EP4698517A1 - <sup2/>? <sub2/>?4?novel compounds as ?? <ns1:sub>7</ns1:sub>?inhibitors - Google Patents

Abstract

Novel compounds that act as inhibitors of α₄β₇ integrins are disclosed. Pharmaceutical compositions and methods of use for inhibitors of α₄β₇ integrins are disclosed. In particular, methods of using the α₄β₇ inhibtors in the treatment of diseases or conditions associated to inflammatory bowel diseases including ulcerative colitis and Crohn's disease.

Description

NOVEL COMPOUNDS AS α4β7 INHIBITORS FIELD OF THE INVENTION The present disclosure relates to novel compounds that act as inhibitors to integrins, in particular α₄β₇ integrins. Additionally, the present disclosure relates to pharmaceutical compositions and methods of using α₄β₇ inhibitors in the treatment of diseases or conditions associated to inflammatory bowel diseases including ulcerative colitis and Crohn’s disease. BACKGROUND OF THE INVENTION Integrins are involved in numerous cellular processes including cell-cell and cell- extracellular matrix interactions. Upon binding of an extracellular ligand, integrins mediate signal transduction to the cell interior resulting in lymphocyte cell capture, adhesion, and infiltration into the tissue. In fact, integrins are heterodimeric cell surface glycoprotein receptors, composed of non-covalently associated α (alpha) and β (beta) subunits. 24 human integrins have been identified using molecular biology and protein chemistry and it is known that they contribute to a diverse set of human diseases, including platelet disorders, atherosclerosis, cancer, osteoporosis, fibrosis, diabetic neuropathy of the kidney, macular degeneration and autoimmune and chronic inflammation diseases. The α₄ integrins, α₄β₁ and α₄β₇, play essential roles in lymphocyte migration on most leukocytes, including B and T lymphocytes. α₄β₁ and α₄β₇ integrin specific adhesion 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 is a selective ligand for α₄β₇ receptor. The MAdCAM-1 is involved in the selective homing of lymphocytes to normal mucosal tissues. In humans, MAdCAM-1 expression has been associated with lymphoid tissues of the gastrointestinal tract and associated lymphoid tissues. The lymphocyte integrin α₄β₇ has been shown to mediate memory T cell adhesion to MAdCAM-1. During inflammation, MAdCAM-1 is upregulated in the gut and is believed to play an important role in inflammatory bowel diseases (IBDs), a group of diseases such as ulcerative colitis (UC) and Crohn’s disease (CD). Inhibiting the interactions of integrins with their respective ligands has been proposed as an effective method for treating a variety of autoimmune and inflammatory disease, and blocking the AdCAM-1 interaction has shown therapeutic benefit 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, 903-917). Currently there are injectable monoclonal antibodies on the market as integrin inhibitors, see for example Natalizumab (Tysabri®) approved for the treatment of highly active relapsing and remitting multiple sclerosis, or Vedolizumab (Entyvio®) approved for both Crohn’s disease and ulcerative colitis. However, orally bioavailable integrin inhibitors are not yet approved. Thus, there is the need to provide integrin inhibitors, preferably α₄β₇-selective inhibitors useful for the prevention and/or treatment of diseases characterized by MAdCAM-1 upregulation, such as inflammatory bowel diseases. The present invention relates to compounds of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R¹ to R⁶, R^x, R^y and Y are defined herein below. DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a compound of Formula (I), or a pharmaceutically acceptable salt thereof: wherein: R^y is -CH(CH₃)₂, -CF₃, -CH₂F, CHF₂, -CH(CF₃)₂ cyclopropyl or cyclobutyl; R^x is hydrogen or methyl; R¹ is -C(O)-R⁷; wherein R⁷ is -C_1-6alkyl, substituted with 0 or 1 pyridine, phenyl and cyclopropyl; or R⁷ is phenyl or a 5-10 membered heterocyclyl each of which is independently substituted with 0, 1, 2, 3 or 4 instances of R⁹; each R⁹ is independently selected from halogen, =O, -C1-6alkyl, -C(O)- R¹⁰, -C1-6haloalkyl, -SO2-C1-6alkyl, -NH-C1-4alkyl, -N(C1-4alkyl)2, -C3- 6cycloalkyl, -O-R¹¹, phenyl and 4-10 membered heterocycle; and each of R⁹ is independently substituted with 0, 1, 2 or 3 independently selected from R¹⁷; R¹⁷ is selected from halogen, -C1-6alkyl, -O-R¹⁵,-C(O)-N(C1-4alkyl)2, - N(R¹²R¹³), cyclopropyl and 4 to 10 membered heterocycle, when R¹⁷ is heterocycle, it is further substituted with 0, 1, 2 or 4 groups independently selected from halogen, -C_1-6alkyl, =O, -C(O)-R¹⁴, -C_{1- 6}haloalkyl, -SO₂-C_1-6alkyl, -NH-C_1-4alkyl, -N(C_1-4alkyl)₂, -C_3-6cycloalkyl, - O-R¹⁸; R¹⁰ is independently selected from -C_1-6alkyl, -C_1-6alkyl-C_{3- 6}cycloalkyl and C_3-6cycloalkyl; R¹¹ is a -C_1-6 alkyl, - C_1-6haloalkyl, 4 to 10 membered heterocycle or -C_1-6 alkyl-N(C_1-6 alkyl)₂ wherein the 4 to 10 membered heterocycle is substituted with 0 or 1 -C_1-6 alkyl; R¹² and R¹³ are independently selected from -C_1-6alkyl, -C_{1- 6}haloalkyl, C_1-6alkyl-cyclopropyl, C_1-6alkyl-(cyclopropyl)₂, cyclobutyl and cyclopropyl, wherein C_1-6alkyl-cyclopropyl, C_1-6alkyl- (cyclopropyl)₂, cyclobutyl and cyclopropyl are substituted with 0, 1, 2 or 3 F; R¹⁴ is independently selected from -C_1-6alkyl and C_3-6cycloalkyl; R¹⁵ is H, a -C_1-6 alkyl, - C_1-6haloalkyl, 4 to 10 membered heterocycle, or -C1-6 alkyl-N(C1-6 alkyl)2 and when R¹⁵ is 4 to 10 membered heterocycle it is substituted with 0 or 1 -C1-6alkyl; R¹⁸ is a -C1-6 alkyl or - C1-6haloalkyl; wherein in each - N(C1-6 alkyl)2 or -N(C1-4alkyl)2 the two alkyl groups attached to N can be the same or different; R² is selected from the group consisting of Br, phenyl, naphthyl, and 5-10 membered heteroaryl, each of which can be independently substituted with 0, 1, 2, 3 or 4 groups independently selected from -CN, -C1-6 alkyl, halogen, -C1-6haloalkyl, -O-C1-6 alkyl, phenyl, 5 to 6 membered heteroaryl, -O-C3-6cycloalkyl, -O-phenyl, and -O-(5 to 6 membered heterocycloalkyl); Y is -N= or -C(R³)=; R³ is halogen, -C1-6haloalkyl, -C 1-4alkyl or -C3-6cycloalkyl; R⁴ is halogen or hydrogen; R⁵ is halogen or hydrogen; R⁶ is -C(O)-O-R⁸, wherein R⁸ is hydrogen, -C1-4alkyl, -C1-4alkyl-R¹⁶, -C1-4alkyl-C(O)N(Me)-R¹⁶ - C1-4alkyl-R¹⁶, -C1-4alkyl-C(O)N(R¹⁶,R^16a)- or -C1-4alkyl-O-C(O)-R¹⁶; R¹⁶ and R^16a are independently selected from -C1-6alkyl, 3 to 6 cycloalkyl, 4 to 6 membered heterocycle, 4 to 6 membered partially saturated heterocycle, wherein the partially saturated heterocycle is further substituted with one or two groups independently selected from =O or -C_1-4alkyl. The present invention also relates to a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein: R^y is -CH(CH3)2, cyclopropyl or cyclobutyl; R^x is hydrogen or methyl; R¹ is -C(O)-R⁷; wherein R⁷ is -C1-6alkyl, substituted with 0 or 1 pyridine, phenyl and cyclopropyl; or R⁷ is phenyl or a 5-10 membered heterocyclyl each of which is independently substituted with 0, 1, 2 or 3 instances of R⁹; each R⁹ is independently selected from halogen, =O, -C1-6alkyl, -C(O)- R¹⁰, -C1-6haloalkyl, -SO2-C1-6alkyl, -NH-C1-4alkyl, -N(C1-4alkyl)2, -C3- 6cycloalkyl, -O-R¹¹, phenyl and 4-10 membered heterocycle; and each of R⁹ is independently substituted with 0, 1, 2 or 3 independently selected from R¹⁷; R¹⁷ is selected from halogen, -C1-6alkyl, -O-R¹⁵,-C(O)-N(C1-4alkyl)2, - N(R¹²R¹³), 4 to 10 membered heterocycle, when R¹⁷ is heterocycle, it is further substituted with 0, 1 or 2 groups independently selected from halogen, -C_1-6alkyl, =O, -C(O)-R¹⁴, -C_1-6haloalkyl, -SO₂-C_1-6alkyl, -NH- C_1-4alkyl, -N(C_1-4alkyl)₂, -C_3-6cycloalkyl, -O-R¹⁸; R¹⁰ is independently selected from -C_1-6alkyl, -C_1-6alkyl-C_{3- 6}cycloalkyl and C_3-6cycloalkyl; R¹¹ is a -C1-6 alkyl, - C1-6haloalkyl , 4 to 10 membered heterocycle or -C1-6 alkyl-N(C1-6 alkyl)2 wherein the 4 to 10 membered heterocycle is substituted with 0 or 1 -C1-6 alkyl; R¹² and R¹³ are independently selected from -C1-6alkyl, -C1- 6haloalkyl and cyclopropyl; R¹⁴ is independently selected from -C1-6alkyl and C3-6cycloalkyl; R¹⁵ is a -C_1-6 alkyl, - C_1-6haloalkyl, 4 to 10 membered heterocycle, or -C_1-6 alkyl-N(C_1-6 alkyl)₂ and when R¹⁵ is 4 to 7 membered heterocycle it is substituted with 0 or 1 -C_1-6alkyl; R¹⁸ is a -C_1-6 alkyl or - C_1-6haloalkyl; wherein in each - N(C_1-6 alkyl)₂ or -N(C_1-4alkyl)₂ the two alkyl groups attached to N can be the same or different; R² is selected from the group consisting of Br, phenyl, naphthyl, and 5-10 membered heteroaryl, each of which can be independently substituted with 0, 1, 2 or 3 groups independently selected from -CN, -C_1-6 alkyl, halogen, -C_1-6haloalkyl, - O-C_1-6 alkyl, phenyl, 5 to 6 membered heteroaryl, -O-C_3-6cycloalkyl, -O-phenyl, and -O-(5 to 6 membered heterocycloalkyl); Y is -N= or -C(R³)=; R³ is halogen, -C_1-6haloalkyl , -C _1-4alkyl or -C_3-6cycloalkyl; R⁴ is halogen or hydrogen; R⁵ is halogen or hydrogen; R⁶ is -C(O)-O-R⁸, wherein R⁸ is hydrogen, -C_1-4alkyl or -C_1-4alkyl-O-C(O)-R16 R¹⁶ is -C1-6alkyl, 3 to 6 cycloalkyl, 4 to 6 membered partially saturated heterocyclyl, wherein the partially saturated heterocyclyl is further substituted with one or two groups independently selected from =O or -C1- 4alkyl. In one embodiment, the invention relates to compounds of formula (Ia), or a pharmaceutically acceptable salt thereof, wherein R¹ to R⁶ , R^x, R^y and Y are as defined herein. In certain embodiments of the compounds of the invention, or a pharmaceutically acceptable salt thereof, R^x is hydrogen. In other embodiments of the compounds of the invention, or a pharmaceutically acceptable salt thereof, R^x is methyl. In certain embodiments of the compounds of the invention, or a pharmaceutically acceptable salt thereof, R^y is -CH(CH₃)₂, -CF₃, cyclopropyl or cyclobutyl. In certain embodiments of the compounds of the invention, or a pharmaceutically acceptable salt thereof, R^y is -CH(CH₃)₂, cyclopropyl or cyclobutyl. In certain embodiments of the compounds of the invention, or a pharmaceutically acceptable salt thereof, R^y is -CH(CH₃)₂. In further embodiments of the compound of the invention, or a pharmaceutically acceptable salt thereof, R^y is cyclopropyl. In further embodiments of the compound of the invention, or a pharmaceutically acceptable salt thereof, R^y is cyclobutyl. In some embodiments of the compounds of the invention, or a pharmaceutically acceptable salt thereof, wherein R¹² and R¹³ are independently selected from -C_1-6alkyl, - C_1-6haloalkyl, C_1-6alkyl-cyclopropyl, C_1-6alkyl-(cyclopropyl)₂, cyclobutyl and cyclopropyl, wherein C_1-6alkyl-cyclopropyl, C_1-6alkyl-(cyclopropyl)₂, cyclobutyl and cyclopropyl are substituted with 0, 1, 2 or 3 F. In some embodiments of the compounds of the invention, or a pharmaceutically acceptable salt thereof, wherein R¹⁷ is selected from halogen, -C_1-6alkyl, -O-R¹⁵,-C(O)- N(C_1-4alkyl)₂, -N(R¹²R¹³) and 4 to 10 membered heterocycle, when R¹⁷ is heterocycle, it is further substituted with 0, 1 or 2 groups independently selected from halogen, -C1-6alkyl, =O, -C(O)-R¹⁴, -C1-6haloalkyl, -SO2-C1-6alkyl, -NH-C1-4alkyl, -N(C1-4alkyl)2, -C3-6cycloalkyl and -O-R¹⁸. In some embodiments of the compounds of the invention, or a pharmaceutically acceptable salt thereof, wherein R¹² and R¹³ are independently selected from -C1-6alkyl, - C1-6haloalkyl and cyclopropyl. In some embodiments of the compounds of the invention, or a pharmaceutically acceptable salt thereof, wherein R¹⁵ is a -C1-6 alkyl, - C1-6haloalkyl, 4 to 10 membered heterocycle, or -C1-6 alkyl-N(C1-6 alkyl)2 and when R¹⁵ is 4 to 10 membered heterocycle it is substituted with 0 or 1 -C1-6alkyl. In some embodiments of the compounds of the invention, or a pharmaceutically acceptable salt thereof, wherein R⁸ is hydrogen, -C1-4alkyl or -C1-4alkyl-O-C(O)-R¹⁶. In some embodiments of the compounds of the invention, or a pharmaceutically acceptable salt thereof, wherein R⁸ is hydrogen, -C1-4alkyl -C1-4alkyl-R¹⁶, -C1-4alkyl- C(O)N(Me)-R¹⁶ -or -C1-4alkyl-O-C(O)-R¹⁶ and R¹⁶ is independently selected from -C1-6alkyl, 3 to 6 cycloalkyl, 4 to 6 membered partially saturated heterocycle, wherein the partially saturated heterocycle is further substituted with one or two groups independently selected from =O or -C1-4alkyl. In some embodiments of the compounds of the invention, or a pharmaceutically acceptable salt thereof, R² is independently substituted with 0, 1, 2, 3 or 4 groups. In further embodiments of the compounds of the invention, or a pharmaceutically acceptable salt thereof, R² is independently substituted with 0, 1, 2 or 3 groups. In some embodiments of the compounds of the invention, or a pharmaceutically acceptable salt thereof, R² is phenyl or 5-10 membered heteroaryl, each of which group is substituted with 1, 2, 3 or 4 groups independently selected from -CN, -C_1-6 alkyl, halogen, - C_1-6haloalkyl. In further embodiments of the compounds of the invention, or a pharmaceutically acceptable salt thereof, R² is phenyl or 5-10 membered heteroaryl, each of which group is substituted with 1, 2 or 3 groups independently selected from -CN, -C_1-6 alkyl, halogen, -C_{1- 6}haloalkyl. In some embodiments of the compounds of the invention, or a pharmaceutically acceptable salt thereof, R² is substituted with 1, 2, 3 or 4 groups independently selected from -CN, -C_1-6 alkyl, halogen and -C_1-6haloalkyl and is selected from . In further embodiments of the compounds of the invention, or a pharmaceutically acceptable salt thereof, R² is substituted with 1, 2, 3 or 4 groups independently selected from -CN, -C_1-6 alkyl, halogen, -C_1-6haloalkyl and is selected from In further embodiments of the compounds of the invention, or a pharmaceutically acceptable salt thereof, R² is substituted with 1, 2 or 3 groups independently selected from -CN, -C1-6 alkyl, halogen, -C1-6haloalkyl and is selected from ^, . In further embodiments of the compounds of the invention, or a pharmaceutically acceptable salt thereof, R² is substituted with 1, 2, 3 or 4 groups independently selected from -CN, methyl, F, Cl and CF3 and is selected from . In further embodiments of the compounds of the invention, or a pharmaceutically acceptable salt thereof, R² is substituted with 1, 2 or 3 groups independently selected from methyl, fluorine or -CF3 and is selected from , . In some embodiments of the compounds of the invention, or a pharmaceutically acceptable salt thereof, Y is -C(R³)=. In some embodiments of the compounds of the invention, or a pharmaceutically acceptable salt thereof, R³ is halogen, -CF3, methyl, ethyl, cyclopropyl. In some embodiments of the compounds of the invention, or a pharmaceutically acceptable salt thereof, Y is -N=. In some embodiments of the compounds of the invention, or a pharmaceutically acceptable salt thereof, Y is -C(R³)= and R³ is halogen, -CF₃, methyl, ethyl, cyclopropyl. In some embodiments of the compounds of the invention, or a pharmaceutically acceptable salt thereof, R⁴ is halogen or hydrogen. In some embodiments of the compounds of the invention, or a pharmaceutically acceptable salt thereof, R⁴ is halogen. In some embodiments of the compounds of the invention, or a pharmaceutically acceptable salt thereof, R⁴ is fluorine. In some embodiments of the compounds of the invention, or a pharmaceutically acceptable salt thereof, R⁵ is fluorine or hydrogen. In some embodiments of the compounds of the invention, or a pharmaceutically acceptable salt thereof, R⁵ is hydrogen. In some embodiments of the compounds of the invention, or a pharmaceutically acceptable salt thereof, R⁶ is -C(O)-O-R⁸, wherein R⁸ is hydrogen, methyl, CF₃, ethyl, isopropyl, –CH₂-(5-methyl-2-oxo-1,3-dioxol-4-yl) or –CH₂-C(O)N(Me)₂. In further embodiments of the compounds of the invention, or a pharmaceutically acceptable salt thereof, R⁶ is -C(O)-O-R⁸, wherein R⁸ is hydrogen, methyl, ethyl or isopropyl, -O-CH₂-O-C(O)-R¹⁶ or -O-C(CH₃)-O-C(O)-R¹⁶, wherein R¹⁶ is methyl, ethyl, isopropyl, isobutyl, cyclobutyl, cyclopentyl, cyclohexane, neopentyl or (5-methyl-2-oxo-1,3- dioxol-4-yl)methyl. In some embodiments of the compounds of the invention, or a pharmaceutically acceptable salt thereof, R⁶ is -C(O)-O-R⁸, wherein R⁸ is hydrogen, methyl, ethyl or isopropyl. In some embodiments of the compounds of the invention, or a pharmaceutically acceptable salt thereof, R⁶ is -C(O)-O-R⁸ and R⁸ is hydrogen. In some embodiments of the compounds of the invention, or a pharmaceutically acceptable salt thereof, R⁷ is -C1-6alkyl, substituted with 0 or 1 pyridine, or R⁷ is phenyl, substituted with 0, 1, 2 or 3 groups selected from -C alkyl, halogen or -O-C alkyl, or R7 1-6 1-6 is 5-10 membered heterocyclyl substituted with 0, 1, 2 or 3 groups independently selected from R⁹ and each R⁹ is independently selected from halogen, =O, -C1-6alkyl, -C(O)-R¹⁰, - C1-6haloalkyl, -SO2-C1-6alkyl, -NH-C1-4alkyl, -N(C1-4alkyl)2, -C3-6cycloalkyl, phenyl, 4 to 7 membered heterocycle, -O-R¹¹; each R⁹ is independently substituted with 0, 1 or 2 independently selected from R¹⁷; R¹⁰ is independently selected from -C1-6alkyl, C3-6cycloalkyl and -C1-6alkyl-C3- 6cycloalkyl; R¹¹ is a -C1-6 alkyl, -C1-6 alkyl-N(-C1-6 alkyl)2, - C1-6haloalkyl or 4 to 7 membered heterocycle; R¹⁷ is selected from halogen, -O-R¹⁵, -C(O)N(C1-4alkyl)2, -N(R¹²R¹³), and 4 to 10 membered heterocycle, when R¹⁷ is 4 to 10 membered heterocycle is substituted with 0, 1 or 2 independently selected halogen, -C1-6alkyl or - C1-6haloalkyl; R¹² and R¹³ are independently selected from -C1-6alkyl, -C1-6haloalkyl and cyclopropyl; R¹⁵ is -C1-6alkyl, - C1-6haloalkyl or 4 to 7 membered heterocycle and when R¹⁵ is 4 to 7 membered heterocycle it is substituted with 0 or 1 -C1-6alkyl; and wherein in each - N(C1-6 alkyl)2 or -N(C1-4alkyl)2 the two alkyl groups attached to N can be the same or different. In some embodiments of the compounds of the invention, or a pharmaceutically acceptable salt thereof, R⁷ is -C1-6alkyl, substituted with 0 or 1 pyridine. In some embodiments of the compounds of the invention, or a pharmaceutically acceptable salt thereof, R⁷ is phenyl, substituted with 0, 1, 2, 3 or 4 groups selected from - C_1-6alkyl, halogen or -O-C_1-6alkyl. In some embodiments of the compounds of the invention, or a pharmaceutically acceptable salt thereof, R⁷ is phenyl, substituted with 0, 1, 2 or 3 groups selected from -C_{1- 6}alkyl, halogen or -O-C_1-6alkyl. In some embodiments of the compounds of the invention, or a pharmaceutically acceptable salt thereof, R⁷ is 5-10 membered heterocyclyl substituted with 0, 1, 2, 3 or 4 groups independently selected from R⁹ and each R⁹ is independently selected from halogen, =O, -C_1-6alkyl, -C(O)-R¹⁰, -C_1-6haloalkyl, -SO₂-C_1-6alkyl, -NH-C_1-4alkyl, -N(C_{1- 4}alkyl)₂, -C_3-6cycloalkyl, phenyl, 4 to 7 membered heterocycle, -O-R¹¹; each R⁹ is independently substituted with 0, 1 or 2 independently selected from R¹⁷; R¹⁰ is independently selected from -C_1-6alkyl, C_3-6cycloalkyl and -C_1-6alkyl- C_3-6cycloalkyl; R¹¹ is a -C_1-6 alkyl, -C_1-6 alkyl-N(-C_1-6 alkyl)₂, - C_1-6haloalkyl or 4 to 7 membered heterocycle; R¹⁷ is selected from halogen, -O-R¹⁵, -C(O)N(C_1-4alkyl)₂, -N(R¹²R¹³), and 4 to 10 membered heterocycle, when R¹⁷ is 4 to 10 membered heterocycle is substituted with 0, 1, 2 or 4 independently selected halogen, -C1-6alkyl or - C1-6haloalkyl; R¹² and R¹³ are independently selected from -C1-6alkyl, -C1-6haloalkyl and cyclopropyl; R¹⁵ is -C1-6alkyl, - C1-6haloalkyl or 4 to 7 membered heterocycle and when R¹⁵ is 4 to 7 membered heterocycle it is substituted with 0 or 1 -C1-6alkyl; and wherein in each - N(C1-6 alkyl)2 or -N(C1-4alkyl)2 the two alkyl groups attached to N can be the same or different. In some embodiments of the compounds of the invention, or a pharmaceutically acceptable salt thereof, R⁷ is 5-10 membered heterocyclyl substituted with 0, 1, 2 or 3 groups and R¹⁷ is 4 to 10 membered heterocycle, wherein R¹⁷ is substituted with 0, 1 or 2 groups. In some embodiments of the compounds of the invention, or a pharmaceutically acceptable salt thereof, R⁷ is 5-10 membered heterocyclyl substituted with 0, 1, 2 or 3 groups independently selected from R⁹ and each R⁹ is independently selected from halogen, =O, -C1-6alkyl, -C(O)-R¹⁰, -C1-6haloalkyl, -SO2-C1-6alkyl, -NH-C1-4alkyl, -N(C1- 4alkyl)2, -C3-6cycloalkyl, phenyl, 4 to 7 membered heterocycle, -O-R¹¹; each R⁹ is independently substituted with 0, 1 or 2 R¹⁷; R¹⁷ is selected from halogen, -O-R¹⁵, -C(O)N(C1-4alkyl)2, -N(R¹²R¹³), and 4 to 10 membered heterocycle, when R¹⁷ is 4 to 10 membered heterocycle is substituted with 0, 1 or 2 halogen, -C_1-6alkyl or - C_1-6haloalkyl; R¹⁰ is independently selected from -C_1-6alkyl, C_3-6cycloalkyl and-C_1-6alkyl-C_{3- 6}cycloalkyl; R¹¹ is a -C_1-6 alkyl, and when R¹¹ is -C_1-6 alkyl, is substituted with 0 or 1 -N(- C_1-6 alkyl)₂, or R¹¹ is - C_1-6haloalkyl or 4 to 7 membered heterocycle; R¹² and R¹³ are independently selected from -C_1-6alkyl, -C_1-6haloalkyl and cyclopropyl; R¹⁵ is -C_1-6alkyl, - C_1-6haloalkyl or 4 to 7 membered heterocycle and when R¹⁵ is 4 to 7 membered heterocycle it is substituted with 0 or 1 -C_1-6alkyl. In some embodiments of the compounds of the invention, or a pharmaceutically acceptable salt thereof, R⁹ is -C_1-6alkyl, substituted with 0, 1, 2 or 3 groups independently selected from -C(O)-N(C_1-4alkyl)₂, -O-R¹⁵, -N(R¹²R¹³), 4 to 10 membered heterocycloalkyl, which heterocycloalkyl is further substituted with 0, 1 or 2 groups independently selected from halogen or -C_1-6alkyl; R¹² and R¹³ are independently selected from -C_1-6alkyl, -C_{1- 6}haloalkyl and cyclopropyl; R¹⁵ is -C_1-6alkyl, - C_1-6haloalkyl or 4 to 7 membered heterocycle and when R¹⁵ is 4 to 7 membered heterocycle it is substituted with 0 or 1 -C_1-6alkyl and wherein in each - N(C1-6 alkyl)2 or -N(C1-4alkyl)2 the two alkyl groups attached to N can be the same or different. In some embodiments of the compounds of the invention, or a pharmaceutically acceptable salt thereof, R⁹ is -C1-6alkyl, substituted with 0, 1, 2 or 3 groups independently selected from -C(O)-N(C1-4alkyl)2, -N(R¹²R¹³), -O-R¹⁵, 4 to 7 membered heterocycloalkyl, which heterocycloalkyl is further substituted with 0, 1 or 2 groups independently selected from halogen or -C1-6alkyl; R¹² and R¹³ are independently selected from -C1-6alkyl, -C1- 6haloalkyl and cyclopropyl; R¹⁵ is -C1-6alkyl, - C1-6haloalkyl or 4 to 7 membered heterocycle and when R¹⁵ is 4 to 7 membered heterocycle it is substituted with 0 or 1 -C1-6alkyl; and wherein in each - N(C1-6 alkyl)2 or -N(C1-4alkyl)2 the two alkyl groups attached to N can be the same or different. In some embodiments of the compounds of the invention, or a pharmaceutically acceptable salt thereof, wherein R⁹ is –C1-6alkyl, substituted with 0, 1, 2 or 3 groups independently selected from -C(O)-N(C1-4alkyl)2, -O-R¹⁵, -N(R¹²R¹³), 4 to 10 membered heterocycloalkyl, which heterocycloalkyl is further substituted with 0, 1 or 2 groups independently selected from halogen or –C1-6alkyl; R¹² and R¹³ are independently selected from –C1-6alkyl, -C1-6haloalkyl and cyclopropyl; R¹⁵ is –C1-6alkyl, - C1-6haloalkyl or 4 to 7 membered heterocycle and when R¹⁵ is 4 to 7 membered heterocycle it is substituted with 0 or 1 –C1-6alkyl and wherein in each - N(C_1-6alkyl)₂ or -N(C_1-4alkyl)₂ the two alkyl groups attached to N can be the same or different. In some embodiments of the compounds of the invention, or a pharmaceutically acceptable salt thereof, wherein R⁷ is selected from a group consisting of substituted or unsubstituted , In some embodiments of the compounds of the invention, or a pharmaceutically acceptable salt thereof, R⁷ is selected from a group consisting of substituted or unsubstituted

In some embodiments of the compounds of the invention, or a pharmaceutically acceptable salt thereof, R⁷ is selected from a group consisting of independently selected from –F, –Cl, oxo, –Me, isobutyl, isopropyl, cyclobutyl, –CH₂F, – CHF₂, –CH₂CF₃, –CF₃, –OMe, –O-CF₃, –O-azetidin-3-yl, –N(Me)₂, –C(O)Me, – C(O)cyclopropyl, 1-Me-azetidin-3-yl, 3-F-azetidin-1-yl, 3-N(Me)2-3-Me-azetidin-1-yl, 3- N(Me)2pyrrolidin-1-yl, 4-Me-piperidin-1-yl, 1-Me-piperidin-4-yl, 1-isopropyl-piperidin-4-yl, 4- N(Me)2-piperidin-1-yl, 4-cyclopropyl-piperazin-1-yl, 4-isopropyl-piperazin-1-yl, 4-Me-1,4- 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]pyridin-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)-azetidin-1-yl, 2-methyl- 2,5-diazabicyclo[2.2.1]heptan-5-yl, –C(O)CH₂cyclopropyl, –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-(3-F-3-Me-azeditin-1-yl), –CH₂-CH₂-CH₂-(3-F-3-Me- azeditin-1-yl), –CH₂-azeditin-1-yl, –CH₂-(3-F-azeditin-1-yl), –CH₂-(1-Me-azetidin-3-yl), – CH₂-azetidin-3-yl, –CH₂CH₂-(3-F-pyrrolidin-1-yl), –CH₂CH₂-(3-CF₃-pyrrolidin-1-yl), – CH₂CH₂-(3,3-diF-pyrrolidin-1-yl), oxetan-3yl, –CH₂CH₂OCH₃, –CH₂CH₂OH, – CH₂C(O)N(Me)₂, –CH₂N(Me)₂, –CH₂CH₂N(Me)₂, –CH₂CH₂N(Me)CH(cyclopropyl)₂, – CH₂CH₂N(Me)CH₂(cyclopropyl), –CH₂CH₂CH₂N(Me)₂, –C(Me)₂CH₂N(Me)₂, – CH₂C(Me)₂N(Me)₂, –CH₂CH₂C(Me)₂N(Me)₂, –CH₂CH₂N(Me)CH₂CF₃, – CH₂CH₂N(Me)CH(Me)₂, –CH₂CH₂N(Me)C(Me)₃, –CH₂CH₂N(Me)cyclopropyl, 4-F-phenyl, – CH₂CH₂-(2-azaspiro[3.4]octan-2yl), –CH₂CH₂CH₂-(2-azaspiro[3.4]octan-2yl), – CH₂CH₂CH₂CH₂-(2-azaspiro[3.4]octan-2yl), –CH₂CH₂-(6-azaspiro[3.4]octan-6-yl), – CH2CH2CH2-(6-azaspiro[3.4]octan-6-yl), –CH2CH2-(2,2-diF-6-azaspiro[3.4]octan-6-yl), – CH2CH2-(2-azaspiro[3.3]heptan-2-yl), –CH2CH2-(6-MeO-2-azaspiro[3.3]heptan-2-yl), – CH2CH2-(2-azaspiro[4.5]decan-2-yl), –CH2CH2-(7-azaspiro[3.5]nonan-7-yl), –CH2CH2-(6- azaspiro[3.5]nonan-6-yl), –CH2CH2-(2-azaspiro[3.5]nonan-2-yl), –CH2CH2-(5-oxa-8- azaspiro[3.5]nonan-8-yl), –CH2CH2-(7-oxa-2-azaspiro[3.5]nonan-2-yl), –CH2CH2CH2CH2- (7-oxa-2-azaspiro[3.5]nonan-2-yl), –CH2CH2-(6,6-diF-2-azaspiro[3.3]heptan-2-yl), – CH2CH2-(8-azabicyclo[3.2.1]octan-8-yl), –CH2CH2-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl), CH2CH2CH2-(2-azabicyclo[2.2.2]octan-2-yl), –CH2CH2CH2-(6-oxa-3- azabicyclo[3.1.1]heptan-3-yl), –CH2CH2-(7,7-diF-1,6-diMe-3-azabicyclo[4.1.0]heptan-3-yl), –CH2CH2-(3-azabicyclo[3.1.1]heptan-3-yl), – CH2CH2CH2-(2-azabicyclo[2.2.1]heptan-2-yl), CH2CH2CH2-(3-azabicyclo[3.1.1]heptan-3-yl), –CH2CH2CH2CH2-(3- azabicyclo[3.1.1]heptan-3-yl), –CH2CH2-(2-azabicyclo[2.1.1]hexan-2-yl), –CH2CH2-(6,6- diMe-3-azabicyclo[3.1.0]hexan-3-yl), –CH2CH2N(Me)cyclobutyl), –CH2CH2N(Me)(3,3- diF)cyclobutyl-1-yl), –CH2-CH2-(4-CF3-piperidin-1-yl), –CH2-CH2-(4,4-diMe-piperidin-1-yl), –CH2-CH2-(morpholin-4-yl), –CH2-CH2-CH2-(morpholin-4-yl), –CH2-CH2-CH2-(2,6-diMe- morpholin-4-yl), –CH2-CH2-CH2-(2,2,6,6-tetraMe-morpholin-4-yl), –CH2-CH2-CH2-(2,2- diMe-morpholin-4-yl), –CH2-CH2-(2,6-diMe-morpholin-4-yl), –CH2-CH2-(1,4-oxazepin-4-yl), –CH2CH2-CH2-(1,4-oxazepin-4-yl), and –S(O)2Me. In some embodiments of the compounds of the invention, or a pharmaceutically acceptable salt thereof, R⁷ is selected from a group consisting of , 1 or 2 substituents independently selected from –F, –Cl, oxo, –Me, isobutyl, isopropyl, cyclobutyl, –CH2F, –CHF2, –CH2CF3, –OMe, –O-CF3, –O-azetidin-3-yl, –N(Me)2, – C(O)Me, –C(O)cyclopropyl, 1-Me-azetidin-3-yl, 3-F-azetidin-1-yl, –-C(O)CH2cyclopropyl, – 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), –CH₂-CH₂-(3,3-diMe-azeditin-1-yl),–CH₂-azeditin-1-yl, – CH₂-(3-F-azeditin-1-yl), –CH₂-(1-Me-azetidin-3-yl), –CH₂-azetidin-3-yl, –CH₂CH₂-(3-F- pyrrolidin-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. In some embodiments of the compounds of the invention, or a pharmaceutically acceptable salt thereof, R⁷ is selected from a group consisting of

