3-{4,4'-difluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl}propionate (5.27 g, 9.39 mmol) in anhydrous DCM (42 mL) was added to a stirred solution of the mixture. The reaction mixture was stirred at room temperature for 18 hours. The mixture was concentrated under vacuum to give the title product (5.75 g, 100% yield) as a white solid.

[0221] LCMS m / z: 461.3 [M+H]+, (ESI+), Rt = 0.86 (S1) 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 9.17 (d, J = 8.0 Hz, 1H), 8.19 (s,3H), 7.02 – 6.93 (m, 4H), 5.55 (q, J = 7.6 Hz, 1H), 4.08 – 3.96 (m, 2H), 3.76– 3.70 (m, 1H), 2.92 – 2.80 (m, 2H), 2.28 – 2.23 (m, 3H), 1.95 – 1.93(m, 6H), 1.49 – 1.38 (m, 3H), 1.11 (t, J = 7.1 Hz, 3H), 0.79 – 0.71 (m, 6H).

[0222] The intermediates in Table 5 were synthesized using the corresponding starting materials according to General Scheme 4, taking intermediate D2 (step AB) as an example. Diastereomers were isolated during final purification or, if necessary, by chiral separation methods. The intermediates were obtained as the title compound or its salts.

[0223] Table 5 .

[0224] Diagram of General Route 5 Synthesis of intermediate E1 (3S)-3-[(2S)-2-{[(tert-butoxy)carbonyl]amino}-4-methylpentamido]-3-[2-fluoro-3-methyl- Ethyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)phenyl]propionate (Step A) It was prepared using intermediate B13 as a starting material in a manner similar to intermediate C2.

[0225] LCMS m / z: 565.5 [M+Na]+, (ESI+), Rt = 1.21 (S1) 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 8.45(d, J = 8.0 Hz, 1H), 7.62 –7.51 (m, 1H), 7.47 (d, J = 7.5 Hz, 1H), 6.74 (d, J = 8.5 Hz, 1H), 5.49 – 5.34(m, 1H), 4.14 – 3.68 (m, 3H), 2.83 – 2.70 (m, 2H), 2.22(s, 3H), 1.56 – 1.43(m, 1H), 1.40 – 1.31 (m, 11H), 1.28 (s, 12H), 1.12 (t, J = 7.1 Hz, 3H), 0.89– 0.77 (m, 6H).

[0226] Synthesis of intermediate E2 (3S)-3-[(2S)-2-{[(tert-butoxycarbonyl)amino]-4-methylpentamido]-3-[5-(2,5-dimethyl] Ethyl [2H-indazole-4-yl]-2-fluoro-3-methylphenyl]propionate (Step B) It was prepared from intermediate E1 and 4-bromo-2,5-dimethylindazole in a manner similar to that of intermediate D1.

[0227] LCMS m / z: 583.5 [M+Na]+, (ESI+), Rt = 1.08 (S1) 1H NMR (400 MHz, DMSO-d6) δ [ppm]: 8.41(d, J = 8.2 Hz, 1H), 7.84 (s,1H), 7.48 (d, J = 8.8 Hz, 1H), 7.27 – 7.21 (m, 2H), 7.16 (d, J = 8.8 Hz, 1H),6.79 (d, J = 8.5 Hz, 1H), 5.59 – 5.51 (m, 1H),4.09 (s, 3H), 4.06 – 4.00 (m,2H), 3.95 – 3.90 (m, 1H), 2.79 (d, J = 7.5 Hz, 2H), 2.30 (s, 3H), 2.21 (s, 3H), 1.50 – 1.41 (m, 1H), 1.29 (s, 9H), 1.25 – 1.18 (m, 2H), 1.16 (t, J = 7.1Hz, 3H), 0.72 (d, J = 6.6 Hz, 6H). Synthesis of intermediate E3 (3S)-3-[(2S)-2-amino-4-methylpentamido]-3-[5-(2,5-dimethyl-2H-indazol-4-yl)-2- Methyl fluoro-3-methylphenyl]propionate (Step C) To a solution of ethyl (3S)-3-[(2S)-2-{[(tert-butoxy)carbonyl]amino}-4-methylpentamido]-3-[5-(2,5-dimethyl-2H-indazol-4-yl)-2-fluoro-3-methylphenyl]propionate (1.5 g, 2.06 mmol) in methanol (2.5 mL), 4 M HCl / dioxane (2.5 mL) was added. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under vacuum, and the residue was partitioned between EtOAc (50 mL) and a saturated NaHCO3 solution (15 mL). The organic layer was passed through a phase separator and concentrated under vacuum to give the title product (804 mg, 67% yield) as a pale brown glassy solid.

[0228] LCMS m / z: 469.4 [M+Na]+, (ESI+), Rt = 0.76 (S1) 1H NMR (500 MHz, DMSO-d6) δ [ppm]: 8.48(d, J = 8.4 Hz, 1H), 7.87 (s,1H), 7.48 (dd, J = 9.0, 1.0 Hz, 1H), 7.27 (dd, J = 6.8, 2.3 Hz, 1H), 7.23(dd, J = 7.0, 2.3 Hz, 1H), 7.17 (d, J = 8.8 Hz, 1H), 5.59 – 5.50 (m, 1H), 4.09(s, 3H), 3.58 (s, 3H), 3.14 (dd, J = 8.7, 5.6 Hz, 1H), 2.89 – 2.79 (m, 2H), 2.31 (s, 3H), 2.22 (s, 3H), 1.62 – 1.52 (m, 1H), 1.37 – 1.28 (m, 1H), 1.21 –1.10 (m, 1H), 0.86 – 0.71 (m, 6H).

[0229] Table 6 .

[0230] Diagram of General Route 6 Synthesis of intermediate F1 (3S)-3-{4,5-difluoro-2',6'-dimethyl-[1,1'-biphenyl]-3-yl}-3-[(2S)-4-methyl-2-[(quinoline) Ethyl porino-8-yl)formamido]pentamido]propionate To a solution of (3S)-3-[(2S)-2-amino-4-methylpentamido]-3-{4,5-difluoro-2',6'-dimethyl-[1,1'-biphenyl]-3-yl}propionate hydrochloride (intermediate B2, 80 mg, 0.154 mmol) and quinoline-8-carboxylic acid (32 mg, 0.185 mmol) in DCM (1.54 mL), DIPEA (0.059 mL, 0.339 mmol) and HATU (64 mg, 0.169 mmol) were added. The reaction mixture was stirred for 18 hours. The reaction mixture was concentrated under vacuum, and the residue was purified by column chromatography (10 g silica, 0–100% EtOAc / heptane) to give the title product as a colorless solid (59 mg, 64% yield).

[0231] LCMS m / z: 602.5 [M+H]+, (ESI+), Rt = 4.71 (S4) 1 H NMR (500 MHz, CDCl3) δ [ppm]: 11.62 (d, J = 7.2 Hz, 1H), 8.94 (dd,J = 4.3, 1.8 Hz, 1H), 8.67 (dd, J = 7.4, 1.6 Hz, 1H), 8.28 (dd, J = 8.3,2.3Hz, 1H), 7.97 (dd, J = 8.1, 1.6 Hz, 1H), 7.77 (d, J = 8.5 Hz, 1H), 7.63 (dd,J = 8.1, 7.3 Hz, 1H), 7.50 (dd, J = 8.3, 4.3 Hz, 1H), 7.20 – 7.13 (m, 1H),7.07 (d, J = 7.7 Hz, 2H), 6.91 – 6.83 (m, 2H), 5.70 (dt, J = 8.5, 6.2 Hz,1H), 4.77 – 4.71 (m, 1H), 3.96 – 3.82 (m, 2H), 2.91 (dd, J = 15.7, 6.1 Hz,1H), 2.84(dd, J = 15.8, 6.3 Hz, 1H), 1.98 (s, 3H), 1.95 (s, 3H), 1.94 – 1.88(m, 1H), 1.86 – 1.75 (m, 2H), 1.03 (t, J = 7.1 Hz, 3H), 0.95 (d, J = 6.5 Hz,3H), 0.93 (d, J = 6.4 Hz, 3H). (N1).

[0232] The intermediates in Table 7 below are prepared using the corresponding starting materials in a manner similar to intermediate F1, as outlined in general route 6.

[0233] Table 7 .

[0234] Synthesis of intermediate F39 (3S)-3-{4,5-difluoro-2',6'-dimethyl-[1,1'-biphenyl]-3-yl}-3-[(2S)-2-[(1,4-dimethyl] [2-oxo-1,2-dihydropyridin-3-yl)formamido]-4-methylpentamido]ethyl propionate A solution of methyl 1,4-dimethyl-2-oxo-1,2-dihydropyridine-3-carboxylate (100 mg, 0.497 mmol) in THF (4 mL) was added to a solution of LiOH·H₂O (104 mg, 2.48 mmol) dissolved in water (1 mL). The reaction mixture was stirred for 48 hours. The reaction mixture was concentrated under vacuum to give an intermediate. The intermediate acid was redissolved in DMF (4 mL), and intermediate B2 (150 mg, 0.311 mmol), DIPEA (190 µL, 1.09 mmol), and HATU (142 mg, 0.373 mmol) were added. The resulting mixture was stirred for 72 hours. The reaction was then quenched with water (10 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine, dried over Na₂SO₄, and concentrated under vacuum to give a crude residue. The title product (20 mg, 9% yield) was purified by column chromatography (12 g Redisep Gold silica, 0–100% EtOAc / heptane) to obtain a colorless gel.

[0235] LCMS m / z: 596.4 [M+H]+, (ESI+), Rt = 2.85 (S6).

[0236] Diagram of General Route 7 Synthesis of intermediate G1 (3S)-3-{2',6'-dichloro-4,5-difluoro-[1,1'-biphenyl]-3-yl}-3-[(2S)-4-methyl-2-[(1-methyl] [2-oxo-1,2-dihydropyridin-3-yl]formamido]pentamido]ethyl propionate Pd(dppf)Cl2 (18 mg, 0.0214 mmol) was added to a degassed suspension of (3S)-3-(5-bromo-2,3-difluorophenyl)-3-[(2S)-4-methyl-2-[(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)formamido]pentamido]propionate (intermediate F6, 70 mg, 0.107 mmol), 2,6-dichlorophenylboronic acid (35 mg, 0.183 mmol), and K3PO4 (70 mg, 0.330 mmol) in 1,4-dioxane (1 mL) and water (0.1 mL). The reaction mixture was heated at 90 °C for 18 hours. The reaction mixture was concentrated under vacuum to obtain a crude residue. Purified by column chromatography (10 g silica, 0-100% EtOAc / heptane), the title product (47 mg, 45% yield) was obtained as orange oil.

[0237] LCMS m / z: 622.4 / 624.3 [M+H]+, (ESI+), Rt = 1.07 (S1) 1 H NMR (500 MHz, CDCl3) δ [ppm]: 10.11 (d, J = 7.6 Hz, 1H), 8.43 (dd,J = 7.2,2.2 Hz, 1H), 7.58 – 7.53 (m, 2H), 7.40 – 7.36 (m, 2H), 7.02 – 6.98(m, 2H), 6.39 (t, J = 6.9 Hz, 1H), 5.69 (dt, J = 8.4, 6.2 Hz, 1H), 4.60 –4.54 (m, 1H),4.02 – 3.97 (m, 2H), 3.64 (s, 3H), 2.91 – 2.81 (m, 4H), 1.81(td, J = 10.1, 5.0 Hz, 1H), 1.72 – 1.70 (m, 1H), 1.14 – 1.11 (m, 3H), 0.92 –0.87 (m, 6H).

[0238] The intermediates in Table 8 below are prepared using the corresponding starting materials in a manner similar to intermediate G1, as outlined in general route 7.

[0239] Table 8 .

[0240] Diagram of General Route 8 Synthesis of intermediate H1 (3S)-3-[2,3-difluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane--2-yl)phenyl]- Ethyl 3-[(2S)-4-methyl-2-[(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)carbamoyl]pentamido]propionate Pd(dppf)Cl2 (6.0 mg, 8.20 μmol) was added to a degassed solution of (3S)-3-(5-bromo-2,3-difluorophenyl)-3-[(2S)-4-methyl-2-[(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)formamido]pentamido]propionate (intermediate F6, 100 mg, 0.153 mmol), B2(pin)2 (58 mg, 0.228 mmol), and KOAc (45 mg, 0.459 mmol) in DMF (1 mL). The reaction mixture was heated at 80 °C for 3 hours. The reaction mixture was cooled to room temperature and filtered through a diatomaceous earth mat, washed with excess EtOAc (3 × 5 mL). The filtrate was concentrated under vacuum to give the title product (142 mg, 77% yield) as a dark brown gel.

[0241] LCMS m / z: 604.6 [M+H]+, (ESI+), Rt = 1.08 (S1) 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 10.14– 10.03 (m, 1H), 9.02 – 8.89(m, 1H), 8.35 – 8.23 ​​(m, 1H), 8.10 – 8.04 (m, 1H), 7.69 – 7.39 (m, 2H), 6.54– 6.41 (m, 1H), 5.59 – 5.38 (m, 1H), 4.64 – 4.43 (m,1H), 4.07 – 3.96 (m, 2H), 3.58 – 3.56 (m, 3H), 2.88 – 2.76 (m, 2H), 1.54 – 1.37 (m, 3H), 1.17 – 1.16 (m, 12H), 1.13 – 1.09 (m, 3H), 0.89 – 0.78 (m, 6H). (N1).

[0242] Synthesis of intermediate H2 (2S)-4-methyl-2-[(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)carbamoyl]valeric acid Using the route outlined in step B of general route 6, the methyl valerate of (2S)-4-methyl-2-[(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)carbamate] is prepared by hydrolysis.

[0243] LCMS m / z: 267.2 [M+H]+, (ESI+), Rt = 0.60,S1 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 12.73(s, 1H), 10.13 (d, J = 7.9Hz, 1H), 8.31 (dd, J = 7.3, 2.2 Hz, 1H), 8.08 (dd, J= 6.5, 2.2 Hz, 1H), 6.51(dd, J = 7.3, 6.5 Hz, 1H), 4.55 – 4.37 (m, 1H), 3.57 (s, 3H), 1.71 – 1.55 (m,3H), 0.98 – 0.80 (m, 6H). (N1).

[0244] Synthesis of intermediate H3 (3S)-3-(5-bromopyridin-3-yl)-3-[(2S)-4-methyl-2-[(1-methyl-2-oxo-1,2-dihydropyridin- [3-yl)formamido]pentamido]ethyl propionate dihydropyridine-3-yl)formamido]pentamido]ethyl propionate Preparation of DMF is initiated from intermediates H2 and A18 in a manner similar to that of intermediate B1.

[0245] LCMS m / z: 521.2 / 523.2 [M+H]+, (ESI+), Rt = 0.79, S1.

[0246] Synthesis of intermediate H3B (3S)-3-[(2S)-4-methyl-2-[(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)carbamate]pentanoyl Ethyl [amino]-3-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)pyridin-3-yl]propionate It was prepared using intermediate H3 as the starting material, in a manner similar to that of intermediate H1.

[0247] LCMS m / z: 547.3 [M+H]+, (ESI+), Rt = 0.82,S1 1H NMR (400 MHz, DMSO) δ 10.10 – 9.98 (m, 1H), 8.82 – 8.70 (m, 1H), 8.55 – 8.48 (m, 1H), 8.28 – 8.15 (m, 2H), 8.08 – 8.01(m, 1H), 7.68 – 7.51 (m,1H), 7.26 – 7.07 (m, 3H), 6.53 – 6.43 (m, 1H), 5.36 – 5.24 (m, 1H), 4.55 –4.44 (m, 1H), 4.07 – 3.92 (m, 2H), 2.92 – 2.81 (m, 2H),2.78 – 2.62 (m, 4H), 1.90 (d, J = 30.4 Hz, 6H), 1.61 – 1.40 (m, 2H), 1.18 – 1.02 (m, 3H), 0.93 –0.76 (m, 6H).

[0248] Diagram of General Route 8B Synthesis of intermediate H4 (3S)-3-[(2S)-2-{[(tert-butoxy)carbonyl]amino}-4-methylpentamido]-3-[2,3-difluoro-5- Ethyl (4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)phenyl]propionate Intermediate B15 was prepared using the same conditions as intermediate H1.

[0249] LCMS m / z: 569.5 [M+H] + , (ESI+), Rt = 1.18 (S1) 1 H NMR (400 MHz, DMSO) δ [ppm]: 8.57 (d,J = 7.8 Hz, 1H), 7.52 (d, J =6.3 Hz, 1H), 7.47 – 7.38 (m, 1H), 6.75 (d, J = 8.3 Hz, 1H), 5.43 (q, J = 7.6Hz, 1H), 4.07 – 3.90 (m, 3H), 2.88 – 2.72 (m, 2H), 1.52 – 1.41 (m, 1H), 1.36 (s, 9H), 1.33 – 1.26 (m, 14H), 1.12 (t, J = 7.1 Hz, 3H), 0.90 – 0.77 (m, 6H).

[0250] Synthesis of intermediate H5 (3S)-3-[(2S)-2-{[(tert-butyloxycarbonyl)amino]-4-methylpentamido}-3-[5-(2,5-dimethyl- Ethyl 2H-indazol-4-yl)-2,3-difluorophenyl]propionate In a MW flask, a mixture of Pd(dppf)₂Cl₂ (33.041 mg, 0.04 mmol), K₂CO₃ (223.673 mg, 1.62 mmol), ethyl (3S)-3-[(2S)-2-{[(tert-butoxy)carbonyl]amino}-4-methylpentamido]-3-[2,3-difluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)phenyl]propionate (460.0 mg, 0.81 mmol), and 4-bromo-2,5-dimethylindazole (204.352 mg, 0.91 mmol) in 1,4-dioxane (4 mL) and water (0.5 mL) was degassed for 5 minutes and then capped. The reaction mixture was heated at 150 °C under MW radiation for 15 minutes. The reaction mixture was filtered through a thiol column and washed with excess EtOAc (3 x 10 mL). The solvent in the filtrate was concentrated under vacuum. Purification was performed by column chromatography (25 g silica, 0-100% EtOAc / heptane) to give the title product as the oil (389 mg, 70% yield).

[0251] LCMS m / z: 587.5 [M+H] + , (ESI+), Rt = 1.07 (S1) 1 H NMR (500 MHz, DMSO-d6) δ [ppm]: 8.51(d, J = 8.1 Hz, 1H), 7.90 (s,1H), 7.51 (d, J = 8.8 Hz, 1H), 7.43 – 7.37 (m, 1H), 7.24 (d, J = 5.7 Hz, 1H),7.17 (d, J = 8.9 Hz, 1H), 6.80 (d, J = 8.3 Hz,1H), 5.55 (q, J = 7.6 Hz, 1H),4.09 (s, 3H), 4.08 – 4.01 (m, 2H), 3.95 – 3.87 (m, 1H), 2.86 (d, J = 7.5 Hz, 2H), 2.22 (s, 3H), 1.46 – 1.39 (m, 1H), 1.30 –1.22 (m, 11H), 1.13 (t, J = 7.1Hz, 3H), 0.73 – 0.68 (m, 6H).

[0252] Synthesis of intermediate H6 (3S)-3-[(2S)-2-amino-4-methylpentanoyl]-3-[5-(2,5-dimethyl-2H-indazol-4-yl)-2, ethyl 3-difluorophenyl]propionate dihydrochloride It was prepared using intermediate H5 as the starting material, in a manner similar to that of intermediate A4.

[0253] LCMS m / z: 487.3 [M+H-HCl] + , (ESI+), Rt = 0.75 (S1) 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 9.37(d, J = 7.7 Hz, 1H), 8.24 (s,2H), 7.95 (s, 1H), 7.53 (d, J = 8.8 Hz, 1H), 7.48 – 7.40 (m, 1H), 7.29 (d, J= 5.7 Hz, 1H), 7.19 (d, J = 8.8 Hz, 1H), 5.57 (q, J= 7.5 Hz, 1H), 4.13 – 4.01(m, 6H), 3.77 – 3.69 (m, 2H), 3.01 – 2.91 (m, 2H), 2.23 (s, 3H), 1.49 – 1.36 (m, 3H), 1.13 (t, J = 7.1 Hz, 3H), 0.73 – 0.63 (m, 6H).

[0254] Synthesis of intermediate H7 {5−[(1S)−1−[(2S)−2−{[(tert-butoxy)carbonyl]amino}−4−methylpentamido]−3−ethoxy−3− [Oxypropyl]pyridin-3-yl}boronic acid To a MW tube containing PdCl2(dppf)2 (40.0 mg, 0.05 mmol), (3S)-3-(5-bromopyridin-3-yl)-3-[(2S)-2-{[(tert-butoxy)carbonyl]amino}-4-methylpentamido]propionate (intermediate B12, 0.45 g, 0.601 mmol), bis(pinacol)diboron (0.23 g, 0.906 mmol), and KOAc (0.18 g, 1.78 mmol), 1,4-dioxane (1.8 mL) and 1 drop of DMF were added. The reaction mixture was degassed for 5 min and then heated at 150 °C under MW radiation for 15 min. The reaction mixture was filtered through a thiol column and washed with EtOAc (2 x 10 mL). The solvent was removed under vacuum to give a dark brown residue. Purified by column chromatography (10 g silica, 75-100% EtOAc / heptane), the title product (200 mg, 42% yield) was obtained as a brown solid.

[0255] LCMS m / z: 452.3 [M+H] + , (ESI+), Rt = 0.65 (S1) 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 8.65 – 8.61 (m, 1H), 8.61 – 8.57 (m, 1H), 8.52 – 8.41 (m, 1H), 8.01 – 7.91 (m, 1H), 6.87 – 6.77 (m, 1H), 5.75(s, 2H), 5.25 – 5.15 (m, 1H), 4.08 – 3.95 (m, 2H), 3.95 – 3.91 (m, 1H), 2.91 –2.81 (m, 2H), 1.54 – 1.44 (m, 1H), 1.32 – 1.29 (m, 9H), 1.26 – 1.21 (m, 2H),1.13 – 1.08 (m, 3H), 0.89 – 0.77 (m, 6H). Synthesis of intermediate H8 (3S)-3-[(2S)-2-{[(tert-butoxy)carbonyl]amino}-4-methylpentamido]-3-{3',5'-dimethyl] Ethyl [3,4'-bipyridine]-5-yl propionate Condition A In a pressure tube flask, a mixture of {5-[(1S)-1-[(2S)-2-{[(tert-butoxy)carbonyl]amino}-4-methylpentamido]-3-ethoxy-3-oxypropyl]pyridin-3-yl}boronic acid (intermediate H7, 42.5 mg, 0.05 mmol), 4-bromo-3,5-dimethylpyridine hydrochloride (22 mg, 0.0989 mmol), Pd(dppf)₂Cl₂ (8.0 mg, 9.77 μmol), and K₂CO₃ (27 mg, 0.195 mmol) in 1,4-dioxane (0.5 mL) and water (50 μL) was degassed. The reaction mixture was sealed and heated at 100 °C for 1 hour. The reaction mixture was diluted with EtOAc (2 mL) and water (2 mL). The organic layer was separated, and the aqueous layer was extracted again with EtOAc (2 x 1 mL). The combined organic layers were washed with brine (2 mL), dried over Na2SO4, and concentrated under vacuum to obtain a brown oil residue. The residue was purified by reversed-phase column chromatography (10 g C-18 silica, 10% to 100% MeCN / H2O, containing 0.1% formic acid) to give the title product (13 mg, 50% yield) as a brown viscous oil.

[0256] Condition B In a pressure flask, {5-[(1S)-1-[(2S)-2-{[(tert-butoxy)carbonyl]amino}-4-methylpentamido]-3-ethoxy-3-oxopropyl]pyridin-3-yl}boronic acid (intermediate H7, 250.0 mg, 0.51 mmol), 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)pyridine (143.777 mg, 0.62 mmol), K3PO4 (464.014 mg, 2.19 mmol), and Pd(dppf)2Cl2.DCM (98.818 mg, 0.12 mmol) were added. 1,4-dioxacyclohexane (4 mL) and water (0.4 mL) were added. The reaction mixture was capped and heated at 100 °C for 3 hours. The reaction mixture was concentrated under vacuum to give a brown residue. Purification was performed by column chromatography (10 g silica, 0-100% EtOAc / heptane) to obtain the title product (39 mg, 15% yield) as colorless oil and the starting material (183 mg, 73% recovery).

[0257] LCMS m / z: 513.3 [M+H] + , (ESI+), Rt = 0.72 (S1) 1H NMR (400 MHz, d3-MeCN) δ [ppm]: 8.58(d, J = 2.2 Hz, 1H), 8.34 (s,2H), 8.28 (d, J = 2.0 Hz, 1H), 7.51 (t, J = 2.2 Hz, 1H), 7.39 (d, J = 8.2 Hz,1H), 5.60 – 5.46 (m, 1H), 5.35 (q, J = 7.3 Hz,1H), 4.04 (q, J = 7.1 Hz, 2H), 3.98 – 3.90 (m, 1H), 2.96 – 2.82 (m, 2H), 1.98 (s, 6H), 1.65 – 1.54 (m, 1H), 1.48 – 1.39 (m, 2H), 1.32 (s, 9H), 1.14 (t, J =7.1 Hz, 3H), 0.89 – 0.84 (m, 6H).

[0258] Synthesis of intermediate H9 (3S)-3-[(2S)-2-amino-4-methylpentanoyl]-3-{3',5'-dimethyl-[3,4'-bipyridine]-5- Ethyl propionate trihydrochloride A solution of ethyl (3S)-3-[(2S)-2-{[(tert-butoxy)carbonyl]amino}-4-methylpentamido]-3-{3',5'-dimethyl-[3,4'-bipyridine]-5-yl}propionate (1.04 g, 1.83 mmol) in 1,4-dioxane (6 mL) was added to a 4M HCl / dioxane (1.9 mL, 7.6 mmol). A gel formed in the flask within 5 minutes. Another 6 mL of 1,4-dioxane was added, the suspended solid was sonicated for 10 minutes, and then the mixture was stirred at room temperature for 18 hours. The reactants were concentrated under vacuum and azeotropically reacted with DCM (2 x 50 mL) to give the title product (1.00 g, 1.55 mmol, 85% yield) as a grayish-white powder.

[0259] LCMS m / z: 413.4 [M+H-3HCl] + , (ESI+), Rt = 0.64 (S2).

[0260] The intermediates in Table 9 were synthesized according to general formula 8B, taking intermediate H6 as an example, using the corresponding starting materials. Diastereomers were isolated during final purification, or, if necessary, by chiral separation methods. The intermediates were obtained as the title compound or its salts.

[0261] Table 9 .

[0262] Diagram of General Route 9

[0263] Synthesis of intermediate I1 (2R)-2-{[(2S)-1-methoxy-4-methyl-1-oxopentane-2-yl]carbamoyl}pyrrolidine-1-methyl tert-butyl ester (Step A) HATU (8.40 g, 22.1 mmol) was added to a stirred solution of (2S)-2-amino-4-methylvalerate hydrochloride (1.75 g, 9.63 mmol), (2R)-1-[(tert-butoxy)carbonyl]pyrrolidine-2-carboxylic acid (1.57 g, 7.29 mmol), and DIPEA (6.3 mL, 36.1 mmol) in DMF (23 mL). The solution was stirred at room temperature for 3 hours, and then EtOAc (30 mL) and water (20 mL) were added. The organic layer was separated, and the aqueous layer was extracted again with EtOAc (3 × 15 mL). The combined organic layers were washed with brine (30 mL), concentrated under vacuum, and purified by column chromatography (50 g silica, 0–100% TBME / heptane) to give the title product (2.30 g, 87% yield).

[0264] LCMS m / z: 365.1 [M+H]+, (ESI+), Rt = 0.88, S1 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 8.26 – 7.95 (m, 1H), 4.39 – 4.29 (m, 1H), 4.13 – 4.06 (m, 1H), 3.64 – 3.58 (m, 3H), 3.50 – 3.35 (m, 1H), 3.30 – 3.18 (m, 1H), 2.18 – 1.99 (m, 1H), 1.82 – 1.69 (m, 3H), 1.67 – 1.57 (m, 2H), 1.55 – 1.43 (m, 1H), 1.43 – 1.25 (m, 9H), 0.92 – 0.77 (m, 6H). (N1).

[0265] Synthesis of intermediate I2 (2S)-2-{[(2R)-1-[(tert-butoxy)carbonyl]pyrrolidine-2-yl]formamido}-4-methylvaleric acid (step) B） A stirred solution of (2R)-2-{[(2S)-1-methoxy-4-methyl-1-oxopentane-2-yl]carbamoyl}pyrrolidine-1-carboxylic acid tert-butyl ester (2.30 g, 6.38 mmol) in THF (57 mL) and MeOH (1.9 mL) was added to a 2M aqueous solution of LiOH (20 mL, 40.8 mmol). The reaction mixture was stirred at 45 °C for 30 min. The solution was cooled, water (10 mL) was added, and the mixture was concentrated under vacuum to remove organic matter. The aqueous phase was acidified to pH 3 with 1M aqueous HCl, and the resulting precipitate was extracted with DCM (3 × 15 mL). The combined organic layers were concentrated under vacuum to give the title product (2.10 g, 95% yield) as a white solid.

[0266] LCMS m / z: 351.3 [M+H]+, (ESI+), Rt = 0.75, S1 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 12.59 – 12.40 (m, 1H), 8.09 – 7.81 (m, 1H), 4.34 – 4.22 (m, 1H), 4.15 – 4.07 (m, 1H), 3.48 – 3.35 (m, 1H),3.29 – 3.21 (m, 1H), 2.17 – 2.01 (m, 1H), 1.87 – 1.68 (m, 3H), 1.68 – 1.54(m, 2H), 1.54 – 1.43(m, 1H), 1.43 – 1.26 (m, 9H), 0.93 – 0.77 (m, 6H). (N1).

[0267] Synthesis of intermediate I3 (2R)-2-{[(1S)-1-{[(1S)-3-ethoxy-1-[4-fluoro-2',6'-dimethyl-5-(trifluoromethyl)-[1, 1'-Biphenyl]yl-3-yl]-3-oxopropyl]carbamoyl]-3-methylbutyl]carbamoyl]pyrrolidine-1-carboxylic acid tert-butyl Ester (Step C) To a solution of (2S)-2-{[(2R)-1-[(tert-butoxy)carbonyl]pyrrolidine-2-yl]formamido}-4-methylvaleric acid (150 mg, 0.434 mmol) and (3S)-3-amino-3-[4-fluoro-2',6'-dimethyl-5-(trifluoromethyl)-[1,1'-biphenyl]-3-yl]propionate (218 mg, 0.478 mmol) in DCM (3 mL), DIPEA (152 µL, 0.870 mmol) and HATU (182 mg, 0.479 mmol) were added. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with DCM (5 mL), washed with water (5 mL), and passed through a phase separator. The solvent was concentrated under vacuum to obtain a crude oil. The title product (314 mg, 98% yield) was purified by rapid column chromatography (10 g silica, 0.100% EtOAc / heptane) to obtain a pale yellow oil.

[0268] LCMS m / z: 716.4 [M+H]+, (ESI+), Rt = 1.25, S1 1 H NMR (500 MHz, CDCl3) δ [ppm]: 7.62 – 7.49 (m, 1H), 7.31 (d, J =6.4 Hz, 2H), 7.21 – 7.13 (m, 1H), 7.13 – 7.06 (m, 2H), 6.89 – 6.29 (m, 1H),5.71 – 5.60 (m, 1H), 4.38 (q, J = 7.1 Hz, 1H), 4.24 – 4.17 (m, 1H), 4.09 –3.99 (m, 2H), 3.38 (d, J = 54.1 Hz, 2H), 2.98 – 2.82 (m, 2H), 2.01 – 1.95 (m, 6H), 1.86 – 1.77 (m, 1H), 1.43 (s, 6H), 1.20 – 1.16 (m, 3H), 0.91 – 0.84 (m, 15H). (N1).

[0269] Synthesis of intermediate I4(6a) (3S)-3-[4-fluoro-2',6'-dimethyl-5-(trifluoromethyl)-[1,1'-biphenyl]-3-yl]-3-[(2S)-4-methyl [(2R)-pyrrolidine-2-yl]formamido}pentamido]ethyl propionate hydrochloride (Step D) Add HCl (4 M in dioxane, 1.5 mL, 6.00 mmol) to a solution of (2R)-2-{[(1S)-1-{[(1S)-3-ethoxy-1-[4-fluoro-2',6'-dimethyl-5-(trifluoromethyl)-[1,1'-biphenyl]-3-yl]-3-oxopropyl]carbamoyl}-3-methylbutyl]carbamoyl}pyrrolidine-1-carboxylic acid tert-butyl ester (314 mg, 0.425 mmol) in DCM (4.5 mL). Stir the reaction mixture at room temperature for 45 minutes. Add HCl (4 M in dioxane, 1.5 mL, 6.00 mmol) again, and continue stirring the reaction mixture for 15 minutes. The reactants were concentrated under vacuum, ground with heptane (2 × 5 mL), the solvent was decanted, and the residue was dried under vacuum to give the title product (193 mg, yield 62%) as a grayish-white powder.

