Novel compounds as α4β7 inhibitors

Abstract

Novel compounds acting as inhibitors of α4β7 integrins are disclosed. Pharmaceutical compositions and methods for use as inhibitors of α4β7 integrins are disclosed. In particular, methods for using α4β7 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. Furthermore, 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 numerous cellular processes, including cell-cell and cell-extracellular matrix interactions. When integrins bind to extracellular ligands, they mediate intracellular signaling, leading to the capture, adhesion, and entry of lymphocytes into tissues. In fact, integrins are heterodimeric cell surface glycoprotein receptors composed of non-covalently bound α (alpha) and β (beta) subunits.

[0003] Using molecular biology and protein chemistry, 24 human integrins have been identified, and these integrins are known to contribute to a diverse range of human diseases, including platelet disorders, atherosclerosis, cancer, osteoporosis, fibrosis, diabetic neuropathy of the kidneys, macular degeneration, and autoimmune and chronic inflammatory diseases.

[0004] α4, α4β1, and α4β7 integrins play essential roles in lymphocyte migration in most leukocytes, including B and T lymphocytes. Specifically, α4β1 and α4β7 integrins are involved in the adhesion of α4β1 and α4β7 integrins to VCAM-1 (vascular cell adhesion molecule 1) and MAdCAM-1 (mucosal addressing 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 tissue. In humans, MAdCAM-1 expression is associated with lymphocyte tissues of the gastrointestinal tract and associated lymphocyte tissues. Lymphocyte integrin α4β7 has been shown to mediate memory T cell adhesion to MAdCAM-1. During inflammation, MAdCAM-1 is upregulated in the intestine and is thought to play a crucial role in inflammatory bowel disease (IBD), a group of diseases including ulcerative colitis (UC) and Crohn's disease (CD). Inhibition of the interaction between integrins and their individual ligands has been proposed as an effective method for treating various autoimmune and inflammatory diseases, and blocking the interaction of AdCAM-1 has been shown to have therapeutic benefits in inflammatory bowel diseases such as ulcerative colitis and Crohn's disease (Hao Li et al., α4β7 integrin inhibitors: a patent review (2018), Vol.28, No.12, pp. 903-917).

[0005] Currently, injectable monoclonal antibodies are available as integrin inhibitors; see, for example, natalizumab (Tysabri®), approved for the treatment of highly active relapsing-remitting multiple sclerosis, or vedolizumab (Entyvio®), approved for both Crohn's disease and ulcerative colitis. However, no orally administered, bioavailable integrin inhibitors have yet been approved. [Prior art documents] [Non-patent literature]

[0006]

Non-Patent Document 1

Summary of the Invention

Problems to be Solved by the Invention

[0007] Therefore, there is a need to provide integrin inhibitors, preferably α4β7-selective inhibitors, useful for the prevention and / or treatment of diseases characterized by upregulation of MAdCAM-1 such as inflammatory bowel disease.

Means for Solving the Problems

[0008] The present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof

Chemical Formula

Modes for Carrying Out the Invention

[0009] The present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof

Chemical Formula

[0010] The present invention also relates to compounds of formula (I) or pharmaceutically acceptable salts thereof. [ka] (In the formula, R y These are -CH(CH3)2, cyclopropyl, or cyclobutyl; R x is hydrogen or methyl; R 1 is -C(O)-R 7 and; Here, R 7 -C is substituted with 0 or 1 pyridine, phenyl, and cyclopropyl 1~6 Is it alkyl? or R 7 These are phenyl or 5-10 member heterocyclines, and these are respectively R 9 It is independently replaced by 0, 1, 2, or 3 instances of; R 9 These are halogen, =O, and -C respectively. 1~6 Alkyl, -C(O)-R 10 , -C 1~6 Haloalkyl, -SO2-C 1~6 Alkyl, -NH-C 1~4 Alkyl, -N(C 1~4 Alkyl)2,-C 3~6 Cycloalkyl, -OR 11 , independently selected from phenyl and 4-10 membered heterocycles; R 9 These are R 17 It is independently replaced by 0, 1, 2, or 3, which are independently selected from; R 17 is halogen, -C 1~6 Alkyl, -OR 15 -C(O)-N(C 1~4 Alkyl)2,-N(R 12 R 13 ), selected from 4- to 10-membered complex rings, R 17If it is a heterocycle, then this is a halogen, -C 1~6 Alkyl, =O, -C(O)-R 14 , -C 1~6 Haloalkyl, -SO2-C 1~6 Alkyl, -NH-C 1~4 Alkyl, -N(C 1~4 Alkyl)2,-C 3~6 Cycloalkyl, -OR 18 It is further replaced by 0, one, or two elements selected independently of it; R 10 is -C 1~6 Alkyl, -C 1~6 Alkyl-C 3~6 Cycloalkyl and C 3~6 Selected independently from cycloalkyl groups; R 11 is -C 1~6 Alkyl, -C 1~6 Haloalkyl, 4-10 membered heterocycle or -C 1~6 Alkyl-N(C 1~6 Alkyl)2, where the 4-10 membered heterocycle has 0 or 1 -C 1~6 Substituted with alkyl; R 12 and R 13 is -C 1~6 Alkyl, -C 1~6 Independently selected from haloalkyl and cyclopropyl; R 14 is -C 1~6 Alkyl and C 3~6 Selected independently from cycloalkyl groups; R 15 is -C 1~6 Alkyl, -C 1~6 Haloalkyl, 4-10 membered heterocycle or -C 1~6 Alkyl-N(C 1~6 It is alkyl)2, and R 15 If it is a 4- to 7-member complex ring, then it is 0 or 1 -C 1~6 Substituted with alkyl; R 18 is -C 1~6 Alkyl or -C 1~6It is a haloalkyl; Here, -N(C 1~6 Alkyl)2 or -N(C 1~4 In each of alkyl)2, the two alkyl groups bonded to N may be the same or different; R 2 These are selected from the group consisting of Br, phenyl, naphthyl, and 5-10 membered heteroaryls, which are respectively -CN, -C 1~6 Alkyl, halogen, -C 1~6 Haloalkyl, -OC 1~6 Alkyl, phenyl, 5-6 member heteroaryl, -OC 3~6 It is independently substituted with 0, 1, 2, or 3 groups independently selected from cycloalkyl, -O-phenyl, and -O-(5-6 membered heterocycloalkyl); Y is -N= or -C(R 3 )= and; R 3 is halogen, -C 1~6 Haloalkyl, -C 1~4 Alkyl or -C 3~6 It is a cycloalkyl; R 4 is a halogen or hydrogen; R 5 is a halogen or hydrogen; R 6 is -C(O)-OR 8 And, Here, R 8 is hydrogen, -C 1~4 Alkyl or -C 1~4 Alkyl-OC(O)-R 16 And, R 16 is -C 1~6 Alkyl, 3-6 cycloalkyl, 4-6 member partially saturated heterocyclyl, where partially saturated heterocyclyl is =O or -C 1~4 (Further substitution with one or two groups independently selected from the alkyl group) Regarding.

[0011] In one embodiment, the present invention relates to a compound of formula (Ia) or a pharmaceutically acceptable salt thereof. [ka] (In the formula, R 1 ~R 6 , R x , R y (and Y are as defined herein) Regarding.

[0012] In certain embodiments of the compound of the present invention or a pharmaceutically acceptable salt thereof, R x It is hydrogen.

[0013] In other embodiments of the compound of the present invention or a pharmaceutically acceptable salt thereof, R x It is methyl.

[0014] In certain embodiments of the compound of the present invention or a pharmaceutically acceptable salt thereof, R y These are -CH(CH3)2, -CF3, cyclopropyl, or cyclobutyl.

[0015] In certain embodiments of the compound of the present invention or a pharmaceutically acceptable salt thereof, R y It is -CH(CH3)2, cyclopropyl, or cyclobutyl.

[0016] In certain embodiments of the compound of the present invention or a pharmaceutically acceptable salt thereof, R y It is -CH(CH3)2.

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

[0018] In further embodiments of the compound of the present invention or a pharmaceutically acceptable salt thereof, R y It is cyclobutyl.

[0019] In some embodiments of the compounds of the present invention or pharmaceutically acceptable salts thereof, R 12 and R 13 is -C 1~6 Alkyl, -C 1~6 Haloalkyl, C 1~6 Alkyl-cyclopropyl, C 1~6 Alkyl-(cyclopropyl)2, cyclobutyl and cyclopropyl are independently selected, where C 1~6 Alkyl-cyclopropyl, C 1~6 Alkyl-(cyclopropyl)2, cyclobutyl, and cyclopropyl are substituted with 0, 1, 2, or 3 fluorine atoms.

[0020] In some embodiments of the compounds of the present invention or pharmaceutically acceptable salts thereof, R 17 is halogen, -C 1~6 Alkyl, -OR 15 -C(O)-N(C 1~4 Alkyl)2,-N(R 12 R 13 ) and selected from 4- to 10-membered heterorings, R 17 If it is a heterocycle, then this is a halogen, -C 1~6 Alkyl, =O, -C(O)-R 14 , -C 1~6 Haloalkyl, -SO2-C 1~6 Alkyl, -NH-C 1~4 Alkyl, -N(C 1~4 Alkyl)2,-C 3~6 Cycloalkyl and -OR 18 It is further replaced by 0, one, or two elements, selected independently of it.

[0021] In some embodiments of the compounds of the present invention or pharmaceutically acceptable salts thereof, R 12 and R 13 is -C 1~6 Alkyl, -C 1~6 It is independently selected from haloalkyl and cyclopropyl.

[0022] In some embodiments of the compounds of the present invention or pharmaceutically acceptable salts thereof, R15 is -C 1~6 Alkyl, -C 1~6 Haloalkyl, 4-10 membered heterocycle or -C 1~6 Alkyl-N(C 1~6 It is alkyl)2, and R 15 If it is a 4- to 10-member complex ring, then it is 0 or 1 -C 1~6 It is substituted with alkyl.

[0023] In some embodiments of the compounds of the present invention or pharmaceutically acceptable salts thereof, R 8 is hydrogen, -C 1~4 Alkyl or -C 1~4 Alkyl-OC(O)-R 16 That is the case.

[0024] In some embodiments of the compounds of the present invention or pharmaceutically acceptable salts thereof, R 8 is hydrogen, -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 is -C 1~6 The elements are independently selected from alkyl groups, 3-6 cycloalkyl groups, and 4-6 member partially saturated heterocycles, where the partially saturated heterocycle is either =O or -C. 1~4 It is further substituted with one or two groups independently selected from the alkyl group.

[0025] In some embodiments of the compounds of the present invention or pharmaceutically acceptable salts thereof, R 2 It is independently substituted by 0, 1, 2, 3, or 4 groups.

[0026] In further embodiments of the compound of the present invention or a pharmaceutically acceptable salt thereof, R 2 It is independently substituted by 0, 1, 2, or 3 groups.

[0027] In some embodiments of the compounds of the present invention or pharmaceutically acceptable salts thereof, R 2 These are phenyl or 5-10 member heteroaryl groups, where these groups are -CN and -C, respectively. 1~6 Alkyl, halogen, -C 1~6 It is substituted with one, two, three, or four groups independently selected from the haloalkyl group.

[0028] In further embodiments of the compound of the present invention or a pharmaceutically acceptable salt thereof, R 2 These are phenyl or 5-10 member heteroaryl groups, where these groups are -CN and -C, respectively. 1~6 Alkyl, halogen, -C 1~6 It is substituted with one, two, or three groups independently selected from the haloalkyl group.

[0029] In some embodiments of the compounds of the present invention or pharmaceutically acceptable salts thereof, R 2 -CN, -C 1~6 Alkyl, halogen, and -C 1~6 Substituted by one, two, three, or four groups independently selected from the haloalkyl group, [ka] Selected from.

[0030] In further embodiments of the compound of the present invention or a pharmaceutically acceptable salt thereof, R 2 -CN, -C 1~6 Alkyl, halogen, -C 1~6 Substituted by one, two, three, or four groups independently selected from the haloalkyl group, [ka] Selected from.

[0031] In further embodiments of the compound of the present invention or a pharmaceutically acceptable salt thereof, R 2 -CN, -C 1~6Alkyl, halogen, -C 1~6 Substituted by one, two, or three groups independently selected from the haloalkyl group, [ka] Selected from.

[0032] In further embodiments of the compound of the present invention or a pharmaceutically acceptable salt thereof, R 2 It is substituted with one, two, three, or four groups independently selected from -CN, methyl, F, Cl, and CF3. [ka] Selected from.

[0033] In further embodiments of the compound of the present invention or a pharmaceutically acceptable salt thereof, R 2 It is substituted with one, two, or three groups independently selected from methyl, fluorine, or -CF3. [ka] Selected from.

[0034] In some embodiments of the compound or pharmaceutically acceptable salt thereof of the present invention, Y is -C(R 3 ) = .

[0035] In some embodiments of the compounds of the present invention or pharmaceutically acceptable salts thereof, R 3 These are halogen, -CF3, methyl, ethyl, and cyclopropyl.

[0036] In some embodiments of the compounds of the present invention or pharmaceutically acceptable salts thereof, Y is -N=.

[0037] In some embodiments of the compound or pharmaceutically acceptable salt thereof of the present invention, Y is -C(R 3 )= and R 3These are halogen, -CF3, methyl, ethyl, and cyclopropyl.

[0038] In some embodiments of the compounds of the present invention or pharmaceutically acceptable salts thereof, R 4 These are halogens or hydrogen.

[0039] In some embodiments of the compounds of the present invention or pharmaceutically acceptable salts thereof, R 4 It is a halogen.

[0040] In some embodiments of the compounds of the present invention or pharmaceutically acceptable salts thereof, R 4 It is fluorine.

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

[0042] In some embodiments of the compounds of the present invention or pharmaceutically acceptable salts thereof, R 5 It is hydrogen.

[0043] In some embodiments of the compounds of the present invention or pharmaceutically acceptable salts thereof, R 6 is -C(O)-OR 8 And here, R 8 These are hydrogen, methyl, CF3, ethyl, isopropyl, -CH2-(5-methyl-2-oxo-1,3-dioxol-4-yl) or -CH2-C(O)N(Me)2.

[0044] In further embodiments of the compound of the present invention or a pharmaceutically acceptable salt thereof, R 6 is -C(O)-OR 8 And here, R 8 This is hydrogen, methyl, ethyl or isopropyl, -O-CH2-OC(O)-R 16 Or -OC(CH3)-OC(O)-R 16 And here, R 16These are methyl, ethyl, isopropyl, isobutyl, cyclobutyl, cyclopentyl, cyclohexane, neopentyl, or (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl.

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

[0046] In some embodiments of the compounds of the present invention or pharmaceutically acceptable salts thereof, R 6 is -C(O)-OR 8 And R 8 It is hydrogen.

[0047] In some embodiments of the compounds of the present invention or pharmaceutically acceptable salts thereof, R 7 -C is substituted with 0 or 1 pyridine. 1~6 Alkyl or R 7 is -C 1~6 Alkyl, halogen, or -OC 1~6 Phenyl substituted with 0, 1, 2, or 3 groups selected from alkyl groups, or R 7 R 9 A 5-10 member heterocycline substituted with 0, 1, 2, or 3 groups independently selected from R, 9 These are halogen, =O, and -C respectively. 1~6 Alkyl, -C(O)-R 10 , -C 1~6 Haloalkyl, -SO2-C 1~6 Alkyl, -NH-C 1~4 Alkyl, -N(C 1~4 Alkyl)2,-C 3~6 Cycloalkyl, phenyl, 4-7 membered heterocycle, -OR 11 Selected independently from; R 9 These are R 17It is independently replaced by 0, one or two, which are independently selected from; R 10 is -C 1~6 Alkyl, C 3~6 Cycloalkyl and -C 1~6 Alkyl-C 3~6 Selected independently from cycloalkyl groups; R 11 is -C 1~6 Alkyl, -C 1~6 Alkyl-N(-C) 1~6 Alkyl)2,-C 1~6 It is a haloalkyl or a 4- to 7-membered heterocycle; R 17 is halogen, -OR 15 , -C(O)N(C 1~4 Alkyl)2,-N(R 12 R 13 ) and selected from 4- to 10-membered heterorings, R 17 However, if it is a 4- to 10-membered heterocycle, this is a halogen, -C 1~6 Alkyl or -C 1~6 Substituted by 0, 1, or 2 atoms, independently selected from the haloalkyl group; R 12 and R 13 is -C 1~6 Alkyl, -C 1~6 Independently selected from haloalkyl and cyclopropyl; R 15 is -C 1~6 Alkyl, -C 1~6 It is a haloalkyl or a 4- to 7-membered heterocycle, R 15 If it is a 4- to 7-member complex ring, then it is 0 or 1 -C 1~6 Substituted with alkyl; Here, -N(C 1~6 Alkyl)2 or -N(C 1~4 In each of alkyl)2, the two alkyl groups bonded to N may be the same or different.

[0048] In some embodiments of the compounds of the present invention or pharmaceutically acceptable salts thereof, R 7-C is substituted with 0 or 1 pyridine. 1~6 It is alkyl.

[0049] In some embodiments of the compounds of the present invention or pharmaceutically acceptable salts thereof, R 7 is -C 1~6 Alkyl, halogen, or -OC 1~6 This is a phenyl molecule substituted with 0, 1, 2, 3, or 4 alkyl groups.

[0050] In some embodiments of the compounds of the present invention or pharmaceutically acceptable salts thereof, R 7 is -C 1~6 Alkyl, halogen, or -OC 1~6 This is a phenyl molecule substituted with 0, 1, 2, or 3 alkyl groups.

[0051] In some embodiments of the compounds of the present invention or pharmaceutically acceptable salts thereof, R 7 R 9 A 5-10 member heterocycline substituted with 0, 1, 2, 3, or 4 groups independently selected from R, 9 These are halogen, =O, and -C respectively. 1~6 Alkyl, -C(O)-R 10 , -C 1~6 Haloalkyl, -SO2-C 1~6 Alkyl, -NH-C 1~4 Alkyl, -N(C 1~4 Alkyl)2,-C 3~6 Cycloalkyl, phenyl, 4-7 membered heterocycle, -OR 11 Selected independently of; R 9 These are R 17 It is independently replaced by 0, one or two, which are independently selected from; R 10 is -C 1~6 Alkyl, C 3~6 Cycloalkyl and -C 1~6 Alkyl-C 3~6 Selected independently from cycloalkyl groups; R 11 is -C 1~6 Alkyl, -C 1~6 Alkyl-N(-C) 1~6 Alkyl)2,-C 1~6 It is a haloalkyl or a 4- to 7-membered heterocycle; R 17 is halogen, -OR 15 , -C(O)N(C 1~4 Alkyl)2,-N(R 12 R 13 ) and selected from 4- to 10-membered heterorings, R 17 However, if it is a 4- to 10-membered heterocycle, this is a halogen, -C 1~6 Alkyl or -C 1~6 Substituted by 0, 1, 2, or 4 elements, independently selected from the haloalkyl group; R 12 and R 13 is -C 1~6 Alkyl, -C 1~6 Independently selected from haloalkyl and cyclopropyl; R 15 is -C 1~6 Alkyl, -C 1~6 It is a haloalkyl or a 4- to 7-membered heterocycle, R 15 If it is a 4- to 7-member complex ring, then it is 0 or 1 -C 1~6 Substituted with alkyl; Here, -N(C 1~6 Alkyl)2 or -N(C 1~4 In each of alkyl)2, the two alkyl groups bonded to N may be the same or different.

[0052] In some embodiments of the compounds of the present invention or pharmaceutically acceptable salts thereof, R 7 R is a 5-10 member heterocycline substituted with 0, 1, 2, or 3 groups, 17 is a complex ring with 4 to 10 members, where R 17 It is replaced by 0, 1, or 2 groups.

[0053] In some embodiments of the compounds of the present invention or pharmaceutically acceptable salts thereof, R 7 R 9 A 5-10 member heterocycline substituted with 0, 1, 2, or 3 groups independently selected from R, 9 These are halogen, =O, and -C respectively. 1~6 Alkyl, -C(O)-R 10 , -C 1~6 Haloalkyl, -SO2-C 1~6 Alkyl, -NH-C 1~4 Alkyl, -N(C 1~4 Alkyl)2,-C 3~6 Cycloalkyl, phenyl, 4-7 membered heterocycle, -OR 11 Selected independently from, R 9 These are 0, one or two R values, respectively. 17 It is independently replaced by; R 17 is halogen, -OR 15 , -C(O)N(C 1~4 Alkyl)2,-N(R 12 R 13 ) and selected from 4- to 10-membered heterorings, R 17 However, if it is a 4- to 10-membered heterocycle, this is 0, 1 or 2 halogens, -C 1~6 Alkyl or -C 1~6 Substituted with a haloalkyl group; R 10 is -C 1~6 Alkyl, C 3~6 Cycloalkyl and -C 1~6 Alkyl-C 3~6 Selected independently from cycloalkyl groups; R 11 is -C 1~6 It is alkyl, R 11 ga-C 1~6 If it is alkyl, then 0 or 1 -N(-C) 1~6 Substituted with alkyl)2, or R 11 is -C 1~6 It is a haloalkyl or a 4- to 7-membered heterocycle; R 12 and R 13 is -C1~6 Alkyl, -C 1~6 Independently selected from haloalkyl and cyclopropyl; R 15 is -C 1~6 Alkyl, -C 1~6 It is a haloalkyl or a 4- to 7-membered heterocycle, R 15 If it is a 4- to 7-member complex ring, then it is 0 or 1 -C 1~6 It is substituted with alkyl.

[0054] In some embodiments of the compounds of the present invention or pharmaceutically acceptable salts thereof, R 9 is -C(O)-N(C 1~4 Alkyl)2, -OR 15 , -N(R 12 R 13 ), substituted with 0, 1, 2, or 3 groups independently selected from 4- to 10-membered heterocycloalkyl groups -C 1~6 Alkyl and heterocycloalkyl are halogens or -C 1~6 Further substituted with 0, 1, or 2 groups independently selected from the alkyl group; R 12 and R 13 is -C 1~6 Alkyl, -C 1~6 Independently selected from haloalkyl and cyclopropyl; R 15 is -C 1~6 Alkyl, -C 1~6 It is a haloalkyl or a 4- to 7-membered heterocycle, R 15 If it is a 4- to 7-member complex ring, then it is 0 or 1 -C 1~6 Substituted with alkyl, Here, -N(C 1~6 Alkyl)2 or -N(C 1~4 In each of alkyl)2, the two alkyl groups bonded to N may be the same or different.

[0055] In some embodiments of the compounds of the present invention or pharmaceutically acceptable salts thereof, R 9 is -C(O)-N(C 1~4Alkyl)2,-N(R 12 R 13 ), -OR 15 -C substituted with 0, 1, 2, or 3 groups independently selected from 4- to 7-membered heterocycloalkyl groups. 1~6 Alkyl and heterocycloalkyl are halogens or -C 1~6 Further substituted with 0, 1, or 2 groups independently selected from the alkyl group; R 12 and R 13 is -C 1~6 Alkyl, -C 1~6 Independently selected from haloalkyl and cyclopropyl; R 15 is -C 1~6 Alkyl, -C 1~6 It is a haloalkyl or a 4- to 7-membered heterocycle, R 15 If it is a 4- to 7-member complex ring, then it is 0 or 1 -C 1~6 Substituted with alkyl; Here, -N(C 1~6 Alkyl)2 or -N(C 1~4 In each of alkyl)2, the two alkyl groups bonded to N may be the same or different.

[0056] In some embodiments of the compounds of the present invention or pharmaceutically acceptable salts thereof, R 9 is -C(O)-N(C 1~4 Alkyl)2, -OR 15 , -N(R 12 R 13 ), substituted with 0, 1, 2, or 3 groups independently selected from 4- to 10-membered heterocycloalkyl groups -C 1~6 Alkyl and heterocycloalkyl are halogens or -C 1~6 Further substituted with 0, 1, or 2 groups independently selected from the alkyl group; R 12 and R 13 is -C 1~6 Alkyl, -C 1~6 Independently selected from haloalkyl and cyclopropyl; R 15is -C 1~6 Alkyl, -C 1~6 It is a haloalkyl or a 4- to 7-membered heterocycle, R 15 If it is a 4- to 7-member complex ring, then it is 0 or 1 -C 1~6 It is substituted with alkyl, where -N(C 1~6 Alkyl)2 or -N(C 1~4 In each of alkyl)2, the two alkyl groups bonded to N may be the same or different.

[0057] In some embodiments of the compounds of the present invention or pharmaceutically acceptable salts thereof, R 7 is substituted or unsubstituted [ka] It is selected from the group consisting of the following.

[0058] In some embodiments of the compounds of the present invention or pharmaceutically acceptable salts thereof, R 7 is substituted or unsubstituted [ka] It is selected from the group consisting of the following.

[0059] In some embodiments of the compounds of the present invention or pharmaceutically acceptable salts thereof, R 7 teeth, [ka] Selected from the group consisting of -F, -Cl, oxo, -Me, isobutyl, isopropyl, cyclobutyl, -CH2F, -CHF2, -CH2CF3, -CF3, -OMe, -O-CF3, -O-azetidine-3-yl, -N(Me)2, -C(O)Me, -C(O)cyclopropyl, 1-Me-azetidine-3-yl, 3-F-azetidine-1-yl, 3-N(Me)2-3-Me-azetidine-1-yl, 3-N(Me)2-pyrrolidine-1-yl, 4-Me-piperidine-1-yl, 1-Me-piperidine-4-yl, 1-isopropyl-piperidine-4-yl, 4-N(Me)2-piperidine-1-yl, 4-cyclopropyl-piperazine-1-yl, 4-isopropyl Pyr-piperazin-1-yl, 4-Me-1,4-diazepan-1-yl, 4-isopropyl-1,4-diazepan-1-yl, 4-cyclopropyl-1,4-diazepan-1-yl, 5-methyl-2,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-2-yl, 2-methyl-2,7-diazaspiro[3.5]nonan-7-yl, 7-methyl-2,7-diazaspiro[3.5]nonan-2-yl, 1-methyl-1,7-diazaspiro[3.5]nonan-7-yl, 2-methyl-2,6-diazaspiro[3.3]heptan-6-yl, 3-(3-azabicyclo[3.1.1]heptan-3-yl)azetidine-1-yl, 2-methyl-2,5-diazabicyclo[2.2.1]Heptan-5-yl,-C(O)CH2-cyclopropyl,-CH2-CH2-azeditin-1-yl,-CH2-CH2-(3-F-azeditin-1-yl),-CH2-CH2-(3-OMe-azeditin-1-yl),-CH2-CH2-CH2-(3-OMe-azeditin-1-yl),-CH2-CH2-C(Me)2-(3-OMe-azeditin-1-yl),-CH2-CH2-(3-CF3-azeditin-1-yl),-CH2-CH2-(3-OCF3-azeditin-1-yl),-CH2- CH2-(3-CHF2-azeditin-1-yl), -CH2-CH2-(3-OCHF2-azeditin-1-yl), -CH2-CH2-(3,3-diF-azeditin-1-yl), -CH2-CH2-(2,2-diMe-azeditin-1-yl), -CH2-CH2-(3,3-diMe-azeditin-1-yl), -CH2-CH2-(3-MeO-3-Me-azeditin-1-yl), -CH2-CH2-(3-CHF2-3-Me-azeditin-1-yl), -CH2-CH2-(3F-3-Me-azeditin-1-yl), -CH 2-CH2-CH2-(3-F-3-Me-azeditin-1-yl), -CH2-azeditin-1-yl, -CH2-(3-F-azeditin-1-yl), -CH2-(1-Me-azetidine-3-yl), -CH2-azetidine-3-yl, -CH2CH2-(3-F-pyrrolidine-1-yl), -CH2CH2-(3-CF3-pyrrolidine-1-yl), -CH2CH2-(3,3-di-F-pyrrolidine-1-yl), oxetane-3-yl, -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), -CH2CH2-(6-azaspiro[3.4]octane-6-yl), -CH2CH2CH2-(6-azaspiro[3.4]octane-6-yl), -CH2CH2-(2,2-diF-6-azaspiro[3.4]octane-6-yl), -CH2CH2-(2-azaspiro[3.3]heptane-2-yl), -CH2CH2-(6-MeO-2-azaspiro[3.4]octane-6-yl), Spiro[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-azaspiro[3.5]nonane-8-yl), -CH2CH2-(7-oxa-2-azaspiro[3.5]nonane-2-yl), -CH2CH2CH2CH2-(7-oxa-2-a Zaspiro[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[3.1.0)Hexane-3-yl), -CH2CH2N(Me)cyclobutyl), -CH2CH2N(Me)(3,3-diF)cyclobutyl-1-yl), -CH2-CH2-(4-CF3-piperidine-1-yl), -CH2-CH2-(4,4-diMe-piperidine-1-yl), -CH2-CH2-(morpholine-4-yl), -CH2-CH2-CH2-(morpholine-4-yl), -CH2-CH2-CH2-(2,6-diMe-morpholine-4-yl), -CH2-CH2-CH2-(2,2,6,6-tetraMe-morpholine-4-yl), -CH2-CH2-CH2-(2,2-diMe-morpholine-4-yl), -CH2-CH2-(2,6-diMe-morpholine-4-yl), -CH2-CH2-(1,4-oxazepine-4-yl), -CH2CH2-CH2-(1,4-oxazepine-4-yl), and -S(O)2Me are substituted with 0, 1, or 2 substituents independently selected from these groups.

[0060] In some embodiments of the compounds of the present invention or pharmaceutically acceptable salts thereof, R 7 teeth, [ka] Selected from the group consisting of -F, -Cl, oxo, -Me, isobutyl, isopropyl, cyclobutyl, -CH2F, -CHF2, -CH2CF3, -OMe, -O-CF3, -O-azetidine-3-yl, -N(Me)2, -C(O)Me, -C(O)cyclopropyl, 1-Me-azetidine-3-yl, 3-F-azetidine-1-yl, --C(O)CH2-cyclopropyl, -CH2-CH2-azeditin-1-yl, -CH2-CH2-(3-F-azeditin-1-yl), -CH2-CH2-(3-CF3-azeditin-1-yl), -CH2-CH2-(3,3-diF-azeditin-1-yl), - Substituted with 0, 1, or 2 substituents independently selected from CH2-CH2-(3,3-diMe-azeditin-1-yl),-CH2-azeditin-1-yl,-CH2-(3-F-azeditin-1-yl),-CH2-(1-Me-azetidine-3-yl),-CH2-azetidine-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 teeth, [ka] The following are selected from the group consisting of -F, -Cl, oxo, -Me, isobutyl, isopropyl, cyclobutyl, -CH2F, -CHF2, -CH2CF3, -OMe, -OCF3, -O-azetidine-3-yl, -N(Me)2, -C(O)Me, -C(O)cyclopropyl, 1-Me-azetidine-3-yl, 3-F-azetidine-1-yl, --C(O)CH2-cyclopropyl, -CH2-CH2-azeditin-1-yl, -CH2-CH2-(3-F-azeditin-1-yl), -CH2-CH2-(3-CF3-azeditin-1-yl), -CH2-CH2-(3,3-diF-azeditin-1-yl), -C Substituted with 0, 1, or 2 substituents independently selected from H2-CH2-(3,3-diMe-azeditin-1-yl),-CH2-azeditin-1-yl,-CH2-(3-F-azeditin-1-yl),-CH2-(1-Me-azetidine-3-yl),-CH2-azetidine-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.

[0062] In some embodiments of the compounds of the present invention or pharmaceutically acceptable salts thereof, R 7 teeth, [ka] Selected from the group consisting of -F, -Cl, oxo, -Me, isobutyl, isopropyl, cyclobutyl, -CH2F, -CHF2, -CH2CF3, -CF3, -OMe, -O-CF3, -O-azetidine-3-yl, -N(Me)2, -C(O)Me, -C(O)cyclopropyl, 1-Me-azetidine-3-yl, 3-F-azetidine-1-yl, 3-N(Me)2-3-Me-azetidine-1-yl, 3-N(Me)2-pyrrolidine-1-yl, 4-Me-piperidine-1-yl, 1-Me-piperidine-4-yl, 1-isopropyl-piperidine-4-yl, 4-N(Me)2-piperidine-1-yl, 4-cyclopropyl-piperazine-1-yl, 4-isopropyl Pyr-piperazin-1-yl, 4-Me-1,4-diazepan-1-yl, 4-isopropyl-1,4-diazepan-1-yl, 4-cyclopropyl-1,4-diazepan-1-yl, 5-methyl-2,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-2-yl, 2-methyl-2,7-diazaspiro[3.5]nonan-7-yl, 7-methyl-2,7-diazaspiro[3.5]nonan-2-yl, 1-methyl-1,7-diazaspiro[3.5]nonan-7-yl, 2-methyl-2,6-diazaspiro[3.3]heptan-6-yl, 3-(3-azabicyclo[3.1.1]heptan-3-yl)azetidine-1-yl, 2-methyl-2,5-diazabicyclo[2.2.1]Heptan-5-yl,-C(O)CH2-cyclopropyl,-CH2-CH2-azeditin-1-yl,-CH2-CH2-(3-F-azeditin-1-yl),-CH2-CH2-(3-OMe-azeditin-1-yl),-CH2-CH2-CH2-(3-OMe-azeditin-1-yl),-CH2-CH2-C(Me)2-(3-OMe-azeditin-1-yl),-CH2-CH2-(3-CF3-azeditin-1-yl),-CH2-CH2-(3-OCF3-azeditin-1-yl),-CH2-CH2-(3-CHF2-azeditin -CH2-CH2-(3-OCHF2-azeditin-1-yl), -CH2-CH2-(3,3-diF-azeditin-1-yl), -CH2-CH2-(2,2-diMe-azeditin-1-yl), -CH2-CH2-(3,3-diMe-azeditin-1-yl), -CH2-CH2-(3-MeO-3-Me-azeditin-1-yl), -CH2-CH2-(3-CHF2-3-Me-azeditin-1-yl), -CH2-CH2-(3F-3-Me-azeditin-1-yl), -CH2-CH2-CH2-(3F-3-Me-azeditin-1-yl) Ditin-1-yl), -CH2-azeditin-1-yl, -CH2-(3-F-azeditin-1-yl), -CH2-(1-Me-azetidine-3-yl), -CH2-azetidine-3-yl, -CH2CH2-(3-F-pyrrolidine-1-yl), -CH2CH2-(3-CF3-pyrrolidine-1-yl), -CH2CH2-(3,3-di-F-pyrrolidine-1-yl), oxetane-3-yl, -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]octan-2yl),-CH2CH2CH2-(2-azaspiro[3.4] Octane-2-yl), -CH2CH2CH2CH2-(2-azaspiro[3.4]octane-2-yl), -CH2CH2-(6-azaspiro[3.4]octane-6-yl), -CH2CH2CH2-(6-azaspiro[3.4]octane-6-yl), -CH2CH2-(2,2-diF-6-azaspiro[3.4]octane-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), -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-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-azabispiro[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[3.1.0)Hexane-3-yl), -CH2CH2N(Me)cyclobutyl), -CH2CH2N(Me)(3,3-diF)cyclobutyl-1-yl), -CH2-CH2-(4-CF3-piperidine-1-yl), -CH2-CH2-(4,4-diMe-piperidine-1-yl), -CH2-CH2-(morpholine-4-yl), -CH2-CH2-CH2-(morpholine-4-yl), -CH2-CH2-CH2-(2,6-diMe-morpholine-4-yl), -CH2-CH2-CH2-(2,2,6,6-tetraMe-morpholine-4-yl), -CH2-CH2-CH2-(2,2-diMe-morpholine-4-yl), -CH2-CH2-(2,6-diMe-morpholine-4-yl), -CH2-CH2-(1,4-oxazepine-4-yl), -CH2CH2-CH2-(1,4-oxazepine-4-yl), and -S(O)2Me are substituted with 0, 1, or 2 substituents independently selected from these groups.