substituents independently selected from –F, –Cl, oxo, –Me, isobutyl, isopropyl, cyclobutyl, –CH2F, –CHF2, –CH2CF3, –OMe, –OCF3, –O-azetidin-3-yl, –N(Me)2, – C(O)Me, –C(O)cyclopropyl, 1-Me-azetidin-3-yl, 3-F-azetidin-1-yl, –-C(O)CH2cyclopropyl, – 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), –CH₂-CH₂-(3,3-diMe-azeditin-1-yl),–CH₂-azeditin-1-yl, – CH₂-(3-F-azeditin-1-yl), –CH₂-(1-Me-azetidin-3-yl), –CH₂-azetidin-3-yl, –CH₂CH₂-(3-F- pyrrolidin-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. In some embodiments of the compounds of the invention, or a pharmaceutically acceptable salt thereof, R⁷ is selected from a group consisting of substituents independently selected from –F, –Cl, oxo, –Me, isobutyl, isopropyl, cyclobutyl, –CH₂F, –CHF₂, –CH₂CF₃, –CF₃, –OMe, –O-CF₃, –O-azetidin-3-yl, –N(Me)₂, – C(O)Me, –C(O)cyclopropyl, 1-Me-azetidin-3-yl, 3-F-azetidin-1-yl, 3-N(Me)₂-3-Me-azetidin- 1-yl, 3-N(Me)₂pyrrolidin-1-yl, 4-Me-piperidin-1-yl, 1-Me-piperidin-4-yl, 1-isopropyl-piperidin- 4-yl, 4-N(Me)₂-piperidin-1-yl, 4-cyclopropyl-piperazin-1-yl, 4-isopropyl-piperazin-1-yl, 4-Me- 1,4-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]pyridin-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)-azetidin-1-yl, 2- methyl-2,5-diazabicyclo[2.2.1]heptan-5-yl, –C(O)CH2cyclopropyl, –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-(3-F-3-Me-azeditin-1-yl), –CH₂-CH₂-CH₂-(3-F-3-Me- azeditin-1-yl), –CH₂-azeditin-1-yl, –CH₂-(3-F-azeditin-1-yl), –CH₂-(1-Me-azetidin-3-yl), – CH₂-azetidin-3-yl, –CH₂CH₂-(3-F-pyrrolidin-1-yl), –CH₂CH₂-(3-CF₃-pyrrolidin-1-yl), – CH₂CH₂-(3,3-diF-pyrrolidin-1-yl), oxetan-3yl, –CH₂CH₂OCH₃, –CH₂CH₂OH, – CH₂C(O)N(Me)₂, –CH₂N(Me)₂, –CH₂CH₂N(Me)₂, –CH₂CH₂N(Me)CH(cyclopropyl)₂, – CH₂CH₂N(Me)CH₂(cyclopropyl), –CH₂CH₂CH₂N(Me)₂, –C(Me)₂CH₂N(Me)₂, – CH₂C(Me)₂N(Me)₂, –CH₂CH₂C(Me)₂N(Me)₂, –CH₂CH₂N(Me)CH₂CF₃, – CH₂CH₂N(Me)CH(Me)₂, –CH₂CH₂N(Me)C(Me)₃, –CH₂CH₂N(Me)cyclopropyl, 4-F-phenyl, – CH₂CH₂-(2-azaspiro[3.4]octan-2yl), –CH₂CH₂CH₂-(2-azaspiro[3.4]octan-2yl), – CH₂CH₂CH₂CH₂-(2-azaspiro[3.4]octan-2yl), –CH₂CH₂-(6-azaspiro[3.4]octan-6-yl), – CH₂CH₂CH₂-(6-azaspiro[3.4]octan-6-yl), –CH₂CH₂-(2,2-diF-6-azaspiro[3.4]octan-6-yl), – CH₂CH₂-(2-azaspiro[3.3]heptan-2-yl), –CH₂CH₂-(6-MeO-2-azaspiro[3.3]heptan-2-yl), – CH₂CH₂-(2-azaspiro[4.5]decan-2-yl), –CH₂CH₂-(7-azaspiro[3.5]nonan-7-yl), –CH₂CH₂-(6- azaspiro[3.5]nonan-6-yl), –CH₂CH₂-(2-azaspiro[3.5]nonan-2-yl), –CH₂CH₂-(5-oxa-8- azaspiro[3.5]nonan-8-yl), –CH₂CH₂-(7-oxa-2-azaspiro[3.5]nonan-2-yl), –CH₂CH₂CH₂CH₂- (7-oxa-2-azaspiro[3.5]nonan-2-yl), –CH₂CH₂-(6,6-diF-2-azaspiro[3.3]heptan-2-yl), – CH₂CH₂-(8-azabicyclo[3.2.1]octan-8-yl), –CH₂CH₂-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl), CH2CH2CH2-(2-azabicyclo[2.2.2]octan-2-yl), –CH2CH2CH2-(6-oxa-3- azabicyclo[3.1.1]heptan-3-yl), –CH2CH2-(7,7-diF-1,6-diMe-3-azabicyclo[4.1.0]heptan-3-yl), –CH2CH2-(3-azabicyclo[3.1.1]heptan-3-yl), – CH2CH2CH2-(2-azabicyclo[2.2.1]heptan-2-yl), CH2CH2CH2-(3-azabicyclo[3.1.1]heptan-3-yl), –CH2CH2CH2CH2-(3- azabicyclo[3.1.1]heptan-3-yl), –CH2CH2-(2-azabicyclo[2.1.1]hexan-2-yl), –CH2CH2-(6,6- diMe-3-azabicyclo[3.1.0]hexan-3-yl), –CH2CH2N(Me)cyclobutyl), –CH2CH2N(Me)(3,3- diF)cyclobutyl-1-yl), –CH2-CH2-(4-CF3-piperidin-1-yl), –CH2-CH2-(4,4-diMe-piperidin-1-yl), –CH2-CH2-(morpholin-4-yl), –CH2-CH2-CH2-(morpholin-4-yl), –CH2-CH2-CH2-(2,6-diMe- morpholin-4-yl), –CH2-CH2-CH2-(2,2,6,6-tetraMe-morpholin-4-yl), –CH2-CH2-CH2-(2,2- diMe-morpholin-4-yl), –CH2-CH2-(2,6-diMe-morpholin-4-yl), –CH2-CH2-(1,4-oxazepin-4-yl), –CH2CH2-CH2-(1,4-oxazepin-4-yl), and –S(O)2Me. In some embodiments of the compounds of the invention, or a pharmaceutically acceptable salt thereof, R¹ is selected from: -C(O)-CH₃,

,

In some embodiments of the compounds of the invention, or a pharmaceutically acceptable salt thereof, R¹ is selected from: -C(O)-CH3,

In some embodiments of the compounds of the invention, or a pharmaceutically acceptable salt thereof, R¹ is selected from: ,

In some embodiments of the compounds of the invention, or a pharmaceutically acceptable salt thereof, R¹ is selected from: -C(O)-CH3, . In some embodiments of the compounds of the invention, or a pharmaceutically acceptable salt thereof, R² is independently selected from a group consisting of -Br, -CF3, , In some embodiments of the compounds of the invention, or a pharmaceutically acceptable salt thereof, R² is independently selected from a group consisting of ,

In some embodiments of the compounds of the invention, or a pharmaceutically acceptable salt thereof, R² is independently selected from a group consisting of -Br, -CF₃, , In some embodiments of the compounds of the invention, or a pharmaceutically acceptable salt thereof, R² is independently selected from a group consisting of -Br, -CF₃, In some embodiments of the compounds of the invention, or a pharmaceutically acceptable salt thereof, R² is independently selected from a group consisting of . In some embodiments of the compounds of the invention, or a pharmaceutically acceptable salt thereof, R³ is independently selected from a group consisting of -F, -CF3 and -CH3. In another embodiment, the invention relates to a compound selected from any one of Examples 1 to 122 described herein or a pharmaceutically acceptable salt thereof. In a further embodiment, the invention relates to a compound selected from any one of Examples 200 to 359, 359A, 360 to 402, 404, 405, 407, 410, 411 described herein or a pharmaceutically acceptable salt thereof. In one embodiment the invention relates to a pharmaceutical composition comprising a pharmaceutically effective amount of the compounds of the invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient. In one embodiment the invention relates to the use of the compound of the invention or a pharmaceutically acceptable salt thereof in the preparation of a medicament. In one embodiment the invention relates to a compound of the invention or a pharmaceutically acceptable salt thereof, for use as a medicament. In certain embodiments, the invention relates to compounds that inhibit α₄β₇- integrin. In certain embodiments, the invention relates to prodrugs of compounds that inhibit α₄β₇- integrin (i.e., compounds that are converted into α₄β₇- integrin inhibitors under physiological conditions or by enzymatic activity in a mammalian host). The compounds will be useful for the treatment of inflammatory bowel disease, ulcerative colitis, Crohn’s disease, small intestinal bacterial overgrowth (SIBO), eosinophilic gastrointestinal disease (EGID), enteritis, enteropathy associated with seronegative arthropathies, gut dysbiosis, microscopic or collagenous colitis, cholecystitis, cholangitis, pericholangitis, familial adenomatous polyposis (FAP) associated inflammation gastrointestinal cancer, intestinal graft-versus-host disease (intestinal GVHD), celiac enteritis, chronic pouchitis, checkpoint inhibitor related colitis. In one embodiment the invention relates to a method of inhibiting the interaction between a α₄β₇ integrins and MAdCAM-1 protein in a subject, the method comprising administering to the subject in need thereof a pharmaceutically effective amount of a compound of the invention or its pharmaceutically acceptable salt. In another embodiment the invention relates to a method of treating inflammatory bowel diseases in a human in need thereof, the method comprising administering to the human a pharmaceutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof. In another embodiment, the invention relates to a compound of the invention or a pharmaceutically acceptable salt of any of the foregoing, for use in the treatment of inflammatory bowel diseases. In another embodiment, the invention relates to a compound of the invention or a pharmaceutically acceptable salt of any of the foregoing, for use in the treatment of inflammatory bowel diseases, wherein the inflammatory bowel diseases is ulcerative colitis. In another embodiment, the invention relates to a compound of the invention or a pharmaceutically acceptable salt of any of the foregoing, for use in the treatment of inflammatory bowel diseases, wherein the inflammatory bowel diseases is Crohn’s disease. In another embodiment, the invention relates to a method of treating ulcerative colon disease in a human, the method comprising administering to the human in need thereof a pharmaceutically effective amount of a compound of the invention or a pharmaceutically acceptable salt thereof. In another embodiment, the invention relates to a compound of the invention, or a pharmaceutically acceptable salt of any of the foregoing, for use in the treatment of ulcerative colon disease. In another embodiment, the invention relates to a compound of the invention, or a pharmaceutically acceptable salt of any of the foregoing, for use in the treatment of ulcerative colon disease, wherein the ulcerative colon disease is ulcerative colitis. In another embodiment, the invention relates to a compound of the invention, or a pharmaceutically acceptable salt of any of the foregoing, for use in the treatment of ulcerative colon disease, wherein the ulcerative colon disease is Crohn’s Disease. In another embodiment, the invention relates to a kit comprising: a) one or more compositions, each composition comprising a pharmaceutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt of any thereof, and a pharmaceutically acceptable carrier or excipient; and b) instructions for administering the one or more compositions to a human in need thereof. Terms employed in the specification, description, examples and claims are collected here. These definitions should be read in light of the remainder of the disclosure and understood as by a person of skill in the art. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by a person of ordinary skill in the art. The terms and phrases are defined below and throughout the specification apply unless stated otherwise. The articles "a", "an" and "the" include plural referents unless context clearly indicates otherwise and are used herein to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, "an element" means one element or more than one element. The phrase "and/or," as used herein in the specification and in the claims, should be understood to mean "either or both" of the elements so conjoined. In the claims, as well as in the specification above, all transitional phrases such as "comprising," "including," "carrying," "having," "containing," "involving," "holding, "composed of," and the like are to be understood to be open-ended, i.e., to mean including but not limited to. Only the transitional phrases "consisting of' and "consisting essentially of' shall be closed or semi-closed transitional phrases, respectively, as set forth in the United States Patent Office Manual of Patent Examining Procedures, Section 2111.03. Certain compounds contained in compositions of the present invention may exist in particular geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis- and trans-isomers, R- and S-enantiomers, diastereomers, (D )- isomers, (L)isomers, the racemic mixtures thereof, and other mixtures thereof, as falling within the scope of the invention. Additional asymmetric carbon atoms may be present in a substituent such as an alkyl group. All such isomers, as well as mixtures thereof, are intended to be included in this invention. Unless stereochemistry is explicitly indicated in a structure, the structure is intended to embrace all possible stereoisomers of the compound depicted. If stereochemistry is explicitly indicated for one portion or portions of a molecule, but not for another portion or portions of a molecule, the structure is intended to embrace all possible stereoisomers for the portion or portions where stereochemistry is not explicitly indicated. If, for instance, a particular enantiomer of compound of the present invention is desired, the desired enantiomer can be isolated from the racemic mixture using chiral separation methods known in the art, such as, for example, chiral chromatography. Alternatively, it may be prepared by asymmetric synthesis, or by derivation with a chiral auxiliary, where the resulting diastereomeric mixture is separated and the auxiliary group cleaved to provide the pure desired enantiomers. Alternatively, where the molecule contains a basic functional group, such as amino, or an acidic functional group, such as carboxyl, diastereomeric salts are formed with an appropriate optically-active acid or base, followed by resolution of the diastereomers thus formed by fractional crystallization or chromatographic means well known in the art, and subsequent recovery of the pure enantiomers. Stereochemistry/Solvates/Hydrates: Unless stated otherwise a structural formula given in the description or in the claims or a chemical name refers to the corresponding compound itself, mixtures of the forms mentioned hereinbefore (if such forms exist) as well as salts, particularly pharmaceutically acceptable salts thereof. The compounds and salts according to the invention may be present in solvated form ( e.g. with pharmaceutically acceptable solvents such as e.g. water, ethanol etc.) or in unsolvated form. Generally, for the purposes of the present invention the solvated forms, e.g. hydrates, are to be regarded as of equal value to the unsolvated forms. An aliphatic chain comprises the classes of alkyl, alkenyl and alkynyl defined below. As used herein, the term "aliphatic group" refers to an unbranched or linear chain, branched-chain, or cyclic aliphatic hydrocarbon group and includes saturated and unsaturated aliphatic groups, such as an alkyl group, an alkenyl group, or an alkynyl group. The term "alkyl" refers to an unbranched or branched hydrocarbon. For example, an alkyl group can have a specified number of chain carbons, such as 1 to 6 carbon atoms (i.e., C1-C6 alkyl or C1-6 alkyl). Examples of suitable alkyl groups include, but are not limited to, methyl (Me, --CH3), ethyl (Et, -CH2CH3), 1-propyl (n-Pr, n-propyl, -CH2CH2CH3), 2- propyl (i-Pr, i-propyl, --CH(CH3)2), 1-butyl (n-Bu, n-butyl, --CH2CH2CH2CH3), 2-methyl-1- propyl (i-Bu, 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 (-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. As used herein, the term "alkylene" refers to an alkyl group having the specified number of carbons, for example from 2 to 12 carbon atoms, that contains two points of attachment to the rest of the compound on its longest carbon chain. Non-limiting examples of alkylene groups include methylene -(CH₂)-, ethylene -(CH₂CH₂)-, n-propylene - (CH₂CH₂CH₂)-, isopropylene -(CH₂CH(CH₃))-, and the like. Alkylene groups can be cyclic or acyclic, branched or unbranched carbon chain moiety, and may be optionally substituted with one or more substituents. "Alkenyl" refers to any cyclic or acyclic, branched or unbranched unsaturated carbon chain moiety having the number of carbon atoms specified, or up to 26 carbon atoms if no limitation on the number of carbon atoms is specified; and having one or more double bonds in the moiety. Alkenyl of 6 to 26 carbon atoms is exemplified by hexenyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, dodecenyl, tridecenyl, tetradecenyl, pentadecenyl, hexadecenyl, heptadecenyl, octadecenyl, nonadecenyl, eicosenyl, heneicosoenyl, docosenyl, tricosenyl, and tetracosenyl, in their various isomeric forms, where the unsaturated bond(s) can be located anywhere in the moiety and can have either the (Z) or the (E) configuration about the double bond(s). "Alkynyl" refers to hydrocarbyl moieties of the scope of alkenyl, but having one or more triple bonds in the moiety. The term "alkoxy" refers to a group having the formula “-O-alkyl,” in which an alkyl group, as defined above, is attached to the parent molecule via an oxygen atom. The alkyl portion of an alkoxy group can have a specified number of carbon chain atoms, such as 1 to 6 carbon atoms (i.e., C1-C6 alkoxy or C1-6 alkoxy). Examples of suitable alkoxy groups include, but are not limited to, methoxy (-O-CH3 or --OMe), ethoxy (-OCH2CH3 or --OEt), t- butoxy (--O--C(CH3)3 or --OtBu) and the like. The term “haloalkyl” refers to a group in which the alkyl group, as defined above, has or more hydrogens replaced by a halogen atom. The alkyl portion of an haloalkyl group can have a specified number of carbon chain atoms, such as 1 to 6 carbon atoms (i.e., -C1-C6 haloalkyl or -C1-6 haloalkyl). Examples include: -CFH2, -CF2H, -CF3, -CF2CF3, - CHFCF3, -CH2CF3, -CF2CH3, -CHFCH3, -CF2CF2CF3, -CF2CH2CH3 etc. The term “carbonyl group” refers to C=O, i.e., with the carbon atom bonded to oxygen via a double bond and further bonded to two other atoms. It is indicated as -CO- or -C(O)- herein. The term “carbocycle” or “carbocyclic group” refers to a chemical ring containing only carbon atoms, including saturated, unsaturated, partially saturated, and aromatic rings. For clarity, “carbocycle” includes “cycloalkyl” and “aryl” as defined herein. "Cycloalkyl" means mono- or bicyclic or bridged or spirocyclic, or polycyclic saturated carbocyclic rings, each having from 3 to 12 carbon atoms. Likewise and unless specified preferred cycloalkyls have from 3-10 carbon atoms in their ring structure, and more preferably have 3-6 carbons in the ring structure. Cycloalkyl groups may be substituted or unsubstituted. In some embodiments, a preferred cycloalkyl is a monocycle having 3 to 6 carbon atoms. The term "aryl" as used herein includes 6- to 12-membered substituted or unsubstituted single-ring 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 adjoining rings wherein at least one of the rings is aromatic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, and/or heterocyclyls, wherein the connection point is on the aromatic ring. Aryl groups include benzene, naphthalene, phenanthrene, phenol, aniline, and the like. Aryl groups also include dihydrobenzofuran, indoline, isoindoline, quinoline, isoquinoline and the like, wherein the attachment point is on the phenyl ring. The terms "heterocyclyl", “heterocycle” or "heterocyclic group" refer to 3- to 12- membered ring structures, more preferably 4- to 12-membered rings, more preferably 5- to 10-membered rings, whose ring structures include one to four heteroatoms selected from N, O, S and oxidized forms thereof. Heterocyclyl can be saturated, partially saturated, unsaturated and/or aromatic. Heterocycles can be monocyclic, bicyclic, spirocyclic, or polycyclic. Heterocyclyl groups include, for example, azetidine, aziridine, thiophene, thianthrene, furan, pyran, isobenzofuran, chromene, xanthene, phenoxathiin, pyrrole, imidazole, pyrazole, isothiazole, isoxazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, pyrimidine, phenanthroline, phenazine, phenarsazine, phenothiazine, furazan, phenoxazine, pyrrolidine, oxolane, thiolane, oxazole, piperidine, piperazine, morpholine, lactones, lactams such as azetidinones, pyridone and pyrrolidinones, sultams, sultones, and the like. For clarity, “heterocyclyl” includes “heteroaryl” and “heterocycloalkyl”. The heterocyclic ring can be substituted at one or more positions with such substituents as described above, as for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, 5 amido, phosphate, phosphonate, phosphinate, carbonyl, carboxyl, silyl, sulfamoyl, sulfinyl, ether, alkylthio, sulfonyl, ketone, aldehyde, ester, a heterocyclyl, an aromatic or heteroaromatic moiety, -CF3, -CN, and the like. It is understood that the general terms for the heterocycles referenced herein include each isomeric form of the heterocycle, such as the term “dithianyl” including 1,2 dithianyl, 1,3-dithianyl, and 1,4-dithianyl groups, the term “thiadiazinyl” including 1,2,5 thiadiazinyl and 1,3,4-thiadiazinyl groups, the term “azaindolyl” including 4-azaindolyl, 5- azaindolyl, 6-azaindolyl, and 7-azaindolyl groups, and “benzothiophenyl” including benzo[b]thiophenyl and benzo[c]thiophenyl groups. Similarly, general heterocycle names include each variance in one or more points of unsaturation. For instance, the term “dihydropyrrolyl” refers to “2,3-dihydro-1H-pyrrolyl” and “2,5-dihydro-1H-pyrrolyl” groups. "Heterocycloalkyl" means saturated heterocyclic rings, each having from 3 to 12 ring members atoms, more preferably 4- to 10-membered rings, more preferably 4- to 7- membered rings, whose ring structures include one to four heteroatoms selected from N, O, S and oxidized forms thereof. Heterocycles can be monocyclic, bicyclic, spirocyclic, or polycyclic. Heterocyclyl groups include, for example, azetidine, oxetane, tetrahydrofuran, pyrrolidine, piperidine, piperazine, morpholine, tetrahydropyran, dioxane, azepane, and the like. Heterocycloalkyl groups may be substituted or unsubstituted. In some embodiments, a preferred heterocycloalkyl is a monocycle having 4 to 6 ring members, including 1 or 2 hetero atoms. Partially saturated heterocycle means heterocyclic ring having at least one carbon- carbon double bond, preferably one or two or three carbon-carbon double bonds, preferably one or two carbon-carbon double bonds, preferably one carbon-carbon double bond. Heteroaryl groups include substituted or unsubstituted aromatic 5- to 12- membered ring structures, more preferably 5- to 10-membered rings, whose ring structures include one to four heteroatoms selected from N, O, S and oxidized forms thereof. The term "heteroaryl" also includes polycyclic ring systems having two or more cyclic rings in which two or more atoms are common to two adjoining rings wherein at least one of the rings is aromatic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls and/or heterocyclyls, wherein the connection point is on an aromatic ring. Heteroaryl groups include, for example, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, triazole, pyrazole, pyridine, pyrazine, pyridazine and pyrimidine, and the like. Heteroaryl groups also include benzofuran, benzothiophene, indole, benzothiazole and the like, regardless of the placement of the attachment point. Aryl and heteroaryl can be monocyclic, bicyclic, or polycyclic. The term “halogen” refers to an atom selected from the group of elements chlorine, fluorine, bromine, and iodine, i.e., -F, -Cl, -Br, or -I. The term “oxo” refers to double-bonded oxygen “=O”. 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 "azido" 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. As used herein, the term "substituted" is contemplated to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds. Illustrative substituents include, for example, those described herein above. The permissible substituents can be one or more and the same or different for appropriate organic compounds. For purposes of this invention, the heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms. This invention is not intended to be limited in any manner by the permissible substituents of organic compounds. It will be understood that "substitution" or "substituted with" includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc. The term "prodrug" as used herein encompasses compounds that, under physiological conditions, are converted into therapeutically active agents. A common method for making a prodrug is to include selected moieties that are hydrolyzed under physiological conditions to reveal the desired molecule. In other embodiments, the prodrug is converted by an enzymatic activity of the mammalian host. Examples of moieties that are hydrolyzed under physiological conditions to reveal the desired molecule include functionalized carboxylic groups, esters of carboxylic acids, which can be converted into the corresponding active molecule under physiological conditions. In the following examples of moieties are shown that are hydrolyzed under physiological conditions to reveal the desired molecule:

For purposes of this invention, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 67th Ed., 1986-87, inside cover. The terms "therapeutically effective amount" and "pharmaceutically effective amount" refer to an amount that is sufficient to effect treatment, as defined below, when administered to a subject (e.g., a mammal, such as a human) in need of such treatment. The therapeutically or pharmaceutically effective amount will vary depending upon the subject and disease condition being treated, the weight and age of the subject, the severity of the disease condition, the manner of administration and the like, which can readily be determined by one of ordinary skill in the art. For example, a "therapeutically effective amount" or a "pharmaceutically effective amount" of a compound of Formula (I), or a pharmaceutically acceptable salt or co-crystal thereof, is an amount sufficient to inhibit, and thereby treat a subject (e.g., a human) suffering an indication, or to ameliorate or alleviate the existing symptoms of the indication. "Treatment" or "treating" is an approach for obtaining beneficial or desired results including clinical results. Beneficial or desired clinical results may include one or more of the following: (i) inhibiting the disease or condition (e.g., decreasing one or more symptoms resulting from the disease or condition, and/or diminishing the extent of the disease or condition); (ii) slowing or arresting the development of one or more clinical symptoms associated with the disease or condition (e.g., stabilizing the disease or condition, preventing or delaying the worsening or progression of the disease or condition, and/or preventing or delaying the spread (e.g., metastasis) of the disease or condition); and/or (iii) relieving the disease, that is, causing the regression of clinical symptoms (e.g., ameliorating the disease state, providing partial or total remission of the disease or condition, enhancing effect of another medication, delaying the progression of the disease, increasing the quality of life, and/or prolonging survival). The terms “inhibitor” indicates a compound of the invention that selectively binds to α₄β₇ integrin preventing the interaction between α₄β₇ integrin and MAdCAM-1 protein. Thus “inhibiting” or "inhibition" indicates a decrease in the baseline activity of a biological activity or process regulated by the interaction between α₄β₇ integrin and MAdCAM-1 protein. In some embodiments, the inhibition of α₄β₇ integrin activity may be compared in the same subject prior to treatment, or other subjects not receiving the treatment. The term “inhibitor” is understood to refer to a compound or agent that, upon administration to a human in need thereof at a pharmaceutically or therapeutically effective dose, provides the inhibitory activity desired. Numerical values in the specification and claims of this application should be understood to include numerical values which are the same when reduced to the same number of significant figures and numerical values which differ from the stated value by less than the experimental error of conventional measurement technique of the type described in the present application to determine the value. All ranges disclosed and/or claimed herein are inclusive of the recited endpoint and independently combinable (for example, the ranges of "from 2 to 10" and “2-10” are inclusive of the endpoints, 2 and 10, and all the intermediate values 3, 4, 5, 6, 7, 8, and 9). By "significant" is meant any detectable change that is statistically significant in a standard parametric test of statistical significance such as Student's T-test, where p<0.05. Salts: The term "pharmaceutically acceptable" is used herein to denote compounds, materials, compositions and/or formulations which are suitable, according to generally recognised medical opinion, for use in conjunction with human and/or animal tissue and do not have or give rise to any excessive toxicity, irritation or immune response or lead to other problems or complications, i.e. correspond overall to an acceptable risk/benefit ratio. The term "pharmaceutically acceptable salts" relates to derivatives of the chemical compounds disclosed in which the parent compound is modified by the addition of acid or base. Examples of pharmaceutically acceptable salts include (without being restricted thereto) salts of mineral or organic acids in relation to basic functional groups such as for example amines, alkali metal or organic salts of acid functional groups such as for example carboxylic acids, etc. These salts include in particular acetate, ascorbate, benzenesulphonate, benzoate, besylate, bicarbonate, bitartrate, bromide/hydrobromide, Ca-edetate/edetate, camsylate, carbonate, chloride/hydrochloride, citrate, edisylate, ethane disulphonate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycolate, glycollylarsnilate, hexylresorcinate, hydrabamine, hydroxymaleate, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, malate, maleate, mandelate, methanesulphonate, mesylate, methylbromide, methylnitrate, methylsulphate, mucate, napsylate, nitrate, oxalate, pamoate, pantothenate, phenyl acetate, phosphate/diphosphate, polygalacturonate, propionate, salicylate, stearate, subacetate, succinate, sulphamide, sulphate, tannate, tartrate, teoclate, toluenesulphonate, triethiodide, ammonium, benzathine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumin and procaine. Other pharmaceutically acceptable salts may be formed with cations of metals such as aluminium, calcium, lithium, magnesium, potassium, sodium, zinc, etc. (cf. also Pharmaceutical salts, Birge, S.M. et al., J. Pharm. Sci., (1977), 66, 1-19). As used herein, the terms “isotope” and “isotopic” in reference to a compound as disclosed herein means that one or more atoms of the compound is replaced with an isotope of such one or more atoms. An “isotope” refers to any of two or more forms of a chemical element, having the same number of protons in the nucleus, but having different numbers of neutrons in the nucleus. For example, an isotopic compound includes a compound in which one or more hydrogen atoms (H) has been replaced with 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) renders the resulting compound an isotopic compound. For example, and in reference to Formula (I), replacing the two methyl groups of the isopropyl moiety (-CH(CH₃)₂) with fully deuterated methyl groups (-CH(CD₃)₂) would be an isotopic compound of Formula (I). In addition to replacing hydrogen with deuterium, other stable (non-radioactive) isotope 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 the like. Accordingly, all reference herein to isotopic compounds of Formula (I), as well as all reference to the various embodiments thereof, refers to a compound having one or more isotopic substitutions, including (but not limited to) substitutions of one or more hydrogen atoms with one or more deuterium atoms and any occurrence(s) in the compound. To this end, the isotopic compounds disclosed herein provide improved advantages relative to their non-isotopic forms. To this end, isotopic modification provides a means of improving existing drugs and/or as a tool in the design of new drugs. For example, isotopic drug design has proven successful in the context of the deuterium (D) kinetic isotope effect. Due to the twofold higher mass of D compared with H, the C-D bond is much more resistant toward oxidative processes (such as its ability to be catalyzed by CYP450 or by other enzymes involved in metabolism), while retaining very similar steric properties. Therefore, H-D isosteric replacement usually retains the pharmacodynamics of the compound, while improving its pharmacokinetics with a repercussion on half-life and/or of area under the curve values and, ultimately, on dose and/or dosing regimen. For example, drug exposure may be enhanced with isotopic modification, and/or a decrease of clearance. Such benefits are provided to the compounds disclosed hereby by way their isotopic derivation. Terms such as "subject" and “patient” refer to an animal, such as a mammal, that has been or will be the object of treatment, observation or experiment. The methods described herein may be useful in both human therapy and veterinary applications. In some embodiments, the subject is a mammal; in some embodiments the subject is human; and in some embodiments the subject is chosen from cats and dogs. "Subject in need thereof" or "human in need thereof" refers to a subject, such as a human, who may have or is suspected to have diseases or conditions that would benefit from certain treatment; for example treatment with a compound of Formula (I), or a pharmaceutically acceptable salt or co-crystal thereof, as described herein. This includes a subject who may be determined to be at risk of or susceptible to such diseases or conditions, such that treatment would prevent the disease or condition from developing. The pharmaceutically acceptable salts of the present invention may be prepared starting from the parent compound which carries a basic or acidic functionality, by conventional chemical methods. Generally, such salts may be synthesised by reacting the free acid or base form of these compounds with a sufficient amount of the corresponding base or acid in water or an organic solvent such as for example ether, ethyl acetate, ethanol, isopropanol, acetonitrile (or mixtures thereof). Salts of acids other than those mentioned above, which are useful for example for purifying or isolating the compounds from the reaction mixtures (e.g. trifluoroacetates), are also to be regarded as part of the invention. The phrase "pharmaceutically acceptable excipient" or "pharmaceutically acceptable carrier" as used herein means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting the subject chemical from one organ or portion of the body, to another organ or portion of the body. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation, not injurious to the patient, and substantially non-pyrogenic. Some examples of materials which can serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose,glucose, and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol, and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as 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 solutions; and (21) other non-toxic compatible substances employed in pharmaceutical formulations. In certain embodiments, pharmaceutical compositions of the present invention are non-pyrogenic, i.e., do not induce significant temperature elevations when administered to a patient. The compounds of the invention may optionally be present as racemates, but may also be obtained as pure enantiomers, i.e. in the (R) or (S) form. Preferred are the compounds with the specific stereochemistry of formula Ia. The invention relates to the compounds in question, optionally in the form of the individual optical isomers, diastereomers, mixtures of diastereomers, mixtures of the individual enantiomers or racemates, in the form of the tautomers as well as in the form of the free bases or the corresponding acid addition salts with pharmacologically acceptable acids -such as for example acid addition salts with hydrohalic acids - for example hydrochloric or hydrobromic acid - or organic acids – such as for example oxalic, fumaric, diglycolic or methanesulphonic acid. The invention relates to the respective compounds of formulas I in the form of the pharmacologically acceptable salts thereof. These pharmacologically acceptable salts of the compounds of formulae I and Ia may also be present in the form of their respective hydrates (e.g. Monohydrates, dihydrates, etc.) as well as in the form of their respective solvates. By a hydrate of the compound according to the formulas I is meant, for the purposes of the invention, a crystalline salt of the compound according to formulas I, containing water of crystallisation. By a solvate of the compound according to formulas I is meant, for the purposes of the invention, a crystalline salt of the compound according to formulas I, which contains solvent molecules (e.g. Ethanol, methanol etc) in the crystal lattice. COMBINATIONS The compounds of formula I may be used on their own or in conjunction with other active substances of formula I according to the invention. The compounds of formula I may optionally also be used in conjunction with other pharmacologically active substances. Preferably the active substances used here may be selected for example from among anti-IL17, bispecific antibodies IL23p19/TNF, fecal transplant, aminosalicylates (5-ASA), cox-2 inhibitors, corticosteroids, Azathioprine, Cyclosporine, Tacrolimus, 6-mercaptopurine and/or Antibiotics (such as Ciprofloxacin, Metronidazole, Ampicillin). FORMULATIONS The compounds of formula I according to the invention also have properties required for the manufacture of suitable pharmaceutical dosage forms. These properties include for instance properties relevant for sufficient bioavailability of the active ingredient, in particular sufficiently high solubilities thereof such as for instance a solubility that is > 2 µg/ml measured in aqueous solution at pH 6,8. Suitable forms for administration are for example tablets, capsules, solutions, syrups, emulsions or inhalable powders or aerosols. The content of the pharmaceutically effective compound(s) in each case should be in the range from 0.1 to 90 wt.%, preferably 0.5 to 50 wt.% of the total composition, i.e. in amounts which are sufficient to achieve the dosage range specified hereinafter. The preparations may be administered orally in the form of a tablet, as a powder, as a powder in a capsule (e.g. a hard gelatine capsule), as a solution or suspension. When administered by inhalation the active substance combination may be given as a powder, as an aqueous or aqueous-ethanolic solution or using a propellant gas formulation. Preferably, therefore, pharmaceutical formulations are characterised by the content of one or more compounds of formula I according to the preferred embodiments above. It is particularly preferable if the compounds of formula I are administered orally, and it is also particularly preferable if they are administered once or twice a day. Suitable tablets may be obtained, for example, by mixing the active substance(s) with known excipients, for example inert diluents such as calcium carbonate, calcium phosphate or lactose, disintegrants such as corn starch or alginic acid, binders such as starch or gelatine, lubricants such as magnesium stearate or talc and/or agents for delaying release, such as carboxymethyl cellulose, cellulose acetate phthalate, or polyvinyl acetate. The tablets may also comprise several layers. Coated tablets may be prepared accordingly by coating cores produced analogously to the tablets with substances normally used for tablet coatings, for example collidone or shellac, gum arabic, talc, titanium dioxide or sugar. To achieve delayed release or prevent incompatibilities the core may also consist of a number of layers. Similarly the tablet coating may consist of a number of layers to achieve delayed release, possibly using the excipients mentioned above for the tablets. Syrups containing the active substances or combinations thereof according to the invention may additionally contain a sweetener such as saccharine, cyclamate, glycerol or sugar and a flavour enhancer, e.g. a flavouring such as vanillin or orange extract. They may also contain suspension adjuvants or thickeners such as sodium carboxymethyl cellulose, wetting agents such as, for example, condensation products of fatty alcohols with ethylene oxide, or preservatives such as p-hydroxybenzoates. Capsules containing one or more active substances or combinations of active substances may for example be prepared by mixing the active substances with inert carriers such as lactose or sorbitol and packing them into gelatine capsules. Suitable suppositories may be made for example by mixing with carriers provided for this purpose, such as neutral fats or polyethyleneglycol or the derivatives thereof. Excipients which may be used include, for example, water, pharmaceutically acceptable organic solvents such as paraffins (e.g. petroleum fractions), vegetable oils (e.g. groundnut or sesame oil), mono- or polyfunctional alcohols (e.g. ethanol or glycerol), carriers such as e.g. natural mineral powders (e.g. kaolins, clays, talc, chalk), synthetic mineral powders (e.g. highly dispersed silicic acid and silicates), sugars (e.g. cane sugar, lactose and glucose), emulsifiers (e.g. lignin, spent sulphite liquors, methylcellulose, starch and polyvinylpyrrolidone) and lubricants (e.g. magnesium stearate, talc, stearic acid and sodium lauryl sulphate). For oral administration the tablets may, of course, contain, apart from the abovementioned carriers, additives such as sodium citrate, calcium carbonate and dicalcium phosphate together with various additives such as starch, preferably potato starch, gelatine and the like. Moreover, lubricants such as magnesium stearate, sodium lauryl sulphate and talc may be used at the same time for the tableting process. In the case of aqueous suspensions the active substances may be combined with various flavour enhancers or colourings in addition to the excipients mentioned above. It is also preferred if the compounds of formula I are administered by inhalation, particularly preferably if they are administered once or twice a day. For this purpose, the compounds of formula I have to be made available in forms suitable for inhalation. Inhalable preparations include inhalable powders, propellant-containing metered-dose aerosols or propellant-free inhalable solutions, which are optionally present in admixture with conventional physiologically acceptable excipients. Within the scope of the present invention, the term propellant-free inhalable solutions also includes concentrates or sterile ready-to-use inhalable solutions. The preparations which may be used according to the invention are described in more detail in the next part of the specification. EXEMPLARY METHODS - INDICATIONS In certain embodiments, the invention relates to a method of treating a disease or condition selected from the group consisting of inflammatory bowel disease, small intestinal bacterial overgrowth (SIBO), eosinophilic gastrointestinal disease (EGID), enteritis, enteropathy associated with seronegative arthropathies, gut dysbiosis, microscopic or collagenous colitis, cholecystitis, cholangitis, pericholangitis, familial adenomatous polyposis associated inflammation (FAP) gastrointestinal cancer, intestinal graft-versus-host disease (intestinal GVHD), celiac enteritis, chronic pouchitis, checkpoint inhibitor related colitis, comprising the step of: administering to a subject in need thereof a therapeutically effective amount of any one of the aforementioned compounds. In certain embodiments, the disease or condition is inflammatory bowel disease. In certain embodiments, the inflammatory bowel disease is colitis, Crohn's disease, ileitis, Celiac disease, nontropical Sprue, enteropathy associated with seronegative arthropathies, gastroenteritis, or pouchitis. In certain embodiments, the disease or condition is Crohn's disease. In certain embodiments, the disease or condition is colitis. In certain embodiments, the disease or condition is ulcerative colitis. In certain embodiments, the invention relates to any one of the aforementioned methods, wherein the subject is a mammal. In certain embodiments, the invention relates to any one of the aforementioned methods, wherein the subject is human. Synthesis The compounds described herein may be prepared by methods known in the art and are exemplified by the following non-limiting descriptions. Unless otherwise stated, all reactions are typically performed under inert atmosphere (for example under Nitrogen). The following abbreviations are used in the text: s.s. = saturated solution ON = overnight List of abbreviations ACN or MeCN CH3CN, acetonitrile AcOH Acetic Acid aq. Aqueous 9-BBN 9-Borabicyclo[3.3.1]nonane BINAP (2,2′-bis(diphenylphosphino)-1,1′-binaphthyl) Boc tert.butoxy carbonyl n_BuLi n-butyllithium CDCl3 deuterated chloroform C6H5N pyridine CO2 carbon dioxide Cs2CO3 cesium carbonate CuCl copper (I) chloride CuI copper (I) iodide CV column volumes DCM dichloromethane DCE 1,2-dichloroethane DIPEA diisopropylethylamine DMAP dimethyl-pyridin-4-yl-amine DMF N,N-dimethylformamide DMSO dimethyl sulfoxide EDTA ethylenediaminetetraacetic acid EtOAc or EA ethyl acetate EtOH Ethanol Et₂O Diethyl Ether FA Formic Acid FC or FCC Flash Chromatography h or hr hour(s) H₂ hydrogen gas H₂O₂ hydrogen peroxide HATU 1-[Bis(dimethylamino)methylene]-1H-1,2,3- triazolo[4,5-b]pyridinium 3-oxide HCl Hydrogen chloride HPLC high performance liquid chromatography KF potassium fluoride KOAc potassium acetate K2CO3 potassium carbonate K3PO4 potassium phosphate LCMS Liquid Chromatography Mass Spectrometry LiHMDS lithium hexamethyl disilazide LiOH lithium hydroxide M Molar MgSO4 Magnesium sulfate MnO2 Manganese dioxide Min minute(s) mL Millilitre MS mass spectrometry MW Micro Wave N Normal (concentration) N2 Nitrogen gas NaBH3CN Sodium cyanoborohydride NaBH4 Sodium borohydride NaH Sodium hydride NaOH Sodium hydroxide Na₂SO₃ Sodium sulfite Na₂SO₄ Sodium sulfate NH₃ Ammonia NH₄Cl Ammonium chloride NH4OH Ammonium hydroxide NaHCO₃ Sodium hydrogen carbonate Na₂CO₃ Sodium carbonate NMR nuclear resonance spectroscopy ON or on Overnight PD/C Palladium on carbon Pd(dppf)Cl₂ cyclopentyl(diphenyl)phosphane dichloromethane dichloropalladium iron Pd(OAc)₂ palladium (II) acetate PE petrol ether pin pinacol PPh₃ triphenylphosphine MeOH Methanol IPA Isopropyl Alcohol Int. Intermediate THF Tetrahydrofuran DIBAL diisobutylaluminium hydride rac racemic RP reversed phase Rpm rounds per minute RT or rt room temperature RTP Room temperature and pressure SFC Supercritical Fluid Chromatography SCX Strong Cation Exchange resin STAB Sodium triacetoxyborohydride TBAB Tetrabutylammonium bromide TBME tert butyl methyl ether TEA triethylamine T3P Propanephosphonic acid anhydride t^ert tertiary TFA trifluoroacetic acid THF tetrahydrofuran T^i(OEt) ₄ titanium tetraethoxide Rt retention time [min] TRIS tris(hydroxymethyl)aminomethane tBuXPhos 2-Di-tert-butylphosphino-2′,4′,6′- triisopropylbiphenyl wt% weight percent sat. Saturated uPLC ultra performance liquid chromatography uL microlitre Ar aromatic Other features and advantages of the present invention will become apparent from the following more detailed Examples which exemplarily illustrate the principles of the invention without restricting its scope. General Unless stated otherwise, all the reactions are carried out in commercially obtainable apparatus using methods that are commonly used in chemical laboratories. Starting materials that are sensitive to air and/or moisture are stored under protective gas and corresponding reactions and manipulations therewith are carried out under protective gas (nitrogen or argon). Analytical Methods LCMS conditions are as follows: System 1 (S1): ACIDIC IPC METHOD Analytical (MET/uPLC/1704) uHPLC-MS were 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 5-100% B (A= 0.1% formic acid in H2O2-H: B= 0.1% formic acid in MeCN) over 1.1 min then 100% B for 0.25 min. A second gradient of 100-5% B was then applied over 0.05 min and held for 0.1 min with an injection volume of 1 µL at a flow rate of 0.9 mL/min. UV spectra were recorded at 215 nm on a Waters Acquity PDA with a spectrum range of 200-400 nm. Mass spectra were obtained using a Waters QDa. Data were integrated and reported using Waters MassLynx and OpenLynx software, retention times (Rt) are reported in min. System 2 (S2): BASIC IPC METHOD Analytical (MET/uPLC/AB2010) (M15) UHPLC-MS were performed in reverse phase using a Waters UPLCTM BEHTM C18 column (2.1 mm × 30 mm, 1.7 μm; temperature 55 °C), with an injection volume of 1 μL at a flow rate of 1.0 mL/min and a gradient of 1 – 100% B over 1.10 min, then 100% B for 0.25 min, where A = 2 mM ammonium bicarbonate in water, buffered to pH 10, and B = acetonitrile. A second gradient of 100 – 1% B was then applied over 0.05 min and held for 0.40 min. UV spectra were recorded at 215 nm; spectrum range: 200 – 400 nm. Mass spectra were obtained using a Waters Quattro Premier XE or a SQD2; ionization mode: electrospray positive or negative. Data were integrated and reported using Waters MassLynx and OpenLynx software, retention times (Rt) are reported in min. System 3 (S3): ACIDIC FINAL METHOD Analytical (MET/uPLC/AB101) uHPLC-MS were 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 5-100% B (A = 0.1% formic acid in H2O; B = 0.1% formic acid in MeCN) over 5.3 min then 100% B for 0.5 min. A second gradient of 100-5% B was then applied over 0.02 min and held for 1.18 min with an injection volume of 1 µL at flow rate of 0.6 mL/min. UV spectra were recorded at 215 nm using a Waters Acquity PDA detector spectrum range: 200-400 nm. Mass spectra were obtained using a Waters SQD or Waters Acquity QDA. Data were integrated and reported using Waters MassLynx and OpenLynx software, retention times (Rt) are reported in min. System 4 (S4): BASIC FINAL METHOD Analytical (MET/uHPLC/AB105) uPLC-MS were 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 min then 100% B for 0.5 min. A second gradient of 100-5% B was then applied over 0.02 min and held for 1.18 min with an injection volume of 1 μL and at flow rate of 0.6 mL/min. UV spectra were recorded at 215 nm using a Waters Acquity photo diode array detector Spectrum range: 200-400 nm. Mass spectra were obtained using a Waters Quattro Premier XE mass detector. Data were integrated and reported using Waters MassLynx and OpenLynx software, retention times (Rt) are reported in min. System 5 (S5): NEUTRAL FINAL METHOD Analytical UHPLC-MS were performed on a Agilent 1260 system using a 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) at 0.8 mL/min over 4.5 min (1%B for 0.25 min, then linear increase until 100%B in 2.25 min, then 100% B for 0.40 min before going back to initial conditions in 0.1 min). Default injection volume was 0.2 µL. UV spectra were recorded at 220 and 254 nm on an Agilent PDA with a spectrum range of 190-400 nm. Mass spectra were obtained using a Agilent 6490A QQQ with either positive or negative electrospray ionisation (Agilent Jet Stream source). Data were exploited using the Agilent MassHunter software suite, retention times (Rt) are reported in min. System 6 (S6): NEUTRAL IPC METHOD 1 Analytical UHPLC-MS were performed on a Agilent 1260 system using a 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) at 0.8 mL/min over 4.2 min (1%B for 0.25 min, then linear increase until 100%B in 2.25 min, then 100% B for 0.40 min before going back to initial conditions in 0.1 min). Default injection volume was 1 µL. UV spectra were recorded at 220 and 254 nm on an Agilent PDA with a spectrum range of 190-400 nm. Mass spectra were obtained using a Agilent 6120B SQ with simultaneous positive and negative electrospray ionisation. Data were exploited using the Agilent OpenLab software, retention times (Rt) are reported in min. System 7 (S7): NEUTRAL IPC METHOD 2 Analytical UHPLC-MS were performed on a Agilent 1260 system using a 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) at 1.0 mL/min over 3.8 min (0.5%B for 0.10 min, then linear increase until 100%B in 1.6 min, then 100% B for 0.40 min before going back to initial conditions in 0.1 min). Default injection volume was 1 µL. UV spectra were recorded at 220 and 254 nm on an Agilent PDA with a spectrum range of 190-400 nm. Mass spectra were obtained using a Agilent 6120B SQ with simultaneous positive and negative electrospray ionisation. Data were exploited using the Agilent OpenLab software, retention times (Rt) are reported in min. System 8 (S8): ACIDIC LATE-ELUTE IPC METHOD Analytical (MET/uPLC/1906) (M12) UHPLC-MS were performed in reverse phase using a Waters UPLCTM CORTECSTM C8 column (2.1 mm × 50 mm, 1.6 μm; temperature: 40 °C), with an injection volume of 1 μL at a flow rate of 0.9 mL/min and a gradient of 5 – 100% B over 1.10 min, then 100% B for 0.30 min, where A = 0.1% formic acid in water, and B = 0.1% formic acid in acetonitrile. A second gradient of 100 – 5% B was then applied over 0.02 min and held for 0.28 min. UV spectra were recorded at 215 nm; spectrum range: 200 – 400 nm. ELS data was collected using a Waters ELS detector when reported. Mass spectra were obtained using a Waters SQD2 or a QDa; ionization mode: electrospray positive or negative. Data were integrated and reported using Waters MassLynx and OpenLynx software, retention times (Rt) are reported in min. Purification methods are as follows: Compounds were purified using one of the following methods: normal or reverse phase automated flash column chromatography on silica or C-18 silica (e.g. Biotage™ Isolera or Selekt instruments); open access reverse phase prep HPLC (methods detailed below, P1–4) and custom developed reverse phase prep HPLC method. Method 1: ACIDIC EARLY ELUTE METHOD (P1) Purifications (P1) LC were performed on a Gilson LC system using a Waters Sunfire C18 column (30 mm × 100 mm, 10 μM; temperature: RT) and a gradient of 10-95% B (A= 0.1% formic acid in H2O; B= 0.1% formic acid in MeCN) over 14.44 min then 95% B for 2.11 min. A second gradient of 95-10% B was then applied over 0.2 min with an injection volume of 1500 μL at flow rate of 40 mL/min. UV spectra were recorded at 215 nm using a Gilson detector. Method 2: ACIDIC STANDARD METHOD (P2) Purifications (P2) LC were performed on a Gilson LC system using a Waters Sunfire C18 column (30 mm × 10 mm, 10 μM; temperature: r.t.) and a gradient of 30-95% B (A= 0.1% formic acid in water; B= 0.1% formic acid in MeCN) over 11.00 min then 95% B for 2.10 min. A second gradient of 95-30% B was then applied over 0.2 min with an injection volume of 1500 μL at flow rate of 40 mL/min. UV spectra were recorded at 215 nm using a Gilson detector. Method 3: BASIC EARLY ELUTE METHOD (P3) Purification (P3) LC were performed in reverse phase using a Waters XBridgeTM C18 column (30 mm × 100 mm, 5 μm; temperature: room temperature), with an injection volume of 1500 μL at a flow rate of 40 mL/min at 10% B for 2.00 min then a gradient of 10 – 95% B over 14.00 min and held for 2.00 min, where A = 0.2% NH4OH in water and B = MeCN. A second gradient of 95 – 10% B was then applied over 0.20 min and held for 1.25 min. UV spectra were recorded at 215 nm. Method 4: BASIC STANDARD METHOD (P4) Purification (P4) LC were performed in reverse phase using a Waters XBridgeTM C18 column (30 mm × 100 mm, 5 μm; temperature: room temperature), with an injection volume of 1500 μL at a flow rate of 40 mL/min at 30% B for 2.00 min then a gradient of 30 – 95% B over 9.50min and held for 1.97 min, where A = 0.2% NH4OH in water and B = MeCN. A second gradient of 95 – 30% B was then applied over 0.33 min and held for 1.65 min. UV spectra were recorded at 215 nm. Chiral Separation Methods: LC Method: Chiral separation on Gilson LC [Column at RT; isocratic eluent; flow rate: 18mL/min; detector wavelength; 215/254 nm; dilution solvent: IPA; injection volume: 100-1000µL] SFC Method: Chiral separation on Waters Thar SFC [Column at 40°C; isocratic eluent; backpressure: 120bar; flow rate: 15mL/min; dilution solvent: MeOH / Acetonitrile; injection volume: 250 µL] NMR Methods are as follows: Method 1, NMR (N1) Unless otherwise stated, ¹H NMR spectra were recorded at 500 MHz, 400 MHz or 250 MHz on either a Bruker Avance III HD 500 MHz spectrometer, Bruker Avance III HD 400 MHz spectrometer or Bruker Avance III HD 250 MHz spectrometer respectively. Chemical shifts, δ, are quoted in parts per million (ppm) and are referenced to the residual solvent peak. The following abbreviations are used to denote the multiplicities and general assignments: s (singlet), d (doublet), t (triplet), q (quartet), dd (doublet of doublets), ddd (doublet of doublet of doublets), dt (doublet of triplets), dq (doublet of quartets), hep (heptet), m (multiplet), pent (pentet), td (triplet of doublets), qd (quartet of doublets), app. (apparent) and br. (broad). Coupling constants, J, are quoted to the nearest 0.1 Hz. Method 2, NMR: (N2) Unless otherwise stated, ¹H NMR spectra were recorded at 300 MHz or 500 MHz on 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 a N2-cooled z-grad broadband CPP BBO probe at 298 K spectrometer respectively. Chemical shifts, δ, are quoted in parts per million (ppm) and are referenced to the residual solvent peak. The following abbreviations are used to denote the multiplicities and general assignments: s (singlet), d (doublet), t (triplet), q (quartet), dd (doublet of doublets), ddd (doublet of doublet of doublets), dt (doublet of triplets), dq (doublet of quartets), hep (heptet), m (multiplet), pent (pentet), td (triplet of doublets), qd (quartet of doublets), app. (apparent) and br. (broad). Coupling constants, J, are quoted to the nearest 0.1 Hz. General synthesis: All the compounds have been synthesised with a purity > 95% unless otherwise specified. Scheme for general route 1a Synthesis of intermediate A1 (R)-N-[(E)-(5-bromo-2,3-difluorophenyl)methylidene]-2-methylpropane-2- sulfinamide (Step B) To a stirring solution of 5-bromo-2,3-difluorobenzaldehyde (25.00 g, 0.113 mol) and (R)-2-methylpropane-2-sulfinamide (15.08 g, 0.124 mol) in anhydrous THF (300 mL) at RT was added titanium(IV) ethoxide (35 mL, 0.170 mol) dropwise. The reaction mixture was stirred at RT for 1 hour and then 40°C for 1.5 hours. The reaction was poured into a mixture of water (300 mL) and EtOAc (200 mL) and stirred vigorously for 10 mins. The suspension was then sonicated and filtered, washing with EtOAc (200 mL). The organic layer was separated, and the aqueous layer extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (2 × 100 mL), dried over MgSO4, and concentrated in vacuo to afford the titled product (33.74 g, 87% Yield) as a white solid. LCMS m/z: 323.9/325.9 [M+H]+, (ESI+), Rt = 1.08 (S1) ¹H 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). Synthesis of intermediate A2 ethyl (3S)-3-(5-bromo-2,3-difluorophenyl)-3-{[(R)-2-methylpropane-2- sulfinyl]amino}propanoate (Step C) Conditions A A stirring suspension of activated zinc dust (26.91 g, 0.411 mol) in anhydrous THF (350 mL) at 65 °C under N₂ was treated dropwise with ethyl 2-bromoacetate (29 mL, 0.257 mol) over 20 mins. The solution was stirred at 65 °C for 1.5 hours then allowed to cool to RT and settle for 30 mins. The organozinc solution was added over 5 minutes to a stirring 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) under N2 at 65°C. The reaction was stirred at 65 °C for 1.5 hours then cooled and poured into a mixture of TBME (400 mL) and 10% citric acid (600 mL). The organic layer was separated, and the aqueous layer extracted with TBME (3 × 150 mL). The combined organic layers were washed with brine (2 × 150 mL), dried over MgSO₄ and concentrated in vacuo to give the crude product. Purification by column chromatography (approx. 300 g silica, 0-70% EtOAc in heptane) afforded the titled product (29.40 g, 55% Yield) as an orange oil. Conditions B To a stirring suspension of activated zinc dust (39.87 g, 0.610 mol) in THF (400 mL) under N2 at RT was added copper (1+) chloride (7.54 g, 76.2 mmol). The suspension was heated at 65°C for 30 mins. The reaction was removed from the heat and ethyl 2- bromoacetate (34 mL, 0.305 mol) was added dropwise over 15 minutes to effect a reflux (caution: very exothermic). Following addition, the reaction mixture was stirred at 65°C for a further 1 hour. The reaction was cooled to -5°C and treated dropwise over 10 mins 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). The reaction was stirred at -5°C for 30 minutes then at 0°C for 45 minutes. The reaction was filtered through celite, washing with TBME (~200 mL). The filtrate was poured into 10% citric acid (300 mL) and the organic layer was separated. The aqueous layer was extracted with TBME (2 x 150 mL) and the combined organic layers were washed with brine (150 mL), dried over MgSO4, and concentrated in vacuo. Purification by column chromatography (340g silica, 20-35% Acetone in heptane) afforded the titled 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) ¹H 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). 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) A solution of 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) in 1,4-Dioxane (110 mL) and Water (8 mL) was degassed for 10 mins. Pd(dppf)Cl₂ (1.57 g, 1.92 mmol) was added and the reaction stirred under N₂ at 100°C for 4 hours. The reaction was cooled, poured into water (400 mL) and extracted with EtOAc (4 × 150 mL). The combined organic layers were washed with brine (2 × 100 mL), dried over MgSO₄ and concentrated to give the crude product. Purifiaction by column chromatography (350 g silica, 10%-100% EtOAc in heptane followed by 0-20% MeOH in EtOAc) afforded the titled product (8.25 g, 44% Yield) as a brown oil. LCMS m/z: 438.4 [M+H]+, (ESI+), Rt = 1.14 (S1) Synthesis of intermediate A4 Step E: ethyl (3S)-3-amino-3-{4,5-difluoro-2',6'-dimethyl-[1,1'-biphenyl]-3- yl}propanoate hydrochloride (Step E) A stirring 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) at RT was treated with HCl (4 M in dioxane, 9.1 mL, 36.5 mmol). The reaction mixture was stirred at RT for 2 h and then concentrated in vacuo. Purification by column chromatography on silica (50 g silica, 0%-40% MeOH in EtOAc) afforded the titled product (7.38 g, 94% Yield) as an orange solid. LCMS m/z: 334.1 [M+H]+, (ESI+), Rt = 0.71 (S1) ¹H 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) Synthesis of Intermediate A5 5-bromo-2-fluoro-3-(trifluoromethyl)benzaldehyde (Step A) To a solution of 4-bromo-1-fluoro-2-(trifluoromethyl)benzene (5.00 g, 20.6 mmol) in THF (39 mL) at -78°C was added LDA (1M in THF, 31 mL, 30.9 mmol) dropwise over 1 hour. After 1 hour at -78°C, DMF (1.6 mL, 20.6 mmol) was added dropwise, the reaction mixture was then stirred at -78 °C for a further 2 hours. The reaction was quenched with NH4Cl (sat aq, 50 mL) at 0 °C and extracted with EtOAc (3 × 60 ml). The combined organic layers were washed with brine (80 mL), dried over MgSO4 and concentrated in vacuo to give a crude residue. Purification by column chromatography (25 g silica, 0-25% EtOAc in heptane) afforded the titled product (2.40 g, 38% Yield) as a yellow oil. LCMS m/z: no mass ion observed, Rt = 0.87, S8 ¹H 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) The intermediates in Table 1 were synthesised according to general scheme 1 as exemplified by intermediate A4 (Steps B-D) using the corresponding starting materials. Diastereomers were either separated during the final purification or by chiral separation methods as required. Intermediates were afforded as the title compound or salt thereof Table 1

Scheme for general route 1b Synthesis of intermediate A11 (R)-N-[(E)-(5-bromo-2-fluoro-3-methylphenyl)methylidene]-2-methylpropane-2- sulfinamide (Step A) Prepared in analogous way to intermediate A1 using 5-bromo-2-fluoro-3- methylbenzaldehyde as starting material. LCMS m/z: 320.1/322.1 [M+H]+, (ESI+), Rt = 1.12 (S1)  ¹H NMR (400 MHz, CDCl3) δ [ppm]: 8.85 (s, 1H), 7.94 (dd, J = 5.6, 2.5 Hz, 1H), 7.49 (dd, J = 6.5, 1.9 Hz, 1H), 2.33 (d, J = 2.2 Hz, 3H), 1.30 (s, 9H). Synthesis of intermediate A12 ethyl (3S)-3-(5-bromo-2-fluoro-3-methylphenyl)-3-{[(R)-2-methylpropane-2- sulfinyl]amino}propanoate (Step B) Prepared in analogous way to intermediate A2, conditions B using intermediate A11 as starting material. 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). Synthesis of intermediate A13 ethyl (3S)-3-amino-3-(5-bromo-2-fluoro-3-methylphenyl)propanoate hydrochloride (Step C) Prepared in analogous way to intermediate A4, conditions B using intermediate A12 as starting material. LCMS m/z: 304.1/306.1 [M+H]+, (ESI+), Rt = 0.57 (S1)  ¹H NMR (400 MHz, DMSO-d6) δ [ppm]: 8.69 (s, 3H), 7.82 – 7.71 (m, 1H), 7.63 – 7.54 (m, 1H), 4.87 – 4.74 (m, 1H), 4.10 – 3.94 (m, 2H), 3.16 (dd, J = 15.9, 6.4 Hz, 1H), 3.05 (dd, J = 16.3, 8.8 Hz, 1H), 2.25 (d, J = 1.5 Hz, 3H), 1.16 – 1.05 (m, 3H). The intermediates in Table 2 were synthesised according to general scheme 1B as exemplified by intermediate A13 (Steps A-C) using the corresponding starting materials. Diastereomers were either separated during the final purification or by chiral separation methods as required. Intermediates were afforded as the title compound or salt thereof Table 2 Scheme for general route 2 Synthesis of Intermediate B1 ethyl (3S)-3-[(2S)-2-{[(tert-butoxy)carbonyl]amino}-4-methylpentanamido]-3-{4,5- difluoro-2',6'-dimethyl-[1,1'-biphenyl]-3-yl}propanoate (Step A) To a stirring 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) was added DIPEA (2.3 mL, 13.0 mmol) followed by HATU (2.31 g, 6.08 mmol). The reaction mixture was stirred for 72 hours at RT. The reaction 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) and stirred for a further 1 hour before being 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 in vacuo to give a crude oil. Purification by column chromatography (50 g silica, 5 ̶ 60 % EtOAc in heptane) afforded the titled product (1.85 g, 70% Yield), as a colourless solid. LCMS m/z: 547.8 [M+H]+, (ESI+), Rt = 0.71 (S2) ¹H NMR (400 MHz, DMSO-d6) δ [ppm]: 8.57 – 8.33 (m, 1H), 7.22 – 7.14 (m, 2H), 7.15 – 7.08 (m, 2H), 7.02 – 6.93 (m, 1H), 6.83 (d, J = 8.2 Hz, 1H), 5.53 (q, J = 7.6 Hz, 1H), 4.02 (qd, J = 7.1, 4.3 Hz, 2H), 3.91 (td, J = 8.7, 6.1 Hz, 1H), 2.83 (d, J = 7.6 Hz, 2H), 1.95 (d, J = 7.7 Hz, 6H), 1.69 – 1.56 (m, 3H), 1.31 (s, 9H), 1.12 (t, J = 6.8 Hz, 3H), 0.88 – 0.83 (m, 6H). Synthesis of Intermediate B2 ethyl (3S)-3-[(2S)-2-amino-4-methylpentanamido]-3-{4,5-difluoro-2',6'-dimethyl- [1,1'-biphenyl]-3-yl}propanoate hydrochloride (Step B) To a stirring solution of ethyl (3S)-3-[(2S)-2-{[(tert-butoxy)carbonyl]amino}-4- methylpentanamido]-3-{4,5-difluoro-2',6'-dimethyl-[1,1'-biphenyl]-3-yl}propanoate (1.85 g, 3.38 mmol) in DCM (15 mL) was added HCl (4 M in dioxane, 3.0 mL, 12.0 mmol). The reaction stirred at RT for 18 hours. The reaction was concentrated in vacuo and the residue dried in a vacuum oven at 40 °C for 2 hours to afford the titled product (1.73 g, 97% Yield) as a white solid. LCMS m/z: 447.6 [M+H]+, (ESI+), Rt = 0.80 (S1) ¹H NMR (400 MHz, DMSO-d6) δ [ppm]: 9.32 – 9.10 (m, 1H), 8.21 (s, 3H), 7.29 – 7.09 (m, 4H), 7.04 – 6.97 (m, 1H), 5.56 (q, J = 7.6 Hz, 1H), 4.03 (qd, J = 7.1, 2.0 Hz, 2H), 3.75 (d, J = 8.4 Hz, 1H), 2.93 (d, J = 7.6 Hz, 2H), 1.96 (d, J = 2.4 Hz, 6H), 1.47 – 1.38 (m, 2H), 1.12 (t, J = 7.1 Hz, 3H), 0.93 – 0.87 (m, 1H), 0.75 (dd, J = 13.0, 5.7 Hz, 6H). (N1) The intermediate in Table 3 were synthesised according to general scheme 2 as exemplified by intermediate B2 (Steps A-B) using the corresponding starting materials. Diastereomers were either separated during the final purification or by chiral separation methods as required. Intermediates were afforded as the title compound or salt thereof Table 3 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 To a solution of intermediate B4 (200 mg, 0.43 mmol) in pyridine (10 mL) was added (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 for 12 hours at RT. The solvent was removed in vacuo to give a residue. The residue was redissolved in EtOAc (25 mL) and washed with NaHCO₃ (sat aq, 25 mL), water (25 mL), dried over MgSO₄ and concentrated in vacuo to afford the titled product (200 mg, 73% Yield), as a light yellow solid. LCMS m/z: 544.2 [M−Boc+H]+, (ESI+), Rt = 3.14 (S6) Synthesis of Intermediate B18 methyl (3S)-3-{4,5-difluoro-2',6'-dimethyl-[1,1'-biphenyl]-3-yl}-3-[(2S)-4-methyl-2- {[(2R)-piperidin-2-yl]formamido}pentanamido]propanoate hydrochloride 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) was added HCl (4 M in dioxane, 0.78 mL, 3.11 mmol). The reaction mixture was stirred at RT for 4 hours. Further HCl (4 M in dioxane, 0.78 mL, 3.11 mmol) was added and the reaction mixture stirred at RT for a further 2 hours. The solvent was removed in vacuo to afford the titled product (180 mg, 100% Yield) as a yellow solid. LCMS m/z: 544.2 [M+H]+, (ESI+), Rt = 2.63 (S6) Synthesis of Intermediate B19 methyl (3S)-3-[(2S)-2-{[(2R)-1-acetylpiperidin-2-yl]formamido}-4- methylpentanamido]-3-{4,5-difluoro-2',6'-dimethyl-[1,1'-biphenyl]-3-yl}propanoate To a solution of methyl (3S)-3-{4,5-difluoro-2',6'-dimethyl-[1,1'-biphenyl]-3-yl}-3- [(2S)-4-methyl-2-{[(2R)-piperidin-2-yl]formamido}pentanamido] (intermediate B18, 180 mg, 0.310 mmol) and DIPEA (0.24 mL, 1.55 mmol) in DCM (5 mL) at RT was added acetyl chloride (0.024 mL, 0.341 mmol) and the reaction stirred for 4 hours at RT. The reaction was then concentrated in vacuo to give the crude residue which was purified by column chromatography (12 g silica, 0–50% EtOAc in heptane, followed by 0-5% MeOH in DCM, followed by 0-2% MeOH in DCM) afforded the titled compound (122 mg, 61% Yield) as a white solid. LCMS m/z: 586.2 [M+H]+, (ESI+), Rt = 2.85 (S6) Scheme for general route 3a Synthesis of intermediate C1 1-fluoro-4-iodo-2,3,5-trimethylbenzene (Step A) To a stirring solution of 4-fluoro-2,3,6-trimethyl-aniline (7.27 g, 42.71 mmol) in MeCN (120 mL) was added CuI (10.6 g, 55.66 mmol) and tert-butyl nitrite (10.0 mL, 84.08 mmol). The solution was stirred at 60°C for 18 hours and then at RT for 48 hours. The reaction mixture was concentrated in vacuo and the residue suspended in EtOAc (100 mL), then filtered. The filtrate was concentrated in vacuo and the residue purified by column chromatography (350 g silica, 0-100% EtOAc in Heptane) afforded the titled product (4.07 g, 33% yield) as an oil. LCMS m/z: no ionisation, (ESI+), Rt = 1.23 (S1)  ¹H 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). Synthesis of intermediate C2 (intermediate 555a) 2-(4-fluoro-2,3,6-trimethylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Step B) 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 pinacol borane (0.31 mL, 2.14 mmol) in anhydrous 1,4-Dioxane (3.5 mL) were added palladium acetate (16.0 mg, 0.07 mmol) and dicyclohexyl-(2-phenylphenyl)phosphane (50.0 mg, 0.14 mmol). The reaction mixture was heated at 80°C for 18 hours. The reaction mixture was concentrated in vacuo and the residue suspended in EtOAc (15 mL). The mixture was filtered, and the filtrate concentrated in vacuo. Purification by column chromatography (10 g silica, 0-100% EtOAc in Heptane) afforded the titled product (181 mg, 86% yield) as a yellow solid. LCMS m/z: no ionisation, (ESI+), Rt = 1.25 (S1)  ¹H 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). Scheme for general route 3b Synthesis of intermediate C3 4,4,5,5-tetramethyl-2-(2,3,6-trimethylphenyl)-1,3,2-dioxaborolane To a degassed suspension of 2-iodo-1,3,4-trimethyl-benzene (0.20 g, 0.813 mmol), B2(pin)2 (310 mg, 1.22 mmol) and potassium acetate (239 mg, 2.44 mmol) in 1,4-Dioxane- Anhydrous (7 mL) was added Pd(dppf)Cl2 (59 mg, 0.0813 mmol). The reaction was heated at 100 °C for 3 hours. The reaction was cooled, sparged with N2 for 2 mins, 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). The reaction mixture was heated at 100 °C for a further 3 hours. The reaction was cooled, diluted with EtOAc (40 mL) and filtered. The filtrate was concentrated in vacuo and the crude purified by column chromatography (25g silica, 0–20% EtOAc in heptane) to afford 4,4,5,5-tetramethyl-2-(2,3,6-trimethylphenyl)-1,3,2- dioxaborolane (86 mg, 0.346 mmol, 43% Yield) as a colourless oil. LCMS m/z: no mass observed, (ESI+), Rt = 1.18 (S1) ¹H 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) The following intermediates were prepared in a manner similar intermediate C3 as outlined in general route 3b, using the corresponding starting materials. Table 4 Scheme for general route 4 Synthesis of intermediate D1 Step A: ethyl (3S)-3-[(2S)-2-{[(tert-butoxy)carbonyl]amino}-4-methylpentanamido]- 3-{4,4'-difluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl}propanoate (Step A) To a stirring solution of ethyl (3S)-3-(5-bromo-2-fluoro-3-methylphenyl)-3-[(2S)-2- {[(tert-butoxy)carbonyl]amino}-4-methylpentanamido]propanoate (5.5 g, 10.6 mmol) and 2- (4-fluoro-2,6-dimethyl-phenyl)-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) was added K₃PO₄ (9.25 g, 42.97 mmol). The mixture was degassed with N₂ for 5 min, followed by the addition of Pd(dppf)Cl₂.DCM (0.83 g, 1.01 mmol). The reaction was stirred at 100°C for 3.5 hours. The mixture was concentrated in vacuo and the residue dissolved in EtOAc (100 mL), washed with water (50 mL) and brine (30 mL). The aqueous phase was further extracted with EtOAc (2 x 50 mL) and the combined organic phases dried over MgSO4 and concentrated in vacuo. Purifiaction by column chromatography (100g silica, 0 – 100% gradient EtOAc in heptane) afforded the titled 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). Synthesis of intermediate D2 ethyl (3S)-3-[(2S)-2-amino-4-methylpentanamido]-3-{4,4'-difluoro-2',5,6'-trimethyl-[1,1'- biphenyl]-3-yl}propanoate hydrochloride (Step B) To a stirring solution of ethyl (3S)-3-[(2S)-2-{[(tert-butoxy)carbonyl]amino}-4- methylpentanamido]-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) was added 4 M HCl in dioxane (11.7 mL, 46.8 mmol). The reaction mixture was stirred at RT for 18 hours. The mixture was concentrated in vacuo to afford the titled 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). The intermediates in Table 5 were synthesised according to general scheme 4 as exemplified by intermediate D2 (Steps A-B) using the corresponding starting materials. Diastereomers were either separated during the final purification or by chiral separation methods as required. Intermediates were afforded as the title compound or salt thereof Table 5