[0270] LCMS m / z: 594.6 [M+H]+, (ESI+), Rt = 1.05, S1 1 H NMR (400 MHz, CDCl3) δ [ppm]: 8.81 (d, J = 7.6 Hz, 1H), 8.49 (d, J= 7.5 Hz, 1H), 7.48 – 7.41 (m, 1H), 7.35 – 7.30 (m, 1H), 7.22 – 7.15 (m,1H),7.14 – 7.07 (m, 2H), 5.74 – 5.63 (m, 1H), 4.67 – 4.48 (m, 1H), 4.16 – 4.02(m, 2H), 3.49 – 3.28 (m, 2H), 3.14 – 2.98 (m, 2H), 2.53 – 2.42 (m, 1H), 2.06–1.75 (m, 11H), 1.58 – 1.47 (m, 2H), 1.25 – 1.16 (m, 3H), 0.95 – 0.78 (m, 7H). (N1).

[0271] Synthesis of intermediate I5 (3S)−3−[(2S)−2−{[(2R)−1−acetylpyrrolidine−2−]formamido}−4−methylpentamido]− Ethyl 3-[4-fluoro-2',6'-dimethyl-5-(trifluoromethyl)-[1,1'-biphenyl]-3-yl]propionate (Step 5) At 0 °C, ethyl propionate hydrochloride (100 mg, 0.136 mmol) and DIPEA (38 µL, 0.218 mmol) in DCM (1.2 mL) were mixed with a stock solution of acetyl chloride (0.1 mL stock solution: 120 µL acetyl chloride / 1 mL DCM). The reaction mixture was stirred and heated to room temperature for 2.5 h. The reaction mixture was cooled to 0 °C, retreated with DIPEA (13 µL, 0.0746 mmol) and acetyl chloride stock solution (0.05 mL), and then allowed to be heated to room temperature for 1 h. The reactants were diluted with DCM (2 mL) and quenched with saturated sodium bicarbonate (water solution, 3 mL). The resulting aqueous phase was extracted with DCM (3 mL). The combined organic layers were passed through a phase separator and concentrated under vacuum. The residue was purified by column chromatography (10 g silica, 0–100% EtOAc / heptane) to give the title product (39 mg, 43% yield) as a grayish-white semi-solid.

[0272] LCMS m / z: 636.6 [M+H]+, (ESI+), Rt = 1.17, (S1) 1 H NMR (400 MHz, CDCl3) δ [ppm]: 7.85 (d, J = 8.6 Hz, 1H), 7.31 –7.26 (m, 2H), 7.19 – 7.04 (m, 3H), 6.80 (d, J = 8.1 Hz, 1H), 5.79 – 5.69 (m,1H), 4.40 – 4.31 (m, 1H), 4.28 (dd, J = 7.6, 3.8 Hz, 1H), 4.13 – 4.00 (m,2H), 3.39 – 3.21 (m, 2H), 3.03 – 2.79 (m, 2H), 2.20 – 2.11 (m, 1H), 2.04 –1.98 (m, 4H), 1.96 (s, 3H), 1.94 – 1.81 (m, 3H), 1.79 (s, 3H), 1.72 – 1.62 (m,1H), 1.54 – 1.45 (m, 1H), 1.20 (t, J = 7.1 Hz, 3H), 0.92 (d, J = 6.6 Hz, 3H),0.88 (d, J= 6.5 Hz, 3H). (N1).

[0273] The following intermediates are prepared using the corresponding starting materials in a manner similar to intermediate I5, as outlined in general route 6.

[0274] .

[0275] Map of General Route 10A Synthesis of intermediate J1 Methyl 1-(1-methylazacyclobutane-3-yl)-2-oxo-1,2-dihydropyridine-3-carboxylate (Step A) At 0 °C, a solution of methyl 2-oxo-2H-pyran-3-carboxylate (800 mg, 5.19 mmol) in DMF (10 mL) was added dropwise to 1-methylazacyclobutane-3-amine (447 mg, 5.19 mmol) in DMF (10 mL). The reaction mixture was stirred at 0 °C for 1 hour, then heated to room temperature. T3P (50% dissolved in EtOAc, 4.6 mL, 7.79 mmol) was then added dropwise. The reaction mixture was stirred for 72 hours, then concentrated under vacuum. Purification by column chromatography (55 g, KPNH silica, 0–100% EtOAc / heptane, 0–20% MeOH / EtOAc) yielded the title product as a red solid (415 mg, 25% yield).

[0276] LCMS m / z: 223.1 [M+H]+, (ESI+), Rt = 0.38 (S1).

[0277] Synthesis of intermediate J2 (intermediate 7a) 1-(1-Methylazacyclobutane-3-yl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (Step B) A solution of methyl 1-(1-methylazacyclobutan-3-yl)-2-oxo-1,2-dihydropyridine-3-carboxylate (415 mg, 1.29 mmol) in methanol (6.9 mL) was added to LiOH (2 M, aqueous solution, 1.3 mL, 2.58 mmol). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under vacuum to give a red solid. Purification by column chromatography (11 g KPNH silica, 0–100% methanol / EtOAc) gave the title product (100 mg, 34% yield) as a red solid.

[0278] LCMS m / z: 209.2 [M+H]+, (ESI+), Rt = 0.18 (S1) 1H NMR (500 MHz, DMSO-d6) δ [ppm]: 8.17 (dd, J = 7.0, 2.2 Hz, 1H), 7.96 (dd, J = 6.8, 2.2 Hz, 1H), 6.49 – 6.43 (m, 1H), 5.00 – 4.91 (m, 1H), 3.75 – 3.66 (m, 2H), 3.15 – 3.09 (m, 2H), 2.27 (s, 3H). (N1).

[0279] Synthesis of intermediate J3 Methyl 1-(oxetane-3-yl)-2-oxo-1,2-dihydropyridine-3-carboxylate (Step A) At room temperature, oxetane-3-amine hydrochloride (0.72 g, 6.56 mmol) and DIPEA (3.4 mL, 19.5 mmol) were added to a solution of methyl 2-oxo-2H-pyran-3-carboxylate (1.00 g, 6.49 mmol) in DMF (33.5 mL). The reaction mixture was stirred for 1 hour, and then EDC.HCl (1.87 g, 9.75 mmol) and DMAP (0.20 g, 1.64 mmol) were added. The reaction mixture was stirred for another 3 hours. The reaction mixture was concentrated under vacuum, suspended in water (150 mL), and extracted with EtOAc (3 x 50 mL). The combined organic layers were free of product. The aqueous layer was extracted with a 4:1 DCM / IPA solution (2 x 60 mL). The combined organic layers were concentrated under vacuum to give the title product (352 mg, 24% yield) as brown oil.

[0280] LCMS m / z: 210.1 [M+H] + , (ESI+), Rt = 1.08 (S4) 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 8.08-8.02 (m, 2H), 6.41 (t, J =6.9Hz, 1H), 5.45 (p, J = 7.2 Hz, 1H), 4.86 (t, J = 7.5 Hz, 2H), 4.72 (t, J =7.2 Hz, 2H), 3.73 (s, 3H).

[0281] Synthesis of intermediate J3 1-(oxetane-3-yl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (Step B) A stirred solution of methyl 1-(oxetane-3-yl)-2-oxo-1,2-dihydropyridine-3-carboxylate (352.2 mg, 1.57 mmol) in methanol (4.5 mL) and THF (65 mL) was added to a 2 M aqueous solution of lithium hydroxide (1.2 mL, 2.4 mmol). The reaction mixture was stirred at room temperature for 72 hours. The reaction mixture was concentrated under vacuum, and the resulting residue was suspended in water (about 20 mL). The suspension was acidified to pH about 1 with a 2 M aqueous solution of HCl and extracted with a 4:1 DCM:IPA solution (3 x 10 mL). The combined organic layers were concentrated under vacuum to give the title product (300 mg, 71% yield) as a pale orange solid.

[0282] LCMS m / z: 196.1 [M+H] + , (ESI+), Rt = 1.04 (S3) 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 14.26(s, 1H), 8.40 (dd, J = 7.3,2.0 Hz, 1H), 8.30 (dd, J = 6.7, 2.0 Hz, 1H), 6.79 (t, J = 7.0 Hz, 1H), 5.68 –5.57 (m, 1H), 4.91 (t, J = 7.4 Hz, 2H), 4.84 (t, J= 7.4 Hz, 2H).

[0283] Map of General Route 10B Synthesis of intermediate K1 To a solution of methyl 2-oxo-1,2-dihydropyridine-3-carboxylate (200 mg, 1.31 mmol) and CsCO3 (1280 mg, 3.93 mmol) in MeCN (5 mL), (2-bromoethyl)dimethylamine hydrobromide (375 mg, 1.58 mmol) was added. The reaction mixture was stirred at room temperature for 24 hours. The reaction was cooled to room temperature, filtered through a diatomaceous earth mat, and washed with excess EtOAc (100 mL) and DCM (2 × 5 mL). The filtrate was collected and concentrated under vacuum to give crude oil. Purification by open preparative high-performance liquid chromatography (P4) yielded the methyl title product (79 mg, 25% yield) as a brown oil.

[0284] LCMS m / z: 225.1 [M+H]+, (ESI+), Rt = 0.40 (S1) 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 8.04 –7.96 (m, 1H), 7.96 – 7.90 (m, 1H), 6.33 – 6.25 (m, 1H), 4.01 (t, J = 6.2 Hz, 2H), 3.77 – 3.70 (m, 3H), 2.55 – 2.51 (m, 2H), 2.23 – 2.10 (m, 6H). (N1).

[0285] Synthesis of intermediate K2 Lithium (1+) 1-[2-(dimethylamino)ethyl]-2-oxo-1,2-dihydropyridine-3-carboxylate (Step B) LiOH (2M, aqueous solution, 900 µL, 1.80 mmol) was added to a solution of methyl 1-[2-(dimethylamino)ethyl]-2-oxo-1,2-dihydropyridine-3-carboxylate (79 mg, 0.333 mmol) in MeOH (190 µL) and THF (1.9 mL), and the mixture was stirred at room temperature for 5 hours. The reaction mixture was concentrated under vacuum and dried overnight in a vacuum oven to give the title product (108 mg, 100% yield) as a colorless solid.

[0286] LCMS m / z: 211.2 [M+H]+, (ESI+), Rt = 0.19 (S1) 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 8.15 (dd, J = 7.0, 2.2 Hz, 1H), 7.76 (dd, J = 6.6, 2.3 Hz, 1H), 6.36 (t, J = 6.8 Hz, 1H), 4.04 (t, J = 6.3Hz, 2H), 2.52 (s, 2H), 2.17 (s, 6H). (N1). The following intermediates are prepared using the corresponding starting materials in a manner similar to intermediate K2, as outlined in general route 10B.

[0287] .

[0288] Synthesis of intermediate K5 methyl 1-[3-(dimethylamino)propyl]-2-oxo-1,2-dihydropyridine-3-carboxylate 3-Dimethylaminopropylhydrochloride (3.36 g, 21.26 mmol) was added to a stirred suspension of methyl 2-hydroxypyridine-3-carboxylate (3.00 g, 19.6 mmol) and K₂CO₃ (6.90 g, 49.9 mmol) in acetone (60 mL). The reaction mixture was heated at 60 °C for 5 hours, and then heated at room temperature for 72 hours. Sodium iodide (2.0 g, 13.34 mmol) was added to the reaction mixture, and stirring was continued at 60 °C for 2 hours. Another portion of 3-dimethylaminopropylhydrochloride (2 g, 12.7 mmol) was added, and stirring was continued at 60 °C for 10 hours. The mixture was filtered through diatomaceous earth, and the filtrate was concentrated under vacuum to obtain a yellow oil. The oil was dissolved in DCM (30 mL), washed with water (30 mL), dried over sodium sulfate, and concentrated under vacuum to obtain a yellow oil. The oil was then dissolved in ethyl acetate (15 mL), diluted with heptane (15 mL), and the resulting solid was filtered off. The filtrate was concentrated under vacuum to give the title product as a yellow oil (2.01 g, yield 36%, purity 83%).

[0289] LCMS m / z: 499.3 [2M+Na] + , (ESI+), Rt = 0.40 (S2).

[0290] Synthesis of intermediate K6 Lithium(1+) 1-[3-(dimethylamino)propyl]-2-oxo-1,2-dihydropyridine-3-carboxylate Intermediate K5 was prepared in a manner similar to that of intermediate K2.

[0291] LCMS m / z: 225.1 [M+H] + , (ESI+), Rt = 0.40 (S2) 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 8.21 – 8.14 (m, 1H), 7.85 – 7.78(m,1H), 6.37 (t, J = 6.8 Hz, 1H), 4.01 – 3.93 (m, 2H), 2.22 – 2.14 (m, 2H), 2.11 (s, 6H), 1.84 – 1.72 (m, 2H).

[0292] General route 10C diagram Synthesis of intermediate K7 methyl 5-chloro-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxylate To a solution of 5-chloro-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid (0.528 g, 2.81 mmol) in DCM (10 mL), 1 M thionyl chloride / DCM (7.04 mL, 7.04 mmol) was added dropwise. The reaction mixture was heated to reflux for 3 hours. The reaction mixture was cooled to room temperature and methanol (0.57 mL, 14.07 mmol) was added. After 30 minutes, the reaction mixture was concentrated under vacuum to give the title product as a solid (560 mg, 88% yield).

[0293] LCMS m / z: 202.1 [M+H] + , (ESI+), Rt = 0.56 (S1) 1 H NMR (400 MHz, CDCl3) δ [ppm]: 8.09 (s, 1H), 3.88 (s, 3H), 2.50 (s, 3H).

[0294] Synthesis of intermediate K8 methyl 5-chloro-6-methyl-2-(prop-2-en-1-oxy)pyridine-3-carboxylate 3-Bromoprop-1-ene (0.59 mL, 6.82 mmol) was added to a stirred suspension of methyl 5-chloro-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxylate (550 mg, 2.73 mmol) and K₂CO₃ (943 mg, 6.82 mmol) in acetone (12 mL) and acetonitrile (10 mL). The reaction mixture was stirred at 60 °C for 48 h. The reaction mixture was filtered and washed with acetone (25 mL). The organic reaction mixture was concentrated under vacuum to give the title product as an oil (715 mg, purity 40%, yield 43%).

[0295] LCMS m / z: 242.1 [M+H] + , (ESI+), Rt = 1.08 (S1). Synthesis of intermediate K9 methyl 5-chloro-6-methyl-2-oxo-1-(prop-2-en-1-yl)-1,2-dihydropyridine-3-carboxylate A solution of methyl 5-chloro-6-methyl-2-(prop-2-en-1-yloxy)pyridine-3-carboxylate (0.715 g, 1.18 mmol) and palladium(II) dichloride (10.493 mg, 0.06 mmol) in anhydrous xylene (2 mL) was stirred at 130 °C for 16 h. The reaction mixture was filtered and washed with ethyl acetate (10 mL). The solvent was removed under vacuum to give the oil. Purification by column chromatography (10 g silica, 10-80% ethyl acetate / heptane) gave the title product as the oil (336 mg, 93% purity, 109% yield).

[0296] LCMS m / z: 242.1 [M+H] + , (ESI+), Rt = 0.69 (S1) 1 H NMR (400 MHz, CDCl3) δ [ppm]: 8.10 (s, 1H), 5.93 – 5.78 (m, 1H), 5.25 – 5.15 (m, 1H), 5.08 – 5.00 (m, 1H), 4.78 – 4.64 (m, 2H), 3.83 (s, 3H),2.48 (s, 3H).

[0297] Synthesis of intermediate K10 methyl 5-chloro-6-methyl-2-oxo-1-(2-oxoethyl)-1,2-dihydropyridine-3-carboxylate Methyl 5-chloro-6-methyl-2-oxo-1-(prop-2-en-1-yl)-1,2-dihydropyridine-3-carboxylate (330.0 mg, 1.37 mmol) was added to a solution of 1,4-dioxane (7 mL) and water (3.5 mL) with dipotassium; dioxido(dioxo)osmium; dihydrate (50.312 mg, 0.14 mmol) and sodium periodate (876.207 mg, 4.1 mmol). The mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with water (10 mL) and extracted with DCM (3 × 20 mL). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, and concentrated under vacuum to give the title product (165 mg, 55% purity, 27% yield) as a black liquid.

[0298] LCMS m / z: 244.1 [M+H] + , (ESI+), Rt = 0.51 (S1) 1 H NMR (400 MHz, CDCl3) δ [ppm]: 9.71 (s, 1H), 8.21 (s, 1H), 5.00 (s, 2H), 3.89 (s, 3H), 3.69 (s, 3H).

[0299] Synthesis of intermediate K11 methyl 5-chloro-1-[2-(dimethylamino)ethyl]-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxylate A solution of crude methyl 5-chloro-6-methyl-2-oxo-1-(2-oxoethyl)-1,2-dihydropyridine-3-carboxylate (160.0 mg, 0.66 mmol) in 1,2-dichloroethane (5 mL) was added to a solution of 2 M dimethylamine / THF (0.82 mL, 1.64 mmol), followed by the addition of acetic acid (0.02 mL, 0.33 mmol). After stirring the solution at room temperature for 1 hour, STAB (167.02 mg, 0.79 mmol) was added, and the reaction mixture was stirred for another 18 hours. The mixture was diluted with 1,2-dichloroethane (10 mL), washed successively with 0.5 M sodium hydroxide solution (5 mL), water (5 mL), and dried over Na₂SO₄. The solvent was removed under vacuum to obtain the oil. Purification by reversed-phase chromatography (12 g C-18, 10-100% CH3CN / H2O solution containing 0.1% formic acid) yielded the title product as the oil (65 mg, yield 36%).

[0300] LCMS m / z: 273.2 [M+H] + , (ESI+), Rt = 0.39 (S1) 1 H NMR (400 MHz, CDCl3) δ [ppm]: 8.15 (s, 1H), 4.21 (dd, J = 8.1, 6.3Hz, 2H), 3.90 (s, 3H), 2.65 – 2.56 (m, 5H), 2.31 (s, 6H).

[0301] Synthesis of intermediate K12 5-Chloro-1-[2-(dimethylamino)ethyl]-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxylate salt At 45 °C, a solution of methyl 5-chloro-1-[2-(dimethylamino)ethyl]-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxylate (60 mg, 0.220 mmol) in THF (3 mL) was added to a 2 M aqueous solution of lithium hydroxide monohydrate (0.16 mL, 0.330 mmol). The reaction was stirred for 1 h and then acidified to pH 2 with 1 N HCl. The solvent was removed under vacuum to give the title product (68 mg, 98% yield).

[0302] LCMS m / z: 259.1 [M+H-HCl] + , (ESI+), Rt = 0.31 (S2).

[0303] General route 10D diagram Synthesis of intermediate K13 2-[[3-(dimethylamino)propyl]carbamoyl]ethyl acetate Ethyl 3-chloro-3-oxopropionate (1.14 mL, 8.91 mmol) was added dropwise to a solution of N,N-dimethylpropane-1,3-diamine (0.7 g, 6.85 mmol) and triethylamine (1.91 mL, 13.7 mmol) in DCM (6.0391 mL) at 0 °C. The reaction mixture was heated to room temperature and stirred for another 5 minutes. The reaction mixture was filtered, and the filtrate was concentrated under vacuum to give the title product as an orange semi-solid (2.36 g, purity 54%, yield 86%).

[0304] LCMS m / z: 217.2 [M+H] + , (ESI+), Rt = 0.34 (S1) 1 H NMR (400 MHz, CDCl3) δ [ppm]: 4.11 – 4.05 (m, 2H), 3.30 (q,J = 6.1Hz, 2H), 3.25 (s, 2H), 2.71 (t, J = 7.0 Hz, 2H), 2.46 (s, 6H), 1.83 – 1.75 (m, 2H), 1.18 (d, J = 7.1 Hz, 3H). Synthesis of intermediate K14 ethyl 1-[3-(dimethylamino)propyl]-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxylate Add (E)-4-ethoxy-1,1,1-trifluoro-but-3-en-2-one (1.01 mL, 7.07 mmol) and DBU (0.93 mL, 6.19 mmol) to a solution of ethyl 2-{[3-(dimethylamino)propyl]carbamoyl}acetate (2.36 g, 5.89 mmol) in THF (10 mL). Stir the reaction mixture at room temperature for 66 hours. Dilute the reaction mixture with EtOAc (75 mL) and water (100 mL). Separate the organic layer, and extract the aqueous layer again with EtOAc (4 x 75 mL). Wash the combined organic layers with brine (50 mL), then pass them through a phase separator and concentrate under vacuum to give a blood-red residue. Purify by column chromatography (10 g Kp-NH silica, 0-100% EtOAc / heptane) to give the title product (0.25 g, 13% yield) as a light brown oil.

[0305] LCMS m / z: 321.3 [M+H] + , (ESI+), Rt = 0.46 (S1) 1 H NMR (400 MHz, CDCl3) δ [ppm]: 8.05 (d, J = 7.4 Hz, 1H), 6.68 (d, J =7.5 Hz, 1H), 4.39 (q, J = 7.1 Hz, 2H), 4.18 – 4.06 (m, 2H), 2.40 (t, J = 6.8Hz, 2H), 2.23 (s, 6H), 1.89 (p, J = 6.8 Hz, 2H), 1.38 (t, J = 7.1Hz, 3H).

[0306] Synthesis of intermediate K15 1-[3-(dimethylamino)propyl]-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxylate salt At 45 °C, a 2 M aqueous solution of lithium hydroxide hydrate (0.53 mL, 1.05 mmol) was added to a stirred solution of ethyl 1-[3-(dimethylamino)propyl]-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxylate (225 mg, 0.702 mmol) in THF (18.75 mL). The reaction mixture was stirred for 1 hour. The mixture was acidified to pH 4 with 1 N aqueous HCl. The reaction mixture was concentrated under vacuum to give the title product (230 mg, 100% yield) as a pale brown solid.

[0307] LCMS m / z: 293.2 [M+H]+ , (ESI+), Rt = 0.32 (S1).

[0308] The following intermediates are prepared using the corresponding starting materials in a manner similar to intermediate K6, as outlined in General Route 10D.

[0309] .

[0310] Synthesis of intermediate K17 2-[(3-{[(tert-butoxy)carbonyl]amino}-3-methylbutyl)carbamoyl]ethyl acetate It was prepared using N-(4-amino-2-methylbut-2-yl)carbamate tert-butyl hydrochloride and ethyl 3-chloro-3-oxopropionate in a manner similar to intermediate K4.

[0311] LCMS m / z: 339.3 [M+Na] + , (ESI+), Rt = 0.76 (S1) 1 H NMR (400 MHz, CDCl3) δ [ppm]: 7.10 (br. s, 1H), 4.52 (br.s, 1H), 4.18 (q, J = 7.2 Hz, 2H), 3.35 – 3.28 (m, 2H), 3.27 (s, 2H), 1.96 – 1.87 (m,2H), 1.42 (s, 9H), 1.30 – 1.25 (m, 9H).

[0312] Diagram of General Route 6 Synthesis of intermediate F1 (3S)-3-{4,5-difluoro-2',6'-dimethyl-[1,1'-biphenyl]-3-yl}-3-[(2S)-4-methyl-2-[(quinoline) Ethyl porino-8-yl)formamido]pentamido]propionate To a solution of (3S)-3-[(2S)-2-amino-4-methylpentamido]-3-{4,5-difluoro-2',6'-dimethyl-[1,1'-biphenyl]-3-yl}propionate hydrochloride (intermediate B2, 80 mg, 0.154 mmol) and quinoline-8-carboxylic acid (32 mg, 0.185 mmol) in DCM (1.54 mL), DIPEA (0.059 mL, 0.339 mmol) and HATU (64 mg, 0.169 mmol) were added. The reaction mixture was stirred for 18 hours. The reaction mixture was concentrated under vacuum, and the residue was purified by column chromatography (10 g silica, 0–100% EtOAc / heptane) to give the title product as a colorless solid (59 mg, 64% yield).

[0313] LCMS m / z: 602.5 [M+H]+, (ESI+), Rt = 4.71 (S4) 1 H NMR (500 MHz, CDCl3) δ [ppm]: 11.62 (d, J = 7.2 Hz, 1H), 8.94 (dd,J = 4.3, 1.8 Hz, 1H), 8.67 (dd, J = 7.4, 1.6 Hz, 1H), 8.28 (dd, J = 8.3,2.3Hz, 1H), 7.97 (dd, J = 8.1, 1.6 Hz, 1H), 7.77 (d, J = 8.5 Hz, 1H), 7.63 (dd,J = 8.1, 7.3 Hz, 1H), 7.50 (dd, J = 8.3, 4.3 Hz, 1H), 7.20 – 7.13 (m, 1H),7.07 (d, J = 7.7 Hz, 2H), 6.91 – 6.83 (m, 2H), 5.70 (dt, J = 8.5, 6.2 Hz,1H), 4.77 – 4.71 (m, 1H), 3.96 – 3.82 (m, 2H), 2.91 (dd, J = 15.7, 6.1 Hz,1H), 2.84(dd, J = 15.8, 6.3 Hz, 1H), 1.98 (s, 3H), 1.95 (s, 3H), 1.94 – 1.88(m, 1H), 1.86 – 1.75 (m, 2H), 1.03 (t, J = 7.1 Hz, 3H), 0.95 (d, J = 6.5 Hz,3H), 0.93 (d, J = 6.4 Hz, 3H). (N1).

[0314] The intermediates in Table 7 below are prepared using the corresponding starting materials in a manner similar to intermediate F1, as outlined in general route 6.

[0315] Table 7 .

[0316] Synthesis of intermediate F39 (3S)-3-{4,5-difluoro-2',6'-dimethyl-[1,1'-biphenyl]-3-yl}-3-[(2S)-2-[(1,4-dimethyl] [2-oxo-1,2-dihydropyridin-3-yl)formamido]-4-methylpentamido]ethyl propionate A solution of methyl 1,4-dimethyl-2-oxo-1,2-dihydropyridine-3-carboxylate (100 mg, 0.497 mmol) in THF (4 mL) was added to a solution of LiOH·H₂O (104 mg, 2.48 mmol) dissolved in water (1 mL). The reaction mixture was stirred for 48 hours. The reaction mixture was concentrated under vacuum to give an intermediate. The intermediate acid was redissolved in DMF (4 mL), and intermediate B2 (150 mg, 0.311 mmol), DIPEA (190 µL, 1.09 mmol), and HATU (142 mg, 0.373 mmol) were added. The resulting mixture was stirred for 72 hours. The reaction was then quenched with water (10 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine, dried over Na₂SO₄, and concentrated under vacuum to give a crude residue. The title product (20 mg, 9% yield) was purified by column chromatography (12 g Redisep Gold silica, 0–100% EtOAc / heptane) to obtain a colorless gel.

[0317] LCMS m / z: 596.4 [M+H]+, (ESI+), Rt = 2.85 (S6).

[0318] Diagram of General Route 7 Synthesis of intermediate G1 (3S)-3-{2',6'-dichloro-4,5-difluoro-[1,1'-biphenyl]-3-yl}-3-[(2S)-4-methyl-2-[(1-methyl] [2-oxo-1,2-dihydropyridin-3-yl]formamido]pentamido]ethyl propionate Pd(dppf)Cl2 (18 mg, 0.0214 mmol) was added to a degassed suspension of (3S)-3-(5-bromo-2,3-difluorophenyl)-3-[(2S)-4-methyl-2-[(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)formamido]pentamido]propionate (intermediate F6, 70 mg, 0.107 mmol), 2,6-dichlorophenylboronic acid (35 mg, 0.183 mmol), and K3PO4 (70 mg, 0.330 mmol) in 1,4-dioxane (1 mL) and water (0.1 mL). The reaction mixture was heated at 90 °C for 18 hours. The reaction mixture was concentrated under vacuum to obtain a crude residue. Purified by column chromatography (10 g silica, 0-100% EtOAc / heptane), the title product (47 mg, 45% yield) was obtained as orange oil.

[0319] LCMS m / z: 622.4 / 624.3 [M+H]+, (ESI+), Rt = 1.07 (S1) 1 H NMR (500 MHz, CDCl3) δ [ppm]: 10.11 (d, J = 7.6 Hz, 1H), 8.43 (dd,J = 7.2,2.2 Hz, 1H), 7.58 – 7.53 (m, 2H), 7.40 – 7.36 (m, 2H), 7.02 – 6.98(m, 2H), 6.39 (t, J = 6.9 Hz, 1H), 5.69 (dt, J = 8.4, 6.2 Hz, 1H), 4.60 –4.54 (m, 1H),4.02 – 3.97 (m, 2H), 3.64 (s, 3H), 2.91 – 2.81 (m, 4H), 1.81(td, J = 10.1, 5.0 Hz, 1H), 1.72 – 1.70 (m, 1H), 1.14 – 1.11 (m, 3H), 0.92 –0.87 (m, 6H).

[0320] The intermediates in Table 8 below are prepared using the corresponding starting materials in a manner similar to intermediate G1, as outlined in general route 7.

[0321] Table 8 .

[0322] Diagram of General Route 8 Synthesis of intermediate H1 (3S)-3-[2,3-difluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane--2-yl)phenyl]- Ethyl 3-[(2S)-4-methyl-2-[(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)carbamoyl]pentamido]propionate Pd(dppf)Cl2 (6.0 mg, 8.20 μmol) was added to a degassed solution of (3S)-3-(5-bromo-2,3-difluorophenyl)-3-[(2S)-4-methyl-2-[(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)formamido]pentamido]propionate (intermediate F6, 100 mg, 0.153 mmol), B2(pin)2 (58 mg, 0.228 mmol), and KOAc (45 mg, 0.459 mmol) in DMF (1 mL). The reaction mixture was heated at 80 °C for 3 hours. The reaction mixture was cooled to room temperature and filtered through a diatomaceous earth mat, washed with excess EtOAc (3 × 5 mL). The filtrate was concentrated under vacuum to give the title product (142 mg, 77% yield) as a dark brown gel.

[0323] LCMS m / z: 604.6 [M+H]+, (ESI+), Rt = 1.08 (S1) 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 10.14– 10.03 (m, 1H), 9.02 – 8.89(m, 1H), 8.35 – 8.23 ​​(m, 1H), 8.10 – 8.04 (m, 1H), 7.69 – 7.39 (m, 2H), 6.54– 6.41 (m, 1H), 5.59 – 5.38 (m, 1H), 4.64 – 4.43 (m,1H), 4.07 – 3.96 (m, 2H), 3.58 – 3.56 (m, 3H), 2.88 – 2.76 (m, 2H), 1.54 – 1.37 (m, 3H), 1.17 – 1.16 (m, 12H), 1.13 – 1.09 (m, 3H), 0.89 – 0.78 (m, 6H). (N1).

[0324] Synthesis of intermediate H2 (2S)-4-methyl-2-[(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)carbamoyl]valeric acid Using the route outlined in step B of general route 6, the methyl valerate of (2S)-4-methyl-2-[(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)carbamate] is prepared by hydrolysis.

[0325] LCMS m / z: 267.2 [M+H]+, (ESI+), Rt = 0.60,S1 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 12.73(s, 1H), 10.13 (d, J = 7.9Hz, 1H), 8.31 (dd, J = 7.3, 2.2 Hz, 1H), 8.08 (dd, J = 6.5, 2.2 Hz, 1H), 6.51(dd, J = 7.3, 6.5 Hz, 1H), 4.55 – 4.37 (m, 1H), 3.57(s, 3H), 1.71 – 1.55 (m,3H), 0.98 – 0.80 (m, 6H). (N1).

[0326] Synthesis of intermediate H3 (3S)-3-(5-bromopyridin-3-yl)-3-[(2S)-4-methyl-2-[(1-methyl-2-oxo-1,2-dihydropyridin- [3-yl)formamido]pentamido]ethyl propionate dihydropyridine-3-yl)formamido]pentamido]ethyl propionate Preparation of DMF is initiated from intermediates H2 and A18 in a manner similar to that of intermediate B1.

[0327] LCMS m / z: 521.2 / 523.2 [M+H]+, (ESI+), Rt = 0.79, S1.

[0328] Synthesis of intermediate H3B (3S)-3-[(2S)-4-methyl-2-[(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)carbamate]pentanoyl Ethyl [amino]-3-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)pyridin-3-yl]propionate It was prepared using intermediate H3 as the starting material, in a manner similar to that of intermediate H1.

[0329] LCMS m / z: 547.3 [M+H]+, (ESI+), Rt = 0.82,S1 1H NMR (400 MHz, DMSO) δ 10.10 – 9.98 (m, 1H), 8.82 – 8.70 (m, 1H), 8.55 – 8.48 (m, 1H), 8.28 – 8.15 (m, 2H), 8.08 – 8.01(m, 1H), 7.68 – 7.51 (m,1H), 7.26 – 7.07 (m, 3H), 6.53 – 6.43 (m, 1H), 5.36 – 5.24 (m, 1H), 4.55 –4.44 (m, 1H), 4.07 – 3.92 (m, 2H), 2.92 – 2.81 (m, 2H),2.78 – 2.62 (m, 4H), 1.90 (d, J = 30.4 Hz, 6H), 1.61 – 1.40 (m, 2H), 1.18 – 1.02 (m, 3H), 0.93 –0.76 (m, 6H).