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

[0064] In some embodiments of the compounds of the present invention or pharmaceutically acceptable salts thereof, R 1 The following is: -C(O)-CH3 [ka] [ka] [ka] Selected from.

[0065] In some embodiments of the compounds of the present invention or pharmaceutically acceptable salts thereof, R 1 The following: [ka] [ka] [ka] [ka] [ka] Selected from.

[0066] In some embodiments of the compounds of the present invention or pharmaceutically acceptable salts thereof, R 1 The following is: -C(O)-CH3 [ka] Selected from.

[0067] In some embodiments of the compounds of the present invention or pharmaceutically acceptable salts thereof, R 2 -Br, -CF3 [ka] It is independently selected from the group consisting of [the specified elements].

[0068] In some embodiments of the compounds of the present invention or pharmaceutically acceptable salts thereof, R 2 teeth, [ka] It is independently selected from the group consisting of [the specified elements].

[0069] In some embodiments of the compounds of the present invention or pharmaceutically acceptable salts thereof, R 2 -Br, -CF3 [ka] It is independently selected from the group consisting of [the specified elements].

[0070] In some embodiments of the compounds of the present invention or pharmaceutically acceptable salts thereof, R 2 -Br, -CF3 [ka] It is independently selected from the group consisting of [the specified elements].

[0071] In some embodiments of the compounds of the present invention or pharmaceutically acceptable salts thereof, R 2 teeth, [ka] It is independently selected from the group consisting of [the specified elements].

[0072] In some embodiments of the compounds of the present invention or pharmaceutically acceptable salts thereof, R 3 It is independently selected from the group consisting of -F, -CF3, and -CH3.

[0073] 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.

[0074] In further embodiments, the present invention relates to a compound selected from any one of Examples 200-359, 359A, 360-402, 404, 405, 407, 410, 411 described herein, or a pharmaceutically acceptable salt thereof.

[0075] 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.

[0076] In one embodiment, the present invention relates to the use of the compound of the present invention or a pharmaceutically acceptable salt thereof in the manufacture of a pharmaceutical product.

[0077] In one embodiment, the present invention relates to a compound of the present invention or a pharmaceutically acceptable salt thereof for use as a pharmaceutical.

[0078] In a particular embodiment, the present invention relates to a compound that inhibits α4β7-integrin.

[0079] In certain 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 in a mammalian host or by enzymatic activity).

[0080] This compound is useful in the treatment of inflammatory bowel disease, ulcerative colitis, Crohn's disease, small intestinal bacterial overgrowth (SIBO), eosinophilic gastrointestinal disease (EGID), enteritis, gastrointestinal disorders associated with seronegative arthropathy, intestinal dysbiosis, microscopic colitis or collagenous colitis, cholecystitis, cholangitis, pericholangitis, familial adenomatous polyposis (FAP)-associated inflammatory gastrointestinal cancer, intestinal graft-versus-host disease (intestinal GVHD), celiac colitis, chronic cystitis, and checkpoint inhibitor-associated colitis.

[0081] In one embodiment, the present invention relates to a method for inhibiting the interaction between α4β7 integrin and MAdCAM-1 protein in a subject, comprising administering a pharmaceutically effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof to a subject requiring such inhibition.

[0082] In another embodiment, the present invention relates to a method for treating inflammatory bowel disease in a person in need thereof, comprising administering to the person a pharmaceutically effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof.

[0083] In another embodiment, the present invention relates to any of the compounds or pharmaceutically acceptable salts of the present invention described above for use in the treatment of inflammatory bowel disease.

[0084] In another embodiment, the present invention relates to any of the compounds or pharmaceutically acceptable salts of the present invention described above for use in the treatment of inflammatory bowel disease, wherein the inflammatory bowel disease is ulcerative colitis.

[0085] In another embodiment, the present invention relates to any of the compounds or pharmaceutically acceptable salts of the present invention described above for use in the treatment of inflammatory bowel disease, wherein the inflammatory bowel disease is Crohn's disease.

[0086] In another embodiment, the present invention relates to a method for treating ulcerative colon disease in humans, comprising administering a pharmaceutically effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof to a person in need thereof.

[0087] In another embodiment, the present invention relates to any of the compounds or pharmaceutically acceptable salts of the present invention described above for use in the treatment of ulcerative colon disease.

[0088] In another embodiment, the present invention relates to any of the compounds or pharmaceutically acceptable salts of the present invention described above for use in the treatment of ulcerative colon disease, wherein the ulcerative colon disease is ulcerative colitis.

[0089] In another embodiment, the present invention relates to any of the compounds or pharmaceutically acceptable salts of the present invention described above for use in the treatment of ulcerative colon disease, wherein the ulcerative colon disease is Crohn's disease.

[0090] In another embodiment, the present invention is as follows: a) One or more compositions, each comprising a pharmaceutically effective amount of a pharmaceutically acceptable salt of the compound of the present invention or any of the compound thereof, and a pharmaceutically acceptable carrier or excipient; and b) Instructions for use for administering one or more compositions to a person who needs them. Regarding the kit that includes this.

[0091] Terms used in this specification, description, examples, and claims are summarized herein. These definitions should be understood by those skilled in the art upon reading them in conjunction with the remainder of this disclosure. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art.

[0092] The terms and phrases defined below apply throughout this specification unless otherwise specified.

[0093] The articles “a,” “an,” and “the” are used herein to refer to one or more than one (i.e., at least one) of the grammatical objects of these articles, including multiple referents, unless the context specifically indicates otherwise. For example, “an element” means one element or more than one element.

[0094] The phrase "and / or" in this specification and in the claims should be understood, when used herein, to mean "one or both" of the elements thus coordinated.

[0095] In the claims and the above specification, all transitional phrases such as “comprising,” “including,” “carrying,” “having,” “containing,” “involving,” “holding,” and “composed of” should be understood to be open-ended, meaning they include but are not limited to them. As described in Section 2111.03 of the U.S. Patent and Trademark Office Patent Examination Procedure Manual, only the transitional phrases “composed of” and “essentially made from” are closed transitional phrases or semi-closed transitional phrases, respectively.

[0096] Certain compounds included in the compositions of the present invention may exist, in particular, as geometric isomers or stereoisomers. The present invention intends to include all such compounds, within its scope, including cis and trans isomers, R-enantiomers and S-enantiomers, diastereomers, (D)-isomers, (L)-isomers, racemic mixtures thereof, and other mixtures thereof. Further chiral carbon atoms may be present in substituents such as alkyl groups. All such isomers, and mixtures thereof, are intended to be included in the present invention. Unless stereochemistry is explicitly indicated in the structure, the structure is intended to encompass all possible stereoisomers of the illustrated compound. If stereochemistry is explicitly indicated with respect to one or more parts of the molecule but not with respect to another or more parts of the molecule, the structure is intended to encompass all possible stereoisomers with respect to the part(s) whose stereochemistry is not explicitly indicated. For example, if a specific enantiomer of the compound of the present invention is desired, the desired enantiomer can be isolated from a racemic mixture using a chiral separation method known in the art, such as chiral chromatography. Alternatively, the enantiomer can be produced by asymmetric synthesis or derivatization with a chiral auxiliary agent, in which case the resulting diastereomer mixture is separated to cleave the auxiliary groups and obtain the pure desired enantiomer. Alternatively, if the molecule contains a basic functional group such as amino or an acidic functional group such as carboxyl, a diastereomer salt can be formed using a suitable optically active acid or base, and then the diastereomer thus formed can be separated by fractional crystallization or chromatographic means known in the art, after which the pure enantiomer can be recovered.

[0097] Stereochemistry / Solvates / Hydrates: Unless otherwise specified, structural formulas or chemical names shown in this description or claims refer to the corresponding compounds themselves, mixtures of the forms previously specified herein (if such forms exist), and salts, in particular pharmaceutically acceptable salts thereof. The compounds and salts according to the present invention may exist in solvated forms (for example, with a pharmaceutically acceptable solvent such as water or ethanol) or in non-solvated forms. Generally, for the purposes of the present invention, solvated forms, such as hydrates, should be considered equivalent to non-solvated forms.

[0098] Aliphatic chains include the classes of alkyl, alkenyl, and alkynyl, as defined below. As used herein, the term “aliphatic group” means an unbranched or linear, branched or cyclic aliphatic hydrocarbon group, and includes saturated and unsaturated aliphatic groups such as alkyl, alkenyl, or alkynyl groups.

[0099] The term "alkyl" refers to unbranched or branched hydrocarbons. For example, an alkyl group is a carbon chain with a specified number of carbon atoms, such as 1 to 6 carbon atoms (i.e., C1-C6 alkyl or C1-C6 alkyl). 1~6It may have an alkyl group. Examples of suitable alkyl groups are, 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, i-butyl, --CH2CH(CH3)2), 2-butyl (s-Bu , s-butyl, --CH(CH3)CH2CH3), 2-methyl-2-propyl(t-Bu, t-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-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 It contains 14L(-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).

[0100] As used herein, the term "alkylene" refers to an alkyl group having a specified number of carbon atoms, e.g., 2 to 12 carbon atoms, in which the longest carbon chain contains two bonding sites in the remainder of the compound. Non-limiting examples of alkylene groups include methylene-(CH2)-, ethylene-(CH2CH2)-, n-propylene-(CH2CH2CH2)-, isopropylene-(CH2CH(CH3))-, and others. Alkylene groups can be cyclic or acyclic, branched or unbranched carbon chain portions, and may be optionally substituted with one or more substituents.

[0101] "Alkenyl" refers to any cyclic or acyclic, branched or unbranched unsaturated carbon chain portion having a specified number of carbon atoms, or up to 26 carbon atoms, unless otherwise specified, and having one or more double bonds in that portion. Alkenyls consisting of 6 to 26 carbon atoms are exemplified by their various isomers hexenyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, dodecenyl, tridecenyl, tetradecenyl, pentadecenyl, hexadecenyl, heptadecenyl, octadecenyl, nonadecenyl, eicocenyl, heneicosoenyl, dococenyl, tricocenyl, and tetracocenyl, in which the unsaturated bond can be located anywhere in the portion and can have either a (Z) configuration or an (E) configuration around the double bond.

[0102] "Alkinyl" refers to the hydrocarbyl portion of an alkenyl molecule, but specifically to the presence of one or more triple bonds in that portion.

[0103] The term "alkoxy" refers to a group having the formula "-O-alkyl" in which the alkyl group defined above is bonded to the parent molecule via an oxygen atom. The alkyl portion of an alkoxy group consists of a specified number of carbon atoms, such as 1 to 6 carbon atoms (i.e., C1-C6 alkoxy or C1-C6 alkoxy). 1~6It may have an alkoxy group. Suitable alkoxy groups include, but are not limited to, methoxy (-O-CH3 or -OMe), ethoxy (-OCH2CH3 or -OEt), t-butoxy (-OC(CH3)3 or -OtBu), etc.

[0104] The term "haloalkyl" refers to a group in which the alkyl group defined above has one or more hydrogen atoms replaced by halogen atoms. The alkyl portion of a haloalkyl group consists of a specified number of carbon atoms, such as 1 to 6 carbon atoms (i.e., -C1 to C6 haloalkyl or -C 1~6 It may have a haloalkyl group. Examples include: -CFH2, -CF2H, -CF3, -CF2CF3, -CHFCF3, -CH2CF3, -CF2CH3, -CHFCH3, -CF2CF2CF3, -CF2CH2CH3, etc.

[0105] The term "carbonyl group" refers to C=O, that is, a carbon atom bonded to oxygen via a double bond, and further bonded to two other atoms. In this specification, the carbonyl group is denoted as -CO- or -C(O)-.

[0106] The term “carbocyclic ring” or “carbocyclic group” refers to a chemical ring containing only carbon atoms, including saturated rings, unsaturated rings, partially saturated rings, and aromatic rings. For clarity, “carbocyclic ring” includes “cycloalkyl” and “aryl” as defined herein.

[0107] "Cycloalkyl" means a monocyclic or bicyclic ring, or a bridging or spirocyclic ring, or a polycyclic saturated carbocyclic ring, each having 3 to 12 carbon atoms. Similarly, and unless otherwise specified, preferred cycloalkyls have 3 to 10 carbon atoms in their ring structure, and more preferably 3 to 6 carbon atoms in their ring structure. Cycloalkyls may be substituted or unsubstituted. In some embodiments, preferred cycloalkyls are monocyclic rings having 3 to 6 carbon atoms.

[0108] As used herein, the term "aryl" includes substituted or unsubstituted 6- to 12-membered monocyclic aromatic groups in which each atom of the ring is carbon. Preferably, aryl groups include 5- to 12-membered rings, more preferably 6- to 10-membered rings. The term "aryl" also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjacent rings, and at least one of the rings is aromatic, for example, the other cyclic ring may be a cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, and / or heterocyclyl, in which case the bond site is located on the aromatic ring. Examples of aryl groups include benzene, naphthalene, phenanthrene, phenol, and aniline. Examples of aryl groups also include dihydrobenzofuran, indoline, isoindoline, quinoline, and isoquinoline, in which case the bond site is located on the phenyl ring.

[0109] The terms “heterocyclyl,” “heterocyclic,” or “heterocyclic group” refer to a ring structure with 3 to 12 members, more preferably 4 to 12 members, and more preferably 5 to 10 members, the ring structure containing 1 to 4 heteroatoms selected from N, O, S and their oxidized forms. Heterocyclyls can be saturated, partially saturated, unsaturated, and / or aromatic. Heterocyclics can be monocyclic, bicyclic, spirocyclic, or polycyclic. Examples of heterocyclyl groups include azetidine, aziridine, thiophene, thianthrene, furan, pyran, isobenzofuran, chromene, xanthene, phenoxatiin, pyrrole, imidazole, pyrazole, isothiazole, isoxazole, pyridine, pyrazine, pyrimidine, pyridazine, indidine, isoindole, indole, indazole, purine, quinoridine, isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carborin, phenanthidine, acridine, pyrimidine, phenanthroline, phenazine, phenalsazine, phenothiazine, furazan, phenoxazine, pyrrolidine, oxolane, thiolan, oxazole, piperidine, piperazine, morpholine, lactone, lactams such as azetidinone, pyridone and pyrrolidinenon, saltum, and sultone.

[0110] For clarity, "heterocyclyl" includes "heteroaryl" and "heterocycloalkyl".

[0111] The heterocyclic ring is substituted at one or more positions with the above substituents, such as halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, 5-amide, phosphate, phosphonate, phosphinate, carbonyl, carboxyl, silyl, sulfamoyl, sulfinyl, ether, alkylthio, sulfonyl, ketone, aldehyde, ester, heterocyclyl, aromatic or heteroaromatic moiety, -CF3, -CN, etc.

[0112] The general terms relating to heterocycles as referenced herein are understood to include each isomer of the heterocycle, such as “dithianyl” including the 1,2-dithianyl, 1,3-dithianyl, and 1,4-dithianyl groups; “thiadiazinyl” including the 1,2,5-thiadiazinyl and 1,3,4-thiadiazinyl groups; “azaindyl” including the 4-azaindyl, 5-azaindyl, 6-azaindyl, and 7-azaindyl groups; and “benzothiophenyl” including the benzo[b]thiophenyl and benzo[c]thiophenyl groups.

[0113] Similarly, common heterocycle names include all different ones with one or more unsaturation points. For example, the term “dihydropyrrolyl” refers to the “2,3-dihydro-1H-pyrrolyl” group and the “2,5-dihydro-1H-pyrrolyl” group.

[0114] "Heterocycloalkyl" means a saturated heterocyclic ring, each having 3 to 12 ring-membered atoms, more preferably 4 to 10-membered rings, and more preferably 4 to 7-membered rings, the ring structure containing 1 to 4 heteroatoms selected from N, O, S and their oxidation forms. The heterocyclic ring can be monocyclic, bicyclic, spirocyclic, or polycyclic. Examples of heterocyclyl groups include azetidine, oxetane, tetrahydrofuran, pyrrolidine, piperidine, piperazine, morpholine, tetrahydropyran, dioxane, and azepane.

[0115] The heterocycloalkyl group may be substituted or unsubstituted. In some embodiments, the preferred heterocycloalkyl group is a monoring having 4 to 6 ring members and containing one or two heteroatoms.

[0116] A partially saturated heterocycle means 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.

[0117] A heteroaryl group comprises a substituted or unsubstituted 5- to 12-membered aromatic ring structure, more preferably a 5- to 10-membered ring, the ring structure containing 1 to 4 heteroatoms selected from N, O, S and their oxidized forms. The term “heteroaryl” also includes a polycyclic ring system having two or more cyclic rings, where two or more atoms are common to two adjacent rings, and at least one of the rings is aromatic, for example, the other cyclic ring may be a cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or heterocyclyl, where the bond site is located on the aromatic ring. Examples of heteroaryl groups include pyrrole, furan, thiophene, imidazole, oxazole, thiazole, triazole, pyrazole, pyridine, pyrazine, pyridazine, and pyrimidine. Heteroaryl groups also include benzofuran, benzothiophene, indole, benzothiazole, and others, regardless of the position of the bond site. Aryl and heteroaryl can be monocyclic, bicyclic, or polycyclic.

[0118] The term "halogen" refers to atoms selected from the group consisting of elements -F, -Cl, -Br, or -I, namely chlorine, fluorine, bromine, and iodine.

[0119] The term "oxo" refers to oxygen atoms with a double bond ("=O").

[0120] As used herein, the term "nitro" means -NO2; the term "sulfhydryl" means -SH; the term "hydroxyl" means -OH; the term "sulfonyl" means -SO2-; the term "azide" means -N3; ​​the term "cyano" means -CN; the term "isocyanato" means -NCO; the term "thiocyanato" means -SCN; the term "isothiocyanato" means -NCS; and the term "cyanato" means -OCN.

[0121] As used herein, the term “substituted” is intended to include all permissible substituents of an organic compound. In broader embodiments, permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of an organic compound. Exemplary substituents include, for example, those listed above herein. There may be one or more permissible substituents, and they may be identical or different for a given organic compound. For the purposes of the present invention, a heteroatom such as nitrogen may have any permissible substituent of the organic compound described herein that satisfies the valence of the hydrogen substituent and / or the heteroatom. The present invention is by no means intended to be limited by the permissible substituents of an organic compound. It will be understood that “substituted” or “substituted by” implies that such substitutions conform to the permissible valences of the substituted atom and substituent, and that the substitution results in a stable compound, such as one that does not spontaneously undergo transformations such as rearrangement, cyclization, or elimination.

[0122] The term “prodrug,” as used herein, encompasses compounds that are converted into therapeutic agents under physiological conditions. A common method for producing a prodrug is to include a selected moiety that undergoes hydrolysis under physiological conditions to reveal a desired molecule. In other embodiments, the prodrug is converted by enzymatic activity in a mammalian host. An example of a moiety that undergoes hydrolysis under physiological conditions to reveal a desired molecule includes a functionalized carboxyl group, which is an ester of a carboxylic acid, and is converted into the corresponding active molecule under physiological conditions. Examples of moieties that undergo hydrolysis under physiological conditions to reveal a desired molecule are shown below: [ka]

[0123] For the purposes of this invention, the chemical elements are identified according to the CAS version of the periodic table of elements inside the cover of the Handbook of Chemistry and Physics, 67th edition, 1986-87.

[0124] The terms “therapeutic dose” and “pharmaceutical dose” refer to an amount sufficient to produce the treatment defined below when administered to a subject (e.g., a mammal such as a human) that requires such treatment. The therapeutic dose or pharmaceutical dose will vary depending on the subject and disease state being treated, the subject’s weight and age, the severity of the disease state, the method of administration, etc., and this is readily determined by those skilled in the art. For example, the therapeutic dose or pharmacovigilance of the compound of formula (I) or a pharmaceutically acceptable salt or cocrystal thereof is sufficient to inhibit the pre-existing symptoms of the indication, thereby treating a subject (e.g., a human) suffering from the indication, or sufficient to improve or alleviate the aforementioned pre-existing symptoms.

[0125] "Treatment" or "doing treatment" is a method for obtaining beneficial or desired outcomes, including clinical outcomes. Beneficial or desired clinical outcomes may include one or more of the following: (i) inhibiting the 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 stopping the onset 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 a regression of clinical symptoms (e.g., improving the disease state, achieving partial or complete remission of the disease or condition, enhancing the effect of another medication, slowing the progression of the disease, improving the quality of life, and / or extending survival).

[0126] The term “inhibitor” refers to a compound of the present invention that selectively binds to α4β7 integrin to block the interaction between α4β7 integrin and the MAdCAM-1 protein. Therefore, “inhibiting” or “restriction” refers to a decrease in baseline activity of a biological activity, or a process regulated by the interaction between α4β7 integrin and the MAdCAM-1 protein. In some embodiments, inhibition of α4β7 integrin activity is compared in the same subject before treatment or in other untreated subjects. The term “inhibitor” is understood to refer to a compound or agent that achieves desired inhibitory activity when administered at a pharmaceutically effective or therapeutically effective dose to a human being requiring it.

[0127] Numerical values ​​in the specification and claims of this application should be understood to include numerical values ​​that, when aligned to the same number of significant figures, are identical, as well as numerical values ​​that differ from the specified values ​​by less than the experimental error of the type of conventional measurement technique described in this application that determines the values.

[0128] All scopes disclosed and / or claimed herein include the enumerated endpoints and those that can be independently combined (for example, the ranges “2 to 10” and “2-10” include the endpoints 2 and 10, as well as all the intermediate values ​​3, 4, 5, 6, 7, 8 and 9).

[0129] "Significant" refers to any statistically significant detectable change in a standard parametric test of statistical significance (in this case, p<0.05), such as the Student's T-test.

[0130] Salt: The term “pharmaceutically acceptable” is used herein to describe a compound, substance, composition and / or formulation that is suitable for use in conjunction with human and / or animal tissues, according to generally recognized medical findings, and that does not have or cause any excessive toxicity, irritation or immune response, or cause any other problems or complications, i.e., corresponds to an overall acceptable risk / benefit ratio. The term “pharmaceutically acceptable salt” refers to a derivative of a disclosed chemical compound 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 respect to basic functional groups such as amines, alkali metals, or organic salts of acidic functional groups such as carboxylic acids. These salts include, in particular, acetate, ascorbate, benzenesulfonate, benzoate, besilate, bicarbonate, hydrogen tartrate, bromide / hydrobromide, calcium edetate / edetate, cansilate, carbonate, chloride / hydrochloride, citrate, edisylate, ethane disulfonate, estrulate, esylate, fumarate, gluceptinate, gluconate, glutamate, glycolate, glycolyl arsanylate, hexylresorcinate, hydravamin, hydroxymaleate, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, and malic acid. Examples include salts, maleates, mandelates, methanesulfons, mesilates, methyl bromides, methylnitrates, methylsulfates, mucinates, napsylates, nitrates, oxalates, pamoates, pantothenates, phenylacetates, phosphates / diphosphates, polygalacturonates, propions, salicylates, stearates, basic acetates, succinates, sulfamides, sulfates, tannates, tartrates, theoclates, toluenesulfons, triethiozides, ammonium, benzathine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine, and procaine.Other pharmaceutically acceptable salts are formed with metal cations such as aluminum, calcium, lithium, magnesium, potassium, sodium, and zinc (see also Pharmaceutical salts, Birge, SM et al., J. Pharm. Sci. (1977), 66, pp. 1-19).

[0131] As used herein, the terms “isotope” and “isotope” in relation to the compounds disclosed herein mean that one or more atoms of a compound are replaced by an isotope of such one or more atoms. “Isotope” refers to any two or more forms of a chemical element that have the same number of protons in the nucleus but different numbers of neutrons in the nucleus. For example, isotopic compounds include compounds in which one or more hydrogen atoms (H) are replaced by one or more deuterium atoms (D). In this example, deuterium is an isotope of hydrogen, and replacing a hydrogen atom with deuterium (at one or more positions) results in an isotopic compound. For example, referring to formula (I), replacing the two methyl groups of the isopropyl moiety (-CH(CH3)2) with fully deuterated methyl groups (-CH(CD3)2) results in the isotopic compound of formula (I). In addition to 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, replacing iodine-127 with iodine-123 or iodine-125, and so on. Accordingly, all references to isotopic compounds of formula (I) in this specification, and all references to their various embodiments, refer to compounds having one or more isotopic substitutions, including (but not limited to) the substitution of one or more hydrogen atoms in the compound with one or more deuterium atoms, and any occurrences. For this purpose, the isotopic compounds disclosed herein offer improved advantages compared to their non-isotopic counterparts. For this purpose, isotopic modification offers a means to improve existing drugs and / or a tool in the design of novel drugs. For example, the design of isotopic drugs has demonstrated success in the context of deuterium(D) kinetic isotope effects. Because the mass of D is twice as high as that of H, the CD bond has considerable resistance to oxidative processes (such as its ability to be catalyzed by CYP450 or other enzymes involved in metabolism) while simultaneously maintaining very similar steric properties.Therefore, H-D isotopic substitution typically preserves the pharmacodynamics of a compound while simultaneously improving its pharmacokinetics, including its effects on half-life and / or area under the curve, and ultimately, its effects on dose and / or administration regimen. For example, drug exposure is enhanced by isotopic modification and / or reduced clearance. Such benefits are borne by the compounds disclosed herein through their isotopic derivatization.

[0132] Terms such as “subject” and “patient” refer to mammalian or other animal subjects who have been, or will be, subjects of treatment, observation, or experimentation. The methods described herein may be useful for both human therapeutic and veterinary use. 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 of it” or “human in need of it” refers to a human-like subject who may have, or is suspected of having, a disease or condition that would be expected to benefit from a particular treatment; for example, treatment with a compound of formula (I) described herein or a pharmaceutically acceptable salt or cocrystal thereof. This includes subjects who are at risk of, or are judged to be susceptible to, such diseases or conditions, and thus the treatment is expected to prevent the onset of the disease or condition.

[0133] The pharmaceutically acceptable salts of the present invention can be prepared by conventional chemical methods, starting from a parent compound having a basic or acidic functional group. Generally, such salts can be synthesized by reacting these compounds in the form of free acids or free bases with a sufficient amount of the corresponding base or acid in water or in an organic solvent such as ether, ethyl acetate, ethanol, isopropanol, acetonitrile (or a mixture thereof). Salts of acids other than the above-mentioned salts (e.g., trifluoroacetates), which are useful for, for example, purifying or isolating compounds from the reaction mixture, should also be considered part of the present invention.

[0134] The terms “pharmaceutically acceptable excipient” or “pharmaceutically acceptable carrier” as used herein mean a pharmaceutically acceptable substance, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulant, that is involved in the transport or delivery of the chemical substance in question from one organ or part of the body to another organ or part of the body. Each carrier must be “acceptable” in the sense that it is compatible with the other components of the formulation, is not harmful to the patient, and is substantially nonpyrogenic. Some examples of substances that can act 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 carboxymethylcellulose, ethylcellulose, and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients such as cocoa butter and suppository wax; (9) peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil. Examples include oils like oil; (10) glycols like propylene glycol; (11) polyols like glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters like ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents like magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) phosphate buffer solution; and (21) other non-toxic compatible substances used in pharmaceutical formulations. In certain embodiments, the pharmaceutical compositions of the present invention are non-pyrogenic, i.e., they do not induce a significant rise in temperature when administered to a patient.

[0135] The compounds of the present invention may sometimes exist as racemates, but can also be obtained as pure enantiomers, i.e., the (R) or (S) isomer. Compounds having the specific stereochemistry of formula Ia are preferred.

[0136] The present invention relates to the compound in question, optionally in the form of individual optical isomers, diastereomers, mixtures of diastereomers, mixtures or racemates of individual enantiomers, tautomers, and corresponding acid addition salts with free bases or pharmacoagulably acceptable acids (e.g., hydrohalic acids (e.g., hydrochloric acid or hydrobromic acid), or organic acids (e.g., oxalic acid, fumaric acid, diglycolic acid or methanesulfonic acid, etc.)).

[0137] This invention relates to the individual compounds of formula I in the form of their pharmacokinetically acceptable salts. These pharmacokinetically acceptable salts of the compounds of formula I and Ia may also exist in the form of their individual hydrates (e.g., monohydrates, dihydrates, etc.) and their individual solvates.

[0138] In the context of the present invention, the hydrate of a compound according to formula I refers to a crystalline salt of the compound according to formula I, which contains water of crystallization.

[0139] For the purposes of this invention, the solvate of a compound according to formula I refers to a crystalline salt of the compound according to formula I that contains solvent molecules (e.g., ethanol, methanol, etc.) in its crystal lattice.

[0140] Combinations Compounds of formula I are used on their own or in conjunction with other active substances of formula I according to the present invention. Compounds of formula I are also used, as may, in conjunction with other pharmacologically active substances. Preferably, the active substances used herein are selected from, for example, anti-IL17, the bispecific antibody IL23p19 / TNF, fecal transplantation, aminosalicylic acid (5-ASA), COX-2 inhibitors, corticosteroids, azathioprine, cyclosporine, tacrolimus, 6-mercaptopurine and / or antibiotics (such as ciprofloxacin, metronidazole, and ampicillin).

[0141] formulation The compound of formula I according to the present invention also possesses properties necessary for the production of suitable pharmaceutical dosage forms. These properties include, for example, those related to the efficient bioavailability of the active ingredient, particularly its sufficiently high solubility, such as a solubility of >2 μg / ml when measured in an aqueous solution at pH 6.8.

[0142] Suitable forms for administration include, for example, tablets, capsules, solutions, syrups, emulsions, or inhalation powders or aerosols. The content of the pharmaceutically effective compound should, in each case, be in the range of 0.1 to 90% by weight, preferably 0.5 to 50% by weight of the whole composition, i.e., an amount sufficient to achieve the dosage range specified herein.

[0143] The preparation is administered orally in the form of tablets, powder, powder in capsules (e.g., hard gelatin capsules), solution, or suspension. When administered by inhalation, the combination of active substances is administered as a powder, aqueous solution or aqueous ethanol solution, or using a propellant gas formulation.

[0144] Preferably, and therefore, the pharmaceutical formulation is characterized by the content of one or more compounds of formula I according to the preferred embodiments described above.

[0145] It is particularly preferred when the compound of formula I is administered orally, and also particularly preferred when the compound of formula I is administered once or twice daily. Suitable tablets can be obtained, for example, by mixing the active substance with known excipients, such as an inert diluent like calcium carbonate, calcium phosphate, or lactose; a disintegrant like corn starch or alginate; a binder like starch or gelatin; a lubricant like magnesium stearate or talc; and / or an agent for delayed release like carboxymethylcellulose, cellulose acetate or polyvinyl acetate. The tablets may also contain several layers.

[0146] Therefore, coated tablets can be manufactured by coating a core, which is produced in the same manner as a tablet, with a substance 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 may also consist of several layers. Similarly, the tablet coating may also consist of several layers to achieve delayed release using the excipients described above for tablets.

[0147] The syrups containing the active substances or combinations thereof according to the present invention may further contain sweeteners such as saccharin, cyclamate, glycerin, or sugar, and flavor enhancers, such as vanillin or orange extract. They may also contain suspended adjuvants or thickeners such as sodium carboxymethylcellulose, wetting agents such as condensation products of fatty alcohols and ethylene oxide, or preservatives such as p-hydroxybenzoate.

[0148] Capsules containing one or more active substances or combinations of active substances can be manufactured, for example, by mixing the active substance with an inert carrier such as lactose or sorbitol and packaging them in gelatin capsules. Suitable suppositories are prepared, for example, by mixing with a carrier that achieves this purpose, such as a neutral fat or polyethylene glycol, or derivatives thereof.

[0149] Excipients that can be used include, for example, water, pharmaceutically acceptable organic solvents (paraffin (e.g., petroleum fraction), vegetable oils (e.g., peanut oil or sesame oil), monofunctional or polyfunctional alcohols (e.g., ethanol or glycerin), carriers (e.g., natural inorganic powders (e.g., kaolin, clay, talc, chalk), synthetic inorganic powders (e.g., highly dispersed silicic acid and silicates), sugars (e.g., sugarcane sugar, lactose and glucose), emulsifiers (e.g., lignin, sulfite pulp wastewater, methylcellulose, starch and polyvinylpyrrolidone), and lubricants (e.g., magnesium stearate, talc, stearic acid and sodium lauryl sulfate).

[0150] For oral administration, tablets may, in addition to the carrier described above, contain additives such as sodium citrate, calcium carbonate, and dicalcium phosphate, along with various other additives such as starch, preferably potato starch, and gelatin. Furthermore, lubricants such as magnesium stearate, sodium lauryl sulfate, and talc may be used simultaneously in the tableting process. In the case of aqueous suspensions, the active substance is combined with the above-mentioned excipients, along with various flavor enhancers or colorants.

[0151] It is also preferable, and particularly preferable, when the compound of formula I is administered by inhalation. For this purpose, the compound of formula I must be prepared to be available in a form suitable for inhalation. Inhalation preparations include inhalation powders, propellant-containing metered aerosols, or propellant-free inhalation solutions, which may be present in mixtures with physiologically acceptable conventional excipients.

[0152] Within the scope of the present invention, the term propellant-free inhalation solution also includes concentrates or ready-to-use sterile inhalation solutions. Preparations that can be used according to the present invention are described in more detail in the following parts of this specification.

[0153] Exemplary methods - Indications In certain 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, gastroenteropathy associated with seronegative arthropathy, intestinal dysbiosis, microscopic colitis or collagenous colitis, cholecystitis, cholangitis, pericholangitis, familial adenomatous polyposis-associated inflammation (FAP), gastrointestinal cancer, intestinal graft-versus-host disease (intestinal GVHD), celiac enteritis, chronic cystitis, and checkpoint inhibitor-associated colitis, comprising the step of administering a therapeutically effective amount of any one of the aforementioned compounds to a subject in need.

[0154] In certain embodiments, the disease or condition is inflammatory bowel disease. In certain embodiments, inflammatory bowel disease is colitis, Crohn's disease, ileitis, celiac disease, non-tropical sprue, gastroenteropathy, gastroenteritis, or cystitis associated with seronegative arthropathy.

[0155] In a particular embodiment, the disease or condition is Crohn's disease.

[0156] In a particular embodiment, the disease or condition is colitis.

[0157] In a particular embodiment, the disease or condition is ulcerative colitis.

[0158] In certain embodiments, the present invention relates to any one of the methods described above, wherein the subject is a mammal. In certain embodiments, the present invention relates to any one of the methods described above, wherein the subject is a human.

[0159] synthesis The compounds described herein can be prepared by methods known in the art, as illustrated by the following non-limiting statements.

[0160] Unless otherwise specified, all reactions are typically carried out under an inert atmosphere (e.g., under nitrogen). The following abbreviations are used in this text: ss=saturated solution Major = overnight

[0161] [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4]

[0162] Other features and advantages of the present invention will become apparent from the following more detailed embodiments, which illustrate the principles of the present invention without limiting their scope.

[0163] general Unless otherwise specified, all reactions are carried out using commercially available equipment and methods commonly used in chemical laboratories. Starting materials sensitive to air and / or moisture are stored under a protective gas, and corresponding reactions and operations are carried out under a protective gas (nitrogen or argon).

[0164] Analysis method The LCMS conditions are 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® BEHTM C18 column (2.1 mm × 50 mm, 1.7 μm; temperature 40°C) and a gradient of B from 5 to 100% (A = 0.1% formic acid in H₂O₂-H: B = 0.1% formic acid in MeCN) over 1.1 minutes, followed by B becoming 100% over 0.25 minutes. Next, a second gradient of B from 100% to 5% was applied over 0.05 minutes at an injection volume of 1 μL and a flow rate of 0.9 mL / min, and held for 0.1 minutes. The UV spectrum at 215 nm was recorded in the spectral range of 200–400 nm using a Waters Acquity PDA. Mass spectra were obtained using a Waters QDa. Data are integrated and reported using Waters MassLynx and OpenLynx software, and retention times (Rt) are reported in minutes.