Scheme for general route 5 Synthesis of intermediate E1 ethyl (3S)-3-[(2S)-2-{[(tert-butoxy)carbonyl]amino}-4-methylpentanamido]-3-[2- fluoro-3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]propanoate (Step A) Prepared in analogous way to intermediate C2 using Intermediate B13 as starting material. LCMS m/z: 565.5 [M+Na]+, (ESI+), Rt = 1.21 (S1)  ¹H 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). Synthesis of intermediate E2 ethyl (3S)-3-[(2S)-2-{[(tert-butoxy)carbonyl]amino}-4-methylpentanamido]-3-[5-(2,5- dimethyl-2H-indazol-4-yl)-2-fluoro-3-methylphenyl]propanoate (Step B) Prepared in analogous way to intermediate D1 from Intermediate E1 and 4-bromo-2,5- dimethyl-indazole. LCMS m/z: 583.5 [M+Na]+, (ESI+), Rt = 1.08 (S1)  ¹H NMR (400 MHz, DMSO-d6) δ [ppm]: 8.41 (d, J = 8.2 Hz, 1H), 7.84 (s, 1H), 7.48 (d, J = 8.8 Hz, 1H), 7.27 – 7.21 (m, 2H), 7.16 (d, J = 8.8 Hz, 1H), 6.79 (d, J = 8.5 Hz, 1H), 5.59 – 5.51 (m, 1H), 4.09 (s, 3H), 4.06 – 4.00 (m, 2H), 3.95 – 3.90 (m, 1H), 2.79 (d, J = 7.5 Hz, 2H), 2.30 (s, 3H), 2.21 (s, 3H), 1.50 – 1.41 (m, 1H), 1.29 (s, 9H), 1.25 – 1.18 (m, 2H), 1.16 (t, J = 7.1 Hz, 3H), 0.72 (d, J = 6.6 Hz, 6H). Synthesis of intermediate E3 methyl (3S)-3-[(2S)-2-amino-4-methylpentanamido]-3-[5-(2,5-dimethyl-2H-indazol- 4-yl)-2-fluoro-3-methylphenyl]propanoate (Step C) To a solution of ethyl (3S)-3-[(2S)-2-{[(tert-butoxy)carbonyl]amino}-4-methylpentanamido]- 3-[5-(2,5-dimethyl-2H-indazol-4-yl)-2-fluoro-3-methylphenyl]propanoate (1.5 g, 2.06 mmol) in MeOH (2.5 mL) was added 4M HCl in dioxane (2.5 mL). The reaction mixture was stirred at RT for 1 hour. The reaction mixture was concentrated in vacuo, and the residue partitioned between EtOAc (50 mL) and sat. NaHCO3 solution (15 mL). The organic layer was passed through phase separator and concentrated in vacuo to afford the titled product (804 mg, 67% Yield) as a light brown glassy solid. LCMS m/z: 469.4 [M+Na]+, (ESI+), Rt = 0.76 (S1)  ¹H NMR (500 MHz, DMSO-d6) δ [ppm]: 8.48 (d, J = 8.4 Hz, 1H), 7.87 (s, 1H), 7.48 (dd, J = 9.0, 1.0 Hz, 1H), 7.27 (dd, J = 6.8, 2.3 Hz, 1H), 7.23 (dd, J = 7.0, 2.3 Hz, 1H), 7.17 (d, J = 8.8 Hz, 1H), 5.59 – 5.50 (m, 1H), 4.09 (s, 3H), 3.58 (s, 3H), 3.14 (dd, J = 8.7, 5.6 Hz, 1H), 2.89 – 2.79 (m, 2H), 2.31 (s, 3H), 2.22 (s, 3H), 1.62 – 1.52 (m, 1H), 1.37 – 1.28 (m, 1H), 1.21 – 1.10 (m, 1H), 0.86 – 0.71 (m, 6H). The intermediates in Table 6 were synthesised according to general scheme 5 as exemplified by intermediate E3 (Steps A-C) using the corresponding starting materials. Diastereomers were either separated during the final purification or by chiral separation methods as required. Intermediates were afforded as the title compound or salt thereof Table 6

Scheme for general route 6 Synthesis of Intermediate F1 ethyl (3S)-3-{4,5-difluoro-2',6'-dimethyl-[1,1'-biphenyl]-3-yl}-3-[(2S)-4-methyl-2- [(quinolin-8-yl)formamido]pentanamido]propanoate To a solution of ethyl (3S)-3-[(2S)-2-amino-4-methylpentanamido]-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) in DCM (1.54 mL) were added DIPEA (0.059 mL, 0.339 mmol) and HATU (64 mg, 0.169 mmol). The reaction mixture was stirred for 18 hours. The reaction was concentrated in vacuo, and the residue purified by column chromatography (10g silica, 0–100% EtOAc in heptane) to afford the titled product (59 mg, 64% yield) as a colourless 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) The following intermediates in Table 7 were prepared in a manner similar to intermediate F1 as outlined in general route 6, using the corresponding starting materials. Table 7

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-dihydropyridin-3-yl)formamido]-4-methylpentanamido]propanoate To a solution of methyl 1,4-dimethyl-2-oxo-1,2-dihydropyridine-3-carboxylate (100 mg, 0.497 mmol) in THF (4 mL) was added LiOH.H2O (104 mg, 2.48 mmol) in water (1 mL). The reaction mixture was stirred for 48 hours. The reaction mixture was concentrated in vacuo to afford the intermediate product. The intermediate acid was redissolved in DMF (4 mL) and intermediate B2 (150 mg, 0.311 mmol), DIPEA (190 µL, 1.09 mmol) and HATU (142 mg, 0.373 mmol) were added. The resulting mixture was stirred for 72 hours. The reaction was then quenched with water (10ml) and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo to give the crude residue. Purification by column chromatography (12g Redisep Gold silica, 0–100% EtOAc in heptane) afforded the titled product (20mg, 9% Yield) as a colourless gum. LCMS m/z: 596.4 [M+H]+, (ESI+), Rt = 2.85 (S6) Scheme for general route 7 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-dihydropyridin-3-yl)formamido]pentanamido]propanoate To a degassed suspension of ethyl (3S)-3-(5-bromo-2,3-difluorophenyl)-3-[(2S)-4- methyl-2-[(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)formamido]pentanamido]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), was added Pd(dppf)Cl2 (18 mg, 0.0214 mmol). The reaction mixture was heated at 90°C for 18 hours. The reaction was concentrated in vacuo to afford the crude residue. Purification by column chromatography (10 g silica, 0-100% EtOAc in heptane) afforded the titled product (47 mg, 45% Yield) as an orange oil. LCMS m/z: 622.4/624.3 [M+H]+, (ESI+), Rt = 1.07 (S1) ¹H 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). The following intermediates in Table 8 were prepared in a manner similar to intermediate G1 as outlined in general route 7, using the corresponding starting materials. Table 8

Scheme for general route 8 B2Pin2 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-dihydropyridin-3- yl)formamido]pentanamido]propanoate To a degassed solution of ethyl (3S)-3-(5-bromo-2,3-difluorophenyl)-3-[(2S)-4- methyl-2-[(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)formamido]pentanamido]propanoate (intermediate F6, 100 mg, 0.153 mmol), B2(pin)2 (58 mg, 0.228 mmol) and KOAc (45 mg, 0.459 mmol) in DMF (1 mL) was added Pd(dppf)Cl2 (6.0 mg, 8.20 μmol). The reaction mixture was heated at 80 °C for 3 hours. The reaction mixture was cooled to RT and filtered through a pad of celite washing with excess EtOAc (3 × 5 mL). The filtrate was concentrated in vacuo to afford the titled product (142 mg, 77% Yield) as a dark brown gum. LCMS m/z: 604.6 [M+H]+, (ESI+), Rt = 1.08 (S1) ¹H 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) Synthesis of Intermediate H2 (2S)-4-methyl-2-[(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)formamido]pentanoic acid Prepared using the route as outlined in general route 6, Step B, from hydrolysis of methyl (2S)-4-methyl-2-[(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)formamido]pentanoate. LCMS m/z: 267.2 [M+H]+, (ESI+), Rt = 0.60, S1 ¹H 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) Synthesis of Intermediate H3 ethyl (3S)-3-(5-bromopyridin-3-yl)-3-[(2S)-4-methyl-2-[(1-methyl-2-oxo-1,2- dihydropyridin-3-yl)formamido]pentanamido]propanoate dihydropyridin-3- yl)formamido]pentanamido]propanoate Prepared in analogous way to intermediate B1 starting from intermediate H2 and intermediate A18 in DMF. LCMS m/z: 521.2/523.2 [M+H]+, (ESI+), Rt = 0.79, S1 Synthesis of Intermediate H3B ethyl (3S)-3-[(2S)-4-methyl-2-[(1-methyl-2-oxo-1,2-dihydropyridin-3- yl)formamido]pentanamido]-3-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3- yl]propanoate Prepared in analogous way to intermediate H1 using intermediate H3 as starting material. 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). Synthesis of Intermediate H4 ethyl (3S)-3-[(2S)-2-{[(tert-butoxy)carbonyl]amino}-4-methylpentanamido]-3-[2,3- difluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]propanoate Prepared using the same conditions as intermediate H1 from intermediate B15. 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). Synthesis of Intermediate H5 ethyl (3S)-3-[(2S)-2-{[(tert-butoxy)carbonyl]amino}-4-methylpentanamido]-3-[5-(2,5- dimethyl-2H-indazol-4-yl)-2,3-difluorophenyl]propanoate In a MW vial, a mixture of Pd(dppf)2Cl2 (33.041 mg, 0.04 mmol), K2CO3 (223.673 mg, 1.62 mmol), ethyl (3S)-3-[(2S)-2-{[(tert-butoxy)carbonyl]amino}-4-methylpentanamido]- 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-dimethyl-indazole (204.352 mg, 0.91 mmol) in 1,4- Dioxane (4 mL) and Water (0.5 mL) was degassed for 5 minutes then capped. The reaction was heated at 150⁰C under MW irradiation for 15 minutes. The reaction mixture was filtered through a thiol cartridge washing with excess EtOAc (3 x 10 mL). The solvent of the filtrate was concentrated in vacuo. Purification by column chromatography (25g silica, 0-100% EtOAc in heptane) afforded the titled product (389 mg, 70% Yield) as an oil. LCMS m/z: 587.5 [M+H]⁺, (ESI+), Rt = 1.07 (S1) ¹H 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). Synthesis of Intermediate H6 ethyl (3S)-3-[(2S)-2-amino-4-methylpentanamido]-3-[5-(2,5-dimethyl-2H-indazol-4- yl)-2,3-difluorophenyl]propanoate dihydrochloride Prepared in analogous way to intermediate A4 using intermediate H5 as starting material. LCMS m/z: 487.3 [M+H-HCl]⁺, (ESI+), Rt = 0.75 (S1) ¹H 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). Synthesis of Intermediate H7 {5-[(1S)-1-[(2S)-2-{[(tert-butoxy)carbonyl]amino}-4-methylpentanamido]-3-ethoxy-3- oxopropyl]pyridin-3-yl}boronic acid To a MW vial containing PdCl₂(dppf)₂ (40.0 mg, 0.05 mmol), ethyl (3S)-3-(5-bromopyridin- 3-yl)-3-[(2S)-2-{[(tert-butoxy)carbonyl]amino}-4-methylpentanamido]propanoate (intermediate B12, 0.45 g, 0.601 mmol), bis(pinacolato)diboron (0.23 g, 0.906 mmol) and KOAc (0.18 g, 1.78 mmol) was added 1,4-Dioxane (1.8 mL) and 1 drop of DMF. The reaction mixture was degassed for 5 mins and then heated at 150°C under MW irradiation for 15 minutes. The reaction mixture was filtered through a thiol cartridge and washed with EtOAc (2 x 10 mL), The solvent was removed in vacuo to give a black-brown residue. Purification by column chromatography (10g silica, 75 - 100% EtOAc in heptane) afforded the titled product (200 mg, 42% Yield) as a brown solid. LCMS m/z: 452.3 [M+H]⁺, (ESI+), Rt = 0.65 (S1) ¹H NMR (400 MHz, DMSO-d6) δ [ppm]: 8.65 – 8.61 (m, 1H), 8.61 – 8.57 (m, 1H), 8.52 – 8.41 (m, 1H), 8.01 – 7.91 (m, 1H), 6.87 – 6.77 (m, 1H), 5.75 (s, 2H), 5.25 – 5.15 (m, 1H), 4.08 – 3.95 (m, 2H), 3.95 – 3.91 (m, 1H), 2.91 – 2.81 (m, 2H), 1.54 – 1.44 (m, 1H), 1.32 – 1.29 (m, 9H), 1.26 – 1.21 (m, 2H), 1.13 – 1.08 (m, 3H), 0.89 – 0.77 (m, 6H). Synthesis of Intermediate H8 ethyl (3S)-3-[(2S)-2-{[(tert-butoxy)carbonyl]amino}-4-methylpentanamido]-3-{3',5'- dimethyl-[3,4'-bipyridin]-5-yl}propanoate Conditions A In a pressure vial, a mixture of {5-[(1S)-1-[(2S)-2-{[(tert-butoxy)carbonyl]amino}-4- methylpentanamido]-3-ethoxy-3-oxopropyl]pyridin-3-yl}boronic acid (intermediate H7, 42.5 mg, 0.05 mmol) 4-bromo-3,5-dimethylpyridine hydrochloride (22 mg, 0.0989 mmol), Pd(dppf)2Cl2 (8.0 mg, 9.77 μmol), and K2CO3 (27 mg, 0.195 mmol) in 1,4-Dioxane (0.5 mL) and Water (50 uL) was degassed. The reaction was sealed and heated at 100°C for 1 hour. The reaction mixture was diluted with EtOAc (2 mL) and H2O (2 mL). The organic layer was separated, and the aqueous layer was re-extracted with EtOAc (2 x 1 mL). The combined organic layers were washed with brine (2 mL), dried over Na2SO4, and concentrated in vacuo to obtain a brown oily residue. Purification by reverse phase column chromatography (10g C-18 silica, 10 to 100% MeCN in H2O containing 0.1% formic acid) afforded the titled product (13 mg, 50% Yield) as a brown viscous oil. Conditions B In a pressure vial, {5-[(1S)-1-[(2S)-2-{[(tert-butoxy)carbonyl]amino}-4-methylpentanamido]- 3-ethoxy-3-oxopropyl]pyridin-3-yl}boronic acid (intermediate H7, 250.0 mg, 0.51 mmol), 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-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.1,4-Dioxane (4 mL) and Water (0.4 mL) were added. The reaction was capped and heated at 100⁰C for 3 hours. The reaction mixture was concentrated in vacuo to give a brown residue. Purification by column chromatography (10g silica, 0-100% EtOAc/heptane) afforded the titled product (39mg, 15% yield) a colourless oil and starting material (183mg, 73% recovery). LCMS m/z: 513.3 [M+H]⁺, (ESI+), Rt = 0.72 (S1) ¹H NMR (400 MHz, d3-MeCN) δ [ppm]: 8.58 (d, J = 2.2 Hz, 1H), 8.34 (s, 2H), 8.28 (d, J = 2.0 Hz, 1H), 7.51 (t, J = 2.2 Hz, 1H), 7.39 (d, J = 8.2 Hz, 1H), 5.60 – 5.46 (m, 1H), 5.35 (q, J = 7.3 Hz, 1H), 4.04 (q, J = 7.1 Hz, 2H), 3.98 – 3.90 (m, 1H), 2.96 – 2.82 (m, 2H), 1.98 (s, 6H), 1.65 – 1.54 (m, 1H), 1.48 – 1.39 (m, 2H), 1.32 (s, 9H), 1.14 (t, J = 7.1 Hz, 3H), 0.89 – 0.84 (m, 6H) Synthesis of Intermediate H9 ethyl (3S)-3-[(2S)-2-amino-4-methylpentanamido]-3-{3',5'-dimethyl-[3,4'-bipyridin]- 5-yl}propanoate trihydrochloride To a solution of ethyl (3S)-3-[(2S)-2-{[(tert-butoxy)carbonyl]amino}-4-methylpentanamido]- 3-{3',5'-dimethyl-[3,4'-bipyridin]-5-yl}propanoate (1.04 g, 1.83 mmol) in 1,4-Dioxane (6 mL) was added 4M HCl in dioxane (1.9 mL, 7.6 mmol). Within 5 minutes a gum formed in the flask. Additional 1,4-Dioxane (6 mL) was added and the suspended solid sonicated for 10 minutes before allowing the mixture to stir at RT for 18 hours. The reaction was concentrated in vacuo, azeotroping with DCM (2 x 50 mL) to afford the titled 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) The intermediates in Table 9 were synthesised according to general scheme 8B as exemplified by intermediate H6 using the corresponding starting materials. Diastereomers were either separated during the final purification or by chiral separation methods as required. Intermediates were afforded as the title compound or salt thereof Table 9 S Synthesis of Intermediate I1 tert-butyl (2R)-2-{[(2S)-1-methoxy-4-methyl-1-oxopentan-2- To a stirred solution of 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) in DMF (23 mL) was added HATU (8.40 g, 22.1 mmol). The solution was stirred at RT for 3 hours before the addition of EtOAc (30 mL) and water (20 mL). The organic layer was separated and the aqueous layer re-extracted with EtOAc (3 × 15 mL). The combined organic layers were washed with brine (30 mL), concentrated in vacuo, and purified by column chromatography (50 g silica, TBME in Heptane 0–100%) to afford the titled product (2.30 g, 87% Yield). LCMS m/z: 365.1 [M+H]+, (ESI+), Rt = 0.88, S1 ¹H 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) Synthesis of Intermediate I2 (2S)-2-{[(2R)-1-[(tert-butoxy)carbonyl]pyrrolidin-2-yl]formamido}-4-methylpentanoic acid (Step B) 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) was added 2M aq. LiOH (aq) (20 mL, 40.8 mmol). The reaction mixture was stirred at 45 ^oC for 30 minutes. The solution was cooled, water (10 mL) added, and the mixture concentrated in vacuo to remove the organics. The aqueous was acidified with 1M HCl (aq) until ~pH 3 and the resulting precipitate extracted with DCM (3 × 15 mL). The combined organic layers were concentrated in vacuo to afford the titled product (2.10 g, 95% Yield) as a white solid. LCMS m/z: 351.3 [M+H]+, (ESI+), Rt = 0.75, S1 ¹H 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) 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) To a solution of (2S)-2-{[(2R)-1-[(tert-butoxy)carbonyl]pyrrolidin-2-yl]formamido}-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) in DCM (3 mL) was added DIPEA (152 µL, 0.870 mmol) and HATU (182 mg, 0.479 mmol). The reaction was stirred at RT for 2 hours. The reaction was diluted with DCM (5 mL), washed with water (5 mL), and passed through a phase separator. The solvent was concentrated in vacuo to afford a crude oil. Purification by flash column chromatography (10g silica, 010̶0% EtOAc in heptane) afforded the titled product (314 mg, 98% Yield) as a pale yellow oil. 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) 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)-pyrrolidin-2-yl]formamido}pentanamido]propanoate hydrochloride (Step D) 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) was added HCl (4 M in dioxane, 1.5 mL, 6.00 mmol). The reaction was stirred at RT for 45 minutes. Further HCl (4 M in dioxane, 1.5 mL, 6.00 mmol) was added, and the reaction stirred for a further 15 minutes. The reaction was concentrated in vacuo, triturated with heptane (2 × 5 mL), solvent decanted, and the residue dried in vacuo to afford the titled product (193 mg, 62% Yield) as an off-white powder. LCMS m/z: 594.6 [M+H]+, (ESI+), Rt = 1.05, S1 ¹H 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) Synthesis of Intermediate I5 ethyl (3S)-3-[(2S)-2-{[(2R)-1-acetylpyrrolidin-2-yl]formamido}-4- methylpentanamido]-3-[4-fluoro-2',6'-dimethyl-5-(trifluoromethyl)-[1,1'-biphenyl]-3- yl]propanoate (Step 5) 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)-pyrrolidin-2- yl]formamido}pentanamido]propanoate hydrochloride (100 mg, 0.136 mmol) and DIPEA (38 µL, 0.218 mmol) in DCM (1.2 mL) at 0 °C, was added a stock solution of acetyl chloride (0.1 mL of stock: 120 µL of acetyl chloride in 1 mL of DCM). The reaction was stirred and warmed to RT for 2.5 hours. The reaction was cooled to 0 °C, and re-treated with DIPEA (13 µL, 0.0746 mmol) and acetyl chloride stock (0.05 mL), then allowed to warm to RT for a further 1 hour. The reaction was diluted with DCM (2 mL), quenched with saturated sodium bicarbonate (aq, 3 mL), and the resulting aqueous extracted with DCM (3 mL). The combined organic layers were passed through a phase separator, concentrated in vacuo, and the resulting residue purified by column chromatography (10 g silica, 0–100% EtOAc in heptane) to afford the titled 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) The following intermediates were prepared in a manner similar to intermediate I5 as outlined in general route 6, using the corresponding starting materials