[0330] Diagram of General Route 8B Synthesis of intermediate H4 (3S)-3-[(2S)-2-{[(tert-butoxy)carbonyl]amino}-4-methylpentamido]-3-[2,3-difluoro-5- Ethyl (4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)phenyl]propionate Intermediate B15 was prepared using the same conditions as intermediate H1.

[0331] LCMS m / z: 569.5 [M+H] + , (ESI+), Rt = 1.18 (S1) 1 H NMR (400 MHz, DMSO) δ [ppm]: 8.57 (d,J = 7.8 Hz, 1H), 7.52 (d, J =6.3 Hz, 1H), 7.47 – 7.38 (m, 1H), 6.75 (d, J = 8.3 Hz, 1H), 5.43 (q, J = 7.6Hz, 1H), 4.07 – 3.90 (m, 3H), 2.88 – 2.72 (m,2H), 1.52 – 1.41 (m, 1H), 1.36(s, 9H), 1.33 – 1.26 (m, 14H), 1.12 (t, J = 7.1 Hz, 3H), 0.90 – 0.77 (m, 6H).

[0332] Synthesis of intermediate H5 (3S)-3-[(2S)-2-{[(tert-butyloxycarbonyl)amino]-4-methylpentamido}-3-[5-(2,5-dimethyl- Ethyl 2H-indazol-4-yl)-2,3-difluorophenyl]propionate In a MW flask, a mixture of Pd(dppf)₂Cl₂ (33.041 mg, 0.04 mmol), K₂CO₃ (223.673 mg, 1.62 mmol), ethyl (3S)-3-[(2S)-2-{[(tert-butoxy)carbonyl]amino}-4-methylpentamido]-3-[2,3-difluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)phenyl]propionate (460.0 mg, 0.81 mmol), and 4-bromo-2,5-dimethylindazole (204.352 mg, 0.91 mmol) in 1,4-dioxane (4 mL) and water (0.5 mL) was degassed for 5 minutes and then capped. The reaction mixture was heated at 150 °C under MW radiation for 15 minutes. The reaction mixture was filtered through a thiol column and washed with excess EtOAc (3 x 10 mL). The solvent in the filtrate was concentrated under vacuum. Purification was performed by column chromatography (25 g silica, 0-100% EtOAc / heptane) to give the title product as the oil (389 mg, 70% yield).

[0333] LCMS m / z: 587.5 [M+H] + , (ESI+), Rt = 1.07 (S1) 1 H NMR (500 MHz, DMSO-d6) δ [ppm]: 8.51(d, J = 8.1 Hz, 1H), 7.90 (s,1H), 7.51 (d, J = 8.8 Hz, 1H), 7.43 – 7.37 (m, 1H), 7.24 (d, J = 5.7 Hz, 1H),7.17 (d, J = 8.9 Hz, 1H), 6.80 (d, J = 8.3 Hz,1H), 5.55 (q, J = 7.6 Hz, 1H),4.09 (s, 3H), 4.08 – 4.01 (m, 2H), 3.95 – 3.87 (m, 1H), 2.86 (d, J = 7.5 Hz, 2H), 2.22 (s, 3H), 1.46 – 1.39 (m, 1H), 1.30 –1.22 (m, 11H), 1.13 (t, J = 7.1Hz, 3H), 0.73 – 0.68 (m, 6H).

[0334] Synthesis of intermediate H6 (3S)-3-[(2S)-2-amino-4-methylpentanoyl]-3-[5-(2,5-dimethyl-2H-indazol-4-yl)-2, ethyl 3-difluorophenyl]propionate dihydrochloride It was prepared using intermediate H5 as the starting material, in a manner similar to that of intermediate A4.

[0335] LCMS m / z: 487.3 [M+H-HCl] + , (ESI+), Rt = 0.75 (S1) 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 9.37(d, J = 7.7 Hz, 1H), 8.24 (s,2H), 7.95 (s, 1H), 7.53 (d, J = 8.8 Hz, 1H), 7.48 – 7.40 (m, 1H), 7.29 (d, J= 5.7 Hz, 1H), 7.19 (d, J = 8.8 Hz, 1H), 5.57 (q, J= 7.5 Hz, 1H), 4.13 – 4.01(m, 6H), 3.77 – 3.69 (m, 2H), 3.01 – 2.91 (m, 2H), 2.23 (s, 3H), 1.49 – 1.36 (m, 3H), 1.13 (t, J = 7.1 Hz, 3H), 0.73 – 0.63 (m, 6H).

[0336] Synthesis of intermediate H7 {5−[(1S)−1−[(2S)−2−{[(tert-butoxy)carbonyl]amino}−4−methylpentamido]−3−ethoxy−3− [Oxypropyl]pyridin-3-yl}boronic acid To a MW tube containing PdCl2(dppf)2 (40.0 mg, 0.05 mmol), (3S)-3-(5-bromopyridin-3-yl)-3-[(2S)-2-{[(tert-butoxy)carbonyl]amino}-4-methylpentamido]propionate (intermediate B12, 0.45 g, 0.601 mmol), bis(pinacol)diboron (0.23 g, 0.906 mmol), and KOAc (0.18 g, 1.78 mmol), 1,4-dioxane (1.8 mL) and 1 drop of DMF were added. The reaction mixture was degassed for 5 min and then heated at 150 °C under MW radiation for 15 min. The reaction mixture was filtered through a thiol column and washed with EtOAc (2 x 10 mL). The solvent was removed under vacuum to give a dark brown residue. Purified by column chromatography (10 g silica, 75-100% EtOAc / heptane), the title product (200 mg, 42% yield) was obtained as a brown solid.

[0337] LCMS m / z: 452.3 [M+H] + , (ESI+), Rt = 0.65 (S1) 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 8.65 – 8.61 (m, 1H), 8.61 – 8.57 (m, 1H), 8.52 – 8.41 (m, 1H), 8.01 – 7.91 (m, 1H), 6.87 – 6.77 (m, 1H), 5.75(s, 2H), 5.25 – 5.15 (m, 1H), 4.08 – 3.95 (m, 2H), 3.95 – 3.91 (m, 1H), 2.91 –2.81 (m, 2H), 1.54 – 1.44 (m, 1H), 1.32 – 1.29 (m, 9H), 1.26 – 1.21 (m, 2H),1.13 – 1.08 (m, 3H), 0.89 – 0.77 (m, 6H). Synthesis of intermediate H8 (3S)-3-[(2S)-2-{[(tert-butoxy)carbonyl]amino}-4-methylpentamido]-3-{3',5'-dimethyl] Ethyl [3,4'-bipyridine]-5-yl propionate Condition A In a pressure tube flask, a mixture of {5-[(1S)-1-[(2S)-2-{[(tert-butoxy)carbonyl]amino}-4-methylpentamido]-3-ethoxy-3-oxypropyl]pyridin-3-yl}boronic acid (intermediate H7, 42.5 mg, 0.05 mmol), 4-bromo-3,5-dimethylpyridine hydrochloride (22 mg, 0.0989 mmol), Pd(dppf)₂Cl₂ (8.0 mg, 9.77 μmol), and K₂CO₃ (27 mg, 0.195 mmol) in 1,4-dioxane (0.5 mL) and water (50 μL) was degassed. The reaction mixture was sealed and heated at 100 °C for 1 hour. The reaction mixture was diluted with EtOAc (2 mL) and water (2 mL). The organic layer was separated, and the aqueous layer was extracted again with EtOAc (2 x 1 mL). The combined organic layers were washed with brine (2 mL), dried over Na2SO4, and concentrated under vacuum to obtain a brown oil residue. The residue was purified by reversed-phase column chromatography (10 g C-18 silica, 10% to 100% MeCN / H2O, containing 0.1% formic acid) to give the title product (13 mg, 50% yield) as a brown viscous oil.

[0338] Condition B In a pressure flask, {5-[(1S)-1-[(2S)-2-{[(tert-butoxy)carbonyl]amino}-4-methylpentamido]-3-ethoxy-3-oxopropyl]pyridin-3-yl}boronic acid (intermediate H7, 250.0 mg, 0.51 mmol), 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)pyridine (143.777 mg, 0.62 mmol), K3PO4 (464.014 mg, 2.19 mmol), and Pd(dppf)2Cl2.DCM (98.818 mg, 0.12 mmol) were added. 1,4-dioxacyclohexane (4 mL) and water (0.4 mL) were added. The reaction mixture was capped and heated at 100 °C for 3 hours. The reaction mixture was concentrated under vacuum to give a brown residue. Purification was performed by column chromatography (10 g silica, 0-100% EtOAc / heptane) to obtain the title product (39 mg, 15% yield) as colorless oil and the starting material (183 mg, 73% recovery).

[0339] LCMS m / z: 513.3 [M+H] + , (ESI+), Rt = 0.72 (S1) 1H NMR (400 MHz, d3-MeCN) δ [ppm]: 8.58(d, J = 2.2 Hz, 1H), 8.34 (s,2H), 8.28 (d, J = 2.0 Hz, 1H), 7.51 (t, J = 2.2 Hz, 1H), 7.39 (d, J = 8.2 Hz,1H), 5.60 – 5.46 (m, 1H), 5.35 (q, J = 7.3 Hz,1H), 4.04 (q, J = 7.1 Hz, 2H), 3.98 – 3.90 (m, 1H), 2.96 – 2.82 (m, 2H), 1.98 (s, 6H), 1.65 – 1.54 (m, 1H), 1.48 – 1.39 (m, 2H), 1.32 (s, 9H), 1.14 (t, J =7.1 Hz, 3H), 0.89 – 0.84 (m, 6H).

[0340] Synthesis of intermediate H9 (3S)-3-[(2S)-2-amino-4-methylpentanoyl]-3-{3',5'-dimethyl-[3,4'-bipyridine]-5- Ethyl propionate trihydrochloride A solution of ethyl (3S)-3-[(2S)-2-{[(tert-butoxy)carbonyl]amino}-4-methylpentamido]-3-{3',5'-dimethyl-[3,4'-bipyridine]-5-yl}propionate (1.04 g, 1.83 mmol) in 1,4-dioxane (6 mL) was added to a 4M HCl / dioxane (1.9 mL, 7.6 mmol). A gel formed in the flask within 5 minutes. Another 6 mL of 1,4-dioxane was added, the suspended solid was sonicated for 10 minutes, and then the mixture was stirred at room temperature for 18 hours. The reactants were concentrated under vacuum and azeotropically reacted with DCM (2 x 50 mL) to give the title product (1.00 g, 1.55 mmol, 85% yield) as a grayish-white powder.

[0341] LCMS m / z: 413.4 [M+H-3HCl] + , (ESI+), Rt = 0.64 (S2).

[0342] The intermediates in Table 9 were synthesized according to general formula 8B, taking intermediate H6 as an example, using the corresponding starting materials. Diastereomers were isolated during final purification, or, if necessary, by chiral separation methods. The intermediates were obtained as the title compound or its salts.

[0343] Table 9 .

[0344] Diagram of General Route 9

[0345] Synthesis of intermediate I1 (2R)-2-{[(2S)-1-methoxy-4-methyl-1-oxopentane-2-yl]carbamoyl}pyrrolidine-1-methyl tert-butyl ester (Step A) HATU (8.40 g, 22.1 mmol) was added to a stirred solution of (2S)-2-amino-4-methylvalerate hydrochloride (1.75 g, 9.63 mmol), (2R)-1-[(tert-butoxy)carbonyl]pyrrolidine-2-carboxylic acid (1.57 g, 7.29 mmol), and DIPEA (6.3 mL, 36.1 mmol) in DMF (23 mL). The solution was stirred at room temperature for 3 hours, and then EtOAc (30 mL) and water (20 mL) were added. The organic layer was separated, and the aqueous layer was extracted again with EtOAc (3 × 15 mL). The combined organic layers were washed with brine (30 mL), concentrated under vacuum, and purified by column chromatography (50 g silica, 0–100% TBME / heptane) to give the title product (2.30 g, 87% yield).

[0346] LCMS m / z: 365.1 [M+H]+, (ESI+), Rt = 0.88, S1 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 8.26 – 7.95 (m, 1H), 4.39 – 4.29 (m, 1H), 4.13 – 4.06 (m, 1H), 3.64 – 3.58 (m, 3H), 3.50 – 3.35 (m, 1H), 3.30 – 3.18 (m, 1H), 2.18 – 1.99 (m, 1H), 1.82 – 1.69 (m, 3H), 1.67 – 1.57 (m, 2H), 1.55 – 1.43 (m, 1H), 1.43 – 1.25 (m, 9H), 0.92 – 0.77 (m, 6H). (N1).

[0347] Synthesis of intermediate I2 (2S)-2-{[(2R)-1-[(tert-butoxy)carbonyl]pyrrolidine-2-yl]formamido}-4-methylvaleric acid (step) B） A stirred solution of (2R)-2-{[(2S)-1-methoxy-4-methyl-1-oxopentane-2-yl]carbamoyl}pyrrolidine-1-carboxylic acid tert-butyl ester (2.30 g, 6.38 mmol) in THF (57 mL) and MeOH (1.9 mL) was added to a 2M aqueous solution of LiOH (20 mL, 40.8 mmol). The reaction mixture was stirred at 45 °C for 30 min. The solution was cooled, water (10 mL) was added, and the mixture was concentrated under vacuum to remove organic matter. The aqueous phase was acidified to pH 3 with 1M aqueous HCl, and the resulting precipitate was extracted with DCM (3 × 15 mL). The combined organic layers were concentrated under vacuum to give the title product (2.10 g, 95% yield) as a white solid.

[0348] LCMS m / z: 351.3 [M+H]+, (ESI+), Rt = 0.75, S1 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 12.59 – 12.40 (m, 1H), 8.09 – 7.81 (m, 1H), 4.34 – 4.22 (m, 1H), 4.15 – 4.07 (m, 1H), 3.48 – 3.35 (m, 1H),3.29 – 3.21 (m, 1H), 2.17 – 2.01 (m, 1H), 1.87 – 1.68 (m, 3H), 1.68 – 1.54(m, 2H), 1.54 – 1.43(m, 1H), 1.43 – 1.26 (m, 9H), 0.93 – 0.77 (m, 6H). (N1).

[0349] Synthesis of intermediate I3 (2R)-2-{[(1S)-1-{[(1S)-3-ethoxy-1-[4-fluoro-2',6'-dimethyl-5-(trifluoromethyl)-[1, 1'-Biphenyl]yl-3-yl]-3-oxopropyl]carbamoyl]-3-methylbutyl]carbamoyl]pyrrolidine-1-carboxylic acid tert-butyl Ester (Step C) To a solution of (2S)-2-{[(2R)-1-[(tert-butoxy)carbonyl]pyrrolidine-2-yl]formamido}-4-methylvaleric acid (150 mg, 0.434 mmol) and (3S)-3-amino-3-[4-fluoro-2',6'-dimethyl-5-(trifluoromethyl)-[1,1'-biphenyl]-3-yl]propionate (218 mg, 0.478 mmol) in DCM (3 mL), DIPEA (152 µL, 0.870 mmol) and HATU (182 mg, 0.479 mmol) were added. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with DCM (5 mL), washed with water (5 mL), and passed through a phase separator. The solvent was concentrated under vacuum to obtain a crude oil. The title product (314 mg, 98% yield) was purified by rapid column chromatography (10 g silica, 0.100% EtOAc / heptane) to obtain a pale yellow oil.

[0350] LCMS m / z: 716.4 [M+H]+, (ESI+), Rt = 1.25, S1 1 H NMR (500 MHz, CDCl3) δ [ppm]: 7.62 – 7.49 (m, 1H), 7.31 (d, J =6.4 Hz, 2H), 7.21 – 7.13 (m, 1H), 7.13 – 7.06 (m, 2H), 6.89 – 6.29 (m, 1H),5.71 – 5.60 (m, 1H), 4.38 (q, J = 7.1 Hz, 1H), 4.24 – 4.17 (m, 1H), 4.09 –3.99 (m, 2H), 3.38 (d, J = 54.1 Hz, 2H), 2.98 – 2.82 (m, 2H), 2.01 – 1.95 (m, 6H), 1.86 – 1.77 (m, 1H), 1.43 (s, 6H), 1.20 – 1.16 (m, 3H), 0.91 – 0.84 (m, 15H). (N1).

[0351] Synthesis of intermediate I4(6a) (3S)-3-[4-fluoro-2',6'-dimethyl-5-(trifluoromethyl)-[1,1'-biphenyl]-3-yl]-3-[(2S)-4-methyl [(2R)-pyrrolidine-2-yl]formamido}pentamido]ethyl propionate hydrochloride (Step D) Add HCl (4 M in dioxane, 1.5 mL, 6.00 mmol) to a solution of (2R)-2-{[(1S)-1-{[(1S)-3-ethoxy-1-[4-fluoro-2',6'-dimethyl-5-(trifluoromethyl)-[1,1'-biphenyl]-3-yl]-3-oxopropyl]carbamoyl}-3-methylbutyl]carbamoyl}pyrrolidine-1-carboxylic acid tert-butyl ester (314 mg, 0.425 mmol) in DCM (4.5 mL). Stir the reaction mixture at room temperature for 45 minutes. Add HCl (4 M in dioxane, 1.5 mL, 6.00 mmol) again, and continue stirring the reaction mixture for 15 minutes. The reactants were concentrated under vacuum, ground with heptane (2 × 5 mL), the solvent was decanted, and the residue was dried under vacuum to give the title product (193 mg, yield 62%) as a grayish-white powder.

[0352] LCMS m / z: 594.6 [M+H]+, (ESI+), Rt = 1.05, S1 1 H NMR (400 MHz, CDCl3) δ [ppm]: 8.81 (d, J = 7.6 Hz, 1H), 8.49 (d, J= 7.5 Hz, 1H), 7.48 – 7.41 (m, 1H), 7.35 – 7.30 (m, 1H), 7.22 – 7.15 (m,1H),7.14 – 7.07 (m, 2H), 5.74 – 5.63 (m, 1H), 4.67 – 4.48 (m, 1H), 4.16 – 4.02(m, 2H), 3.49 – 3.28 (m, 2H), 3.14 – 2.98 (m, 2H), 2.53 – 2.42 (m, 1H), 2.06–1.75 (m, 11H), 1.58 – 1.47 (m, 2H), 1.25 – 1.16 (m, 3H), 0.95 – 0.78 (m, 7H). (N1).

[0353] Synthesis of intermediate I5 (3S)−3−[(2S)−2−{[(2R)−1−acetylpyrrolidine−2−]formamido}−4−methylpentamido]− Ethyl 3-[4-fluoro-2',6'-dimethyl-5-(trifluoromethyl)-[1,1'-biphenyl]-3-yl]propionate (Step 5) At 0 °C, ethyl propionate hydrochloride (100 mg, 0.136 mmol) and DIPEA (38 µL, 0.218 mmol) in DCM (1.2 mL) were mixed with a stock solution of acetyl chloride (0.1 mL stock solution: 120 µL acetyl chloride / 1 mL DCM). The reaction mixture was stirred and heated to room temperature for 2.5 h. The reaction mixture was cooled to 0 °C, retreated with DIPEA (13 µL, 0.0746 mmol) and acetyl chloride stock solution (0.05 mL), and then allowed to be heated to room temperature for 1 h. The reactants were diluted with DCM (2 mL) and quenched with saturated sodium bicarbonate (water solution, 3 mL). The resulting aqueous phase was extracted with DCM (3 mL). The combined organic layers were passed through a phase separator and concentrated under vacuum. The residue was purified by column chromatography (10 g silica, 0–100% EtOAc / heptane) to give the title product (39 mg, 43% yield) as a grayish-white semi-solid.

[0354] LCMS m / z: 636.6 [M+H]+, (ESI+), Rt = 1.17, (S1) 1 H NMR (400 MHz, CDCl3) δ [ppm]: 7.85 (d, J = 8.6 Hz, 1H), 7.31 –7.26 (m, 2H), 7.19 – 7.04 (m, 3H), 6.80 (d, J = 8.1 Hz, 1H), 5.79 – 5.69 (m,1H), 4.40 – 4.31 (m, 1H), 4.28 (dd, J = 7.6, 3.8 Hz, 1H), 4.13 – 4.00 (m,2H), 3.39 – 3.21 (m, 2H), 3.03 – 2.79 (m, 2H), 2.20 – 2.11 (m, 1H), 2.04 –1.98 (m, 4H), 1.96 (s, 3H), 1.94 – 1.81 (m, 3H), 1.79 (s, 3H), 1.72 – 1.62 (m,1H), 1.54 – 1.45 (m, 1H), 1.20 (t, J = 7.1 Hz, 3H), 0.92 (d, J = 6.6 Hz, 3H),0.88 (d, J= 6.5 Hz, 3H). (N1).

[0355] The following intermediates are prepared using the corresponding starting materials in a manner similar to intermediate I5, as outlined in general route 6.

[0356] .

[0357] Map of General Route 10A Synthesis of intermediate J1 Methyl 1-(1-methylazacyclobutane-3-yl)-2-oxo-1,2-dihydropyridine-3-carboxylate (Step A) At 0 °C, a solution of methyl 2-oxo-2H-pyran-3-carboxylate (800 mg, 5.19 mmol) in DMF (10 mL) was added dropwise to 1-methylazacyclobutane-3-amine (447 mg, 5.19 mmol) in DMF (10 mL). The reaction mixture was stirred at 0 °C for 1 hour, then heated to room temperature. T3P (50% dissolved in EtOAc, 4.6 mL, 7.79 mmol) was then added dropwise. The reaction mixture was stirred for 72 hours, then concentrated under vacuum. Purification by column chromatography (55 g, KPNH silica, 0–100% EtOAc / heptane, 0–20% MeOH / EtOAc) yielded the title product as a red solid (415 mg, 25% yield).

[0358] LCMS m / z: 223.1 [M+H]+, (ESI+), Rt = 0.38 (S1).

[0359] Synthesis of intermediate J2 (intermediate 7a) 1-(1-Methylazacyclobutane-3-yl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (Step B) A solution of methyl 1-(1-methylazacyclobutan-3-yl)-2-oxo-1,2-dihydropyridine-3-carboxylate (415 mg, 1.29 mmol) in methanol (6.9 mL) was added to LiOH (2 M, aqueous solution, 1.3 mL, 2.58 mmol). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under vacuum to give a red solid. Purification by column chromatography (11 g KPNH silica, 0–100% methanol / EtOAc) gave the title product (100 mg, 34% yield) as a red solid.

[0360] LCMS m / z: 209.2 [M+H]+, (ESI+), Rt = 0.18 (S1) 1H NMR (500 MHz, DMSO-d6) δ [ppm]: 8.17 (dd, J = 7.0, 2.2 Hz, 1H), 7.96 (dd, J = 6.8, 2.2 Hz, 1H), 6.49 – 6.43 (m, 1H), 5.00 – 4.91 (m, 1H), 3.75 – 3.66 (m, 2H), 3.15 – 3.09 (m, 2H), 2.27 (s, 3H). (N1).

[0361] Synthesis of intermediate J3 Methyl 1-(oxetane-3-yl)-2-oxo-1,2-dihydropyridine-3-carboxylate (Step A) At room temperature, oxetane-3-amine hydrochloride (0.72 g, 6.56 mmol) and DIPEA (3.4 mL, 19.5 mmol) were added to a solution of methyl 2-oxo-2H-pyran-3-carboxylate (1.00 g, 6.49 mmol) in DMF (33.5 mL). The reaction mixture was stirred for 1 hour, and then EDC.HCl (1.87 g, 9.75 mmol) and DMAP (0.20 g, 1.64 mmol) were added. The reaction mixture was stirred for another 3 hours. The reaction mixture was concentrated under vacuum, suspended in water (150 mL), and extracted with EtOAc (3 x 50 mL). The combined organic layers were free of product. The aqueous layer was extracted with a 4:1 DCM / IPA solution (2 x 60 mL). The combined organic layers were concentrated under vacuum to give the title product (352 mg, 24% yield) as brown oil.

[0362] LCMS m / z: 210.1 [M+H] + , (ESI+), Rt = 1.08 (S4) 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 8.08-8.02 (m, 2H), 6.41 (t, J =6.9Hz, 1H), 5.45 (p, J = 7.2 Hz, 1H), 4.86 (t, J = 7.5 Hz, 2H), 4.72 (t, J =7.2 Hz, 2H), 3.73 (s, 3H).

[0363] Synthesis of intermediate J3 1-(oxetane-3-yl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (Step B) A stirred solution of methyl 1-(oxetane-3-yl)-2-oxo-1,2-dihydropyridine-3-carboxylate (352.2 mg, 1.57 mmol) in methanol (4.5 mL) and THF (65 mL) was added to a 2 M aqueous solution of lithium hydroxide (1.2 mL, 2.4 mmol). The reaction mixture was stirred at room temperature for 72 hours. The reaction mixture was concentrated under vacuum, and the resulting residue was suspended in water (about 20 mL). The suspension was acidified to pH about 1 with a 2 M aqueous solution of HCl and extracted with a 4:1 DCM:IPA solution (3 x 10 mL). The combined organic layers were concentrated under vacuum to give the title product (300 mg, 71% yield) as a pale orange solid.

[0364] LCMS m / z: 196.1 [M+H] + , (ESI+), Rt = 1.04 (S3) 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 14.26(s, 1H), 8.40 (dd, J = 7.3,2.0 Hz, 1H), 8.30 (dd, J = 6.7, 2.0 Hz, 1H), 6.79 (t, J = 7.0 Hz, 1H), 5.68 –5.57 (m, 1H), 4.91 (t, J = 7.4 Hz, 2H), 4.84 (t, J= 7.4 Hz, 2H).

[0365] Map of General Route 10B Synthesis of intermediate K1 To a solution of methyl 2-oxo-1,2-dihydropyridine-3-carboxylate (200 mg, 1.31 mmol) and CsCO3 (1280 mg, 3.93 mmol) in MeCN (5 mL), (2-bromoethyl)dimethylamine hydrobromide (375 mg, 1.58 mmol) was added. The reaction mixture was stirred at room temperature for 24 hours. The reaction was cooled to room temperature, filtered through a diatomaceous earth mat, and washed with excess EtOAc (100 mL) and DCM (2 × 5 mL). The filtrate was collected and concentrated under vacuum to give crude oil. Purification by open preparative high-performance liquid chromatography (P4) yielded the methyl title product (79 mg, 25% yield) as a brown oil.

[0366] LCMS m / z: 225.1 [M+H]+, (ESI+), Rt = 0.40 (S1) 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 8.04 –7.96 (m, 1H), 7.96 – 7.90 (m, 1H), 6.33 – 6.25 (m, 1H), 4.01 (t, J = 6.2 Hz, 2H), 3.77 – 3.70 (m, 3H), 2.55 – 2.51 (m, 2H), 2.23 – 2.10 (m, 6H). (N1).

[0367] Synthesis of intermediate K2 Lithium (1+) 1-[2-(dimethylamino)ethyl]-2-oxo-1,2-dihydropyridine-3-carboxylate (Step B) LiOH (2M, aqueous solution, 900 µL, 1.80 mmol) was added to a solution of methyl 1-[2-(dimethylamino)ethyl]-2-oxo-1,2-dihydropyridine-3-carboxylate (79 mg, 0.333 mmol) in MeOH (190 µL) and THF (1.9 mL), and the mixture was stirred at room temperature for 5 hours. The reaction mixture was concentrated under vacuum and dried overnight in a vacuum oven to give the title product (108 mg, 100% yield) as a colorless solid.

[0368] LCMS m / z: 211.2 [M+H]+, (ESI+), Rt = 0.19 (S1) 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 8.15 (dd, J = 7.0, 2.2 Hz, 1H), 7.76 (dd, J = 6.6, 2.3 Hz, 1H), 6.36 (t, J = 6.8 Hz, 1H), 4.04 (t, J = 6.3Hz, 2H), 2.52 (s, 2H), 2.17 (s, 6H). (N1). The following intermediates are prepared using the corresponding starting materials in a manner similar to intermediate K2, as outlined in general route 10B.

[0369] .

[0370] Synthesis of intermediate K5 methyl 1-[3-(dimethylamino)propyl]-2-oxo-1,2-dihydropyridine-3-carboxylate 3-Dimethylaminopropylhydrochloride (3.36 g, 21.26 mmol) was added to a stirred suspension of methyl 2-hydroxypyridine-3-carboxylate (3.00 g, 19.6 mmol) and K₂CO₃ (6.90 g, 49.9 mmol) in acetone (60 mL). The reaction mixture was heated at 60 °C for 5 hours, and then heated at room temperature for 72 hours. Sodium iodide (2.0 g, 13.34 mmol) was added to the reaction mixture, and stirring was continued at 60 °C for 2 hours. Another portion of 3-dimethylaminopropylhydrochloride (2 g, 12.7 mmol) was added, and stirring was continued at 60 °C for 10 hours. The mixture was filtered through diatomaceous earth, and the filtrate was concentrated under vacuum to obtain a yellow oil. The oil was dissolved in DCM (30 mL), washed with water (30 mL), dried over sodium sulfate, and concentrated under vacuum to obtain a yellow oil. The oil was then dissolved in ethyl acetate (15 mL), diluted with heptane (15 mL), and the resulting solid was filtered off. The filtrate was concentrated under vacuum to give the title product as a yellow oil (2.01 g, yield 36%, purity 83%).

[0371] LCMS m / z: 499.3 [2M+Na] + , (ESI+), Rt = 0.40 (S2).

[0372] Synthesis of intermediate K6 Lithium(1+) 1-[3-(dimethylamino)propyl]-2-oxo-1,2-dihydropyridine-3-carboxylate Intermediate K5 was prepared in a manner similar to that of intermediate K2.

[0373] LCMS m / z: 225.1 [M+H] + , (ESI+), Rt = 0.40 (S2) 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 8.21 – 8.14 (m, 1H), 7.85 – 7.78(m,1H), 6.37 (t, J = 6.8 Hz, 1H), 4.01 – 3.93 (m, 2H), 2.22 – 2.14 (m, 2H), 2.11 (s, 6H), 1.84 – 1.72 (m, 2H).

[0374] General route 10C diagram Synthesis of intermediate K7 methyl 5-chloro-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxylate To a solution of 5-chloro-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid (0.528 g, 2.81 mmol) in DCM (10 mL), 1 M thionyl chloride / DCM (7.04 mL, 7.04 mmol) was added dropwise. The reaction mixture was heated to reflux for 3 hours. The reaction mixture was cooled to room temperature and methanol (0.57 mL, 14.07 mmol) was added. After 30 minutes, the reaction mixture was concentrated under vacuum to give the title product as a solid (560 mg, 88% yield).

[0375] LCMS m / z: 202.1 [M+H] + , (ESI+), Rt = 0.56 (S1) 1 H NMR (400 MHz, CDCl3) δ [ppm]: 8.09 (s, 1H), 3.88 (s, 3H), 2.50 (s, 3H).

[0376] Synthesis of intermediate K8 methyl 5-chloro-6-methyl-2-(prop-2-en-1-oxy)pyridine-3-carboxylate 3-Bromoprop-1-ene (0.59 mL, 6.82 mmol) was added to a stirred suspension of methyl 5-chloro-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxylate (550 mg, 2.73 mmol) and K₂CO₃ (943 mg, 6.82 mmol) in acetone (12 mL) and acetonitrile (10 mL). The reaction mixture was stirred at 60 °C for 48 h. The reaction mixture was filtered and washed with acetone (25 mL). The organic reaction mixture was concentrated under vacuum to give the title product as an oil (715 mg, purity 40%, yield 43%).

[0377] LCMS m / z: 242.1 [M+H] + , (ESI+), Rt = 1.08 (S1). Synthesis of intermediate K9 methyl 5-chloro-6-methyl-2-oxo-1-(prop-2-en-1-yl)-1,2-dihydropyridine-3-carboxylate A solution of methyl 5-chloro-6-methyl-2-(prop-2-en-1-yloxy)pyridine-3-carboxylate (0.715 g, 1.18 mmol) and palladium(II) dichloride (10.493 mg, 0.06 mmol) in anhydrous xylene (2 mL) was stirred at 130 °C for 16 h. The reaction mixture was filtered and washed with ethyl acetate (10 mL). The solvent was removed under vacuum to give the oil. Purification by column chromatography (10 g silica, 10-80% ethyl acetate / heptane) gave the title product as the oil (336 mg, 93% purity, 109% yield).

[0378] LCMS m / z: 242.1 [M+H] + , (ESI+), Rt = 0.69 (S1) 1 H NMR (400 MHz, CDCl3) δ [ppm]: 8.10 (s, 1H), 5.93 – 5.78 (m, 1H), 5.25 – 5.15 (m, 1H), 5.08 – 5.00 (m, 1H), 4.78 – 4.64 (m, 2H), 3.83 (s, 3H),2.48 (s, 3H).

[0379] Synthesis of intermediate K10 methyl 5-chloro-6-methyl-2-oxo-1-(2-oxoethyl)-1,2-dihydropyridine-3-carboxylate Methyl 5-chloro-6-methyl-2-oxo-1-(prop-2-en-1-yl)-1,2-dihydropyridine-3-carboxylate (330.0 mg, 1.37 mmol) was added to a solution of 1,4-dioxane (7 mL) and water (3.5 mL) with dipotassium; dioxido(dioxo)osmium; dihydrate (50.312 mg, 0.14 mmol) and sodium periodate (876.207 mg, 4.1 mmol). The mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with water (10 mL) and extracted with DCM (3 × 20 mL). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, and concentrated under vacuum to give the title product (165 mg, 55% purity, 27% yield) as a black liquid.