[0165] System 2 (S2): Basic IPC method Analytical (MET / uPLC / AB2010)(M15) UHPLC-MS was performed in reverse phase using a Waters UPLC™ BEH™ C18 column (2.1 mm × 30 mm, 1.7 μm; temperature 55 °C) with an injection volume of 1 μL and a flow rate of 1.0 mL / min, and a gradient of B from 1 to 100% over 1.10 minutes, followed by B to 100% over 0.25 minutes (A = 2 mM ammonium bicarbonate in water (buffered to pH 10) and B = acetonitrile). A second gradient of B from 100% to 1% was then applied over 0.05 minutes and held for 0.40 minutes. UV spectra were recorded at 215 nm; spectral range: 200–400 nm. Mass spectra were obtained using a Waters Quattro Premier XE or SQD2 with ionization mode: electrospray positive or negative. Data are integrated and reported using Waters MassLynx and OpenLynx software, and retention times (Rt) are reported in minutes.

[0166] System 3 (S3): Acidic final method Analytical (MET / uPLC / AB101) uHPLC-MS was performed on a Waters Acquity uPLC system using a Phenomenex Kinetex-XB C18 column (2.1 mm × 100 mm, 1.7 μM; temperature: 40°C) and a gradient of B from 5 to 100% (A = 0.1% formic acid in H2O; B = 0.1% formic acid in MeCN) over 5.3 minutes, followed by B to 100% over 0.5 minutes. Next, a second gradient of B from 100% to 5% was applied over 0.02 minutes with an injection volume of 1 μL and a flow rate of 0.6 mL / min, and held for 1.18 minutes. 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 Waters SQD or Waters Acquity QDA. Data are integrated and reported using Waters MassLynx and OpenLynx software, and retention times (Rt) are reported in minutes.

[0167] System 4 (S4): Basic final method Analytical (MET / uHPLC / AB105) uPLC-MS was performed on a Waters Acquity uPLC system using a Waters UPLC® BEHTM C18 column (2.1 mm × 100 mm, 1.7 μm column; temperature: 40°C) and a gradient of 5–100% (A = 2 mM ammonium bicarbonate (buffered to pH 10); B = MeCN) over 5.3 minutes, followed by a gradient of B to 100% over 0.5 minutes. Next, a second gradient of B from 100–5% was applied over 0.02 minutes with an injection volume of 1 μL and a flow rate of 0.6 mL / min, and held for 1.18 minutes. 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 are integrated and reported using Waters MassLynx and OpenLynx software, and retention times (Rt) are reported in minutes.

[0168] System 5 (S5): Neutral final method Analytical UHPLC-MS was performed on an Agilent 1260 system using an Agilent Poroshell 120EC-C18 column (2.1 mm × 50 mm, 1.9 μm; temperature 50°C) in binary gradient mode (A=10 mM NH4OAc in H2O:B=ACN) over 4.5 minutes at a flow rate of 0.8 mL / min (linearly increasing B to 1% over 0.25 minutes, then to 100% over 2.25 minutes, then to 100% B over 0.40 minutes, and then returning to the initial conditions over 0.1 minutes). The initial injection volume was 0.2 μL. UV spectra at 220 nm and 254 nm were recorded using an Agilent PDA in the spectral range of 190–400 nm. Mass spectra were obtained using either positive or negative electrospray ionization (Agilent Jet Stream source) with an Agilent 6490A QQQ. The data was used with the Agilent MassHunter software suite, and retention times (Rt) are reported in minutes.

[0169] 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 in H2O:B=ACN) over 4.2 minutes at a flow rate of 0.8 mL / min (linearly increasing B to 1% for 0.25 minutes, then to 100% B for 2.25 minutes, then 100% B for 0.40 minutes, followed by a return to the initial conditions for 0.1 minutes). The initial injection volume was 1 μL. UV spectra at 220 nm and 254 nm were recorded using an Agilent PDA in the spectral range of 190–400 nm. Mass spectra were obtained using an Agilent 6120B SQ with simultaneous positive and negative electrospray ionization. Agilent OpenLab software will be used to access the data, and retention time (Rt) will be reported in minutes.

[0170] 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 in H2O:B=ACN) over 3.8 minutes at a flow rate of 1.0 mL / min (linearly increasing B to 0.5% for 0.10 minutes, then to 100% B over 1.6 minutes, then 100% B for 0.40 minutes, and returning to the initial condition over 0.1 minutes). The initial injection volume was 1 μL. UV spectra at 220 nm and 254 nm were recorded with an Agilent PDA in the spectral range of 190–400 nm. Mass spectra were obtained using an Agilent 6120B SQ with simultaneous positive and negative electrospray ionization. Agilent OpenLab software will be used to access the data, and retention time (Rt) will be reported in minutes.

[0171] System 8 (S8): Acidic late-stage elution IPC method Analytical (MET / uPLC / 1906)(M12) UHPLC-MS was performed in reverse phase using a Waters UPLC™ CORTECS™ C8 column (2.1 mm × 50 mm, 1.6 μm; temperature: 40°C) with an injection volume of 1 μL and a flow rate of 0.9 mL / min, and a gradient of B from 5 to 100% over 1.10 minutes, followed by B reaching 100% over 0.30 minutes (A = 0.1% formic acid in water and B = 0.1% formic acid in acetonitrile). A second gradient of B from 100% to 5% was then applied over 0.02 minutes and held for 0.28 minutes. The UV spectrum was recorded at 215 nm; spectral range: 200–400 nm. ELS data was collected using a Waters ELS detector at reporting time. Mass spectra were obtained using Waters SQD2 or QDa, with ionization mode: electrospray positive or negative. Data are integrated and reported using Waters MassLynx and OpenLynx software, and retention times (Rt) are reported in minutes.

[0172] The purification method is as follows: The compounds were purified using the following methods: normal-phase or reverse-phase automated flash column chromatography on silica or C-18 silica (e.g., Biotage® Isolera or Selekt instruments); open-access reverse-phase preparative HPLC (methods are detailed below, pp. 1-4); and one of the custom-developed reverse-phase preparative HPLC methods.

[0173] Method 1: Acidic early elution method (P1) Purification (P1) LC was performed on a Gilson LC system using a Waters Sunfire C18 column (30 mm × 100 mm, 10 μM; temperature: room temperature) and a gradient of B from 10–95% (A = 0.1% formic acid in H2O; B = 0.1% formic acid in MeCN) over 14.44 minutes, followed by a gradient of B from 95% over 2.11 minutes. Next, a second gradient of B from 95–10% was applied over 0.2 minutes with an injection volume of 1500 μL and a flow rate of 40 mL / min. The UV spectrum was recorded at 215 nm using a Gilson detector.

[0174] Method 2: Acidic standard method (P2) Purification (P2) LC was performed on a Gilson LC system using a Waters Sunfire C18 column (30 mm × 10 mm, 10 μM; temperature: room temperature) and a gradient of B from 30 to 95% (A = 0.1% formic acid in water; B = 0.1% formic acid in MeCN) over 11.00 minutes, followed by a gradient of B from 95% over 2.10 minutes. Next, a second gradient of B from 95% to 30% was applied over 0.2 minutes with an injection volume of 1500 μL and a flow rate of 40 mL / min. The UV spectrum was recorded at 215 nm using a Gilson detector.

[0175] Method 3: Basic early elution method (P3) Purified (P3)LC was performed in reverse phase using a Waters XBridge® C18 column (30 mm × 100 mm, 5 μm; temperature: room temperature) with an injection volume of 1500 μL and a flow rate of 40 mL / min, applying a gradient of 10% B over 2.00 minutes, followed by a gradient of 10% B to 95% B over 14.00 minutes, and a retention period of 2.00 minutes (A = 0.2% NH4OH in water and B = MeCN). A second gradient of 95% to 10% B was then applied over 0.20 minutes and held for 1.25 minutes. The UV spectrum was recorded at 215 nm.

[0176] Method 4: Basic standard method (P4) Purified (P4)LC was performed in reverse phase using a Waters XBridge® C18 column (30 mm × 100 mm, 5 μm; temperature: room temperature) with an injection volume of 1500 μL and a flow rate of 40 mL / min, applying a gradient of B to 30% over 2.00 minutes, followed by a gradient of B from 30% to 95% over 9.50 minutes, and a retention of 1.97 minutes (A = 0.2% NH4OH in water and B = MeCN). A second gradient of B from 95% to 30% was then applied over 0.33 minutes and held for 1.65 minutes. The UV spectrum was recorded at 215 nm.

[0177] Chiral separation method: LC method: Chiral separation using Gilson LC [column at room temperature; isocratic eluent; flow rate: 18 mL / min; detector wavelength: 215 / 254 nm; diluent: IPA; injection volume: 100-1000 μL]

[0178] SFC method: Chiral separation using Waters Thar SFC [column at 40°C; isocratic eluent; back pressure: 120 bar; flow rate: 15 mL / min; diluent: MeOH / acetonitrile; injection volume: 250 μL]

[0179] The NMR method is as follows: Method 1, NMR (N1) Unless otherwise specified, 1 ¹H NMR spectra were recorded at 500 MHz, 400 MHz, or 250 MHz using one of the following Bruker Avance III HD 500 MHz, Bruker Avance III HD 400 MHz, or Bruker Avance III HD 250 MHz spectrometers, respectively. Chemical shift δ is expressed in parts per million (ppm) and referenced to the residual solvent peak. The following abbreviations are used to represent multiplicity and general assignment: s (singlet), d (doublet), t (triplet), q (quartet), dd (doublet of doublets), ddd (doublet of doublets of doublets), dt (doublet of triplets), dq (doublet of quartets), hep (heptet), m (multiplet), penta (pentet), td (triplet of doublets), qd (quartet of doublets), app. (apparent), and br. (broad). The coupling constant J is quoted to the nearest 0.1 Hz.

[0180] Method 2, NMR: (N2) Unless otherwise specified, 1¹H NMR spectra were recorded at 300 MHz or 500 MHz, respectively, using either a Bruker 300 MHz Fourier spectrometer with a dual z-grad 1H / 13C probe at 300 K, or a Bruker 500 MHz AVIII HD spectrometer with an N2-cooled z-grad broadband CPP BBO probe at 298 K. Chemical shift δ is expressed in parts per million (ppm) and referenced to the residual solvent peak. The following abbreviations are used to represent multiplicity and general assignment: s (singlet), d (doublet), t (triplet), q (quartet), dd (doublet of doublets), ddd (doublet of doublets of doublets), dt (doublet of triplets), dq (doublet of quartets), hep (heptet), m (multiplet), penta (pentet), td (triplet of doublets), qd (quartet of doublets), app. (apparent), and br. (broad). The coupling constant J is quoted to the nearest 0.1 Hz. General synthesis:

[0181] All compounds were synthesized to a purity of >95% unless otherwise specified.

[0182] Scheme for general route 1a [ka]

[0183] Synthesis of intermediate A1 (R)-N-[(E)-(5-bromo-2,3-difluorophenyl)methylidene]-2-methylpropane-2-sulfinamide (Step B) [ka] 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), titanium(IV) ethoxide (35 mL, 0.170 mol) was added dropwise at room temperature. The reaction mixture was stirred at room temperature for 1 hour, then at 40°C for 1.5 hours. The reaction mixture was poured into a mixture of water (300 mL) and pharmaceutically acceptable solution (200 mL) and stirred vigorously for 10 minutes. The suspension was then sonicated, filtered, and washed with pharmaceutically acceptable solution (200 mL). The organic layer was separated, and the aqueous layer was extracted with pharmaceutically acceptable solution (3 × 100 mL). The combined organic layers were washed with brine (2 × 100 mL), dehydrated with MgSO4, and concentrated under vacuum to obtain the title product (33.74 g, 87% yield) as a white solid. 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).

[0184] Synthesis of intermediate A2 Ethyl(3S)-3-(5-bromo-2,3-difluorophenyl)-3-{[(R)-2-methylpropane-2-sulfinyl]amino}propanoate (Step C) [ka]

[0185] Condition A A stirred suspension of activated zinc powder (26.91 g, 0.411 mol) in anhydrous THF (350 mL) was treated by adding 2-ethyl bromoethyl (29 mL, 0.257 mol) dropwise over 20 minutes at 65°C under N2. This solution was stirred at 65°C for 1.5 hours, then cooled to room temperature and allowed to precipitate for 30 minutes. This organozinc solution was added to a stirred solution of (R)-N-[(E)-(5-bromo-2,3-difluorophenyl)methylidene]-2-methylpropane-2-sulfinamide (35.10 g, 0.103 mol) in anhydrous THF (350 mL) over 5 minutes at 65°C under N2. The reaction mixture 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), dehydrated with MgSO4, and concentrated under vacuum to obtain the crude product. Purification by column chromatography (approximately 300 g of silica, 0-70% siRNA in heptane) yielded the title product (29.40 g, 55% yield) as an orange oily substance.

[0186] Condition B To a stirred suspension of activated zinc powder (39.87 g, 0.610 mol) in THF (400 mL), copper(1+) chloride (7.54 g, 76.2 mmol) was added under N2 at room temperature. This suspension was heated at 65°C for 30 minutes. The reaction mixture was removed from the heat and 2-ethyl bromo (34 mL, 0.305 mol) was added dropwise over 15 minutes under reflux (Caution: This will cause severe exothermic reaction). After the addition, the reaction mixture was stirred at 65°C for a further 1 hour. The reaction mixture was cooled to -5°C and treated dropwise with a solution of (R)-N-[(E)-(5-bromo-2,3-difluorophenyl)methylidene]-2-methylpropane-2-sulfinamide (95%, 52.00 g, 0.152 mol) in THF (200 mL) over 10 minutes. The reaction mixture was stirred at -5°C for 30 minutes, then at 0°C for 45 minutes. The reaction mixture was filtered through Celite and washed with TBME (approximately 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), and the combined organic layers were washed with brine (150 mL), dehydrated with MgSO4, and concentrated under vacuum. Purification by column chromatography (340 g silica, 20-35% acetone in heptane) yielded the title product (63.26 g, 84% pure, 85% yield) as a yellow oil. 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, 7.2 Hz, 1H), 2.90 (dd, J = 15.8, 7.5 Hz, 1H), 1.13 (t, J = 7.1 Hz, 3H), 1.06 (s, 9H).

[0187] Synthesis of intermediate A3 Ethyl(3S)-3-{4,5-difluoro-2',6'-dimethyl-[1,1'-biphenyl]-3-yl}-3-{[(R)-2-methylpropane-2-sulfinyl]amino}propanoate (Step D) [ka] Ethyl(3S)-3-(5-bromo-2,3-difluorophenyl)-3-{[(R)-2-methylpropane-2-sulfinyl]amino}propanoate (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) were degassed in 1,4-dioxane (110 mL) and water (8 mL) for 10 minutes. Pd(dppf)Cl2 (1.57 g, 1.92 mmol) was added, and the reaction mixture was stirred under N2 at 100°C for 4 hours. The reaction mixture was cooled and poured into water (400 mL), and extracted with SiO2 (4 × 150 mL). The combined organic layers were washed with brine (2 × 100 mL), dehydrated with MgSO4, and concentrated to obtain the crude product. Purification by column chromatography (350 g silica, 10% to 100% butyl in heptane, followed by 0 to 20% MeOH in butyl) yielded the title product (8.25 g, 44% yield) as a brown oily substance. LCMS m / z:438.4[M+H]+, (ESI+), Rt=1.14(S1)

[0188] Synthesis of intermediate A4 Process E: Ethyl(3S)-3-amino-3-{4,5-difluoro-2',6'-dimethyl-[1,1'-biphenyl]-3-yl}propanoate hydrochloride (Process E) [ka] A stirred solution of ethyl(3S)-3-{4,5-difluoro-2',6'-dimethyl-[1,1'-biphenyl]-3-yl}-3-{[(R)-2-methylpropane-2-sulfinyl]amino}propanoate (9.63 g, 18.3 mmol) 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 (50 g silica, 0%-40% MeOH in ethylethanol) yielded the title product (7.38 g, 94% yield) as an orange solid. 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)

[0189] Synthesis of intermediate A5 5-Bromo-2-fluoro-3-(trifluoromethyl)benzaldehyde (Step A) [ka] To a solution of 4-bromo-1-fluoro-2-(trifluoromethyl)benzene (5.00 g, 20.6 mmol) in THF (39 mL), LDA (1 M in THF, 31 mL, 30.9 mmol) was added dropwise over 1 hour at -78°C. 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 a further 2 hours. This reaction was quenched with NH4Cl (saturated aqueous solution, 50 mL) at 0°C and extracted with SiO2 (3 × 60 mL). The combined organic layers were washed with brine (80 mL), dehydrated with MgSO4, and concentrated under vacuum to obtain the crude residue. Purification by column chromatography (25 g silica, 0-25% SiO2 in heptane) yielded the title product (2.40 g, 38% yield) as a yellow oily substance. LCMS m / z: no mass ion 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)

[0190] The intermediates in Table 1 were synthesized using the corresponding starting materials in accordance with General Scheme 1 (steps B-D), as exemplified by intermediate A4. The diastereomers were separated either during final purification or, if necessary, by chiral separation. The intermediates were obtained as the title compound or its salts.

[0191] [Table 2-1] [Table 2-2] [Table 2-3]

[0192] Scheme for general route 1b [ka]

[0193] Synthesis of intermediate A11 (R)-N-[(E)-(5-bromo-2-fluoro-3-methylphenyl)methylidene]-2-methylpropane-2-sulfinamide (Step A) [ka] Using 5-bromo-2-fluoro-3-methylbenzaldehyde as the starting material, it was produced by a method similar to that used for intermediate A1. LCMS m / z: 320.1 / 322.1 [M+H]+, (ESI+), Rt = 1.12 (S1) 1 H NMR (400 MHz, CDCl3) δ [ppm]: 8.85 (s, 1H), 7.94 (dd, J = 5.6, 2.5 Hz, 1H), 7.49 (dd, J = 6.5, 1.9 Hz, 1H), 2.33 (d, J = 2.2 Hz, 3H), 1.30 (s, 9H).

[0194] Synthesis of intermediate A12 Ethyl(3S)-3-(5-bromo-2-fluoro-3-methylphenyl)-3-{[(R)-2-methylpropane-2-sulfinyl]amino}propanoate (Step B) [ka] Intermediate A11 was used as the starting material, and intermediate A2 was produced using a method similar to that used under condition B. LCMS m / z: 408.0 / 410.0 [M+H]+, (ESI+), Rt = 1.02 (S1) 1H 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 Ethyl(3S)-3-amino-3-(5-bromo-2-fluoro-3-methylphenyl)propanoate hydrochloride (Process C) [ka] Intermediate A4 was produced using intermediate A12 as the starting material, in a manner similar to that of condition B. LCMS m / z: 304.1 / 306.1 [M+H]+, (ESI+), Rt = 0.57 (S1) 1 H 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).

[0196] The intermediates in Table 2 were synthesized using the corresponding starting materials in accordance with general scheme 1B (steps A-C), as exemplified by intermediate A13. The diastereomers were separated either during final purification or, if necessary, by chiral separation. The intermediates were obtained as the title compound or its salts.

[0197] [Table 3-1] [Table 3-2]

[0198] Scheme for General Route 2 [ka]

[0199] Synthesis of intermediate B1 Ethyl (3S)-3-[(2S)-2-{[(tert-butoxy)carbonyl]amino}-4-methylpentanamide]-3-{4,5-difluoro-2',6'-dimethyl-[1,1'-biphenyl]-3-yl}propanoate (Step A) [ka] To a stirred 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), DIPEA (2.3 mL, 13.0 mmol) was added, followed by HATU (2.31 g, 6.08 mmol). The reaction mixture was stirred at room temperature for 72 hours. The reaction product was retreated with (2S)-2-{[(tert-butoxy)carbonyl]amino}-4-methylpentanoic acid (1.30 g, 5.63 mmol) and HATU (2.31 g, 6.08 mmol), stirred for a further 1 hour, and then diluted 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 obtain a crude oily product. Purification by column chromatography (50 g silica, 5-60% phosphate in heptane) yielded the title product (1.85 g, 70% yield) as a colorless solid. 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 = 7.7Hz, 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).

[0200] Synthesis of intermediate B2 Ethyl(3S)-3-[(2S)-2-amino-4-methylpentanamide]-3-{4,5-difluoro-2',6'-dimethyl-[1,1'-biphenyl]-3-yl}propanoate hydrochloride (Step B) [ka] To a stirred solution of ethyl(3S)-3-[(2S)-2-{[(tert-butoxy)carbonyl]amino}-4-methylpentanamide]-3-{4,5-difluoro-2',6'-dimethyl-[1,1'-biphenyl]-3-yl}propanoate (1.85 g, 3.38 mmol) in 15 mL of DCM, HCl (4 M in dioxane, 3.0 mL, 12.0 mmol) was added. The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated under vacuum, and the residue was dried in a vacuum oven at 40°C for 2 hours to obtain the title product (1.73 g, 97% yield) as a white solid. LCMS m / z: 447.6 [M+H]+, (ESI+), Rt = 0.80 (S1) 1 H 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)

[0201] The intermediates in Table 3 were synthesized using the corresponding starting materials in accordance with General Scheme 2 (Steps A-B), as exemplified by Intermediate B2. The diastereomers were separated either during final purification or, if necessary, by chiral separation. The intermediates were obtained as the title compound or its salts.

[0202] [Table 4-1] [Table 4-2] [Table 4-3] [Table 4-4] [Table 4-5] [Table 4-6] [Table 4-7] [Table 4-8] [Table 4-9] [Table 4-10] [Table 4-11]

[0203] Synthesis of intermediate B17 tert-butyl(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 [ka] To a solution of intermediate B4 (200 mg, 0.43 mmol) in pyridine (10 mL), (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 ELISA (25 mL), washed with NaHCO3 (saturated aqueous solution, 25 mL) and water (25 mL), dehydrated with MgSO4, and concentrated under vacuum to obtain the title product (200 mg, 73% yield) as a bright yellow solid. LCMS m / z:544.2[M-Boc+H]+, (ESI+), Rt=3.14(S6)

[0204] Synthesis of intermediate B18 Methyl(3S)-3-{4,5-difluoro-2',6'-dimethyl-[1,1'-biphenyl]-3-yl}-3-[(2S)-4-methyl-2-{[(2R)-piperidine-2-yl]formamide}pentanamide]propanoate hydrochloride [ka] To a solution of tert-butyl(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), HCl (4 M in dioxane, 0.78 mL, 3.11 mmol) was added. The reaction mixture was stirred at room temperature for 4 hours. Further HCl (4 M in dioxane, 0.78 mL, 3.11 mmol) was added, and the reaction mixture was stirred at room temperature for a further 2 hours. After removing the solvent under vacuum, the title product (180 mg, 100% yield) was obtained as a yellow solid. LCMS m / z:544.2[M+H]+, (ESI+), Rt=2.63(S6)

[0205] Synthesis of intermediate B19 Methyl(3S)-3-[(2S)-2-{[(2R)-1-acetylpiperidine-2-yl]formamide}-4-methylpentanamide]-3-{4,5-difluoro-2',6'-dimethyl-[1,1'-biphenyl]-3-yl}propanoate [ka] Methyl(3S)-3-{4,5-difluoro-2',6'-dimethyl-[1,1'-biphenyl]-3-yl}-3-[(2S)-4-methyl-2-{[(2R)-piperidine-2-yl]formamide}pentanamide] (intermediate B18, 180 mg, 0.310 mmol) and DIPEA (0.24 mL, 1.55 mmol) were mixed in DCM (5 mL) and acetyl chloride (0.024 mL, 0.341 mmol) at room temperature. The reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was then concentrated under vacuum to obtain a crude residue, which was purified by column chromatography (12 g silica, 0-50% ethyl phosphate in heptane, then 0-5% MeOH in DCM, then 0-2% MeOH in DCM) to obtain the title compound (122 mg, 61% yield) as a white solid. LCMS m / z:586.2[M+H]+, (ESI+), Rt=2.85(S6)

[0206] Scheme for general route 3a [ka]

[0207] Synthesis of intermediate C1 1-Fluoro-4-iodo-2,3,5-trimethylbenzene (Step A) [ka] To a stirred solution of 4-fluoro-2,3,6-trimethylaniline (7.27 g, 42.71 mmol) in MeCN (120 mL), CuI (10.6 g, 55.66 mmol) and tert-butyl nitrite (10.0 mL, 84.08 mmol) were added. This solution was stirred at 60°C for 18 hours, then at room temperature for 48 hours. The reaction mixture was concentrated under vacuum, and the residue was suspended in HCl (100 mL) and then filtered. The filtrate was concentrated under vacuum, and the residue was purified by column chromatography (350 g silica, 0-100% HCl in heptane) to obtain the title product (4.07 g, 33% yield) as an oily substance. LCMS m / z: no ionisation, (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).

[0208] Synthesis of intermediate C2 (intermediate 555a) 2-(4-fluoro-2,3,6-trimethylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Step B) [ka] 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)phosphane (50.0 mg, 0.14 mmol) were added. This reaction mixture was heated at 80°C for 18 hours. The reaction mixture was concentrated under vacuum, and the residue was suspended in ethyl acetate (15 mL). This mixture was filtered, and the filtrate was concentrated under vacuum. Purification by column chromatography (10 g silica, 0-100% ethyl acetate in heptane) yielded the title product (181 mg, 86% yield) as a yellow solid. LCMS m / z: no ionisation, (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).

[0209] Scheme for general route 3b [ka]

[0210] Synthesis of intermediate C3 4,4,5,5-Tetramethyl-2-(2,3,6-trimethylphenyl)-1,3,2-dioxaborolane [ka] 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), Pd(dppf)Cl2 (59 mg, 0.0813 mmol) was added. This reaction mixture was heated at 100 °C for 3 hours. The reaction mixture was cooled and treated with Cs2CO3 (397 mg, 1.22 mmol), tris(4-methoxyphenyl)phosphane (3.2 mg, 8.94 μmol), and Pd(OAc)2 (18 mg, 0.0813 mmol) by blowing N2 for 2 minutes. This reaction mixture was heated at 100 °C for a further 3 hours. The reaction mixture was cooled and diluted with SiO2 (40 mL) and filtered. The filtrate was concentrated under vacuum, and the crude product was purified by column chromatography (25 g silica, 0-20% ethyl phosphate in heptane) to obtain 4,4,5,5-tetramethyl-2-(2,3,6-trimethylphenyl)-1,3,2-dioxaborolane (86 mg, 0.346 mmol, 43% yield) as a colorless oil. 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)

[0211] The following intermediates were prepared using the corresponding starting materials in a manner similar to that of intermediate C3 outlined in general route 3b.

[0212] [Table 5]

[0213] Scheme for General Route 4 [ka]

[0214] Synthesis of intermediate D1 Process A: Ethyl (3S)-3-[(2S)-2-{[(tert-butoxy)carbonyl]amino}-4-methylpentanamide]-3-{4,4'-difluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl}propanoate (Process A) [ka] To a stirred solution of ethyl(3S)-3-(5-bromo-2-fluoro-3-methylphenyl)-3-[(2S)-2-{[(tert-butoxy)carbonyl]amino}-4-methylpentanamide]propanoate (5.5 g, 10.6 mmol) and 2-(4-fluoro-2,6-dimethylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (3.07 g, 12.15 mmol) in 1,4-dioxane (90 mL) and water (9 mL), K3PO4 (9.25 g, 42.97 mmol) was added. This mixture was degassed with N2 for 5 minutes, 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 hours. This mixture was concentrated under vacuum, and the residue was dissolved in HCl (100 mL) and washed with water (50 mL) and brine (30 mL). The aqueous phase was further extracted with HCl (2 × 50 mL), and the combined organic phase was dehydrated with MgSO4 and concentrated under vacuum. Purification by column chromatography (100 g silica, 0-100% HCl gradient in heptane) yielded the title product (5.29 g, 88% yield) as an off-white solid. LCMS m / z: 583.4 [M+Na]+, (ESI+), Rt = 1.23 (S1) 1H 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).

[0215] Synthesis of intermediate D2 Ethyl(3S)-3-[(2S)-2-amino-4-methylpentanamide]-3-{4,4'-difluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl}propanoate hydrochloride (Step B) [ka] To a stirred solution of ethyl(3S)-3-[(2S)-2-{[(tert-butoxy)carbonyl]amino}-4-methylpentanamide]-3-{4,4'-difluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl}propanoate (5.27 g, 9.39 mmol) in anhydrous DCM (42 mL), 4M HCl (11.7 mL, 46.8 mmol) in dioxane was added. The reaction mixture was stirred at room temperature for 18 hours. The mixture was concentrated under vacuum to obtain the title product (5.75 g, 100% yield) as a white solid. LCMS m / z: 461.3 [M+H]+, (ESI+), Rt = 0.86 (S1) 1H 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).

[0216] The intermediates in Table 5 were synthesized using the corresponding starting materials in accordance with General Scheme 4 (Steps A-B), as exemplified by Intermediate D2. The diastereomers were separated either during final purification or, if necessary, by chiral separation. The intermediates were obtained as the title compound or its salts.

[0217] [Table 6-1] [Table 6-2] [Table 6-3] [Table 6-4] [Table 6-5] [Table 6-6] [Table 6-7] [Table 6-8]

[0218] Scheme for general route 5 [ka]

[0219] Synthesis of intermediate E1 Ethyl (3S)-3-[(2S)-2-{[(tert-butoxy)carbonyl]amino}-4-methylpentanamide]-3-[2-fluoro-3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]propanoate (Step A) [ka] Intermediate B13 was used as the starting material, and it was manufactured using a method similar to that for intermediate C2. 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).

[0220] Synthesis of intermediate E2 Ethyl (3S)-3-[(2S)-2-{[(tert-butoxy)carbonyl]amino}-4-methylpentanamide]-3-[5-(2,5-dimethyl-2H-indazole-4-yl)-2-fluoro-3-methylphenyl]propanoate (Step B) [ka] Intermediate E1 and 4-bromo-2,5-dimethylindazole were prepared using a method similar to that used for intermediate D1. LCMS m / z: 583.5 [M+Na]+, (ESI+), Rt = 1.08 (S1) 1 H 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 = 7.1 Hz, 3H), 0.72 (d, J = 6.6 Hz, 6H).

[0221] Synthesis of intermediate E3 Methyl(3S)-3-[(2S)-2-amino-4-methylpentanamide]-3-[5-(2,5-dimethyl-2H-indazole-4-yl)-2-fluoro-3-methylphenyl]propanoate (Process C) [ka] To a solution of ethyl(3S)-3-[(2S)-2-{[(tert-butoxy)carbonyl]amino}-4-methylpentanamide]-3-[5-(2,5-dimethyl-2H-indazole-4-yl)-2-fluoro-3-methylphenyl]propanoate (1.5 g, 2.06 mmol) in MeOH (2.5 mL), 4 M HCl (2.5 mL) in dioxane was added. The reaction mixture was stirred at room temperature for approximately 1 hour. The reaction mixture was concentrated under vacuum, and the residue was partitioned between Depositphotos (50 mL) and saturated NaHCO3 solution (15 mL). The organic layer was passed through a phase separator and concentrated under vacuum to obtain the title product (804 mg, 67% yield) as a light brown glassy solid. LCMS m / z: 469.4 [M+Na]+, (ESI+), Rt = 0.76 (S1) 1 H 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).

[0222] The intermediates in Table 6 were synthesized using the corresponding starting materials in accordance with general scheme 5 (steps A-C), as exemplified by intermediate E3. The diastereomers were separated either during final purification or, if necessary, by chiral separation. The intermediates were obtained as the title compound or its salts.

[0223] [Table 7-1] [Table 7-2]

[0224] Scheme for General Route 6 [ka]

[0225] Synthesis of intermediate F1 Ethyl(3S)-3-{4,5-difluoro-2',6'-dimethyl-[1,1'-biphenyl]-3-yl}-3-[(2S)-4-methyl-2-[(quinoline-8-yl)formamide]pentanamide]propanoate [ka] Ethyl(3S)-3-[(2S)-2-amino-4-methylpentanamide]-3-{4,5-difluoro-2',6'-dimethyl-[1,1'-biphenyl]-3-yl}propanoate hydrochloride (intermediate B2, 80 mg, 0.154 mmol) and quinoline-8-carboxylic acid (32 mg, 0.185 mmol) were dissolved in DCM (1.54 mL), to which 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 product was concentrated under vacuum, and the residue was purified by column chromatography (10 g silica, 0-100% ethyl phosphate in heptane) to obtain the title product (59 mg, 64% yield) as a colorless solid. LCMS m / z: 602.5 [M+H]+, (ESI+), Rt = 4.71 (S4) 1H 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, 2.3 Hz, 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)

[0226] The intermediates listed in Table 7 were prepared using the corresponding starting materials in a manner similar to that of intermediate F1 outlined in General Route 6.

[0227] [Table 8-1] [Table 8-2] [Table 8-3] [Table 8-4] Table 8-5 Table 8-6 Table 8-7 Table 8-8 Table 8-9 Table 8-10 Table 8-11 Table 8-12 Table 8-13 Table 8-14 Table 8-15 Table 8-16 Table 8-17 Table 8-18 Table 8-19 Table 8-20 Table 8-21 [Table 8-22] [Table 8-23] [Table 8-24] [Table 8-25] [Table 8-26] [Table 8-27] [Table 8-28] [Table 8-29] [Table 8-30] [Table 8-31] [Table 8-32] [Table 8-33] [Table 8-34] [Table 8-35] [Table 8-36]

[0228] Synthesis of intermediate F39 Ethyl(3S)-3-{4,5-difluoro-2',6'-dimethyl-[1,1'-biphenyl]-3-yl}-3-[(2S)-2-[(1,4-dimethyl-2-oxo-1,2-dihydropyridine-3-yl)formamide]-4-methylpentanamide]propanoate [ka] To a solution of methyl 1,4-dimethyl-2-oxo-1,2-dihydropyridine-3-carboxylate (100 mg, 0.497 mmol) in THF (4 mL), LiOH.H2O (104 mg, 2.48 mmol) in water (1 mL) was added. This reaction mixture was stirred for 48 hours. The reaction mixture was concentrated under vacuum to obtain an intermediate product. The acid of the intermediate 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. Next, this reaction was quenched with water (10 mL) and extracted with SiO2 (3 × 10 mL). The combined organic layers were washed with brine, dehydrated with Na2SO4, and concentrated under vacuum to obtain a crude residue. Purification by column chromatography (12 g Redisep Gold silica, 0-100% ethyl acetate in heptane) yielded the title product (20 mg, 9% yield) as a colorless gum-like substance. LCMS m / z:596.4[M+H]+, (ESI+), Rt=2.85(S6)

[0229] Scheme for general route 7 [ka]

[0230] Synthesis of intermediate G1 Ethyl(3S)-3-{2',6'-dichloro-4,5-difluoro-[1,1'-biphenyl]-3-yl}-3-[(2S)-4-methyl-2-[(1-methyl-2-oxo-1,2-dihydropyridine-3-yl)formamide]pentanamide]propanoate [ka] Pd(dppf)Cl2 (18 mg, 0.0214 mmol) was added to a degassed suspension of ethyl(3S)-3-(5-bromo-2,3-difluorophenyl)-3-[(2S)-4-methyl-2-[(1-methyl-2-oxo-1,2-dihydropyridine-3-yl)formamide]pentanamide]propanoate (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 product was concentrated under vacuum to obtain a crude residue. Purification by column chromatography (10 g silica, 0-100% phenylethylamine in heptane) yielded the title product (47 mg, 45% yield) as an orange oily substance. 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).

[0231] The intermediates listed in Table 8 were prepared using the corresponding starting materials in a manner similar to that of intermediate G1 outlined in General Route 7.