Scheme for general route 10A Synthesis of Intermediate J1 methyl 1-(1-methylazetidin-3-yl)-2-oxo-1,2-dihydropyridine-3-carboxylate (Step A) To a solution of methyl 2-oxo-2H-pyran-3-carboxylate (800 mg, 5.19 mmol) in DMF (10 mL) at 0⁰C was added 1-methylazetidin-3-amine (447 mg, 5.19 mmol) in DMF (10 mL) dropwise. The reaction was stirred at 0⁰C for 1 hour before being warmed to RT. T3P (50% in EtOAc, 4.6 mL, 7.79 mmol) was then added dropwise. The reaction mixture was stirred for 72 hours and then concentrated in vacuo. Purification by column chromatography (55 g, KPNH silica, 0–100% EtOAc in heptane, 0–20% MeOH in EtOAc) afforded the titled product (415 mg, 25% Yield) as a red solid. LCMS m/z: 223.1 [M+H]+, (ESI+), Rt = 0.38 (S1) Synthesis of Intermediate J2 (intermediate 7a) 1-(1-methylazetidin-3-yl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (Step B) To a solution of methyl 1-(1-methylazetidin-3-yl)-2-oxo-1,2-dihydropyridine-3- carboxylate (415 mg, 1.29 mmol) in MeOH (6.9 mL) was added LiOH (2M, aq, 1.3 mL, 2.58 mmol). The reaction was stirred at RT for 2 hours. The reaction mixture was concentrated in vacuo to afford a red solid. Purification by column chromatography (11 g KPNH silica, 0– 100% methanol in EtOAc) afforded the titled 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) Synthesis of intermediate J3 methyl 1-(oxetan-3-yl)-2-oxo-1,2-dihydropyridine-3-carboxylate (Step A) To a solution of methyl 2-oxo-2H-pyran-3-carboxylate (1.00 g, 6.49 mmol) in DMF (33.5 mL) at room temperature was added oxetan-3-amine hydrochloride (0.72 g, 6.56 mmol) and DIPEA (3.4 mL, 19.5 mmol). The reaction mixture was stirred for 1 hour 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. The reaction mixture was concentrated in vacuo, suspended in water (150 mL), and extracted with EtOAc (3 x 50 mL). The combined organic layers contained no product. The aqueous layer was extracted with 4:1 DCM/IPA solution (2 x 60 mL). the combined organic layers were concentrated in vacuo to afford the titled product (352 mg, 24% Yield) as a brown oil. 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) Synthesis of intermediate J4 1-(oxetan-3-yl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (Step B) To a stirred solution of methyl 1-(oxetan-3-yl)-2-oxo-1,2-dihydropyridine-3- carboxylate (352.2 mg, 1.57 mmol) in Methanol (4.5 mL) and THF (65 mL) was added 2 M aq. lithium hydroxide (1.2 mL, 2.4 mmol). The reaction mixture was stirred at room temperature for 72 hours. The reaction mixture was concentrated in vacuo and the resulting residue suspended in water (~20 mL). The suspension was acidified to pH ~ 1 using 2 M aq. HCl and extracted with a 4:1 DCM:IPA solution (3 x 10 mL).The combined organic layers were concentrated in vacuo to afford the titled product (300 mg, 71% Yield) as a light orange solid. LCMS m/z: 196.1 [M+H]⁺, (ESI+), Rt = 1.04 (S3) ¹H 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). Scheme for general route 10B Synthesis of intermediate K1 methyl 1-[2-(dimethylamino)ethyl]-2-oxo-1,2-dihydropyridine-3-carboxylate (Step A) 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), was added (2- bromoethyl)dimethylamine hydrobromide (375 mg, 1.58 mmol).The reaction mixture stirred for 24 hours at RT. The reaction was cooled to RT, filtered through a pad of celite washing with excess EtOAc (100 mL) and DCM (2 × 5 mL). The filtrate was collected and concentrated in vacuo to afford the crude oil. Purification by open access prep HPLC (P4) afforded methyl the titled product (79 mg, 25% Yield) as a brown oil. LCMS m/z: 225.1 [M+H]+, (ESI+), Rt = 0.40 (S1) ¹H 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) Synthesis of intermediate K2 lithium(1+) 1-[2-(dimethylamino)ethyl]-2-oxo-1,2-dihydropyridine-3-carboxylate (Step B) LiOH (2M, aq, 900 µL, 1.80 mmol) was added to a solution of methyl 1-[2- (dimethylamino)ethyl]-2-oxo-1,2-dihydropyridine-3-carboxylate (79 mg, 0.333 mmol) in MeOH (190 µL) and THF (1.9 mL), and stirred at RT for 5 hours. The reaction was concentrated in vacuo, drying in a vacuum oven overnight to afford the titled product (108 mg, 100% Yield) as a colourless solid. LCMS m/z: 211.2 [M+H]+, (ESI+), Rt = 0.19 (S1) ¹H 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) The following intermediates were prepared in a manner similar to intermediate K2 as outlined in general route 10B, using the corresponding starting materials Synthesis of intermediate K5 methyl 1-[3-(dimethylamino)propyl]-2-oxo-1,2-dihydropyridine-3-carboxylate To a stirred suspension of methyl 2-hydroxypyridine-3-carboxylate (3.00 g, 19.6 mmol) and K₂CO₃ (6.90 g, 49.9 mmol) in acetone (60 mL) was added 3- dimethylaminopropyl chloride hydrochloride (3.36 g, 21.26 mmol). The reaction was heated at 60^⁰C for 5 hours and then room temperature for 72 hours. Sodium iodide (2.0 g, 13.34 mmol) was added to the reaction mixture which was then stirred at 60^⁰C for a further 2 hours. Another portion of 3-dimethylaminopropyl chloride hydrochloride (2 g, 12.7 mmol) was added and stirring at 60^⁰C continued for a further 10 hours. The mixture was filtered through celite and the filtrate concentrated in vacuo to give a yellow oil. The oil was dissolved in DCM (30 mL) and washed with water (30 mL), dried over sodium sulfate and concentrated in vacuo to give a yellow oil. The oil was then dissolved in ethyl acetate (15 mL) and diluted with heptane (15 mL), the resulting solid was filtered. The filtrate was concentrated in vacuo to afford the titled product (2.01 g, 36% yield, 83% purity) as a yellow oil. LCMS m/z: 499.3 [2M+Na]⁺, (ESI+), Rt = 0.40 (S2) Synthesis of intermediate K6 lithium (1+) 1-[3-(dimethylamino)propyl]-2-oxo-1,2-dihydropyridine-3-carboxylate Prepared in analogous way to intermedediate K2 using intermediate K5. 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). Scheme for general route 10C Synthesis of intermediate K7 methyl 5-chloro-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxylate To a solution of 5-chloro-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid (0.528 g, 2.81 mmol) in DCM (10ml) was added 1 M thionyl chloride in DCM (7.04 mL, 7.04 mmol) dropwise. The reaction mixture was heated to reflux for 3 hours. The reaction mixture was cooled to room temp and methanol (0.57 mL, 14.07 mmol) was added. After 30 minutes the reaction mixture was concentrated in vacuo to afford the titled product (560mg, 88% yield) as a solid. LCMS m/z: 202.1 [M+H]⁺, (ESI+), Rt = 0.56 (S1) ¹H NMR (400 MHz, CDCl₃) δ [ppm]: 8.09 (s, 1H), 3.88 (s, 3H), 2.50 (s, 3H). Synthesis of intermediate K8 methyl 5-chloro-6-methyl-2-(prop-2-en-1-yloxy)pyridine-3-carboxylate To a stirred suspension of methyl 5-chloro-6-methyl-2-oxo-1,2-dihydropyridine-3- carboxylate (550 mg, 2.73 mmol) and K2CO3 (943 mg, 6.82 mmol) in Acetone (12 mL) and acetonitrile (10 mL) was added 3-bromoprop-1-ene (0.59 mL, 6.82 mmol). The reaction was stirred at 60^⁰C for 48 hours. The reaction mixture was filtered and washed with acetone (25 mL). The organic reaction mixture was concentrated in vacuo to afford the titled product (715mg, 40% pure, 43% yield) as an oil. LCMS m/z: 242.1 [M+H]⁺, (ESI+), Rt = 1.08 (S1) Synthesis of intermediate K9 methyl 5-chloro-6-methyl-2-oxo-1-(prop-2-en-1-yl)-1,2-dihydropyridine-3- carboxylate A solution of methyl 5-chloro-6-methyl-2-(prop-2-en-1-yloxy)pyridine-3-carboxylate (0.715 g, 1.18 mmol) and palladium (II) dichloride (10.493 mg, 0.06 mmol) in dry xylene (2mL) was stirred at 130°C for 16 hours. The reaction mixture was filtered and washed with ethyl acetate (10ml). The solvent was removed in vacuo to give an oil. Purification by column chromatography (10g silica, 10-80% ethyl acetate in heptane) afforded the titled product (336 mg, 93% pure, 109% Yield) as an oil. 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). Synthesis of intermediate K10 methyl 5-chloro-6-methyl-2-oxo-1-(2-oxoethyl)-1,2-dihydropyridine-3-carboxylate To a solution of methyl 5-chloro-6-methyl-2-oxo-1-(prop-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) was added dipotassium;dioxido(dioxo)osmium;dihydrate (50.312 mg, 0.14 mmol) and sodium periodate (876.207 mg, 4.1 mmol). The mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with water (10ml) and extracted with DCM (3 x 20 mL). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate and concentrated in vacuo to afford the titled product (165 mg, 55% pure, 27% Yield) as a black liquid. LCMS m/z: 244.1 [M+H]⁺, (ESI+), Rt = 0.51 (S1) ¹H 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). Synthesis of intermediate K11 methyl 5-chloro-1-[2-(dimethylamino)ethyl]-6-methyl-2-oxo-1,2-dihydropyridine-3- carboxylate 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 (5ml) was added 2 M dimethylamine in THF (0.82 mL, 1.64 mmol) followed by acetic acid (0.02 mL, 0.33 mmol). After stirring the solution for 1 hour at ambient temperature, STAB (167.02 mg, 0.79 mmol) was added and the reaction mixture was stirred for a further 18 hours. The mixture was diluted with 1,2-dichloroethane (10 ml) and washed with 0.5M sodium hydroxide solution (5 ml), water (5 ml) and dried over Na₂SO₄. The solvent was removed in vacuo to give an oil. Purification by reverse phase chromatography (12g C-18, 10-100% CH3CN in H2O containing 0.1% formic acid) afforded the titled product (65 mg, 36% Yield) as an oil. LCMS m/z: 273.2 [M+H]⁺, (ESI+), Rt = 0.39 (S1) ¹H 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). Synthesis of intermediate K12 5-chloro-1-[2-(dimethylamino)ethyl]-6-methyl-2-oxo-1,2-dihydropyridine-3- carboxylic acid hydrochloride 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) at 45°C was added 2M aq. lithium hydroxide monohydrate (0.16 mL, 0.330 mmol). The reaction was stirred for 1 hour then acidified with 1N HCl to pH2. The solvent was removed in vacuo to afford the titled product (68mg, 98% yield). LCMS m/z: 259.1 [M+H-HCl]⁺, (ESI+), Rt = 0.31 (S2) Scheme for general route 10D Synthesis of intermediate K13 ethyl 2-{[3-(dimethylamino)propyl]carbamoyl}acetate To a solution of N,N-dimethylpropane-1,3-diamine (0.7 g, 6.85 mmol) and triethylamine (1.91 mL, 13.7 mmol) in DCM (6.0391 mL) at 0⁰C was added ethyl 3- chloro-3-oxopropanoate (1.14 mL, 8.91 mmol) dropwise. The reaction allowed to warm to RT and stirred for an additional 5 minutes. The reaction mixture was filtered and the filtrate was concentrated in vacuo to afford the titled 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). Synthesis of intermediate K14 ethyl 1-[3-(dimethylamino)propyl]-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3- carboxylate To a solution of ethyl 2-{[3-(dimethylamino)propyl]carbamoyl}acetate (2.36 g, 5.89 mmol) in THF (10 mL) was added (E)-4-ethoxy-1,1,1-trifluoro-but-3-en-2-one (1.01 mL, 7.07 mmol) and DBU (0.93 mL, 6.19 mmol). The reaction mixture was stirred at RT for 66 hours. The reaction mixture was diluted with EtOAc (75 mL) and water (100 mL). The organic layer was separated, and the aqueous layer was re-extracted with EtOAc (4 x 75 mL). The combined organic layers were washed with brine (50 mL) then passed through a phase separator and concentrated in vacuo to give a blood-red residue. Purification by column chromatography (10g Kp-NH silica, 0-100% EtOAc in heptane) afforded the titled product (0.25 g, 13% Yield) as a light brown oil. 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). Synthesis of intermediate K15 1-[3-(dimethylamino)propyl]-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxylic acid hydrochloride 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) at 45 °C was added 2 M aq. lithium hydroxide hydrate (0.53 mL, 1.05 mmol). The reaction mixture was stirred for 1 hour. The mixture was acidified to pH4 using 1N aq. HCl. The reaction mixture was concentrated in vacuo to afford the titled product (230mg, 100% yield) as a light brown solid. LCMS m/z: 293.2 [M+H]⁺, (ESI+), Rt = 0.32 (S1) The following intermediates were prepared in a manner similar to intermediate K6 as outlined in general route 10D, using the corresponding starting materials Synthesis of intermediate K17 ethyl 2-[(3-{[(tert-butoxy)carbonyl]amino}-3-methylbutyl)carbamoyl]acetate Prepared in analogous way to intermediate K4 using tert-butyl N-(4-amino-2-methylbutan- 2-yl)carbamate hydrochloride and ethyl 3-chloro-3-oxo-propanoate LCMS m/z: 339.3 [M+Na]⁺, (ESI+), Rt = 0.76 (S1) ¹H 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) Synthesis of intermediate K18 ethyl 1-(3-{[(tert-butoxy)carbonyl]amino}-3-methylbutyl)-2-oxo-6-(trifluoromethyl)- 1,2-dihydropyridine-3-carboxylate 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) was added (E)-4- ethoxy-1,1,1-trifluoro-but-3-en-2-one (400 uL, 2.81 mmol) and DBU (370 uL, 2.47 mmol). The reaction mixture was heated at 50ºC for 2 hours. The reaction mixture was concentrated in vacuo and then re-suspended in EtOAc (40 mL) and washed successively with brine (30 mL), sat. aq. NH4Cl solution (30 mL) and brine (30 mL). The organic layer was dried over MgSO4 and concentrated in vacuo to give a 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 110ºC for 1 hour. The reaction mixture was cooled to RT then diluted with EtOAc (10 mL) and washed successively with brine (25 mL), sat. aq. NaHCO3 solution (25 mL) and brine (25 mL). The organic layer was dried over MgSO4 and concentrated in vacuo to give a dark red oil. Purification by column chromatography (10g silica, 0 - 55 % EtOAc in heptane) afforded the titled 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) ¹H 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). Synthesis of intermediate K19 ethyl 1-(3-amino-3-methylbutyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxylate hydrochloride 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) was added 4 M HCl in dioxane (2.0 mL, 8.00 mmol). The reaction mixture was stirred at RT for 3 hours. The reaction mixture was concentrated in vacuo to afford the titled 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) ¹H 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). Synthesis of intermediate K20 Synthesis of intermediate ethyl 1-[3-(dimethylamino)-3-methylbutyl]-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3- carboxylate To a solution of ethyl 1-(3-amino-3-methylbutyl)-2-oxo-6-(trifluoromethyl)-1,2- dihydropyridine-3-carboxylate hydrochloride (306 mg, 0.858 mmol) and triethylamine (0.3 mL, 2.15 mmol) in DCE (5 mL) 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 then STAB (1.00 g, 4.72 mmol) was added. The reaction mixture was stirred at RT for 24 hours then heated at 40ºC 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 sat. aq. NaHCO3 solution (15 mL). The organic layer was separated and the aqueous layer was further extracted with DCM (2 x 15 mL). The combined organic layers were washed with brine (20 mL), dried over MgSO4 and concentrated in vacuo to afford the titled product (258 mg, 85% pure, 73% Yield) as a pale yellow oil. LCMS m/z: 349.1 [M+H]⁺, (ESI+), Rt = 0.84 (S2) ¹H 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). Synthesis of intermediate K21 lithium (1+) 1-[3-(dimethylamino)-3-methylbutyl]-2-oxo-6-(trifluoromethyl)-1,2- dihydropyridine-3-carboxylate Prepared in analogous way to intermediate K6, using intermediate K20. Lithium salt isolated, (no acidification of the reaction mixture). LCMS m/z: 321.3 [M+H]⁺, (ESI+), Rt = 0.46 (S1) ¹H NMR (500 MHz, DMSO-d6) δ [ppm]: 8.03 (d, J = 7.3 Hz, 1H), 6.99 (d, J = 7.4 Hz, 1H), 4.08 – 3.95 (m, 2H), 2.16 (s, 6H), 1.76 – 1.65 (m, 2H), 0.99 (s, 6H). Synthesis of intermediate K22 ethyl 2-{[2-(dimethylamino)ethyl]carbamoyl}acetate Prepared in analogous way to intermediate K14 using N,N-dimethylethane-1,2- diamine LCMS m/z: 203.2 [M+H]⁺, (ESI+), Rt = 0.36 (S2) ¹H 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). Synthesis of intermediate K23 ethyl 1-[2-(dimethylamino)ethyl]-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxylate To a suspension of ethyl 2-{[2-(dimethylamino)ethyl]carbamoyl}acetate (intermediate K22, 500 mg, 1.83 mmol) in THF (7 mL) was added DBU (0.3 mL, 2.01 mmol) followed by (3E)-4-methoxybut-3-en-2-one (0.22 mL, 2.16 mmol). The reaction mixture was stirred at RT for 18 hours. Magnesium chloride (200.0 mg, 2.06 mmol) was added and the reaction mixture was stirred at RT for 22 hours and 60 ºC for a further 4 hours. The reaction mixture was concentrated in vacuo to give a residue. The residue was suspended in water (40 mL) and extracted with DCM (3 x 30 mL). The combined organic layers were washed with brine (30 mL) and passed through a phase separator. The solvent was removed in vacuo to give a brown oil. Purification by column chromatography (10g Kp- NH, 0-100% EtOAc in heptane) afforded the titled product (131 mg, 74% pure, 21% Yield) as a colourless oil. LCMS m/z: 253.2 [M+H]⁺, (ESI+), Rt = 0.49 (S2) ¹H 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). Synthesis of intermediate K24 lithium (1+) 1-[2-(dimethylamino)ethyl]-6-methyl-2-oxo-1,2-dihydropyridine-3- carboxylate Prepared in analogous way to intermediate K6 using intermediate K23 as starting material. LCMS m/z: 225.2 [M+H]⁺, (ESI+), Rt = 0.21 (S2) ¹H NMR (500 MHz, DMSO-d6) δ [ppm]: 8.05 (d, J = 7.3 Hz, 1H), 6.28 (d, J = 7.3 Hz, 1H), 4.09 (t, J = 7.1 Hz, 2H), 2.49 – 2.43 (m, 5H), 2.20 (s, 6H). Scheme for general route 10E

Synthesis of intermediate K25 methyl 1-(1-{[(tert-butoxy)carbonyl]amino}-2-methylpropan-2-yl)-2-oxo-1,2- dihydropyridine-3-carboxylate Prepared in analogous way to intermediate J3 using tert-butyl N-(2-amino-2- methylpropyl)carbamate and methyl 2-oxo-2H-pyran-3-carboxylate LCMS m/z: 325.3 [M+H]⁺, (ESI+), Rt = 0.60 (S2) ¹H 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). Synthesis of intermediate K26 methyl 1-(1-amino-2-methylpropan-2-yl)-2-oxo-1,2-dihydropyridine-3-carboxylate hydrochloride 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) was added 4M HCl in dioxane (0.65 mL, 2.60 mmol). The reaction mixture was stirred for 2.5 hours at RT. The solvent was removed in vacuo to afford the titled product (73 mg, 91% pure, 100% Yield) as a beige powder. LCMS m/z: 225.1 [M+H]⁺, (ESI+), Rt = 0.38 (S2) ¹H 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). Synthesis of intermediate K27 methyl 1-[1-(dimethylamino)-2-methylpropan-2-yl]-2-oxo-1,2-dihydropyridine-3- carboxylate 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 uL, 0.29 mmol) in DCE (1.5 mL) at RT was added paraformaldehyde (45 mg, 1.45 mmol) followed by acetic acid (85 uL, 1.48 mmol). The mixture was stirred for 60 minutes then STAB (310 mg, 1.46 mmol) was then added. The reaction was stirred at RT for a further 18 hours. The reaction mixture was diluted with sat. aq. NaHCO3 (5 mL) and then extracted with DCM (2 x 2 mL). The combined organic layers were passed through a phase separator and concentrated in vacuo to give an oil. Purification by column chromatography (12g KP-NH silica, 0- 100% Ethyl acetate in hexane followed by 0 - 20 % MeOH in Ethyl acetate) afforded the titled product (50 mg, 90% pure, 70% Yield) as an orange oil. LCMS m/z: 253.2 [M+H]⁺, (ESI+), Rt = 0.50 (S2) ¹H 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). Synthesis of intermediate K28 lithium (1+) 1-[1-(dimethylamino)-2-methylpropan-2-yl]-2-oxo-1,2-dihydropyridine- 3-carboxylate 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) was added 2 M aq. lithium hydroxide (100 uL, 0.200 mmol). The solution was stirred at room temperature for 2 hours. The solvent was removed in vacuo to afford the titled product (50 mg, 87% pure, 100% Yield) as a white solid. LCMS m/z: 239.1 [M+H]⁺, (ESI+), Rt = 0.31 (S2) The following intermediates were prepared in a manner similar to intermediate K as outlined in general route 10E, using the corresponding starting materials Scheme for general route 10F Synthesis of intermediate L1 methyl 2-oxo-1-(2-oxoethyl)-1,2-dihydropyridine-3-carboxylate; trifluoroacetic acid (Step A) 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), the reaction was stirred at 70 °C for 1 h. The reaction was cooled to RT and stood in a sealed vial overnight. The reaction was concentrated in vacuo, the resulting oil was triturated with DCM (3 × 5 mL) and dried in vacuo to afford a pale brown oil. The oil was re-dissolved in water (125 µL) and TFA (500 µL, 6.53 mmol), the reaction was stirred at 80 °C for 1 hours. The reaction was concentrated in vacuo, the remaining oil was triturated with DCM (3 × 5 mL) and dried in vacuo to afford the titled product (125 mg, 71% Yield) as an oil. LCMS m/z: 193.9 [M+H]+, (ESI+), Rt = 0.29 (S4) Synthesis of intermediate L2 methyl 1-[2-(azetidin-1-yl)ethyl]-2-oxo-1,2-dihydropyridine-3-carboxylate (Step B) To a solution of methyl 2-oxo-1-(2-oxoethyl)-1,2-dihydropyridine-3-carboxylate trifluoracetic acid (125 mg, 0.290 mmol) in DCM (1.4 mL) was added acetic acid (17 µL, 0.290 mmol) and azetidine (29 µL, 0.436 mmol). After 20 minutes STAB (93 mg, 0.439 mmol) was added and the reaction was stirred at room temperature for 90 hours. The reaction mixture was diluted with MeOH and purified using an SCX cartridge (1 g), eluting with NH₃ in MeOH (3.5 M) to afford the titled product (32 mg, 46% Yield) as a dark orange/brown gum. 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) Synthesis of intermediate L3 lithium(1+) 1-[2-(azetidin-1-yl)ethyl]-2-oxo-1,2-dihydropyridine-3-carboxylate (Step C) To a solution of methyl 1-[2-(azetidin-1-yl)ethyl]-2-oxo-1,2-dihydropyridine-3- carboxylate (32 mg, 0.135 mmol) in THF (750 µL) and Methanol (75 µL) was added LiOH 2M, aq, 230 µL, 0.460 mmol). The reaction was stirred at RT for 3.5 hours. The reaction was concentrated and dried in vacuo to afford the titled product (37 mg, 100% Yield) as a yellow solid. LCMS m/z: 223.1 [M+H]+, (ESI+), Rt = 0.18 (S1) ¹H NMR (400 MHz, CDCl₃) δ [ppm]: 8.37 (d, J = 7.1 Hz, 1H), 7.38 (d, J = 6.5 Hz, 1H), 6.25 – 6.19 (m, 1H), 3.95 – 3.87 (m, 2H), 3.13 (t, J = 7.0 Hz, 4H), 2.74 – 2.68 (m, 2H), 2.07 – 1.95 (m, 2H). (N1) The following intermediates were prepared in a manner similar to intermediate L3 as outlined in general route 10F, using the corresponding starting materials Scheme for general route 10g Synthesis of intermediate M1 methyl 1-(3-hydroxypropyl)-2-oxo-1,2-dihydropyridine-3-carboxylate 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) was added 3-bromopropan-1-ol (3.5 mL, 38.7 mmol). The reaction was heated at 60°C for 4 hours. An extra 1 mL of 3- bromopropan-1-ol was added and the reaction was heated to 60°C for a further 3 hours. The mixture was filtered to remove the excess K2CO3 and the filtrate concentrated in vacuo to give crude material as a pale yellow oil. Purification by column chromatography (50g silica, 0 - 30 % MeOH in EtOAc) afforded the titled 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). Synthesis of intermediate M2 methyl 1-(3-{2-azaspiro[3.4]octan-2-yl}propyl)-2-oxo-1,2-dihydropyridine-3- carboxylate In a pressure 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 for 5 minutes at RT. The mixture was cooled to 0°C and treated with methanesulfonyl methanesulfonate (225.0 mg, 1.29 mmol). The reaction was allowed to warm to room and stirred for a further 30 minutes. The reaction mixture was treated further with methanesulfonyl methanesulfonate (50.0 mg, 0.29 mmol) at 0⁰C then stirred for a further 90 minutes at room temperature. The solvent was removed in vacuo to give an oil. The oil was redissolved in DMF (2 mL) and 2-azaspiro[3.4]octane (150.0 mg, 1.35 mmol) and potassium carbonate (300 mg, 2.17 mmol) were added. The reaction mixture was stirred vigorously 50⁰C for 16 hours. The reaction was quenched with ice-cold water (5 mL) and extracted with EtOAc (2 x 5 mL). The combined organic layers were washed with brine (2 x 10 mL), dried over Na2SO4 and concentrated in vacuo. Purification by reverse column chromatography (12g C-18 silica, 10 to 100% MeCN in H2O with 0.1% ammonium hydroxide modifier) afforded the titled product (75 mg, 95% pure, 17% Yield) as a colourless gum. LCMS m/z: 305.3 [M+H]⁺, (ESI+), Rt = 0.63 (S2) ¹H NMR (400 MHz, CDCl3) δ [ppm]: 8.15 (dd, J = 7.2, 2.3 Hz, 1H), 7.63 (dd, J = 6.6, 2.3 Hz, 1H), 6.23 – 6.19 (m, 1H), 4.03 (t, J = 6.9 Hz, 2H), 3.90 (s, 3H), 3.01 (s, 4H), 2.40 (t, J = 6.7 Hz, 2H), 1.80 (p, J = 6.8 Hz, 2H), 1.72 – 1.68 (m, 4H), 1.56 – 1.51 (m, 4H) Synthesis of intermediate M3 1-(3-{2-azaspiro[3.4]octan-2-yl}propyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid Prepared in analogous way to intermediate K15 using intermediate M2. LCMS m/z: 345.2 [M+H]⁺, (ESI+), Rt = 0.44 (S1) ¹H 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). The following intermediates were prepared in a manner similar to intermediate M3 as outlined in general route 10g, using the corresponding starting materials Scheme for general route 10g** Synthesis of intermediate M7 methyl 1-(2-hydroxyethyl)-2-oxo-1,2-dihydropyridine-3-carboxylate Prepared in analogous way to intermediate M1 using methyl 2-hydroxypyridine-3- carboxylate and 2-bromoethanol. LCMS m/z: 220.1 [M+H]⁺, (ESI+), Rt = 0.27 (S2) ¹H 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). Synthesis of intermediate M8 methyl 1-[2-(methanesulfonyloxy)ethyl]-2-oxo-1,2-dihydropyridine-3-carboxylate To a stirring solution methyl 1-[2-(methanesulfonyloxy)ethyl]-2-oxo-1,2- dihydropyridine-3-carboxylate (250.0 mg, 1.26 mmol) in DCM (7 mL) at 0⁰C was added DMAP (16.0 mg, 0.13 mmol) and triethylamine (0.45 mL, 3.23 mmol) followed by dropwise addition of methanesulfonyl chloride (0.15 mL, 1.94 mmol). The reaction mixture was stirred for 45 minutes at 0°C then poured into water (20 mL) and extracted with DCM (3 x 10 mL). The combined organic layers were passed through a phase separator and concentrated in vacuo to afford the titled product (401 mg, 80% pure, 93% Yield) as an orange gum. ¹H 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). Amine displacement of the mesylate of intermediate M8 Conditions A A suspension 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 was diluted with EtOAc (10 mL), filtered and the filtrate was concentrated in vacuo to give an oil. Purification by column chromatography (5g SCX, 0-100% 7M NH3 in MeOH) afforded methyl 2-oxo-1-{2- [3-(trifluoromethoxy)azetidin-1-yl]ethyl}-1,2-dihydropyridine-3-carboxylate (intermediate M9, 126 mg, 54% pure, 32% Yield) as a brown gum. Conditions 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) was added N-ethylethanamine (0.1 mL, 0.97 mmol). The reaction mixture was heated to 60⁰C for 2 hours and then concentrated in vacuo to give a red oil. Purification by column chromatography (5g SCX, 0-100% 7M NH₃ in MeOH) afforded methyl 1-[2-(diethylamino)ethyl]-2-oxo-1,2-dihydropyridine-3- carboxylate (120 mg, 43% Yield) as a red oil. Conditions C To a suspension of methyl 1-[2-(methanesulfonyloxy)ethyl]-2-oxo-1,2- dihydropyridine-3-carboxylate (95%, 200 mg, 0.690 mmol) and triethylamine (0.35 mL, 2.51 mmol) in DMF (3.8 mL) was added 4-(trifluoromethyl)piperidine hydrochloride (1:1) (125.0 mg, 0.66 mmol). The reaction was heated at 60°C for 3 hours. The reaction was cooled and concentrated in vacuo to give an oil. Purification by column chromatography (5g SCX, 0-100% 7M NH3 in MeOH) afforded methyl2-oxo-1-{2-[4-(trifluoromethyl)piperidin-1- yl]ethyl}-1,2-dihydropyridine-3-carboxylate (130 mg, 94% pure, 53% Yield) as an orange oil. Conditions 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) was added K2CO3 (500 mg, 3.62 mmol) and 6-azaspiro[3.5]nonane hydrochloride (250 mg, 1.55 mmol). The mixture was heated at 70°C for 5 hours. The reaction mixture was cooled to room temperature and poured over crushed ice (5 mL) and extracted with ethyl acetate (2 x 5 mL). The combined organic layers were washed with brine (2 x 10 mL), dried over sodium sulphate and concentrated in vacuo to give a gum. Purification by reverse phase column chromatography (12g C-18 silica, 10-100% MeCN in H2O with 0.1% ammonium hydroxide modifier) afforded methyl 1-[2-(6-azaspiro[3.5]nonan-6-yl)ethyl]-2-oxo-pyridine-3-carboxylate (270 mg, 90% pure, 52% Yield) as light orange oil. Synthesis of intermediate M9 methyl 2-oxo-1-{2-[3-(trifluoromethoxy)azetidin-1-yl]ethyl}-1,2-dihydropyridine-3- carboxylate Prepared using conditions A (actual example) with 3-(trifluoromethoxy)azetidine hydrochloride. LCMS m/z: 321.1 [M+H]⁺, (ESI+), Rt = 0.55 (S2) ¹H 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). Synthesis of intermediate M10 lithium (1+) 2-oxo-1-{2-[3-(trifluoromethoxy)azetidin-1-yl]ethyl}-1,2-dihydropyridine- 3-carboxylate Prepared in analogous way to intermediate L3 using intermediate M9. LCMS m/z: 307.1 [M+H]⁺, (ESI+), Rt = 0.26 (S2) ¹H 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). The following intermediates were prepared in a manner similar to intermediate M10 as outlined in general route 10g**, using the corresponding starting materials

Scheme for general route 10h Synthesis of intermediate N1 ethyl 1-(2,2-dimethoxyethyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3- carboxylate To a stirring solution of 2,2-dimethoxyethanamine (2.59 mL, 23.78 mmol) and triethylamine (3.48 mL, 24.97 mmol) in DCM (125 mL) was slowly added ethyl 3-chloro- 3-oxopropanoate (3.04 mL, 23.78 mmol). The reaction mixture was stirred at RT for 45 minutes then approximately half the solvent was removed in vacuo and the resulting precipitate was filtered. The solvent of the filtrate was removed in vacuo to give an oil. The oil was redissolved in DCM (15ml) and DBU (3.73 mL, 24.97 mmol) and (3E)-4-ethoxy- 1,1,1-trifluorobut-3-en-2-one (4.07 mL, 28.53 mmol) were added. The reaction mixture was stirred for 14 hours and then the solvent was removed in vacuo to give an oil. The oil was partitioned between DCM (100 mL) with water (100 mL). The organic layer was separated, and the aqueous layer was further extracted with DCM (2 x 100ml). The combined organic layers were washed with brine (100 mL), passed through a phase separator and concentrated in vacuo to give a reddish-brown oil. Purification by column chromatography (50g silica, 0-30% EtOAc in heptane) afforded the titled product (1.94 g, 95% pure, 24% Yield) as an orange-yellow oil. LCMS m/z: 324.2 [M+H]⁺, (ESI+), Rt = 0.85 (S1) ¹H 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). Synthesis of intermediate N2 ethyl 2-oxo-1-(2-oxoethyl)-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxylate A solution of ethyl 1-(2,2-dimethoxyethyl)-2-oxo-6-(trifluoromethyl)-1,2- dihydropyridine-3-carboxylate (1.94 g, 5.7 mmol) and 4 M HCl (in dioxane) (35.0 mL, 140.0 mmol) was stirred at RT for 20 minutes. The solvent was removed in vacuo to give an oil which was re-treated with 4 M HCl in dioxane (35.0 mL, 140.0 mmol), stirring for 1 hour. The reaction mixture was slowly poured into stirring sat. aq. NaHCO₃ solution (200 mL). The solution was extracted with EtOAc (2 x 150 mL). The combined organic layers were washed with brine (50 mL), passed through a phase separator and concentrated in vacuo to afford the titled product (1.70 g, 82% pure, 88% Yield) as an orange solid. LCMS m/z: 278.1 [M+H]⁺, (ESI+), Rt = 0.73 (S1) ¹H 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). Synthesis of intermediate N3 ethyl 1-(2-{2-azaspiro[3.4]octan-2-yl}ethyl)-2-oxo-6-(trifluoromethyl)-1,2- dihydropyridine-3-carboxylate To a stirring 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) was added 2- azaspiro[3.4]octane (750.0 mg, 6.75 mmol) and DIPEA (2.35 mL, 13.46 mmol) followed by STAB (2.88 g, 13.59 mmol). The reaction was stirred at RT for 18 hours. The reaction mixture was concentrated in vacuo to give an oily residue. Purification by column chromatography (12g KP-NH silica, 0-100% EtOAc in heptane) afforded the titled product (703 mg, 90% pure, 38% Yield) as a yellow oil. LCMS m/z: 373.3 [M+H]⁺, (ESI+), Rt = 0.57 (S1) ¹H NMR (400 MHz, CDCl₃) δ [ppm]: 8.04 (d, J = 7.4 Hz, 1H), 6.67 (d, J = 7.5 Hz, 1H), 4.39 (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). Synthesis of intermediate N4 1-(2-{2-azaspiro[3.4]octan-2-yl}ethyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine- 3-carboxylic acid Prepared in analogous way to intermediate O7 using intermediate N3 as starting material. 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). The following intermediates were prepared in a manner similar to intermediate N4 as outlined in general route 10h, using the corresponding starting materials

Scheme for general route 10j Synthesis of intermediate O1 (3-aminopropoxy)(tert-butyl)dimethylsilane To a solution of 3-aminopropan-1-ol (6.00 g, 79.9 mmol) in DCM (90 mL) at 0⁰C was added triethylamine (13.36 mL, 95.86 mmol) and TBDMSCl (13.244 g, 87.87 mmol). After 5 minutes the reaction was allowed to warm to room temperature and stirred for an additional 18 hours. The reaction mixture washed with water (100 mL) and brine (50 mL). The organic layer was dried over Na₂SO₄ and concentrated in vacuo to afford the titled product (15.30 g, 101% Yield) an as oil. LCMS m/z: 190.2 [M+H]⁺, (ESI+), Rt = 0.57 (S1) ¹H 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). Synthesis of intermediate O2 ethyl 2-({3-[(tert-butyldimethylsilyl)oxy]propyl}carbamoyl)acetate 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) was added ethyl 3-chloro-3- oxopropanoate (5.1 mL, 39.9 mmol). The reaction mixture was stirred at RT for 1 hour. The reaction mixture was diluted with Water and extracted using DCM (2 x 100 mL). The combined organic layers were dried over sodium sulfate and concentrated in vacuo to give a brown oil. Purification by column chromatography (100g silica, 0-100% EtOAc/heptane) afforded the titled 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) ¹H 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). Synthesis of intermediate O3 ethyl 1-{3-[(tert-butyldimethylsilyl)oxy]propyl}-2-oxo-6-(trifluoromethyl)-1,2- dihydropyridine-3-carboxylate To a solution of ethyl 2-({3-[(tert-butyldimethylsilyl)oxy]propyl}carbamoyl)acetate (6.55 g, 16.8 mmol) in THF (60 mL) was added (3E)-4-ethoxy-1,1,1-trifluorobut-3-en-2-one (4.4 mL, 31.1 mmol) and DBU (4.1 mL, 27.3 mmol). The reaction mixture was stirred at RT for 18 hours. The reaction mixture was concentrated in vacuo to give an oil. Purification by column chromatography (50g silica, 0-30% EtOAc in heptane) afforded the titled product (1.83 g, 97% pure, 26% Yield) as an oil. LCMS m/z: 408.2 [M+H]⁺, (ESI+), Rt = 1.25 (S1) ¹H 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). Synthesis of intermediate O4 ethyl 1-(3-hydroxypropyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3- carboxylate 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) at 0⁰C was added 1 M tetrabutylammonium fluoride (11 mL, 10.8 mmol) dropwise. The reaction mixture was stirred at RT for 90 minutes. The reaction mixture was quenched with water (10ml) and extracted with ethyl acetate (3 x 30 mL). The combined organic layers were dried over sodium sulfate and concentrated in vacuo to give an oil. Purification by column chromatography (25g silica, 0-100% EtOAc in heptane) afforded the titled product (1.11 g, 96% pure, 84% Yield) as an oil. LCMS m/z: 294.2 [M+H]⁺, (ESI+), Rt = 0.64 (S1) ¹H 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). Synthesis of intermediate O5 Synthesis of intermediate ethyl 1-[3-(methanesulfonyloxy)propyl]-2-oxo-6-(trifluoromethyl)-1,2- dihydropyridine-3-carboxylate To a stirring 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) at 0⁰C was added 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). The reaction mixture was stirred at 0⁰C for 1 hour. The reaction was poured into water (30 mL) and the organic layer was separated. The aqueous was further extracted with DCM (2 x 20 mL) and the combined organic layers passed through a hydrophobic frit and concentrated in vacuo to afford the titled product (1.52 g, 89% pure, 101% Yield) as an orange gum. LCMS m/z: 372.1 [M+H]⁺, (ESI+), Rt = 0.75 (S1) ¹H 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). Synthesis of intermediate O6 ethyl 1-(3-{2-azaspiro[3.4]octan-2-yl}propyl)-2-oxo-6-(trifluoromethyl)-1,2- dihydropyridine-3-carboxylate In a pressure vial, a suspension of ethyl 1-[3-(methanesulfonyloxy)propyl]-2-oxo-6- (trifluoromethyl)-1,2-dihydropyridine-3-carboxylate (250 mg, 0.599 mmol), 2- azaspiro[3.4]octane (100 mg, 0.899 mmol), K₂CO₃ (0.25 g, 1.80 mmol) and sodium iodide (9.0 mg, 0.0599 mmol) in DMF (5 mL) was heated at 50°C for 2 hours. The reaction mixture was diluted with EtOAc (20 mL) and water (20 mL). The organic layer was separated, and the aqueous layer further extracted with EtOAc (2 x 20 mL). The combined organic layers were dried over Na2SO4 and concentrated in vacuo to give an oil. Purification by column chromatography (10g silica, 0-10% MeOH in DCM) afforded the titled product (108 mg, 98% pure, 46% Yield) as a light brown liquid. LCMS m/z: 387.2 [M+H]⁺, (ESI+), Rt = 0.58 (S1) ¹H NMR (400 MHz, CDCl3) δ [ppm]: 8.04 (d, J = 7.4 Hz, 1H), 6.67 (d, J = 7.5 Hz, 1H), 4.38 (q, J = 7.1 Hz, 2H), 4.17 – 4.04 (m, 2H), 3.08 (s, 4H), 2.53 (t, J = 6.9 Hz, 2H), 1.83 – 1.76 (m, 2H), 1.72 (h, J = 3.0 Hz, 4H), 1.58 – 1.50 (m, 4H), 1.38 (t, J = 0.7 Hz, 3H). Synthesis of intermediate O7 1-(3-{2-azaspiro[3.4]octan-2-yl}propyl)-2-oxo-6-(trifluoromethyl)-1,2- dihydropyridine-3-carboxylic acid 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) at 45°C was added 2 M lithium hydroxide hydrate (0.81 mL, 1.61 mmol). The reaction mixture was stirred for 4 hours. The mixture was acidified to pH4 using 1N aq. hydrochloric acid. The reaction mixture was concentrated in vacuo to afford the titled product (172 mg, 99% yield) as a light brown solid. LCMS m/z: 359.2 [M+H]⁺, (ESI+), Rt = 0.50 (S1) The following intermediates were prepared in a manner similar to intermediate O7 as outlined in general route 10j, using the corresponding starting materials