[0380] LCMS m / z: 244.1 [M+H] + , (ESI+), Rt = 0.51 (S1) 1 H NMR (400 MHz, CDCl3) δ [ppm]: 9.71 (s, 1H), 8.21 (s, 1H), 5.00 (s, 2H), 3.89 (s, 3H), 3.69 (s, 3H).

[0381] Synthesis of intermediate K11 methyl 5-chloro-1-[2-(dimethylamino)ethyl]-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxylate A solution of crude methyl 5-chloro-6-methyl-2-oxo-1-(2-oxoethyl)-1,2-dihydropyridine-3-carboxylate (160.0 mg, 0.66 mmol) in 1,2-dichloroethane (5 mL) was added to a solution of 2 M dimethylamine / THF (0.82 mL, 1.64 mmol), followed by the addition of acetic acid (0.02 mL, 0.33 mmol). After stirring the solution at room temperature for 1 hour, STAB (167.02 mg, 0.79 mmol) was added, and the reaction mixture was stirred for another 18 hours. The mixture was diluted with 1,2-dichloroethane (10 mL), washed successively with 0.5 M sodium hydroxide solution (5 mL), water (5 mL), and dried over Na₂SO₄. The solvent was removed under vacuum to obtain the oil. Purification by reversed-phase chromatography (12 g C-18, 10-100% CH3CN / H2O solution containing 0.1% formic acid) yielded the title product as the oil (65 mg, yield 36%).

[0382] LCMS m / z: 273.2 [M+H] + , (ESI+), Rt = 0.39 (S1) 1 H NMR (400 MHz, CDCl3) δ [ppm]: 8.15 (s, 1H), 4.21 (dd, J = 8.1, 6.3Hz, 2H), 3.90 (s, 3H), 2.65 – 2.56 (m, 5H), 2.31 (s, 6H).

[0383] Synthesis of intermediate K12 5-Chloro-1-[2-(dimethylamino)ethyl]-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxylate salt At 45 °C, a solution of methyl 5-chloro-1-[2-(dimethylamino)ethyl]-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxylate (60 mg, 0.220 mmol) in THF (3 mL) was added to a 2 M aqueous solution of lithium hydroxide monohydrate (0.16 mL, 0.330 mmol). The reaction was stirred for 1 h and then acidified to pH 2 with 1 N HCl. The solvent was removed under vacuum to give the title product (68 mg, 98% yield).

[0384] LCMS m / z: 259.1 [M+H-HCl] + , (ESI+), Rt = 0.31 (S2).

[0385] General route 10D diagram Synthesis of intermediate K13 2-[[3-(dimethylamino)propyl]carbamoyl]ethyl acetate Ethyl 3-chloro-3-oxopropionate (1.14 mL, 8.91 mmol) was added dropwise to a solution of N,N-dimethylpropane-1,3-diamine (0.7 g, 6.85 mmol) and triethylamine (1.91 mL, 13.7 mmol) in DCM (6.0391 mL) at 0 °C. The reaction mixture was heated to room temperature and stirred for another 5 minutes. The reaction mixture was filtered, and the filtrate was concentrated under vacuum to give the title product as an orange semi-solid (2.36 g, purity 54%, yield 86%).

[0386] LCMS m / z: 217.2 [M+H] + , (ESI+), Rt = 0.34 (S1) 1 H NMR (400 MHz, CDCl3) δ [ppm]: 4.11 – 4.05 (m, 2H), 3.30 (q,J = 6.1Hz, 2H), 3.25 (s, 2H), 2.71 (t, J = 7.0 Hz, 2H), 2.46 (s, 6H), 1.83 – 1.75 (m, 2H), 1.18 (d, J = 7.1 Hz, 3H). Synthesis of intermediate K14 ethyl 1-[3-(dimethylamino)propyl]-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxylate Add (E)-4-ethoxy-1,1,1-trifluoro-but-3-en-2-one (1.01 mL, 7.07 mmol) and DBU (0.93 mL, 6.19 mmol) to a solution of ethyl 2-{[3-(dimethylamino)propyl]carbamoyl}acetate (2.36 g, 5.89 mmol) in THF (10 mL). Stir the reaction mixture at room temperature for 66 hours. Dilute the reaction mixture with EtOAc (75 mL) and water (100 mL). Separate the organic layer, and extract the aqueous layer again with EtOAc (4 x 75 mL). Wash the combined organic layers with brine (50 mL), then pass them through a phase separator and concentrate under vacuum to give a blood-red residue. Purify by column chromatography (10 g Kp-NH silica, 0-100% EtOAc / heptane) to give the title product (0.25 g, 13% yield) as a light brown oil.

[0387] LCMS m / z: 321.3 [M+H] + , (ESI+), Rt = 0.46 (S1) 1 H NMR (400 MHz, CDCl3) δ [ppm]: 8.05 (d, J = 7.4 Hz, 1H), 6.68 (d, J =7.5 Hz, 1H), 4.39 (q, J = 7.1 Hz, 2H), 4.18 – 4.06 (m, 2H), 2.40 (t, J = 6.8Hz, 2H), 2.23 (s, 6H), 1.89 (p, J = 6.8 Hz, 2H), 1.38 (t, J = 7.1Hz, 3H).

[0388] Synthesis of intermediate K15 1-[3-(dimethylamino)propyl]-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxylate salt At 45 °C, a 2 M aqueous solution of lithium hydroxide hydrate (0.53 mL, 1.05 mmol) was added to a stirred solution of ethyl 1-[3-(dimethylamino)propyl]-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxylate (225 mg, 0.702 mmol) in THF (18.75 mL). The reaction mixture was stirred for 1 hour. The mixture was acidified to pH 4 with 1 N aqueous HCl. The reaction mixture was concentrated under vacuum to give the title product (230 mg, 100% yield) as a pale brown solid.

[0389] LCMS m / z: 293.2 [M+H]+ , (ESI+), Rt = 0.32 (S1).

[0390] The following intermediates are prepared using the corresponding starting materials in a manner similar to intermediate K6, as outlined in General Route 10D.

[0391] .

[0392] Synthesis of intermediate K17 2-[(3-{[(tert-butoxy)carbonyl]amino}-3-methylbutyl)carbamoyl]ethyl acetate It was prepared using N-(4-amino-2-methylbut-2-yl)carbamate tert-butyl hydrochloride and ethyl 3-chloro-3-oxopropionate in a manner similar to intermediate K4.

[0393] LCMS m / z: 339.3 [M+Na] + , (ESI+), Rt = 0.76 (S1) 1 H NMR (400 MHz, CDCl3) δ [ppm]: 7.10 (br. s, 1H), 4.52 (br.s, 1H), 4.18 (q, J = 7.2 Hz, 2H), 3.35 – 3.28 (m, 2H), 3.27 (s, 2H), 1.96 – 1.87 (m,2H), 1.42 (s, 9H), 1.30 – 1.25 (m, 9H).

[0394] Synthesis of intermediate K18 1-(3-{[(tert-butoxy)carbonyl]amino}-3-methylbutyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydro Ethyl pyridine-3-carboxylate Add (E)-4-ethoxy-1,1,1-trifluoro-but-3-en-2-one (400 μL, 2.81 mmol) and DBU (370 μL, 2.47 mmol) to a solution of ethyl 2-[(3-{[(tert-butoxy)carbonyl]amino}-3-methylbutyl)carbamoyl]ethyl acetate (721.0 mg, 2.28 mmol) in THF (7 mL). Heat the reaction mixture at 50 °C for 2 hours. Concentrate the reaction mixture under vacuum, then resuspend it in EtOAc (40 mL) and wash successively with brine (30 mL), saturated NH4Cl aqueous solution (30 mL), and brine (30 mL). Dry the organic layer in MgSO4 and concentrate under vacuum to obtain the residue. Resuspend the residue in toluene (15 mL) and add 4-methylbenzenesulfonic acid monohydrate (26 mg, 0.137 mmol). Stir the reaction mixture at 110 °C for 1 hour. The reaction mixture was cooled to room temperature and then diluted with EtOAc (10 mL), followed by washing with brine (25 mL), saturated NaHCO3 aqueous solution (25 mL), and brine (25 mL) sequentially. The organic layer was dried over MgSO4 and concentrated under vacuum to give a deep red oil. Purification by column chromatography (10 g silica, 0-55% EtOAc / heptane) yielded the title product as a pale orange oil (389 mg, 0.842 mmol, 37% yield).

[0395] LCMS m / z: 421.4 [M+H] + , (ESI+), Rt = 1.05 (S1) 1 H NMR (500 MHz, DMSO-d6) δ [ppm]: 8.02(d, J = 7.4 Hz, 1H), 6.92 (d,J = 7.5 Hz, 1H), 6.56 (br. s, 1H), 4.25 (q, J = 7.1 Hz, 2H), 3.99 – 3.92 (m,2H), 1.95 – 1.88 (m, 2H), 1.39 (s, 9H), 1.27 (t, J= 7.1 Hz, 3H), 1.24 (s,6H).

[0396] Synthesis of intermediate K19 1-(3-amino-3-methylbutyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxylic acid ethyl ester hydrochloride Salt To a solution of ethyl 1-(3-{[(tert-butoxy)carbonyl]amino}-3-methylbutyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxylate (91%, 389 mg, 0.842 mmol) in DCM (4 mL), 4 M HCl / dioxane (2.0 mL, 8.00 mmol) was added. The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under vacuum to give the title product (306 mg, 0.815 mmol, 97% yield) as a grayish-white solid.

[0397] LCMS m / z: 321.3 [M+H] + , (ESI+), Rt = 0.55 (S1) 1 H NMR (500 MHz, DMSO-d6) δ [ppm]: 8.13 (br. s, 3H), 8.06 (d, J = 7.4Hz,1H), 6.98 (d, J = 7.5 Hz, 1H), 4.26 (q, J = 7.1 Hz, 2H), 4.06 – 3.99 (m,2H), 1.93 – 1.86 (m, 2H), 1.33 (s, 6H), 1.27 (t, J = 7.1 Hz, 3H).

[0398] Synthesis of intermediate K20 1-[3-(dimethylamino)-3-methylbutyl]-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxylic acid ethyl ester To a solution of ethyl 1-(3-amino-3-methylbutyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxylate hydrochloride (306 mg, 0.858 mmol) and triethylamine (0.3 mL, 2.15 mmol) in DCE (5 mL), paraformaldehyde (150 mg, 4.83 mmol) was added, followed by acetic acid (0.30 mL, 5.24 mmol). The reaction mixture was stirred for 20 min, and then STAB (1.00 g, 4.72 mmol) was added. The reaction mixture was stirred at room temperature for 24 h, and then heated at 40 °C for 4 h. The reaction mixture was diluted with DCM (10 mL) and filtered through a phase separator. The filtrate was washed with saturated NaHCO3 aqueous solution (15 mL). The organic layer was separated, and the aqueous layer was further extracted with DCM (2 x 15 mL). The combined organic layers were washed with brine (20 mL), dried over MgSO4, and concentrated under vacuum to give the title product as a pale yellow oil (258 mg, purity 85%, yield 73%).

[0399] LCMS m / z: 349.1 [M+H] + , (ESI+), Rt = 0.84 (S2) 1 H NMR (500 MHz, CDCl3) δ [ppm]: 8.03 (d, 1H), 6.69 (d, J = 7.5 Hz,1H), 4.39 (q, J = 7.1 Hz, 2H), 4.22 – 4.14 (m, 2H), 2.29 (s, 6H), 1.87 – 1.79 (m, 2H), 1.38 (t, J = 7.1 Hz, 3H), 1.11 (s, 6H).

[0400] Synthesis of intermediate K21 Lithium (1+) 1-[3-(dimethylamino)-3-methylbutyl]-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine- 3-Formate Prepared using intermediate K20 in a manner similar to intermediate K6. The lithium salt was isolated (the reaction mixture was not acidified).

[0401] LCMS m / z: 321.3 [M+H] + , (ESI+), Rt = 0.46 (S1) 1H NMR (500 MHz, DMSO-d6) δ [ppm]:8.03 (d, J = 7.3 Hz, 1H), 6.99 (d,J = 7.4 Hz, 1H), 4.08 – 3.95 (m, 2H), 2.16 (s, 6H), 1.76 – 1.65 (m, 2H), 0.99 (s, 6H).

[0402] Synthesis of intermediate K22 2-[[2-(dimethylamino)ethyl]carbamoyl]ethyl acetate It was prepared using N,N-dimethylethane-1,2-diamine in a manner similar to intermediate K14.

[0403] LCMS m / z: 203.2 [M+H] + , (ESI+), Rt = 0.36 (S2) 1 H NMR (400 MHz, DMSO-d6) δ [ppm]:8.38 – 8.31 (m, 1H), 3.32 (q, J =7.3 Hz, 2H), 3.25 (s, 2H), 3.36 – 3.18 (m, 2H), 2.78 (t, J = 6.5 Hz, 2H),1.18 (t, J = 7.2 Hz, 3H).

[0404] Synthesis of intermediate K23 ethyl 1-(2-dimethylaminoethyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxylate DBU (0.3 mL, 2.01 mmol) was added to a suspension of ethyl 2-{[2-(dimethylamino)ethyl]carbamoyl}acetate (intermediate K22, 500 mg, 1.83 mmol) in THF (7 mL), followed by (3E)-4-methoxybut-3-en-2-one (0.22 mL, 2.16 mmol). The reaction mixture was stirred at room temperature for 18 hours. Magnesium chloride (200.0 mg, 2.06 mmol) was added, and the reaction mixture was stirred at room temperature for 22 hours, followed by stirring at 60 °C for 4 hours. The reaction mixture was concentrated under vacuum to obtain a residue. The residue was suspended in water (40 mL) and extracted with DCM (3 x 30 mL). The combined organic layers were washed with brine (30 mL) and passed through a phase separator. The solvent was removed under vacuum to obtain a brown oil. Purified by column chromatography (10 g Kp-NH, 0-100% EtOAc / heptane), the title product (131 mg, purity 74%, yield 21%) was obtained as a colorless oil.

[0405] LCMS m / z: 253.2 [M+H] + , (ESI+), Rt = 0.49 (S2) 1 H NMR (500 MHz, DMSO-d6) δ [ppm]: 7.90(d, J = 7.5 Hz, 1H), 6.22 (d,J = 7.5 Hz, 1H), 4.18 (q, J = 7.1 Hz, 2H), 4.05 (t, J = 7.1 Hz, 2H), 2.48 (s,3H), 2.44 (t, 2H), 2.20 (s, 6H), 1.24 (t, J = 7.1Hz, 3H).

[0406] Synthesis of intermediate K24 Lithium(1+) 1-[2-(dimethylamino)ethyl]-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxylate It was prepared using intermediate K23 as the starting material, in a manner similar to that of intermediate K6.

[0407] LCMS m / z: 225.2 [M+H] + , (ESI+), Rt = 0.21 (S2) 1H NMR (500 MHz, DMSO-d6) δ [ppm]: 8.05(d, J = 7.3 Hz, 1H), 6.28 (d,J = 7.3 Hz, 1H), 4.09 (t, J = 7.1 Hz, 2H), 2.49 – 2.43 (m, 5H), 2.20 (s, 6H).

[0408] Map of general route 10E Synthesis of intermediate K25 1-(1-{[(tert-butoxy)carbonyl]amino}-2-methylpropyl-2-yl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid Methyl ester It was prepared using N-(2-amino-2-methylpropyl)carbamate tert-butyl ester and methyl 2-oxo-2H-pyran-3-carbamate in a manner similar to intermediate J3.

[0409] LCMS m / z: 325.3 [M+H] + , (ESI+), Rt = 0.60 (S2) 1 H NMR (400 MHz, CDCl3) δ [ppm]: 8.11 (dd, J = 7.1, 2.1 Hz, 1H), 7.72– 7.67 (m, 1H), 6.22 (t, J = 7.1 Hz, 1H), 4.95 (br. m., 1H), 3.90 (s, 3H), 3.84 (d, J = 7.0 Hz, 2H), 1.64 (s, 6H), 1.40 (s, 9H).

[0410] Synthesis of intermediate K26 1-(1-Amino-2-methylpropyl-2-yl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid methyl ester hydrochloride A solution of methyl 1-(1-{[(tert-butoxycarbonyl)amino]-2-methylpropane-2-yl)-2-oxo-1,2-dihydropyridine-3-carboxylate (92%, 90 mg, 0.255 mmol) in DCM (2 mL) was added to 4 M HCl / dioxane (0.65 mL, 2.60 mmol). The reaction mixture was stirred at room temperature for 2.5 hours. The solvent was removed under vacuum to give the title product (73 mg, 91% purity, 100% yield) as a beige powder.

[0411] LCMS m / z: 225.1 [M+H]+ , (ESI+), Rt = 0.38 (S2) 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 8.00 (dd, J = 7.0, 2.0 Hz, 1H), 7.93 –7.81 (m, 4H), 6.35 (t, J = 7.1 Hz, 1H), 3.74 (s, 3H), 3.60 (s, 2H),1.64 (s, 6H).

[0412] Synthesis of intermediate K27 methyl 1-[1-(dimethylamino)-2-methylpropyl-2-yl]-2-oxo-1,2-dihydropyridine-3-carboxylate At room temperature, paraformaldehyde (45 mg, 1.45 mmol) was added to a solution of methyl 1-(1-amino-2-methylpropyl-2-yl)-2-oxo-1,2-dihydropyridine-3-carboxylate hydrochloride (73 mg, 0.255 mmol) and triethylamine (40 μL, 0.29 mmol) in DCE (1.5 mL), followed by acetic acid (85 μL, 1.48 mmol). The mixture was stirred for 60 min, and then STAB (310 mg, 1.46 mmol) was added. The reaction mixture was stirred at room temperature for another 18 h. The reaction mixture was diluted with saturated aqueous NaHCO3 solution (5 mL) and then extracted with DCM (2 x 2 mL). The combined organic layers were passed through a phase separator and concentrated under vacuum to give an oil. The title product (50 mg, 90% purity, 70% yield) was purified by column chromatography (12 g KP-NH silica, 0-100% ethyl acetate / hexane, followed by 0-20% MeOH / ethyl acetate) to obtain the orange oil.

[0413] LCMS m / z: 253.2 [M+H] + , (ESI+), Rt = 0.50 (S2) 1 H NMR (400 MHz, CDCl3) δ [ppm]: 8.09 (dd, 1H), 7.75 (dd, J =7.1, 2.2Hz, 1H), 6.16 (t, J = 7.1 Hz, 1H), 3.89 (s, 3H), 3.00 (s, 2H), 2.14 (s, 6H),1.67 – 1.65 (m, 6H).

[0414] Synthesis of intermediate K28 Lithium(1+) 1-[1-(dimethylamino)-2-methylpropyl-2-yl]-2-oxo-1,2-dihydropyridine-3-carboxylate A solution of methyl 1-[1-(dimethylamino)-2-methylpropyl-2-yl]-2-oxo-1,2-dihydropyridine-3-carboxylate (90%, 50 mg, 0.178 mmol) in THF (1 mL) was added to a 2 M aqueous solution of lithium hydroxide (100 μL, 0.200 mmol). The solution was stirred at room temperature for 2 hours. The solvent was removed under vacuum to give the title product as a white solid (50 mg, purity 87%, yield 100%).

[0415] LCMS m / z: 239.1 [M+H] + , (ESI+), Rt = 0.31 (S2).

[0416] The following intermediates are prepared using the corresponding starting materials in a manner similar to intermediate K, as outlined in general route 10E.

[0417] Map of the general route on the 10th floor Synthesis of intermediate L1 Methyl 2-oxo-1-(2-oxoethyl)-1,2-dihydropyridine-3-carboxylate; trifluoroacetic acid (step A) Methyl 1-[(1,3-dioxolane-2-yl)methyl]-2-oxo-1,2-dihydropyridine-3-carboxylate (intermediate K3b, 100 mg, 0.410 mmol) was dissolved in water (125 µL) and TFA (500 µL, 6.53 mmol), and the reaction was stirred at 70°C for 1 hour. The reaction was cooled to room temperature and left overnight in a sealed vial. The reaction was concentrated under vacuum, and the resulting oil was milled with DCM (3 × 5 mL) and dried under vacuum to give a light brown oil. The oil was redissolved in water (125 µL) and TFA (500 µL, 6.53 mmol), and the reaction was stirred at 80°C for 1 hour. The reaction was concentrated under vacuum, and the remaining oil was milled with DCM (3 × 5 mL) and dried under vacuum to give the title product (125 mg, 71% yield) as the oil.

[0418] LCMS m / z: 193.9 [M+H]+, (ESI+), Rt = 0.29 (S4).

[0419] Synthesis of intermediate L2 1-[2-(azacyclobutan-1-yl)ethyl]-2-oxo-1,2-dihydropyridine-3-carboxylic acid methyl ester (Step B) Acetic acid (17 µL, 0.290 mmol) and aziridine (29 µL, 0.436 mmol) were added to a solution of methyl 2-oxo-1-(2-oxoethyl)-1,2-dihydropyridine-3-carboxylate trifluoroacetic acid (125 mg, 0.290 mmol) in DCM (1.4 mL). After 20 minutes, STAB (93 mg, 0.439 mmol) was added, and the reaction was stirred at room temperature for 90 hours. The reaction mixture was diluted with MeOH and purified using an SCX column (1 g), eluting with NH3 / MeOH (3.5 M) to give the title product (32 mg, 46% yield) as a deep orange / brown gel.

[0420] LCMS m / z: 237.1 [M+H]+, (ESI+), Rt = 0.42 (S2) 1 H NMR (400 MHz, CDCl3) δ [ppm]: 8.16 (dd, J = 7.2, 2.3 Hz, 1H), 7.56 (dd, J = 6.6, 2.3 Hz, 1H), 6.23 (dd, J = 7.2, 6.6 Hz, 1H), 3.93 (t, J = 6.1Hz, 2H), 3.90 (s, 3H), 3.20 (t, J =7.1 Hz, 4H), 2.78 (t, J = 6.1 Hz, 2H), 2.10 – 2.04 (m, 2H). (N1).

[0421] Synthesis of intermediate L3 Lithium (1+) 1-[2-(azacyclobutane-1-yl)ethyl]-2-oxo-1,2-dihydropyridine-3-carboxylate (step) C） To a solution of methyl 1-[2-(azacyclobutan-1-yl)ethyl]-2-oxo-1,2-dihydropyridine-3-carboxylate (32 mg, 0.135 mmol) in THF (750 µL) and methanol (75 µL), 230 µL (0.460 mmol) of 2M LiOH aqueous solution was added. The reaction was stirred at room temperature for 3.5 h. The reaction mixture was concentrated and dried under vacuum to give the title product (37 mg, 100% yield) as a yellow solid.

[0422] LCMS m / z: 223.1 [M+H]+, (ESI+), Rt = 0.18 (S1) 1H NMR (400 MHz, CDCl3) δ [ppm]: 8.37 (d, J = 7.1 Hz, 1H), 7.38 (d, J= 6.5 Hz, 1H), 6.25 – 6.19 (m, 1H), 3.95 – 3.87 (m, 2H), 3.13 (t, J = 7.0 Hz, 4H), 2.74 – 2.68 (m, 2H), 2.07 – 1.95 (m, 2H). (N1).

[0423] The following intermediates are prepared using the corresponding starting materials in a manner similar to intermediate L3, as outlined in general route 10F.

[0424] General route 10g diagram Synthesis of intermediate M1 methyl 1-(3-hydroxypropyl)-2-oxo-1,2-dihydropyridine-3-carboxylate 3-bromoprop-1-ol (3.5 mL, 38.7 mmol) was added to a suspension of methyl 2-oxo-1,2-dihydropyridine-3-carboxylate (3.00 g, 19.6 mmol) and K₂CO₃ (4.10 g, 29.7 mmol) in acetone (50 mL). The reaction was heated at 60°C for 4 hours. An additional 1 mL of 3-bromoprop-1-ol was added, and the reaction was heated again to 60°C for 3 hours. The mixture was filtered to remove excess K₂CO₃, and the filtrate was concentrated under vacuum to give a crude material as a pale yellow oil. Purification by column chromatography (50 g silica, 0–30% MeOH / EtOAc) gave the title product (3.00 g, 87% purity, 63% yield) as a very pale yellow oil.

[0425] LCMS m / z: 212.1 [M+H] + , (ESI+), Rt = 0.40 (S1) 1H NMR (500 MHz, DMSO-d6) δ [ppm]: 8.01(dd, J = 7.2, 2.2 Hz, 1H), 7.96 (dd, J = 6.6, 2.2 Hz, 1H), 6.34 – 6.27 (m, 1H), 4.60 (t, J = 5.1 Hz, 1H), 4.04 – 3.95 (m, 2H), 3.74 (s, 3H), 3.45 – 3.37 (m,2H), 1.84 – 1.74 (m,2H).

[0426] Synthesis of intermediate M2 methyl 1-(3-{2-azaspiro[3.4]octane-2-yl}propyl)-2-oxo-1,2-dihydropyridine-3-carboxylate In a pressure vessel, methyl 1-(3-hydroxypropyl)-2-oxo-1,2-dihydropyridine-3-carboxylate (300 mg, 1.24 mmol) and DIPEA (0.7 mL, 4.01 mmol) were stirred in DCM (2 mL) at room temperature for 5 minutes. The mixture was then cooled to 0. 0 C, treated with methanesulfonyl methanesulfonate (225.0 mg, 1.29 mmol). The reaction mixture was heated to room temperature and then stirred for 30 minutes. The reaction mixture was then subjected to a reaction at 0°C. 0 The mixture was further treated with methanesulfonyl methanesulfonate (50.0 mg, 0.29 mmol) at C, followed by stirring at room temperature for another 90 minutes. The solvent was removed under vacuum to obtain the oil. The oil was redissolved in DMF (2 mL), and 2-azaspiro[3,4]octane (150.0 mg, 1.35 mmol) and potassium carbonate (300 mg, 2.17 mmol) were added. The reaction mixture was stirred at 50 °C. 0 The mixture was stirred vigorously at C for 16 hours. The reaction was quenched with ice water (5 mL) and extracted with EtOAc (2 x 5 mL). The combined organic layers were washed with brine (2 x 10 mL), dried over Na2SO4, and concentrated under vacuum. The product was purified by reversed-phase column chromatography (12 g C-18 silica, 10% to 100% MeCN / H2O, containing 0.1% ammonium hydroxide modifier) ​​to give the title product (75 mg, 95% purity, 17% yield) as a colorless colloidal substance.

[0427] LCMS m / z: 305.3 [M+H] + , (ESI+), Rt = 0.63 (S2) 1H NMR (400 MHz, CDCl3) δ [ppm]: 8.15 (dd, J = 7.2, 2.3 Hz, 1H), 7.63 (dd, J = 6.6, 2.3 Hz, 1H), 6.23 – 6.19 (m, 1H), 4.03 (t, J = 6.9 Hz, 2H), 3.90 (s, 3H), 3.01 (s, 4H), 2.40 (t, J = 6.7 Hz, 2H), 1.80 (p, J = 6.8 Hz, 2H), 1.72 – 1.68 (m, 4H), 1.56 – 1.51 (m, 4H).

[0428] Synthesis of intermediate M3 1-(3-{2-azaspiro[3.4]octane-2-yl}propyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid It is prepared using intermediate M2 in a manner similar to that of intermediate K15.

[0429] LCMS m / z: 345.2 [M+H] + , (ESI+), Rt = 0.44 (S1) 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 8.23 ​​(d, J = 7.5 Hz, 1H), 7.15 (d,J =7.5 Hz, 1H), 4.09 (q, J = 6.6 Hz, 2H), 3.91 (s, 1H), 3.09 – 2.84 (m, 5H), 2.11 – 1.86 (m, 4H), 1.59 (dd, J = 30.4, 9.9 Hz, 3H), 1.41 (t, J = 8.5 Hz, 1H).

[0430] The following intermediates were prepared using the corresponding starting materials in a manner similar to intermediate M3, as outlined in General Route 10g.

[0431] General route 10g** diagram Synthesis of intermediate M7 Methyl 1-(2-hydroxyethyl)-2-oxo-1,2-dihydropyridine-3-carboxylate It was prepared using methyl 2-hydroxypyridine-3-carboxylate and 2-bromoethanol in a manner similar to intermediate M1.

[0432] LCMS m / z: 220.1 [M+H] + , (ESI+), Rt = 0.27 (S2) 1 H NMR (500 MHz, DMSO) δ [ppm]: 8.01 (dd,J = 7.2, 2.2 Hz, 1H), 7.88(dd, J = 6.6, 2.2 Hz, 1H), 6.29 (t, J = 6.9 Hz, 1H), 4.90 (t, J = 5.3 Hz,1H), 3.98 (t, J = 5.4 Hz, 2H), 3.73 (s, 3H), 3.62 (q, J =5.3 Hz, 2H).

[0433] Synthesis of intermediate M8 methyl 1-[2-(methanesulfonyloxy)ethyl]-2-oxo-1,2-dihydropyridine-3-carboxylate At 0 °C, DMAP (16.0 mg, 0.13 mmol) and triethylamine (0.45 mL, 3.23 mmol) were added to a stirred solution of methyl 1-[2-(methanesulfonyloxy)ethyl]-2-oxo-1,2-dihydropyridine-3-carboxylate (250.0 mg, 1.26 mmol) in DCM (7 mL), followed by dropwise addition of methanesulfonyl chloride (0.15 mL, 1.94 mmol). The reaction mixture was stirred at 0 °C for 45 min, then poured into water (20 mL) and extracted with DCM (3 x 10 mL). The combined organic layers were passed through a phase separator and concentrated under vacuum to give the title product (401 mg, 80% pure, 93% yield) as an orange gel.

[0434] 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 8.93 (dd, J = 6.2, 1.6 Hz, 1H), 8.84 (dd, J = 7.8, 1.6 Hz, 1H), 7.69 – 7.61 (m, 1H), 5.20 – 5.11 (m, 2H), 4.99 – 4.90 (m, 2H), 3.92 (s, 3H), 2.29 (s, 3H).

[0435] Amine substitution of methanesulfonate in intermediate M8 Condition A A suspension of methyl 1-[2-(methanesulfonyloxy)ethyl]-2-oxo-1,2-dihydropyridine-3-carboxylate (80%, 374 mg, 1.09 mmol), 3-(trifluoromethoxy)azacyclobutane hydrochloride (119 mg, 0.670 mmol), K₂CO₃ (140 mg, 1.01 mmol), and sodium iodide (15 mg, 0.100 mmol) in THF or DMF (3 mL) was stirred at 50°C for 3 hours. The reaction solution was diluted with EtOAc (10 mL), filtered, and the filtrate was concentrated under vacuum to obtain the oil. The product was purified by column chromatography (5g SCX, 0-100% 7M NH3 / MeOH) to obtain methyl 2-oxo-1-{2-[3-(trifluoromethoxy)azacyclobutane-1-yl]ethyl}-1,2-dihydropyridine-3-carboxylate (intermediate M9, 126 mg, purity 54%, yield 32%) as a brown gel.

[0436] Condition B N-ethylethylamine (0.1 mL, 0.97 mmol) was added to a solution of methyl 1-[2-(methanesulfonyloxy)ethyl]-2-oxo-1,2-dihydropyridine-3-carboxylate (312 mg, 1.00 mmol) in DMF (5 mL). The reaction mixture was heated to 60 °C and maintained for 2 hours, then concentrated under vacuum to give a red oil. Purification by column chromatography (5 g SCX, 0-100% 7 M NH3 / MeOH) yielded methyl 1-[2-(diethylamino)ethyl]-2-oxo-1,2-dihydropyridine-3-carboxylate (120 mg, 43% yield) as the red oil.

[0437] Condition C 4-(trifluoromethyl)piperidine-3-carboxylate (1:1) (125.0 mg, 0.66 mmol) was added to a suspension of methyl 1-[2-(methanesulfonyloxy)ethyl]-2-oxo-1,2-dihydropyridine-3-carboxylate (95%, 200 mg, 0.690 mmol) and triethylamine (0.35 mL, 2.51 mmol) in DMF (3.8 mL). The reaction was heated at 60°C for 3 hours. The reaction was cooled and concentrated under vacuum to give an oil. Purification by column chromatography (5 g SCX, 0-100% 7M NH3 / MeOH) gave methyl 2-oxo-1-{2-[4-(trifluoromethyl)piperidin-1-yl]ethyl}-1,2-dihydropyridine-3-carboxylate (130 mg, 94% purity, 53% yield) as an orange oil.