[0232] [Table 9-1] [Table 9-2]

[0233] Scheme for general route 8 [ka]

[0234] Synthesis of intermediate H1 Ethyl(3S)-3-[2,3-difluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-3-[(2S)-4-methyl-2-[(1-methyl-2-oxo-1,2-dihydropyridine-3-yl)formamide]pentanamide]propanoate [ka] Ethyl(3S)-3-(5-bromo-2,3-difluorophenyl)-3-[(2S)-4-methyl-2-[(1-methyl-2-oxo-1,2-dihydropyridine-3-yl)formamide]pentanamide]propanoate (intermediate F6, 100 mg, 0.153 mmol), B2(pin)2 (58 mg, 0.228 mmol), and KOAc (45 mg, 0.459 mmol) were dissolved in degassed DMF (1 mL) to which Pd(dppf)Cl2 (6.0 mg, 8.20 μmol) was added. This reaction mixture was heated at 80°C for 3 hours. The reaction mixture was cooled to room temperature, filtered through a Celite pad, and washed with excess SiO2 (3 × 5 mL). The filtrate was concentrated under vacuum to obtain the title product (142 mg, 77% yield) as a dark brown gum-like substance. 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)

[0235] Synthesis of intermediate H2 (2S)-4-methyl-2-[(1-methyl-2-oxo-1,2-dihydropyridine-3-yl)formamide]pentanoic acid [ka] It was produced by hydrolysis of methyl(2S)-4-methyl-2-[(1-methyl-2-oxo-1,2-dihydropyridine-3-yl)formamide]pentanoate using the general route 6 and the route outlined in step B. 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 = 7.9 Hz, 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)

[0236] Synthesis of intermediate H3 Ethyl(3S)-3-(5-bromopyridine-3-yl)-3-[(2S)-4-methyl-2-[(1-methyl-2-oxo-1,2-dihydropyridine-3-yl)formamide]pentanamide]propanoate dihydropyridine-3-yl)formamide]pentanamide]propanoate [ka] Starting with intermediates H2 and A18 in DMF, intermediate B1 was prepared using a method similar to that used for intermediate B1. LCMS m / z:521.2 / 523.2[M+H]+, (ESI+), Rt=0.79, S1

[0237] Synthesis of intermediate H3B Ethyl(3S)-3-[(2S)-4-methyl-2-[(1-methyl-2-oxo-1,2-dihydropyridine-3-yl)formamide]pentanamide]-3-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-3-yl]propanoate [ka] Intermediate H3 was used as the starting material, and the intermediate H1 was produced using a method similar to that used for intermediate H1. 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).

[0238] Scheme for general route 8B [ka]

[0239] Synthesis of intermediate H4 Ethyl(3S)-3-[(2S)-2-{[(tert-butoxy)carbonyl]amino}-4-methylpentanamide]-3-[2,3-difluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]propanoate [ka] Intermediate B15 was produced using the same conditions as intermediate H1. LCMS m / z: 569.5 [M+H] + , (ESI+), Rt = 1.18 (S1) 1H 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 = 7.6 Hz, 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).

[0240] Synthesis of intermediate H5 Ethyl(3S)-3-[(2S)-2-{[(tert-butoxy)carbonyl]amino}-4-methylpentanamide]-3-[5-(2,5-dimethyl-2H-indazole-4-yl)-2,3-difluorophenyl]propanoate [ka] In a MW vial, a mixture consisting of 1,4-dioxane (4 mL) and water (0.5 mL) containing 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-methylpentanamide]-3-[2,3-difluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]propanoate (460.0 mg, 0.81 mmol), and 4-bromo-2,5-dimethylindazole (204.352 mg, 0.91 mmol) was degassed for 5 minutes, and then the vial was stoppered. The reaction mixture was heated under MW irradiation at 150°C for 15 minutes. The reaction mixture was filtered through a thiol cartridge and washed with excess toluene (3 × 10 mL). The solvent of the filtrate was concentrated under vacuum. Purification by column chromatography (25 g silica, 0-100% toluene in heptane) yielded the title product (389 mg, 70% yield) as an oily substance. 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 = 7.1 Hz, 3H), 0.73 - 0.68 (m, 6H).

[0241] Synthesis of intermediate H6 Ethyl(3S)-3-[(2S)-2-amino-4-methylpentanamide]-3-[5-(2,5-dimethyl-2H-indazole-4-yl)-2,3-difluorophenyl]propanoate dihydrochloride [ka] Intermediate H5 was used as the starting material, and it was manufactured using a method similar to that for intermediate A4. 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).

[0242] Synthesis of intermediate H7 {5-[(1S)-1-[(2S)-2-{[(tert-butoxy)carbonyl]amino}-4-methylpentanamide]-3-ethoxy-3-oxopropyl]pyridine-3-yl}boronic acid [ka] 1,4-dioxane (1.8 mL) and one drop of DMF were added to an MW vial containing PdCl2(dppf)2 (40.0 mg, 0.05 mmol), ethyl(3S)-3-(5-bromopyridine-3-yl)-3-[(2S)-2-{[(tert-butoxy)carbonyl]amino}-4-methylpentanamide]propanoate (intermediate B12, 0.45 g, 0.601 mmol), bis(pinacolato)diborone (0.23 g, 0.906 mmol), and KOAc (0.18 g, 1.78 mmol). The reaction mixture was degassed for 5 minutes and heated under MW irradiation at 150°C for 15 minutes. The reaction mixture was filtered through a thiol cartridge and washed with SiO2 (2 × 10 mL). After removing the solvent under vacuum, a dark brown residue was obtained. Purification by column chromatography (10 g silica, 75-100% ethyl acetate in heptane) yielded the title product (200 mg, 42% yield) as a brown solid. 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).

[0243] Synthesis of intermediate H8 Ethyl(3S)-3-[(2S)-2-{[(tert-butoxy)carbonyl]amino}-4-methylpentanamide]-3-{3',5'-dimethyl-[3,4'-bipyridine]-5-yl}propanoate [ka]

[0244] Condition A In a pressure-resistant vial, a mixture consisting of 1,4-dioxane (0.5 mL) and water (50 μL) containing {5-[(1S)-1-[(2S)-2-{[(tert-butoxy)carbonyl]amino}-4-methylpentanamide]-3-ethoxy-3-oxopropyl]pyridine-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) was degassed. The reaction mixture was sealed and heated at 100°C for 1 hour. The reaction mixture was diluted with ELISA (2 mL) and H2O (2 mL). The organic layer was separated, and the aqueous layer was re-extracted with SiO2 (2 × 1 mL). The combined organic layers were washed with brine (2 mL), dehydrated with Na2SO4, and concentrated under vacuum to obtain a brown oily residue. Purification by reverse-phase column chromatography (10-100% MeCN in H2O containing 10 g of C-18 silica and 0.1% formic acid) yielded the title product (13 mg, 50% yield) as a brown, viscous oil.

[0245] Condition B {5-[(1S)-1-[(2S)-2-{[(tert-butoxy)carbonyl]amino}-4-methylpentanamide]-3-ethoxy-3-oxopropyl]pyridine-3-yl}boronic acid (intermediate H7, 250.0 mg, 0.51 mmol), 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-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 placed in a pressure-resistant vial. 1,4-dioxane (4 mL) and water (0.4 mL) were added. The reaction mixture was stoppered and heated at 100°C for 3 hours. When this reaction mixture was concentrated under vacuum, a brown residue was obtained. Purification by column chromatography (10 g silica, 0-100% phenylethylamine / heptane) yielded the title product (39 mg, 15% yield) as a colorless oil and the starting material (183 mg, 73% recovery). LCMS m / z: 513.3 [M+H] + , (ESI+), Rt = 0.72 (S1) 1 H 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)

[0246] Synthesis of intermediate H9 Ethyl(3S)-3-[(2S)-2-amino-4-methylpentanamide]-3-{3',5'-dimethyl-[3,4'-bipyridine]-5-yl}propanoate trihydrochloride [ka] To a solution of ethyl(3S)-3-[(2S)-2-{[(tert-butoxy)carbonyl]amino}-4-methylpentanamide]-3-{3',5'-dimethyl-[3,4'-bipyridine]-5-yl}propanoate (1.04 g, 1.83 mmol) in 1,4-dioxane (6 mL), 4 M HCl (1.9 mL, 7.6 mmol) was added in the dioxane. Within 5 minutes, a gum-like substance formed in the flask. Additional 1,4-dioxane (6 mL) was added, and the suspended solid was sonicated for 10 minutes. The mixture was then stirred at room temperature for 18 hours. The reaction was concentrated under vacuum and azeotropically mixed with DCM (2 × 50 mL) to obtain the title product (1.00 g, 1.55 mmol, 85% yield) as an off-white powder. LCMS m / z:413.4[M+H-3HCl] + (ESI+), Rt=0.64(S2)

[0247] The intermediates in Table 9 were synthesized using the corresponding starting materials in accordance with general scheme 8B, exemplified by intermediate H6. Diastereomers were separated either during final purification or, if necessary, by chiral separation methods. The intermediates were obtained as the title compound or its salts.

[0248] [Table 10-1] [Table 10-2]

[0249] Scheme for general route 9 [ka]

[0250] Synthesis of intermediate I1 tert-butyl(2R)-2-{[(2S)-1-methoxy-4-methyl-1-oxopentan-2-yl]carbamoyl}pyrrolidine-1-carboxylate (Step A) [ka] Methyl(2S)-2-amino-4-methylpentanoate 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) were mixed in 23 mL of DMF, to which HATU (8.40 g, 22.1 mmol) was added. This solution was stirred at room temperature for 3 hours, after which HCl (30 mL) and water (20 mL) were added. The organic layer was separated, and the aqueous layer was re-extracted with HCl (3 × 15 mL). The combined organic layers were washed with brine (30 mL), concentrated under vacuum, and purified by column chromatography (50 g silica, TBME 0-100% in heptane) to obtain the title product (2.30 g, 87% yield). 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)

[0251] Synthesis of intermediate I2 (2S)-2-{[(2R)-1-[(tert-butoxy)carbonyl]pyrrolidine-2-yl]formamide}-4-methylpentanoic acid (Step B) [ka] To a stirred solution of tert-butyl(2R)-2-{[(2S)-1-methoxy-4-methyl-1-oxopentan-2-yl]carbamoyl}pyrrolidine-1-carboxylate (2.30 g, 6.38 mmol) in THF (57 mL) and MeOH (1.9 mL), 2 M aqueous LiOH (aqueous) (20 mL, 40.8 mmol) was added. The reaction mixture was stirred at 45 °C for 30 minutes. The solution was cooled, water (10 mL) was added, and the mixture was concentrated under vacuum to remove organic matter. The water was acidified with 1 M aqueous HCl (aqueous) to approximately pH 3, and the resulting precipitate was extracted by DCM (3 × 15 mL). The combined organic layers were concentrated under vacuum to obtain the title product (2.10 g, 95% yield) as a white solid. 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)

[0252] Synthesis of intermediate I3 tert-butyl(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-carboxylate (Step C) [ka] (2S)-2-{[(2R)-1-[(tert-butoxy)carbonyl]pyrrolidine-2-yl]formamide}-4-methylpentanoic acid (150 mg, 0.434 mmol) and ethyl(3S)-3-amino-3-[4-fluoro-2',6'-dimethyl-5-(trifluoromethyl)-[1,1'-biphenyl]-3-yl]propanoate (218 mg, 0.478 mmol) were dissolved in DCM (3 mL), to which 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 oily product. Purification by flash column chromatography (10 g silica, 0-100% phenyl in heptane) yielded the title product (314 mg, 98% yield) as a pale yellow oily substance. LCMS m / z: 716.4 [M+H]+, (ESI+), Rt = 1.25, S1 1H 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)

[0253] Synthesis of intermediate I4(6a) Ethyl (3S)-3-[4-fluoro-2',6'-dimethyl-5-(trifluoromethyl)-[1,1'-biphenyl]-3-yl]-3-[(2S)-4-methyl-2-{[(2R)-pyrrolidine-2-yl]formamide}pentanamide]propanoate hydrochloride (Process D) [ka] To a solution of tert-butyl(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-carboxylate (314 mg, 0.425 mmol) in DCM (4.5 mL), HCl (4 M in dioxane, 1.5 mL, 6.00 mmol) was added. The reaction mixture was stirred at room temperature for 45 minutes. Further HCl (4 M in dioxane, 1.5 mL, 6.00 mmol) was added, and the reaction mixture was stirred for a further 15 minutes. The reaction mixture was concentrated under vacuum, triturated with heptane (2 × 5 mL), the solvent was decanted, and the residue was dried under vacuum to obtain the title product (193 mg, 62% yield) as an off-white powder. 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)

[0254] Synthesis of intermediate I5 Ethyl (3S)-3-[(2S)-2-{[(2R)-1-acetylpyrrolidine-2-yl]formamide}-4-methylpentanamide]-3-[4-fluoro-2',6'-dimethyl-5-(trifluoromethyl)-[1,1'-biphenyl]-3-yl]propanoate (Step 5) [ka] To a solution of ethyl(3S)-3-[4-fluoro-2',6'-dimethyl-5-(trifluoromethyl)-[1,1'-biphenyl]-3-yl]-3-[(2S)-4-methyl-2-{[(2R)-pyrrolidine-2-yl]formamide}pentanamide]propanoate hydrochloride (100 mg, 0.136 mmol) and DIPEA (38 μL, 0.218 mmol) in DCM (1.2 mL), a preservative solution of acetyl chloride (0.1 mL of preservative solution: 120 μL of acetyl chloride in 1 mL of DCM) was added at 0°C. The reaction mixture was stirred and warmed to room temperature for 2.5 hours. The reaction mixture was cooled to 0°C and treated again with DIPEA (13 μL, 0.0746 mmol) and acetyl chloride preservative solution (0.05 mL), and then warmed to room temperature for a further 1 hour. The reaction mixture was diluted with DCM (2 mL), quenched with saturated sodium bicarbonate (aqueous solution, 3 mL), and the resulting water was extracted with DCM (3 mL). The combined organic layer was passed through a phase separator and concentrated under vacuum. The resulting residue was purified by column chromatography (10 g silica, 0-100% ethyl phosphate in heptane) to obtain the title product (39 mg, 43% yield) as an off-white semi-solid. LCMS m / z: 636.6 [M+H]+, (ESI+), Rt = 1.17, (S1) 1H 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)

[0255] The following intermediates were prepared using the corresponding starting materials in a manner similar to that of intermediate I5 outlined in General Route 6.

[0256] [Table 11-1] [Table 11-2]

[0257] Scheme for general route 10A [ka]

[0258] Synthesis of intermediate J1 Methyl 1-(1-methylazetidine-3-yl)-2-oxo-1,2-dihydropyridine-3-carboxylate (Step A) [ka] To a solution of methyl 2-oxo-2H-pyran-3-carboxylate (800 mg, 5.19 mmol) in DMF (10 mL), 1-methylazetidine-3-amine (447 mg, 5.19 mmol) in DMF (10 mL) was added dropwise at 0°C. The reaction mixture was stirred at 0°C for 1 hour, and then warmed to room temperature. Next, T3P (50% in ethyl acetate, 4.6 mL, 7.79 mmol) was added dropwise. The reaction mixture was stirred for 72 hours and then concentrated under vacuum. Purification by column chromatography (55 g, KPNH silica, 0-100% ethyl acetate in heptane, 0-20% MeOH in ethyl acetate) yielded the title product (415 mg, 25% yield) as a red solid. LCMS m / z:223.1[M+H]+, (ESI+), Rt=0.38(S1)

[0259] Synthesis of intermediate J2 (intermediate 7a) 1-(1-methylazetidine-3-yl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (Step B) [ka] To a solution of methyl 1-(1-methylazetidine-3-yl)-2-oxo-1,2-dihydropyridine-3-carboxylate (415 mg, 1.29 mmol) in MeOH (6.9 mL), LiOH (2 M, aqueous, 1.3 mL, 2.58 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours. When the reaction mixture was concentrated under vacuum, a red solid was obtained. Purification by column chromatography (11 g KPNH silica, 0-100% methanol in butyl) yielded the title product (100 mg, 34% yield) as a red solid. 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)

[0260] Synthesis of intermediate J3 Methyl 1-(oxetan-3-yl)-2-oxo-1,2-dihydropyridine-3-carboxylate (Step A) [ka] To a solution of methyl 2-oxo-2H-pyran-3-carboxylate (1.00 g, 6.49 mmol) in DMF (33.5 mL), oxetane-3-amine hydrochloride (0.72 g, 6.56 mmol) and DIPEA (3.4 mL, 19.5 mmol) were added at room temperature. 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 a further 3 hours. This reaction mixture was concentrated under vacuum, suspended in water (150 mL), and extracted with RINKAN (3 × 50 mL). The combined organic layer did not contain any product. The aqueous layer was extracted with a 4:1 DCM / IPA solution (2 × 60 mL). The combined organic layer was concentrated under vacuum to obtain the title product (352 mg, 24% yield) as a brown oily substance. LCMS m / z: 210.1 [M+H] + , (ESI+), Rt = 1.08 (S4) 1H NMR (400 MHz, DMSO-d6) δ [ppm]: 8.08-8.02 (m, 2H), 6.41 (t, J = 6.9 Hz, 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)

[0261] Synthesis of intermediate J4 1-(oxetan-3-yl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (Step B) [ka] To a stirred methanol (4.5 mL) and THF (65 mL) solution of methyl 1-(oxetan-3-yl)-2-oxo-1,2-dihydropyridine-3-carboxylate (352.2 mg, 1.57 mmol) was added, along with 2 M aqueous 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 (approximately 20 mL). The suspension was acidified to approximately pH 1 using 2 M aqueous HCl and extracted with a 4:1 DCM:IPA solution (3 × 10 mL). The combined organic layers were concentrated under vacuum to obtain the title product (300 mg, 71% yield) as a light orange solid. 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).

[0262] Scheme for general route 10B [ka]

[0263] Synthesis of intermediate K1 Methyl 1-[2-(dimethylamino)ethyl]-2-oxo-1,2-dihydropyridine-3-carboxylate (Step A) [ka] (2-bromoethyl)dimethylamine hydrobromide (375 mg, 1.58 mmol) was added 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). The reaction mixture was stirred at room temperature for 24 hours. The reaction mixture was cooled to room temperature, filtered through a Celite pad, and washed with excess  (100 mL) and DCM (2 × 5 mL). The filtrate was collected and concentrated under vacuum to obtain a crude oil. Purification by open-access preparative HPLC (P4) yielded the title product (79 mg, 25% yield) as a brown oil. 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)

[0264] Synthesis of intermediate K2 Lithium (1+)1-[2-(dimethylamino)ethyl]-2-oxo-1,2-dihydropyridine-3-carboxylate (Step B) [ka] 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), LiOH (2 M, aqueous, 900 μL, 1.80 mmol) was added 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 obtain the title product (108 mg, 100% yield) as a colorless solid. 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 = 6.3 Hz, 2H), 2.52 (s, 2H), 2.17 (s, 6H). (N1)

[0265] The following intermediates were prepared using the corresponding starting materials in a manner similar to that of intermediate K2 outlined in general route 10B.

[0266] [Table 12-1] [Table 12-2]

[0267] Synthesis of intermediate K5 Methyl 1-[3-(dimethylamino)propyl]-2-oxo-1,2-dihydropyridine-3-carboxylate [ka] To a suspension of methyl 2-hydroxypyridine-3-carboxylate (3.00 g, 19.6 mmol) and K2CO3 (6.90 g, 49.9 mmol) stirred in acetone (60 mL), 3-dimethylaminopropyl chloride (3.36 g, 21.26 mmol) was added. This reaction mixture was heated at 60°C for 5 hours, then at room temperature for 72 hours. Sodium iodide (2.0 g, 13.34 mmol) was added to this reaction mixture, and it was stirred for a further 2 hours at 60°C. A further amount of 3-dimethylaminopropyl chloride (2 g, 12.7 mmol) was added, and stirring at 60°C was continued for a further 10 hours. The mixture was filtered through Celite, 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), dehydrated with sodium sulfate, and concentrated under vacuum to obtain a yellow oil. Next, the oily substance was dissolved in ethyl acetate (15 mL) and diluted with heptane (15 mL), and the resulting solid was filtered. The filtrate was concentrated under vacuum to obtain the title product (2.01 g, 36% yield, 83% purity) as a yellow oily substance. LCMS m / z:499.3[2M+Na] + (ESI+), Rt=0.40(S2)

[0268] Synthesis of intermediate K6 Lithium(1+)1-[3-(dimethylamino)propyl]-2-oxo-1,2-dihydropyridine-3-carboxylate [ka] Intermediate K5 was used to produce intermediate K2 using a method similar to that used for intermediate K2. LCMS m / z: 225.1 [M+H] + , (ESI+), Rt = 0.40 (S2) 1H 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).

[0269] Scheme for general route 10C [ka]

[0270] Synthesis of intermediate K7 Methyl 5-chloro-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxylate [ka] 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 (7.04 mL, 7.04 mmol) in DCM was added dropwise. The reaction mixture was heated under 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, yielding the title product (560 mg, 88% yield) as a solid. 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).

[0271] Synthesis of intermediate K8 Methyl 5-chloro-6-methyl-2-(propa-2-en-1-yloxy)pyridine-3-carboxylate [ka] To a 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) stirred in acetone (12 mL) and acetonitrile (10 mL), 3-bromopropa-1-ene (0.59 mL, 6.82 mmol) was added. The reaction mixture was stirred at 60 °C for 48 hours. The reaction mixture was filtered and washed with acetone (25 mL). The organic reaction mixture was concentrated under vacuum to obtain the title product (715 mg, 40% pure, 43% yield) as an oily substance. LCMS m / z:242.1[M+H] + (ESI+), Rt=1.08(S1)

[0272] Synthesis of intermediate K9 Methyl 5-chloro-6-methyl-2-oxo-1-(propa-2-en-1-yl)-1,2-dihydropyridine-3-carboxylate [ka] A solution of methyl 5-chloro-6-methyl-2-(propa-2-en-1-yloxy)pyridine-3-carboxylate (0.715 g, 1.18 mmol) and palladium(II) dichloride (10.493 mg, 0.06 mmol) in dry xylene (2 mL) was stirred at 130 °C for 16 hours. The reaction mixture was filtered and washed with ethyl acetate (10 mL). After removing the solvent under vacuum, an oily substance was obtained. Purification by column chromatography (10 g silica, 10-80% ethyl acetate in heptane) yielded the title product (336 mg, 93% pure, 109% yield) as an oily substance. LCMS m / z: 242.1 [M+H] + , (ESI+), Rt = 0.69 (S1) 1H 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).

[0273] Synthesis of intermediate K10 Methyl 5-chloro-6-methyl-2-oxo-1-(2-oxoethyl)-1,2-dihydropyridine-3-carboxylate [ka] To a solution of methyl 5-chloro-6-methyl-2-oxo-1-(propa-2-en-1-yl)-1,2-dihydropyridine-3-carboxylate (330.0 mg, 1.37 mmol) in 1,4-dioxane (7 mL) and water (3.5 mL), dipotassium dioxide (dioxo)osmium dihydrate (50.312 mg, 0.14 mmol) and sodium periodate (876.207 mg, 4.1 mmol) were added. This 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), dehydrated with sodium sulfate, and concentrated under vacuum to obtain the title product (165 mg, 55% pure, 27% yield) as a black liquid. 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).

[0274] Synthesis of intermediate K11 Methyl 5-chloro-1-[2-(dimethylamino)ethyl]-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxylate [ka] To 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), 2 M dimethylamine in THF (0.82 mL, 1.64 mmol) was added, followed by acetic acid (0.02 mL, 0.33 mmol). This solution was stirred at ambient temperature for 1 hour, then STAB (167.02 mg, 0.79 mmol) was added, and the reaction mixture was stirred for a further 18 hours. This mixture was diluted with 1,2-dichloroethane (10 ml), washed with 0.5 M sodium hydroxide solution (5 ml), and water (5 ml), and dehydrated with Na2SO4. After removing the solvent under vacuum, an oily substance was obtained. Purification by reverse-phase chromatography (12 g of C-18, 10-100% CH3CN in H2O containing 0.1% formic acid) yielded the title product (65 mg, 36% yield) as an oily substance. 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, 6.3 Hz, 2H), 3.90 (s, 3H), 2.65 - 2.56 (m, 5H), 2.31 (s, 6H).

[0275] Synthesis of intermediate K12 5-Chloro-1-[2-(dimethylamino)ethyl]-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxylate hydrochloride [ka] To a stirred 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), 2 M aqueous lithium hydroxide monohydrate (0.16 mL, 0.330 mmol) was added at 45 °C. The reaction mixture was stirred for 1 hour, and then the pH was acidified to 2 with 1 N HCl. After removing the solvent under vacuum, the title product (68 mg, 98% yield) was obtained. LCMS m / z:259.1[M+H-HCl] + (ESI+), Rt=0.31(S2)

[0276] Scheme for general route 10D [ka]

[0277] Synthesis of intermediate K13 Ethyl 2-{[3-(dimethylamino)propyl]carbamoyl}acetate [ka] 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), ethyl 3-chloro-3-oxopropanoate (1.14 mL, 8.91 mmol) was added dropwise at 0°C. The reaction mixture was warmed to room temperature and stirred for a further 5 minutes. The reaction mixture was filtered, and the filtrate was concentrated under vacuum to obtain the title product (2.36 g, 54% pure, 86% yield) as an orange semi-solid. LCMS m / z: 217.2 [M+H] + , (ESI+), Rt = 0.34 (S1) 1H NMR (400 MHz, CDCl3) δ [ppm]: 4.11 - 4.05 (m, 2H), 3.30 (q, J = 6.1 Hz, 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).

[0278] Synthesis of intermediate K14 Ethyl 1-[3-(dimethylamino)propyl]-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxylate [ka] To a solution of ethyl 2-{[3-(dimethylamino)propyl]carbamoyl}acetate (2.36 g, 5.89 mmol) in THF (10 mL), (E)-4-ethoxy-1,1,1-trifluorobuta-3-en-2-one (1.01 mL, 7.07 mmol) and DBU (0.93 mL, 6.19 mmol) were added. The reaction mixture was stirred at room temperature for 66 hours. The reaction mixture was diluted with ELISA (75 mL) and water (100 mL). The organic layer was separated, and the aqueous layer was re-extracted with ELISA (4 × 75 mL). The combined organic layers were washed with brine (50 mL), then passed through a phase separator and concentrated under vacuum to obtain a blood-red residue. Purification by column chromatography (10 g of Kp-NH silica, 0-100% phenyl in heptane) yielded the title product (0.25 g, 13% yield) as a light brown oily substance. LCMS m / z: 321.3 [M+H] + , (ESI+), Rt = 0.46 (S1) 1H 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 = 6.8 Hz, 2H), 2.23 (s, 6H), 1.89 (p, J = 6.8 Hz, 2H), 1.38 (t, J = 7.1 Hz, 3H).

[0279] Synthesis of intermediate K15 1-[3-(dimethylamino)propyl]-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxylate hydrochloride [ka] 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), 2 M aqueous lithium hydroxide hydrate (0.53 mL, 1.05 mmol) was added at 45 °C. The reaction mixture was stirred for 1 hour. The mixture was acidified to pH 4 using 1 N aqueous HCl. The reaction mixture was concentrated under vacuum to obtain the title product (230 mg, 100% yield) as a light brown solid. LCMS m / z:293.2[M+H] + (ESI+), Rt=0.32(S1)

[0280] The following intermediates were prepared using the corresponding starting materials in a manner similar to that of intermediate K6 outlined in general route 10D.

[0281] [Table 13]

[0282] Synthesis of intermediate K17 Ethyl 2-[(3-{[(tert-butoxy)carbonyl]amino}-3-methylbutyl)carbamoyl]acetate [ka] It was prepared using tert-butyl N-(4-amino-2-methylbutan-2-yl)carbamate hydrochloride and ethyl 3-chloro-3-oxo-propanoate in a manner similar to that of intermediate K4. 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)

[0283] Synthesis of intermediate K18 Ethyl 1-(3-{[(tert-butoxy)carbonyl]amino}-3-methylbutyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxylate [ka] To a solution of ethyl 2-[(3-{[(tert-butoxy)carbonyl]amino}-3-methylbutyl)carbamoyl]acetate (721.0 mg, 2.28 mmol) in THF (7 mL), (E)-4-ethoxy-1,1,1-trifluorobuta-3-en-2-one (400 μL, 2.81 mmol) and DBU (370 μL, 2.47 mmol) were added. The reaction mixture was heated at 50 °C for 2 hours. The reaction mixture was concentrated under vacuum and then resuspended in ELISA (40 mL), followed by sequential washing with brine (30 mL), saturated NH4Cl aqueous solution (30 mL), and brine (30 mL). The organic layer was dehydrated with MgSO4 and concentrated under vacuum to obtain the residue. The residue was suspended in toluene (15 mL), and 4-methylbenzenesulfonic acid monohydrate (26 mg, 0.137 mmol) was added. The reaction mixture was stirred at 110°C for 1 hour. The reaction mixture was cooled to room temperature, then diluted with toluene (10 mL), and successively washed with brine (25 mL), saturated NaHCO3 aqueous solution (25 mL), and brine (25 mL). The organic layer was dehydrated with MgSO4 and concentrated under vacuum to obtain a dark red oil. Purification by column chromatography (10 g silica, 0-55% toluene in heptane) yielded the title product (389 mg, 0.842 mmol, 37% yield) as a pale orange oil. 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).

[0284] Synthesis of intermediate K19 Ethyl 1-(3-amino-3-methylbutyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxylate hydrochloride [ka] 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 (2.0 mL, 8.00 mmol) in dioxane was added. The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under vacuum to obtain the title product (306 mg, 0.815 mmol, 97% yield) as an off-white solid. 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 = 7.4 Hz, 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).

[0285] Synthesis of intermediate K20 Synthesis of intermediates Ethyl 1-[3-(dimethylamino)-3-methylbutyl]-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxylate [ka] 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) was treated with paraformaldehyde (150 mg, 4.83 mmol), followed by acetic acid (0.30 mL, 5.24 mmol). The reaction mixture was stirred for 20 minutes, and then STAB (1.00 g, 4.72 mmol) was added. The reaction mixture was stirred at room temperature for 24 hours, and then heated at 40°C for a further 4 hours. 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 × 15 mL). The combined organic layers were washed with brine (20 mL), dehydrated with MgSO4, and concentrated under vacuum to obtain the title product (258 mg, 85% pure, 73% yield) as a pale yellow oil. 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).

[0286] Synthesis of intermediate K21 Lithium(1+)1-[3-(dimethylamino)-3-methylbutyl]-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxylate [ka] Using intermediate K20, the lithium salt was prepared in a manner similar to that of intermediate K6. The reaction mixture was not acidified. LCMS m / z: 321.3 [M+H] + , (ESI+), Rt = 0.46 (S1) 1 H 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).

[0287] Synthesis of intermediate K22 Ethyl 2-{[2-(dimethylamino)ethyl]carbamoyl}acetate [ka] It was prepared using N,N-dimethylethane-1,2-diamine in a manner similar to that of intermediate K14. 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).

[0288] Synthesis of intermediate K23 Ethyl 1-[2-(dimethylamino)ethyl]-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxylate [ka] To a suspension of ethyl 2-{[2-(dimethylamino)ethyl]carbamoyl}acetate (intermediate K22, 500 mg, 1.83 mmol) in THF (7 mL), DBU (0.3 mL, 2.01 mmol) was added, followed by (3E)-4-methoxybuta-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, and then at 60°C for a further 4 hours. The reaction mixture was concentrated under vacuum to obtain a residue. This residue was suspended in water (40 mL) and extracted with DCM (3 × 30 mL). The combined organic layers were washed with brine (30 mL) and passed through a phase separator. After removing the solvent under vacuum, a brown oily substance was obtained. Purification by column chromatography (10g Kp-NH, 0-100% phenyl in heptane) yielded the title product (131 mg, 74% pure, 21% yield) as a colorless oil. 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 = 7.1 Hz, 3H).

[0289] Synthesis of intermediate K24 Lithium(1+)1-[2-(dimethylamino)ethyl]-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxylate [ka] Intermediate K23 was used as the starting material, and it was manufactured using a method similar to that of intermediate K6. LCMS m / z: 225.2 [M+H]+ , (ESI+), Rt = 0.21 (S2) 1 H 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).

[0290] Scheme for general route 10E [ka]

[0291] Synthesis of intermediate K25 Methyl 1-(1-{[(tert-butoxy)carbonyl]amino}-2-methylpropan-2-yl)-2-oxo-1,2-dihydropyridine-3-carboxylate [ka] It was prepared using tert-butyl N-(2-amino-2-methylpropyl)carbamate and methyl 2-oxo-2H-pyran-3-carboxylate in a manner similar to that of intermediate J3. 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).

[0292] Synthesis of intermediate K26 Methyl 1-(1-amino-2-methylpropan-2-yl)-2-oxo-1,2-dihydropyridine-3-carboxylate hydrochloride [ka] To a solution of methyl 1-(1-{[(tert-butoxy)carbonyl]amino}-2-methylpropan-2-yl)-2-oxo-1,2-dihydropyridine-3-carboxylate (92%, 90 mg, 0.255 mmol) in DCM (2 mL), 4 M HCl (0.65 mL, 2.60 mmol) in dioxane was added. The reaction mixture was stirred at room temperature for 2.5 hours. After removing the solvent under vacuum, the title product (73 mg, 91% pure, 100% yield) was obtained as a beige powder. 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).

[0293] Synthesis of intermediate K27 Methyl 1-[1-(dimethylamino)-2-methylpropan-2-yl]-2-oxo-1,2-dihydropyridine-3-carboxylate [ka] To a solution of methyl 1-(1-amino-2-methylpropan-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), paraformaldehyde (45 mg, 1.45 mmol) was added at room temperature, followed by acetic acid (85 μL, 1.48 mmol). The mixture was stirred for 60 minutes, and then STAB (310 mg, 1.46 mmol) was added. The reaction mixture was stirred for a further 18 hours at room temperature. The reaction mixture was diluted with saturated aqueous NaHCO3 (5 mL) and then extracted with DCM (2 × 2 mL). The combined organic layers were passed through a phase separator and concentrated under vacuum to obtain an oily substance. Purification by column chromatography (12 g of KP-NH silica, 0-100% ethyl acetate in hexane, followed by 0-20% MeOH in ethyl acetate) yielded the title product (50 mg, 90% pure, 70% yield) as an orange oily substance. 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, 2.2 Hz, 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).

[0294] Synthesis of intermediate K28 Lithium(1+)1-[1-(dimethylamino)-2-methylpropan-2-yl]-2-oxo-1,2-dihydropyridine-3-carboxylate [ka] To a solution of methyl 1-[1-(dimethylamino)-2-methylpropan-2-yl]-2-oxo-1,2-dihydropyridine-3-carboxylate (90%, 50 mg, 0.178 mmol) in THF (1 mL), 2 M aqueous lithium hydroxide (100 uL, 0.200 mmol) was added. The solution was stirred at room temperature for 2 hours. Upon removal of the solvent under vacuum, the title product (50 mg, 87% pure, 100% yield) was obtained as a white solid. LCMS m / z:239.1[M+H] + (ESI+), Rt=0.31(S2)

[0295] The following intermediates were prepared using the corresponding starting materials in a manner similar to that of intermediate K outlined in general route 10E.