Scheme for general route 10k Synthesis of intermediate O21 ethyl 2-({4-[(tert-butyldimethylsilyl)oxy]butyl}carbamoyl)acetate Prepared in analogous way to intermediate O2 using 4-[tert-butyl(dimethyl)silyl]oxybutan- 1-amine and ethyl 3-chloro-3-oxopropanoate. ¹H 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). Synthesis of intermediate O22 ethyl 1-{4-[(tert-butyldimethylsilyl)oxy]butyl}-2-oxo-6-(trifluoromethyl)-1,2- dihydropyridine-3-carboxylate Prepared in analogous way to intermediate O3 using intermediate O21. LCMS m/z: 444.2 [M+H]⁺, (ESI+), Rt = 1.27 (S1) ¹H 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). Synthesis of intermediate O23 ethyl 1-(4-hydroxybutyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxylate Prepared in analogous way to intermediate O4 using intermediate O22. LCMS m/z: 330.2 [M+Na]⁺, (ESI+), Rt = 0.69 (S1) Synthesis of intermediate O24 ethyl 2-oxo-1-(4-oxobutyl)-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxylate 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) at 0⁰C was added Dess- Martin periodinane (166 mg, 0.391 mmol). The reaction was stirred at 0⁰C for 10 minutes then RT for 2 hours. The reaction was quenched by addition of 50% sat. aq. sodium thiosulfate/sat. aq. NaHCO3 solution (15ml), vigorously stirring for 10 minutes. The organic layer was separated and washed further with sat NaHCO3 solution (10ml) and dried over MgSO4. The solvent was removed in vacuo to give a brown oil. Purification by column chromatography (10g silica, 0-60% EtOAc in heptane) afforded the titled product (144mg, 72% pure, 104% yield) as an orange gum. 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). 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 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) was added 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). The reaction was stirred at room temperature for 72 hours. The reaction was quenched with a mixture of water (10 mL) and sat. aq. NaHCO3 (10 mL). The reaction mixture was then extracted with DCM (3 x 5 mL). The combined organic layers were concentrated in vacuo to give a residue. Purification by SCX chromatography (5g, eluting with 7M NH3 in MeOH) afforded the titled product (111mg, 95% pure, 83% yield) as a yellow oil. 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). 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 Prepared in analogous way to intermediate O7 using intermediate O25 ¹H NMR (400 MHz, DMSO-d6) δ [ppm]: 8.32 (d, J = 7.5 Hz, 1H), 7.20 (d, J = 7.6 Hz, 1H), 4.15 – 4.02 (m, 2H), 2.97 – 2.85 (m, 3H), 2.38 (t, J = 6.0 Hz, 3H), 2.13 – 2.02 (m, 3H), 1.78 – 1.67 (m, 5H), 1.67 – 1.53 (m, 2H). The following intermediates were prepared in a manner similar to intermediate O26 as outlined in general route 10k, using the corresponding starting materials Scheme for general route 10l

Synthesis of intermediate O28 methyl 1-(4-hydroxybutyl)-2-oxo-1,2-dihydropyridine-3-carboxylate 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) was added 4-bromobutan-1-ol (9.60 g, 62.7 mmol). The reaction mixture was stirred at 60°C for 4 h. Another portion of 4-bromobutan-1-ol (7.00 g, 45.7 mmol) was added to the reaction mixture and was stirred at room temperature for 24 hours. The reaction mixture was filtered through celite and the filtrate concentrated in vacuo to give a yellow oil. Purification by column chromatography 50g silica, 0-100% ethyl acetate in heptane then 0-20% methanol in ethyl acetate) afforded the titled 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). Synthesis of intermediate O29 methyl 1-(4-{2-azaspiro[3.4]octan-2-yl}butyl)-2-oxo-1,2-dihydropyridine-3- carboxylate Prepared in analogous way to intermediate M2 using intermediate O28 and 2- azaspiro[3.4]octane LCMS m/z: 319.4 [M+H]⁺, (ESI+), Rt = 0.49 (S1) Synthesis of intermediate O30 1-(4-{2-azaspiro[3.4]octan-2-yl}butyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid Prepared in analogous way to intermediate O7 using intermediate O29. LCMS m/z: 305.4 [M+H]⁺, (ESI+), Rt = 0.49 (S1) Scheme for general route 11A Synthesis of intermediate P1 methyl 6-[(azetidin-1-yl)methyl]pyridine-2-carboxylate (Step A) 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) at room temperature was added STAB (349 mg, 1.60 mmol). The reaction mixture was stirred at 50 °C for 3 hours. The reaction mixture was quenched with water (10 mL) and then EtOAc (15 mL) was added. The organic layer was separated and the aqueous layer was extracted further with EtOAc (2 x 10 mL). The aqueous phase was basified with a saturated aqueous solution of NaHCO3 to pH9 and extracted with EtOAc (2 x 10 mL). The combined organic layers were passed through a phase separator and concentrated in vacuo. Purification by column chromatography (10g silica, 0-10% MeOH in DCM) afforded the title product (90 mg, 43 % yield) as a colorless oil. LCMS m/z: 206.9 [M+H]+, (ESI+), Rt = 1.60 (S7) Synthesis of intermediate P2 Prepared in analogous way to intermediate L3 using intermediate P1. LCMS m/z: 192.7 [M+H]+, (ESI+), Rt = 0.25 (S6) Scheme for general route 11B Synthesis of intermediate P3 Step A ethyl 6-[(3-fluoroazetidin-1-yl)methyl]pyridine-2-carboxylate (Step A) To a stirred suspension 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 Cs2CO3 (1.00 g, 3.07 mmol) and the resulting mixture stirred at RT for 6 hours under nitrogen in a sealed tube. Further 3-fluoroazetidine hydrochloride (90 mg, 0.81 mmol) was added and stirring continued at RT for 18 hours. The reaction mixture was filtered through celite, washing with EtOAc (50 mL). The filtrate was concentrated in vacuo to give a yellow oil. Purification by column chromatography (10 g silica, 0–100% EtOAc in heptane, then 0–10% MeOH in EtOAc) afforded the titled product (277 mg, 76% yield) as a yellow oil. LCMS m/z: 239.2 [M+H]+, (ESI+), Rt = 0.51 (S2) ¹H 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 Synthesis of intermediate P4 Step B 6-[(3-fluoroazetidin-1-yl)methyl]pyridine-2-carboxylic acid lithium salt To a stirred solution of ethyl 6-[(3-fluoroazetidin-1-yl)methyl]pyridine-2-carboxylate (273 mg, 1.12 mmol) in THF (5 mL) and methanol (0.3 mL) was added 2M LiOH (aq) (620 µL, 1.24 mmol). The reaction mixture was stirred at RT for 1.5 hours. The reaction mixture was concentrated in vacuo to afford the titled product (219 mg, 86% yield) as a brown solid. LCMS m/z: 211.1 [M+H]+, (ESI+), Rt = 0.24 (S2) ¹H 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). The following intermediates were prepared in a manner similar to intermediate P4 as outlined in general route 11c, using the corresponding starting materials Scheme for general route 11C Tributyl(vinyl)tin or vinyl(trifluoro)borate, Pd catalyst, water, THF, MeOH Synthesis of intermediate P5 ethyl 6-ethenylpyridine-2-carboxylate (Step A) To a degassed solution of ethyl 6-bromopyridine-2-carboxylate (1.00 g, 4.35 mmol) in anhydrous 1,4-Dioxane (30 mL) was added tributyl(vinyl)tin (1.5 mL, 5.13 mmol) and palladium triphenylphosphane (0.50 g, 0.433 mmol). The mixture was heated at 100°C for 3 hours. The mixture was cooled, diluted with EtOAc (50 mL) and washed with 1M aq. KF solution (50 mL). The organic layer was separated and the aqueous layer extracted with EtOAc (3 x 20 mL). The combined organic layers were dried over Na2SO4 and concentrated in vacuo. Purification by column chromatography (55 g Sfar Amino-D silica, 0-50% EtOAc in heptane) afforded the titled product (715 mg, 84% Yield) as a yellow free-flowing oil. LCMS m/z: 178.3 [M+H]+, (ESI+), Rt = 0.77 (S1)  ¹H NMR (500 MHz, CDCl3) δ [ppm]: 7.98 (dd, J = 7.7, 1.0 Hz, 1H), 7.79 (t, J = 7.8 Hz, 1H), 7.59 (dd, J = 7.9, 1.0 Hz, 1H), 6.94 (dd, J = 17.6, 10.9 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). Synthesis of intermediate P6 ethyl 6-[2-(dimethylamino)ethyl]pyridine-2-carboxylate (Step B) 2 M dimethylamine (in THF) (1.0 mL, 2.00 mmol) was added to a stirred solution of ethyl 6-ethenylpyridine-2-carboxylate (200 mg, 1.02 mmol) in EtOH (4 mL). The solution was heated at 80°C for 24 hours. The mixture was concentrated in vacuo and the residue purified by reverse phase column chromatography (12 g Sfar C18-silica, 10-100% MeCN in H2O with 0.1% formic acid modifier) to afford the crude product. The crude product was dissolved in EtOAc (2 mL) and washed with sat. NaHCO₃ solution (2 x 3 mL). The organic layer was dried over Na₂SO₄ and concentrated in vacuo to afford the titled product (160 mg, 71% Yield) as a colourless oil. LCMS m/z: 223.2 [M+H]+, (ESI+), Rt = 0.39 (S1)  ¹H 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). Synthesis of intermediate P7 lithium(1+) 6-[2-(dimethylamino)ethyl]pyridine-2-carboxylate (Step C) To a solution of ethyl 6-[2-(dimethylamino)ethyl]pyridine-2-carboxylate (1.72 g, 7.2 mmol) in THF (33 mL) was added 2 M aq. LiOH solution (4.02 mL, 8.05 mmol). The reaction mixture was stirred at RT for 18 hours. The reaction mixture was concentrated in vacuo to afford the titled product (1.5g, 95% pure, 100% yield) as a pale yellow solid. LCMS m/z: 195.2 [M+H]+, (ESI+), Rt = 0.44 (S1)  ¹H 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). The following intermediates were prepared in a manner similar to intermediate P7 as outlined in general route 11c, using the corresponding starting materials

Synthesis of intermediate P8 ethyl 6-ethenyl-5-methylpyridine-2-carboxylate (Step A) To a solution of ethyl 6-bromo-5-methylpyridine-2-carboxylate (350.0 mg, 1.43 mmol) in EtOH (5 mL) was added 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]iron dichloromethane dichloropalladium (58.0 mg, 0.07 mmol). The mixture was degassed with N₂ for 10 mins and then stirred at 80°C for 1 hour. The mixture was filtered and the filtrate concentrated in vacuo to give an oil. Purification by column chromatography (25 g silica, 0-25% EtOAc in heptane) afforded the titled product (211 mg, 77% Yield) as a light 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). Synthesis of intermediate P9 ethyl 6-[2-(dimethylamino)ethyl]-5-methylpyridine-2-carboxylate (Step B) A mixture of ethyl 6-ethenyl-5-methylpyridine-2-carboxylate (211 mg, 1.10 mmol), 2 M dimethylamine in THF (5.5 mL, 11.0 mmol) and AcOH (0.84 mL) were stirred at 100^⁰C via microwave irradiation for 30 minutes. Dimethylamine hydrochloride (450 mg, 5.52 mmol) was added and the mixture stirred at 150^oC for 2 hours via microwave irradiation. The reaction mixture was concentrated in vacuo to give a residue. Purificiation by FCC (25 g silica, 0-100% EtOAc in heptane then 0-10% MeOH in EtOAc) afforded the titled 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). Synthesis of intermediate P10 lithium (1+) 6-[2-(dimethylamino)ethyl]-5-methylpyridine-2-carboxylate (Step C) 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) was added 2 M aq. LiOH (0.48 mL, 0.952 mmol). The mixture was stirred at RT for 1 hour then concentrated in vacuo to afford the titled product (150 mg, 95% Yield) as an orange solid. LCMS m/z: 209.2 [M+H]+, (ESI+), Rt = 0.30 (S1)  ¹H 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). Synthesis of intermediate P11 ethyl 6-(2-methoxyethyl)pyridine-2-carboxylate (Step A) To a stirring solution of ethyl 6-ethenylpyridine-2-carboxylate (350.0 mg, 2.26 mmol) in anhydrous MeOH (10 mL) was added 4 M HCl in 1,4-dioxane (1.12 mL, 4.48 mmol). The reaction mixture was stirred at 80°C for 18 hours. The reaction mixture was adjusted to pH 7 with sat. aq. NaHCO3 solution and then concentrated in vacuo to give a residue. Purification by column chromatography (20 g SCX, 0-100% 7M NH3 in MeOH) afforded the titled product (427 mg, 77% yield) as a yellow oil. LCMS m/z: 210.2 [M+H]+, (ESI+), Rt = 0.62 (S1)  Synthesis of intermediate P12 lithium (1+) 6-(2-methoxyethyl)pyridine-2-carboxylate (Step B) Prepared in analogous way to intermediate L3 using intermediate P11. ¹H NMR (400 MHz, DMSO-d6) δ [ppm]: 7.97 – 7.76 (m, 2H), 7.33 (dd, J = 7.2, 1.6 Hz, 1H), 3.58 (t, J = 6.8 Hz, 2H), 3.17 (s, 3H), 3.05 – 2.86 (m, 2H). Scheme for general route 11d Synthesis of intermediate P13 ethyl 6-(2-hydroxyethyl)pyridine-2-carboxylate (Step A) To a stirring solution of ethyl 6-ethenylpyridine-2-carboxylate (2.5 g, 14.1 mmol) in THF (10 mL) at 0°C was added 0.5 M 9-BBN in THF (85 mL, 42.5 mmol) dropwise over 15 minutes. The reaction was stirred at 0°C for 5 min then allowed to warm to RT and stirred for 22 hours. The reaction mixture was cooled to 0°C and H2O2 (50% in H2O) (1.75 mL, 58.14 mmol) was added dropwise, followed by 2 M NaOH (aq.) (0.35 mL, 0.7 mmol). The mixture was stirred at 0°C for 5 min then allowed to warm to RT. Further H2O2 (50% in H2O) (3.5 mL, 116.3 mmol) and 2 M NaOH (aq.) (0.35 mL, 0.7 mmol) were added at RT. The reaction was quenched with sat. Na2S2O3 (aq.) (30 mL), stirred for 15 minutes at RT and concentrated in vacuo. The residue was diluted with EtOAc (100 mL), water (30 mL) and brine (30 mL), followed by adjustment to pH 8 with sat. NaHCO3 solution (5 mL). The phases were then separated and the aqueous phase extracted with EtOAc (50 mL x 2). The combined organic phases were dried over MgSO₄ and concentrated in vacuo. The residue was purified by reverse phase FCC (30g C-18 silica, 10-100% MeCN:H₂O + 0.1%v/v NH₄OH modifier) to afford the titled product (1.78 g, 64% yield) as a yellow oil. LCMS m/z: 196.1 [M+H]+, (ESI+), Rt = 0.44 (S2)  ¹H NMR (400 MHz, DMSO-d6) δ [ppm]: 7.94 – 7.85 (m, 2H), 7.58 – 7.49 (m, 1H), 4.70 (t, J = 5.3 Hz, 1H), 4.35 (q, J = 7.1 Hz, 2H), 3.81 – 3.72 (m, 2H), 2.95 (t, J = 6.6 Hz, 2H), 1.33 (t, J = 7.1 Hz, 3H). Synthesis of intermediate P14 ethyl 6-(2-{2-azaspiro[3.4]octan-2-yl}ethyl)pyridine-2-carboxylate (Step B) A solution of ethyl 6-(2-hydroxyethyl)pyridine-2-carboxylate (250 mg, 1.27 mmol) in anhydrous DCM (3 mL) was treated with DIPEA (663 uL, 3.8 mmol). The mixture was cooled to 0°C and treated with trifluoromethanesulfonic anhydride (229 uL, 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 stirred for 5 minutes at 0°C and then at RT for 30 minutes. The reaction mixture was concentrated in vacuo to give a residue. Purification by reverse phase FCC (30 g C18 silica, 10-100% MeCN + 0.1%v/v NH4OH) afforded the titled product (220 mg, 46% yield) as a light brown oil. LCMS m/z: 289.2 [M+H]+, (ESI+), Rt = 0.89 (S1)  ¹H 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). Synthesis of intermediate P15 lithium(1+) 6-(2-{2-azaspiro[3.4]octan-2-yl}ethyl)pyridine-2-carboxylate (Step C) Prepared in analogous way to intermediate L3 using intermediate P13. LCMS m/z: 261.2 [M+H]+, (ESI+), Rt = 0.39 (S1)  ¹H 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). The following intermediates were prepared in a manner similar to intermediate P14 as outlined in general route 11d, using the corresponding starting materials Scheme for general route 11e Synthesis of intermediate P16 ethyl 6-(3-oxopropyl)pyridine-2-carboxylate (Step A) A suspension of ethyl 6-bromopyridine-2-carboxylate (5.0 g, 21.7 mmol), prop-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 stirred at 85°C under N₂ for 6 hours, cooled and then concentrated in vacuo. The residue was suspended in water (100 mL) and extracted with EtOAc (4 x 30 mL). The combined organic layers were washed with water (40 mL), brine (2 x 30 mL), dried over MgSO4 and concentrated in vacuo. The residue was purified by FCC (50 g silica, 10%-100% EtOAc in heptane) afforded the titled product (1.72 g, 30% Yield) as an orange oil. LCMS m/z: 208.2 [M+H]+, (ESI+), Rt = 0.55 (S1)  ¹H NMR (400 MHz, DMSO-d6) δ [ppm]: 9.77 (t, J = 1.2 Hz, 1H), 7.93 – 7.84 (m, 2H), 7.55 (dd, J = 7.1, 1.8 Hz, 1H), 4.33 (q, J = 7.1 Hz, 2H), 3.09 (t, J = 7.1 Hz, 2H), 2.93 – 2.86 (m, 2H), 1.32 (t, J = 7.1 Hz, 3H). Synthesis of intermediate P17 ethyl 6-(3-{2-azaspiro[3.4]octan-2-yl}propyl)pyridine-2-carboxylate (Step B) To a stirring solution of ethyl 6-(3-oxopropyl)pyridine-2-carboxylate (135.0 mg, 0.58 mmol) , 2-azaspiro[3.4]octane (77.4 mg, 0.7 mmol) and TEA (0.23 mL, 1.74 mmol) in DCM (4 mL) at RT was added STAB (369 mg, 1.74 mmol). The reaction mixture was heated at 40°C for 1 hour. The reaction was poured into water (30 mL), diluted with sat. aq. NaHCO3 solution (20 mL) and then extracted with DCM (4 x 10 mL). The combined organic layers were dried over MgSO4 and concentrated in vacuo. Purifcation by column chromatography (5g SCX, 0-100% 7M NH3 in MeOH) afforded the titled product (151 mg, 73% Yield) as a pale yellow oil. LCMS m/z: 303.3 [M+H]+, (ESI+), Rt = 0.61 (S1)  ¹H 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). Synthesis of intermediate P18 lithium (1+) 6-(3-{2-azaspiro[3.4]octan-2-yl}propyl)pyridine-2-carboxylate (Step C) Prepared in analogous way to intermediate L3 using intermediate P17. LCMS m/z: 275.2 [M+H]+, (ESI+), Rt = 0.35 (S1)  The following intermediates were prepared in a manner similar to intermediate P18 as outlined in general route 11d, using the corresponding starting materials

Scheme for general route 11f Synthesis of intermediate P22 3-methoxy-1-(2-methylbut-3-yn-2-yl)azetidine (Step A) To a stirred solution of 2-methylbut-3-yn-2-ol (1.2 mL, 11.9 mmol) in anhydrous DCM (1.8 mL) at 0°C was added acetyl chloride (0.95 mL, 13.4 mmol) dropwise. The reaction mixture was stirred at RT for 1 hour. The solvent was removed under vacuum to give 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 then concentrated in vacuo. The residue was dissolved in water (20 mL) and EtOAc (20 mL) and then basified to pH 10-11 with sat. aq. NaHCO3. The phases were separated, and the aqueous phase was extracted with EtOAc (3 x 20 mL). The combined organic phases were concentrated in vacuo to give a residue. Purification by SCX-2 cartridge (20 g), eluting with MeOH (3 CVs), followed by 7N NH3 in MeOH (4 CVs) afforded the titled product (448 mg, 22% yield) as a dark orange oil. 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). Synthesis of intermediate P23 ethyl 6-[3-(3-methoxyazetidin-1-yl)-3-methylbut-1-yn-1-yl]pyridine-2-carboxylate (Step B) To a degassed solution of ethyl 6-bromopyridine-2-carboxylate (722 mg, 3.14 mmol) and 3-methoxy-1-(2-methylbut-3-yn-2-yl)azetidine (445 mg, 2.61 mmol) in anhydrous THF (15 mL) was added CuI (104 mg, 0.546 mmol), Pd(PPh3)2Cl2 (153 mg, 0.218 mmol) and diisopropylamine (1.6 mL, 11.6 mmol) at RT. The reaction mixture was stirred at 70^oC for 20 hours. The reaction mixture was concentrated in vacuo and the residue purified by FCC (50 g Sfar duo, 0-100% EtOAc in heptane) to afford the titled product (513 mg, 58% yield) as a light orange oil. LCMS m/z: 303.1 [M+H]+, (ESI+), Rt = 0.49 (S2)  ¹H 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). Synthesis of intermediate P24 ethyl 6-[3-(3-methoxyazetidin-1-yl)-3-methylbutyl]pyridine-2-carboxylate (Step C) To a solution of Ethyl 6-[3-(3-methoxyazetidin-1-yl)-3-methylbut-1-yn-1-yl]pyridine- 2-carboxylate (512 mg, 1.52 mmol) in EtOH (10 mL) under nitrogen was added 10% Pd/C (205 mg, 0.193 mmol). The reaction mixture was then stirred under H2 for 19 hours. The mixture was filtered through Celite washing with MeOH (30 mL). The filtrate was concentrated in vacuo to give a residue. Purification by FCC (5 g silica, 0-100 % EtOAc in heptane, 0-30 % MeOH in DCM) afforded the titled product (236.0 mg, 40 % Yield) as an amber oil. LCMS m/z: 307.2 [M+H]+, (ESI+), Rt = 2.72 (S4)  ¹H 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). Synthesis of intermediate P25 lithium (1+) 6-[3-(3-methoxyazetidin-1-yl)-3-methylbutyl]pyridine-2-carboxylate (Step D) To a stirring solution of ethyl 6-[3-(3-methoxyazetidin-1-yl)-3-methylbutyl]pyridine-2- carboxylate (236 mg, 0.616 mmol) in anhydrous THF (2 mL) and MeOH (2 mL) was added 2 M aq. LiOH (463 uL, 0.926 mmol). The reaction mixture was stirred at RT for 17 hours. The mixture was concentrated in vacuo then suspended in 1:1 DCM in heptane (20 mL), sonicated and concentrated to afford the titled product (197 mg, 100% Yield) as a tan solid. LCMS m/z: 279.1 [M+H]+, (ESI+), Rt = 0.32 (S2). Scheme for general route 11g Synthesis of intermediate P26 1'-tert-butyl 6-ethyl 1',2',3',6'-tetrahydro-[2,4'-bipyridine]-1',6-dicarboxylate (Step A) 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) was added Na2CO3 (1.38 g, 13.0 mmol) in water (7.5 mL). The mixture was degassed with a N2 stream and then Pd(dppf)2Cl2.DCM (180 mg, 0.217 mmol) was added. The mixture was stirred at 110^oC for 3 hours. The reaction mixture was cooled, filtered and the filtrate concentrated in vacuo. The residue was partitioned between EtOAc (40 mL) and brine (20 mL). The organic layer was separated, dried over MgSO4 and concentrated in vacuo. The residue was purified by FCC (25g silica, 0-30% EtOAc/heptane) to afford the titled product (1.43 g, 99% yield) as a colourless oil. ¹H 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). Synthesis of intermediate P27 ethyl 6-{1-[(tert-butoxy)carbonyl]piperidin-4-yl}pyridine-2-carboxylate (Step B) 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) under nitrogen was added 10% Pd/C (206 mg, 0.19 mmol). The mixture was evacuated and stirred under a H2 atmosphere for 18 hours. The Pd residues were filtered off through Celite and the filtrate concentrated in vacuo to afford the titled product (1.25g, 87% yield) as a colourless oil. LCMS m/z: 357.3 [M+Na]+, (ESI+), Rt = 0.98 (S2)  ¹H 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). Synthesis of intermediate P28 ethyl 6-(piperidin-4-yl)pyridine-2-carboxylate hydrochloride (Step C) To a solution of ethyl 6-{1-[(tert-butoxy)carbonyl]piperidin-4-yl}pyridine-2- carboxylate (1.24 g, 3.71 mmol) in DCM (4 mL) was added 4 M HCl in dioxane (3.7 mL, 14.8 mmol). The solution was stirred at RT for 18 hours. The reaction mixture was concentrated in vacuo to afford the titled product (1.00g, 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). Synthesis of intermediate P29 ethyl 6-(1-methylpiperidin-4-yl)pyridine-2-carboxylate (Step D) To a solution of ethyl 6-(piperidin-4-yl)pyridine-2-carboxylate hydrochloride (500 mg, 1.85 mmol) in EtOH (6 mL) was added 37% aq. formaldehyde solution (0.61 mL, 7.48 mmol). The mixture was stirred for 15 minutes then NaBH₃CN (469.977 mg, 7.48 mmol) was added. The solution was stirred at RT for 2 hours. The reaction was quenched with water (5 mL) and DCM (20 mL) was added. The aqueous layer was basified to pH9 using sat. aq. NaHCO₃ solution. The organic layer was separated, and the aqueous layer was further extracted with DCM (2 x 10mL). The combined organic layers were dried over MgSO₄ and concentrated in vacuo to afford the titled product (440mg, 81% yield) as a pale brown oil. 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 = 7.1 Hz, 3H). Synthesis of intermediate P30 6-(1-methylpiperidin-4-yl)pyridine-2-carboxylic acid (Step E) To a solution of ethyl 6-(1-methylpiperidin-4-yl)pyridine-2-carboxylate (430 mg, 1.73 mmol) in THF (7.5 mL) was added 1 M LiOH (2.6 mL, 2.6 mmol). The reaction was stirred at 40^oC for 2 hours.1N HCl was added until pH8 was achieved (~0.8 mL). The mixture was concentrated in vacuo to afford the titled product (380mg, 90% yield) as a white solid. LCMS m/z: 221.2 [M+H]+, (ESI+), Rt = 0.33 (S1)  ¹H 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). The following intermediates were prepared in a manner similar to intermediate P30 as outlined in general route 11g, using the corresponding starting materials Scheme for general route 12a Synthesis of intermediate Q1 ethyl (3S)-3-{4'-chloro-4-fluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl}-3-[(2S)-2-[(6- fluoropyridin-2-yl)formamido]-4-methylpentanamido]propanoate TEA (0.68 mL, 4.87 mmol) was added to a solution of 6-fluoropyridine-2-carboxylic acid (302 mg, 2.14 mmol) and T3P (50% in DMF) (1.71 mL, 2.92 mmol) in DCM (7 mL) and stirred at RT for 10 mins before the addition of ethyl (3S)-3-[(2S)-2-amino-4- methylpentanamido]-3-{4'-chloro-4-fluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl}propanoate hydrochloride (1.0 g, 1.95 mmol). The reaction was stirred for 3 hours, water (5 mL) was added and the mixture extracted with EtOAc (3 x 15 mL). The combined organic layers were washed with brine (10 mL), dried over MgSO₄ and concentrated in vacuo. The residue was purified by reverse phase FCC (30 g, C18 Silica, 10 - 100% MeCN in water with 0.1% NH₄OH modifier) to afford the titled product (556 mg, 48% Yield) as a white solid. LCMS m/z: 600.3/602.3 [M+H]+, (ESI+), Rt = 1.12 (S2) ¹H NMR (500 MHz, DMSO-d6) δ [ppm]: 8.74 (d, J = 8.4 Hz, 1H), 8.39 (d, J = 8.9 Hz, 1H), 8.16 (q, J = 8.0 Hz, 1H), 7.93 – 7.86 (m, 1H), 7.45 – 7.37 (m, 1H), 7.18 (d, J = 2.2 Hz, 1H), 7.11 (d, J = 2.2 Hz, 1H), 7.00 – 6.87 (m, 2H), 5.61 – 5.45 (m, 1H), 4.57 – 4.42 (m, 1H), 4.17 – 3.82 (m, 2H), 2.86 – 2.67 (m, 2H), 2.29 – 2.21 (m, 3H), 1.93 (s, 3H), 1.83 (s, 3H), 1.61 – 1.32 (m, 3H), 1.07 (t, J = 7.1 Hz, 3H), 0.91 – 0.70 (m, 6H). The following intermediates were prepared in a manner similar to intermediate Q1 as outlined in general route 12a, using the corresponding starting materials