[0438] Condition D To a solution of methyl 1-[2-(methanesulfonyloxy)ethyl]-2-oxo-1,2-dihydropyridine-3-carboxylate (70%, 600 mg, 1.53 mmol) in DMF (2 mL), K₂CO₃ (500 mg, 3.62 mmol) and 6-azaspiro[3.5]nonane hydrochloride (250 mg, 1.55 mmol) were added. The mixture was heated at 70°C for 5 hours. The reaction mixture was cooled to room temperature, poured into crushed ice (5 mL), and extracted with ethyl acetate (2 x 5 mL). The combined organic layers were washed with brine (2 x 10 mL), dried over sodium sulfate, and concentrated under vacuum to obtain a gel. Methyl 1-[2-(6-azaspiro[3.5]nonane-6-yl)ethyl]-2-oxopyridine-3-carboxylate (270 mg, purity 90%, yield 52%) was purified by reversed-phase column chromatography (12 g C-18 silica, 10-100% MeCN / H2O, containing 0.1% ammonium hydroxide modifier) ​​as a light orange oil.

[0439] Synthesis of intermediate M9 2-O-1-{2-[3-(trifluoromethoxy)azacyclobutan-1-yl]ethyl}-1,2-dihydropyridine-3-carboxylic acid Methyl ester Use condition A (practical example) is prepared with 3-(trifluoromethoxy)azacyclobutane hydrochloride.

[0440] LCMS m / z: 321.1 [M+H] + , (ESI+), Rt = 0.55 (S2) 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 8.02 –7.97 (m, 1H), 7.93 – 7.89(m, 1H), 6.35 – 6.25 (m, 1H), 4.95 – 4.85 (m, 1H), 3.88 (t, J = 6.0 Hz, 2H), 3.73 (s, 3H), 3.67 – 3.59 (m, 2H), 3.15 – 3.07 (m, 2H), 2.73 (t, J = 6.0 Hz, 2H).

[0441] Synthesis of intermediate M10 Lithium(1+) 2-oxo-1-{2-[3-(trifluoromethoxy)azacyclobutane-1-yl]ethyl}-1,2-dihydropyridine- 3-Formate It is prepared using intermediate M9 in a manner similar to that of intermediate L3.

[0442] LCMS m / z: 307.1 [M+H] + , (ESI+), Rt = 0.26 (S2) 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 8.16 (dd, J = 7.1, 2.2 Hz, 1H), 7.76 (dd, J = 6.5, 2.3 Hz, 1H), 6.40 – 6.31 (m, 1H), 4.94 – 4.86 (m, 1H), 3.93 (t, J = 5.9 Hz, 2H), 3.67 – 3.59 (m, 2H), 3.15 – 3.07 (m, 2H), 2.75 (t, J = 6.0 Hz, 2H).

[0443] The following intermediates were prepared using the corresponding starting materials in a manner similar to intermediate M10, as outlined in General Route 10g**.

[0444] .

[0445] Map of a typical 10-hour route Synthesis of intermediate N1 1-(2,2-Dimethoxyethyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxylic acid ethyl ester Ethyl 3-chloro-3-oxopropionate (3.04 mL, 23.78 mmol) was slowly added to a stirred solution of 2,2-dimethoxyethylamine (2.59 mL, 23.78 mmol) and triethylamine (3.48 mL, 24.97 mmol) in DCM (125 mL). The reaction mixture was stirred at room temperature for 45 minutes, then approximately half of the solvent was removed under vacuum, and the resulting precipitate was filtered off. The solvent in the filtrate was removed under vacuum to obtain the oil. The oil was redissolved in DCM (15 mL), and DBU (3.73 mL, 24.97 mmol) and (3E)-4-ethoxy-1,1,1-trifluorobut-3-en-2-one (4.07 mL, 28.53 mmol) were added. The reaction mixture was stirred for 14 hours, then the solvent was removed under vacuum to obtain the oil. The oil was partitioned between water (100 mL) and DCM (100 mL). The organic layer was separated, and the aqueous layer was further extracted with DCM (2 x 100 mL). The combined organic layers were washed with brine (100 mL), and concentrated under vacuum through a phase separator to give a reddish-brown oil. Purification was performed by column chromatography (50 g silica, 0-30% EtOAc / heptane) to give the title product (1.94 g, 95% purity, 24% yield) as the orange-yellow oil.

[0446] LCMS m / z: 324.2 [M+H] + , (ESI+), Rt = 0.85 (S1) 1 H NMR (500 MHz, DMSO-d6) δ [ppm]: 8.06(d, J = 7.5 Hz, 1H), 6.94 (d,J = 7.5 Hz, 1H), 4.79 (t, J = 5.5 Hz, 1H), 4.26 (q, J = 7.1 Hz, 2H), 4.04 (d,J = 5.6 Hz, 2H), 3.30 (s, 6H), 1.28 (t,J = 7.1Hz, 3H).

[0447] Synthesis of intermediate N2 2-Oxo-1-(2-Oxoethyl)-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxylic acid ethyl ester A solution of ethyl 1-(2,2-dimethoxyethyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxylate (1.94 g, 5.7 mmol) and 4 M HCl (dioxane) (35.0 mL, 140.0 mmol) was stirred at room temperature for 20 min. The solvent was removed under vacuum to obtain an oil, which was then retreated with 4 M HCl / dioxane (35.0 mL, 140.0 mmol) and stirred for 1 h. The reaction mixture was slowly poured into a stirred saturated aqueous solution of NaHCO3 (200 mL). The solution was extracted with EtOAc (2 x 150 mL). The combined organic layers were washed with brine (50 mL), passed through a phase separator, and concentrated under vacuum to give the title product as an orange solid (1.70 g, 82% purity, 88% yield).

[0448] LCMS m / z: 278.1 [M+H] + , (ESI+), Rt = 0.73 (S1) 1 H NMR (500 MHz, DMSO-d6) δ [ppm]: 9.63(s, 1H), 8.12 (d, J = 7.4 Hz,1H), 7.01 (d, J = 7.5 Hz, 1H), 4.97 (s, 2H), 4.26 (q, J = 7.1 Hz, 2H), 1.27(t, J = 7.1 Hz, 3H).

[0449] Synthesis of intermediate N3 1-(2-{2-azaspiro[3.4]octane-2-yl}ethyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine- Ethyl 3-formate Ethyl 2-oxo-1-(2-oxoethyl)-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxylate (1.55 g, 4.47 mmol) was added to a stirred solution of 2-azaspiro[3,4]octane (750.0 mg, 6.75 mmol) and DIPEA (2.35 mL, 13.46 mmol), followed by STAB (2.88 g, 13.59 mmol). The reaction was stirred at room temperature for 18 hours. The reaction mixture was concentrated under vacuum to give an oily residue. Purification by column chromatography (12 g KP-NH silica, 0-100% EtOAc / heptane) gave the title product as a yellow oil (703 mg, 90% purity, 38% yield).

[0450] LCMS m / z: 373.3 [M+H] +, (ESI+), Rt = 0.57 (S1) 1 H NMR (400 MHz, CDCl3) δ [ppm]: 8.04 (d, J = 7.4 Hz, 1H), 6.67 (d, J= 7.5 Hz, 1H), 4.39 (q, J = 7.1 Hz, 2H), 4.08 – 4.01 (m, 2H), 3.22 (s, 4H), 2.76 – 2.69 (m, 2H), 1.75 – 1.71 (m, 4H), 1.55 – 1.51 (m, 4H), 1.38 (t, J =7.1 Hz, 3H).

[0451] Synthesis of intermediate N4 1-(2-{2-azaspiro[3.4]octane-2-yl}ethyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine- 3-Formic acid It was prepared using intermediate N3 as the starting material, similar to intermediate O7.

[0452] LCMS m / z: 345.2 [M+H] + , (ESI+), Rt = 0.48 (S1) 1 H NMR (500 MHz, CDCl3) δ [ppm]: 8.53 (d, J = 7.4 Hz, 1H), 7.02 (d, J= 7.5 Hz, 1H), 4.38 – 4.31 (m, 2H), 3.69 (s, 4H), 3.18 – 3.11 (m, 2H), 1.88 –1.80 (m, 4H), 1.65 – 1.56 (m, 4H).

[0453] The following intermediates were prepared using the corresponding starting materials in a manner similar to that of intermediate N4, as outlined in general route 10h.

[0454] .

[0455] General route 10j diagram Synthesis of intermediate O1 (3-Aminopropoxy)(tert-butyl)dimethylsilane At 0 °C, triethylamine (13.36 mL, 95.86 mmol) and TBDMSCl (13.244 g, 87.87 mmol) were added to a solution of 3-aminoprop-1-ol (6.00 g, 79.9 mmol) in DCM (90 mL). After 5 minutes, the reaction mixture was heated to room temperature and stirred for another 18 hours. The reaction mixture was washed with water (100 mL) and brine (50 mL). The organic layer was dried over Na2SO4 and concentrated under vacuum to give the title product as an oil (15.30 g, 101% yield).

[0456] LCMS m / z: 190.2 [M+H] + , (ESI+), Rt = 0.57 (S1) 1 H NMR (400 MHz, CDCl3) δ [ppm]: 3.67 (t, J = 6.0 Hz, 2H), 2.80 (t, J= 6.8 Hz, 2H), 2.37 (s, 2H), 1.71 – 1.61 (m, 2H), 0.86 (d, J = 0.9 Hz, 9H),0.02 (d, J = 0.7 Hz, 6H).

[0457] Synthesis of intermediate O2 2-({3-[(tert-butyldimethylsilyl)oxy]propyl}carbamoyl)ethyl acetate Ethyl 3-chloro-3-oxopropionate (5.1 mL, 39.9 mmol) was added to a solution of (3-aminopropoxy)(tert-butyl)dimethylsilane (7.944 g, 39.85 mmol) and triethylamine (11 mL, 79.7 mmol) in DCM (60 mL). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with water and extracted with DCM (2 x 100 mL). The combined organic layers were dried over sodium sulfate and concentrated under vacuum to give a brown oil. Purification by column chromatography (100 g silica, 0-100% EtOAc / heptane) gave the title product (6.80 g, 78% purity, 44% yield) as a light brown oil.

[0458] LCMS m / z: 304.3 [M+H] +, (ESI+), Rt = 1.01 (S1) 1 H NMR (400 MHz, CDCl3) δ [ppm]: 4.25 – 4.13 (m, 2H), 3.74 – 3.65 (m,2H), 3.44 – 3.36 (m, 2H), 3.26 (d, J = 1.4 Hz, 2H), 1.78 – 1.71 (m, 2H), 1.32– 1.25 (m, 3H), 0.89 (d, J = 0.8 Hz, 9H), 0.08 – 0.02 (m, 6H).

[0459] Synthesis of intermediate O3 1-{3-[(tert-butyldimethylsilyl)oxy]propyl}-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine Ethyl pyridine-3-carboxylate A solution of ethyl 2-({3-[(tert-butyldimethylsilyl)oxy]propyl}carbamoyl)ethyl acetate (6.55 g, 16.8 mmol) in THF (60 mL) was added with (3E)-4-ethoxy-1,1,1-trifluorobut-3-en-2-one (4.4 mL, 31.1 mmol) and DBU (4.1 mL, 27.3 mmol). The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated under vacuum to give an oil. Purification by column chromatography (50 g silica, 0-30% EtOAc / heptane) gave the title product (1.83 g, 97% purity, 26% yield) as the oil.

[0460] LCMS m / z: 408.2 [M+H] + , (ESI+), Rt = 1.25 (S1) 1 H NMR (500 MHz, CDCl3) δ [ppm]: 8.12 – 7.99 (m, 1H), 6.68 (d, J = 7.5Hz, 1H), 4.38 (q, J = 7.1 Hz, 2H), 4.22 – 4.17 (m, 2H), 3.74 (t, J = 5.7 Hz,2H), 2.00 – 1.89 (m, 2H), 1.38 (t, J= 7.1 Hz, 3H), 0.89 (s, 9H), 0.05 (s,6H).

[0461] Synthesis of intermediate O4 ethyl 1-(3-hydroxypropyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxylate At 0 °C, 1 M tetrabutylammonium fluoride (11 mL, 10.8 mmol) was added dropwise to a solution of ethyl 1-{3-[(tert-butyldimethylsilyl)oxy]propyl}-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxylate (1.82 g, 4.33 mmol) in THF (5 mL). The reaction mixture was stirred at room temperature for 90 min. The reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic layers were dried over sodium sulfate and concentrated under vacuum to give an oil. Purification by column chromatography (25 g silica, 0-100% EtOAc / heptane) gave the title product (1.11 g, 96% purity, 84% yield) as the oil.

[0462] LCMS m / z: 294.2 [M+H] + , (ESI+), Rt = 0.64 (S1) 1 H NMR (500 MHz, CDCl3) δ [ppm]: 8.06 (d, J = 7.4 Hz, 1H), 6.75 (d, J= 7.4 Hz, 1H), 4.39 (q, J = 7.1 Hz, 2H), 4.29 (t, J = 7.0 Hz, 2H), 3.67 (t, J= 5.7 Hz, 2H), 1.97 (d, J = 6.2 Hz, 2H), 1.38 (t, J = 7.1 Hz, 3H).

[0463] Synthesis of intermediate O5 1-[3-(methanesulfonyloxy)propyl]-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxylic acid ethyl ester At 0 °C, DMAP (43.994 mg, 0.36 mmol) and triethylamine (1.25 mL, 9.0 mmol) were added to a stirred solution of ethyl 1-(3-hydroxypropyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxylate (1.1 g, 3.6 mmol) in DCM (20 mL), followed by the addition of methanesulfonyl chloride (0.42 mL, 5.4 mmol). The reaction mixture was stirred at 0 °C for 1 hour. The reaction mixture was poured into water (30 mL), and the organic layer was separated. The aqueous phase was further extracted with DCM (2 x 20 mL), and the combined organic layers were filtered through a hydrophobic glass buffer and concentrated under vacuum to give the title product (1.52 g, 89% purity, 101% yield) as an orange gel.

[0464] LCMS m / z: 372.1 [M+H] + , (ESI+), Rt = 0.75 (S1) 1 H NMR (500 MHz, CDCl3) δ [ppm]: 8.06 (d,J = 7.4 Hz, 1H), 6.75 (d, J= 7.4 Hz, 1H), 4.39 (q, J = 7.1 Hz, 2H), 4.29 (t, J = 7.0 Hz, 2H), 3.67 (t, J= 5.7 Hz, 2H), 1.97 (d, J = 6.2 Hz, 2H), 1.38 (t, J =7.1 Hz, 3H).

[0465] Synthesis of intermediate O6 1-(3-{2-azaspiro[3.4]octane-2-yl}propyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine- Ethyl 3-formate In a pressure tube, a suspension of ethyl 1-[3-(methanesulfonyloxy)propyl]-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxylate (250 mg, 0.599 mmol), 2-azaspiro[3,4]octane (100 mg, 0.899 mmol), K₂CO₃ (0.25 g, 1.80 mmol), and sodium iodide (9.0 mg, 0.0599 mmol) in DMF (5 mL) was heated at 50°C for 2 hours. The reaction mixture was diluted with EtOAc (20 mL) and water (20 mL). The organic layer was separated, and the aqueous layer was further extracted with EtOAc (2 x 20 mL). The combined organic layers were dried over Na₂SO₄ and concentrated under vacuum to obtain an oil. The title product (108 mg, 98% purity, 46% yield) was purified by column chromatography (10 g silica, 0-10% MeOH / DCM) to obtain a light brown liquid.

[0466] LCMS m / z: 387.2 [M+H] + , (ESI+), Rt = 0.58 (S1) 1H NMR (400 MHz, CDCl3) δ [ppm]: 8.04 (d, J = 7.4 Hz, 1H), 6.67 (d, J= 7.5 Hz, 1H), 4.38 (q, J = 7.1 Hz, 2H), 4.17 – 4.04 (m, 2H), 3.08 (s, 4H), 2.53 (t, J = 6.9 Hz, 2H), 1.83 – 1.76 (m, 2H), 1.72 (h, J = 3.0 Hz, 4H), 1.58– 1.50 (m, 4H), 1.38 (t, J = 0.7 Hz, 3H).

[0467] Synthesis of intermediate O7 1-(3-{2-azaspiro[3.4]octane-2-yl}propyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine- 3-Formic acid At 45°C, 2 M lithium hydroxide hydrate (0.81 mL, 1.61 mmol) was added to a stirred solution of ethyl 1-[3-(2-azaspiro[3.4]oct-2-yl)propyl]-2-oxo-6-(trifluoromethyl)pyridine-3-carboxylate (98%, 106 mg, 0.269 mmol) in THF (2.94 mL). The reaction mixture was stirred for 4 hours. The mixture was acidified to pH 4 with 1N hydrochloric acid aqueous solution. The reaction mixture was concentrated under vacuum to give the title product (172 mg, 99% yield) as a light brown solid.

[0468] LCMS m / z: 359.2 [M+H] + , (ESI+), Rt = 0.50 (S1).

[0469] The following intermediates are prepared using the corresponding starting materials in a manner similar to intermediate O7, as outlined in general route 10j.

[0470] .

[0471] Map of a typical 10k route Synthesis of intermediate O21 2-({4-[(tert-butyldimethylsilyl)oxy]butyl}carbamoyl)ethyl acetate It was prepared using 4-[tert-butyl(dimethyl)silyl]oxybut-1-amine and ethyl 3-chloro-3-oxopropionate in a manner similar to intermediate O2.

[0472] 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 8.01(t, J = 5.6 Hz, 1H), 4.04 (q,J = 7.1 Hz, 2H), 3.60 – 3.50 (m, 2H), 3.15 (s, 2H), 3.03 (q,J = 6.3 Hz, 2H), 1.42 (qt, J = 4.2, 2.0 Hz, 4H), 1.15 (t, J = 7.1Hz, 3H), 0.83 (s, 9H), -0.00 (s, 6H).

[0473] Synthesis of intermediate O22 1-{4-[(tert-butyldimethylsilyl)oxy]butyl}-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine Ethyl pyridine-3-carboxylate It is prepared using intermediate O21 in a manner similar to that of intermediate O3.

[0474] LCMS m / z: 444.2 [M+H] + , (ESI+), Rt = 1.27 (S1) 1 H NMR (500 MHz, DMSO-d6) δ [ppm]: 7.97(d, J = 7.3 Hz, 1H), 6.88 (d,J = 7.4 Hz, 1H), 3.93 – 3.87 (m, 2H), 3.56 (q, J = 5.7 Hz, 2H), 1.62 (p, J =7.9 Hz, 2H), 1.57 – 1.37 (m, 2H), 1.28 – 1.13 (m,3H), 0.81 (d, J = 2.9 Hz,9H), -0.02 (s, 6H).

[0475] Synthesis of intermediate O23 ethyl 1-(4-hydroxybutyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxylate It is prepared using intermediate O22 in a manner similar to that of intermediate O4.

[0476] LCMS m / z: 330.2 [M+Na] +, (ESI+), Rt = 0.69 (S1).

[0477] Synthesis of intermediate O24 2-Oxo-1-(4-Oxobutyl)-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxylic acid ethyl ester At 0 °C, a solution of ethyl 1-(4-hydroxybutyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxylate (100 mg, 0.33 mmol) in DCM (2 mL) was added to a solution of DCM containing DSM-Martin oxidant (166 mg, 0.391 mmol). The reaction mixture was stirred at 0 °C for 10 min, then at room temperature for 2 h. The reaction was quenched by adding 50% saturated sodium thiosulfate aqueous solution / saturated NaHCO3 aqueous solution (15 mL) and stirring vigorously for 10 min. The organic layer was separated, further washed with saturated NaHCO3 solution (10 mL), and dried over magnesium sulfate. The solvent was removed under vacuum to give a brown oil. Purification by column chromatography (10 g silica, 0-60% EtOAc / heptane) gave the title product as an orange gel (144 mg, 72% purity, 104% yield).

[0478] 1 H NMR (400 MHz, CDCl3) δ [ppm]: 9.79 (t, 1H), 8.06 (dt, J =Hz, 1H), 6.71 (t, J = Hz,1H), 4.39 (q, J = Hz, 2H), 4.12 (m,, 2H), 2.60 (qt, J = Hz,2H), 2.00-2.10 (m, 2H), 1.38 (t, J = Hz, 3H).

[0479] Synthesis of intermediate O25 1-(4-{3-azabicyclo[3.1.1]heptane-3-yl}butyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine Ethyl pyridine-3-carboxylate To a solution of ethyl 2-oxo-1-(4-oxobutyl)-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxylate (140 mg, 0.330 mmol) in DCM (2 mL), triethylamine (0.14 mL, 1.07 mmol) and 3-azabicyclo[3.1.1]heptane hydrochloride (58 mg, 0.438 mmol) were added, followed by STAB (225 mg, 1.06 mmol). The reaction was stirred at room temperature for 72 hours. The reaction was quenched by a mixture of water (10 mL) and saturated aqueous NaHCO3 solution (10 mL). The reaction mixture was then extracted with dichloromethane (DCM) (3 x 5 mL). The combined organic layers were concentrated under vacuum to give the residue. Purification was performed by SCX chromatography (5 g, eluted with 7 M NH3 / MeOH) to give the title product as a yellow oil (111 mg, 95% purity, 83% yield).

[0480] LCMS m / z: 387.3 [M+H] + , (ESI+), Rt = 0.60 (S1) 1 H NMR (400 MHz, MeOD-d4) δ [ppm]: 8.10 (dd, J = 7.7, 0.9 Hz, 1H), 6.86 (d, J = 7.5 Hz, 1H), 4.26 (q, J = 7.1 Hz, 2H), 4.12 – 3.96 (m, 2H), 2.86– 2.69 (m, 4H), 2.55 – 2.38 (m, 2H), 2.25 (ddd, J =7.5, 4.4, 1.6 Hz, 2H), 1.95 (qd, J = 5.9, 2.6 Hz, 2H), 1.73 – 1.59 (m, 2H), 1.59 – 1.47 (m, 2H),1.49 – 1.35 (m, 2H), 1.28 (t, J = 7.1 Hz, 3H).

[0481] Synthesis of intermediate O26 1-(4-{3-azabicyclo[3.1.1]heptane-3-yl}butyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine pyridine-3-carboxylic acid It is prepared using intermediate O25 in a manner similar to that of intermediate O74.

[0482] 1H NMR (400 MHz, DMSO-d6) δ [ppm]: 8.32(d, J = 7.5 Hz, 1H), 7.20 (d,J = 7.6 Hz, 1H), 4.15 – 4.02 (m, 2H), 2.97 – 2.85 (m, 3H), 2.38 (t, J = 6.0Hz, 3H), 2.13 – 2.02 (m, 3H), 1.78 – 1.67 (m, 5H), 1.67 – 1.53 (m, 2H).

[0483] The following intermediates are prepared using the corresponding starting materials in a manner similar to that of intermediate O26, as outlined in general route 10k.

[0484] .

[0485] General route 10j diagram Synthesis of intermediate O28 Methyl 1-(4-hydroxybutyl)-2-oxo-1,2-dihydropyridine-3-carboxylate 4-Bromobut-1-ol (9.60 g, 62.7 mmol) was added to a stirred suspension of methyl 2-oxo-1,2-dihydropyridine-3-carboxylate (8.00 g, 52.2 mmol) and cesium carbonate (17.80 g, 54.6 mmol) in acetonitrile (120 mL). The reaction mixture was stirred at 60°C for 4 hours. Another portion of 4-bromobut-1-ol (7.00 g, 45.7 mmol) was added to the reaction mixture, and the mixture was stirred at room temperature for 24 hours. The reaction mixture was filtered through diatomaceous earth, and the filtrate was concentrated under vacuum to give a yellow oil. Purification was performed by column chromatography (50 g silica, 0-100% ethyl acetate / heptane, followed by 0-20% methanol / ethyl acetate) to give the title product as the yellow oil (2.35 g, yield 17%, purity 84%).

[0486] LCMS m / z: 248.1 [M+Na] + , (ESI+), Rt = 0.39 (S2) 1H NMR (500 MHz, CDCl3) δ [ppm]: 8.15 (dd, J = 7.2, 2.3 Hz, 1H), 7.54 (dd, J = 6.6, 2.3 Hz, 1H), 6.27 – 6.22 (m, 1H), 4.07 – 4.00 (m, 2H), 3.90 (s, 3H), 3.71 (t, J = 6.2 Hz, 2H), 1.91– 1.85 (m, 2H), 1.70 – 1.66 (m, 1H), 1.64– 1.58 (m, 2H).

[0487] Synthesis of intermediate O29 methyl 1-(4-{2-azaspiro[3.4]octane-2-yl}butyl)-2-oxo-1,2-dihydropyridine-3-carboxylate It was prepared using intermediate O28 and 2-azaspiro[3.4]octane in a manner similar to intermediate M2.

[0488] LCMS m / z: 319.4 [M+H] + , (ESI+), Rt = 0.49 (S1).

[0489] Synthesis of intermediate O30 1-(4-{2-azaspiro[3.4]octane-2-yl}butyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid It is prepared using intermediate O29 in a manner similar to that of intermediate O7.

[0490] LCMS m / z: 305.4 [M+H] + , (ESI+), Rt = 0.49 (S1).

[0491] Diagram of General Route 11A Synthesis of intermediate P1 6-[(azacyclobutan-1-yl)methyl]pyridine-2-carboxylate (Step A) STAB (349 mg, 1.60 mmol) was added to a stirred solution of aziridine (0.071 mL, 0.998 mmol) and methyl 6-formylpyridine-2-carboxylate (219 mg, 1.30 mmol) in a DCE (10 mL) at room temperature. The reaction mixture was stirred at 50 °C for 3 h. The reaction mixture was quenched with water (10 mL) and then EtOAc (15 mL) was added. The organic layer was separated, and the aqueous layer was further extracted with EtOAc (2 x 10 mL). The aqueous phase was alkalized to pH 9 with a saturated NaHCO3 aqueous solution and extracted with EtOAc (2 x 10 mL). The combined organic layers were passed through a phase separator and concentrated under vacuum. Purification by column chromatography (10 g silica, 0-10% MeOH / DCM) gave the title product (90 mg, 43% yield) as a colorless oil.

[0492] LCMS m / z: 206.9 [M+H]+, (ESI+), Rt = 1.60 (S7).

[0493] Synthesis of intermediate P2 Step C: Methyl 6-[(azacyclobutan-1-yl)methyl]pyridine-2-carboxylate (Step B) It is prepared using intermediate P1 in a manner similar to that of intermediate L3.

[0494] LCMS m / z: 192.7 [M+H]+, (ESI+), Rt = 0.25 (S6).

[0495] Diagram of General Route 11B Synthesis of intermediate P3 Step A: Ethyl 6-[(3-fluorozacricyclobutan-1-yl)methyl]pyridine-2-carboxylate (Step A) Cs₂CO₃ (1.00 g, 3.07 mmol) was added to a stirred suspension of ethyl 6-(chloromethyl)pyridine-2-carboxylate (300 mg, 1.50 mmol) and 3-fluoroazacyclobutane hydrochloride (180 mg, 1.61 mmol) in acetonitrile (6 mL). The resulting mixture was stirred in a sealed tube under nitrogen for 6 hours at room temperature. Then, 3-fluoroazacyclobutane hydrochloride (90 mg, 0.81 mmol) was added, and stirring was continued for 18 hours at room temperature. The reaction mixture was filtered through diatomaceous earth and washed with EtOAc (50 mL). The filtrate was concentrated under vacuum to give a yellow oil. Purification was performed by column chromatography (10 g silica, 0–100% EtOAc / heptane, followed by 0–10% MeOH / EtOAc) to give the title product as the yellow oil (277 mg, 76% yield).

[0496] LCMS m / z: 239.2 [M+H]+, (ESI+), Rt = 0.51 (S2) 1 H NMR (500 MHz, CDCl3) δ [ppm]: 8.02 – 7.97 (m, 1H), 7.80 (t, J =7.8 Hz, 1H), 7.58 – 7.53 (m, 1H), 5.28 – 5.07 (m, 1H), 4.46 (q, J = 7.1 Hz,2H), 3.97 (s, 2H), 3.83 – 3.73 (m, 2H), 3.44 – 3.38 (m, 1H), 3.38 – 3.32 (m,1H), 1.42 (t, J = 7.1 Hz, 3H).

[0497] Synthesis of intermediate P4 Step B: Lithium 6-[(3-fluorozacricyclobutane-1-yl)methyl]pyridine-2-carboxylate A stirred solution of ethyl 6-[(3-fluorozacyclobutan-1-yl)methyl]pyridine-2-carboxylate (273 mg, 1.12 mmol) in THF (5 mL) and methanol (0.3 mL) was added to a 2 M LiOH aqueous solution (620 µL, 1.24 mmol). The reaction mixture was stirred at room temperature for 1.5 h. The reaction mixture was concentrated under vacuum to give the title product (219 mg, 86% yield) as a brown solid.

[0498] LCMS m / z: 211.1 [M+H]+, (ESI+), Rt = 0.24 (S2) 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 7.88 –7.82 (m, 2H), 7.41 – 7.35(m, 1H), 5.26 – 5.04 (m, 1H), 3.67 (s, 2H), 3.60 – 3.50 (m, 2H), 3.18 – 3.12(m, 1H), 3.12 – 3.05(m, 1H).

[0499] The following intermediates are prepared using the corresponding starting materials in a manner similar to that of intermediate O26, as outlined in general route 10k.

[0500] .

[0501] Diagram of General Route 11C Synthesis of intermediate P5 Ethyl 6-vinylpyridine-2-carboxylate (Step A) Tributyltin (1.5 mL, 5.13 mmol) and triphenylphosphine palladium (0.50 g, 0.433 mmol) were added to a degassed solution of ethyl 6-bromopyridine-2-carboxylate (1.00 g, 4.35 mmol) in anhydrous 1,4-dioxane (30 mL). The mixture was heated at 100 °C for 3 hours. The mixture was cooled, diluted with EtOAc (50 mL), and washed with 1 M KF aqueous solution (50 mL). The organic layer was separated, and the aqueous layer was extracted with EtOAc (3 x 20 mL). The combined organic layers were dried over Na2SO4 and concentrated under vacuum. Purification by column chromatography (55 g Sfar Amino-D silica, 0-50% EtOAc / heptane) gave the title product (715 mg, 84% yield) as a yellow free-flowing oil.

[0502] LCMS m / z: 178.3 [M+H]+, (ESI+), Rt = 0.77 (S1) 1H NMR (500 MHz, CDCl3) δ [ppm]: 7.98 (dd, J = 7.7, 1.0 Hz, 1H), 7.79 (t, J = 7.8 Hz, 1H), 7.59 (dd, J = 7.9, 1.0 Hz, 1H), 6.94 (dd, J = 17.6, 10.9Hz, 1H), 6.23 (dd, J = 17.7, 0.9 Hz, 1H), 5.58 (dd, J = 10.9, 0.9 Hz, 1H), 4.48 (q, J = 7.1 Hz, 2H), 1.44 (t, J = 7.1 Hz, 3H).

[0503] Synthesis of intermediate P6 6-[2-(dimethylamino)ethyl]pyridine-2-carboxylic acid ethyl ester (Step B) 2 M dimethylamine (in THF) (1.0 mL, 2.00 mmol) was added to a stirred solution of ethyl 6-vinylpyridine-2-carboxylate (200 mg, 1.02 mmol) in ethanol (4 mL). The solution was heated at 80 °C for 24 hours. The mixture was concentrated under vacuum, and the residue was purified by reversed-phase column chromatography (12 g Sfar C18-silica, 10-100% formonitrile / H2O, containing 0.1% formic acid modifier) ​​to give a crude product. The crude product was dissolved in EtOAc (2 mL) and washed with saturated NaHCO3 solution (2 x 3 mL). The organic layer was dried over sodium sulfate and concentrated under vacuum to give the title product (160 mg, 71% yield) as a colorless oil.

[0504] LCMS m / z: 223.2 [M+H]+, (ESI+), Rt = 0.39 (S1) 1 H NMR (400 MHz, CDCl3) δ [ppm]: 7.95 – 7.92 (m, 1H), 7.73 (t, J = 7.8Hz, 1H), 7.40 – 7.36 (m, 1H), 4.46 (q, J = 7.1 Hz, 2H), 3.10 – 3.05 (m, 2H), 2.74 – 2.69 (m, 2H), 2.29 (s, 6H), 1.42 (t, J = 7.1 Hz, 3H).

[0505] Synthesis of intermediate P7 Lithium(1+)-6-[(2-dimethylamino)ethyl]pyridine-2-carboxylate (Step C) A solution of ethyl 6-[2-(dimethylamino)ethyl]pyridine-2-carboxylate (1.72 g, 7.2 mmol) in THF (33 mL) was added to a 2 M LiOH aqueous solution (4.02 mL, 8.05 mmol). The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated under vacuum to give the title product (1.5 g, 95% purity, 100% yield) as a pale yellow solid.

[0506] LCMS m / z: 195.2 [M+H]+, (ESI+), Rt = 0.44 (S1) 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 7.87 –7.75 (m, 2H), 7.34 (dd, J =7.1, 1.4 Hz, 1H), 2.83 – 2.73 (m, 2H), 2.46 (d, J = 7.7 Hz, 2H), 2.07 (s,6H).

[0507] The following intermediates are prepared using the corresponding starting materials in a manner similar to intermediate P7, as outlined in general route 11c.