[0296] [Table 14]

[0297] Scheme for general route 10F [ka]

[0298] Synthesis of intermediate L1 Methyl 2-oxo-1-(2-oxoethyl)-1,2-dihydropyridine-3-carboxylate; trifluoroacetic acid (Step A) [ka] Methyl 1-[(1,3-dioxolan-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 mixture was stirred at 70°C for 1 hour. The reaction mixture was cooled to room temperature and allowed to stand overnight in a sealed vial. The reaction mixture was concentrated under vacuum, and the resulting oily substance was triturated with DCM (3 × 5 mL) and dried under vacuum to obtain a light brown oily substance. This oily substance was redissolved in water (125 μL) and TFA (500 μL, 6.53 mmol), and the reaction mixture was stirred at 80°C for 1 hour. The reaction mixture was concentrated under vacuum, and the resulting oily substance was triturated with DCM (3 × 5 mL) and dried under vacuum to obtain the title product (125 mg, 71% yield) as an oily substance. LCMS m / z:193.9[M+H]+, (ESI+), Rt=0.29(S4)

[0299] Synthesis of intermediate L2 Methyl 1-[2-(azetidine-1-yl)ethyl]-2-oxo-1,2-dihydropyridine-3-carboxylate (Step B) [ka] To a solution of methyl 2-oxo-1-(2-oxoethyl)-1,2-dihydropyridine-3-carboxylate trifluoroacetate (trifluoracetic acid) (125 mg, 0.290 mmol) in DCM (1.4 mL), acetic acid (17 μL, 0.290 mmol) and azetidine (29 μL, 0.436 mmol) were added. After 20 minutes, STAB (93 mg, 0.439 mmol) was added, and the reaction mixture was stirred at room temperature for 90 hours. The reaction mixture was diluted with MeOH, and purified using an SCX cartridge (1 g) from which NH3 (3.5 M) had been eluted from the MeOH, yielding the title product (32 mg, 46% yield) as a dark orange / brown gum-like substance. LCMS m / z: 237.1 [M+H]+, (ESI+), Rt = 0.42 (S2) 1H 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 = 6.1 Hz, 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)

[0300] Synthesis of intermediate L3 Lithium (1+)1-[2-(azetidine-1-yl)ethyl]-2-oxo-1,2-dihydropyridine-3-carboxylate (Step C) [ka] To a solution of methyl 1-[2-(azetidine-1-yl)ethyl]-2-oxo-1,2-dihydropyridine-3-carboxylate (32 mg, 0.135 mmol) in THF (750 μL) and methanol (75 μL), LiOH (2 M (aqueous), 230 μL, 0.460 mmol) was added. The reaction mixture was stirred at room temperature for 3.5 hours. The reaction mixture was concentrated and dried under vacuum to obtain the title product (37 mg, 100% yield) as a yellow solid. LCMS m / z: 223.1 [M+H]+, (ESI+), Rt = 0.18 (S1) 1 H 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)

[0301] The following intermediates were prepared using the corresponding starting materials in a manner similar to that of intermediate L3 outlined in general route 10F.

[0302] [Table 15]

[0303] Scheme for general route 10g [ka]

[0304] Synthesis of intermediate M1 Methyl 1-(3-hydroxypropyl)-2-oxo-1,2-dihydropyridine-3-carboxylate [ka] 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), 3-bromopropan-1-ol (3.5 mL, 38.7 mmol) was added. This reaction was heated at 60°C for 4 hours. An additional 1 mL of 3-bromopropan-1-ol was added, and the reaction was heated further at 60°C for 3 hours. The mixture was filtered to remove excess K2CO3, and the filtrate was concentrated under vacuum to obtain the crude product as a pale yellow oil. Purification by column chromatography (50 g silica, 0-30% MeOH in toluene) yielded the title product (3.00 g, 87% pure, 63% yield) as a very pale yellow oil. 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).

[0305] Synthesis of intermediate M2 Methyl 1-(3-{2-azaspiro[3,4]octan-2-yl}propyl)-2-oxo-1,2-dihydropyridine-3-carboxylate [ka] In a pressure-resistant vial, methyl 1-(3-hydroxypropyl)-2-oxo-1,2-dihydropyridine-3-carboxylate (300 mg, 1.24 mmol) and DIPEA (0.7 mL, 4.01 mmol) in DCM (2 mL) were stirred at room temperature for 5 minutes. This mixture was cooled to 0°C and treated with methanesulfonic anhydride (225.0 mg, 1.29 mmol). The reaction mixture was warmed to room temperature and stirred for a further 30 minutes. The reaction mixture was further treated with methanesulfonic anhydride (50.0 mg, 0.29 mmol) at 0°C and then stirred at room temperature for a further 90 minutes. After removing the solvent under vacuum, an oily substance was obtained. The oily substance 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 vigorously stirred at 50°C for 16 hours. The reaction was quenched with ice-cold water (5 mL) and extracted with SiO2 (2 × 5 mL). The combined organic layer was washed with brine (2 × 10 mL), dehydrated with Na2SO4, and concentrated under vacuum. Purification by reverse-phase column chromatography (12 g C-18 silica, 10-100% MeCN in H2O containing 0.1% ammonium hydroxide modifier) ​​yielded the title product (75 mg, 95% pure, 17% yield) as a colorless gum. LCMS m / z: 305.3 [M+H] + , (ESI+), Rt = 0.63 (S2) 1 H 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)

[0306] Synthesis of intermediate M3 1-(3-{2-azaspiro[3,4]octan-2-yl}propyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid [ka] Intermediate M2 was used to produce intermediate K15 using a similar method. 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).

[0307] The following intermediates were prepared using the corresponding starting materials in a similar manner to intermediate M3 outlined in General Route 10g.

[0308] [Table 16]

[0309] 10g via general route ** scheme [ka]

[0310] Synthesis of intermediate M7 Methyl 1-(2-hydroxyethyl)-2-oxo-1,2-dihydropyridine-3-carboxylate [ka] It was prepared using methyl 2-hydroxypyridine-3-carboxylate and 2-bromoethanol in a manner similar to that of intermediate M1. 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).

[0311] Synthesis of intermediate M8 Methyl 1-[2-(methanesulfonyloxy)ethyl]-2-oxo-1,2-dihydropyridine-3-carboxylate [ka] 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), DMAP (16.0 mg, 0.13 mmol) and triethylamine (0.45 mL, 3.23 mmol), followed by methanesulfonyl chloride (0.15 mL, 1.94 mmol), were added dropwise at 0°C. The reaction mixture was stirred at 0°C for 45 minutes, then poured into water (20 mL) and extracted with DCM (3 × 10 mL). The combined organic layers were passed through a phase separator and concentrated under vacuum to obtain the title product (401 mg, 80% pure, 93% yield) as an orange gum-like substance. 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).

[0312] Amine substitution of the mesylate ester of intermediate M8 [ka]

[0313] Condition A A suspension consisting of methyl 1-[2-(methanesulfonyloxy)ethyl]-2-oxo-1,2-dihydropyridine-3-carboxylate (80%, 374 mg, 1.09 mmol), 3-(trifluoromethoxy)azetidine 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 mixture was diluted with ELISA (10 mL), filtered, and the filtrate was concentrated under vacuum to obtain an oily substance. Purification by column chromatography (5g SCX, 0-100% 7M NH3 in MeOH) yielded methyl 2-oxo-1-{2-[3-(trifluoromethoxy)azetidine-1-yl]ethyl}-1,2-dihydropyridine-3-carboxylate (intermediate M9, 126mg, 54% pure, 32% yield) as a brown gum-like substance.

[0314] Condition B 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), N-ethylethanamine (0.1 mL, 0.97 mmol) was added. The reaction mixture was heated to 60°C for 2 hours, and then concentrated under vacuum to obtain a red oil. Purification by column chromatography (5 g SCX, 0-100% 7M NH3 in MeOH) yielded methyl 1-[2-(diethylamino)ethyl]-2-oxo-1,2-dihydropyridine-3-carboxylate (120 mg, 43% yield) as a red oil.

[0315] Condition C 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) was to which 4-(trifluoromethyl)piperidine hydrochloride (1:1) (125.0 mg, 0.66 mmol) was added. The reaction mixture was heated at 60°C for 3 hours. The reaction mixture was cooled and concentrated under vacuum to obtain an oily substance. Purification by column chromatography (5 g SCX, 0-100% 7M NH3 in MeOH) yielded methyl 2-oxo-1-{2-[4-(trifluoromethyl)piperidine-1-yl]ethyl}-1,2-dihydropyridine-3-carboxylate (130 mg, 94% pure, 53% yield) as an orange oily substance.

[0316] 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. This mixture was heated at 70°C for 5 hours. The reaction mixture was cooled to room temperature, poured over crushed ice (5 mL), and extracted with ethyl acetate (2 × 5 mL). The combined organic layers were washed with brine (2 × 10 mL), dehydrated with sodium sulfate, and concentrated under vacuum to obtain a gum-like substance. Purification by reverse-phase column chromatography (12 g of C-18 silica, 10-100% MeCN in H2O containing 0.1% ammonium hydroxide modifier) ​​yielded methyl 1-[2-(6-azaspiro[3.5]nonane-6-yl)ethyl]-2-oxopyridine-3-carboxylate (270 mg, 90% pure, 52% yield) as a light orange oil.

[0317] Synthesis of intermediate M9 Methyl 2-oxo-1-{2-[3-(trifluoromethoxy)azetidine-1-yl]ethyl}-1,2-dihydropyridine-3-carboxylate [ka] It was prepared using 3-(trifluoromethoxy)azetidine hydrochloride under condition A (actual example). 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).

[0318] Synthesis of intermediate M10 Lithium(1+)2-oxo-1-{2-[3-(trifluoromethoxy)azetidine-1-yl]ethyl}-1,2-dihydropyridine-3-carboxylate [ka] Intermediate M9 was used to produce intermediate L3 using a similar method. 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).

[0319] The following intermediates can be prepared using the corresponding starting materials via the general route, 10g ** It was manufactured using the same method as intermediate M10, which is outlined in [reference].

[0320] [Table 17-1] [Table 17-2] [Table 17-3] [Table 17-4] [Table 17-5] [Table 17-6] [Table 17-7] [Table 17-8] [Table 17-9] [Table 17-10] [Table 17-11] [Table 17-12] [Table 17-13] [Table 17-14] [Table 17-15] [Table 17-16] [Table 17-17] [Table 17-18] [Table 17-19] [Table 17-20]

[0321] Scheme for general route 10h [ka]

[0322] Synthesis of intermediate N1 Ethyl 1-(2,2-dimethoxyethyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxylate [ka] Ethyl 3-chloro-3-oxopropanoate (3.04 mL, 23.78 mmol) was slowly added to a stirred solution of 2,2-dimethoxyethaneamine (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. After removing the solvent from the filtrate under vacuum, an oily substance was obtained. The oily substance was redissolved in DCM (15 mL), and DBU (3.73 mL, 24.97 mmol) and (3E)-4-ethoxy-1,1,1-trifluorobuta-3-en-2-one (4.07 mL, 28.53 mmol) were added. This reaction mixture was stirred for 14 hours, then the solvent was removed under vacuum, and an oily substance was obtained. This oily substance was partitioned between DCM (100 mL) and water (100 mL). The organic layer was separated, and the aqueous layer was further extracted with DCM (2 × 100 mL). The combined organic layers were washed with brine (100 mL), passed through a phase separator, and concentrated under vacuum to obtain a reddish-brown oily substance. Purification by column chromatography (50 g silica, 0-30% ethyl phosphate in heptane) yielded the title product (1.94 g, 95% pure, 24% yield) as an orange-yellow oily substance. 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 = 7.1 Hz, 3H).

[0323] Synthesis of intermediate N2 Ethyl 2-oxo-1-(2-oxoethyl)-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxylate [ka] A solution of ethyl 1-(2,2-dimethoxyethyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxylate (1.94 g, 5.7 mmol) and 4M HCl (in dioxane) (35.0 mL, 140.0 mmol) was stirred at room temperature for 20 minutes. The solvent was removed under vacuum to obtain an oily substance, which was retreated with 4M HCl in dioxane (35.0 mL, 140.0 mmol) and stirred for 1 hour. This reaction mixture was slowly poured into a stirred saturated NaHCO3 aqueous solution (200 mL). The solution was extracted with ELISA (2 × 150 mL). The combined organic layers were washed with brine (50 mL) and concentrated under vacuum through a phase separator to obtain the title product (1.70 g, 82% pure, 88% yield) as an orange solid. 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).

[0324] Synthesis of intermediate N3 Ethyl 1-(2-{2-azaspiro[3,4]octan-2-yl}ethyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxylate [ka] To a stirred solution of ethyl 2-oxo-1-(2-oxoethyl)-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxylate (1.55 g, 4.47 mmol) in DCM (30 mL), 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) were added. The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated under vacuum to obtain an oily residue. Purification by column chromatography (12 g KP-NH silica, 0-100% ethyl phosphate in heptane) yielded the title product (703 mg, 90% pure, 38% yield) as a yellow oil. 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).

[0325] Synthesis of intermediate N4 1-(2-{2-azaspiro[3,4]octan-2-yl}ethyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxylic acid [ka] It was produced using intermediate N3 as the starting material, in a method similar to that used for intermediate O7. LCMS m / z: 345.2 [M+H] + , (ESI+), Rt = 0.48 (S1) 1H 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).

[0326] The following intermediates were prepared using the corresponding starting materials in a similar manner to intermediate N4 outlined in general route 10h.

[0327] [Table 18-1] [Table 18-2] [Table 18-3] [Table 18-4] [Table 18-5] [Table 18-6] [Table 18-7] [Table 18-8] [Table 18-9] [Table 18-10]

[0328] Scheme for general route 10j [ka]

[0329] Synthesis of intermediate O1 (3-aminopropoxy)(tert-butyl)dimethylsilane [ka] To a solution of 3-aminopropan-1-ol (6.00 g, 79.9 mmol) in DCM (90 mL), triethylamine (13.36 mL, 95.86 mmol) and TBDMSCl (13.244 g, 87.87 mmol) were added at 0°C. After 5 minutes, the reaction mixture was warmed to room temperature and stirred for a further 18 hours. The reaction mixture was washed with water (100 mL) and brine (50 mL). The organic layer was dehydrated with Na2SO4 and concentrated under vacuum to obtain the title product (15.30 g, 101% yield) as an oily substance. 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).

[0330] Synthesis of intermediate O2 Ethyl 2-({3-[(tert-butyldimethylsilyl)oxy]propyl}carbamoyl) acetate [ka] Ethyl 3-chloro-3-oxopropanoate (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 using DCM (2 × 100 mL). The combined organic layer was dehydrated with sodium sulfate and concentrated under vacuum to obtain a brown oil. Purification by column chromatography (100 g silica, 0-100% toluene / heptane) yielded the title product (6.80 g, 78% pure, 44% yield) as a light brown oil. 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).

[0331] Synthesis of intermediate O3 Ethyl 1-{3-[(tert-butyldimethylsilyl)oxy]propyl}-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxylate [ka] To a solution of ethyl 2-({3-[(tert-butyldimethylsilyl)oxy]propyl}carbamoyl) acetate (6.55 g, 16.8 mmol) in THF (60 mL), (3E)-4-ethoxy-1,1,1-trifluorobuta-3-en-2-one (4.4 mL, 31.1 mmol) and DBU (4.1 mL, 27.3 mmol) were added. The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated under vacuum to obtain an oily substance. Purification by column chromatography (50 g silica, 0-30% ethyl phosphate in heptane) yielded the title product (1.83 g, 97% pure, 26% yield) as an oily substance. 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 = 7.5 Hz, 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).

[0332] Synthesis of intermediate O4 Ethyl 1-(3-hydroxypropyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxylate [ka] 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), 1 M tetrabutylammonium fluoride (11 mL, 10.8 mmol) was added dropwise at 0 °C. The reaction mixture was stirred at room temperature for 90 minutes. The reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (3 × 30 mL). The combined organic layers were dehydrated with sodium sulfate and concentrated under vacuum to obtain an oily substance. Purification by column chromatography (25 g silica, 0-100% ethyl phosphate in heptane) yielded the title product (1.11 g, 96% pure, 84% yield) as an oily substance. 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).

[0333] Synthesis of intermediate O5 Synthesis of intermediate Ethyl 1-[3-(methanesulfonyloxy)propyl]-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxylate [ka] 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), DMAP (43.994 mg, 0.36 mmol) and triethylamine (1.25 mL, 9.0 mmol), followed by methanesulfonyl chloride (0.42 mL, 5.4 mmol), were added at 0°C. The reaction mixture was stirred at 0°C for 1 hour. The reaction product was poured into water (30 mL) and the organic layer was separated. The water was further extracted with DCM (2 × 20 mL), and the combined organic layers were concentrated under vacuum through a hydrophobic frit to obtain the title product (1.52 g, 89% pure, 101% yield) as an orange gum-like substance. 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).

[0334] Synthesis of intermediate O6 Ethyl 1-(3-{2-azaspiro[3,4]octan-2-yl}propyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxylate [ka] In a pressure-resistant vial, a suspension consisting 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 ELISA (20 mL) and water (20 mL). The organic layer was separated, and the aqueous layer was further extracted with ELISA (2 × 20 mL). The combined organic layers were dehydrated with Na2SO4 and concentrated under vacuum to obtain an oily substance. Purification by column chromatography (10 g silica, 0-10% MeOH in DCM) yielded the title product (108 mg, 98% pure, 46% yield) as a light brown liquid. LCMS m / z: 387.2 [M+H] + , (ESI+), Rt = 0.58 (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), 4.38 (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).

[0335] Synthesis of intermediate O7 1-(3-{2-azaspiro[3,4]octan-2-yl}propyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxylic acid [ka] To a stirred solution of ethyl 1-[3-(2-azaspiro[3,4]octan-2-yl)propyl]-2-oxo-6-(trifluoromethyl)pyridine-3-carboxylate (98%, 106 mg, 0.269 mmol) in THF (2.94 mL), 2 M lithium hydroxide hydrate (0.81 mL, 1.61 mmol) was added at 45 °C. The reaction mixture was stirred for 4 hours. The mixture was acidified to pH 4 using 1 N aqueous hydrochloric acid. The reaction mixture was concentrated under vacuum to obtain the title product (172 mg, 99% yield) as a light brown solid. LCMS m / z:359.2[M+H] + (ESI+), Rt=0.50(S1)

[0336] The following intermediates were prepared using the corresponding starting materials in a manner similar to that of intermediate O7 outlined in general route 10j.

[0337] [Table 19-1] [Table 19-2] [Table 19-3] [Table 19-4] [Table 19-5]

[0338] Scheme for general route 10k [ka]

[0339] Synthesis of intermediate O21 Ethyl 2-({4-[(tert-butyldimethylsilyl)oxy]butyl}carbamoyl) acetate [ka] It was prepared using 4-[tert-butyl(dimethyl)silyl]oxybutan-1-amine and ethyl 3-chloro-3-oxopropanoate in a manner similar to that of intermediate O2. 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 = 7.1 Hz, 3H), 0.83 (s, 9H), -0.00 (s, 6H).

[0340] Synthesis of intermediate O22 Ethyl 1-{4-[(tert-butyldimethylsilyl)oxy]butyl}-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxylate [ka] Intermediate O21 was used to produce intermediate O3 using a similar method. 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).

[0341] Synthesis of intermediate O23 Ethyl 1-(4-hydroxypropyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxylate [ka] It was prepared using intermediate O22 in a manner similar to that used for intermediate O4. LCMS m / z:330.2[M+Na] + (ESI+), Rt=0.69(S1)

[0342] Synthesis of intermediate O24 Ethyl 2-oxo-1-(4-oxobutyl)-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxylate [ka] To 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), des-martin periodinane (166 mg, 0.391 mmol) was added at 0°C. The reaction mixture was stirred at 0°C for 10 minutes, then at room temperature for 2 hours. The reaction was quenched by adding 50% aqueous saturated sodium thiosulfate / saturated NaHCO3 aqueous solution (15 ml) and vigorously stirred for 10 minutes. The organic layer was separated, further washed with saturated NaHCO3 solution (10 ml), and dehydrated with MgSO4. After removing the solvent under vacuum, a brown oily substance was obtained. Purification by column chromatography (10 g silica, 0-60% phenylethylamine in heptane) yielded the title product (144 mg, 72% pure, 104% yield) as an orange, gum-like substance. 1H 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).

[0343] Synthesis of intermediate O25 Ethyl 1-(4-{3-azabicyclo[3.1.1]heptan-3-yl}butyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxylate [ka] 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), followed by STAB (225 mg, 1.06 mmol) were added. The reaction mixture was stirred at room temperature for 72 hours. This reaction was quenched with a mixture of water (10 mL) and saturated aqueous solution NaHCO3 (10 mL). The reaction mixture was then extracted with DCM (3 × 5 mL). The combined organic layers were concentrated under vacuum to obtain the residue. Purification by SCX chromatography (5 g, eluted with 7 M NH3 in MeOH) yielded the title product (111 mg, 95% pure, 83% yield) as a yellow oily substance. LCMS m / z: 387.3 [M+H] + , (ESI+), Rt = 0.60 (S1) 1H 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).

[0344] Synthesis of intermediate O26 1-(4-{3-azabicyclo[3.1.1]heptan-3-yl}butyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxylic acid [ka] It was prepared using intermediate O25 in a manner similar to that used for intermediate O7. 1 H 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 = 6.0 Hz, 3H), 2.13 - 2.02 (m, 3H), 1.78 - 1.67 (m, 5H), 1.67 - 1.53 (m, 2H).

[0345] The following intermediates were prepared using the corresponding starting materials in a manner similar to that of intermediate O26 outlined in general route 10k.

[0346] [Table 20]

[0347] Scheme for general route 10l [ka]

[0348] Synthesis of intermediate O28 Methyl 1-(4-hydroxybutyl)-2-oxo-1,2-dihydropyridine-3-carboxylate [ka] 4-bromobutan-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. A further amount of 4-bromobutan-1-ol (7.00 g, 45.7 mmol) was added to this reaction mixture, and the mixture was stirred at room temperature for 24 hours. The reaction mixture was filtered through Celite, and the filtrate was concentrated under vacuum to obtain a yellow oil. Purification by column chromatography (50 g silica, 0-100% ethyl acetate in heptane, then 0-20% methanol in ethyl acetate) yielded the title product (2.35 g, 17% yield, 84% purity) as a yellow oil. 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).

[0349] Synthesis of intermediate O29 Methyl 1-(4-{2-azaspiro[3,4]octan-2-yl}butyl)-2-oxo-1,2-dihydropyridine-3-carboxylate [ka] Intermediate O28 and 2-azaspiro[3.4]octane were used to prepare intermediate M2 in a similar manner. LCMS m / z:319.4[M+H] + (ESI+), Rt=0.49(S1)

[0350] Synthesis of intermediate O30 1-(4-{2-azaspiro[3,4]octan-2-yl}butyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid [ka] It was prepared using intermediate O29 in a similar manner to that used for intermediate O7. LCMS m / z:305.4[M+H] + (ESI+), Rt=0.49(S1)

[0351] Scheme for general route 11A [ka]

[0352] Synthesis of intermediate P1 Methyl 6-[(azetidine-1-yl)methyl]pyridine-2-carboxylate (Step A) [ka] To a stirred solution of azetidine (0.071 mL, 0.998 mmol) and methyl 6-formylpyridine-2-carboxylate (219 mg, 1.30 mmol) in DCE (10 mL), STAB (349 mg, 1.60 mmol) was added at room temperature. This reaction mixture was stirred at 50 °C for 3 hours. The reaction mixture was quenched with water (10 mL), and then toluene (15 mL) was added. The organic layer was separated, and the aqueous layer was further extracted with toluene (2 × 10 mL). This aqueous phase was made basic to pH 9 with a saturated aqueous solution of NaHCO3, and extracted with toluene (2 × 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 in DCM) yielded the title product (90 mg, 43% yield) as a colorless oil. LCMS m / z:206.9[M+H]+, (ESI+), Rt=1.60(S7)

[0353] Synthesis of intermediate P2 Step C: Methyl 6-[(azetidine-1-yl)methyl]pyridine-2-carboxylate (Step B) [ka] Intermediate P1 was used to produce intermediate L3 using a similar method. LCMS m / z:192.7[M+H]+, (ESI+), Rt=0.25(S6)

[0354] Scheme for general route 11B [ka]

[0355] Synthesis of intermediate P3 Process A: Ethyl 6-[(3-fluoroazetidine-1-yl)methyl]pyridine-2-carboxylate (Process A) [ka] In a sealed tube under nitrogen, a stirred suspension consisting of ethyl 6-(chloromethyl)pyridine-2-carboxylate (300 mg, 1.50 mmol) and 3-fluoroazetidine hydrochloride (180 mg, 1.61 mmol) in acetonitrile (6 mL) was added, and the resulting mixture was stirred at room temperature for 6 hours. Further 3-fluoroazetidine hydrochloride (90 mg, 0.81 mmol) was added, and stirring was continued at room temperature for 18 hours. The reaction mixture was filtered through Celite and washed with toluene (50 mL). The filtrate was concentrated under vacuum to obtain a yellow oil. Purification by column chromatography (10 g silica, 0-100% toluene in heptane, then 0-10% MeOH in toluene) yielded the title product (277 mg, 76% yield) as a yellow oil. 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

[0356] Synthesis of intermediate P4 Step B 6-[(3-fluoroazetidine-1-yl)methyl]pyridine-2-carboxylate lithium salt [ka] To a stirred solution of ethyl 6-[(3-fluoroazetidine-1-yl)methyl]pyridine-2-carboxylate (273 mg, 1.12 mmol) in THF (5 mL) and methanol (0.3 mL), 2 M LiOH (aqueous solution) (620 μL, 1.24 mmol) was added. The reaction mixture was stirred at room temperature for 1.5 hours. The reaction mixture was concentrated under vacuum to obtain the title product (219 mg, 86% yield) as a brown solid. 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).

[0357] The following intermediates were prepared using the corresponding starting materials in a manner similar to that of intermediate P4 outlined in general route 11c.

[0358] [Table 21]

[0359] Scheme for general route 11C [ka]

[0360] Synthesis of intermediate P5 Ethyl 6-ethenylpyridine-2-carboxylate (Step A) [ka] To a solution of ethyl 6-bromopyridine-2-carboxylate (1.00 g, 4.35 mmol) in degassed anhydrous 1,4-dioxane (30 mL), tributyl(vinyl)tin (1.5 mL, 5.13 mmol) and palladium triphenylphosphan (0.50 g, 0.433 mmol) were added. This mixture was heated at 100°C for 3 hours. The mixture was cooled, diluted with toluene (50 mL), and washed with 1 M KF aqueous solution (50 mL). The organic layer was separated, and the aqueous layer was extracted with toluene (3 × 20 mL). The combined organic layers were dehydrated with Na₂SO₄ and concentrated under vacuum. Purification by column chromatography (55 g Sfar amino-D silica, 0-50% toluene in heptane) yielded the title product (715 mg, 84% yield) as a free-flowing yellow oil. LCMS m / z: 178.3 [M+H]+, (ESI+), Rt = 0.77 (S1) 1 H 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, 10.9 Hz, 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).

[0361] Synthesis of intermediate P6 Ethyl 6-[2-(dimethylamino)ethyl]pyridine-2-carboxylate (Step B) [ka] To a stirred EtOH (4 mL) solution of ethyl 6-ethenylpyridine-2-carboxylate (200 mg, 1.02 mmol), 2 M dimethylamine (in THF) (1.0 mL, 2.00 mmol) was added. This solution was heated at 80°C for 24 hours. The mixture was concentrated under vacuum, and the residue was purified by reverse-phase column chromatography (12 g Sfar C18-silica, 10-100% MeCN in H2O containing 0.1% formic acid modifier) ​​to obtain the crude product. The crude product was dissolved in ELISA (2 mL) and washed with saturated NaHCO3 solution (2 × 3 mL). The organic layer was dehydrated with Na2SO4 and concentrated under vacuum to obtain the title product (160 mg, 71% yield) as a colorless oil. 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 = 7.8 Hz, 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).

[0362] Synthesis of intermediate P7 Lithium (1+)6-[2-(dimethylamino)ethyl]pyridine-2-carboxylate (Step C) [ka] To a solution of ethyl 6-[2-(dimethylamino)ethyl]pyridine-2-carboxylate (1.72 g, 7.2 mmol) in THF (33 mL), 2 M LiOH aqueous solution (4.02 mL, 8.05 mmol) was added. The reaction mixture was stirred at room temperature for 18 hours. When the reaction mixture was concentrated under vacuum, the title product (1.5 g, 95% pure, 100% yield) was obtained as a pale yellow solid. 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).

[0363] The following intermediates were prepared using the corresponding starting materials in a manner similar to that of intermediate P7 outlined in general route 11c.

[0364] [Table 22]

[0365] Synthesis of intermediate P8 Ethyl 6-ethenyl-5-methylpyridine-2-carboxylate (Step A) [ka] To a solution of ethyl 6-bromo-5-methylpyridine-2-carboxylate (350.0 mg, 1.43 mmol) in EtOH (5 mL), potassium ethenyl(trifluoro)borate (396.0 mg, 2.87 mmol), TEA (0.2 mL, 1.43 mmol), and bis[3-(diphenylphosphanyl)cyclopenta-2,4-dien-1-yl]ferric dichloromethane palladium chloride (58.0 mg, 0.07 mmol) were added. This mixture was degassed with N2 for 10 minutes and then stirred at 80°C for 1 hour. The mixture was filtered, and the filtrate was concentrated under vacuum to obtain an oily substance. Purification by column chromatography (25 g silica, 0-25% ethyl phosphate in heptane) yielded the title product (211 mg, 77% yield) as a bright yellow oil. 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, 2.4 Hz, 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).

[0366] Synthesis of intermediate P9 Ethyl 6-[2-(dimethylamino)ethyl]-5-methylpyridine-2-carboxylate (Step B) [ka] A mixture consisting of ethyl 6-ethenyl-5-methylpyridine-2-carboxylate (211 mg, 1.10 mmol), 2M dimethylamine in THF (5.5 mL, 11.0 mmol), and AcOH (0.84 mL) was stirred at 100°C for 30 minutes by microwave irradiation. Dimethylamine hydrochloride (450 mg, 5.52 mmol) was added, and the mixture was stirred at 150°C for 2 hours by microwave irradiation. The reaction mixture was concentrated under vacuum to obtain the residue. Purification by FCC (25 g silica, 0-100% ethyl in heptane, then 0-10% MeOH in ethyl) yielded the title product (150 mg, 45% yield) as an oil. LCMS m / z: 237.2 [M+H]+, (ESI+), Rt = 0.52 (S1) 1H 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).

[0367] Synthesis of intermediate P10 Lithium (1+)6-[2-(dimethylamino)ethyl]-5-methylpyridine-2-carboxylate (Step C) [ka] To 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), 2 M aqueous LiOH (0.48 mL, 0.952 mmol) was added. This mixture was stirred at room temperature for 1 hour, and then concentrated under vacuum to obtain the title product (150 mg, 95% yield) as an orange solid. 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).

[0368] Synthesis of intermediate P11 Ethyl 6-(2-methoxyethyl)pyridine-2-carboxylate (Step A) [ka] To a stirred solution of ethyl 6-ethenylpyridine-2-carboxylate (350.0 mg, 2.26 mmol) in anhydrous MeOH (10 mL), 4 M HCl (1.12 mL, 4.48 mmol) in 1,4-dioxane was added. This reaction mixture was stirred at 80°C for 18 hours. The reaction mixture was adjusted to pH=7 with saturated NaHCO3 aqueous solution, and then concentrated under vacuum to obtain the residue. Purification by column chromatography (SCX 20 g, 0-100% 7 M NH3 in MeOH) yielded the title product (427 mg, 77% yield) as a yellow oily substance. LCMS m / z:210.2[M+H]+, (ESI+), Rt=0.62(S1)

[0369] Synthesis of intermediate P12 Lithium (1+)6-(2-methoxyethyl)pyridine-2-carboxylate (Step B) [ka] Intermediate P11 was used to produce intermediate L3 using a similar method. 1 H 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).

[0370] Scheme for general route 11d [ka]

[0371] Synthesis of intermediate P13 Ethyl 6-(2-hydroxyethyl)pyridine-2-carboxylate (Process A) [ka] To a stirred solution of ethyl 6-ethenylpyridine-2-carboxylate (2.5 g, 14.1 mmol) in THF (10 mL), 0.5 M 9-BBN (85 mL, 42.5 mmol) in THF was added dropwise over 15 minutes at 0°C. The reaction mixture was stirred at 0°C for 5 minutes, then warmed to room temperature and stirred for 22 hours. The reaction mixture was cooled to 0°C, and H2O2 (50% in H2O) (1.75 mL, 58.14 mmol), followed by 2 M NaOH (aqueous solution) (0.35 mL, 0.7 mmol) was added dropwise. The mixture was stirred at 0°C for 5 minutes, then warmed to room temperature. Further H2O2 (50% in H2O) (3.5 mL, 116.3 mmol) and 2 M NaOH (aqueous solution) (0.35 mL, 0.7 mmol) were added at room temperature. The reaction 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 HCl (100 mL), water (30 mL), and brine (30 mL), and then adjusted to pH 8 with saturated NaHCO3 solution (5 mL). Next, the phases were separated, and the aqueous phase was extracted with HCl (50 mL x 2). The combined organic phase was dehydrated with 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 obtain the title product (1.78 g, 64% yield) as a yellow oily substance. LCMS m / z: 196.1 [M+H]+, (ESI+), Rt = 0.44 (S2) 1 H 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).

[0372] Synthesis of intermediate P14 Ethyl 6-(2-{2-azaspiro[3,4]octan-2-yl}ethyl)pyridine-2-carboxylate (Step B) [ka] A solution of ethyl 6-(2-hydroxyethyl)pyridine-2-carboxylate (250 mg, 1.27 mmol) in anhydrous DCM (3 mL) was treated with DIPEA (663 μL, 3.8 mmol). This mixture was cooled to 0°C and treated with trifluoromethanesulfonic acid anhydride (229 μL, 1.39 mmol), and stirred at 0°C for 10 minutes. 2-Azaspiro[3,4]octane (171 mg, 1.54 mmol) was added, and the reaction mixture was stirred at 0°C for 5 minutes, then at room temperature for 30 minutes. The reaction mixture was concentrated under vacuum to obtain the residue. Purification by reverse-phase FCC (30 g C18 silica, 10-100% MeCN + 0.1% v / v NH4OH) yielded the title product (220 mg, 46% yield) as a light brown oil. 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).

[0373] Synthesis of intermediate P15 Lithium (1+)6-(2-{2-azaspiro[3,4]octan-2-yl}ethyl)pyridine-2-carboxylate (Step C) [ka] Intermediate P13 was used to produce intermediate L3 using a similar method. 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).

[0374] The following intermediates were prepared using the corresponding starting materials in a manner similar to that of intermediate P14 outlined in general route 11d.

[0375] [Table 23]

[0376] Scheme for general route 11e [ka]

[0377] Synthesis of intermediate P16 Ethyl 6-(3-oxopropyl)pyridine-2-carboxylate (Step A) [ka] A suspension consisting of ethyl 6-bromopyridine-2-carboxylate (5.0 g, 21.7 mmol), propa-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 minutes. Pd(OAc)2 (0.244 g, 1.09 mmol) was added, and the reaction mixture was stirred and cooled under N2 at 85°C for 6 hours, then concentrated under vacuum. The residue was suspended in water (100 mL) and extracted with siRNA (4 × 30 mL). The combined organic layers were washed with water (40 mL) and brine (2 × 30 mL), dehydrated with MgSO4, and concentrated under vacuum. When the residue was purified by FCC (50 g silica, 10% to 100% phenyl in heptane), the title product (1.72 g, 30% yield) was obtained as an orange oily substance. LCMS m / z: 208.2 [M+H]+, (ESI+), Rt = 0.55 (S1) 1 H 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).

[0378] Synthesis of intermediate P17 Ethyl 6-(3-{2-azaspiro[3,4]octan-2-yl}propyl)pyridine-2-carboxylate (Step B) [ka] To a stirred 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), STAB (369 mg, 1.74 mmol) was added at room temperature. This reaction mixture was heated at 40°C for 1 hour. The reaction product was poured into water (30 mL), diluted with saturated NaHCO3 aqueous solution (20 mL), and then extracted with DCM (4 × 10 mL). The combined organic layer was dehydrated with MgSO4 and concentrated under vacuum. Purification by column chromatography (SCX 5 g, 0-100% 7M NH3 in MeOH) yielded the title product (151 mg, 73% yield) as a pale yellow oil. 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).