Synthesis of intermediate Q3 Step 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-methylazetidin-1-yl]pyridin-2-yl}formamido)-4- methylpentanamido]propanoate To a solution of ethyl (3S)-3-{4,4'-difluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl}-3- [(2S)-2-[(6-fluoropyridin-2-yl)formamido]-4-methylpentanamido]propanoate (100 mg, 0.171 mmol) in DMF (1 mL) was added K₂CO₃ (71 mg, 0.51 mmol) followed by N,N,3- trimethylazetidin-3-amine dihydrochloride (64 mg, 0.343 mmol). The mixture was heated at 80°C for 18 hours. The reaction mixture was concentrated in vacuo to give a residue. Purification by reverse phase FCC (12 g C18 Silica, 10 - 100% water in MeCN with 0.1% NH4OH modifier) afforded the titled compound (57 mg, 37% Yield) as a yellow glassy solid. LCMS m/z: 678.4 [M+H]+, (ESI+), Rt = 0.94 (S1) Scheme for general route 12b Synthesis of intermediate Q4 lithium (1+) 6-chloropyridine-2-carboxylate (Step A) To a stirring solution of ethyl 6-chloropyridine-2-carboxylate (500 mg, 2.69 mmol) in THF (5 mL) and MeOH (5 mL) was added 2 M aq. LiOH (2 mL, 4 mmol). The reaction was stirred at RT for 1 hour. The reaction mixture was concentrated in vacuo, suspended in 1:1 DCM-heptane (20 mL), sonicated and concentrated in vacuo to afford the titled product (491 mg, 100% Yield) as a white solid. LCMS m/z: 158.1 [M+H]+, (ESI+), Rt = 0.47 (S1) Synthesis of intermediate Q5 ethyl (3S)-3-[(2S)-2-[(6-chloropyridin-2-yl)formamido]-4-methylpentanamido]-3- {4,4'-difluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl}propanoate (Step B) A solution of ethyl (3S)-3-[[(2S)-2-amino-4-methyl-pentanoyl]amino]-3-[2-fluoro-5- (4-fluoro-2,6-dimethyl-phenyl)-3-methyl-phenyl]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 uL, 1.03 mmol) in DMF (5 mL) was stirred at RT for 1.5 hours. The mixture was diluted with EtOAc (15 mL) and water added (25 mL). The phases were separated and aqueous phase extracted with EtOAc (15 mL). The combined organic layers were washed with brine, filtered through a phase separator and concentrated in vacuo. The residue was purified by FCC (0-40 % EtOAc in heptane, Sfar Duo 25 g) to afford the titled product (247 mg, 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). Scheme for general route 12d Synthesis of intermediate Q10 methyl 5-methyl-6-{2-methyl-2,7-diazaspiro[3.5]nonan-7-yl}pyridine-2-carboxylate (Step A) 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) was added Cs2CO3 (1.416 g, 4.35 mmol) and methyl 6-bromo-5-methylpyridine-2-carboxylate (250 mg, 1.09 mmol). The solution was flushed with N2 for 20 mins, 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 RT, and filtered through celite, washing with EtOAc (2 x 10 mL). The filtrate was concentrated in vacuo and the residue purified by FCC (28g Kp-NH silica, 0-100% EtOAc in heptane) to afford the titled product (110 mg, 28 % Yield) as a white solid. LCMS m/z: 290.3 [M+H]+, (ESI+), Rt = 0.56 (S1)  ¹H NMR (400 MHz, DMSO-d6) δ [ppm]: 7.65 – 7.62 (m, 1H), 7.59 – 7.55 (m, 1H), 3.82 (s, 3H), 3.01 – 2.96 (m, 4H), 2.95 (s, 4H), 2.28 (d, J = 0.8 Hz, 3H), 2.23 (s, 3H), 1.82 – 1.74 (m, 4H). Synthesis of intermediate Q11 lithium (1+) 5-methyl-6-{2-methyl-2,7-diazaspiro[3.5]nonan-7-yl}pyridine-2- carboxylate (Step B) 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 (aq.) (0.23 mL, 0.460 mmol) and stirred at RT for 3 hours. The reaction mixture was vigorously concentrated in vacuo and the residue 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 in vacuo to afford the titled product (112 mg, 98 % yield) as a white solid. LCMS m/z: 276.3 [M+H]+, (ESI+), Rt = 0.38 (S1)  ¹H 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). Synthesis of intermediate Q12 methyl 6-[4-(dimethylamino)piperidin-1-yl]-5-methylpyridine-2-carboxylate (Step A) Prepared in analogous way to intermediate Q10 using methyl 6-bromo-5- methylpyridine-2-carboxylate and N,N-dimethylpiperidin-4-amine. 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). Synthesis of intermediate Q13 6-[4-(dimethylamino)piperidin-1-yl]-5-methylpyridine-2-carboxylic acid (Step B) To a solution of methyl 6-[4-(dimethylamino)piperidin-1-yl]-5-methylpyridine-2- carboxylate (80 mg, 0.288 mmol) in THF (3 mL) was added 2 M LiOH (aq.) (0.87 mL, 1.73 mmol). The solution was stirred at 40^oC for 2 hours. The reaction mixture was cooled and acidified to pH5 using 1N HCl. The solvent was removed in vacuo to afford the titled product (76mg, 100% yield) as a colourless gum. LCMS m/z: 264.2 [M+H]+, (ESI+), Rt = 0.33 (S1) The following intermediates were prepared in a manner similar to intermediate Q13 as outlined in general route 12d, using the corresponding starting materials Scheme for general route 12e Synthesis of intermediate Q15 tert-butyl 6-[6-(methoxycarbonyl)-3-methylpyridin-2-yl]-2,6-diazaspiro[3.5]nonane- 2-carboxylate (Step A) Prepared in analogous way to intermediate Q10 using methyl 6-bromo-5- methylpyridine-2-carboxylate and tert-butyl 2,6-diazaspiro[3.5]nonane-2-carboxylate LCMS m/z: 398.3 [M+H]+, (ESI+), Rt = 1.05 (S1)  ¹H 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). Synthesis of intermediate Q16 methyl 6-{2,6-diazaspiro[3.5]nonan-6-yl}-5-methylpyridine-2-carboxylate hydrochloride (Step B) To a solution of tert-butyl 6-[6-(methoxycarbonyl)-3-methylpyridin-2-yl]-2,6- diazaspiro[3.5]nonane-2-carboxylate (166 mg, 0.442 mmol) in DCM (1 mL) was added 4M HCl in 1,4-dioxane (0.442 mL, 1.77 mmol). The solution was stirred at RT for 2 hours. The solvent was concentrated in vacuo to afford the titled product (200mg, 74% yield) as a colourless gum. LCMS m/z: 276.2 [M+H]+, (ESI+), Rt = 0.53 (S1)  ¹H 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). Synthesis of intermediate Q17 methyl 5-methyl-6-{2-methyl-2,6-diazaspiro[3.5]nonan-6-yl}pyridine-2-carboxylate (Step C) 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) was added formaldehyde [37% in water] (0.137 mL, 1.69 mmol). The mixture was stirred for 15 minutes then NaBH3CN (106 mg, 1.69 mmol) was added and the solution stirred at RT for 18 hours. The reaction was quenched with sat. aq. NaHCO3 solution (10 mL) and DCM (20 mL) was added. The organic layer was separated, and the aqueous layer further extracted with DCM (2 x 10mL). The combined organic layers were dried over MgSO₄ and concentrated in vacuo to give a residue. Purification by FCC (10g silica, 0-10% 7M NH3 in MeOH/DCM) afforded the titled product (55 mg, 41% yield) as a colourless oil. LCMS m/z: 290.4 [M+H]+, (ESI+), Rt = 0.56 (S1)  ¹H 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). Synthesis of intermediate Q18 5-methyl-6-{2-methyl-2,6-diazaspiro[3.5]nonan-6-yl}pyridine-2-carboxylic acid (Step D) Prepared in analogous way to intermediate Q13 using intermediate Q17. LCMS m/z: 276.4 [M+H]+, (ESI+), Rt = 0.43 (S1)  Scheme for general route 12f Synthesis of intermediate Q19 ethyl 2-[2-(dimethylamino)ethoxy]-6-(trifluoromethyl)pyridine-3-carboxylate (Step A) To a stirred suspension of ethyl 2-hydroxy-6-(trifluoromethyl)pyridine-3-carboxylate (500 mg, 2.13 mmol) and potassium carbonate (735 mg, 5.32 mmol) in acetone (10 mL) was added (2-chloroethyl)dimethylamine hydrochloride (1:1) (766 mg, 5.32 mmol). The reaction was stirred at 60^⁰C for 18 hours, cooled then filtered and washed with acetone (25 mL). The filtrate was concentrated in vacuo and the residue purified by FCC (25 g silica, 0- 10% MeOH in EtOAc) to afford the titled product (370 mg, 55% yield) as a solid. LCMS m/z: 307.2 [M+H]+, (ESI+), Rt = 0.59 (S1)    ¹H 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). Synthesis of intermediate Q20 (int 110a) 2-[2-(dimethylamino)ethoxy]-6-(trifluoromethyl)pyridine-3-carboxylic acid hydrochloride (Step B) 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) at 45°C was added 2 N aq. LiOH (0.88 mL, 1.76 mmol)/ The reaction mixture was stirred at 45°C for 1 hour. The recation mixture was cooled and acidified with 1 N aq. HCl solution. The solution was concentrated in vacuo to afford the titled product (400 mg, 100% yield) as a white solid. LCMS m/z: 279.1 [M+H]+, (ESI+), Rt = 0.48 (S1)    ¹H NMR (400 MHz, DMSO-d6) δ [ppm]: 7.60 (s, 1H), 7.27 (d, J = 7.2 Hz, 1H), 4.32 (t, J = 6.2 Hz, 2H), 2.58 (t, J = 6.2 Hz, 2H), 2.21 (s, 6H). The following intermediates were prepared in a manner similar to intermediate Q20 as outlined in general route 12f, using the corresponding starting materials Scheme for general route 13 Synthesis of intermediate R1 methyl 2-fluoro-3-(4-methylpiperazin-1-yl)benzoate (Step A) A stirred mixture of methyl 3-bromo-2-fluorobenzoate (1.0 g, 4.29 mmol), 1- methylpiperazine (625 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 stirred at 80^oC for 18 hours. The reaction mixture was cooled to RT, filtered over Celite and washed with EtOAc (30 mL). The filtrate was concentrated in vacuo to give a residue. Purification by column chromatography (25 g silica, 0-100% EtOAc in heptane followed by a 0-15% MeOH in EtOAc) afforded impure product. Further purification by SCX column chromatography (0- 100% 7M NH₃ in MeOH) afforded the titled product (660 mg, 59% yield) as a yellow oil. LCMS m/z: 253.1 [M+H]+, (ESI+), Rt = 0.66 (S2)  ¹H 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). Synthesis of intermediate R2 lithium(1+) 2-fluoro-3-(4-methylpiperazin-1-yl)benzoate (Step B) 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) was added 2 M aq. LiOH (1.5 mL, 3.00 mmol). Te reaction mixture was stirred at RT for 3 hours. Further 2 M aq. LiOH (1.5 mL, 3.00 mmol) was added and the mixture stirred at 50^⁰C for 1 hour. The reaction mixture was concentrated in vacuo to afford the titled product (723 mg, 100% yield) as a yellow solid. ¹H 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). Section for general amines Synthesis of intermediate S1 benzyl 3-{3-azabicyclo[3.1.1]heptan-3-yl}azetidine-1-carboxylate To a solution of 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) in DCM (5.5 mL) at RT was added STAB (450.0 mg, 2.12 mmol). The treaction mixture was stirred at RT for 2 hours. The reaction mixture was poured into water (30 mL) and diluted with sat. aq. NaHCO3 (20 mL). The mixture was extracted with DCM (4 x 10 mL) and the combined organic layers were concentrated in vacuo to give an oil. Purification by SCX (5g, 0-100% 7M NH3 in MeOH) afforded the titled product (217 mg, 93 % yield) as a pale yellow oil. LCMS m/z: 287.3 [M+H]+, (ESI+), Rt = 0.50 (S1) ¹H 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). Synthesis of intermediate S2 3-(azetidin-3-yl)-3-azabicyclo[3.1.1]heptane trifluoroacetic acid salt 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 RT for 18 hours. The catalyst was filtered off through Celite and the solvent was evaporated in vacuo to give the crude product which was dissolved in TFA (0.063 mL, 0.818 mmol) and concentrated in vacuo to afford the titled product (130 mg, 71% Yield) as a white solid. LCMS m/z: 153.2 [M+H]+, (ESI+), Rt = 0.63 (S2) ¹H 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). Scheme for general route 14a Synthesis of intermediate S3 Step A: methyl 7-(propan-2-yl)-5,6,7,8-tetrahydro-1,7-naphthyridine-2-carboxylate (Step A) To a solution of methyl 5,6,7,8-tetrahydro-1,7-naphthyridine-2-carboxylate dihydrochloride (300 mg, 1.13 mmol) and TEA (0.75 mL, 5.66 mmol) in Acetone (0.9 mL) and DCM (5 mL) at RT was added STAB (719 mg, 3.39 mmol). The reaction mixture was stirred at RT for 16 hours. The reaction mixture was diluted with water (15 mL) and sat. NaHCO3 solution (15 mL) and then extracted with DCM (3 x 10 mL). The combined organic layers were dried over MgSO₄ concentrated in vacuo to afford the titled product (330 mg, 100% Yield) as a yellow oil. LCMS m/z: 235.2 [M+H]+, (ESI+), Rt = 0.55 (S2) ¹H 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). Synthesis of intermediate S4 lithium (1+) 7-(propan-2-yl)-5,6,7,8-tetrahydro-1,7-naphthyridine-2-carboxylate (Step B) A solution of methyl 7-(propan-2-yl)-5,6,7,8-tetrahydro-1,7-naphthyridine-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 RT for 2 hours. The reaction mixture was concentrated in vacuo to give a residue. The residue was sonicated in DCM (10 mL) and heptane (1 mL) was added and the suspension concentrated in vacuo to afford the titled product (264 mg, 99% Yield) as a beige powder. LCMS m/z: 221.2 [M+H]+, (ESI+), Rt = 0.28 (S2) ¹H NMR (400 MHz, DMSO-d6) δ [ppm]: 7.73 (d, J = 7.8 Hz, 1H), 7.59 (d, J = 7.8 Hz, 1H), 3.53 (s, 2H), 2.81 (t, J = 6.0 Hz, 3H), 2.72 – 2.65 (m, 2H), 1.00 (d, J = 6.5 Hz, 6H). The following intermediates were prepared in a manner similar to intermediate S4 as outlined in general route 14a, using the corresponding starting materials Scheme for general route 14b Synthesis of intermediate S6 ethyl 7-methyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazine-2-carboxylate (Step A) A solution of ethyl 5H,6H,7H,8H-imidazo[1,2-a]pyrazine-2-carboxylate (400 mg, 2.05 mmol) in anhydrous DCM (6 mL) at RT under N2 was treated with paraformaldehyde (190 mg, 6.12 mmol) followed by AcOH (0.40 mL, 6.99 mmol) and stirred for 10 mins. STAB (1.50 g, 7.08 mmol) was then added in portions over 2 mins and the reaction stirred at RT for 2 hours. Another portion of STAB (1.5 g, 7.08 mmol) was added and stirring continued for 16 hours. The reaction mixture was diluted with sat. aq. aqueous NaHCO3 solution and then extracted with DCM (2 x 6 mL). The combined organic layers were separated and concentrated in vacuo. The residue was purified by reverse phase column chromatography (12g C-18 silica, 10-100% MeCN in water with 0.1% ammonium hydroxide modifier) to afford the titled product (120 mg, 23% Yield) as a colourless oil. LCMS m/z: 210.1 [M+H]+, (ESI+), Rt = 0.38 (S2) ¹H NMR (400 MHz, CDCl3) δ [ppm]: 7.52 (s, 1H), 4.35 (q, J = 7.1 Hz, 2H), 4.05 (t, J = 5.5 Hz, 2H), 3.68 (s, 2H), 2.86 – 2.82 (m, 2H), 2.49 (s, 3H), 1.37 (t, J = 7.1 Hz, 3H). Synthesis of intermediate S7 lithium (1+) 7-methyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazine-2-carboxylate (Step B) To a solution of ethyl 7-methyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazine-2-carboxylate (130 mg, 0.509 mmol) in THF (3 mL) was added 1 M aq. LiOH (563 uL, 0.563 mmol). The reaction mixture was stirred at RT for 4 hours. Another portion of 1 M aq. LiOH (100 uL, 0.1 mmol) was added and the mixture stirred at 40^oC for 2 hours. The reaction mixture was concentrated in vacuo to afford the titled product (116 mg, 100% Yield) as a white powder. LCMS m/z: 182.3 [M+H]+, (ESI+), Rt = 0.17 (S1) ¹H 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). Synthesis of intermediate S8 ethyl 7-cyclopropyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazine-2-carboxylate (Step A) 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) was added (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) portionwise. The reaction was then allowed to stir at RT for 10 minutes before heating to 80°C for 4 hours. The reaction mixture was cooled, concentrated in vacuo. The residue was diluted with water (15 mL) and extracted with DCM (3 x 10 mL). The combined organic layers were dried over MgSO4 and concentrated in vacuo. Purification by column chromatography (10 g silica, 0 - 10% MeOH in EtOAc) afforded the titled product (190 mg, 56% Yield) as a colourless viscous oil. LCMS m/z: 236.1 [M+H]+, (ESI+), Rt = 0.48 (S1) ¹H 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). Synthesis of intermediate S9 lithium (1+) 7-cyclopropyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazine-2-carboxylate (Step B) To a stirred solution of 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) was added 2 M aq. LiOH (0.35 mL, 0.700 mmol). The reaction mixture was stirred at RT for 18 hours. The reaction mixture was concentrated in vacuo to afford the titled product (198 mg, quantitative yield) as a yellow solid. LCMS m/z: 208.1 [M+H]+, (ESI+), Rt = 0.21 (S1) ¹H 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). Scheme for general route 14c Synthesis of intermediate S10 4-bromo-5,7-dimethyl-1H-indazole (Step A) To a mixture of 3-bromo-2,4,6-trimethylaniline (1.0 mL, 6.13 mmol) and potassium acetate (903 mg, 9.2 mmol) in chloroform (10 mL) was added 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 in vacuo then water (50 mL) and EtOAc (100 mL) were added. The organic phase was separated, washed with water (50 mL) and brine (50 mL), passed through a phase separator and concentrated in vacuo. The residue was purified by FCC (25 g silica, 0-100% EtOAc in heptane) to afford the titled product (400 mg, 29% Yield) as a light orange solid. LCMS m/z: 225.1/227.1 [M+H]+, (ESI+), Rt = 0.90 (S1). Synthesis of intermediate S11 4-bromo-2,5,7-trimethyl-2H-indazole (Step B) To a solution of 4-bromo-5,7-dimethyl-1H-indazole (500.0 mg, 2.22 mmol) in EtOAc (20 mL) was added trimethyloxonium tetrafluoroborate (739 mg, 5.0 mmol) at RT. The reaction mixture was stirred for 18 hours. The reaction mixture was diluted with water and extracted with EtOAc (3 x15ml). The combined organic layers were passed through a phase separator and concentrated in vacuo. The residue was purified by FCC (10g silica, 0-100% EtOAc in heptane) to afford the titled product (350 mg, 44% Yield) as a white powder. ¹H 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). Scheme for general route 14d C6H5N, perchloric acid, DCM, DMF, 1,4-dioxane Step A NaBH4, Step B THF, MeOH Synthesis of intermediate S12 ethyl 8-bromo-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylate (Step A) To a solution of (E)-(ethyl N-[(2,4,6-trimethylbenzenesulfonyl)oxy]ethanimidate) (2.47 g, 8.67 mmol) in 1,4-Dioxane (20 mL) at 0°C was added perchloric acid (9.97 mL, 115.6 mmol) dropwise. After 10 minutes at 0°C, ice-cold water (20ml) was added. The resulting precipitate was collected by vacuum filtration and washed with ice-cold water (5ml). 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-bromopyridin-2-amine (1.0 g, 5.78 mmol) in DCM (20 mL). The reaction was allowed to warm to RT and stirred for 1 hour. The reaction mixture was evaporated and to the residue was added pyridine (0.93 mL, 11.56 mmol) in DMF (5 mL). The solution was cooled to 0⁰C then ethyl 2-chloro-2-oxo-acetate (0.97 mL, 8.67 mmol) was added. The reaction mixture was stirred at RT for 30 minutes. The reaction mixture was concentrated in vacuo, water (150 mL) was added and the solid was filtered, washed with water (20 mL) and sat. NaHCO₃ (20 mL) and dried over MgSO₄. The residue was purified by FCC (25g silica, 0-100% EtOAc in heptane) to afford the titled product (620 mg, 39% Yield) as a beige powder. LCMS m/z: 270.0/272.0 [M+H]+, (ESI+), Rt = 0.65 (S1) ¹H 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). Synthesis of intermediate S13 {8-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-yl}methanol (Step B) To a solution of ethyl 8-bromo-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylate (350.0 mg, 1.3 mmol) in THF (5 mL) was added NaBH₄ (98 mg, 2.59 mmol) and MeOH (1 mL) slowly. The reaction mixture was stirred at RT for 5 minutes. The reaction mixture was quenched with sat. NaHCO₃ solution (2 mL) and extracted with EtOAc (10 mL). The organic layer was filtered through a phase separator and the filtrate concentrated in vacuo to afford the titled product (200 mg, 68% Yield) as a white solid. LCMS m/z: 228.0/230.0 [M+H]+, (ESI+), Rt = 0.44 (S1) ¹H 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). Synthesis of intermediate S14 8-bromo-[1,2,4]triazolo[1,5-a]pyridine-2-carbaldehyde (Step C) To a solution of {8-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-yl}methanol (200 mg, 0.877 mmol) in DCM (20 mL) at RT was added MnO2 (762 mg, 8.77 mmol). The reaction mixture was stirred at reflux for 2 hours. Additional MnO2 (762 mg, 8.77 mmol) and MeCN (10 mL) were added and the reaction mixture stirred at 40^oC for 18 hours. The reaction mixture was filtered through Celite and the filtrate concentrated in vacuo to afford the titled 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). Synthesis of intermediate S15 ({8-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-yl}methyl)dimethylamine (Step D) To 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 [2 M in THF] (2.0 mL, 4.0 mmol) was added STAB (400.0 mg, 1.83 mmol). The reaction mixture was stirred at RT for 18 hours before being quenched with MeOH (2 mL) and concentrated in vacuo. The residue was purified by FCC (11g Kp- NH silica, 0-100% EtOAc in heptane) to afford the titled product (170 mg, 75% Yield) as a light yellow solid. LCMS m/z: 255.1/257.1 [M+H]+, (ESI+), Rt = 0.35 (S1) ¹H NMR (400 MHz, DMSO-d6) δ [ppm]: 8.94 (dd, J = 6.8, 1.0 Hz, 1H), 7.98 (dd, J = 7.5, 1.0 Hz, 1H), 7.10 (dd, J = 7.6, 6.7 Hz, 1H), 3.67 (s, 2H), 2.25 (s, 6H). Synthesis of intermediate S16 2-[(dimethylamino)methyl]-[1,2,4]triazolo[1,5-a]pyridine-8-carboxylic acid hydrochloride (Step E) To a solution of ({8-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-yl}methyl)dimethylamine (170.0 mg, 0.67 mmol) in anhydrous THF (1 mL) at 0⁰C was added 2.5 M butyllithium in hexanes (0.4 mL, 1.0 mmol). The reaction mixture was maintained at 0⁰C for 15 minutes before crushed dry ice was added in one portion to the reaction mixture. The cooling bath was removed and the reaction stirred at RT for 1 hour. The reaction mixture was acidified with 1M HCl and then concentrated in vacuo to afford the titled product (170 mg, 70% yield) as a yellow solid. LCMS m/z: 221.1 [M+H]+, (ESI+), Rt = 0.20 (S1) ¹H 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). Scheme for general route 14e Synthesis of intermediate S17 ethyl 6-(dimethylamino)pyrazolo[1,5-a]pyrimidine-3-carboxylate (Step A) To a degassed solution of ethyl 6-bromopyrazolo[1,5-a]pyrimidine-3-carboxylate (188 mg, 0.696 mmol), NaOtBu (117 mg, 1.217 mmol) and dimethylamine (2M, THF, 2.8 mL, 5.55 mmol) in dioxane (3.7 mL) was added tBuXPhos Pd G3 (22 mg, 0.028 mmol). The reaction mixture was heated at 100 °C for 4 hours. The reaction was cooled to RT, filtered, and the filtrate concentrated in vacuo. The residue was purified by open access prep HPLC (P3) to afford the titled product (27.6mg, 17% yield), as a dark brown solid. LCMS m/z: 235.3 [M+H]+, (ESI+), Rt = 2.21 (S4) ¹H 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) Synthesis of intermediate S18 6-(dimethylamino)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (Step B) To a stirring solution of ethyl 6-(dimethylamino)pyrazolo[1,5-a]pyrimidine-3- carboxylate (45 mg, 0.190 mmol) in THF (2 mL) was added 2M aq. LiOH (0.48 mL, 0.950 mmol). The reaction mixture was stirred at RT for 18 hours. MeOH (1 mL) was added and the reaction heated to 100 °C for 30 min, cooled to RT, and concentrated in vacuo. The resulting residue was dissolved in water (4 mL), acidified to pH 0 with 2M HCl, sonicated, and allowed to precipitate. The solid was dried in a vacuum oven overnight, to afford the titled product (16.5mg, 42% yield) as a light pink powder. LCMS m/z: 207.3 [M+H]+, (ESI+), Rt = 0.13 (S2) The following intermediates were prepared in a manner similar to intermediate S18 as outlined in general route 14e, using the corresponding starting materials

Scheme for general route 14f Synthesis of intermediate S19 ethyl (2S)-2-({5H,6H,7H,8H-imidazo[1,2-a]pyrazine-7-carbonyl}amino)-4- methylpentanoate (Step A) To a solution of ethyl (2S)-2-amino-4-methylpentanoate hydrochloride (200 mg, 1.10 mmol) in MeCN (7 mL) at -10⁰C was added DIPEA (0.96 mL, 5.50 mmol) followed by dropwise addition of bis(trichloromethyl) carbonate (121 mg, 0.407 mmol) in MeCN (2 mL). The reaction mixture was stirred for 1 hour. 5H,6H,7H,8H-imidazo[1,2-a]pyrazine hydrochloride (176 mg, 1.10 mmol) in MeCN (7 mL) was added, the reaction was heated to 65 °C for 2 hours, before being cooled to RT and stirring for 18 hours. The reaction was concentrated in vacuo to give the crude oil. Purification by column chromatography (25 g silica, 0–5% MeOH in DCM) afforded the titled product (169 mg, 35% Yield) as a yellow oil. LCMS m/z: 294 [M+H]+, (ESI+), Rt = 2.05 (S7) Synthesis of intermediate S20 lithium (1+) (2S)-2-({5H,6H,7H,8H-imidazo[1,2-a]pyrazine-7-carbonyl}amino)-4- methylpentanoate (Step B) To 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) at RT was added LiOH.H2O (47 mg, 1.12 mmol) in water (1.7 mL). the reaction mixture was stirred at RT °C for 4 hours. The reaction mixture was concentrated in vacuo to afford the titled product (106 mg, 69% Yield) as a yellow solid. LCMS m/z: 281 [M+H]+, (ESI+), Rt = 1.68 (S7) Scheme for general route 15 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 tert-butyl 1-{[(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) A stirring 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) at 0°C was added 4-nitrophenylchloroformate (109.0 mg, 0.54 mmol). The reaction mixture was stirred at RT for 1.5 hours. Ethyl (3S)-3-[(2S)-2-amino-4-methylpentanamido]- 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 stirred at RT for a further 18 hours. The reaction was diluted with water (10 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed sat. NaHCO3 solution (2 x 5 mL), brine (2 x 10 mL), dried over MgSO4, and concentrated in vacuo. Purification by FCC (25 g silica, 0%-100% EtOAc in heptane) afforded a mixture of the titled compounds (382 mg, 76% Yield) as a colourless gum. 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). 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)pentanamido]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)pentanamido]propanoate (Step B) To a solution of intermediates T1 (380.0 mg, 0.37 mmol) in DCM (2 mL) was added TFA (0.11 mL, 1.44 mmol) and the reaction mixture stirred at RT for 5 hours. The reaction mixture was concentrated in vacuo and the residue. Purification by column chromatography (5g SCX, 0-100% 7M NH3 in MeOH) afforded a mixture of the titled compounds (237 mg, 93% Yield) as a yellow oil. LCMS m/z: 610.4 [M+H]+, (ESI+), Rt = 0.93/0.94 (S1) ¹H NMR (500 MHz, DMSO-d6) δ [ppm]: 8.70 (dd, J = 13.9, 8.3 Hz, 1H), 8.15 – 7.39 (m, 2H), 7.05 – 6.84 (m, 4H), 5.57 – 5.43 (m, 1H), 4.45 – 4.29 (m, 1H), 4.06 – 3.99 (m, 2H), 3.99 – 3.66 (m, 2H), 2.87 – 2.72 (m, 4H), 2.46 – 2.39 (m, 2H), 2.27 – 2.22 (m, 3H), 1.96 – 1.92 (m, 3H), 1.91 – 1.85 (m, 3H), 1.61 – 1.31 (m, 3H), 1.10 – 1.05 (m, 3H), 0.82 – 0.73 (m, 6H). 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}pentanamido]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}pentanamido]propanoate (Step C) To a stirring solution of intermediate T2 (235.0 mg, 0.35 mmol) and TEA (0.23 mL, 1.75 mmol) in acetone (0.27 mL) and DCM (1.5 mL) at RT was added STAB (221 mg, 1.04 mmol). The reaction mixture was stirred at RT for 20 hours. The reaction mixture was diluted with water (15 mL) and sat. NaHCO₃ solution (15 mL) and then extracted with DCM (3 x 10 mL). The combined organics were passed through a phase separator and concentrated in vacuo. The residue was purified by FCC (10 g, 0-100% EtOAc heptane, then 0-15% MeOH EtOAc) to afford a mixture of the titled compounds (148 mg, 62% Yield) as a colourless gum. LCMS m/z: 652.5 [M+H]+, (ESI+), Rt = 0.98/0.99 (S1). Synthesis of intermediate U1 ethyl (3S)-3-{4,5-difluoro-2’,6’-dimethyl-[1,1’-biphenyl]-3-yl}-3-[(2S)-4-methyl-2- (phenylformamido)pentanamido]propanoate To a solution of intermediate B2 (80 mg, 0.170 mmol) in DCM (5 mL) was added DIPEA (0.044 mL, 0.255 mmol) followed by benzoyl chloride (0.020 mL, 0.170 mmol). The reaction mixture was stirred at RT for 18 hours. The reaction was concentrated in vacuo and purified by flash column chromatography on silica (10 g, 0-100 % EtOAc in Heptane) to afford the titled 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) Synthesis of intermediate U2 (3S)-3-[(2S)-2-amino-4-methylpentanamido]-3-{4,5-difluoro-2’,6’-dimethyl-[1,1’- biphenyl]-3-yl}propanoic acid hydrochloride To a solution of ethyl (3S)-3-[(2S)-2-amino-4-methylpentanamido]-3-{4,5-difluoro- 2’,6’-dimethyl-[1,1’-biphenyl]-3-yl}propanoate hydrochloride (intermediate B2, 75 mg, 0.155 mmol) in MeOH (0.19 mL) and THF (1.9 mL) at 40 °C was added and 2M aq. LiOH (0.31 mL, 0.621 mmol). The reaction mixture was stirred at 40 °C for 18 hours. The reaction mixture was concentrated in vacuo and water (5 mL) was added to the resulting residue. The mixture was neutralized with 1M aq. HCl solution and extracted with CHCl₃/IPA (2:1, 3 × 10 mL). The combined organics were passed through a hydrophobic frit and concentrated in vacuo to afford the titled product (55 mg, 71% Yield) as a white solid. LCMS m/z: 419.2 [M+H]+, (ESI+), Rt = 0.80 (S1) ¹H 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) Scheme for general route 16 Synthesis of intermediate V1 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 (Step A) To a solution of ethyl (3S)-3-[(2S)-2-amino-4-methylpentanamido]-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) was added DIPEA (75 µL, 0.429 mmol) followed by HATU (88 mg, 0.231 mmol). The resulting mixture was stirred at RT for 1 hour. Water (4 mL) was added to the reaction mixture, which was then separated through a Telos phase separator. The aqueous was extracted with DCM (2 × 2 mL) and the combined organic components concentrated in vacuo to afford the crude residue. Purification by column chromatography (12 g silica, 0– 50% EtOAc in heptane) afforded the titled product (122 mg, 86% Yield) as an off-white solid. LCMS m/z: 711.6 [M+H]+, (ESI+), Rt = 1.28 (S1) ¹H 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) Synthesis of intermediate V2 ethyl (3S)-3-[(2S)-4-methyl-2-({5H,6H,7H-pyrrolo[3,4-b]pyridin-2- yl}formamido)pentanamido]-3-{4,4',5-trifluoro-2',6'-dimethyl-[1,1'-biphenyl]-3-yl}propanoate hydrochloride (Step B) 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) was added of HCl (4 M in dioxane) (440 µL, 1.76 mmol). The resulting mixture was stirred for 2.5 hours at RT under N2, and then concentrated in vacuo to afford the titled product (85 mg, 78% Yield) as a light yellow solid. LCMS m/z: 611.6 [M+H]+, (ESI+), Rt = 0.86 (S1) ¹H 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) Synthesis of intermediate V3 ethyl (3S)-3-[(2S)-4-methyl-2-({6-methyl-5H,6H,7H-pyrrolo[3,4-b]pyridin-2- yl}formamido)pentanamido]-3-{4,4',5-trifluoro-2',6'-dimethyl-[1,1'-biphenyl]-3-yl}propanoate (Step C) To a stirred solution of ethyl (3S)-3-[(2S)-4-methyl-2-({5H,6H,7H-pyrrolo[3,4- b]pyridin-2-yl}formamido)pentanamido]-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) was added paraformaldehyde (14 mg, 0.459 mmol). The reaction mixture was stirred at RT for 2 hours. Sodium cyanoborohydride (29 mg, 0.454 mmol) was added and the mixture stirred for a further 3 hours. The reaction was cooled to 0⁰C and quenched with saturated NaHCO3 (2 mL). The organic layer was separated and the aqueous layer extracted with DCM (2 × 2 mL). The combined organic layers were concentrated in vacuo to afford the crude residue. Purification by column chromatography on silica (11g KP-NH silica, 0–60% EtOAc in heptane) afforded the titled 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) The following intermediates were prepared in a manner similar to intermediate V3 as outlined in general route 15, using the corresponding starting materials Scheme for general route 17 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-quinolizin-3-yl)formamido]pentanamido]propanoate To a stirred mixture of ethyl 4-oxo-4H-quinolizine-3-carboxylate (74 mg, 0.330 mmol) in THF (3 mL) at RT were added successively LiOH.H2O (42 mg, 0.990 mmol) and water (0.5 mL), and the resulting mixture was stirred at RT for 2 hours. Further water (2.5 mL) and LiOH.H2O (42 mg, 0.990 mmol) was added, and the reaction stirred for 18 hours. The reaction was then concentrated in vacuo, diluted with toluene and concentrated in vacuo to dryness (2 × 25 mL) to afford the intermediate residue. The residue was then dissolved in DCM (5 mL) at RT followed by addition of HATU (121 mg, 0.318 mmol), Intermediate B2 (153 mg, 0.318 mmol) and DIPEA (0.17 mL, 0.953 mmol), and stirred for 12 hours. Further HATU (121 mg, 0.318 mmol) and DIPEA (0.17 mL, 0.953 mmol) was added, and the reaction stirred at RT for 2 hours. DMF (5 mL) was added, and the DCM removed in vacuo, and the reaction then stirred at 45 °C for 2 hours. The reaction was then concentrated in vacuo and purified by flash column chromatography (12 g silica, 0–100% EtOAc in heptane) to afford the titled product (140 mg, 66% Yield) as a powder. 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). Scheme for general route 18 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-2lambda4-indazol-7-yl)formamido]pentanamido]propanoate To a stirred solution of 2-methyl-3aH-2lambda4-indazole-7-carboxylic acid (110 mg, 0.600 mmol) in toluene (5 mL) at RT under N2 were added successively thionyl chloride (0.44 mL, 6.00 mmol) and N,N-dimethylformamide (0.023 mL, 0.300 mmol). The reaction mixture was stirred at 110 °C for 4 hours, allowed cool to RT, and concentrated in vacuo. The crude was co-evaporated with toluene (2 × 10 ml) and dried under vacuum to afford the intermediate product. To a stirred solution of methyl (3S)-3-[(2S)-2-amino-4- methylpentanamido]-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) at RT under N2 was added successively the intermediate (138 mg, 0.597 mmol) and DIPEA (0.37 mL, 2.13 mmol), and the mixture stirred at RT for 12 hours. The reaction mixture was concentrated in vacuo to afford the crude material. Purification by column chromatography (10 g silica, 0– 50% EtOAc in heptane) afforded the titled 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). Exemplar compounds Scheme for general route 19 Example 1 (3S)-3-{4,5-difluoro-2',6'-dimethyl-[1,1'-biphenyl]-3-yl}-3-[(2S)-4-methyl- 2-[(quinolin-8-yl)formamido]pentanamido]propanoic acid LiOH (2M, aq, 0.25 mL, 0.490 mmol) was added to a solution of intermediate F1 (59 mg, 0.0981 mmol) in THF (1.5 mL) at RT for 18 h. The reaction was acidified to pH 1 by addition of HCl (2M, aq), and concentrated in vacuo, the residue was purified by FC (10 g silica, 50-100% EtOAc in Heptane, 10% MeOH in EtOAc), and then HPLC (P1) to afford (3S)-3-{4,5-difluoro-2',6'-dimethyl-[1,1'-biphenyl]-3-yl}-3-[(2S)-4-methyl-2-[(quinolin-8- yl)formamido]pentanamido]propanoic acid Example 1 (16.6 mg, 30% yield) as a solid. m/z: 574.3 [M+H]+, (ESI+), RT = 4.08 (S3) ¹H 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). The examples in Table 9 were synthesised according to general scheme 19 as exemplified by example 1 using the corresponding starting materials. Diastereomers were either separated during the final purification or by chiral separation methods as required. Examples were afforded as the title compound or salt thereof. Table 9 201

Scheme for general route 20 Example 37, (3S)-3-{4,5-difluoro-2',6'-dimethyl-[1,1'-biphenyl]-3-yl}-3-[(2S)-4- methyl-2-[(1-methyl-1H-pyrazol-4-yl)formamido]pentanamido]propanoic acid To a stirring 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) was added DIPEA (0.066 mL, 0.376 mmol) followed by HATU (67 mg, 0.176 mmol), and stirred 3hr at rt. The reaction mixture was concentrated in vacuo, redissolved in THF (2 mL) and Methanol (0.2 mL), LiOH (2M, aq, 0.33 mL, 0.652 mmol) was added, and the reaction was stirred for 3 h. The reaction mixture was concentrated in vacuo to remove organics, acidified with HCl (2M, aq), extracted with DCM (2 × 30 mL), dried using a phase separator, and concentrated to give crude residue. This was purified by prep HPLC (P1) to afford 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). 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- methoxyazetidin-1-yl)propyl]pyridin-2-yl}formamido)-4-methylpentanamido]propanoic acid To a solution of ethyl (3S)-3-[(2S)-2-amino-4-methylpentanamido]-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-methoxyazetidin-1-yl)propyl]pyridine-2-carboxylic acid lithium salt (162 mg, 0.424 mmol) and TEA (215 uL, 1.54 mmol) in DMF (4 mL) at RT was added T3P (50% in EtOAc) (459 uL, 0.771 mmol). The reaction mixture was stirred at RT for 16 hours. The reaction was diluted with EtOAc (20 mL) and washed with water (2 x 20 mL) then brine (2 x 10 mL) then concentrated in vacuo. The residue was dissolved in THF (4 mL) and 2 M LiOH (aq.) (1.33 mL, 2.67 mmol) was added. After stirring at RT for 2 hours, the reaction mixture was diluted with water (10 mL), concentrated in vacuo and acidified to ~pH3 using 10% citric acid (aq.). The suspension was filtered and the solid purified by HPLC (P4) to afford the titled 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 = 5.9 Hz, 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). The examples in Table 10 were synthesised according to general route 20 as exemplified by example 37 and example 303 using the corresponding starting materials. HATU conditions were used unless stated in the table. Diastereomers were either separated during the final purification or by chiral separation methods as required. Examples were afforded as the title compound or salt thereof. Table 10

2

Scheme for general route 21 Example 58, (3S)-3-{4,5-difluoro-2',6'-dimethyl-[1,1'-biphenyl]-3-yl}-3-[(2S)-2-[(2- fluorophenyl)formamido]-4-methylpentanamido]propanoic acid To a stirred solution of intermediate B2 (73 mg, 0.106 mmol) and DIPEA (55 µL, 0.315 mmol) in DCM (2 mL) was added 2-fluorobenzoyl chloride (16 µL, 0.134 mmol). The mixture was stirred at room temperature under N2 for 1 h. The reaction mixture was concentrated and the residue dissolved in THF (2 mL) and MeOH (0.2 mL). To the solution was added LiOH (2M, aq, 280 µL, 0.560 mmol) and the mixture stirred at rt for 2 h. The reaction mixture was concentrated in vacuo to remove organics, acidified to pH 1 with HCl (2M, aq), diluted with water (5 mL) and extracted with DCM (3 × 5 mL). The organic components were dried over Na2SO4, concentrated in vacuo and purified by prep HPLC (P2) to afford the title compound (36 mg, 62% yield) as a solid. m/z: 541.4 [M+H]+, (ESI+), RT = 4.05 (S3) ¹H 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) The exemplar compounds Table 11 were synthesised according to general scheme 21 as exemplified by example 58 using the corresponding starting materials. Diastereomers were either separated during the final purification or by chiral separation methods as required. Examples were afforded as the title compound or salt thereof. Table 11

Scheme for general route 22 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-dihydropyridin-3- yl)formamido]pentanamido]propanoic acid 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 min, then treated with Pd(dppf)Cl₂ (13 mg, 0.0162 mmol), and stirred at 90 °C for 2 h. The reaction was then cooled to rt, diluted with EtOAc (15 mL), and washed with water (15 mL). The water was then extracted with EtOAc (3 × 10 mL), and the organic components were combined, washed with brine (15 mL), dried using a phase separator, and concentrated in vacuo. The residue was dissolved in THF (1 mL) and LiOH (2M, aq, 0.31 mL, 0.618 mmol) was added, and the reaction stirred for 18 hr at rt. The reaction mixture was concentrated to remove organics then diluted with water, acidified to pH 1 with HCl (1M, aq) and sonicated. The resulting precipitate was purified by prep HPLC P1, to afford (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-dihydropyridin-3- yl)formamido]pentanamido]propanoic acid the title compound (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). The exemplar compounds in Table 12 were synthesised according to general route 22 as exemplified by example 64 using the corresponding starting materials. Diastereomers were either separated during the final purification or by chiral separation methods as required. Examples were afforded as the title compound or salt thereof.