[0508] Synthesis of intermediate P8 Ethyl 6-vinyl-5-methylpyridine-2-carboxylate (Step A) To a solution of ethyl 6-bromo-5-methylpyridine-2-carboxylate (350.0 mg, 1.43 mmol) in EtOH (5 mL), potassium vinyl(trifluoro)borate (396.0 mg, 2.87 mmol), triethylamine (0.2 mL, 1.43 mmol), and bis[3-(diphenylphosphino)cyclopentan-2,4-dien-1-yl]ferric dichloromethane dichloropalladium (58.0 mg, 0.07 mmol) were added. The mixture was degassed with nitrogen for 10 min and then stirred at 80 °C for 1 h. The mixture was filtered, and the filtrate was concentrated under vacuum to give an oil. Purification by column chromatography (25 g silica, 0-25% EtOAc / heptane) gave the title product (211 mg, 77% yield) as a pale yellow oil.

[0509] LCMS m / z: 192.1 [M+H]+, (ESI+), Rt = 0.86 (S1) 1H NMR (500 MHz, DMSO-d6) δ [ppm]: 7.84(d, J = 7.8 Hz, 1H), 7.77 (d,J = 0.8 Hz, 1H), 7.08 (dd, J = 16.9, 10.6 Hz, 1H), 6.35 (dd, J = 16.9, 2.4Hz, 1H), 5.57 (dd, J = 10.7, 2.5 Hz, 1H), 4.34 (q,J = 7.1 Hz, 2H), 2.41 (s,3H), 1.33 (t, J = 7.1 Hz, 3H).

[0510] Synthesis of intermediate P9 6-[2-(dimethylamino)ethyl]-5-methylpyridine-2-carboxylic acid ethyl ester (Step B) A mixture of ethyl 6-vinyl-5-methylpyridine-2-carboxylate (211 mg, 1.10 mmol), 2 M dimethylamine / THF (5.5 mL, 11.0 mmol), and AcOH (0.84 mL) was prepared at 100 mL. o Stirred under microwave radiation at C for 30 minutes. Add dimethylamine hydrochloride (450 mg, 5.52 mmol), and heat the mixture at 150 °C. o Stirred under microwave radiation at C for 2 hours. The reaction mixture was concentrated under vacuum to obtain a residue. Purified by FCC (25 g silica, 0-100% EtOAc / heptane, followed by 0-10% MeOH in EtOAc solution) to give the title product as oil (150 mg, 45% yield).

[0511] LCMS m / z: 237.2 [M+H]+, (ESI+), Rt = 0.52 (S1) 1 H NMR (500 MHz, DMSO-d6) δ [ppm]: 7.79(d, J = 7.8 Hz, 1H), 7.70 (d,J = 7.8 Hz, 1H), 4.32 (q, J = 7.1 Hz, 2H), 2.94 (m, 2H), 2.56 (m, 2H), 2.37 (s, 3H), 2.21 (s, 6H), 1.32 (t, J = 7.1 Hz, 3H).

[0512] Synthesis of intermediate P10 Lithium (1+) 6-[2-(dimethylamino)ethyl]-5-methylpyridine-2-carboxylate (Step C) A solution of ethyl 6-[2-(dimethylamino)ethyl]-5-methylpyridine-2-carboxylate (150 mg, 0.635 mmol) in THF (2.5 mL) and MeOH (0.25 mL) was added to a 2 M LiOH aqueous solution (0.48 mL, 0.952 mmol). The mixture was stirred at room temperature for 1 hour, and then concentrated under vacuum to give the title product (150 mg, 95% yield) as an orange solid.

[0513] LCMS m / z: 209.2 [M+H]+, (ESI+), Rt = 0.30 (S1) 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 7.72(d, J = 7.7 Hz, 1H), 7.61 (d,J = 7.9 Hz, 1H), 2.87 – 2.78 (m, 2H), 2.45 – 2.36 (m, 2H), 2.32 (s, 3H), 2.12(s, 6H).

[0514] Synthesis of intermediate P11 6-(2-Methoxyethyl)pyridine-2-carboxylic acid ethyl ester (Step A) To a stirred solution of ethyl 6-vinylpyridine-2-carboxylate (350.0 mg, 2.26 mmol) in anhydrous MeOH (10 mL), 4 M HCl / 1,4-dioxane (1.12 mL, 4.48 mmol) was added. The reaction mixture was stirred at 80 °C for 18 hours. The pH of the reaction mixture was adjusted to 7 with a saturated aqueous solution of NaHCO3, and then concentrated under vacuum to obtain the residue. Purification by column chromatography (20 g SCX, 0-100% 7M NH3 / MeOH) gave the title product (427 mg, 77% yield) as a yellow oil.

[0515] LCMS m / z: 210.2 [M+H]+, (ESI+), Rt = 0.62 (S1). Synthesis of intermediate P12 Lithium(1+)-6-(2-methoxyethyl)pyridine-2-carboxylate (Step B) It was prepared using intermediate P11 in a manner similar to that of intermediate L3.

[0516] 1H NMR (400 MHz, DMSO-d6) δ [ppm]: 7.97 –7.76 (m, 2H), 7.33 (dd, J =7.2, 1.6 Hz, 1H), 3.58 (t, J = 6.8 Hz, 2H), 3.17 (s, 3H), 3.05 – 2.86 (m,2H).

[0517] Diagram of general route 11d Synthesis of intermediate P13 6-(2-hydroxyethyl)pyridine-2-carboxylic acid ethyl ester (Step A) At 0 °C, a stirred solution of ethyl 6-vinylpyridine-2-carboxylate (2.5 g, 14.1 mmol) in THF (10 mL) was added dropwise over 15 minutes with 0.5 M 9-BBN in THF (85 mL, 42.5 mmol). The reaction mixture was stirred at 0 °C for 5 minutes, then heated to room temperature and stirred for 22 hours. The reaction mixture was cooled to 0 °C, and H₂O₂ (50% aqueous solution) (1.75 mL, 58.14 mmol) was added dropwise, followed by 2 M NaOH (aqueous solution) (0.35 mL, 0.7 mmol). The mixture was stirred at 0 °C for 5 minutes, then heated to room temperature. Further dropwise addition of H₂O₂ (50% aqueous solution) (3.5 mL, 116.3 mmol) and 2 M NaOH (aqueous solution) (0.35 mL, 0.7 mmol) was made at room temperature. The reaction mixture was quenched with saturated Na₂S₂O₃ (aqueous solution) (30 mL), stirred at room temperature for 15 minutes, and concentrated under vacuum. The residue was diluted with EtOAc (100 mL), water (30 mL), and brine (30 mL), and then the pH was adjusted to 8 with saturated NaHCO3 solution (5 mL). The phases were then separated, and the aqueous phase was extracted with EtOAc (50 mL x 2). The combined organic phases were dried over MgSO4 and concentrated under vacuum. The residue was purified by reverse-phase FCC (30 g C-18 silica, 10-100% MeCN:H2O + 0.1% v / v NH4OH modifier) ​​to give the title product (1.78 g, 64% yield) as a yellow oil.

[0518] LCMS m / z: 196.1 [M+H]+, (ESI+), Rt = 0.44 (S2) 1H NMR (400 MHz, DMSO-d6) δ [ppm]: 7.94 –7.85 (m, 2H), 7.58 – 7.49(m, 1H), 4.70 (t, J = 5.3 Hz, 1H), 4.35 (q, J = 7.1 Hz, 2H), 3.81 – 3.72 (m,2H), 2.95 (t, J = 6.6 Hz, 2H), 1.33 (t, J = 7.1 Hz,3H).

[0519] Synthesis of intermediate P14 6-(2-{2-azaspiro[3.4]oct-2-yl}ethyl)pyridine-2-carboxylic acid ethyl ester (Step B) A solution of ethyl 6-(2-hydroxyethyl)pyridine-2-carboxylate (250 mg, 1.27 mmol) in anhydrous DCM (3 mL) was treated with diisopropylethylamine (663 μL, 3.8 mmol). The mixture was cooled to 0 °C, treated with trifluoromethanesulfonic anhydride (229 μL, 1.39 mmol), and stirred at 0 °C for 10 min. 2-azaspiro[3,4]octane (171 mg, 1.54 mmol) was added, and the reaction mixture was stirred at 0 °C for 5 min, then at room temperature for 30 min. The reaction mixture was concentrated under vacuum to give the residue. Purification by reversed-phase rapid chromatography (30 g C18 silica, 10-100% MeCN + 0.1% v / v NH4OH) gave the title product (220 mg, 46% yield) as a light brown oil.

[0520] LCMS m / z: 289.2 [M+H]+, (ESI+), Rt = 0.89 (S1) 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 7.90 –7.85 (m, 2H), 7.55 – 7.50(m, 1H), 4.34 (q, J = 7.1 Hz, 2H), 3.03 (s, 4H), 2.81 – 2.70 (m, 4H), 1.67 – 1.63 (m, 4H), 1.50 – 1.46 (m, 4H), 1.33 (t, J = 7.1 Hz, 3H).

[0521] Synthesis of intermediate P15 Lithium(1+) 6-(2-{2-azaspiro[3.4]octane-2-yl}ethyl)pyridine-2-carboxylate (step C) It was prepared using intermediate P13 in a manner similar to that of intermediate L3.

[0522] LCMS m / z: 261.2 [M+H]+, (ESI+), Rt = 0.39 (S1) 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 7.83 –7.75 (m, 2H), 7.31 (dd, J =7.1, 1.8 Hz, 1H), 2.89 (s, 4H), 2.67 – 2.55 (m, 4H), 1.63 – 1.58 (m, 4H),1.50 – 1.44 (m, 4H).

[0523] The following intermediates are prepared using the corresponding starting materials in a manner similar to intermediate P14, as outlined in general route 11d.

[0524] Diagram of General Route 11e Synthesis of intermediate P16 Ethyl 6-(3-oxopropyl)pyridine-2-carboxylate (Step A) A suspension of ethyl 6-bromopyridine-2-carboxylate (5.0 g, 21.7 mmol), propan-2-en-1-ol (3.7 mL, 54.3 mmol), NaHCO3 (5.48 g, 65.2 mmol), and TBAB (7.0 g, 21.7 mmol) in anhydrous DMF (60 mL) was degassed with N2 for 5 min. Pd(OAc)2 (0.244 g, 1.09 mmol) was added, and the reaction mixture was stirred at 85 °C for 6 h under N2. After cooling, the mixture was concentrated under vacuum. The residue was resuspended in water (100 mL) and extracted with EtOAc (4 x 30 mL). The combined organic layers were washed with water (40 mL) and brine (2 x 30 mL), dried over MgSO4, and concentrated under vacuum. The residue was purified by FCC (50 g silica, 10%-100% EtOAc / heptane) to give the title product (1.72 g, 30% yield) as orange oil.

[0525] LCMS m / z: 208.2 [M+H]+, (ESI+), Rt = 0.55 (S1) 1H NMR (400 MHz, DMSO-d6) δ [ppm]: 9.77(t, J = 1.2 Hz, 1H), 7.93 –7.84 (m, 2H), 7.55 (dd, J = 7.1, 1.8 Hz, 1H), 4.33 (q, J = 7.1 Hz, 2H), 3.09 (t, J = 7.1 Hz, 2H), 2.93 – 2.86 (m, 2H), 1.32 (t, J = 7.1 Hz, 3H).

[0526] Synthesis of intermediate P17 6-(3-{2-azaspiro[3.4]octane-2-yl}propyl)pyridine-2-carboxylic acid ethyl ester (Step B) STAB (369 mg, 1.74 mmol) was added to a solution of ethyl 6-(3-oxopropyl)pyridine-2-carboxylate (135.0 mg, 0.58 mmol), 2-azaspiro[3,4]octane (77.4 mg, 0.7 mmol), and TEA (0.23 mL, 1.74 mmol) in DCM (4 mL) at room temperature. The reaction mixture was heated at 40 °C for 1 hour. The reaction mixture was poured into water (30 mL), diluted with saturated NaHCO3 aqueous solution (20 mL), and extracted with DCM (4 x 10 mL). The combined organic layers were dried over MgSO4 and concentrated under vacuum. Purification by column chromatography (5 g SCX, 0-100% 7M NH3 / MeOH) gave the title product (151 mg, 73% yield) as a pale yellow oil.

[0527] LCMS m / z: 303.3 [M+H]+, (ESI+), Rt = 0.61 (S1) 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: .92 –7.80 (m, 2H), 7.49 (dd, J =6.8, 2.1 Hz, 1H), 4.33 (q, J = 7.1 Hz, 2H), 2.94 (s, 4H), 2.80 – 2.74 (m,2H), 2.38 – 2.31 (m, 2H), 1.68 – 1.59 (m, 6H), 1.52 –1.41 (m, 4H), 1.32 (t, J= 7.1 Hz, 3H).

[0528] Synthesis of intermediate P18 Lithium(1+) 6-(3-{2-azaspiro[3.4]octane-2-yl}propyl)pyridine-2-carboxylate (Step C) It was prepared using intermediate P17 in a manner similar to that of intermediate L3.

[0529] The following intermediates are prepared using the corresponding starting materials in a manner similar to intermediate P18, as outlined in general route 11d.

[0530] Diagram of general route 11f Synthesis of intermediate P22 3-Methoxy-1-(2-methylbut-3-yn-2-yl)azacyclobutane (Step A) Acetyl chloride (0.95 mL, 13.4 mmol) was added dropwise to a stirred solution of 2-methylbut-3-yn-2-ol (1.2 mL, 11.9 mmol) in anhydrous DCM (1.8 mL) at 0 °C. The reaction mixture was stirred at room temperature for 1 hour. The solvent was removed under vacuum to obtain the residue. The residue was dissolved in anhydrous THF (12 mL), and 3-methoxyazinobutane hydrochloride (1:1) (1.0 g, 8.09 mmol), triethylamine (3.5 mL, 25.1 mmol), and CuCl (118 mg, 1.19 mmol) were added. The reaction mixture was stirred at 70 °C for 3 hours, and then concentrated under vacuum. The residue was dissolved in water (20 mL) and EtOAc (20 mL), and then alkalized to pH 10–11 with a saturated aqueous solution of NaHCO3. The phases were separated, and the aqueous phase was extracted with EtOAc (3 x 20 mL). The combined organic phases were concentrated under vacuum to obtain the residue. Purification was performed by an SCX-2 column (20 g), eluted with MeOH (3 CVs) followed by 7N NH3 / MeOH (4 CVs) to give the title product as a deep orange oil (448 mg, 22% yield).

[0531] 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 4.05 – 3.98 (m, 1H), 3.52 – 3.48 (m, 2H), 3.33 – 3.20 (m, 5H), 2.39 (s, 1H), 1.23 (s, 6H).

[0532] Synthesis of intermediate P23 6-[3-(3-methoxyazacyclobutane-1-yl)-3-methylbut-1-yn-1-yl]pyridine-2-carboxylic acid ethyl ester (step) Step B) At room temperature, CuI (104 mg, 0.546 mmol), Pd(PPh3)2Cl2 (153 mg, 0.218 mmol), and diisopropylamine (1.6 mL, 11.6 mmol) were added to a degassed solution of ethyl 6-bromopyridine-2-carboxylate (722 mg, 3.14 mmol) and 3-methoxy-1-(2-methylbut-3-yn-2-yl)azacyclobutane (445 mg, 2.61 mmol) in anhydrous THF (15 mL). The reaction mixture was stirred at 70 °C for 20 h. The reaction mixture was concentrated under vacuum, and the residue was purified by FCC (50 g Sfar duo, 0-100% EtOAc / heptane) to give the title product (513 mg, 58% yield) as a pale orange oil.

[0533] LCMS m / z: 303.1 [M+H]+, (ESI+), Rt = 0.49 (S2) 1 H NMR (400 MHz, CDCl3) δ [ppm]: 8.06 (dd, J = 7.8, 1.1 Hz, 1H), 7.81(t, J = 7.8 Hz, 1H), 7.69 – 7.64 (m, 1H), 4.50 (q, J = 7.1 Hz, 2H), 4.08 –4.03 (m, 1H), 3.62 – 3.56 (m, 2H), 3.37 – 3.29 (m, 5H), 1.50 – 1.44 (m, 3H), 1.34 (s, 6H).

[0534] Synthesis of intermediate P24 6-[3-(3-methoxyazacyclobutane-1-yl)-3-methylbutyl]pyridine-2-carboxylic acid ethyl ester (Step C) Under nitrogen atmosphere, 10% Pd / C (205 mg, 0.193 mmol) was added to a solution of ethyl 6-[3-(3-methoxyazacyclobutan-1-yl)-3-methylbut-1-yn-1-yl]pyridine-2-carboxylate (512 mg, 1.52 mmol) in EtOH (10 mL). The reaction mixture was then stirred under hydrogen atmosphere for 19 hours. The mixture was filtered through diatomaceous earth and washed with MeOH (30 mL). The filtrate was concentrated under vacuum to give the residue. Purification was performed by FCC (5 g silica, 0-100% EtOAc / heptane, 0-30% MeOH / DCM) to give the title product (236.0 mg, 40% yield) as an amber oil.

[0535] LCMS m / z: 307.2 [M+H]+, (ESI+), Rt = 2.72 (S4) 1 H NMR (500 MHz, CDCl3) δ [ppm]: 7.92 (dd, J = 7.7, 1.1 Hz, 1H), 7.72(t, J = 7.7 Hz, 1H), 7.35 (d, J = 7.7 Hz, 1H), 4.46 (q, J = 7.1 Hz, 2H), 4.14– 4.06 (m, 1H), 3.73 - 3.51 (m,2H), 3.33 - 3.16 (m, 5H), 2.98 - 2.88 (m, 2H),1.83 - 1.74 (m, 2H), 1.43 (t, J = 7.2 Hz, 3H), 1.09 (br s, 6H).

[0536] Synthesis of intermediate P25 Lithium(1+) 6-[[3-(3-methoxyazacyclobutane-1-yl)-3-methylbutyl]pyridine-2-carboxylate (step) D） Ethyl 6-[3-(3-methoxyazacyclobutan-1-yl)-3-methylbutyl]pyridine-2-carboxylate (236 mg, 0.616 mmol) was added to a stirred solution of anhydrous THF (2 mL) and MeOH (2 mL) in 2 M LiOH aqueous solution (463 μL, 0.926 mmol). The reaction mixture was stirred at room temperature for 17 hours. The mixture was concentrated under vacuum, then suspended in 1:1 DCM / heptane (20 mL), sonicated, and concentrated to give the title product (197 mg, 100% yield) as a brown solid.

[0537] LCMS m / z: 279.1 [M+H]+, (ESI+), Rt = 0.32 (S2).

[0538] General route 11g diagram Synthesis of intermediate P26 1'-tert-butyl-6-ethyl-1',2',3',6'-tetrahydro-[2,4'-bipyridine]-1',6-dicarboxylate (Step A) A solution of ethyl 6-bromopyridine-2-carboxylate (1.00 g, 4.35 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate tert-butyl ester (1.61 g, 5.22 mmol) in 1,4-dioxane (30 mL) was added to a solution of Na₂CO₃ (1.38 g, 13.0 mmol) / water (7.5 mL). The mixture was degassed with a stream of N₂, and then Pd(dppf)₂Cl₂·DCM (180 mg, 0.217 mmol) was added. The mixture was stirred at 110 °C for 3 hours. The reaction mixture was cooled, filtered, and the filtrate was concentrated under vacuum. The residue was partitioned between EtOAc (40 mL) and brine (20 mL). The organic layer was separated, dried over MgSO₄, and concentrated under vacuum. The residue was purified by FCC (25 g silica, 0-30% EtOAc / heptane) to give the title product (1.43 g, 99% yield) as a colorless oil.

[0539] 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 8.01 –7.86 (m, 2H), 7.78 (dd, J =7.8, 1.2 Hz, 1H), 6.75 (s, 1H), 4.34 (q, J = 7.1 Hz, 2H), 4.10 – 3.96 (m,2H), 3.54 (t, J = 5.7 Hz, 2H), 2.58 (dq, J = 5.3, 2.7 Hz,2H), 1.42 (s, 9H), 1.32 (t, J = 7.1 Hz, 3H).

[0540] Synthesis of intermediate P27 Ethyl 6-{1-[(tert-butoxy)carbonyl]piperidin-4-yl}pyridine-2-carboxylate (Step B) Under nitrogen protection, 10% Pd / C (206 mg, 0.19 mmol) was added to a solution of 1'-tert-butyl-6-ethyl-1',2',3',6'-tetrahydro-[2,4'-bipyridine]-1',6-dicarboxylate (1.43 g, 4.30 mmol) in ethanol (15 mL). The mixture was evacuated and stirred under hydrogen for 18 hours. Palladium residue was filtered through diatomaceous earth, and the filtrate was concentrated under vacuum to give the title product (1.25 g, 87% yield) as a colorless oil.

[0541] LCMS m / z: 357.3 [M+Na]+, (ESI+), Rt = 0.98(S2) 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 7.95 – 7.83 (m, 2H), 7.54 (dd, J =7.5, 1.5 Hz, 1H), 4.40 – 4.28 (m, 2H), 4.05 (dd, J = 9.8, 5.8 Hz, 2H), 3.01 –2.73 (m, 3H), 1.86 – 1.76 (m, 2H), 1.58 (qd, J = 12.6, 4.3 Hz, 2H), 1.40 (s,9H), 1.31 (t, J = 7.1 Hz, 3H).

[0542] Synthesis of intermediate P28 6-(piperidin-4-yl)pyridine-2-carboxylic acid ethyl ester hydrochloride (Step C) To a solution of ethyl 6-{1-[(tert-butoxycarbonyl)piperidin-4-yl]pyridine-2-carboxylate (1.24 g, 3.71 mmol) in DCM (4 mL), 4 M HCl / dioxane (3.7 mL, 14.8 mmol) was added. The solution was stirred at room temperature for 18 hours. The reaction mixture was concentrated under vacuum to give the title product (1.00 g, 100% yield) as a white solid.

[0543] LCMS m / z: 235.2 [M+H]+, (ESI+), Rt = 0.46 (S2) 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 8.94 (d, J = 152.6 Hz, 2H), 8.04 –7.89 (m, 2H), 7.55 (dd, J = 7.6, 1.3 Hz, 1H), 4.36 (q, J = 7.1 Hz, 2H), 3.39(s, 2H), 3.20 – 2.96 (m, 3H), 2.13 – 1.88 (m,4H), 1.33 (t, J = 7.1 Hz, 3H).

[0544] Synthesis of intermediate P29 Ethyl 6-(1-methylpiperidin-4-yl)pyridine-2-carboxylate (Step D) To a solution of ethyl 6-(piperidin-4-yl)pyridine-2-carboxylate hydrochloride (500 mg, 1.85 mmol) in EtOH (6 mL), 0.61 mL of 37% formaldehyde aqueous solution (7.48 mmol) was added. The mixture was stirred for 15 minutes, and then NaBH3CN (469.977 mg, 7.48 mmol) was added. The solution was stirred at room temperature for 2 hours. The reaction was quenched with water (5 mL), and DCM (20 mL) was added. The aqueous layer was alkalized to pH 9 with saturated NaHCO3 aqueous solution. The organic layer was separated, and the aqueous layer was extracted again with DCM (2 x 10 mL). The combined organic layers were dried over MgSO4 and concentrated under vacuum to give the title product (440 mg, 81% yield) as a light brown oil.

[0545] LCMS m / z: 249.2 [M+H]+, (ESI+), Rt = 0.45 (S2) 1 H NMR (400 MHz, CDCl3) δ [ppm]: 7.88 (dd, J = 7.7, 1.1 Hz, 1H), 7.71(t, J = 7.8 Hz, 1H), 7.37 – 7.28 (m, 1H), 4.39 (q, J = 7.1 Hz, 2H), 3.05 –2.92 (m, 2H), 2.85 (m, 1H), 2.28 (d,J = 13.6 Hz, 3H), 2.17 – 2.04 (m, 2H),2.00 – 1.90 (m, 2H), 1.89 – 1.73 (m, 2H), 1.36 (t, J = 7.1 Hz, 3H).

[0546] Synthesis of intermediate P30 6-(1-Methylpiperidin-4-yl)pyridine-2-carboxylic acid (Step E) 1 M LiOH (2.6 mL, 2.6 mmol) was added to a THF (7.5 mL) solution of ethyl 6-(1-methylpiperidin-4-yl)pyridine-2-carboxylate (430 mg, 1.73 mmol). The reaction mixture was stirred at 40 °C for 2 hours. 1 N HCl was added until the pH reached 8 (approximately 0.8 mL). The mixture was concentrated under vacuum to give the title product (380 mg, 90% yield) as a white solid.

[0547] LCMS m / z: 221.2 [M+H]+, (ESI+), Rt = 0.33 (S1) 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 7.87 –7.77 (m, 2H), 7.36 – 7.27(m, 1H), 4.34 – 4.25 (m, 1H), 2.89 – 2.76 (m, 2H), 2.16 (d, J = 2.3 Hz, 3H), 1.89 – 1.76 (m, 2H), 1.76 – 1.61 (m, 4H).

[0548] The following intermediates were prepared using the corresponding starting materials in a manner similar to intermediate P30, as outlined in general route 11g.

[0549] Diagram of General Route 12a Synthesis of intermediate Q1 (3S)-3-{4'-chloro-4-fluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl}-3-[(2S)-2-[(6-fluoro] [Pyridin-2-yl)formamido]-4-methylpentamido]ethyl propionate TEA (0.68 mL, 4.87 mmol) was added to a solution of 6-fluoropyridine-2-carboxylic acid (302 mg, 2.14 mmol) and T3P (50% in DMF) (1.71 mL, 2.92 mmol) in DCM (7 mL). The mixture was stirred at room temperature for 10 minutes, and then (3S)-3-[(2S)-2-amino-4-methylpentamido]-3-{4'-chloro-4-fluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl}propionate ethyl hydrochloride (1.0 g, 1.95 mmol) was added. After stirring for 3 hours, water (5 mL) was added, and the mixture was extracted with EtOAc (3 x 15 mL). The combined organic layers were washed with brine (10 mL), dried over MgSO4, and concentrated under vacuum. The residue was purified by reverse-phase FCC (30 g, C18 silica, 10-100% MeCN / water, with 0.1% NH4OH modifier) ​​to give the title product as a white solid (556 mg, yield 48%).

[0550] LCMS m / z: 600.3 / 602.3 [M+H]+, (ESI+), Rt =1.12 (S2) 1H NMR (500 MHz, DMSO-d6) δ [ppm]: 8.74 (d, J = 8.4 Hz, 1H), 8.39 (d,J = 8.9 Hz, 1H), 8.16 (q, J = 8.0 Hz, 1H), 7.93 – 7.86 (m,1H), 7.45 – 7.37(m, 1H), 7.18 (d, J = 2.2 Hz, 1H), 7.11 (d, J = 2.2 Hz, 1H), 7.00 – 6.87 (m,2H), 5.61 – 5.45 (m, 1H), 4.57 – 4.42 (m, 1H), 4.17 – 3.82 (m,2H), 2.86 –2.67 (m, 2H), 2.29 – 2.21 (m, 3H), 1.93 (s, 3H), 1.83 (s, 3H), 1.61 – 1.32(m, 3H), 1.07 (t, J = 7.1 Hz, 3H), 0.91 – 0.70 (m, 6H).

[0551] The following intermediates are prepared using the corresponding starting materials in a manner similar to intermediate Q1, as outlined in general route 12a.

[0552] Synthesis of intermediate Q3 Step B (Part 1): (3S)-3-{4,4'-difluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl}-3- [(2S)-2-({6-[3-(dimethylamino)-3-methylazacyclobutane-1-yl]pyridin-2-yl}carboxamido)-4-methyl Ethyl propionate [pentamido] K₂CO₃ (71 mg, 0.51 mmol) was added to a solution of ethyl (3S)-3-{4,4'-difluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl}-3-[(2S)-2-[(6-fluoropyridin-2-yl)carbamate]-4-methylpentamido]propionate (100 mg, 0.171 mmol) in DMF (1 mL), followed by N,N,3-trimethylazacyclobutane-3-amine dihydrochloride (64 mg, 0.343 mmol). The mixture was heated at 80 °C for 18 hours. The reaction mixture was concentrated under vacuum to give the residue. Purification was performed by reverse-phase FCC (12 g C₁₈ silica, 10-100% water / MeCN, with 0.1% NH₄OH modifier) ​​to give the title compound (57 mg, 37% yield) as a yellow glassy solid.

[0553] LCMS m / z: 678.4 [M+H]+, (ESI+), Rt = 0.94 (S1).

[0554] Diagram of General Route 12b Synthesis of intermediate Q4 Lithium (1+)-6-chloropyridine-2-carboxylate (Step A) To a stirred solution of ethyl 6-chloropyridine-2-carboxylate (500 mg, 2.69 mmol) in THF (5 mL) and MeOH (5 mL), 2 M LiOH aqueous solution (2 mL, 4 mmol) was added. The reaction was stirred at room temperature for 1 hour. The reaction mixture was concentrated under vacuum, suspended in 1:1 DCM-heptane (20 mL), sonicated, and concentrated under vacuum to give the title product as a white solid (491 mg, 100% yield).

[0555] LCMS m / z: 158.1 [M+H]+, (ESI+), Rt = 0.47 (S1).

[0556] Synthesis of intermediate Q5 (3S)-3-[(2S)-2-[(6-chloropyridin-2-yl)carbamate]-4-methylpentamido]-3-{4,4'-di- Ethyl fluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl propionate (Step B) A solution of ethyl (3S)-3-[[(2S)-2-amino-4-methyl-valeryl]amino]-3-[2-fluoro-5-(4-fluoro-2,6-dimethyl-phenyl)-3-methyl-phenyl]propionate hydrochloride (150 mg, 0.257 mmol), lithium (1+)-6-chloropyridine-2-carboxylate (115 mg, 0.63 mmol), HATU (327 mg, 0.860 mmol), and DIPEA (179 μL, 1.03 mmol) in DMF (5 mL) was stirred at room temperature for 1.5 hours. The mixture was diluted with EtOAc (15 mL) and water (25 mL) was added. The phases were separated, and the aqueous phase was extracted with EtOAc (15 mL). The combined organic layers were washed with brine, filtered through a phase separator, and concentrated under vacuum. The residue was purified by FCC (0-40% EtOAc / heptane, SfarDuo 25 g) to give the title product as a white solid (247 mg, 65% yield).

[0557] LCMS m / z: 600.4 / 602.4 [M+H]+, (ESI+), Rt = 1.26 (S1) 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 8.78 (d, J = 8.4 Hz, 1H), 8.39 (d,J = 8.9 Hz, 1H), 8.04 (t, J = 7.7 Hz, 1H), 7.94(dd, J = 7.6, 1.0 Hz, 1H),7.74 (dd, J = 7.9, 0.9 Hz, 1H), 6.98 – 6.87 (m, 4H), 5.60 – 5.50 (m, 1H),4.59 – 4.49 (m, 1H), 4.07 – 3.91 (m, 2H), 2.83 – 2.68 (m,2H), 2.27 – 2.22 (m,3H), 1.96 – 1.92 (m, 3H), 1.87 (s, 3H), 1.58 – 1.38 (m, 3H), 1.06 (t, J = 7.1Hz, 3H), 0.82 – 0.76 (m, 6H).

[0558] A typical route 12d diagram Synthesis of intermediate Q10 5-Methyl-6-{2-methyl-2,7-diazaspiro[3.5]nonane-7-yl}pyridine-2-carboxylate (Step A) Cs₂CO₃ (1.416 g, 4.35 mmol) and methyl 6-bromo-5-methylpyridine-2-carboxylate (250 mg, 1.09 mmol) were added to a stirred solution of 2-methyl-2,7-diazaspiro[3.5]nonane dihydrochloride (301 mg, 1.41 mmol) in anhydrous 1,4-dioxane (10.5 mL). The solution was purged with nitrogen for 20 min, and then Pd(OAc)₂ (19.5 mg, 0.09 mmol) and BINAP (101.5 mg, 0.16 mmol) were added. The reaction mixture was stirred at 80 °C for 18 h, cooled to room temperature, filtered through diatomaceous earth, and washed with ethyl acetate (2 x 10 mL). The filtrate was concentrated under vacuum, and the residue was purified by FCC (28 g Kp-NH2 silica, 0-100% EtOAc / heptane) to give the title product as a white solid (110 mg, yield 28%).

[0559] LCMS m / z: 290.3 [M+H]+, (ESI+), Rt = 0.56 (S1) 1H NMR (400 MHz, DMSO-d6) δ [ppm]: 7.65 –7.62 (m, 1H), 7.59 – 7.55(m, 1H), 3.82 (s, 3H), 3.01 – 2.96 (m, 4H), 2.95 (s, 4H), 2.28 (d, J = 0.8Hz, 3H), 2.23 (s, 3H), 1.82 – 1.74 (m, 4H).

[0560] Synthesis of intermediate Q11 Lithium (1+) 5-methyl-6-{2-methyl-2,7-diazaspiro[3.5]nonane-7-yl}pyridine-2-carboxylate (step) B） A stirred solution of methyl 5-methyl-6-{2-methyl-2,7-diazaspiro[3.5]nonane-7-yl}pyridine-2-carboxylate (110 mg, 0.304 mmol) in THF (1.5 mL) and MeOH (0.15 mL) was treated with 2 M LiOH aqueous solution (0.23 mL, 0.460 mmol) and stirred at room temperature for 3 hours. The reaction mixture was vigorously concentrated under vacuum, and the residue was suspended in DCM (5 mL) and heptane (3 mL), sonicated, and concentrated. The residue was resuspended in DCM (5 mL) and heptane (3 mL), sonicated, and concentrated under vacuum to give the title product (112 mg, 98% yield) as a white solid.