[0379] Synthesis of intermediate P18 Lithium (1+)6-(3-{2-azaspiro[3,4]octan-2-yl}propyl)pyridine-2-carboxylate (Step C) [ka] Intermediate P17 was used to produce intermediate L3 using a similar method. LCMS m / z:275.2[M+H]+, (ESI+), Rt=0.35(S1)

[0380] The following intermediates were prepared using the corresponding starting materials in a manner similar to that of intermediate P18 outlined in general route 11d.

[0381] [Table 24]

[0382] Scheme for general route 11f [ka]

[0383] Synthesis of intermediate P22 3-Methoxy-1-(2-methylbuta-3-in-2-yl)azetidine (Step A) [ka] To a stirred solution of 2-methylbuta-3-in-2-ol (1.2 mL, 11.9 mmol) in anhydrous DCM (1.8 mL), acetyl chloride (0.95 mL, 13.4 mmol) was added dropwise at 0°C. The reaction mixture was stirred at room temperature for approximately 1 hour. The solvent was removed under vacuum to obtain a residue. The residue was dissolved in anhydrous THF (12 mL), and 3-methoxyazetidine hydrochloride (1:1) (1.0 g, 8.09 mmol), TEA (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 toluene (20 mL), and then made basic with saturated aqueous solution NaHCO3 to pH 10-11. The phases were separated, and the aqueous phase was extracted with toluene (3 × 20 mL). The combined organic phases were concentrated under vacuum to obtain a residue. Purification using an SCX-2 cartridge (20 g) eluted with MeOH (3 CV) and then 7N NH3 (4 CV) in MeOH yielded the title product (448 mg, 22% yield) as a dark orange oily substance. 1H 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).

[0384] Synthesis of intermediate P23 Ethyl 6-[3-(3-methoxyazetidine-1-yl)-3-methylbuta-1-in-1-yl]pyridine-2-carboxylate (Step B) [ka] To a degassed solution (15 mL) of ethyl 6-bromopyridine-2-carboxylate (722 mg, 3.14 mmol) and 3-methoxy-1-(2-methylbuta-3-in-2-yl)azetidine (445 mg, 2.61 mmol) in anhydrous THF (15 mL), CuI (104 mg, 0.546 mmol), Pd(PPh3)2Cl2 (153 mg, 0.218 mmol), and diisopropylamine (1.6 mL, 11.6 mmol) were added at room temperature. The reaction mixture was stirred at 70°C for 20 hours. The reaction mixture was concentrated under vacuum, and the residue was purified by FCC (Sfar duo 50 g, 0-100% ethyl phosphate in heptane) to obtain the title product (513 mg, 58% yield) as a light orange oil. 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).

[0385] Synthesis of intermediate P24 Ethyl 6-[3-(3-methoxyazetidine-1-yl)-3-methylbutyl]pyridine-2-carboxylate (Step C) [ka] To a solution of ethyl 6-[3-(3-methoxyazetidine-1-yl)-3-methylbuta-1-in-1-yl]pyridine-2-carboxylate (512 mg, 1.52 mmol) in EtOH (10 mL), 10% Pd / C (205 mg, 0.193 mmol) was added under nitrogen. The reaction mixture was then stirred under H2 for 19 hours. The mixture was filtered through Celite and washed with MeOH (30 mL). The filtrate was concentrated under vacuum to obtain the residue. Purification by FCC (5 g silica, 0-100% siRNA in heptane, 0-30% MeOH in DCM) yielded the title product (236.0 mg, 40% yield) as an amber-colored oil. 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).

[0386] Synthesis of intermediate P25 Lithium (1+)6-[3-(3-methoxyazetidine-1-yl)-3-methylbutyl]pyridine-2-carboxylate (Step D) [ka] To a stirred solution of ethyl 6-[3-(3-methoxyazetidine-1-yl)-3-methylbutyl]pyridine-2-carboxylate (236 mg, 0.616 mmol) in anhydrous THF (2 mL) and MeOH (2 mL), 2 M aqueous LiOH (463 μL, 0.926 mmol) was added. The reaction mixture was stirred at room temperature for 17 hours. The mixture was concentrated under vacuum and then suspended in DCM (1:1) in heptane (20 mL), and concentrated by sonication to obtain the title product (197 mg, 100% yield) as a yellowish-brown solid. LCMS m / z:279.1[M+H]+, (ESI+), Rt=0.32(S2).

[0387] Scheme for general route 11g [ka]

[0388] Synthesis of intermediate P26 1'-tert-butyl 6-ethyl 1',2',3',6'-tetrahydro-[2,4'-bipyridine]-1',6-dicarboxylate (Step A) [ka] To a solution of ethyl 6-bromopyridine-2-carboxylate (1.00 g, 4.35 mmol) and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (1.61 g, 5.22 mmol) in 1,4-dioxane (30 mL), Na2CO3 (1.38 g, 13.0 mmol) in water (7.5 mL) was added. This mixture was degassed with a stream of N2, and then Pd(dppf)2Cl2.DCM (180 mg, 0.217 mmol) was added. This mixture was stirred at 110 °C for 3 hours. The reaction mixture was cooled and filtered, and the filtrate was concentrated under vacuum. The residue was partitioned between ELISA (40 mL) and brine (20 mL). The organic layer was separated, dehydrated with MgSO4, and concentrated under vacuum. When the residue was purified by FCC (25 g silica, 0-30% phenylethylamine / heptane), the title product (1.43 g, 99% yield) was obtained as a colorless oil. 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).

[0389] Synthesis of intermediate P27 Ethyl 6-{1-[(tert-butoxy)carbonyl]piperidine-4-yl}pyridine-2-carboxylate (Step B) [ka] 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 EtOH (15 mL), 10% Pd / C (206 mg, 0.19 mmol) was added under nitrogen. The mixture was evacuated and stirred under H2 atmosphere for 18 hours. The Pd residue was filtered through Celite, and the filtrate was concentrated under vacuum to obtain the title product (1.25 g, 87% yield) as a colorless oil. 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).

[0390] Synthesis of intermediate P28 Ethyl 6-(piperidine-4-yl)pyridine-2-carboxylate hydrochloride (Process C) [ka] To a solution of ethyl 6-{1-[(tert-butoxy)carbonyl]piperidine-4-yl}pyridine-2-carboxylate (1.24 g, 3.71 mmol) in DCM (4 mL), 4 M HCl (3.7 mL, 14.8 mmol) in dioxane was added. This solution was stirred at room temperature for 18 hours. The reaction mixture was concentrated under vacuum to obtain the title product (1.00 g, 100% yield) as a white solid. LCMS m / z: 235.2 [M+H]+, (ESI+), Rt = 0.46 (S2) 1H 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).

[0391] Synthesis of intermediate P29 Ethyl 6-(1-methylpiperidine-4-yl)pyridine-2-carboxylate (Step D) [ka] To a solution of ethyl 6-(piperidine-4-yl)pyridine-2-carboxylate hydrochloride (500 mg, 1.85 mmol) in EtOH (6 mL), 37% formaldehyde aqueous solution (0.61 mL, 7.48 mmol) was added. This mixture was stirred for 15 minutes, and then NaBH3CN (469.977 mg, 7.48 mmol) was added. This solution was stirred at room temperature for 2 hours. This reaction was quenched with water (5 mL), and DCM (20 mL) was added. The aqueous layer was made basic to pH 9 using saturated NaHCO3 aqueous solution. The organic layer was separated, and the aqueous layer was further extracted with DCM (2 × 10 mL). The combined organic layers were dehydrated with MgSO4 and concentrated under vacuum to obtain the title product (440 mg, 81% yield) as a light brown oily substance. LCMS m / z: 249.2 [M+H]+, (ESI+), Rt = 0.45 (S2) 1H 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 = 7.1Hz, 3H).

[0392] Synthesis of intermediate P30 6-(1-methylpiperidine-4-yl)pyridine-2-carboxylic acid (Step E) [ka] To a solution of ethyl 6-(1-methylpiperidine-4-yl)pyridine-2-carboxylate (430 mg, 1.73 mmol) in THF (7.5 mL), 1 M LiOH (2.6 mL, 2.6 mmol) was added. The reaction mixture was stirred at 40 °C for 2 hours. 1 N HCl was added (approximately 0.8 mL) until the pH reached 8. When the mixture was concentrated under vacuum, the title product (380 mg, 90% yield) was obtained as a white solid. 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).

[0393] The following intermediates were prepared using the corresponding starting materials in a manner similar to that of intermediate P30 outlined in general route 11g.

[0394] [Table 25]

[0395] Scheme for general route 12a [ka]

[0396] Synthesis of intermediate Q1 Ethyl(3S)-3-{4'-chloro-4-fluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl}-3-[(2S)-2-[(6-fluoropyridine-2-yl)formamide]-4-methylpentanamide]propanoate [ka] 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), TEA (0.68 mL, 4.87 mmol) was added and the mixture was stirred at room temperature for 10 minutes. Then, ethyl (3S)-3-[(2S)-2-amino-4-methylpentanamide]-3-{4'-chloro-4-fluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl}propanoate hydrochloride (1.0 g, 1.95 mmol) was added. The reaction mixture was stirred for 3 hours, water (5 mL) was added, and the mixture was extracted with RINKAN (3 × 15 mL). The combined organic layers were washed with brine (10 mL), dehydrated with MgSO4, and concentrated under vacuum. The residue was purified by reverse-phase FCC (30 g, C18 silica, 10-100% MeCN in water containing 0.1% NH4OH modifier) ​​to obtain the title product (556 mg, 48% yield) as a white solid. LCMS m / z: 600.3 / 602.3 [M+H]+, (ESI+), Rt = 1.12 (S2) 1 H 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).

[0397] The following intermediates were prepared using the corresponding starting materials in a manner similar to that of intermediate Q1 outlined in general route 12a.

[0398] [Table 26]

[0399] Synthesis of intermediate Q3 Process B (Part 1): Ethyl(3S)-3-{4,4'-difluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl}-3-[(2S)-2-({6-[3-(dimethylamino)-3-methylazetidine-1-yl]pyridine-2-yl}formamide)-4-methylpentanamide]propanoate [ka] To a solution of ethyl(3S)-3-{4,4'-difluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl}-3-[(2S)-2-[(6-fluoropyridine-2-yl)formamide]-4-methylpentanamide]propanoate (100 mg, 0.171 mmol) in DMF (1 mL), K2CO3 (71 mg, 0.51 mmol) was added, followed by N,N,3-trimethylazetidine-3-amine dihydrochloride (64 mg, 0.343 mmol). This mixture was heated at 80°C for 18 hours. The reaction mixture was concentrated under vacuum to obtain the residue. Purification by reverse-phase FCC (10-100% water in MeCN containing 12g of C18 silica and 0.1% NH4OH modifier) ​​yielded the title compound (57 mg, 37% yield) as a yellow glassy solid. LCMS m / z:678.4[M+H]+, (ESI+), Rt=0.94(S1)

[0400] Scheme for general route 12b [ka]

[0401] Synthesis of intermediate Q4 Lithium(1+)6-chloropyridine-2-carboxylate (Step A) [ka] 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 aqueous LiOH (2 mL, 4 mmol) was added. The reaction mixture 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 obtain the title product (491 mg, 100% yield) as a white solid. LCMS m / z:158.1[M+H]+, (ESI+), Rt=0.47(S1)

[0402] Synthesis of intermediate Q5 Ethyl (3S)-3-[(2S)-2-[(6-chloropyridine-2-yl)formamide]-4-methylpentanamide]-3-{4,4'-difluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl}propanoate (Step B) [ka] A solution of ethyl(3S)-3-[[(2S)-2-amino-4-methylpentanoyl]amino]-3-[2-fluoro-5-(4-fluoro-2,6-dimethylphenyl)-3-methylphenyl]propanoate 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. This mixture was diluted with RINKAN (15 mL) and water (25 mL) was added. The phases were separated, and the aqueous phase was extracted with RINKAN (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% ethyl acetate in heptane, 25g of Sfar Duo) to obtain the title product (247mg, 65% yield) as a white solid. LCMS m / z: 600.4 / 602.4 [M+H]+, (ESI+), Rt = 1.26 (S1) 1H 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 = 7.1 Hz, 3H), 0.82 - 0.76 (m, 6H).

[0403] Scheme for general route 12d [ka]

[0404] Synthesis of intermediate Q10 Methyl 5-methyl-6-{2-methyl-2,7-diazaspiro[3.5]nonan-7-yl}pyridine-2-carboxylate (Step A) [ka] 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), Cs2CO3 (1.416 g, 4.35 mmol) and methyl 6-bromo-5-methylpyridine-2-carboxylate (250 mg, 1.09 mmol) were added. N2 was vigorously passed through this solution for 20 minutes, 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 hours, cooled to room temperature, filtered through Celite, and washed with siRNA (2 × 10 mL). The filtrate was concentrated under vacuum, and the residue was purified by FCC (28 g of Kp-NH silica, 0-100% dimethyl in heptane) to obtain the title product (110 mg, 28% yield) as a white solid. LCMS m / z: 290.3 [M+H]+, (ESI+), Rt = 0.56 (S1) 1 H 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 = 0.8 Hz, 3H), 2.23 (s, 3H), 1.82 - 1.74 (m, 4H).

[0405] Synthesis of intermediate Q11 Lithium (1+)5-methyl-6-{2-methyl-2,7-diazaspiro[3.5]nonan-7-yl}pyridine-2-carboxylate (Step B) [ka] A stirred solution of methyl 5-methyl-6-{2-methyl-2,7-diazaspiro[3.5]nonan-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) (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 obtain the title product (112 mg, 98% yield) as a white solid. 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).

[0406] Synthesis of intermediate Q12 Methyl 6-[4-(dimethylamino)piperidine-1-yl]-5-methylpyridine-2-carboxylate (Step A) [ka] It was prepared using methyl 6-bromo-5-methylpyridine-2-carboxylate and N,N-dimethylpiperidine-4-amine in a manner similar to that of intermediate Q10. LCMS m / z: 278.2 [M+H]+, (ESI+), Rt = 0.49 (S1) 1H 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).

[0407] Synthesis of intermediate Q13 6-[4-(dimethylamino)piperidine-1-yl]-5-methylpyridine-2-carboxylic acid (Step B) [ka] To a solution of methyl 6-[4-(dimethylamino)piperidine-1-yl]-5-methylpyridine-2-carboxylate (80 mg, 0.288 mmol) in THF (3 mL), 2 M LiOH (0.87 mL, 1.73 mmol) was added. This solution was stirred at 40 °C for 2 hours. The reaction mixture was cooled and acidified to pH 5 using 1 N HCl. After removing the solvent under vacuum, the title product (76 mg, 100% yield) was obtained as a colorless gum. LCMS m / z:264.2[M+H]+, (ESI+), Rt=0.33(S1)

[0408] The following intermediates were prepared using the corresponding starting materials in a manner similar to that of intermediate Q13 outlined in general route 12d.

[0409] [Table 27]

[0410] Scheme for general route 12e [ka]

[0411] Synthesis of intermediate Q15 tert-butyl 6-[6-(methoxycarbonyl)-3-methylpyridine-2-yl]-2,6-diazaspiro[3.5]nonane-2-carboxylate (Step A) [ka] Methyl 6-bromo-5-methylpyridine-2-carboxylate and tert-butyl 2,6-diazaspiro[3.5]nonane-2-carboxylate were used to prepare intermediate Q10 in a similar manner. 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).

[0412] Synthesis of intermediate Q16 Methyl 6-{2,6-diazaspiro[3.5]nonan-6-yl}-5-methylpyridine-2-carboxylate hydrochloride (Step B) [ka] To a solution of tert-butyl 6-[6-(methoxycarbonyl)-3-methylpyridine-2-yl]-2,6-diazaspiro[3.5]nonane-2-carboxylate (166 mg, 0.442 mmol) in DCM (1 mL), 4 M HCl (0.442 mL, 1.77 mmol) in 1,4-dioxane was added. This solution was stirred at room temperature for 2 hours. The solvent was concentrated under vacuum to obtain the title product (200 mg, 74% yield) as a colorless gum. 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).

[0413] Synthesis of intermediate Q17 Methyl 5-methyl-6-{2-methyl-2,6-diazaspiro[3.5]nonan-6-yl}pyridine-2-carboxylate (Step C) [ka] To a solution of methyl 6-{2,6-diazaspiro[3.5]nonan-6-yl}-5-methylpyridine-2-carboxylate hydrochloride (130 mg, 0.417 mmol) in MeOH (1.4 mL), formaldehyde [37% in water] (0.137 mL, 1.69 mmol) was added. This mixture was stirred for 15 minutes, then NaBH3CN (106 mg, 1.69 mmol) was added, and the solution was stirred at room temperature for 18 hours. This reaction was quenched with saturated NaHCO3 aqueous solution (10 mL), and DCM (20 mL) was added. The organic layer was separated, and the aqueous layer was further extracted with DCM (2 × 10 mL). The combined organic layers were dehydrated with MgSO4 and concentrated under vacuum to obtain the residue. Purification by FCC (10g silica, 0-10% 7M NH3 in MeOH / DCM) yielded the title product (55mg, 41% yield) as a colorless oil. 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).

[0414] Synthesis of intermediate Q18 5-methyl-6-{2-methyl-2,6-diazaspiro[3.5]nonan-6-yl}pyridine-2-carboxylic acid (Step D) [ka] Intermediate Q17 was used to produce intermediate Q13 using a similar method. LCMS m / z:276.4[M+H]+, (ESI+), Rt=0.43(S1)

[0415] Scheme for general route 12f [ka]

[0416] Synthesis of intermediate Q19 Ethyl 2-[2-(dimethylamino)ethoxy]-6-(trifluoromethyl)pyridine-3-carboxylate (Step A) [ka] To a stirred suspension consisting 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, and then 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 in ethyl phosphate) to obtain the title product (370 mg, 55% yield) as a solid. 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).

[0417] Synthesis of intermediate Q20 (intermediate 110a) 2-[2-(dimethylamino)ethoxy]-6-(trifluoromethyl)pyridine-3-carboxylate hydrochloride (Step B) [ka] To a stirred solution of ethyl 2-[2-(dimethylamino)ethoxy]-6-(trifluoromethyl)pyridine-3-carboxylate (359 mg, 1.17 mmol) in THF (5 mL) and MeOH (0.5 mL), 2N aqueous LiOH (0.88 mL, 1.76 mmol) was added at 45°C. The reaction mixture was stirred at 45°C for 1 hour. The reaction mixture was cooled and acidified with 1N aqueous HCl. When this solution was concentrated under vacuum, the title product (400 mg, 100% yield) was obtained as a white solid. LCMS m / z: 279.1 [M+H]+, (ESI+), Rt = 0.48 (S1) 1 H 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).

[0418] The following intermediates were prepared using the corresponding starting materials in a manner similar to that of intermediate Q20 outlined in general route 12f.

[0419] [Table 28]

[0420] Scheme for General Route 13 [ka]

[0421] Synthesis of intermediate R1 Methyl 2-fluoro-3-(4-methylpiperazine-1-yl)benzoate (Step A) [ka] A stirred mixture consisting of methyl 3-bromo-2-fluorobenzoate (1.0 g, 4.29 mmol), 1-methylpiperazine (625 uL, 5.63 mmol), and Cs2CO3 (4.19 g, 12.86 mmol) in anhydrous 1,4-dioxane (40 mL) was degassed with N2 for 5 minutes. 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 hours. The reaction mixture was cooled to room temperature, filtered through Celite, and washed with SiO2 (30 mL). The filtrate was concentrated under vacuum to obtain the residue. Purification by column chromatography (25 g silica, 0-100% SiO2 in heptane, then 0-15% MeOH in SiO2) yielded an impure product. Further purification by SCX column chromatography (0-100% 7M NH3 in MeOH) yielded the title product (660 mg, 59% yield) as a yellow oily substance. 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).

[0422] Synthesis of intermediate R2 Lithium (1+)2-fluoro-3-(4-methylpiperazine-1-yl)benzoate (Step B) [ka] To 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), 2 M aqueous LiOH (1.5 mL, 3.00 mmol) was added. The reaction mixture was stirred at room temperature for 3 hours. Another 2 M aqueous LiOH (1.5 mL, 3.00 mmol) was added, and the mixture was stirred at 50°C for 1 hour. The reaction mixture was concentrated under vacuum to obtain the title product (723 mg, 100% yield) as a yellow solid. 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).

[0423] General amines Synthesis of intermediate S1 Benzyl 3-{3-azabicyclo[3.1.1]heptan-3-yl}azetidine-1-carboxylate [ka] Benzyl 3-oxoazetidine-1-carboxylate (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) were dissolved in DCM (5.5 mL), to which STAB (450.0 mg, 2.12 mmol) was added at room temperature. The reaction mixture was stirred at room temperature for 2 hours. This reaction mixture was poured into water (30 mL) and diluted with saturated aqueous NaHCO3 (20 mL). This mixture was extracted with DCM (4 × 10 mL), and the combined organic layers were concentrated under vacuum to obtain an oily substance. Purification with SCX (5 g, 0-100% 7M NH3 in MeOH) yielded the title product (217 mg, 93% yield) as a pale yellow oil. 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).

[0424] Synthesis of intermediate S2 3-(azetidine-3-yl)-3-azabicyclo[3.1.1]heptanetrifluoroacetate [ka] A mixture of benzyl 3-(3-azabicyclo[3.1.1]heptan-3-yl)azetidine-1-carboxylate (217.0 mg, 0.68 mmol) and 10% Pd / C (109 mg, 0.102 mmol) in ethanol (9 mL) was stirred under H2 at room temperature for 18 hours. The catalyst was filtered off by passing it through Celite, and the solvent was evaporated under vacuum to obtain the crude product. This was dissolved in TFA (0.063 mL, 0.818 mmol) and concentrated under vacuum to obtain the title product (130 mg, 71% yield) as a white solid. 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).

[0425] Scheme for general route 14a [ka]

[0426] Synthesis of intermediate S3 Process A: Methyl 7-(propan-2-yl)-5,6,7,8-tetrahydro-1,7-naphthyridine-2-carboxylate (Process A) [ka] 300 mg, 1.13 mmol of methyl 5,6,7,8-tetrahydro-1,7-naphthirizine-2-carboxylate dihydrochloride and 0.75 mL, 5.66 mmol of TEA were dissolved in acetone (0.9 mL) and DCM (5 mL). STAB (719 mg, 3.39 mmol) was added 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 × 10 mL). The combined organic layers were dehydrated with MgSO4 and concentrated under vacuum to obtain the title product (330 mg, 100% yield) as a yellow oil. 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).

[0427] Synthesis of intermediate S4 Lithium(1+)7-(propan-2-yl)-5,6,7,8-tetrahydro-1,7-naphthyrizine-2-carboxylate (Step B) [ka] A solution of methyl 7-(propan-2-yl)-5,6,7,8-tetrahydro-1,7-naphthirizine-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), and heptane (1 mL) was added. This suspension was concentrated under vacuum to obtain the title product (264 mg, 99% yield) as a beige powder. LCMS m / z: 221.2 [M+H]+, (ESI+), Rt = 0.28 (S2) 1 H 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).

[0428] The following intermediates were prepared using the corresponding starting materials in a manner similar to that of intermediate S4 outlined in general route 14a.

[0429] [Table 29]

[0430] Scheme for general route 14b [ka]

[0431] Synthesis of intermediate S6 Ethyl 7-methyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazine-2-carboxylate (Step A) [ka] A solution of 5H,6H,7H,8H-imidazo[1,2-a]pyrazine-2-carboxylate ethyl (400 mg, 2.05 mmol) in anhydrous DCM (6 mL) was treated with paraformaldehyde (190 mg, 6.12 mmol) and then AcOH (0.40 mL, 6.99 mmol) under N2 at room temperature, and stirred for 10 minutes. Next, STAB (1.50 g, 7.08 mmol) was added in small amounts over 2 minutes, and the reaction mixture was stirred at room temperature for 2 hours. A further amount of STAB (1.5 g, 7.08 mmol) was added, and stirring was continued for 16 hours. The reaction mixture was diluted with saturated aqueous NaHCO3 solution and then extracted with DCM (2 × 6 mL). The combined organic layers were separated and concentrated under vacuum. The residue was purified by reverse-phase column chromatography (10-100% MeCN in water containing 12 g of C-18 silica and 0.1% ammonium hydroxide modifier), yielding the title product (120 mg, 23% yield) as a colorless oil. LCMS m / z: 210.1 [M+H]+, (ESI+), Rt = 0.38 (S2) 1 H 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).

[0432] Synthesis of intermediate S7 Lithium (1+)7-methyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazine-2-carboxylate (Step B) [ka] To a solution of 7-methyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazine-2-carboxylate ethyl (130 mg, 0.509 mmol) in THF (3 mL), 1 M aqueous LiOH (563 μL, 0.563 mmol) was added. This reaction mixture was stirred at room temperature for 4 hours. A further volume of 1 M aqueous 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 obtain the title product (116 mg, 100% yield) as a white powder. 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).

[0433] Synthesis of intermediate S8 Ethyl 7-cyclopropyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazine-2-carboxylate (Step A) [ka] To 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), (1-ethoxycyclopropoxy)-trimethyl-silane (310.0 mg, 1.74 mmol), followed by AcOH (0.2 mL, 3.5 mmol) and NaBH3CN (140.0 mg, 2.23 mmol) were added in fractions. The reaction mixture was then stirred at room temperature for 10 minutes, followed by heating to 80°C for 4 hours. The reaction mixture was cooled and concentrated under vacuum. The residue was diluted with water (15 mL) and extracted with DCM (3 × 10 mL). The combined organic layers were dehydrated with MgSO4 and concentrated under vacuum. Purification by column chromatography (10 g silica, 0-10% MeOH in ethyl acetate) yielded the title product (190 mg, 56% yield) as a viscous, colorless oil. 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).

[0434] Synthesis of intermediate S9 Lithium (1+)7-cyclopropyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazine-2-carboxylate (Step B) [ka] To a stirred solution of ethyl 7-cyclopropyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazine-2-carboxylate (190 mg, 0.606 mmol) in THF (1 mL) and MeOH (0.05 mL), 2 M aqueous LiOH (0.35 mL, 0.700 mmol) was added. This reaction mixture was stirred at room temperature for 18 hours. When the reaction mixture was concentrated under vacuum, the title product (198 mg, quantitative yield) was obtained as a yellow solid. 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).

[0435] Scheme for general route 14c [ka]

[0436] Synthesis of intermediate S10 4-bromo-5,7-dimethyl-1H-indazole (Step A) [ka] 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) was to be mixed with acetic anhydride (0.87 mL, 9.2 mmol) dropwise. 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 a further 18 hours. The mixture was concentrated under vacuum, and then water (50 mL) and ethyl acetate (100 mL) were added. The organic phase was separated, washed with water (50 mL) and brine (50 mL), and concentrated under vacuum through a phase separator. The residue was purified by FCC (25 g silica, 0-100% ethyl acetate in heptane) to obtain the title product (400 mg, 29% yield) as a light orange solid. LCMS m / z:225.1 / 227.1[M+H]+, (ESI+), Rt=0.90(S1).

[0437] Synthesis of intermediate S11 4-bromo-2,5,7-trimethyl-2H-indazole (Step B) [ka] 4-bromo-5,7-dimethyl-1H-indazole (500.0 mg, 2.22 mmol) was dissolved in 20 mL of ethylethanol (HCl) and trimethyloxonium tetrafluoroborate (739 mg, 5.0 mmol) was added at room temperature. The reaction mixture was stirred for 18 hours. The reaction mixture was diluted with water and extracted with HCl (3 × 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% HCl in heptane) to obtain the title product (350 mg, 44% yield) as a white powder. 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).

[0438] Scheme for general route 14d [ka]

[0439] Synthesis of intermediate S12 Ethyl 8-bromo-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylate (Step A) [ka] (E)-(ethyl N-[(2,4,6-trimethylbenzenesulfonyl)oxy]ethaneimidate) (2.47 g, 8.67 mmol) was added dropwise to a solution of 1,4-dioxane (20 mL) at 0°C with perchloric acid (9.97 mL, 115.6 mmol). After 10 minutes at 0°C, ice-cold water (20 mL) was added. The resulting precipitate was collected by vacuum filtration and washed with ice-cold 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 warmed to room temperature and stirred for 1 hour. The reaction mixture was evaporated, and pyridine (0.93 mL, 11.56 mmol) 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 and washed with water (20 mL) and saturated NaHCO3 (20 mL), and dehydrated with MgSO4. The residue was purified by FCC (25 g silica, 0-100% ethyl phosphate in heptane) to obtain the title product (620 mg, 39% yield) as a beige powder. 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).

[0440] Synthesis of intermediate S13 {8-bromo-[1,2,4]triazolo[1,5-a]pyridine-2-yl}methanol (Step B) [ka] 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 ₹ (10 mL). The organic layer was filtered through a phase separator, and the filtrate was concentrated under vacuum to obtain the title product (200 mg, 68% yield) as a white solid. 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).

[0441] Synthesis of intermediate S14 8-Bromo-[1,2,4]triazolo[1,5-a]pyridine-2-carbaldehyde (Step C) [ka] To a solution of {8-bromo-[1,2,4]triazolo[1,5-a]pyridine-2-yl}methanol (200 mg, 0.877 mmol) in DCM (20 mL), MnO2 (762 mg, 8.77 mmol) was added at room temperature. 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 Celite, and the filtrate was concentrated under vacuum to obtain the title product (0.24 g, 77% yield) as a solid. 1H 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).

[0442] Synthesis of intermediate S15 ({8-bromo-[1,2,4]triazolo[1,5-a]pyridine-2-yl}methyl)dimethylamine (Step D) [ka] A mixture of 8-bromo-[1,2,4]triazolo[1,5-a]pyridine-2-carbaldehyde (200.0 mg, 0.88 mmol) and N,N-dimethylamine [2M in THF] (2.0 mL, 4.0 mmol) was mixed with STAB (400.0 mg, 1.83 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% ethyl phosphate in heptane) to obtain the title product (170 mg, 75% yield) as a bright yellow solid. LCMS m / z: 255.1 / 257.1 [M+H]+, (ESI+), Rt = 0.35 (S1) 1 H 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).

[0443] Synthesis of intermediate S16 2-[(dimethylamino)methyl]-[1,2,4]triazolo[1,5-a]pyridine-8-carboxylate hydrochloride (Step E) [ka] To a solution of ({8-bromo-[1,2,4]triazolo[1,5-a]pyridine-2-yl}methyl)dimethylamine (170.0 mg, 0.67 mmol) in anhydrous THF (1 mL), 2.5 M butyllithium (0.4 mL, 1.0 mmol) in hexane was added at 0°C. The reaction mixture was maintained at 0°C for 15 minutes, after which 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 hour. The reaction mixture was acidified with 1 M HCl, and then concentrated under vacuum to obtain the title product (170 mg, 70% yield) as a yellow solid. 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).

[0444] Scheme for general route 14e [ka]

[0445] Synthesis of intermediate S17 Ethyl 6-(dimethylamino)pyrazolo[1,5-a]pyrimidine-3-carboxylate (Step A) [ka] 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) were dissolved in degassed dioxane (3.7 mL), to which tBuXPhos Pd G3 (22 mg, 0.028 mmol) was added. This reaction mixture was heated at 100 °C for 4 hours. The reaction mixture was cooled to room temperature, filtered, and the filtrate was concentrated under vacuum. The residue was purified by open-access preparative HPLC (P3) to obtain the title product (27.6 mg, 17% yield) as a dark brown solid. 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)

[0446] Synthesis of intermediate S18 6-(dimethylamino)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (Step B) [ka] To a stirred solution of ethyl 6-(dimethylamino)pyrazolo[1,5-a]pyrimidine-3-carboxylate (45 mg, 0.190 mmol) in THF (2 mL), 2 M aqueous LiOH (0.48 mL, 0.950 mmol) was added. This reaction mixture was stirred at room temperature for approximately 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, and precipitated by sonication. The solid was dried overnight in a vacuum oven to obtain the title product (16.5 mg, 42% yield) as a light pink powder. LCMS m / z:207.3[M+H]+, (ESI+), Rt=0.13(S2)

[0447] The following intermediates were prepared using the corresponding starting materials in a manner similar to that of intermediate S18 outlined in general route 14e.

[0448] [Table 30]

[0449] Scheme for general route 14f [ka]

[0450] Synthesis of intermediate S19 Ethyl(2S)-2-({5H,6H,7H,8H-imidazo[1,2-a]pyrazine-7-carbonyl}amino)-4-methylpentanoate (Step A) [ka] To a solution of ethyl(2S)-2-amino-4-methylpentanoate hydrochloride (200 mg, 1.10 mmol) in MeCN (7 mL), DIPEA (0.96 mL, 5.50 mmol) was added at -10°C, followed by the dropwise addition of bis(trichloromethyl) carbonate (121 mg, 0.407 mmol) in MeCN (2 mL). This reaction mixture was stirred for 1 hour. 5H,6H,7H,8H-imidazo[1,2-a]pyrazine hydrochloride (176 mg, 1.10 mmol) in MeCN (7 mL) was added, and the reaction mixture was heated to 65°C for 2 hours, then cooled to room temperature and stirred for 18 hours. The reaction mixture was concentrated under vacuum to obtain a crude oily product. Purification by column chromatography (25 g silica, 0-5% MeOH in DCM) yielded the title product (169 mg, 35% yield) as a yellow oily substance. LCMS m / z:294[M+H]+, (ESI+), Rt=2.05(S7)

[0451] Synthesis of intermediate S20 Lithium (1+)(2S)-2-({5H,6H,7H,8H-imidazo[1,2-a]pyrazine-7-carbonyl}amino)-4-methylpentanoate (Process B) [ka] A suspension of ethyl(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 to be mixed with LiOH.H2O (47 mg, 1.12 mmol) in water (1.7 mL) at room temperature. The reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated under vacuum to obtain the title product (106 mg, 69% yield) as a yellow solid. LCMS m / z:281[M+H]+, (ESI+), Rt=1.68(S7)

[0452] Scheme for General Route 15 [ka]

[0453] Synthesis of intermediate T1 tert-butyl 2-{[(1S)-1-{[(1S)-1-{4,4'-difluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl}-3-ethoxy-3-oxopropyl]carbamoyl}-3-methylbutyl]carbamoyl}-2H,4H,5H,6H,7H-pyrazolo[3,4-c]pyridine-6-carboxylate and t ert-butyl1-{[(1S)-1-{[(1S)-1-{4,4'-difluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl}-3-ethoxy-3-oxopropyl]carbamoyl}-3-methylbutyl]carbamoyl}-1H,4H,5H,6H,7H-pyrazolo[3,4-c]pyridine-6-carboxylate (Step A) [ka] To a stirred solution of tert-butyl 1H,4H,5H,6H,7H-pyrazolo[3,4-c]pyridine-6-carboxylate (110.0 mg, 0.49 mmol) and DIPEA (0.25 mL, 1.44 mmol) in anhydrous THF (4.4 mL), 4-nitrophenyl chloroformate (109.0 mg, 0.54 mmol) was added at 0°C. This reaction mixture was stirred at room temperature for 1.5 hours. Ethyl (3S)-3-[(2S)-2-amino-4-methylpentanamide]-3-{4,4'-difluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl}propanoate hydrochloride (300.0 mg, 0.49 mmol) was added, and the reaction mixture was stirred at room temperature for a further 18 hours. The reaction product was diluted with water (10 mL) and extracted with SiO2 (3 × 10 mL). The combined organic layers consisted of washed saturated NaHCO3 solution (2 × 5 mL) and brine (2 × 10 mL), which were dehydrated with MgSO4 and concentrated under vacuum. Purification by FCC (25 g silica, 0% to 100% SiO2 in heptane) yielded a mixture of the title compound (382 mg, 76% yield) as a colorless gum-like substance. 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).