[0561] LCMS m / z: 276.3 [M+H]+, (ESI+), Rt = 0.38 (S1) 1 H NMR (500 MHz, DMSO-d6) δ [ppm]: 7.72 – 7.37 (m, 2H), 2.93 – 2.86 (m, 8H), 2.27 – 2.11 (m, 6H), 1.86 – 1.70 (m, 4H).

[0562] Synthesis of intermediate Q12 Methyl 6-[4-(dimethylamino)piperidin-1-yl]-5-methylpyridine-2-carboxylate (Step A) It was prepared using methyl 6-bromo-5-methylpyridine-2-carboxylate and N,N-dimethylpiperidine-4-amine in a manner similar to intermediate Q10.

[0563] LCMS m / z: 278.2 [M+H]+, (ESI+), Rt = 0.49 (S1) 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 7.65 (dd, J = 7.6, 0.9 Hz, 1H), 7.58 (d, J = 7.5 Hz, 1H), 3.83 (s, 3H), 3.49 (d, J = 12.8 Hz, 2H), 3.17 (d, J= 5.1 Hz, 1H), 2.79 – 2.65 (m, 2H), 2.30 (s, 3H), 2.21(s, 6H), 1.91 – 1.80(m, 2H), 1.52 (qd, J = 12.1, 3.8 Hz, 2H).

[0564] Synthesis of intermediate Q13 6-[4-(dimethylamino)piperidin-1-yl]-5-methylpyridin-2-carboxylic acid (Step B) A solution of methyl 6-[4-(dimethylamino)piperidin-1-yl]-5-methylpyridin-2-carboxylate (80 mg, 0.288 mmol) in THF (3 mL) was added to a 2 M LiOH aqueous solution (0.87 mL, 1.73 mmol). The solution was stirred at 40 °C for 2 hours. The reaction mixture was cooled and acidified to pH 5 with 1N HCl. The solvent was removed under vacuum to give the title product (76 mg, 100% yield) as a colorless gel.

[0565] LCMS m / z: 264.2 [M+H]+, (ESI+), Rt = 0.33 (S1).

[0566] The following intermediates are prepared using the corresponding starting materials in a manner similar to intermediate Q13, as outlined in general route 12d.

[0567] Diagram of general route 12e Synthesis of intermediate Q15 6-[6-(methoxycarbonyl)-3-methylpyridin-2-yl]-2,6-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (Step A) It was prepared in a manner similar to intermediate Q10, using methyl 6-bromo-5-methylpyridine-2-carboxylate and tert-butyl 2,6-diazaspiro[3.5]nonane-2-carboxylate.

[0568] LCMS m / z: 398.3 [M+H]+, (ESI+), Rt = 1.05 (S1) 1 H NMR (500 MHz, DMSO-d6) δ [ppm]: 7.68 (dd, J = 7.5, 0.9 Hz, 1H), 7.62 (d, J = 7.6 Hz, 1H), 3.84 (s, 3H), 3.57 (s, 4H), 3.19 – 3.08 (m, 2H), 2.99 – 2.89 (m, 2H), 2.31 (d, J = 0.8 Hz, 3H), 1.76 –1.67 (m, 2H), 1.64 (q, J= 5.5 Hz, 2H), 1.37 (s, 9H).

[0569] Synthesis of intermediate Q16 6-{2,6-diazaspiro[3.5]nonane-6-yl}-5-methylpyridine-2-carboxylic acid methyl ester hydrochloride (Step B) To a solution of 6-[6-(methoxycarbonyl)-3-methylpyridin-2-yl]-2,6-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (166 mg, 0.442 mmol) in DCM (1 mL), 4 M HCl / 1,4-dioxane (0.442 mL, 1.77 mmol) was added. The solution was stirred at room temperature for 2 hours. The solvent was concentrated under vacuum to give the title product (200 mg, 74% yield) as a colorless gum.

[0570] LCMS m / z: 276.2 [M+H]+, (ESI+), Rt = 0.53 (S1) 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 9.20(1H, br s), 7.75 – 7.58 (m,2H), 3.84 (s, 3H), 3.77 – 3.54 (m, 6H), 2.90 (t, J = 5.3 Hz, 2H), 2.33 (s,3H), 1.84 – 1.68 (m, 2H), 1.68 – 1.55 (m, 2H).

[0571] Synthesis of intermediate Q17 5-Methyl-6-{2-methyl-2,6-diazaspiro[3.5]nonane-6-yl}pyridine-2-carboxylate (Step C) Formaldehyde [37% in water] (0.137 mL, 1.69 mmol) was added to a solution of methyl 6-{2,6-diazaspiro[3.5]nonane-6-yl}-5-methylpyridine-2-carboxylate hydrochloride (130 mg, 0.417 mmol) in MeOH (1.4 mL). The mixture was stirred for 15 min, and then NaBH3CN (106 mg, 1.69 mmol) was added, and the solution was stirred at room temperature for 18 h. The reaction was quenched with a saturated aqueous solution of NaHCO3 (10 mL), and dichloromethane (DCM) (20 mL) was added. The organic layer was separated, and the aqueous layer was extracted again with DCM (2 x 10 mL). The combined organic layers were dried over MgSO4 and concentrated under vacuum to give the residue. The residue was purified by FCC (10 g silica, 0-10% 7M NH3 in MeOH / DCM) to give the title product (55 mg, 41% yield) as a colorless oil.

[0572] LCMS m / z: 290.4 [M+H]+, (ESI+), Rt = 0.56 (S1) 1 H NMR (500 MHz, DMSO-d6) δ [ppm]: 7.67(d, J = 7.5 Hz, 1H), 7.49 (dd,J = 7.5, 0.9 Hz, 1H), 3.94 (s, 3H), 3.28 (s, 2H), 3.16 (d, J = 7.5 Hz, 2H), 3.09 – 2.95 (m, 4H), 2.38 – 2.31 (m, 6H), 1.81 – 1.73 (m, 2H), 1.73 – 1.62 (m, 2H).

[0573] Synthesis of intermediate Q18 5-Methyl-6-{2-methyl-2,6-diazaspiro[3.5]nonane-6-yl}pyridine-2-carboxylic acid (Step D) It is prepared using intermediate Q17 in a manner similar to that of intermediate Q13.

[0574] LCMS m / z: 276.4 [M+H]+, (ESI+), Rt = 0.43 (S1).

[0575] Diagram of general route 12f Synthesis of intermediate Q19 2-[2-(dimethylamino)ethoxy]-6-(trifluoromethyl)pyridine-3-carboxylic acid ethyl ester (Step A) To a stirred suspension of ethyl 2-hydroxy-6-(trifluoromethyl)pyridine-3-carboxylate (500 mg, 2.13 mmol) and potassium carbonate (735 mg, 5.32 mmol) in acetone (10 mL), (2-chloroethyl)dimethylamine hydrochloride (1:1) (766 mg, 5.32 mmol) was added. The reaction mixture was stirred at 60 °C for 18 hours, cooled, filtered, and washed with acetone (25 mL). The filtrate was concentrated under vacuum, and the residue was purified by FCC (25 g silica, 0-10% MeOH / EtOAc) to give the title product as a solid (370 mg, 55% yield).

[0576] LCMS m / z: 307.2 [M+H]+, (ESI+), Rt = 0.59 (S1) 1 H NMR (400 MHz, CDCl3) δ [ppm]: 8.19 (dd, J = 7.7, 1.0 Hz, 1H), 7.22(d, J = 7.7 Hz, 1H), 4.52 (t, J = 5.8 Hz, 2H), 4.31 (q, J = 7.2 Hz, 2H), 2.71 (t, J = 5.9 Hz, 2H), 2.29 (s, 6H), 1.32 (t, J = 7.1 Hz, 3H).

[0577] Synthesis of intermediate Q20 (illustration on page 110a) 2-[2-(dimethylamino)ethoxy]-6-(trifluoromethyl)pyridine-3-carboxylate (Step B) At 45 °C, ethyl 2-[2-(dimethylamino)ethoxy]-6-(trifluoromethyl)pyridine-3-carboxylate (359 mg, 1.17 mmol) was added to a stirred solution of 2 N LiOH aqueous solution (0.88 mL, 1.76 mmol) in THF (5 mL) and MeOH (0.5 mL). The reaction mixture was stirred at 45 °C for 1 hour. The reaction mixture was cooled and acidified with 1 N HCl aqueous solution. The solution was concentrated under vacuum to give the title product (400 mg, 100% yield) as a white solid.

[0578] LCMS m / z: 279.1 [M+H]+, (ESI+), Rt = 0.48 (S1) 1H NMR (400 MHz, DMSO-d6) δ [ppm]: 7.60(s, 1H), 7.27 (d, J = 7.2 Hz,1H), 4.32 (t, J = 6.2 Hz, 2H), 2.58 (t, J = 6.2 Hz, 2H), 2.21 (s, 6H).

[0579] The following intermediates are prepared using the corresponding starting materials in a manner similar to intermediate Q20, as outlined in general route 12f.

[0580] Diagram of General Route 13 Synthesis of intermediate R1 Methyl 2-fluoro-3-(4-methylpiperazin-1-yl)benzoate (Step A) A stirred mixture of methyl 3-bromo-2-fluorobenzoate (1.0 g, 4.29 mmol), 1-methylpiperazine (625 μL, 5.63 mmol), and Cs₂CO₃ (4.19 g, 12.86 mmol) in anhydrous 1,4-dioxane (40 mL) was degassed with nitrogen for 5 min. Pd(OAc)₂ (71 mg, 0.316 mmol) and rac-BINAP (400.0 mg, 0.64 mmol) were added, and the mixture was stirred at 80 °C for 18 h. The reaction mixture was cooled to room temperature, filtered through diatomaceous earth, and washed with EtOAc (30 mL). The filtrate was concentrated under vacuum to obtain the residue. Purification by column chromatography (25 g silica, 0-100% EtOAc / heptane, followed by 0-15% MeOH / EtOAc) yielded an impure product. Further purification was performed by SCX column chromatography (0-100% 7M NH3 / MeOH) to give the title product as the yellow oil (660 mg, yield 59%).

[0581] LCMS m / z: 253.1 [M+H]+, (ESI+), Rt = 0.66 (S2) 1 H NMR (500 MHz, CDCl3) δ [ppm]: 7.51 – 7.46 (m, 1H), 7.15 – 7.06 (m,2H), 3.91 (s, 3H), 3.17 – 3.07 (m, 4H), 2.65 – 2.55 (m, 4H), 2.35 (s, 3H).

[0582] Synthesis of intermediate R2 Lithium (1+) 2-Fluoro-3-(4-methylpiperazin-1-yl)benzoate (Step B) A solution of methyl 2-fluoro-3-(4-methylpiperazin-1-yl)benzoate (655 mg, 2.52 mmol) in THF (10 mL) and MeOH (1 mL) was added to a solution of methyl 2-fluoro-3-(4-methylpiperazin-1-yl)benzoate, with an aqueous solution of 2 M LiOH (1.5 mL, 3.00 mmol). The reaction mixture was stirred at room temperature for 3 hours. Then, another 2 M LiOH aqueous solution (1.5 mL, 3.00 mmol) was added, and the mixture was stirred at 50 °C. 0 The mixture was stirred at C for 1 hour. The reaction mixture was concentrated under vacuum to give the title product (723 mg, 100% yield) as a yellow solid.

[0583] 1 H NMR (500 MHz, DMSO-d6) δ [ppm]: 7.02 – 6.96 (m, 1H), 6.88 (t, J =7.7 Hz, 1H), 6.79(td, J = 7.9, 1.8 Hz, 1H), 3.00 – 2.88 (m, 4H), 2.48 – 2.40 (m, 4H), 2.21 (s, 3H).

[0584] General ammonia components Synthesis of intermediate S1 3-{3-azabicyclo[3.1.1]heptane-3-yl}azacyclobutane-1-carboxylic acid benzyl ester STAB (450.0 mg, 2.12 mmol) was added to a solution of 3-oxazacyclobutane-1-carboxylic acid benzyl ester (150 mg, 0.731 mmol), 3-azabicyclo[3.1.1]heptane hydrochloride (100 mg, 0.748 mmol), and TEA (0.30 mL, 2.15 mmol) in DCM (5.5 mL). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into water (30 mL) and diluted with a saturated aqueous solution of NaHCO3 (20 mL). The mixture was extracted with DCM (4 x 10 mL), and the combined organic layers were concentrated under vacuum to give an oil. Purification was performed by SCX (5 g, 0-100% 7M NH3 / MeOH) to give the title product (217 mg, 93% yield) as a pale yellow oil.

[0585] LCMS m / z: 287.3 [M+H]+, (ESI+), Rt = 0.50 (S1) 1 H NMR (500 MHz, DMSO-d6) δ [ppm]: 7.41 – 7.28 (m, 5H), 5.04 (s, 2H), 4.04 – 3.83 (m, 4H), 3.51 (pent., 1H), 2.79 – 2.74 (m, 4H), 2.35 – 2.29 (m,2H), 2.01 – 1.91 (m, 2H), 1.46 – 1.38 (m, 2H).

[0586] Synthesis of intermediate S2 3-(azacyclobutane-3-yl)-3-azabicyclo[3.1.1]heptane trifluoroacetate A mixture of 3-(3-azabicyclo[3.1.1]heptane-3-yl)azacyclobutane-1-carboxylic acid benzyl ester (217.0 mg, 0.68 mmol) and 10% Pd / C (109 mg, 0.102 mmol) in ethanol (9 mL) was stirred under hydrogen at room temperature for 18 hours. The catalyst was filtered off through diatomaceous earth, the solvent was evaporated under vacuum to give a crude product, which was dissolved in TFA (0.063 mL, 0.818 mmol) and concentrated under vacuum to give the title product (130 mg, 71% yield) as a white solid.

[0587] LCMS m / z: 153.2 [M+H]+, (ESI+), Rt = 0.63 (S2) 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 9.49 – 8.96 (m, 2H), 4.58 – 4.22(m, 3H), 4.22 – 4.01 (m, 2H), 3.42 – 2.96 (m, 4H), 2.48 – 2.37 (m, 2H), 2.20–2.10 (m, 2H), 1.70–1.45 (m, 2H).

[0588] Diagram of General Route 14a Synthesis of intermediate S3 Step A: Methyl 7-(propyl-2-yl)-5,6,7,8-tetrahydro-1,7-naphthyl-2-carboxylate (Step A) STAB (719 mg, 3.39 mmol) was added to a solution of methyl 5,6,7,8-tetrahydro-1,7-naphthyl-2-carboxylate dihydrochloride (300 mg, 1.13 mmol) and TEA (0.75 mL, 5.66 mmol) in acetone (0.9 mL) and DCM (5 mL) at room temperature. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with water (15 mL) and saturated NaHCO3 solution (15 mL), and then extracted with DCM (3 x 10 mL). The combined organic layers were dried over MgSO4 and concentrated under vacuum to give the title product (330 mg, 100% yield) as a yellow oil.

[0589] LCMS m / z: 235.2 [M+H]+, (ESI+), Rt = 0.55 (S2) 1 H NMR (500 MHz, DMSO-d6) δ [ppm]: 7.83 (d, J = 7.9 Hz, 1H), 7.71 (d,J = 7.9 Hz, 1H), 3.85 (s, 3H), 3.71 (s, 2H), 2.95 – 2.89 (m, 1H), 2.87 (t, J = 5.7 Hz, 2H), 2.73 (t, J = 5.8 Hz, 2H), 1.07 (d, J = 6.6 Hz, 6H).

[0590] Synthesis of intermediate S4 Lithium(1+) 7-(propyl-2-yl)-5,6,7,8-tetrahydro-1,7-naphthidine-2-carboxylate (Step B) A solution of methyl 7-(propyl-2-yl)-5,6,7,8-tetrahydro-1,7-naphthyl-2-carboxylate (330 mg, 1.13 mmol) and LiOH hydrate (1:1:1) (57 mg, 1.35 mmol) in THF (10 mL) and water (3 mL) was stirred at room temperature for 2 hours. The reaction mixture was concentrated under vacuum to obtain a residue. The residue was sonicated in DCM (10 mL), heptane (1 mL) was added, and the suspension was concentrated under vacuum to give the title product (264 mg, 99% yield) as a beige powder.

[0591] LCMS m / z: 221.2 [M+H]+, (ESI+), Rt = 0.28 (S2) 1H NMR (400 MHz, DMSO-d6) δ [ppm]: 7.73 (d, J = 7.8 Hz, 1H), 7.59 (d,J = 7.8 Hz, 1H), 3.53 (s, 2H), 2.81 (t, J = 6.0 Hz, 3H), 2.72 – 2.65 (m, 2H),1.00 (d, J = 6.5 Hz, 6H).

[0592] The following intermediates are prepared using the corresponding starting materials in a manner similar to intermediate S4, as outlined in general route 14a.

[0593] Diagram of General Route 14b Synthesis of intermediate S6 7-Methyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazine-2-carboxylic acid ethyl ester (Step A) A solution of ethyl 5H,6H,7H,8H-imidazo[1,2-a]pyrazine-2-carboxylate (400 mg, 2.05 mmol) in anhydrous DCM (6 mL) was treated with paraformaldehyde (190 mg, 6.12 mmol) under nitrogen atmosphere, followed by AcOH (0.40 mL, 6.99 mmol) and stirred for 10 min. STAB (1.50 g, 7.08 mmol) was then added in fractions over 2 min, and the reaction mixture was stirred at room temperature for 2 h. Another fraction of STAB (1.5 g, 7.08 mmol) was added, and stirring continued for 16 h. The reaction mixture was diluted with saturated aqueous NaHCO3 solution and then extracted with DCM (2 x 6 mL). The organic layers were combined and concentrated under vacuum. The residue was purified by reversed-phase column chromatography (12 g C-18 silica, 0.1% ammonium hydroxide modifier, 10-100% MeCN aqueous solution) to give the title product as colorless oil (120 mg, yield 23%).

[0594] LCMS m / z: 210.1 [M+H]+, (ESI+), Rt = 0.38 (S2) 1H NMR (400 MHz, CDCl3) δ [ppm]: 7.52 (s, 1H), 4.35 (q, J = 7.1 Hz,2H), 4.05 (t, J = 5.5 Hz, 2H), 3.68 (s, 2H), 2.86 – 2.82 (m, 2H), 2.49 (s,3H), 1.37 (t, J = 7.1 Hz, 3H).

[0595] Synthesis of intermediate S7 Lithium (1+) 7-methyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazine-2-carboxylate (Step B) A solution of ethyl 7-methyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazine-2-carboxylate (130 mg, 0.509 mmol) in THF (3 mL) was added to a 1 M aqueous solution of LiOH (563 μL, 0.563 mmol). The reaction mixture was stirred at room temperature for 4 hours. Another portion of the 1 M aqueous solution of LiOH (100 μL, 0.1 mmol) was added, and the mixture was stirred at 40 °C for 2 hours. The reaction mixture was concentrated under vacuum to give the title product (116 mg, 100% yield) as a white powder.

[0596] LCMS m / z: 182.3 [M+H]+, (ESI+), Rt = 0.17 (S1) 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 7.13 (s, 1H), 3.95 (t, J = 5.5 Hz,2H), 3.43 (s, 2H), 2.74 (t, 2H), 2.37 (s, 3H).

[0597] Synthesis of intermediate S8 7-Cyclopropyl-5H,6H,7H,8H-Imidazo[1,2-a]pyrazine-2-carboxylic acid ethyl ester (Step A) A solution of ethyl 5H,6H,7H,8H-imidazo[1,2-a]pyrazine-2-carboxylate (210.0 mg, 1.08 mmol) in MeOH (20 mL) was reacted with (1-ethoxycyclopropoxy)-trimethylsilane (310.0 mg, 1.74 mmol), followed by AcOH (0.2 mL, 3.5 mmol) and NaBH3CN (140.0 mg, 2.23 mmol). The reaction mixture was stirred at room temperature for 10 min, then heated to 80 °C and held for 4 h. The reaction mixture was cooled and concentrated under vacuum. The residue was diluted with water (15 mL) and extracted with DCM (3 x 10 mL). The combined organic layers were dried over MgSO4 and concentrated under vacuum. Purification by column chromatography (10 g silica, 0-10% MeOH / EtOAc solution) gave the title product (190 mg, 56% yield) as a colorless viscous oil.

[0598] LCMS m / z: 236.1 [M+H]+, (ESI+), Rt = 0.48 (S1) 1 H NMR (500 MHz, DMSO-d6) δ [ppm]: 7.84 – 7.80 (m, 1H), 4.24 (q, J =7.0 Hz, 2H), 4.06 – 3.98 (m, 2H), 3.78 (s, 2H), 3.08 – 3.02 (m, 2H), 2.02 –1.94 (m, 1H), 1.30 (t, J = 7.1 Hz,3H), 0.62 – 0.53 (m, 2H), 0.52 – 0.43 (m,2H).

[0599] Synthesis of intermediate S9 Lithium (1+) 7-Cyclopropyl-5H,6H,7H,8H-Imidazo[1,2-a]pyrazine-2-carboxylate (Step B) To a stirred solution of 7-cyclopropyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazine-2-carboxylic acid ethyl ester (190 mg, 0.606 mmol) in THF (1 mL) and MeOH (0.05 mL), 2 M LiOH aqueous solution (0.35 mL, 0.700 mmol) was added. The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated under vacuum to give the title product (198 mg, quantitative yield) as a yellow solid.

[0600] LCMS m / z: 208.1 [M+H]+, (ESI+), Rt = 0.21 (S1) 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 7.04 – 6.98 (m, 1H), 3.86 – 3.73(m, 2H), 3.54 (s, 2H), 2.97 – 2.85 (m, 2H), 1.86 – 1.76 (m, 1H), 0.48 – 0.36 (m, 2H), 0.36 – 0.27 (m, 2H).

[0601] Diagram of general route 14c Synthesis of intermediate S10 4-Bromo-5,7-dimethyl-1H-indazole (Step A) Acetic anhydride (0.87 mL, 9.2 mmol) was added dropwise to a mixture of 3-bromo-2,4,6-trimethylaniline (1.0 mL, 6.13 mmol) and potassium acetate (903 mg, 9.2 mmol) in chloroform (10 mL). The reaction mixture was stirred at 60 °C for 1 hour. 3-Methylbutyl nitrite (2.0 mL, 14.89 mmol) was added, and the reaction mixture was stirred at 60 °C for another 18 hours. The mixture was concentrated under vacuum, and then water (50 mL) and EtOAc (100 mL) were added. The organic phase was separated, washed with water (50 mL) and brine (50 mL), passed through a phase separator, and concentrated under vacuum. The residue was purified by FCC (25 g silica, 0-100% EtOAc / heptane) to give the title product (400 mg, 29% yield) as a pale orange solid.

[0602] LCMS m / z: 225.1 / 227.1 [M+H]+, (ESI+), Rt = 0.90 (S1).

[0603] Synthesis of intermediate S11 4-Bromo-2,5,7-Trimethyl-2H-indazole (Step B) At room temperature, trimethoxyonium tetrafluoroborate (739 mg, 5.0 mmol) was added to a solution of 4-bromo-5,7-dimethyl-1H-indazole (500.0 mg, 2.22 mmol) in EtOAc (20 mL). The reaction mixture was stirred for 18 hours. The reaction mixture was diluted with water and extracted with EtOAc (3 x 15 mL). The combined organic layers were passed through a phase separator and concentrated under vacuum. The residue was purified by FCC (10 g silica, 0-100% EtOAc / heptane) to give the title product (350 mg, 44% yield) as a white powder.

[0604] 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 8.23 ​​(s, 1H), 6.97 (s, 1H), 4.16 (s, 3H), 2.43 (s, 3H), 2.36 (s, 3H).

[0605] General route 14d diagram Synthesis of intermediate S12 8-Bromo-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylic acid ethyl ester (Step A) At 0 °C, perchloric acid (9.97 mL, 115.6 mmol) was added dropwise to a solution of (E)-(N-[(2,4,6-trimethylbenzenesulfonyl)oxy]acetamidine ester (2.47 g, 8.67 mmol) in 1,4-dioxane (20 mL). After maintaining the solution at 0 °C for 10 minutes, ice water (20 mL) was added. The resulting precipitate was collected by vacuum filtration and washed with ice water (5 mL). The white solid was dissolved in DCM (20 mL) and filtered through a phase separator. The filtrate was added dropwise to a solution of 3-bromopyridine-2-amine (1.0 g, 5.78 mmol) in DCM (20 mL). The reaction mixture was heated to room temperature and stirred for 1 hour. The reaction mixture was evaporated, and pyridine (0.93 mL, 11.56 mmol) dissolved in DMF (5 mL) was added to the residue. The solution was cooled to 0 °C, and then ethyl 2-chloro-2-oxoacetate (0.97 mL, 8.67 mmol) was added. The reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under vacuum, water (150 mL) was added, the solid was filtered off, washed with water (20 mL) and saturated NaHCO3 (20 mL), and dried over MgSO4. The residue was purified by FCC (25 g silica, 0-100% EtOAc / heptane) to give the title product (620 mg, 39% yield) as a beige powder.

[0606] LCMS m / z: 270.0 / 272.0 [M+H]+, (ESI+), Rt = 0.65 (S1) 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 9.09 (dd, J = 6.8, 1.0 Hz, 1H), 8.13 (dd, J = 7.6, 1.0 Hz, 1H), 7.30 (dd, J = 7.6, 6.8 Hz, 1H), 4.43 (q, J =7.1 Hz, 2H), 1.37 (t, J = 7.1 Hz,3H).

[0607] Synthesis of intermediate S13 {8-Bromo-[1,2,4]triazolo[1,5-a]pyridin-2-yl}methanol (Step B) To a solution of ethyl 8-bromo-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylate (350.0 mg, 1.3 mmol) in THF (5 mL), NaBH4 (98 mg, 2.59 mmol) and MeOH (1 mL) were slowly added. The reaction mixture was stirred at room temperature for 5 minutes. The reaction mixture was quenched with saturated NaHCO3 solution (2 mL) and extracted with EtOAc (10 mL). The organic layer was filtered through a phase separator, and the filtrate was concentrated under vacuum to give the title product (200 mg, 68% yield) as a white solid.

[0608] LCMS m / z: 228.0 / 230.0 [M+H]+, (ESI+), Rt = 0.44 (S1) 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 8.94 (dd, J = 6.8, 1.0 Hz, 1H), 7.99 (dd, J = 7.6, 1.0 Hz, 1H), 7.11 (dd, J = 7.6, 6.7 Hz, 1H), 5.57 (s, 1H),4.66 (s, 2H).

[0609] Synthesis of intermediate S14 8-Bromo-[1,2,4]triazolo[1,5-a]pyridine-2-carboxaldehyde (Step C) At room temperature, MnO2 (762 mg, 8.77 mmol) was added to a solution of {8-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-yl}methanol (200 mg, 0.877 mmol) in DCM (20 mL). The reaction mixture was stirred under reflux for 2 hours. Additional MnO2 (762 mg, 8.77 mmol) and MeCN (10 mL) were added, and the reaction mixture was stirred at 40 °C for 18 hours. The reaction mixture was filtered through diatomaceous earth, and the filtrate was concentrated under vacuum to give the title product as a solid (0.24 g, 77% yield).

[0610] 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 10.16 (s, 1H), 9.14 (dd, J = 6.8,0.9 Hz, 1H), 8.15 (dd, J = 4.0, 0.9 Hz, 1H), 7.32 (d, J = 7.2 Hz, 1H).

[0611] Synthesis of intermediate S15 ( { 8-Bromo-[1,2,4]triazolo[1,5-a]pyridin-2-yl } Methyldimethylamine (Step D) STAB (400.0 mg, 1.83 mmol) was added to a mixture of 8-bromo-[1,2,4]triazolo[1,5-a]pyridine-2-carboxaldehyde (200.0 mg, 0.88 mmol) and N,N-dimethylamine [2 M in THF] (2.0 mL, 4.0 mmol). The reaction mixture was stirred at room temperature for 18 hours, then quenched with MeOH (2 mL) and concentrated under vacuum. The residue was purified by FCC (11 g Kp-NH silica, 0-100% EtOAc / heptane) to give the title product (170 mg, 75% yield) as a pale yellow solid.

[0612] LCMS m / z: 255.1 / 257.1 [M+H]+, (ESI+), Rt = 0.35 (S1) 1H NMR (400 MHz, DMSO-d6) δ [ppm]: 8.94 (dd, J = 6.8, 1.0 Hz, 1H), 7.98 (dd, J = 7.5, 1.0 Hz, 1H), 7.10 (dd, J = 7.6, 6.7 Hz, 1H), 3.67 (s, 2H),2.25 (s, 6H).

[0613] Synthesis of intermediate S16 2-[(dimethylamino)methyl]-[1,2,4]triazolo[1,5-a]pyridine-8-carboxylate (Step E) At 0 °C, 2.5 M butyllithium / hexane (0.4 mL, 1.0 mmol) was added to a solution of ({8-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-yl}methyl)dimethylamine (170.0 mg, 0.67 mmol) in anhydrous THF (1 mL). The reaction mixture was maintained at 0 °C for 15 min, and then crushed dry ice was added to the reaction mixture in a single addition. The cooling bath was removed, and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was acidified with 1 M HCl and then concentrated under vacuum to give the title product (170 mg, 70% yield) as a yellow solid.

[0614] LCMS m / z: 221.1 [M+H]+, (ESI+), Rt = 0.20 (S1) 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 10.92 – 10.45 (m, 1H), 8.17 – 8.11(m, 1H), 7.87 – 7.83 (m, 2H), 4.68 (s, 2H), 2.90 (s, 6H).

[0615] Diagram of General Route 14e Synthesis of intermediate S17 6-(dimethylamino)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid ethyl ester (Step A) To a degassed solution of ethyl 6-bromopyrazolo[1,5-a]pyrimidine-3-carboxylate (188 mg, 0.696 mmol), NaOtBu (117 mg, 1.217 mmol), and dimethylamine (2 M, THF, 2.8 mL, 5.55 mmol) in dioxane (3.7 mL), tBuXPhos Pd G3 (22 mg, 0.028 mmol) was added. The reaction mixture was heated at 100 °C for 4 hours. The reaction was cooled to room temperature, filtered, and the filtrate was concentrated under vacuum. The residue was purified by open preparative high-performance liquid chromatography (P3) to give the title product (27.6 mg, 17% yield) as a dark brown solid.

[0616] LCMS m / z: 235.3 [M+H]+, (ESI+), Rt = 2.21 (S4) 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 8.68(d, J = 7.9 Hz, 1H), 8.18 (s,1H), 6.70 (d, J = 7.9 Hz, 1H), 4.19 (q, J = 7.1 Hz, 2H), 3.19 (s, 6H), 1.28(t, J = 7.1 Hz, 3H). (N1).

[0617] Synthesis of intermediate S18 6-(dimethylamino)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (Step B) A stirred solution of ethyl 6-(dimethylamino)pyrazolo[1,5-a]pyrimidine-3-carboxylate (45 mg, 0.190 mmol) in THF (2 mL) was added to a 2 M LiOH aqueous solution (0.48 mL, 0.950 mmol). The reaction mixture was stirred at room temperature for 18 hours. MeOH (1 mL) was added, and the reaction mixture was heated to 100 °C for 30 minutes, cooled to room temperature, and concentrated under vacuum. The resulting residue was dissolved in water (4 mL), acidified to pH 0 with 2 M HCl, sonicated, and precipitated. The solid was dried overnight in a vacuum oven to give the title product (16.5 mg, 42% yield) as a light pink powder.

[0618] LCMS m / z: 207.3 [M+H]+, (ESI+), Rt = 0.13 (S2).

[0619] The following intermediates are prepared using the corresponding starting materials in a manner similar to intermediate S18, as outlined in general route 14e.

[0620] Diagram of general route 14f Synthesis of intermediate S19 (2S)-2-((5H,6H,7H,8H-imidazo[1,2-a]pyrazine-7-carbonyl)amino)-4-methylpentanoate ethyl ester (step) Step A) At -10 0 At C, DIPEA (0.96 mL, 5.50 mmol) was added to a solution of (2S)-2-amino-4-methylvalerate ethyl hydrochloride (200 mg, 1.10 mmol) in MeCN (7 mL), followed by dropwise addition of bis(trichloromethyl) carbonate (121 mg, 0.407 mmol) dissolved in MeCN (2 mL). The reaction mixture was stirred for 1 hour. 5H,6H,7H,8H-imidazo[1,2-a]pyrazine hydrochloride (176 mg, 1.10 mmol) / MeCN (7 mL) was added, and the reaction mixture was heated to 65 °C and maintained for 2 hours, then cooled to room temperature and stirred for 18 hours. The reaction mixture was concentrated under vacuum to give a crude oil. Purification by column chromatography (25 g silica, 0–5% MeOH / DCM) yielded the title product as a yellow oil (169 mg, 35% yield).

[0621] LCMS m / z: 294 [M+H]+, (ESI+), Rt = 2.05 (S7).