[0454] Synthesis of intermediate T2 Ethyl(3S)-3-{4,4'-difluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl}-3-[(2S)-4-methyl-2-({2H,4H,5H,6H,7H-pyrazolo[3,4-c]pyridine-2-carbonyl}amino)pentanamide]propanoate and Ethyl(3S)-3-{4,4'-difluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl}-3-[(2S)-4-methyl-2-({1H,4H,5H,6H,7H-pyrazolo[3,4-c]pyridine-1-carbonyl}amino)pentanamide]propanoate (Step B) [ka] To a solution of intermediate T1 (380.0 mg, 0.37 mmol) in DCM (2 mL), TFA (0.11 mL, 1.44 mmol) was added, and the reaction mixture was stirred at room temperature for 5 hours. The reaction mixture was concentrated under vacuum, and the residue was obtained. Purification by column chromatography (5 g SCX, 0-100% 7 M NH3 in MeOH) yielded a mixture of the title compound (237 mg, 93% yield) as a yellow oily substance. LCMS m / z: 610.4 [M+H]+, (ESI+), Rt = 0.93 / 0.94 (S1) 1 H 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).

[0455] Synthesis of intermediate T3 Ethyl(3S)-3-{4,4'-difluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl}-3-[(2S)-4-methyl-2-{[6-(propan-2-yl)-2H,4H,5H,6H,7H-pyrazolo[3,4-c]pyridine-2-carbonyl]amino}pentanamide]propanoate and Ethyl(3S)-3-{4,4'-difluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl}-3-[(2S)-4-methyl-2-{[6-(propan-2-yl)-1H,4H,5H,6H,7H-pyrazolo[3,4-c]pyridine-1-carbonyl]amino}pentanamide]propanoate (Step C) [ka] To a stirred solution of intermediates 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), STAB (221 mg, 1.04 mmol) was added at room temperature. This 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 × 10 mL). The combined organic matter was passed through a phase separator and concentrated under vacuum. The residue was purified by FCC (10 g, 0-100% HCl in heptane, then 0-15% MeOH in HCl) to obtain a mixture of the title compound (148 mg, 62% yield) as a colorless gum-like substance. LCMS m / z:652.5[M+H]+, (ESI+), Rt=0.98 / 0.99(S1).

[0456] Synthesis of intermediate U1 Ethyl(3S)-3-{4,5-difluoro-2',6'-dimethyl-[1,1'-biphenyl]-3-yl}-3-[(2S)-4-methyl-2-(phenylformamide)pentanamide]propanoate [ka] To a solution of intermediate B2 (80 mg, 0.170 mmol) in DCM (5 mL), DIPEA (0.044 mL, 0.255 mmol) was added, followed by benzoyl chloride (0.020 mL, 0.170 mmol). The reaction mixture was stirred at room temperature for 18 hours. The reaction product was concentrated under vacuum and purified by flash column chromatography on silica (10 g, 0-100% siRNA in heptane) to obtain the title product (111 mg, 100% yield) as a white powder. LCMS m / z: 551.3 [M+H]+, (ESI+), Rt = 1.16 (S1) 1H 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 (m, 2H), 1.68 - 1.55 (m, 4H), 1.36 - 1.21 (m, 5H), 1.13 (t, J = 7.1 Hz, 3H). (N1)

[0457] Synthesis of intermediate U2 (3S)-3-[(2S)-2-amino-4-methylpentanamide]-3-{4,5-difluoro-2',6'-dimethyl-[1,1'-biphenyl]-3-yl}propanoate [ka] Ethyl(3S)-3-[(2S)-2-amino-4-methylpentanamide]-3-{4,5-difluoro-2',6'-dimethyl-[1,1'-biphenyl]-3-yl}propanoate hydrochloride (intermediate B2, 75 mg, 0.155 mmol) was dissolved in MeOH (0.19 mL) and THF (1.9 mL), to which 2 M aqueous LiOH (0.31 mL, 0.621 mmol) was added at 40 °C. The reaction mixture was stirred at 40 °C for 18 hours. The reaction mixture was concentrated under vacuum, and water (5 mL) was added to the resulting residue. This mixture was neutralized with 1 M aqueous HCl and extracted with CHCl3 / IPA (2:1, 3 × 10 mL). The combined organic matter was passed through hydrophobic frit and concentrated under vacuum to obtain the title product (55 mg, 71% yield) as a white solid. LCMS m / z: 419.2 [M+H]+, (ESI+), Rt = 0.80 (S1) 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 9.00 (s, 1H), 7.18 - 7.12 (m, 1H), 7.12 - 7.05 (m, 3H), 6.96 - 6.90 (m, 1H), 5.43 - 5.31 (m, 1H), 3.17 - 3.09 (m, 1H), 2.56 - 2.52 (m, 2H), 1.94 (d, J = 12.1 Hz, 6H), 1.58 - 1.46 (m, 1H), 1.33 - 1.24 (m, 1H), 1.20 - 1.06 (m, 1H), 0.83 - 0.70 (m, 6H). (N1)

[0458] Scheme for general route 16 [ka]

[0459] Synthesis of intermediate V1 tert-butyl2-{[(1S)-1-{[(1S)-3-ethoxy-3-oxo-1-{4,4',5-trifluoro-2',6'-dimethyl-[1,1'-biphenyl]-3-yl}propyl]carbamoyl}-3-methylbutyl]carbamoyl}-5H,6H,7H-pyrrolo[3,4-b]pyridine-6-carboxylate (Step A) [ka] To a solution of ethyl(3S)-3-[(2S)-2-amino-4-methylpentanamide]-3-{4,4',5-trifluoro-2',6'-dimethyl-[1,1'-biphenyl]-3-yl}propanoate (100 mg, 0.190 mmol) and 6-[(tert-butoxy)carbonyl]-5H,6H,7H-pyrrolo[3,4-b]pyridine-2-carboxylic acid (63 mg, 0.226 mmol) in DCM (2 mL), DIPEA (75 μL, 0.429 mmol) was added, followed by HATU (88 mg, 0.231 mmol). The resulting mixture was stirred at room temperature for 1 hour. Water (4 mL) was added to this reaction mixture, and the reaction mixture was then separated using a Telos phase separator. Water was extracted by DCM (2 × 2 mL), and the combined organic components were concentrated under vacuum to obtain a crude residue. Purification by column chromatography (12 g silica, 0-50% ethyl phosphate in heptane) yielded the title product (122 mg, 86% yield) as an off-white solid. LCMS m / z: 711.6 [M+H]+, (ESI+), Rt = 1.28 (S1) 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 8.89 - 8.83 (m, 1H), 8.53 - 8.42 (m, 1H), 7.98 - 7.83 (m, 2H), 7.21 - 7.11 (m, 1H), 6.96 - 6.91 (m, 2H), 6.90 - 6.81 (m, 1H), 5.57 - 5.47 (m, 1H), 4.71 - 4.56 (m, 4H), 4.54 - 4.40 (m, 1H), 4.06 - 3.93 (m, 2H), 2.85 - 2.77 (m, 2H), 1.94 (d, J = 2.7 Hz, 3H), 1.80 (d, J = 6.8 Hz, 3H), 1.55 - 1.39 (m, 12H), 1.12 - 1.02 (m, 3H), 0.92 - 0.74 (m, 6H). (N1)

[0460] Synthesis of intermediate V2 Ethyl(3S)-3-[(2S)-4-methyl-2-({5H,6H,7H-pyrrolo[3,4-b]pyridine-2-yl}formamide)pentanamide]-3-{4,4',5-trifluoro-2',6'-dimethyl-[1,1'-biphenyl]-3-yl}propanoate hydrochloride (Process B) [ka] To a solution of tert-butyl 2-{[(1S)-1-{[(1S)-3-ethoxy-3-oxo-1-{4,4',5-trifluoro-2',6'-dimethyl-[1,1'-biphenyl]-3-yl}propyl]carbamoyl}-3-methylbutyl]carbamoyl}-5H,6H,7H-pyrrolo[3,4-b]pyridine-6-carboxylate (120 mg, 0.160 mmol) in DCM (1.9 mL), HCl (4 M in dioxane) (440 μL, 1.76 mmol) was added. The resulting mixture was stirred under N2 at room temperature for 2.5 hours, and then concentrated under vacuum to obtain the title product (85 mg, 78% yield) as a bright yellow solid. LCMS m / z: 611.6 [M+H]+, (ESI+), Rt = 0.86 (S1) 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 9.69 (s, 2H), 8.96 - 8.89 (m, 1H), 8.45 - 8.38 (m, 1H), 8.06 - 7.95 (m, 2H), 7.23 - 7.19 (m, 1H), 7.04 - 6.94 (m, 3H), 5.56 - 5.50 (m, 1H), 4.67 - 4.62 (m, 5H), 4.04 - 3.95 (m, 2H), 2.85 (d, J = 7.6 Hz, 2H), 1.99 - 1.91 (m, 6H), 1.50 - 1.45 (m, 2H), 1.10 - 1.01 (m, 3H), 0.83 - 0.73 (m, 6H). (N1)

[0461] Synthesis of intermediate V3 Ethyl(3S)-3-[(2S)-4-methyl-2-({6-methyl-5H,6H,7H-pyrrolo[3,4-b]pyridine-2-yl}formamide)pentanamide]-3-{4,4',5-trifluoro-2',6'-dimethyl-[1,1'-biphenyl]-3-yl}propanoate (Step C) [ka] To a stirred solution of ethyl(3S)-3-[(2S)-4-methyl-2-({5H,6H,7H-pyrrolo[3,4-b]pyridine-2-yl}formamide)pentanamide]-3-{4,4',5-trifluoro-2',6'-dimethyl-[1,1'-biphenyl]-3-yl}propanoate hydrochloride (50 mg, 0.0734 mmol) and acetic acid (29 μL, 0.498 mmol) in DCE (3.3 mL), paraformaldehyde (14 mg, 0.459 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours. Sodium borocyanohydride (29 mg, 0.454 mmol) was added, and the mixture was stirred for a further 3 hours. The reaction mixture was cooled to 0°C and quenched with saturated NaHCO3 (2 mL). The organic layer was separated, and the aqueous layer was extracted by DCM (2 × 2 mL). The combined organic layers were concentrated under vacuum to obtain the crude residue. Purification by column chromatography on silica (11 g KP-NH silica, 0-60% siRNA in heptane) yielded the title product (23 mg, 45% yield) as an off-white solid. LCMS m / z: 625.4 [M+H]+, (ESI+), Rt = 0.88 (S1) 1H NMR (400 MHz, DMSO-d6) δ [ppm]: 8.84 (d, 1H), 8.41 (d, J = 8.9 Hz, 1H), 7.84 - 7.75 (m, 2H), 7.22 - 7.13 (m, 1H), 7.00 - 6.89 (m, 3H), 5.57 - 5.47 (m, 1H), 4.57 - 4.52 (m, 1H), 4.00 - 3.94 (m, 2H), 3.91 - 3.79 (m, 4H), 2.85 - 2.78 (m, 2H), 2.51 (s, 3H), 1.94 (s, 3H), 1.86 (s, 3H), 1.49 - 1.44 (m, 3H), 1.05 (t, J = 7.1 Hz, 3H), 0.79 (d, J = 5.8 Hz, 3H), 0.76 (d, J = 5.8 Hz, 3H). (N1)

[0462] The following intermediates were prepared using the corresponding starting materials in a manner similar to that of intermediate V3 outlined in general route 15.

[0463] [Table 31-1] [Table 31-2]

[0464] Scheme for General Route 17 [ka]

[0465] Synthesis of intermediate W1 Ethyl(3S)-3-{4,5-difluoro-2',6'-dimethyl-[1,1'-biphenyl]-3-yl}-3-[(2S)-4-methyl-2-[(4-oxo-4H-quinoridine-3-yl)formamide]pentanamide]propanoate [ka] To a stirred mixture of ethyl 4-oxo-4H-quinolidine-3-carboxylate (74 mg, 0.330 mmol) in THF (3 mL), LiOH.H2O (42 mg, 0.990 mmol) and water (0.5 mL) were sequentially added at room temperature, and the resulting mixture was stirred at room temperature for 2 hours. Further water (2.5 mL) and LiOH.H2O (42 mg, 0.990 mmol) were added, and the reaction mixture was stirred for 18 hours. Next, the reaction mixture was concentrated under vacuum, diluted with toluene, and concentrated under vacuum to dryness (2 × 25 mL) to obtain an intermediate residue. Next, the residue was dissolved in DCM (5 mL) at room temperature, and then HATU (121 mg, 0.318 mmol), intermediate B2 (153 mg, 0.318 mmol), and DIPEA (0.17 mL, 0.953 mmol) were added, and the mixture was stirred for 12 hours. Further HATU (121 mg, 0.318 mmol) and DIPEA (0.17 mL, 0.953 mmol) were added, and the reaction mixture was stirred at room temperature for 2 hours. DMF (5 mL) was added, DCM was removed under vacuum, and the reaction mixture was then stirred at 45°C for 2 hours. The reaction mixture was then concentrated under vacuum and purified by flash column chromatography (12 g silica, 0-100% ethyl phosphate in heptane) to obtain the title product (140 mg, 66% yield) in powder form. LCMS m / z: 618.4 [M+H]+, (ESI+), Rt = 2.92 (S7) 1H NMR (300 MHz, DMSO-d6) δ [ppm]: 9.89 (d, J = 8.0 Hz, 1H), 9.24 (d, J = 7.4 Hz, 1H), 8.81 (d, J = 7.9 Hz, 1H), 8.39 (dd, J = 8.4, 2.0 Hz, 1H), 7.99 (d, J = 8.7 Hz, 1H), 7.86 (dd, J = 8.7, 6.9 Hz, 1H), 7.54 - 7.43 (m, 1H), 7.24 - 7.02 (m, 5H), 6.99 (d, J = 5.7 Hz, 1H), 5.55 (q, J = 7.5 Hz, 1H), 4.59 (d, J = 7.8 Hz, 1H), 4.09 - 3.93 (m, 2H), 3.30 (s, 5H), 2.83 (d, J = 7.6 Hz, 2H), 2.02 - 1.88 (m, 7H), 1.44 (d, J = 5.5 Hz, 2H), 1.27 - 1.10 (m, 1H), 1.06 (td, J = 7.1, 2.0 Hz, 3H), 0.79 (t, J = 5.8 Hz, 6H).

[0466] Scheme for General Route 18 [ka]

[0467] Synthesis of intermediate X1 Methyl(3S)-3-{4,5-difluoro-2',6'-dimethyl-[1,1'-biphenyl]-3-yl}-3-[(2S)-4-methyl-2-[(2-methyl-3aH-2-lambda4-indazole-7-yl)formamide]pentanamide]propanoate [ka] To a stirred toluene (5 mL) solution of 2-methyl-3aH-2-lambda4-indazole-7-carboxylic acid (110 mg, 0.600 mmol), thionyl chloride (0.44 mL, 6.00 mmol) and N,N-dimethylformamide (0.023 mL, 0.300 mmol) were sequentially added under N2 at room temperature. The reaction mixture was stirred at 110 °C for 4 hours, cooled to room temperature, and concentrated under vacuum. The crude product was co-evaporated with toluene (2 × 10 mL) and dried under vacuum to obtain an intermediate product. To a stirred solution of methyl(3S)-3-[(2S)-2-amino-4-methylpentanamide]-3-{4,5-difluoro-2',6'-dimethyl-[1,1'-biphenyl]-3-yl}propanoate hydrochloride (intermediate B2, 200 mg, 0.427 mmol) in DCM (5 mL), the intermediate (138 mg, 0.597 mmol) and DIPEA (0.37 mL, 2.13 mmol) were sequentially added under N2 at room temperature, and the mixture was stirred at room temperature for 12 hours. The reaction mixture was concentrated under vacuum to obtain the crude product. Purification by column chromatography (10 g silica, 0-50% SiO in heptane) yielded the title product. LCMS m / z: 591.2 [M+H]+, (ESI+), Rt = 2.95 (S6) 1H NMR (300 MHz, DMSO-d6) δ [ppm]: 9.34 (d, J = 7.9 Hz, 1H), 8.86 (d, J = 7.9 Hz, 1H), 8.57 (d, J = 1.9 Hz, 1H), 7.93 (t, J = 8.2 Hz, 2H), 7.25 - 7.08 (m, 5H), 6.98 (d, J = 5.8 Hz, 1H), 5.56 (q, J = 7.7 Hz, 1H), 4.65 (q, J = 7.2 Hz, 1H), 4.23 (d, J = 2.0 Hz, 3H), 3.52 (d, J = 2.0 Hz, 3H), 2.87 (d, J = 7.5 Hz, 2H), 1.96 (d, J = 3.1 Hz, 6H), 1.49 (d, J = 6.6 Hz, 3H), 1.24 (s, 2H), 0.82 (q, J = 6.7 Hz, 7H). (N2).

[0468] Example compound Scheme of General Route 19 [ka]

[0469] [Example 1] (3S)-3-{4,5-difluoro-2',6'-dimethyl-[1,1'-biphenyl]-3-yl}-3-[(2S)-4-methyl-2-[(quinoline-8-yl)formamide]pentanamide]propanoic acid [ka] To a solution of intermediate F1 (59 mg, 0.0981 mmol) in THF (1.5 mL), LiOH (2 M, aqueous, 0.25 mL, 0.490 mmol) was added and incubated at room temperature for 18 hours. The reaction mixture was acidified to pH 1 by adding HCl (2 M, aqueous) and concentrated under vacuum. The residue was purified by FC (10 g silica, 50-100% HCl in heptane, 10% MeOH in HCl), and then by HPLC (P1) to obtain (3S)-3-{4,5-difluoro-2',6'-dimethyl-[1,1'-biphenyl]-3-yl}-3-[(2S)-4-methyl-2-[(quinoline-8-yl)formamide]pentanamide]propanoic acid (16.6 mg, 30% yield), which was Example 1, as a solid. m / z: 574.3 [M+H]+, (ESI+), RT = 4.08 (S3) 1 H NMR (500 MHz, DMSO-d6) δ [ppm]: 12.41 (s, 1H), 11.26 (d, J = 7.9 Hz, 1H), 9.03 (dd, J = 4.3, 1.8 Hz, 1H), 8.85 (d, J = 7.9 Hz, 1H), 8.58 (dd, J = 8.4, 1.8 Hz, 1H), 8.50 (dd, J = 7.3, 1.6 Hz, 1H), 8.21 (dd, J = 8.2, 1.6 Hz, 1H), 7.75 - 7.70 (m, 1H), 7.68 (dd, J = 8.3, 4.3 Hz, 1H), 7.23 - 7.15 (m, 2H), 7.12 (d, J = 7.6 Hz, 2H), 6.98 (d, J = 5.7 Hz, 1H), 5.62 - 5.49 (m, 1H), 4.74 - 4.65 (m, 1H), 2.83 - 2.72 (m, 2H), 1.97 (s, 3H), 1.95 (s, 3H), 1.61 - 1.50 (m, 3H), 0.84 (d, J = 6.1 Hz, 3H), 0.81 (d, J = 6.2 Hz, 3H).

[0470] The examples in Table 9 were synthesized using the corresponding starting materials and in accordance with General Scheme 19, as illustrated by Example 1. The diastereomers were separated either during final purification or, if necessary, by chiral separation. The examples were obtained as the title compound or its salts.

[0471] [Table 32-1] [Table 32-2] [Table 32-3] [Table 32-4] [Table 32-5] [Table 32-6] [Table 32-7] [Table 32-8] [Table 32-9] [Table 32-10] [Table 32-11] [Table 32-12] [Table 32-13] [Table 32-14] Table 32-15 Table 32-16 Table 32-17 Table 32-18 Table 32-19 Table 32-20 Table 32-21 Table 32-22 Table 32-23 Table 32-24 Table 32-25 Table 32-26 Table 32-27 Table 32-28 Table 32-29 Table 32-30 Table 32-31

[0472] Scheme for general route 20 [ka]

[0473] [Example 37] (3S)-3-{4,5-difluoro-2',6'-dimethyl-[1,1'-biphenyl]-3-yl}-3-[(2S)-4-methyl-2-[(1-methyl-1H-pyrazole-4-yl)formamide]pentanamide]propanoic acid [ka] To a stirred solution of intermediate B2 (90 mg, 0.130 mmol) and 1-methyl-1H-pyrazole-4-carboxylic acid (20 mg, 0.157 mmol) in DCM (2 mL), DIPEA (0.066 mL, 0.376 mmol) was added, followed by HATU (67 mg, 0.176 mmol), and the mixture was stirred at room temperature for 3 hours. This reaction mixture was concentrated under vacuum and redissolved in THF (2 mL). Methanol (0.2 mL) and LiOH (2 M, aqueous, 0.33 mL, 0.652 mmol) were added, and the reaction mixture was stirred for 3 hours. The reaction mixture was concentrated under vacuum to remove organic matter, acidified with HCl (2 M, aqueous), extracted with DCM (2 × 30 mL), and dried and concentrated using a phase separator to obtain a crude residue. This was purified by preparative HPLC (P1) to obtain the title compound (40 mg, 58% yield) as a solid. m / z: 527.4 [M+H]+, (ESI+), RT = 3.47 (S3) 1H NMR (500 MHz, DMSO-d6) δ [ppm]: 12.44 (s, 1H), 8.64 (d, J = 7.9 Hz, 1H), 8.12 (s, 1H), 7.98 (d, J = 8.4 Hz, 1H), 7.84 (d, J = 0.7 Hz, 1H), 7.31 - 7.05 (m, 4H), 7.01 - 6.88 (m, 1H), 5.48 (q, J = 7.5 Hz, 1H), 4.58 - 4.37 (m, 1H), 3.83 (s, 3H), 2.80 - 2.69 (m, 2H), 2.01 - 1.89 (m, 6H), 1.56 - 1.20 (m, 3H), 0.76 (dd, J = 6.5, 3.9 Hz, 6H).

[0474] T3P conditions [Example 303] (3S)-3-{4'-chloro-4-fluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl}-3-[(2S)-2-({6-[3-(3-methoxyazetidine-1-yl)propyl]pyridine-2-yl}formamide)-4-methylpentanamide]propanoic acid [ka] Ethyl (3S)-3-[(2S)-2-amino-4-methylpentanamide]-3-{4'-chloro-4-fluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl}propanoate hydrochloride (intermediate D3, 200 mg, 0.386 mmol), 6-[3-(3-methoxyazetidine-1-yl)propyl]pyridine-2-carboxylate lithium salt (162 mg, 0.424 mmol), and TEA (215 μL, 1.54 mmol) were dissolved in DMF (4 mL) at room temperature. 50% of T3P (in ethyl) (459 μL, 0.771 mmol) was added to this mixture. The reaction mixture was stirred at room temperature for 16 hours. The reaction product was diluted with ethyl (20 mL), washed with water (2 × 20 mL), then with brine (2 × 10 mL), and then concentrated under vacuum. The residue was dissolved in THF (4 mL), and 2 M LiOH (aqueous solution) (1.33 mL, 2.67 mmol) was added. After stirring at room temperature for 2 hours, the reaction mixture was diluted with water (10 mL), concentrated under vacuum, and the pH was acidified to approximately 3 using 10% citric acid (aqueous solution). The suspension was filtered, and the solid was purified by HPLC (P4) to obtain the title product (122 mg, 46% yield) as a solid. LCMS m / z: 681.5 / 683.5 [M+H]+, (ESI+), Rt = 3.29 (S4) 1H NMR (400 MHz, DMSO-d6) δ [ppm]: 8.95 (d, J = 8.2 Hz, 1H), 8.58 (d, J = 9.0 Hz, 1H), 7.82 (t, J = 7.7 Hz, 1H), 7.75 - 7.65 (m, 1H), 7.44 - 7.38 (m, 1H), 7.13 - 7.08 (m, 2H), 6.91 - 6.87 (m, 1H), 6.82 - 6.76 (m, 1H), 5.53 - 5.35 (m, 1H), 4.58 - 4.47 (m, 1H), 3.99 (p, J = 5.9Hz, 1H), 3.75 - 3.50 (m, 4H), 3.13 (s, 3H), 3.11 - 3.06 (m, 1H), 3.02 - 2.97 (m, 1H), 2.87 - 2.78 (m, 1H), 2.74 - 2.53 (m, 4H), 2.46 - 2.35 (m, 1H), 2.28 - 2.20 (m, 3H), 1.87 - 1.80 (m, 6H), 1.67 - 1.34 (m, 3H), 0.83 - 0.76 (m, 6H).

[0475] The examples in Table 10 were synthesized using the corresponding starting materials and in accordance with general route 20, as illustrated by Examples 37 and 303. Unless otherwise specified in the table, HATU conditions were used. Diastereomers were separated either during final purification or, if necessary, by chiral separation methods. The examples were obtained as the title compound or a salt thereof.

[0476] [Table 33-1] [Table 33-2] [Table 33-3] [Table 33-4] Table 33-5 Table 33-6 Table 33-7 Table 33-8

[0477] Table 34-1 Table 34-2 Table 34-3 Table 34-4 Table 34-5 Table 34-6 Table 34-7 Table 34-8 Table 34-9 Table 34-10 Table 34-11 Table 34-12 Table 34-13 Table 34-14 Table 34-15 Table 34-16 Table 34-17 Table 34-18 Table 34-19 Table 34-20 Table 34-21 Table 34-22 Table 34-23 Table 34-24 Table 34-25 Table 34-26 Table 34-27 Table 34-28 Table 34-29 Table 34-30 Table 34-31 Table 34-32

[0478] Table 35-1 Table 35-2 Table 35-3 Table 35-4

[0479] Table 36-1 Table 36-2 Table 36-3 Table 36-4

[0480] Table 37-1 Table 37-2 Table 37-3 Table 37-4

[0481] Table 38-1 Table 38-2 Table 38-3 Table 38-4 Table 38-5 Table 38-6 Table 38-7 Table 38-8 Table 38-9 Table 38-10 Table 38-11 Table 38-12 Table 38-13 Table 38-14 Table 38-15 Table 38-16 Table 38-17 Table 38-18 Table 38-19 Table 38-20 Table 38-21

[0482] Table 39-1 Table 39-2 Table 39-3 Table 39-4 Table 39-5 Table 39-6 Table 39-7 Table 39-8 Table 39-9 Table 39-10 Table 39-11 Table 39-12 Table 39-13 Table 39-14 Table 39-15 Table 39-16 Table 39-17 Table 39-18 Table 39-19 Table 39-20 Table 39-21 Table 39-22 Table 39-23 Table 39-24 Table 39-25 Table 39-26 Table 39-27 Table 39-28 Table 39-29 Table 39-30 Table 39-31

[0483] Table 40-1 Table 40-2 Table 40-3

[0484] Table 41-1 Table 41-2 Table 41-3 Table 41-4 Table 41-5 Table 41-6 Table 41-7 Table 41-8 Table 41-9 Table 41-10 Table 41-11 Table 41-12 Table 41-13 Table 41-14 Table 41-15 Table 41-16

[0485] Table 42-1 Table 42-2 Table 42-3 Table 42-4 Table 42-5

[0486] Table 43-1 Table 43-2 Table 43-3

[0487] Table 44-1 Table 44-2 Table 44-3 Table 44-4 Table 44-5 Table 44-6 Table 44-7 Table 44-8 Table 44-9 Table 44-10 Table 44-11

[0488] Table 45-1 Table 45-2 Table 45-3 Table 45-4 Table 45-5

[0489] [Table 46-1] [Table 46-2] [Table 46-3] [Table 46-4]

[0490] Scheme for general route 21 [ka]

[0491] [Example 58] (3S)-3-{4,5-difluoro-2',6'-dimethyl-[1,1'-biphenyl]-3-yl}-3-[(2S)-2-[(2-fluorophenyl)formamide]-4-methylpentanamide]propanoic acid [ka] To a stirred solution of intermediate B2 (73 mg, 0.106 mmol) and DIPEA (55 μL, 0.315 mmol) in DCM (2 mL), 2-fluorobenzoyl chloride (16 μL, 0.134 mmol) was added. This mixture was stirred under N2 at room temperature for 1 hour. The reaction mixture was concentrated, and the residue was dissolved in THF (2 mL) and MeOH (0.2 mL). LiOH (2 M, aqueous, 280 μL, 0.560 mmol) was added to this solution, and the mixture was stirred at room temperature for 2 hours. This reaction mixture was concentrated under vacuum to remove organic matter, acidified to pH 1 with HCl (2 M, aqueous), diluted with water (5 mL), and extracted with DCM (3 × 5 mL). The organic components were dehydrated with Na₂SO₄, concentrated under vacuum, and purified by preparative HPLC (P₂) to obtain the title compound (36 mg, 62% yield) as a solid. m / z: 541.4 [M+H]+, (ESI+), RT = 4.05 (S3) 1 H NMR (500 MHz, DMSO-d6) δ [ppm]: 12.46 (s, 1H), 8.75 - 8.61 (m, 1H), 8.26 (dd, J = 8.3, 2.9 Hz, 1H), 7.54 - 7.47 (m, 2H), 7.28 - 7.14 (m, 4H), 7.14 - 7.07 (m, 2H), 6.96 - 6.91 (m, 1H), 5.49 (q, J = 7.4 Hz, 1H), 4.52 - 4.44 (m, 1H), 2.75 (d, J = 7.3 Hz, 2H), 1.98 - 1.92 (m, 6H), 1.60 - 1.51 (m, 1H), 1.51 - 1.42 (m, 1H), 1.41 - 1.32 (m, 1H), 0.84 - 0.75 (m, 6H). (N1)

[0492] The example compounds in Table 11 were synthesized using the corresponding starting materials in accordance with General Scheme 21, as illustrated by Example 58. Diastereomers were separated either during final purification or, if necessary, by chiral separation methods. The examples were obtained as the title compound or its salts.

[0493] [Table 47-1] [Table 47-2] [Table 47-3]

[0494] Scheme for general route 22 [ka]

[0495] [Example 64] (3S)-3-{4'-chloro-4,5-difluoro-2',6'-dimethyl-[1,1'-biphenyl]-3-yl}-3-[(2S)-4-methyl-2-[(1-methyl-2-oxo-1,2-dihydropyridine-3-yl)formamide]pentanamide]propanoic acid [ka] A solution of ethyl intermediate F6 (80 mg, 0.122 mmol), (4-chloro-2,6-dimethylphenyl)boronic acid (25 mg, 0.134 mmol), and K3PO4 (79 mg, 0.374 mmol) in 1,4-dioxane (0.8 mL) and water (97 μL) was purged with N2 for 5 minutes, then treated with Pd(dppf)Cl2 (13 mg, 0.0162 mmol), and stirred at 90°C for 2 hours. The reaction product was then cooled to room temperature, diluted with SiO2 (15 mL), and washed with water (15 mL). The water was then extracted with SiO2 (3 × 10 mL), the organic components were washed together with brine (15 mL), dried using a phase separator, and concentrated under vacuum. The residue was dissolved in THF (1 mL), LiOH (2 M, aqueous, 0.31 mL, 0.618 mmol) was added, and the reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated to remove organic matter, then diluted with water, acidified to pH 1 with HCl (1 M, aqueous), and sonicated. The resulting precipitate was purified by preparative HPLC P1 to obtain the title compound, (3S)-3-{4'-chloro-4,5-difluoro-2',6'-dimethyl-[1,1'-biphenyl]-3-yl}-3-[(2S)-4-methyl-2-[(1-methyl-2-oxo-1,2-dihydropyridine-3-yl)formamide]pentanamide]propanoic acid (20 mg, 27% yield), as a solid. m / z: 588.3 / 590.3 [M+H]+, (ESI+), RT = 3.81 (S3) 1H NMR (400 MHz, DMSO-d6) δ [ppm]: 12.42 (br. s, 1H), 10.04 (d, J = 8.0 Hz, 1H), 8.77 (d, J = 7.9 Hz, 1H), 8.18 (dd, J = 7.3, 2.2 Hz, 1H), 8.05 (dd, J = 6.5, 2.2 Hz, 1H), 7.25 - 7.14 (m, 3H), 6.95 - 6.88 (m, 1H), 6.44 (dd, J = 7.3, 6.5 Hz, 1H), 5.47 (q, J = 7.6 Hz, 1H), 4.55 - 4.45 (m, 1H), 3.54 (s, 3H), 2.79 - 2.70 (m, 2H), 1.98 - 1.89 (m, 6H), 1.47 - 1.35 (m, 3H), 0.77 (dd, J = 6.1, 4.6 Hz, 6H).

[0496] The example compounds in Table 12 were synthesized using the corresponding starting materials in accordance with general route 22, as illustrated by Example 64. Diastereomers were separated either during final purification or, if necessary, by chiral separation methods. The examples were obtained as the title compound or its salt.

[0497] [Table 48-1] [Table 48-2] [Table 48-3] [Table 48-4] [Table 48-5] [Table 48-6]

[0498] Scheme for general route 23 [ka]

[0499] Synthesis of Example 67 (3S)-3-[2,3-difluoro-5-(2-methyl-2H-indazole-3-yl)phenyl]-3-[(2S)-4-methyl-2-[(1-methyl-2-oxo-1,2-dihydropyridine-3-yl)formamide]pentanamide]propanoic acid [ka] In a sealed vial, a solution of ethyl(3S)-3-[2,3-difluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-3-[(2S)-4-methyl-2-[(1-methyl-2-oxo-1,2-dihydropyridine-3-yl)formamide]pentanamide]propanoate (intermediate H1) (90%, 88 mg, 0.131 mmol) and 3-bromo-2-methyl-indazole (42 mg, 0.199 mmol) in 1,4-dioxane (2.5 mL) was added, to which K2CO3 (55 mg, 0.398 mmol) and water (0.2 mL). The mixture was degassed for 5 minutes, and then Pd(dppf)2Cl2.DCM (11 mg, 0.0134 mmol) was added. The reaction mixture was sealed and heated at 100°C for 18 hours. The reaction mixture was diluted with ELISA (15 mL), H₂O (10 mL), and saturated brine aqueous solution (5 mL). The organic layer was separated, and the aqueous layer was further extracted with ELISA (2 × 10 mL). The combined organic phase was dehydrated with MgSO₄, filtered, and concentrated under vacuum to obtain the residue. The residue was redissolved in THF (2.9 mL) and methanol (1 mL), and then treated with 2 M lithium hydroxide (0.68 mL, 1.37 mmol). This solution was stirred at room temperature for 90 minutes. The reaction mixture was concentrated under vacuum at 40°C to obtain the residue. The residue was dissolved in H₂O, and the pH was adjusted to pH 3. The aqueous layer was extracted with ELISA (2 × 10 mL), the combined organic phase was dehydrated with MgSO₄, filtered, and concentrated under vacuum to obtain the residue. Purification by reverse-phase chromatography (Method 1) yielded (3S)-3-[2,3-difluoro-5-(2-methyl-2H-indazole-3-yl)phenyl]-3-[(2S)-4-methyl-2-[(1-methyl-2-oxo-1,2-dihydropyridine-3-yl)formamide]pentanamide]propanoic acid (46 mg, 60% yield) as a white solid. LCMS m / z: 580.2 [M+H] + , (ESI+), Rt = 2.94 (S3) 1H NMR (400 MHz, DMSO-d6) δ [ppm]: 12.57 (s, 1H), 10.08 (d, J = 7.9 Hz, 1H), 8.94 (s, 1H), 8.17 (dd, J = 7.3, 2.2 Hz, 1H), 8.05 (dd, J = 6.5, 2.2 Hz, 1H), 7.77 - 7.70 (m, 1H), 7.65 (d, J = 8.7 Hz, 1H), 7.59 (d, J = 8.4 Hz, 1H), 7.48 (d, J = 5.6 Hz, 1H), 7.35 - 7.27 (m, 1H), 7.13 - 7.04 (m, 1H), 6.44 (t, J = 6.9 Hz, 1H), 5.51 (q, J = 7.4 Hz, 1H), 4.55 - 4.45 (m, 1H), 4.14 (s, 3H), 3.56 (s, 3H), 2.84 - 2.78 (m, 2H), 1.49 - 1.43 (m, 3H), 0.80 - 0.73 (m, 6H).