[0622] Synthesis of intermediate S20 Lithium(1+)(2S)-2-({5H,6H,7H,8H-imidazo[1,2-a]pyrazine-7-carbonyl}amino)-4-methylpentanoic acid Salt (Step B) At room temperature, a suspension of (2S)-2-({5H,6H,7H,8H-imidazo[1,2-a]pyrazine-7-carbonyl}amino)-4-methylpentanoate (169 mg, 0.373 mmol) in THF (8.5 mL) was added to LiOH·H₂O (47 mg, 1.12 mmol) / water (1.7 mL). The reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated under vacuum to give the title product (106 mg, 69% yield) as a yellow solid.

[0623] LCMS m / z: 281 [M+H]+, (ESI+), Rt = 1.68 (S7).

[0624] Diagram of General Route 15 Synthesis of intermediate T1 2-{[(1S)-1-{[(1S)-1-{4,4'-difluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl}-3-ethyl [Oxy-3-oxopropyl]carbamoyl}-3-methylbutyl]carbamoyl}-2H,4H,5H,6H,7H-pyrazolo[3,4-] c] tert-butyl pyridine-6-carboxylate and 1-{[(1S)-1-{[(1S)-1-{4,4'-difluoro-2',5,6'-trimethyl-[1,1'-bi] [Benzene]-3-yl]-3-ethoxy-3-oxopropyl]carbamoyl]-3-methylbutyl]carbamoyl]-1H,4H,5H,6H, 7H-pyrazolo[3,4-c]pyridine-6-carboxylic acid tert-butyl ester (Step A) At 0 °C, 4-nitrophenyl chloroformate (109.0 mg, 0.54 mmol) was added to a stirred solution of 1H,4H,5H,6H,7H-pyrazolo[3,4-c]pyridine-6-carboxylic acid tert-butyl ester (110.0 mg, 0.49 mmol) and DIPEA (0.25 mL, 1.44 mmol) in anhydrous THF (4.4 mL). The reaction mixture was stirred at room temperature for 1.5 h. Ethyl (3S)-3-[(2S)-2-amino-4-methylpentamido]-3-{4,4'-difluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl}propionate hydrochloride (300.0 mg, 0.49 mmol) was added, and the reaction mixture was stirred at room temperature for another 18 h. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with saturated NaHCO3 solution (2 x 5 mL) and brine (2 x 10 mL), dried over MgSO4, and concentrated under vacuum. Purification was performed by FCC (25 g silica, 0%–100% EtOAc / heptane) to give a mixture of the title compound (382 mg, 76% yield) as a colorless colloidal substance.

[0625] LCMS m / z: 710.5 [M+H]+, (ESI+), Rt = 1.33 (S1) 1H NMR (500 MHz, DMSO-d6) δ [ppm]: 8.70 (t, J = 12.2 Hz, 1H), 8.04(d, J = 8.8 Hz, 1H), 7.99 – 7.55 (m, 1H), 6.96 – 6.85 (m, 4H), 5.57 – 5.48(m, 1H), 4.71 – 4.43 (m, 2H), 4.39 –4.29 (m, 1H), 4.06 – 3.94 (m, 2H), 3.62 –3.42 (m, 2H), 2.82 – 2.69 (m, 2H), 2.26 – 2.23 (m, 3H), 1.95 – 1.91 (m, 3H),1.88 – 1.85 (m, 3H), 1.61 – 1.44 (m,3H), 1.43 – 1.40 (m, 9H), 1.08 (t, J =7.0 Hz, 3H), 0.90 – 0.82 (m, 2H), 0.82 – 0.77 (m, 6H).

[0626] Synthesis of intermediate T2 (3S)-3-{4,4'-difluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl}-3-[(2S)-4-methyl-2-yl] ({2H,4H,5H,6H,7H-pyrazolo[3,4-c]pyridine-2-carbonyl}amino)pentamido]ethyl propionate and (3S)-3-{4, 4'-Difluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl}-3-[(2S)-4-methyl-2-({1H,4H,5H,6H,7H-pyridine] Ethyl azido[3,4-c]pyridine-1-carbonyl}amino)pentamido]propionate (Step B) TFA (0.11 mL, 1.44 mmol) was added to a solution of intermediate T1 (380.0 mg, 0.37 mmol) in DCM (2 mL), and the reaction mixture was stirred at room temperature for 5 hours. The reaction mixture was concentrated under vacuum to obtain the residue. Purification was performed by column chromatography (5 g SCX, 0-100% 7 M NH3 / MeOH) to give a mixture of the title compounds as a yellow oil (237 mg, 93% yield).

[0627] LCMS m / z: 610.4 [M+H]+, (ESI+), Rt = 0.93 / 0.94 (S1) 1H NMR (500 MHz, DMSO-d6) δ [ppm]: 8.70 (dd, J = 13.9, 8.3 Hz, 1H), 8.15 – 7.39 (m, 2H), 7.05 – 6.84 (m, 4H), 5.57 – 5.43 (m, 1H), 4.45 – 4.29(m, 1H), 4.06 – 3.99 (m, 2H), 3.99 –3.66 (m, 2H), 2.87 – 2.72 (m, 4H), 2.46 –2.39 (m, 2H), 2.27 – 2.22 (m, 3H), 1.96 – 1.92 (m, 3H), 1.91 – 1.85 (m, 3H), 1.61 – 1.31 (m, 3H), 1.10 – 1.05 (m, 3H), 0.82 – 0.73 (m, 6H).

[0628] Synthesis of intermediate T3 (3S)-3-{4,4'-difluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl}-3-[(2S)-4-methyl-2-yl] Ethyl propionate {[6-(propyl-2-yl)-2H,4H,5H,6H,7H-pyrazolo[3,4-c]pyridine-2-carbonyl]amino}pentamido] and (3S)-3-{4,4'-difluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl}-3-[(2S)-4-methyl-2-{[6- (propyl-2-yl)-1H,4H,5H,6H,7H-pyrazolo[3,4-c]pyridine-1-carbonyl]amino}pentamido]ethyl propionate (step) C） STAB (221 mg, 1.04 mmol) was added to a stirred solution of intermediate T2 (235.0 mg, 0.35 mmol) and TEA (0.23 mL, 1.75 mmol) in acetone (0.27 mL) and DCM (1.5 mL) at room temperature. The reaction mixture was stirred at room temperature for 20 hours. The reaction mixture was diluted with water (15 mL) and saturated NaHCO3 solution (15 mL), and then extracted with DCM (3 x 10 mL). The combined organic phases were passed through a phase separator and concentrated under vacuum. The residue was purified by FCC (10 g, 0-100% EtOAc / heptane, followed by 0-15% MeOH / EtOAc) to give a mixture of the title compounds as a colorless gel (148 mg, 62% yield).

[0629] LCMS m / z: 652.5 [M+H]+, (ESI+), Rt = 0.98 / 0.99 (S1).

[0630] Synthesis of intermediate U1 (3S)-3-{4,5-difluoro-2',6'-dimethyl-[1,1'-biphenyl]-3-yl}-3-[(2S)-4-methyl-2-(benzyl) Ethyl propionate (formamido)pentamido] DIPEA (0.044 mL, 0.255 mmol) was added to a solution of intermediate B2 (80 mg, 0.170 mmol) in DCM (5 mL), followed by benzoyl chloride (0.020 mL, 0.170 mmol). The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated under vacuum and purified by rapid column chromatography on silica gel (10 g, 0-100% EtOAc / heptane) to give the title product (111 mg, 100% yield) as a white powder.

[0631] LCMS m / z: 551.3 [M+H]+, (ESI+), Rt = 1.16 (S1) 1 H NMR (500 MHz, CDCl3) δ [ppm]: 7.79 – 7.71 (m, 2H), 7.53 – 7.46 (m,1H), 7.44 – 7.36 (m, 2H), 7.17 (t, J = 7.5 Hz, 1H), 7.12 – 7.04 (m, 2H), 6.94– 6.85 (m, 2H), 5.68 (dt, J = 8.3, 6.1 Hz, 1H), 4.82 – 4.59 (m, 1H), 4.08 – 3.90 (m, 2H), 3.06 – 2.75 (m, 2H), 2.01 – 1.95 (m, 6H), 1.76 – 1.66 (...

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof: in: R y It is -CH(CH3)2, -CF3, -CH2F, CHF2, -CH(CF3)2, cyclopropyl or cyclobutyl; R x It is hydrogen or methyl; R 1 It is -C(O)-R 7 ; Where R 7 It is a -C substituted with 0 or 1 pyridine, phenyl, or cyclopropyl groups. 1-6 alkyl; Or R 7 It is a phenyl or a 5-10 membered heterocyclic group, each independently of R 9 Replace with 0, 1, 2, 3, or 4 instances; Each R 9 Independently selected from halogens, =O, -C 1-6 Alkyl, -C(O)-R 10 -C 1-6 Halogenated groups, -SO2-C 1-6 Alkyl, -NH-C 1-4 Alkyl, -N(C) 1-4 Alkyl)2, -C 3-6 cycloalkyl, -OR 11 , phenyl and 4-10 membered heterocycles; and each R 9 Independently selected from R by 0, 1, 2 or 3 independent selections. 17 Substitution of groups; R 17 Selected from halogens, -C 1-6 Alkyl, -OR 15 -C(O)-N(C) 1-4 Alkyl)2, -N(R 12 R 13 ), cyclopropyl and 4 to 10 membered heterocycles, when R 17 When it is a heterocyclic ring, it is further selected independently by 0, 1, 2, or 4 ions from halogens, -C 1-6 Alkyl, =O, -C(O)-R 14 -C 1-6 Halogenated groups, -SO2-C 1-6 Alkyl, -NH-C 1-4 Alkyl, -N(C) 1-4 Alkyl)2, -C 3-6 cycloalkyl, -OR 18 Substitution of groups; R 10 Independently selected from -C 1-6 Alkyl, -C 1-6 Alkyl-C 3-6 cycloalkyl and C 3-6 cycloalkyl; R 11 It is -C 1-6 Alkyl, -C 1-6 Halogenated groups, 4- to 10-membered heterocycles, or -C 1-6 Alkyl-N(C) 1-6 Alkyl)2, wherein the 4 to 10-membered heterocycle is separated by 0 or 1 -C 1-6 Alkyl substitution; R 12 and R 13 Independently selected from -C 1-6 Alkyl, -C 1-6 Halogenated, C 1-6 alkyl-cyclopropyl, C 1-6 Alkyl-(cyclopropyl)2, cyclobutyl, and cyclopropyl, wherein C 1-6 alkyl-cyclopropyl, C 1-6 Alkyl-(cyclopropyl)2, cyclobutyl, and cyclopropyl are substituted with 0, 1, 2, or 3 F atoms; R 14 Independently selected from -C 1-6 Alkyl and C 3-6 cycloalkyl; R 15 It is H, -C 1-6 Alkyl, -C 1-6 Halogenated groups, 4- to 10-membered heterocycles, or -C 1-6 Alkyl-N(C) 1-6 Alkyl)2, when R 15 When it is a 4- to 10-membered heterocyclic ring, it is affected by 0 or 1 -C 1-6 Alkyl substitution; R 18 It is -C 1-6 Alkyl or -C 1-6 Halogenated groups; Among them, in each -N(C 1-6 alkyl)2 or -N(C 1-4 In alkyl)2, the two alkyl groups attached to N can be the same or different; R 2 The group consisting of Br, phenyl, naphthyl and 5-10 heteroaryl groups, each of which can be independently selected by 0, 1, 2, 3 or 4 independently selected from -CN, -C 1-6 Alkyl, halogen, -C 1-6 Halogenated, -OC 1-6 Alkyl, phenyl, 5- to 6-membered heteroaryl, -OC 3-6 Substitution with cycloalkyl, -O-phenyl, and -O- (5- to 6-membered heterocycloalkyl) groups; Y is -N= or -C(R) 3 = R 3 It is halogen, -C 1-6 Halogenated groups, -C 1-4 Alkyl or -C 3-6 cycloalkyl; R 4 It is halogen or hydrogen; R 5 It is halogen or hydrogen; R 6 It is -C(O)-OR 8 , Where R 8 Is it hydrogen or -C? 1-4 Alkyl, -C 1-4 Alkyl-R 16 -C 1-4 Alkyl-C(O)N(Me)-R 16 -C 1-4 Alkyl-R 16 -C 1-4 Alkyl-C(O)N(R) 16 ,R 16a - or -C 1-4 Alkyl-OC(O)-R 16 ; R 16 and R 16a Independently selected from -C 1-6 Alkyl, 3- to 6-cycloalkyl, 4- to 6-membered heterocycles, 4- to 6-membered partially saturated heterocycles, wherein the partially saturated heterocycles are further selected by one or two independently from =O or -C. 1-4 Alkyl groups are substituted.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, having formula Ia Where R 1 To R 6 R x R y And Y as defined in claim 1.

3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein: R x It is hydrogen.

4. The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein R x It is a methyl group.

5. The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein R y It is -CH(CH3)2, -CF3, cyclopropyl or cyclobutyl.

6. The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein R y It is -CH(CH3)2, cyclopropyl or cyclobutyl.

7. The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein R y It is -CH(CH3)2.

8. The compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein R y It is cyclopropyl.

9. The compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein R y It is cyclobutyl.

10. The compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein R 12 and R 13 Independently selected from -C 1-6 Alkyl, -C 1-6 Halogenated, C 1-6 alkyl-cyclopropyl, C 1-6 Alkyl-(cyclopropyl)2, cyclobutyl, and cyclopropyl, wherein C 1-6 alkyl-cyclopropyl, C 1-6 Alkyl-(cyclopropyl)2, cyclobutyl and cyclopropyl are substituted with 0, 1, 2 or 3 F.

11. The compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein R 17 Selected from halogens, -C 1-6 Alkyl, -OR 15 -C(O)-N(C) 1-4 Alkyl)2, -N(R 12 R 13 ) and 4 to 10-membered heterocyclic rings, when R 17 When it is a heterocyclic ring, it is further selected by 0, 1, or 2 independently selected from halogens, -C 1-6 Alkyl, =O, -C(O)-R 14 -C 1-6 Halogenated groups, -SO2-C 1-6 Alkyl, -NH-C 1-4 Alkyl, -N(C) 1-4 Alkyl)2, -C 3-6 cycloalkyl and -OR 18 The group is substituted.

12. The compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, wherein R 12 and R 13 Independently selected from -C 1-6 Alkyl, -C 1-6 Halogenated and cyclopropyl groups.

13. The compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, wherein R 15 It is -C 1-6 Alkyl, -C 1-6 Halogenated groups, 4- to 10-membered heterocycles, or -C 1-6 Alkyl-N(C) 1-6 Alkyl)2, when R 15 When it is a 4- to 10-membered heterocyclic ring, it is affected by 0 or 1 -C 1-6 Alkyl substitution.

14. The compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, wherein R 2 It can be independently replaced by 0, 1, 2 or 3 groups.

15. The compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, wherein R 8 Is it hydrogen or -C? 1-4 Alkyl or -C 1-4 Alkyl-OC(O)-R 16 .

16. The compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, wherein R 8 Is it hydrogen or -C? 1-4 Alkyl-C 1-4 Alkyl-R 16 -C 1-4 Alkyl-C(O)N(Me)-R 16 -or-C 1-4 Alkyl-OC(O)-R 16 And R 16 Independently selected from -C 1-6 Alkyl, 3- to 6-cycloalkyl, 4- to 6-membered partially saturated heterocycles, wherein the partially saturated heterocycles are further selected by one or two independently from =O or -C. 1-4 Alkyl groups are substituted.

17. The compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, wherein: R 2 It is a phenyl or a 5-10-membered heteroaryl group, each of which is independently selected from -CN, -C by 1, 2, 3 or 4 groups. 1-6 Alkyl, halogen, -C 1-6 Substitution of haloalkyl groups.

18. The compound according to any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, wherein: R 2 Selected independently by 1, 2, 3 or 4 from -CN, -C 1-6 Alkyl, halogen and -C 1-6 The alkyl group is substituted and selected from... 。 19. The compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, wherein: R 2 It is substituted by 1, 2, 3 or 4 independently selected groups chosen from -CN, methyl, F, Cl and -CF3, and selected from 。 20. The compound according to any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof, wherein: R 2 Selected independently by 1, 2, 3 or 4 from -CN, -C 1-6 Alkyl, halogen, -C 1-6 The alkyl group is substituted and selected from... 。 21. The compound according to any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, wherein Y is -C(R) 3 = ).

22. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 21, wherein Y is -N=.

23. The compound according to any one of claims 1 to 22, or a pharmaceutically acceptable salt thereof, wherein Y is -C(R 3 = and R 3 It is halogen, -CF3, methyl, ethyl, cyclopropyl.

24. The compound according to any one of claims 1 to 23, or a pharmaceutically acceptable salt thereof, wherein... R 4 It is either halogen or hydrogen.

25. The compound of claim 24 or a pharmaceutically acceptable salt thereof, wherein R 4 It is halogen.

26. The compound of claim 25 or a pharmaceutically acceptable salt thereof, wherein R 4 It is F.

27. The compound according to any one of claims 1 to 26, or a pharmaceutically acceptable salt thereof, wherein R 5 It is either fluorine or hydrogen.

28. The compound according to claim 27, wherein R 5 It is hydrogen.

29. The compound according to any one of claims 1 to 28, or a pharmaceutically acceptable salt thereof, wherein R 6 It is -C(O)-OR 8 , where R 8 It is hydrogen, methyl, CF3, ethyl, isopropyl, –CH2-(5-methyl-2-oxo-1,3-m-dioxacyclopenten-4-yl) or –CH2-C(O)N(Me)2.

30. The compound according to any one of claims 1 to 29, or a pharmaceutically acceptable salt thereof, wherein R 6 It is -C(O)-OR 8 , where R 8 It is hydrogen, methyl, ethyl, or isopropyl.

31. The compound according to any one of claims 1 to 30, or a pharmaceutically acceptable salt thereof, wherein R 8 It is hydrogen.

32. The compound according to any one of claims 1 to 31, or a pharmaceutically acceptable salt thereof, wherein R 7 -C is replaced by 0 or 1 pyridine 1-6 alkyl.

33. The compound according to any one of claims 1 to 31, or a pharmaceutically acceptable salt thereof, wherein R 7 It is selected from 0, 1, 2, 3 or 4 of -C 1-6 Alkyl, halogen or -OC 1-6 Phenyl groups substituted with alkyl groups.

34. The compound according to any one of claims 1 to 31, or a pharmaceutically acceptable salt thereof, wherein R 7 It is selected from 0, 1, 2 or 3 of -C 1-6 Alkyl, halogen or -OC 1-6 Phenyl groups substituted with alkyl groups.

35. The compound according to any one of claims 1 to 31, or a pharmaceutically acceptable salt thereof, wherein... R 7 It is selected independently from R by 0, 1, 2, 3 or 4. 9 5-10 membered heterocyclic groups substituted with the group, and Each R 9 Independently selected from halogens, =O, -C 1-6 Alkyl, -C(O)-R 10 -C 1-6 Halogenated groups, -SO2-C 1-6 Alkyl, -NH-C 1-4 Alkyl, -N(C) 1-4 Alkyl)2, -C 3-6 Cycloalkyl, phenyl, 4- to 7-membered heterocycles, -OR 11 Each R 9 Independently selected from R by 0, 1, or 2 independent selections. 17 Substitution of groups; R 10 Independently selected from -C 1-6 Alkyl, C 3-6 cycloalkyl and -C 1-6 Alkyl-C 3-6 cycloalkyl; R 11 It is -C 1-6 Alkyl, -C 1-6 Alkyl-N(-C) 1-6 Alkyl)2, -C 1-6 Halogenated alkyl groups or 4- to 7-membered heterocyclic rings; R 17 Selected from halogens, -OR 15 -C(O)N(C 1-4 Alkyl)2, -N(R 12 R 13 ) and 4 to 10-membered heterocyclic rings, when R 17 When it is a 4- to 10-membered heterocycle, it is selected by 0, 1, 2, or 4 independently chosen halogens and -C. 1-6 Alkyl or -C 1-6 Halogenated alkylation; R 12 and R 13 Independently selected from -C 1-6 Alkyl, -C 1-6 Halogenated alkyl groups and cyclopropyl groups; R 15 It is -C 1-6 Alkyl, -C 1-6 Halogenated alkyl groups or 4- to 7-membered heterocycles, and when R 15 When it is a 4- to 7-membered heterocyclic ring, it is affected by 0 or 1 -C 1-6 Alkyl substitution; And in each -N(C 1-6 alkyl)2 or -N(C 1-4 In alkyl)2, the two alkyl groups attached to N can be the same or different.

36. The compound of claim 35 or a pharmaceutically acceptable salt thereof, wherein... R 7 It is a 5-10 membered heterocyclic group substituted with 0, 1, 2, or 3 groups, and R 17 It is a 4- to 10-membered heterocyclic ring, in which R 17 It can be replaced by 0, 1, or 2 groups.

37. The compound according to any one of claims 1 to 36, or a pharmaceutically acceptable salt thereof, wherein R 9 It is selected independently by 0, 1, 2 or 3 from -C(O)-N(C) 1-4 Alkyl)2, -OR 15 -N(R) 12 R 13 -C groups substituted with 4 to 10-membered heterocyclic alkyl groups 1-6 Alkyl groups, wherein the heterocyclic alkyl groups are further selected independently of halogens or -C. 1-6 Alkyl group substitution; R 12 and R 13 Independently selected from -C 1-6 Alkyl, -C 1-6 Halogenated alkyl groups and cyclopropyl groups; R 15 It is -C 1-6 Alkyl, -C 1-6 Halogenated alkyl groups or 4- to 7-membered heterocycles, and when R 15 When it is a 4- to 7-membered heterocyclic ring, it is affected by 0 or 1 -C 1-6 Alkyl substitution, and wherein in each -N(C) 1-6 alkyl)2 or -N(C 1-4 In alkyl)2, the two alkyl groups attached to N can be the same or different.

38. The compound according to any one of claims 1 to 37, or a pharmaceutically acceptable salt thereof, wherein R 7 Choose from the following groups: Each of the following groups is substituted by 0, 1, or 2 independent substituents selected from the following: –F, –Cl, oxo, –Me, –isobutyl, –isopropyl, cyclobutyl, –CH2F, –CHF2, –CH2CF3, –CF3, –OMe, –OCF3, –O-azacyclobutane-3-yl, –N(Me)2, –C(O)Me, –C(O)cyclopropyl, 1-Me-azacyclobutane-3-yl, 3-F-azacyclobutane-1-yl, 3-N(Me)2-3-Me-azacyclobutane-1-yl, 3-N(Me)2-pyrrolidine-1-yl, 4-Me-piperidin-1-yl, 1-Me-piperidin-4-yl, 1-isopropyl-piperidin-4-yl, 4-N(Me )2-piperidin-1-yl, 4-cyclopropyl-piperazin-1-yl, 4-isopropyl-piperazin-1-yl, 4-Me-1,4-diazacycloheptane-1-yl, 4-isopropyl-1,4-diazacycloheptane-1-yl, 4-cyclopropyl-1,4-diazacycloheptane-1-yl, 5-methyl-2,4,6,7-tetrahydropyrazole[4,3-c]pyridin-2-yl, 2-methyl-2,7-diazaspiro[3.5]nonane-7-yl, 7-methyl-2,7-diazaspiro[3.5]nonane-2-yl, 1-methyl-1,7-diazaspiro[3.5]nonane-7-yl, 2-methyl-2,6-diazaspiro[3.3]heptane-6-yl, 3-(3-azabicyclo[ 3.1.1] Heptane-3-yl)-azacyclobutane-1-yl, 2-methyl-2,5-diazabicyclo[2.2.1] heptane-5-yl, –C(O)CH2cyclopropyl, –CH2-CH2-azacyclobutane-1-yl, –CH2-CH2-(3-F-azacyclobutane-1-yl), –CH2-CH2-(3-OMe-azacyclobutane-1-yl), –CH2-CH2-CH2-(3-OMe-azacyclobutane-1-yl), –CH2-CH2-C(Me)2-(3-OMe-azacyclobutane-1-yl), –CH2-CH2-(3-CF3-azacyclobutane-1-yl), –CH2-CH2-(3-OCF3-azacyclobutane-1-yl), –CH2-CH2-(3-CHF2-azacyclobutane-1-yl), –CH2-CH2-(3-OCHF2-azacyclobutane-1-yl), –CH2-CH2-(3,3-diF-azacyclobutane-1-yl), –CH2-CH2-(2,2-diMe-azacyclobutane-1-yl), –CH2-CH2-(3,3-diMe-azacyclobutane-1-yl), –CH2-CH2-(3-MeO-3-Me-azacyclobutane-1-yl), –CH2-CH2-(3-CHF2-3-Me-azacyclobutane-1-yl), –CH2-CH2-(3-F-3-Me-azacyclobutane-1-yl) ), –CH2-CH2-CH2-(3-F-3-Me-azacyclobutane-1-yl), –CH2-azacyclobutane-1-yl, –CH2-(3-F-azacyclobutane-1-yl), –CH2-(1-Me-azacyclobutane-3-yl), –CH2-azacyclobutane-3-yl, –CH2CH2-(3-F-pyrrolidine-1-yl), –CH2CH2-(3-CF3-pyrrolidine-1-yl), –CH2CH2-(3,3-diF-pyrrolidine-1-yl), Oxycyclobutane-3yl, –CH2CH2OCH3, –CH2CH2OH, –CH2C(O)N(Me)2, –CH2N(Me)2, –CH2CH2N(Me)2, –CH2CH2N(Me)CH(cyclopropyl)2, –CH2CH2N(Me)CH2(cyclopropyl), –CH2CH2CH2N(Me)2, –C(Me)2CH2N(Me)2, –CH2C(Me) )2N(Me)2、–CH2CH2C(Me)2N(Me)2、–CH2CH2N(Me)CH2CF3、–CH2CH2N(Me)CH(Me)2、–CH2CH2N(Me)C(Me)3、–CH2CH2N(Me)cyclopropyl、4-F-phenyl、–CH2CH2-(2-azaspiro[3.4]octane-2-yl、–CH2CH2CH2-(2-azaspiro[3.4]octane-2-yl)4] Octane-2-yl), –CH2CH2CH2CH2-(2-azaspiro[3.4]octan-2-yl), –CH2CH2-(6-azaspiro[3.4]octan-6-yl), –CH2CH2CH2-(6-azaspiro[3.4]octan-6-yl), –CH2CH2-(2,2-diF-6-azaspiro[3.4]octan-6-yl), –CH2CH2-(2-azaspiro[3.3]heptane-2- –CH2CH2-(6-MeO-2-azaspiro[3.3]heptane-2-yl), –CH2CH2-(2-azaspiro[4.5]decane-2-yl), –CH2CH2-(7-azaspiro[3.5]nonane-7-yl), –CH2CH2-(6-azaspiro[3.5]nonane-6-yl), –CH2CH2-(2-azaspiro[3.5]nonane-2-yl), –CH2CH2-(5-oxa-8-yl) -azaspiro[3.5]nonane-8-yl), –CH2CH2-(7-oxa-2-azaspiro[3.5]nonane-2-yl), –CH2CH2CH2CH2-(7-oxa-2-azaspiro[3.5]nonane-2-yl), –CH2CH2-(6,6-diF-2-azaspiro[3.3]heptane-2-yl), –CH2CH2-(8-azabicyclo[3.2.1]octane-8-yl), –CH2CH2- (8-oxa-3-azabicyclo[3.2.1]octan-3-yl), CH2CH2CH2-(2-azabicyclo[2.2.2]octan-2-yl), –CH2CH2CH2-(6-oxa-3-azabicyclo[3.1.1]heptane-3-yl), –CH2CH2-(7,7-diF-1,6-diMe-3-azabicyclo[4.1.0]heptane-3-yl), –CH2CH2-(3-azabicyclo[... 3.1.1] heptane-3-yl), – CH2CH2CH2-(2-azabicyclo[2.2.1] heptane-2-yl), CH2CH2CH2-(3-azabicyclo[ 3.1.1] heptane-3-yl), –CH2CH2CH2CH2-(3-azabicyclic[ 3.1.1] heptane-3-yl), –CH2CH2-(2-azabicyclo[ 2.1.1] Hexane-2-yl), –CH2CH2-(6,6-diMe-3-azabicyclo[3.1.0] Hexane-3-yl), –CH2CH2N(Me)cyclobutyl), –CH2CH2N(Me)(3,3-diF)cyclobutyl-1-yl), –CH2-CH2-(4-CF3-piperidin-1-yl), –CH2-CH2-(4,4-diMe-piperidin-1-yl), –CH2-CH2-(morpholin-4-yl), –CH2-CH2-CH2-(morpholin-4-yl) –CH2-CH2-CH2-(2,6-diMe-morpholin-4-yl), –CH2-CH2-CH2-(2,2,6,6-tetra-Me-morpholin-4-yl), –CH2-CH2-CH2-(2,2-diMe-morpholin-4-yl), –CH2-CH2-(2,6-diMe-morpholin-4-yl), –CH2-CH2-(1,4-oxazaza-4-yl), –CH2CH2-CH2-(1,4-oxazaza-4-yl) and –S(O)2Me.

39. The compound according to any one of claims 1 to 38, or a pharmaceutically acceptable salt thereof, wherein R 7 Choose from the following groups: Each of these groups is substituted by 0, 1, or 2 independent substituents selected from the following: –F, –Cl, oxo, –Me, isobutyl, isopropyl, cyclobutyl, –CH2F, –CHF2, –CH2CF3, –OMe, –O-CF3, –O-azacyclobutane-3-yl, –N(Me)2, –C(O)Me, –C(O)cyclopropyl, 1-Me-azacyclobutane-3-yl, 3-F-azacyclobutane-1-yl, –C(O)CH2cyclopropyl, –CH2-CH2-azacyclobutane-1-yl, –CH2-CH2-(3-F-azacyclobutane-1-yl), –CH2-CH2-(3-CF3-azacyclobutane-1-yl). –CH2-CH2-(3,3-diF-azacyclobutane-1-yl), –CH2-CH2-(3,3-diMe-azacyclobutane-1-yl), –CH2-azacyclobutane-1-yl, –CH2-(3-F-azacyclobutane-1-yl), –CH2-(1-Me-azacyclobutane-3-yl), –CH2-azacyclobutane-3-yl, –CH2CH2-(3-F-pyrrolidine-1-yl), –CH2CH2OCH3, –CH2C(O)N(Me)2, –CH2CH2N(Me)2, –CH2CH2CH2N(Me)2, –CH2CH2N(Me)CH2CF3, –CH2CH2N(Me)cyclopropyl, 4-F-phenyl and –S(O)2Me.

40. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 39, wherein each R 2 Independently select from the following groups: -Br, -CF3, 。 41. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 40, wherein each R 2 Choose independently from the following groups: 。 42. The compound according to any one of claims 1 to 41, or a pharmaceutically acceptable salt thereof, wherein each R 2 Independently select from the following groups: -Br, -CF3, 。 43. The compound according to any one of claims 1 to 42, or a pharmaceutically acceptable salt thereof, wherein each R 2 Choose independently from the following groups: 。 44. The compound according to any one of claims 1 to 43, or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from: -C(O)-CH3, 。 45. The compound according to any one of claims 1 to 44, or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from: 。 46. ​​The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from... 。 47. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from... 。 48. A pharmaceutical composition comprising a pharmaceutically effective amount of the compound of any one of claims 1 to 47 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

49. Use of the compound of any one of claims 1 to 47 or a pharmaceutically acceptable salt thereof in the preparation of a pharmaceutical preparation.

50. The compound of any one of claims 1 to 47 or a pharmaceutically acceptable salt thereof, used as a pharmaceutical agent.

51. A method for inhibiting the interaction between α4β7 integrin and MAdCAM-1 protein in a subject, the method comprising administering to a subject in need a pharmaceutically effective amount of the compound of any one of claims 1 to 47 or a pharmaceutically acceptable salt thereof.

52. A method for treating inflammatory bowel disease in a person in need, the method comprising administering to the person a pharmaceutically effective amount of the compound of any one of claims 1 to 47 or a pharmaceutically acceptable salt thereof.

53. A compound selected from any one of claims 1 to 47 or a pharmaceutically acceptable salt thereof, used for the treatment of inflammatory bowel disease.

54. The method according to claim 52 or 53, wherein the inflammatory bowel disease is ulcerative colitis.

55. The method according to claim 52 or 53, wherein the inflammatory bowel disease is Crohn's disease.

56. A method for treating ulcerative colitis in humans, the method comprising administering to a person in need a pharmaceutically effective amount of any one of claims 1 to 47 or a pharmaceutically acceptable salt thereof.

57. The compound of any one of claims 1 to 47 or a pharmaceutically acceptable salt thereof, for the treatment of ulcerative colitis.

58. The method of claim 56, wherein the ulcerative colitis is ulcerative colitis.

59. The method of claim 56, wherein the ulcerative colitis is Crohn's disease.

60. A medicine box comprising: a) One or more compositions, each composition comprising a pharmaceutically effective amount of the compound of any one of claims 1 to 47 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient; and b) Instructions for use of one or more of the compositions in a person in need.

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