[0500] The following compounds were synthesized using the corresponding starting materials in accordance with general route 23, as illustrated by Example 67. Diastereomers were separated either during final purification or, if necessary, by chiral separation methods. The examples were obtained as the title compound or its salts.

[0501] [Table 49-1] [Table 49-2] [Table 49-3] [Table 49-4] [Table 49-5]

[0502] Scheme for general route 24 [ka]

[0503] [Example 360] Process C: (3S)-3-{4,4'-difluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl}-3-[(2S)-4-methyl-2-{[6-(4-methyl-1,4-diazepan-1-yl)pyridine-2-yl]formamide}pentanamide]propanoic acid [ka] To a stirred 1,4-dioxane (1.5 mL) solution of 1-methyl-1,4-diazepane (32 μL, 0.26 mmol), Cs2CO3 (227.0 mg, 0.7 mmol) and ethyl(3S)-3-[(2S)-2-[(6-chloropyridine-2-yl)formamide]-4-methylpentanamide]-3-{4,4'-difluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl}propanoate (intermediate Q5, 115 mg, 0.172 mmol) were added. Nitrogen was vigorously flowed through this solution for 20 minutes, and then Pd(OAc)2 (6.0 mg, 0.03 mmol) and BINAP (34.0 mg, 0.05 mmol) were added, and the reaction mix was stirred at 100°C for 19 hours. The reaction mixture was cooled, diluted with SiO2 (8 mL), filtered on Celite, washed with SiO2 (2 × 10 mL), and concentrated. The residue was purified by HPLC (P4) to obtain (3S)-3-{4,4'-difluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl}-3-[(2S)-4-methyl-2-{[6-(4-methyl-1,4-diazepan-1-yl)pyridine-2-yl]formamide}pentanamide]propanoic acid (30 mg, 26% yield) as a solid. LCMS m / z: 650.5 [M+H]+, (ESI+), Rt = 2.78 (S3) 1H NMR (400 MHz, DMSO-d6) δ [ppm]: 9.99 (s, 1H), 8.33 (d, J = 8.7 Hz, 1H), 7.60 (dd, J = 8.6, 7.2 Hz, 1H), 7.14 (d, J = 7.1 Hz, 1H), 6.94 - 6.88 (m, 2H), 6.88 - 6.84 (m, 2H), 6.82 (d, J = 8.7 Hz, 1H), 5.26 (q, J = 6.0 Hz, 1H), 4.50 - 4.42 (m, 1H), 3.80 - 3.65 (m, 2H), 3.61 (t, J = 6.3 Hz, 2H), 2.63 - 2.55 (m, 2H), 2.48 - 2.38 (m, 2H), 2.35 - 2.18 (m, 8H), 1.93 (s, 3H), 1.91 - 1.85 (m, 5H), 1.50 - 1.40 (m, 3H), 0.80 - 0.70 (m, 6H).

[0504] [Example 358] Process C: (3S)-3-{4,4'-difluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl}-3-[(2S)-4-methyl-2-{[6-(4-methylpiperazine-1-yl)pyridine-2-yl]formamide}pentanamide]propanoic acid [ka] In a manner similar to that described for Example 360, ethyl(3S)-3-[(2S)-2-[(6-chloropyridine-2-yl)formamide]-4-methylpentanamide]-3-{4,4'-difluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl}propanoate (intermediate Q5) and 1-methylpiperazine were prepared using the general route outlined in step C of general route 77. LCMS m / z: 636.5 [M+H]+, (ESI+), Rt = 2.68 (S3) 1H NMR (400 MHz, DMSO-d6) δ [ppm]: 8.76 (d, J = 8.0 Hz, 1H), 8.29 (d, J = 9.0 Hz, 1H), 7.68 (dd, J = 8.6, 7.2 Hz, 1H), 7.25 (d, J = 7.2 Hz, 1H), 7.05 (d, J = 8.6 Hz, 1H), 6.99 - 6.87 (m, 4H), 5.50 (q, J = 7.5 Hz, 1H), 4.58 - 4.49 (m, 1H), 3.59 - 3.48 (m, 4H), 2.69 (d, J = 7.4 Hz, 2H), 2.49 - 2.43 (m, 4H), 2.31 - 2.23 (m, 6H), 1.95 (s, 3H), 1.90 (s, 3H), 1.49 - 1.38 (m, 3H), 0.84 - 0.72 (m, 6H).

[0505] Scheme for General Route 25 [ka]

[0506] [Example 361] Process B: (3S)-3-{4'-chloro-4-fluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl}-3-[(2S)-4-methyl-2-{[6-(4-methylpiperazine-1-yl)pyridine-2-yl]formamide}pentanamide]propanoic acid [ka] To a solution of ethyl(3S)-3-{4'-chloro-4-fluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl}-3-[(2S)-2-[(6-fluoropyridine-2-yl)formamide]-4-methylpentanamide]propanoate (100 mg, 0.167 mmol) in DMF (1 mL), K2CO3 (70.0 mg, 0.51 mmol) and N-methylpiperazine (35 mg, 0.339 mmol) were added. The mixture was then stirred at 80°C overnight. The reaction mixture was cooled, 2M LiOH hydrate (0.1 mL, 0.2 mmol) was added, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was dissolved in water (3 mL) and extracted with RINKAN (4 × 5 mL). The organic matter was washed with brine (5 mL), dehydrated with MgSO4, and concentrated. When the residue was purified using RP FCC (12g, C18 silica, 14CV, 10-100% MeCN in water containing 0.1% NH4OH modifier), (3S)-3-{4'-chloro-4-fluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl}-3-[(2S)-4-methyl-2-{[6-(4-methylpiperazine-1-yl)pyridine-2-yl]formamide}pentanamide]propanoic acid (57.7mg, 51% yield) was obtained as a solid. LCMS m / z: 652.4 / 654.4 [M+H]+, (ESI+), Rt = 2.85 (S3) 1H NMR (500 MHz, DMSO-d6) δ [ppm]: 9.28 (s, 1H), 8.31 (d, J = 8.9 Hz, 1H), 7.72 - 7.63 (m, 1H), 7.24 (d, J = 7.2 Hz, 1H), 7.20 - 7.12 (m, 2H), 7.05 - 7.01 (m, 1H), 6.93 - 6.86 (m, 2H), 5.44 - 5.36 (m, 1H), 4.55 - 4.47 (m, 1H), 3.54 - 3.50 (m, 4H), 2.55 (s, 2H), 2.43 - 2.39 (m, 4H), 2.28 - 2.24 (m, 3H), 2.23 - 2.21 (m, 3H), 1.95 - 1.85 (m, 6H), 1.51 - 1.38 (m, 3H), 0.83 - 0.73 (m, 6H).

[0507] Condition B [Example 398] Process B: (3S)-3-{4'-chloro-4-fluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl}-3-[(2S)-2-({6-[(3R)-3-(dimethylamino)pyrrolidine-1-yl]pyridine-2-yl}formamide)-4-methylpentanamide]propanoic acid [ka] To a solution of ethyl(3S)-3-{4'-chloro-4-fluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl}-3-[(2S)-2-[(6-fluoropyridine-2-yl)formamide]-4-methylpentanamide]propanoate (80 mg, 0.133 mmol) dissolved in DMSO (1 mL) and DIPEA (0.05 mL, 0.27 mmol), (3R)-N,N-dimethylpyrrolidine-3-amine (30 mg, 0.267 mmol) was added. The mixture was then stirred at 80°C for 20 hours. The reaction mixture was diluted with THF (0.5 mL) and MeOH (0.2 mL) and treated with 2 M LiOH hydrate (aqueous) (0.09 mL, 0.17 mmol). The reaction mixture was stirred and concentrated at room temperature for 3 hours, diluted with water (5 mL), and acidified to approximately 4 pH with 10% citric acid (aqueous solution). The resulting solid was collected by vacuum filtration and purified by HPLC (P3) to obtain (3S)-3-{4'-chloro-4-fluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl}-3-[(2S)-2-({6-[(3R)-3-(dimethylamino)pyrrolidine-1-yl]pyridine-2-yl}formamide)-4-methylpentanamide]propanoic acid (61.1 mg, 69% yield) as a solid. LCMS m / z: 666.6 / 668.6 [M+H]+, (ESI+), Rt = 2.95 (S3) 1H NMR (400 MHz, DMSO-d6) δ [ppm]: 8.92 - 8.79 (m, 1H), 8.39 (d, J = 9.0 Hz, 1H), 7.61 (dd, J = 8.5, 7.2 Hz, 1H), 7.21 - 7.13 (m, 2H), 7.09 (d, J = 2.2 Hz, 1H), 6.96 - 6.88 (m, 2H), 6.64 (d, J = 8.4 Hz, 1H), 5.48 (q, J = 7.4 Hz, 1H), 4.57 - 4.45 (m, 1H), 3.72 - 3.57 (m, 2H), 3.33 - 3.26 (m, 1H), 3.15 - 3.07 (m, 1H), 2.89 - 2.74 (m, 1H), 2.71 - 2.60 (m, 2H), 2.27 - 2.22 (m, 3H), 2.21 (s, 6H), 2.17 - 2.06 (m, 1H), 1.94 (s, 3H), 1.85 (s, 3H), 1.84 - 1.73 (m, 1H), 1.57 - 1.29 (m, 3H), 0.90 - 0.69 (m, 6H).

[0508] The following examples were synthesized using the corresponding starting materials in accordance with General Scheme 25, as illustrated by Examples 361 and 398. Diastereomers were separated either during final purification or, if necessary, by chiral separation methods. The examples were obtained as the title compound or its salts.

[0509] [Table 50-1] [Table 50-2] [Table 50-3] [Table 50-4]

[0510] [Table 51-1] [Table 51-2] [Table 51-3] [Table 51-4] [Table 51-5] [Table 51-6]

[0511] Other example compounds The diastereomers were either separated during the final purification process or, if necessary, sent for chiral separation. The examples were obtained as the title compound or a salt thereof.

[0512] [Example 67] (3S)-3-[2,3-difluoro-5-(2-methyl-2H-indazole-3-yl)phenyl]-3-[(2S)-4-methyl-2-[(1-methyl-2-oxo-1,2-dihydropyridine-3-yl)formamide]pentanamide]propanoic acid, (alternative synthesis) [ka] Ethyl (3S)-3-[2,3-difluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pheny...

Claims

1. Compounds of formula (I) or pharmaceutically acceptable salts thereof: 【Chemistry 1】 (In the formula, R ｙ is -CH(CH ３ ) ２ , -CF ３ ien-CH ２ F, CHF ２ ,-CH(CF ３ ) ２ It is cyclopropyl or cyclobutyl; R ｘ is hydrogen or methyl; R １ is -C(O)-R ７ And; Here, R ７ -C is substituted with 0 or 1 pyridine, phenyl, and cyclopropyl １～６ Is it alkyl? or R ７ These are phenyl or 5-10 membered heterocyclyls, and these are respectively R ９ It is independently replaced by 0, 1, 2, 3, or 4 instances of; R ９ These are halogen, =O, and -C respectively. １～６ Alkyl, -C(O)-R １０ , -C １～６ Haloalkyl, -SO ２ -C １～６ Alkyl, -NH-C １～４ Alkyl, -N(C) １～４ Alkyl) ２ , -C ３～６ Cycloalkyl, -O-R １１ , independently selected from phenyl and 4- to 10-membered heterocycles; R ９ These are R １７ It is independently replaced by 0, 1, 2, or 3, which are independently selected from; R １７ is halogen, -C １～６ Alkyl, -O-R １５ , -C(O)-N(C １～４ Alkyl) ２ , -N(R １２ R １３ ), selected from cyclopropyl and 4-10 membered heterocycles, R １７ If it is a heterocycle, then this is a halogen, -C １～６ Alkyl, =O, -C(O)-R １４ , -C １～６ Haloalkyl, -SO ２ -C １～６ Alkyl, -NH-C １～４ Alkyl, -N(C) １～４ Alkyl) ２ , -C ３～６ Cycloalkyl, -O-R １８ It is further substituted by 0, 1, 2, or 4 groups independently selected from it; R １０ is, -C １～６ Alkyl, -C １～６ Alkyl-C ３～６ Cycloalkyl and C ３～６ Selected independently from cycloalkyl; R １１ is, -C １～６ Alkyl, -C １～６ Haloalkyl, 4-10 membered heterocycle or -C １～６ Alkyl-N(C) １～６ Alkyl) ２ Here, a 4- to 10-membered complex ring has 0 or 1 -C １～６ Substituted with alkyl; R １２ and R １３ is, -C １～６ Alkyl, -C １～６ Haloalkyl, C １～６ Alkyl-cyclopropyl, C １～６ Alkyl-(cyclopropyl) ２ , independently selected from cyclobutyl and cyclopropyl, where 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 is, -C １～６ Alkyl and C ３～６ Selected independently from cycloalkyl; R １５ H, -C １～６ Alkyl, -C １～６ Haloalkyl, 4-10 membered heterocycle or -C １～６ Alkyl-N(C) １～６ Alkyl) ２ And R １５ If it is a 4- to 10-membered complex ring, then it has 0 or 1 -C １～６ Substituted with alkyl; R １８ is, -C １～６ Alkyl or -C １～６ It is a haloalkyl; Here, -N(C) １～６ Alkyl) ２ or -N(C) １～４ Alkyl) ２ In each of these, the two alkyl groups bonded to N may be the same or different; R ２ is selected from the group consisting of Br, phenyl, naphthyl and 5- to 10-membered heteroaryl, each of which is independently substituted by 0, 1, 2, 3 or 4 groups independently selected from -CN, -C １～６ alkyl, halogen, -C １～６ haloalkyl, -O-C １～６ alkyl, phenyl, 5- to 6-membered heteroaryl, -O-C ３～６ cycloalkyl, -O-phenyl and -O-(5- to 6-membered heterocycloalkyl); Y is -N = or -C(R ３ ) = and; R ３ is halogen, -C １～６ Haloalkyl, -C １～４ Alkyl or -C ３～６ It is a cycloalkyl; R ４ is halogen or hydrogen; R ５ is a halogen or hydrogen; R ６ is -C(O)-O-R ８ And, Here, R ８ is hydrogen, -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-O-C(O)-R １６ And; R １６ and R １６ａ is, -C １～６ A molecule is independently selected from alkyl groups, 3-6 cycloalkyl groups, 4-6 membered heterocycles, and 4-6 membered partially saturated heterocycles, where the partially saturated heterocycle is either =O or -C. １～４ (Further substitution with one or two groups independently selected from the alkyl group).

2. A compound according to claim 1 having formula Ia, or a pharmaceutically acceptable salt thereof. 【Chemistry 2】 (In the formula, R １ ~R ６ , R ｘ , R ｙ (and Y are as defined in claim 1).

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

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

5. R ｙ However, -CH(CH ３ ) ２ , -CF ３ A compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, which is cyclopropyl or cyclobutyl.

6. R ｙ However, -CH(CH ３ ) ２ , cyclopropyl or cyclobutyl, the compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof.

7. R ｙ However, -CH(CH ３ ) ２ The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 6.

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

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

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

11. R １７ However, halogen, -C １～６ Alkyl, -O-R １５ , -C(O)-N(C １～４ Alkyl) ２ , -N(R １２ R １３ ) and selected from 4- to 10-membered heterorings, R １７ If it is a heterocycle, then this is a halogen, -C １～６ Alkyl, =O, -C(O)-R １４ , -C １～６ Haloalkyl, -SO ２ -C １～６ Alkyl, -NH-C １～４ Alkyl, -N(C) １～４ Alkyl) ２ , -C ３～６ Cycloalkyl and -O-R １８ A compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof, further substituted with 0, 1, or 2 groups independently selected from thereto.

12. R １２ and R １３ However, -C １～６ Alkyl, -C １～６ A compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, independently selected from haloalkyl and cyclopropyl.

13. R １５ However, -C １～６ Alkyl, -C １～６ Haloalkyl, 4-10 membered heterocycle or -C １～６ Alkyl-N(C) １～６ Alkyl) ２ And R １５ If it is a 4- to 10-membered complex ring, then it has 0 or 1 -C １～６ A compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, which is substituted with an alkyl group.

14. R ２ The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 13, wherein the compound is independently substituted by 0, 1, 2, or 3 groups.

15. R ８ However, hydrogen, -C １～４ Alkyl or -C １～４ Alkyl-O-C(O)-R １６ The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 14.

16. R ８ However, hydrogen, -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-O-C(O)-R １６ And R １６ However, -C １～６ A molecule is independently selected from alkyl groups, 3-6 cycloalkyl groups, and 4-6 member partially saturated heterocycles, where the partially saturated heterocycle is either =O or -C. １～４ A compound according to any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof, further substituted with one or two groups independently selected from alkyl.

17. R ２ However, these are phenyl or 5-10 membered heteroaryl groups, where these groups are -CN and -C respectively. １～６ Alkyl, halogen, -C １～６ Substituted by one, two, three, or four groups independently selected from the haloalkyl group. A compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 16.

18. R ２ However, -CN, -C １～６ Alkyl, halogen, and -C １～６ Substituted by one, two, three, or four groups independently selected from the haloalkyl group, 【Transformation 3】 Selected from, A compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 17.

19. R ２ However, -CN, methyl, F, Cl and CF ３ It is replaced by one, two, three, or four groups independently selected from it. 【Chemistry 4】 Selected from, A compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 18.

20. R ２ However, -CN, -C １～６ Alkyl, halogen, -C １～６ Substituted by one, two, three, or four groups independently selected from the haloalkyl group, 【Transformation 5】 Selected from, A compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 19.

21. Y is -C(R ３ A compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 20, wherein ) =

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

23. Y is -C(R ３ ) = R ３ However, halogen, -CF ３ A compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 22, wherein the compound is methyl, ethyl, or cyclopropyl.

24. R ４ However, it is a halogen or hydrogen. A compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 23.

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

26. R ４ The compound or pharmaceutically acceptable salt thereof according to claim 25, wherein F is F.

27. R ５ The compound or pharmaceutically acceptable salt thereof according to any one of the embodiments 1 to 26, wherein the compound is fluorine or hydrogen.

28. R ５ A compound or pharmaceutically acceptable salt thereof according to any one of claims 27, wherein is hydrogen.

29. R ６ ga-C(O)-O-R ８ And here, R ８ However, hydrogen, methyl, CF ３ ethyl, isopropyl, -CH ２ -(5-methyl-2-oxo-1,3-dioxol-4-yl) or -CH ２ -C(O)N(Me) ２ The compound or pharmaceutically acceptable salt thereof according to any one of the embodiments 1 to 28 of the claims.

30. R ６ However, -C(O)-O-R ８ And here, R ８ The compound or pharmaceutically acceptable salt thereof according to any one of the embodiments 1 to 29, wherein the compound is hydrogen, methyl, ethyl, or isopropyl.

31. R ６ ga-C(O)-O-R ８ And R ８ A compound or pharmaceutically acceptable salt thereof according to any one of the embodiments 1 to 30, wherein is hydrogen.

32. R ７ However, it is substituted with 0 or 1 pyridine -C １～６ A compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 31, which is alkyl.

33. R ７ However, -C １～６ Alkyl, halogen, or -O-C １～６ A compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 31, which is a phenyl substituted with 0, 1, 2, 3, or 4 groups selected from alkyl groups.

34. R ７ However, -C １～６ Alkyl, halogen, or -O-C １～６ A compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 31, which is a phenyl substituted with 0, 1, 2, or 3 groups selected from alkyl groups.

35. R ７ However, R ９ A 5-10 member heterocycline substituted with 0, 1, 2, 3, or 4 groups independently selected from R, ９ These are halogen, =O, and -C respectively. １～６ Alkyl, -C(O)-R １０ , -C １～６ Haloalkyl, -SO ２ -C １～６ Alkyl, -NH-C １～４ Alkyl, -N(C) １～４ Alkyl) ２ , -C ３～６ Cycloalkyl, phenyl, 4-7 membered heterocycle, -O-R １１ Selected independently of; R ９ Each of them is R １７ It is independently replaced by one or two 0s, which are independently selected from; R １０ However, -C １～６ Alkyl, C ３～６ Cycloalkyl and -C １～６ Alkyl-C ３～６ Selected independently from cycloalkyl; R １１ However, -C １～６ Alkyl, -C １～６ Alkyl-N(-C) １～６ Alkyl) ２ , -C １～６ It is a haloalkyl or a 4- to 7-membered heterocycle; R １７ However, halogen, -OR-R １５ , -C(O)N(C １～４ Alkyl) ２ , -N(R １２ R １３ ) and selected from 4- to 10-membered heterorings, R １７ However, in the case of a 4- to 10-membered heterocycle, this is a halogen, -C １～６ Alkyl or -C １～６ Substituted by 0, 1, 2, or 4 atoms, independently selected from the haloalkyl group; R １２ and R １３ However, -C １～６ Alkyl, -C １～６ Independently selected from haloalkyl and cyclopropyl; R １５ However, -C １～６ Alkyl, -C １～６ It is a haloalkyl or a 4- to 7-membered heterocycle, R １５ If it is a complex ring with 4 to 7 members, then it has 0 or 1 -C １～６ Substituted with alkyl; Here, -N(C) １～６ Alkyl) ２ or -N(C) １～４ Alkyl) ２ In each of these, the two alkyl groups bonded to N may be the same or different. A compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 31.

36. R ７ However, it is a 5- to 10-membered heterocycline substituted with 0, 1, 2, or 3 groups, where R １７ However, it is a complex ring with 4 to 10 members, where R １７ The compound according to claim 35 or a pharmaceutically acceptable salt thereof, wherein the compound is substituted with 0, 1, or 2 groups.

37. R ９ However, -C(O)-N(C １～４ Alkyl) ２ , -O-R １５ , -N(R １２ R １３ ), substituted with 0, 1, 2, or 3 groups independently selected from 4- to 10-membered heterocycloalkyl groups -C １～６ It is alkyl, and heterocycloalkyl is halogen or -C １～６ Further substituted with 0, 1, or 2 groups independently selected from the alkyl group; R １２ and R １３ However, -C １～６ Alkyl, -C １～６ Independently selected from haloalkyl and cyclopropyl; R １５ However, -C １～６ Alkyl, -C １～６ It is a haloalkyl or a 4- to 7-membered heterocycle, R １５ If it is a complex ring with 4 to 7 members, then it has 0 or 1 -C １～６ It is substituted with alkyl, where -N(C １～６ Alkyl) ２ or -N(C) １～４ Alkyl) ２ In each of these, the two alkyl groups bonded to N may be the same or different. A compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 36.

38. R ７ but, 【Transformation 6】 A selection is made from the group consisting of -F, -Cl, oxo, -Me, isobutyl, isopropyl, cyclobutyl, and -CH ２ F, -CHF ２ ien-CH ２ CF ３ , -CF ３ , -OMe, -O-CF ３ -O-azetidine-3-yl, -N(Me) ２ -C(O)Me, -C(O)cyclopropyl, 1-Me-azetidine-3-yl, 3-F-azetidine-1-yl, 3-N(Me) ２ -3-Me-azetidine-1-yl,3-N(Me) ２ Pyrrolidine-1-yl, 4-Me-piperidine-1-yl, 1-Me-piperidine-4-yl, 1-isopropyl-piperidine-4-yl, 4-N(Me) ２ -Piperidin-1-yl, 4-Cyclopropyl-piperazine-1-yl, 4-Isopropyl-piperazine-1-yl, 4-Me-1,4-Diazepan-1-yl, 4-Isopropyl-1,4-Diazepan-1-yl, 4-Cyclopropyl-1,4-Diazepan-1-yl, 5-Methyl-2,4,6,7-Tetrahydropyrazolo[4,3-c]pyridine-2-yl, 2-Methyl-2,7-Diazaspiro[3. 5] Nonan-7-yl, 7-methyl-2,7-diazaspiro[3.5]nonan-2-yl, 1-methyl-1,7-diazaspiro[3.5]nonan-7-yl, 2-methyl-2,6-diazaspiro[3.3]heptan-6-yl, 3-(3-azabicyclo[3.1.1]heptan-3-yl)-azetidine-1-yl, 2-methyl-2,5-diazabicyclo[2.2.1]heptan-5-yl, -C(O)CH ２ Cyclopropyl, -CH ２ -CH ２ -Azeditin-1-yl, -CH ２ -CH ２ -(3-F-azeditin-1-yl),-CH ２ -CH ２ -(3-OMe-azeditin-1-yl),),-CH ２ -CH ２ -CH ２ -(3-OMe-azeditin-1-yl),-CH ２ -CH ２ -C(Me) ２ -(3-OMe-azeditin-1-yl),-CH ２ -CH ２ - (3-CF) ３ -Azeditin-1-yl), -CH ２ -CH ２ - (3-OCF) ３ -Azeditin-1-yl), -CH ２ -CH ２ - (3-CHF ２ -Azeditin-1-yl), -CH ２ -CH ２ - (3-OCHF) ２ -Azeditin-1-yl), -CH ２ -CH ２ -(3,3-di-F-azeditin-1-yl),-CH ２ -CH ２ -(2,2-diMe-azeditin-1-yl),-CH ２ -CH ２ -(3,3-diMe-azeditin-1-yl),-CH ２ -CH ２ -(3-MeO-3-Me-azeditin-1-yl),-CH ２ -CH ２ - (3-CHF ２ -3-Me-azeditin-1-yl),-CH ２ -CH ２ -(3-F-3-Me-azeditin-1-yl),-CH ２ -CH ２ -CH ２ -(3-F-3-Me-azeditin-1-yl),-CH ２ -Azeditin-1-yl, -CH ２ -(3-F-azeditin-1-yl),-CH ２ -(1-Me-azetidine-3-yl),-CH ２ -Azetidine-3-yl, -CH ２ CH ２ -(3-F-pyrrolidine-1-yl),-CH ２ CH ２ - (3-CF) ３ -pyrrolidine-1-yl), -CH ２ CH ２ -(3,3-di-F-pyrrolidine-1-yl), oxetane-3-yl, -CH ２ CH ２ OCH ３ ien-CH ２ CH ２ OH, -CH ２ C(O)N(Me) ２ ien-CH ２ N(Me) ２ ien-CH ２ CH ２ N(Me) ２ ien-CH ２ CH ２ N(Me)CH(cyclopropyl) ２ ien-CH ２ CH ２ N(Me)CH ２ (Cyclopropyl), -CH ２ CH ２ CH ２ N(Me) ２ , -C(Me) ２ CH ２ N(Me) ２ ien-CH ２ C(Me) ２ N(Me) ２ ien-CH ２ CH ２ C(Me) ２ N(Me) ２ ien-CH ２ CH ２ N(Me)CH ２ CF ３ ien-CH ２ CH ２ N(Me)CH(Me) ２ ien-CH ２ CH ２ N(Me)C(Me) ３ ien-CH ２ CH ２ N(Me)cyclopropyl, 4-F-phenyl, -CH ２ CH ２ - (2-azaspiro[3.4]octane-2yl), -CH ２ CH ２ CH ２ - (2-azaspiro[3.4]octane-2yl), -CH ２ CH ２ CH ２ CH ２ - (2-azaspiro[3.4]octane-2yl), -CH ２ CH ２ - (6-azaspiro[3.4]octane-6-yl), -CH ２ CH ２ CH ２ - (6-azaspiro[3.4]octane-6-yl), -CH ２ CH ２ -(2,2-diF-6-azaspiro[3.4]octane-6-yl),-CH ２ CH ２ - (2-azaspiro[3.3]heptane-2-yl), -CH ２ CH ２ -(6-MeO-2-azaspiro[3.3]heptane-2-yl),-CH ２ CH ２ - (2-Azaspiro[4.5]decane-2-yl), -CH ２ CH ２ - (7-Azaspiro[3.5]nonan-7-il), -CH ２ CH ２ - (6-Azaspiro[3.5]nonan-6-il), -CH ２ CH ２ - (2-Azaspiro[3.5]nonan-2-il), -CH ２ CH ２ - (5-oxa-8-azaspiro[3.5]nonane-8-yl), -CH ２ CH ２ -(7-oxa-2-azaspiro[3.5]nonane-2-yl),-CH ２ CH ２ CH ２ CH ２ -(7-oxa-2-azaspiro[3.5]nonane-2-yl),-CH ２ CH ２ -(6,6-diF-2-azaspiro[3.3]heptane-2-yl),-CH ２ CH ２ - (8-azabicyclo[3.2.1]octan-8-yl), -CH ２ CH ２ - (8-oxa-3-azabicyclo[3.2.1]octan-3-yl), CH ２ CH ２ CH ２ - (2-azabicyclo[2.2.2]octan-2-yl), -CH ２ CH ２ CH ２ -(6-oxa-3-azabicyclo[3.1.1]heptan-3-yl),-CH ２ CH ２ -(7,7-diF-1,6-diMe-3-azabicyclo[4.1.0]heptane-3-yl),-CH ２ CH ２ - (3-azabicyclo[3.1.1]heptane-3-yl), -CH ２ CH ２ CH ２ - (2-azabicyclo[2.2.1]heptan-2-yl), CH ２ CH ２ CH ２ - (3-azabicyclo[3.1.1]heptane-3-yl), -CH ２ CH ２ CH ２ CH ２ - (3-azabicyclo[3.1.1]heptane-3-yl), -CH ２ CH ２ -(2-azabicyclo[2.1.1]hexane-2-yl),-CH ２ CH ２ -(6,6-diMe-3-azabicyclo[3.1.0]hexane-3-yl),-CH ２ CH ２ N(Me)cyclobutyl), -CH ２ CH ２ N(Me)(3,3-diF)cyclobutyl-1-yl),-CH ２ -CH ２ - (4-CF) ３ -Piperidin-1-yl), -CH ２ -CH ２ -(4,4-diMe-piperidine-1-yl),-CH ２ -CH ２ -(morpholine-4-yl),-CH ２ -CH ２ -CH ２ -(morpholine-4-yl),-CH ２ -CH ２ -CH ２ -(2,6-diMe-morpholin-4-yl),-CH ２ -CH ２ -CH ２ -(2,2,6,6-tetraMe-morpholine-4-yl),-CH ２ -CH ２ -CH ２ -(2,2-diMe-morpholin-4-yl),-CH ２ -CH ２ -(2,6-diMe-morpholin-4-yl),-CH ２ -CH ２ -(1,4-oxazepine-4-yl),-CH ２ CH ２ -CH ２ -(1,4-oxazepine-4-yl), and -S(O) ２ A compound according to any one of claims 1 to 37 or a pharmaceutically acceptable salt thereof, substituted with 0, 1, or 2 substituents independently selected from Me.

39. R ７ but, 【Transformation 7】 A selection is made from the group consisting of -F, -Cl, oxo, -Me, isobutyl, isopropyl, cyclobutyl, and -CH ２ F, -CHF ２ ien-CH ２ CF ３ , -OMe, -O-CF ３ -O-azetidine-3-yl, -N(Me) ２ -C(O)Me, -C(O)cyclopropyl, 1-Me-azetidine-3-yl, 3-F-azetidine-1-yl, --C(O)CH ２ Cyclopropyl, -CH ２ -CH ２ -Azeditin-1-yl, -CH ２ -CH ２ -(3-F-azeditin-1-yl),-CH ２ -CH ２ - (3-CF) ３ -Azeditin-1-yl), -CH ２ -CH ２ -(3,3-di-F-azeditin-1-yl),-CH ２ -CH ２ -(3,3-diMe-azeditin-1-yl),-CH ２ -Azeditin-1-yl, -CH ２ -(3-F-azeditin-1-yl),-CH ２ -(1-Me-azetidine-3-yl),-CH ２ -Azetidine-3-yl, -CH ２ CH ２ -(3-F-pyrrolidine-1-yl),-CH ２ CH ２ OCH ３ ien-CH ２ C(O)N(Me) ２ ien-CH ２ CH ２ N(Me) ２ ien-CH ２ CH ２ CH ２ N(Me) ２ -CH ２ CH ２ N(Me)CH ２ CF ３ ien-CH ２ CH ２ N(Me)cyclopropyl, 4-F-phenyl and -S(O) ２ A compound according to any one of claims 1 to 38 or a pharmaceutically acceptable salt thereof, substituted with 0, 1, or 2 substituents independently selected from Me.

40. R ２ -Br, -CF ３ 【Transformation 8】 A compound according to any one of claims 1 to 39, or a pharmaceutically acceptable salt thereof, independently selected from the group consisting of the above.

41. R ２ Each of them, 【Chemistry 9】 A compound according to any one of claims 1 to 40, or a pharmaceutically acceptable salt thereof, independently selected from the group consisting of the above.

42. R ２ -Br, -CF ３ 【Chemistry 10】 A compound according to any one of claims 1 to 41, or a pharmaceutically acceptable salt thereof, independently selected from the group consisting of the above.

43. R ２ Each of them, 【Chemistry 11】 A compound according to any one of claims 1 to 42, or a pharmaceutically acceptable salt thereof, independently selected from the group consisting of the above.

44. R １ However, the following: -C(O)-CH ３ 【Chemistry 12-1】 【Chemistry 12-2】 【Chemistry 12-3】 A compound or a pharmaceutically acceptable salt thereof, selected from any one of claims 1 to 43.

45. R １ However, the following: Table 1-1 Table 1-2 Table 1-3 Table 1-4 Table 1-5 A compound or a pharmaceutically acceptable salt thereof, selected from any one of claims 1 to 44. 【Request Item 46】 【Table 2-1】 Table 2-2 Table 2-3 Table 2-4 Table 2-5 Table 2-6 Table 2-7 Table 2-8 Table 2-9 Table 2-10 A compound according to claim 1 or a pharmaceutically acceptable salt thereof, selected from the above. 【Request Item 47】 【Table 3-1】 Table 3-2 Table 3-3 Table 3-4 Table 3-5 Table 3-6 Table 3-7 Table 3-8 Table 3-9 Table 3-10 Table 3-11 Table 3-12 Table 3-13 Table 3-14 Table 3-15 Table 3-16 Table 3-17 Table 3-18 Table 3-19 Table 3-20 A compound according to claim 1 or a pharmaceutically acceptable salt thereof, selected from the above.

48. A pharmaceutical composition comprising a pharmaceutically effective amount of a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 47, and a pharmaceutically acceptable carrier or excipient.

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

50. A compound according to any one of claims 1 to 47 or a pharmaceutically acceptable salt thereof, for use as a pharmaceutical.

51. α in the subject ４ β ７ A method for inhibiting the interaction between an integrin and the MAdCAM-1 protein, comprising administering a pharmaceutically effective amount of a compound according to any one of claims 1 to 47 or a pharmaceutically acceptable salt thereof to a subject in need thereof.

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

53. A compound according to any one of claims 1 to 47 or a pharmaceutically acceptable salt thereof, for use in 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 colon disease in humans, comprising administering to a person in need of such treatment a pharmaceutically effective amount of a compound according to any one of claims 1 to 47 or a pharmaceutically acceptable salt thereof.

57. A compound according to any one of claims 1 to 47 or a pharmaceutically acceptable salt thereof, for use in the treatment of ulcerative colon disease.

58. The method according to claim 56, wherein the ulcerative colon disease is ulcerative colitis.

59. The method according to claim 56, wherein the ulcerative colon disease is Crohn's disease.

60. It's a kit: a) One or more compositions, each comprising a pharmaceutically effective amount of a compound or a pharmaceutically acceptable salt thereof described in any one of claims 1 to 47, and a pharmaceutically acceptable carrier or excipient; and b) Instructions for use for administering one or more compositions to a person who needs them. A kit that includes this.

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