Table 12 Scheme for general route 23 Synthesis of Example 67 (3S)-3-[2,3-difluoro-5-(2-methyl-2H-indazol-3-yl)phenyl]-3-[(2S)-4-methyl-2-[(1-methyl-2- oxo-1,2-dihydropyridin-3-yl)formamido]pentanamido]propanoic acid In a sealed vial, to 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-dihydropyridin-3- yl)formamido]pentanamido]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 K₂CO₃ (55 mg, 0.398 mmol) and Water (0.2 mL). The mixture was degassed for 5 minutes 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 EtOAc (15 mL), H2O (10 mL) and sat. aq. brine solution (5 mL). The organic layer was separated and the aqueous layer further extracted with EtOAc (2 x 10 mL). The combined organic phases were dried over MgSO₄, filtered and concentrated in vacuo to give a residue. The residue was re- dissolved in THF (2.9 mL) and Methanol (1 mL), then treated with 2 M lithium hydroxide (0.68 mL, 1.37 mmol). The solution was stirred at room temperature for 90 minutes. The reaction mixture concentrated in vacuo at 40 °C to give a residue. The residue was dissolved in H₂O and the pH adjusted to pH3. The aqueous layer was extracted with EtOAc (2 x10 ml) and the combined organic phases were dried over MgSO₄, filtered and concentrated in vacuo to give a residue. Purification by reverse phase chromatography (Method 1) afforded (3S)-3-[2,3-difluoro-5-(2-methyl-2H-indazol-3-yl)phenyl]-3-[(2S)-4- methyl-2-[(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)formamido]pentanamido]propanoic acid (46mg, 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). The following compounds were synthesized according to general route 23 as exemplified by example 67 using the corresponding starting materials. Diastereomers were either separated during the final purification or by chiral separation methods as required. Examples were afforded as the title compound or salt thereof Scheme for general route 24 . Example 360 Step 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)pyridin-2-yl]formamido}pentanamido]propanoic acid To a stirred solution of 1-methyl-1,4-diazepane (32 uL, 0.26 mmol) in 1,4-Dioxane (1.5 mL) was added Cs2CO3 (227.0 mg, 0.7 mmol) and ethyl (3S)-3-[(2S)-2-[(6- chloropyridin-2-yl)formamido]-4-methylpentanamido]-3-{4,4'-difluoro-2',5,6'-trimethyl-[1,1'- biphenyl]-3-yl}propanoate (intermediate Q5, 115 mg, 0.172 mmol). The solution was flushed with nitrogen for 20 mins, then Pd(OAc)2 (6.0 mg, 0.03 mmol) and BINAP (34.0 mg, 0.05 mmol) were added and the reaction mix stirred at 100°C for 19 h. The reaction mixture was cooled, diluted with EtOAc (8 mL), filtered over celite, washed with EtOAc (2 x 10 mL) and concentrated. The residue was purified by HPLC (P4) to afford (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)pyridin-2-yl]formamido}pentanamido]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). Example 358 Step C: (3S)-3-{4,4'-difluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl}-3-[(2S)-4-methyl- 2-{[6-(4-methylpiperazin-1-yl)pyridin-2-yl]formamido}pentanamido]propanoic acid Prepared using the route as outlined in general route 77, step C, from ethyl (3S)-3- [(2S)-2-[(6-chloropyridin-2-yl)formamido]-4-methylpentanamido]-3-{4,4'-difluoro-2',5,6'- trimethyl-[1,1'-biphenyl]-3-yl}propanoate (intermediate Q5) and 1-methylpiperazine in a manner similar to that described for example 360. 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). Scheme for general route 25 Example 361 Step B: (3S)-3-{4'-chloro-4-fluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl}-3-[(2S)-4- methyl-2-{[6-(4-methylpiperazin-1-yl)pyridin-2-yl]formamido}pentanamido]propanoic acid To a solution of ethyl (3S)-3-{4'-chloro-4-fluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl}- 3-[(2S)-2-[(6-fluoropyridin-2-yl)formamido]-4-methylpentanamido]propanoate (100 mg, 0.167 mmol) in DMF (1 mL) was added K2CO3 (70.0 mg, 0.51 mmol) and N- methylpiperazine (35 mg, 0.339 mmol). The mixture was then stirred overnight at 80°C. The reaction mixture was allowed to cool and 2 M LiOH hydrate (0.1 mL, 0.2 mmol) was added and the mixture stirred for 3 h at RT. The reaction mixture was dissolved in water (3 mL) and extracted with EtOAc (4 x 5 mL). The organics were combined, washed with brine (5 mL), dried over MgSO₄ and concentrated. The residue was purified using RP FCC (12 g, C18 Silica, 14 CVs, 10 - 100% MeCN in water with 0.1% NH4OH modifier) to afford (3S)-3- {4'-chloro-4-fluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl}-3-[(2S)-4-methyl-2-{[6-(4- methylpiperazin-1-yl)pyridin-2-yl]formamido}pentanamido]propanoic acid (57.7 mg, 51 % yield) 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). Conditions B Example 398 Step B: (3S)-3-{4'-chloro-4-fluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl}-3-[(2S)-2-({6- [(3R)-3-(dimethylamino)pyrrolidin-1-yl]pyridin-2-yl}formamido)-4- methylpentanamido]propanoic acid To a solution of ethyl (3S)-3-{4'-chloro-4-fluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl}- 3-[(2S)-2-[(6-fluoropyridin-2-yl)formamido]-4-methylpentanamido]propanoate (80 mg, 0.133 mmol) dissolved in DMSO (1 mL) and DIPEA (0.05 mL, 0.27 mmol) was added (3R)-N,N- dimethylpyrrolidin-3-amine (30 mg, 0.267 mmol). The mixture was then stirred for 20 h at 80°C. The reaction mixture was diluted with THF (0.5 mL) and MeOH (0.2 mL) and treated with 2 M LiOH hydrate (aq.) (0.09 mL, 0.17 mmol). The reaction mixture was stirred at RT for 3 h, concentrated, diluted with water (5 mL) and acidified with 10% citric acid (aq.) to ~pH4. The resulting solid was collected by vacuum filtration and purified by HPLC (P3) to afford (3S)-3-{4'-chloro-4-fluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl}-3-[(2S)-2-({6-[(3R)-3- (dimethylamino)pyrrolidin-1-yl]pyridin-2-yl}formamido)-4-methylpentanamido]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). The following examples were synthesised according to general scheme 25 as exemplified by example 361 & 398 using the corresponding starting materials. Diastereomers were either separated during the final purification or by chiral separation methods as required. Examples were afforded as the title compound or salt thereof

392

Other exemplar compounds Diastereomers were either separated during the final purification or sent for chiral separation methods as required. Examples were afforded as the title compound or salt thereof. Example 67, (3S)-3-[2,3-difluoro-5-(2-methyl-2H-indazol-3-yl)phenyl]-3-[(2S)-4- methyl-2-[(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)formamido]pentanamido]propanoic acid, (alternative synthesis) To a pressure vial was added 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-dihydropyridin-3- yl)formamido]pentanamido]propanoate (88 mg, 0.131 mmol), 3-bromo-2-methyl-indazole (42 mg, 0.199 mmol) and dipotassium carbonate (55 mg, 0.398 mmol), which was dissolved in 1,4-Dioxane (2.5 mL) and water (0.2 mL). This was sparged with N2 for 5 mins, followed by addition of [PdCl2(dppf).CH2Cl2] (11 mg, 0.0134 mmol), further sparged with N2 for 5 mins, and then the reaction was stirred at 100 °C. The reaction mixture was diluted with EtOAc (15 mL), H2O (10 mL) and sat brine (5 mL), followed by pH adjustment to pH 7 using HCl (1M, aq) then the phases were separated and the aqueous was extracted with EtOAc (2 × 10 mL). The organic phases were combined and concentrated in vacuo, the resultant residue was dissolved in THF (2.9 mL) and methanol (1 mL), then treated with lithium hydroxide (aq, 2 M, 0.68 mL, 1.37 mmol) and stirred at RT for 1.5 h. The reaction was then concentrated in vacuo and dissolved in EtOAc (10 mL) followed by H2O (10 mL) and the pH was adjusted to pH 3 using HCl (1M, aq). The phases were separated and the aqueous was extracted with EtOAc (2 × 10 mL), the organic phases were dried over MgSO4, the flask and filter cake were washed with EtOAc (3 × 15 mL). The combined organic phase was concentrated in vacuo, the resultant residue was purified via acidic open access prep (P2, Method 2). Product containing fractions were combined and concentrated in vacuo, and freeze dried to afford 3S)-3-[2,3-difluoro-5-(2-methyl-2H-indazol-3-yl)phenyl]-3-[(2S)-4- methyl-2-[(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)formamido]pentanamido]propanoic acid ( 7.4 mg, 9.7% yield) as a white solid. m/z: 580.2 [M+H]+, (ESI+), RT = 2.94 (S3) 1H NMR (400 MHz, DMSO-d6) δ [ppm]: 12.57 (s, 1H), δ 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). (N1) Example 70, 3S)-3-{4,5-difluoro-2',6'-dimethyl-[1,1'-biphenyl]-3-yl}-3-[(2S)-4- methyl-2-[(1-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)formamido]pentanamido]propanoic acid Step A (3S)-3-[(2S)-2-[(2E)-2-(aminomethylidene)-2-(methylcarbamoyl)acetamido]- 4-methylpentanamido]-3-{4,5-difluoro-2',6'-dimethyl-[1,1'-biphenyl]-3-yl}propanoate lithium To a stirring solution of intermediate B2 (100 mg, 0.213 mmol) and 1-methyl-6-oxo- 1,6-dihydropyrimidine-5-carboxylic acid (36 mg, 0.224 mmol) in DCM (1.3 mL) was added DIPEA (0.093 mL, 0.533 mmol) followed by HATU (97 mg, 0.256 mmol), and stirred at rt for 17 h. The reaction mixture was concentrated in vacuo, redissolved in THF (4 mL), LiOH (46 mg, 1.07 mmol) was added, followed by water (0.9 mL), and the reaction was stirred for 16 h. Further LiOH (23 mg, 0.533 mmol) and water (0.5 mL) was added, and the reaction stirred for 6 h. The mixture was diluted with toluene and MeOH, concentrated in vacuo, to afford the title intermediate (151 mg, 100% yield) as a gum. m/z: 545.6 [M+H]+, (ESI+), RT = 2.22/2.23 min (S6)

A solution of (3S)-3-[(2S)-2-[(2E)-2-(aminomethylidene)-2- (methylcarbamoyl)acetamido]-4-methylpentanamido]-3-{4,5-difluoro-2',6'-dimethyl-[1,1'- biphenyl]-3-yl}propanoate lithium (75 mg, 0.107 mmol) from step A and (dimethoxymethyl)dimethylamine (0.021 mL, 0.160 mmol) in DMF (1 mL) was stirred at 90 °C for 3h. Further (dimethoxymethyl)dimethylamine (0.021 mL, 0.160 mmol) was added at 90 °C and the mixture stirred for 3h. The reaction was concentrated in vacuo to give the crude residue, which was purified by reverse-phase FC using a gradient of 20% to 70% acetonitrile in water over 25 minutes (0.05% TFA in water), to the title compound (21 mg, 35% yield) as a powder. m/z: 555.4 [M+H]+, (ESI+), RT = 1.92 min (S7) ¹H NMR (500 MHz, DMSO-d6) δ [ppm]: 12.42 (s, 1H), 9.43 (d, J = 8.3 Hz, 1H), 8.84 (d, J = 7.8 Hz, 1H), 8.73 (s, 1H), 8.61 (s, 1H), 7.22 – 7.15 (m, 2H), 7.15 – 7.09 (m, 2H), 6.96 – 6.91 (m, 1H), 5.49 (q, J = 7.5 Hz, 1H), 4.61 – 4.53 (m, 1H), 3.51 (s, 3H), 2.76 (d, J = 7.5 Hz, 2H), 2.03 – 1.88 (m, 6H), 1.40 (dq, J = 12.6, 6.3 Hz, 3H), 0.81 – 0.73 (m, 6H). (N2) Example 71, (3S)-3-{4,5-difluoro-2',6'-dimethyl-[1,1'-biphenyl]-3-yl}-3-[(2S)-2-{[1- (difluoromethyl)-2-oxo-1,2-dihydropyridin-3-yl]formamido}-4-methylpentanamido]propanoic acid, Over ice, a solution of 2,2-dimethylpropanoyl chloride (19 mg, 0.159 mmol) in THF (1 mL), was added to a solution of 1-(difluoromethyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (30 mg, 0.159 mmol) and DIPEA (23 mg, 0.031 mL, 0.174 mmol) in THF (1 mL). The reaction mixture was allowed to warm to rt and stirred for 1 h. Additional DIPEA (23 mg, 0.031 mL, 0.174 mmol) and a suspension of intermediate B2 (55 mg, 0.131 mmol) in THF (1 mL) were added to the reaction mixture. The reaction mixture was stirred for 1 h, then concentrated in vacuo and the resulting residue purified reverse phase column chromatography with a gradient of 10-100% MeCN in water, to afford a white solid. This was further purified by preparative HPLC (P3), to the title compound (6.9 mg, 7.4% Yield) as a solid. m/z: 590.5 [M+H]+, (ESI+), RT = 2.62 min (S4) ¹H NMR (500 MHz, CDCl3) δ [ppm]: 9.69 (d, J = 6.5 Hz, 1H), 8.38 (dd, J = 7.2, 2.1 Hz, 1H), 7.81 – 7.54 (m, 2H), 7.19 – 7.12 (m, 1H), 7.10 – 7.04 (m, 2H), 6.91 – 6.83 (m, 2H), 6.67 – 6.58 (m, 1H), 5.78 – 5.69 (m, 1H), 4.61 – 4.45 (m, 1H), 2.88 (d, J = 6.4 Hz, 2H), 1.97 (d, J = 9.3 Hz, 6H), 1.69 – 1.54 (m, 3H), 1.25 (s, 1H), 0.81 (dd, J = 11.8, 6.2 Hz, 6H). (N1) Example 72, (3S)-3-[4,5-difluoro-2',6'-dimethyl-4'-(trifluoromethyl)-[1,1'-biphenyl]-3- yl]-3-[(2S)-4-methyl-2-[(1-methyl-2-oxo-1,2-dihydropyridin-3- yl)formamido]pentanamido]propanoic acid, To a degassed suspension of 2-bromo-1,3-dimethyl-5-(trifluoromethyl)benzene (27 mg, 0.107 mmol), intermediate H1 (146 mg, 0.0941 mmol) and K₂CO₃ (39 mg, 0.282 mmol) in 1,4-dioxane (1.5 mL) and water (150 µL) was added Pd(dppf)Cl2.CH2Cl2 (15 mg, 0.0184 mmol). The reaction was heated at 110 °C for 16 hours. The reaction was allowed to cool to RT and the mixture was filtered through Celite washing with excess EtOAc (3 x 10 mL). The filtrate was collected and concentrated in vacuo to afford a brown solid, which was suspended in THF (1 mL), MeOH (0.1 mL) and 2M LiOH (aq) (235 µL, 0.470 mmol), the reaction was stirred at RT for 4 hours. The reaction was concentrated in vacuo and the residue purified by prep HPLC (P1), to afford the titled product (13 mg, 22% Yield) as a powder. m/z: 622.3 [M+H]+, (ESI+), RT = 3.95 min (S4) ¹H NMR (400 MHz, DMSO-d6) δ [ppm]: 12.43 (s, 1H), 10.05 (d, J = 8.0 Hz, 1H), 8.77 (d, J = 7.7 Hz, 1H), 8.15 (dd, J = 7.3, 2.2 Hz, 1H), 8.04 (dd, J = 6.6, 2.2 Hz, 1H), 7.51 (d, J = 3.3 Hz, 2H), 7.30 – 7.20 (m, 1H), 7.00 – 6.88 (m, 1H), 6.47 – 6.37 (m, 1H), 5.47 (q, J = 7.5 Hz, 1H), 4.49 (q, J = 7.4 Hz, 1H), 3.54 (s, 3H), 2.74 (d, J = 7.4 Hz, 2H), 2.03 (d, J = 3.7 Hz, 6H), 1.48 – 1.35 (m, 3H), 0.80 – 0.73 (m, 6H). (N1) Synthesis of example 73, (3S)-3-{4,5-difluoro-2',6'-dimethyl-[1,1'-biphenyl]-3-yl}- 3-[(2S)-4-methyl-2-({2-[(1-methylazetidin-3-yl)oxy]pyridin-3- yl}formamido)pentanamido]propanoic acid A solution of 1-methylazetidin-3-ol (12 mg, 0.143 mmol) in DMF (1 mL) was added dropwise to a suspension of NaH in mineral oil (60%, 10 mg, 0.239 mmol) in DMF (0.5 mL) at 0 °C, and the resulting solution stirred for 1 h. After which intermediate F21 (70 mg, 0.119 mmol) in DMF-Anhydrous (1 mL) was added dropwise and the resultant solution allowed to warm to RT, then heated to 50 °C and stirred for 5.5 h. The reaction was quenched with water (0.5 mL), the solvent was removed under vacuum to give the crude residue. This was purified by prep HPLC (P1), concentrated in vacuo, and then re-purified by prep HPLC (P3) to afford the title compound (3.5 mg, 4.6% yield) as a solid. m/z: 609.5 [M+H]+, (ESI+), RT = 2.65 min (S4) ¹H NMR (500 MHz, DMSO-d6) δ [ppm]: 8.90 (d, J = 8.0 Hz, 1H), 8.40 (d, J = 8.1 Hz, 1H), 8.26 (dd, J = 5.0, 1.9 Hz, 1H), 8.08 (dd, J = 7.6, 2.0 Hz, 1H), 7.21 – 7.14 (m, 3H), 7.14 – 7.10 (m, 2H), 6.99 – 6.94 (m, 1H), 5.59 – 5.51 (m, 1H), 5.40 (s, 1H), 4.61 – 4.53 (m, 1H), 4.24 (s, 2H), 4.05 – 3.80 (m, 2H), 2.79 – 2.66 (m, 4H), 1.97 – 1.93 (m, 7H), 1.54 – 1.44 (m, 3H), 0.82 (d, J = 6.2 Hz, 3H), 0.79 (d, J = 6.3 Hz, 3H). (N1) Synthesis of Example 205 (5-methyl-2-oxo-2H-1,3-dioxol-4-yl)methyl (3S)-3-{4,5-difluoro-2',4',6'-trimethyl- [1,1'-biphenyl]-3-yl}-3-[(2S)-4-methyl-2-[(1-methyl-2-oxo-1,2-dihydropyridin-3- yl)formamido]pentanamido]propanoate To an ice-cold solution of (3S)-3-{4,5-difluoro-2',4',6'-trimethyl-[1,1'-biphenyl]-3-yl}- 3-[(2S)-4-methyl-2-[(1-methyl-2-oxo-1,2-dihydropyridin-3- yl)formamido]pentanamido]propanoic acid (Example 16, 86%, 125 mg, 0.189 mmol) and 4- (hydroxymethyl)-5-methyl-2H-1,3-dioxol-2-one (100%, 35 mg, 0.269 mmol) in DCM (1.3 mL) was added K₂CO₃ (40 mg, 0.289 mmol), 4-methylbenzenesulfonyl chloride (50 mg, 0.262 mmol) and DMAP (4.0 mg, 0.0327 mmol). The solution was stirred over an ice bath for 2 hours before warming to room temperature and stirring for a further 18 hours. The solution was diluted with water (1 mL) and acidified to pH ~5 with 2N HCl, a white solid precipitated out of solution. The mixture was extracted with DCM (4 x 10 mL). The combined organic layers were dried over MgSO4 and concentrated in vacuo to give a solid. Purification by reverse phase chromatography (Method 1) afforded (5-methyl-2-oxo-2H-1,3-dioxol-4- yl)methyl (3S)-3-{4,5-difluoro-2',4',6'-trimethyl-[1,1'-biphenyl]-3-yl}-3-[(2S)-4-methyl-2-[(1- methyl-2-oxo-1,2-dihydropyridin-3-yl)formamido]pentanamido]propanoate (19 mg, 0.0285 mmol, 15% Yield) as a white solid. LCMS m/z: 680.5 [M+H]⁺, (ESI+), Rt = 4.23 (S3) ¹H NMR (500 MHz, DMSO-d6) δ [ppm]: 10.04 (d, J = 8.0 Hz, 1H), 8.79 (d, J = 8.0 Hz, 1H), 8.20 (dd, J = 7.3, 2.2 Hz, 1H), 8.05 (dd, J = 6.5, 2.2 Hz, 1H), 7.15 – 7.07 (m, 1H), 6.96 – 6.89 (m, 3H), 6.50 – 6.41 (m, 1H), 5.52 (q, J = 7.8 Hz, 1H), 4.91 (s, 2H), 4.47 (q, J = 7.4 Hz, 1H), 3.54 (s, 3H), 2.97 – 2.82 (m, 2H), 2.26 (s, 3H), 2.13 – 2.05 (m, 3H), 1.89 (s, 6H), 1.49 – 1.33 (m, 3H), 0.81 – 0.71 (m, 6H). Synthesis of Example 359 (dimethylcarbamoyl)methyl (3S)-3-[5-(4-cyano-2,6-dimethylphenyl)pyridin-3-yl]-3- [(2S)-4-methyl-2-[(1-methyl-2-oxo-1,2-dihydropyridin-3- yl)formamido]pentanamido]propanoate To a suspension of (3S)-3-[5-(4-cyano-2,6-dimethyl-phenyl)-3-pyridyl]-3-[[(2S)-4- methyl-2-[(1-methyl-2-oxo-pyridine-3-carbonyl)amino]pentanoyl]amino]propanoic acid (intermediate 359A 100 mg, 0.166 mmol), and 2-chloro-N,N-dimethylacetamide (47 mg, 0.381 mmol) in DMF (2 mL) was added, potassium iodide (33 mg, 0.199 mmol) and cesium carbonate (216 mg, 0.662 mmol). The reaction mixture was stirred at RT for 6 hours then diluted with H₂O (10 mL) and extracted with CH₂Cl₂ (3 x 10 mL). The combined organic layers were washed with sat. aq. LiCl solution (2 x 10 mL), passed through phase separator and concentrated in vacuo to give a residue. Purification by reverse phase prep (Method 1) afforded the titled product (51.0mg, 95% pure, 47% yield). LCMS m/z: 629.4 [M+H]⁺, (ESI+), Rt = 2.68 (S3) ¹H NMR (500 MHz, DMSO) δ 10.06 (d, J = 7.8 Hz, 1H), 8.81 (d, J = 8.4 Hz, 1H), 8.59 (d, J = 2.2 Hz, 1H), 8.28 (d, J = 2.0 Hz, 1H), 8.20 (dd, J = 7.2, 2.2 Hz, 1H), 8.06 (dd, J = 6.5, 2.2 Hz, 1H), 7.69 – 7.64 (m, 2H), 7.57 (t, J = 2.1 Hz, 1H), 6.51 – 6.43 (m, 1H), 5.36 (q, J = 7.2 Hz, 1H), 4.76 - 4.69 (m, 2H), 4.51 – 4.45 (m, 1H), 3.55 (s, 3H), 3.04 – 2.95 (m, 2H), 2.87 (s, 3H), 2.75 (s, 3H), 1.98 (m, 6H), 1.50 – 1.41 (m, 3H), 0.82 – 0.78 (m, 6H). Scheme for route to Example 407 Step A: 6-{5-[(tert-butoxy)carbonyl]-2H,4H,5H,6H,7H-pyrazolo[4,3-c]pyridin-2- yl}pyridine-2-carboxylic acid To a stirred solution of tert-butyl 2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5- carboxylate (233 mg, 1.04 mmol) in anhydrous DMF (6 mL) was added NaH (60% in mineral oil) (70 mg, 1.75 mmol) and the resulting mixture stirred at RT under nitrogen for 10 minutes. Then ethyl 6-bromopyridine-2-carboxylate (200 mg, 0.869 mmol) was added in one portion and the mixture stirred at RT for 16 h. The reaction mixture was stirred at 60^oC for 5 h and then at 90^oC for 2 h before cooling to RT. The mixture was diluted with EtOAc (20 mL) and washed with water (2 x 15 mL). The combined aqueous layers were acidified to ~pH 3 using 10% citric acid (aq.) and extracted with EtOAc (2 x 15 mL). The combined organic layers were dried over Na2SO4 and concentrated. The residue was triturated in 10% EtOAc in heptane (2 x 5 mL). The solvent was decanted and the residue dried to afford 6-{5-[(tert- butoxy)carbonyl]-2H,4H,5H,6H,7H-pyrazolo[4,3-c]pyridin-2-yl}pyridine-2-carboxylic acid (114 mg, 33% yield) as a yellow solid. LCMS m/z: 345.3 [M+H]+, (ESI+), Rt = 0.81 (S1)    ¹H NMR (500 MHz, DMSO-d6) δ [ppm]: 8.58 (s, 1H), 8.14 – 8.09 (m, 1H), 8.05 (dd, J = 8.4, 1.0 Hz, 1H), 7.93 (dd, J = 7.5, 1.0 Hz, 1H), 4.50 (s, 2H), 3.66 (t, J = 5.9 Hz, 2H), 2.78 – 2.73 (m, 2H), 1.43 (s, 9H). Step B tert-butyl 2-(6-{[(1S)-1-{[(1S)-1-{4,4'-difluoro-2',5,6'-trimethyl-[1,1'-biphenyl]- 3-yl}-3-ethoxy-3-oxopropyl]carbamoyl}-3-methylbutyl]carbamoyl}pyridin-2-yl)- 2H,4H,5H,6H,7H-pyrazolo[4,3-c]pyridine-5-carboxylate To a stirred solution of 6-{5-[(tert-butoxy)carbonyl]-2H,4H,5H,6H,7H-pyrazolo[4,3- c]pyridin-2-yl}pyridine-2-carboxylic acid (108.0 mg, 0.27 mmol) in DMF (5 mL) was added DIPEA (150 uL, 0.859 mmol) followed by HATU (122 mg, 0.321 mmol). The resulting mixture was stirred at RT for 10 minutes and then solid ethyl (3S)-3-[(2S)-2-amino-4- methylpentanamido]-3-{4,4'-difluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl}propanoate hydrochloride (Intermediate D2) (130 mg, 0.248 mmol) was added and the mixture stirred at RT for 2 h under N₂. The reaction mixture was diluted with EtOAc (25 mL) and washed with water (2 x 20 mL) and brine (20 mL). The organic layer was dried over Na2SO4 and concentrated and the residue purified by Biotage Selekt™ FCC (10 g Sfar duo column, eluting with EtOAc in heptane, 0 – 100% gradient) to afford tert-butyl 2-(6-{[(1S)-1-{[(1S)-1- {4,4'-difluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl}-3-ethoxy-3-oxopropyl]carbamoyl}-3- methylbutyl]carbamoyl}pyridin-2-yl)-2H,4H,5H,6H,7H-pyrazolo[4,3-c]pyridine-5- carboxylate (111 mg, 50% yield) as a yellow oil. LCMS m/z: 787.7 [M+H]+, (ESI+), Rt = 1.33 (S1)    ¹H NMR (500 MHz, CDCl₃) δ [ppm]: 8.33 (s, 1H), 8.25 – 8.15 (m, 1H), 8.06 (d, J = 8.0 Hz, 1H), 7.99 – 7.95 (m, 1H), 7.92 (t, J = 7.8 Hz, 1H), 7.34 (d, J = 8.9 Hz, 1H), 6.88 – 6.82 (m, 2H), 6.80 – 6.74 (m, 2H), 5.69 – 5.62 (m, 1H), 4.68 (q, J = 7.7 Hz, 1H), 4.64 – 4.53 (m, 2H), 4.07 – 3.92 (m, 2H), 3.81 – 3.69 (m, 2H), 2.92 – 2.82 (m, 4H), 2.30 – 2.29 (m, 3H), 1.96 – 1.94 (m, 6H), 1.50 (s, 9H), 1.27 – 1.25 (m, 3H), 1.13 (t, J = 7.1 Hz, 3H), 0.91 – 0.88 (m, 6H). Step C: ethyl (3S)-3-{4,4'-difluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl}-3-[(2S)-4- methyl-2-[(6-{2H,4H,5H,6H,7H-pyrazolo[4,3-c]pyridin-2-yl}pyridin-2- yl)formamido]pentanamido]propanoate dihydrochloride A solution of tert-butyl 2-(6-{[(1S)-1-{[(1S)-1-{4,4'-difluoro-2',5,6'-trimethyl-[1,1'- biphenyl]-3-yl}-3-ethoxy-3-oxopropyl]carbamoyl}-3-methylbutyl]carbamoyl}pyridin-2-yl)- 2H,4H,5H,6H,7H-pyrazolo[4,3-c]pyridine-5-carboxylate (111.0 mg, 0.12 mmol) and 4 M HCl in dioxane (500 uL, 2.0 mmol) in DCM (3 mL) was stirred at RT under nitrogen for 5 h. The reaction mixture was concentrated to afford ethyl (3S)-3-{4,4'-difluoro-2',5,6'-trimethyl-[1,1'- biphenyl]-3-yl}-3-[(2S)-4-methyl-2-[(6-{2H,4H,5H,6H,7H-pyrazolo[4,3-c]pyridin-2-yl}pyridin- 2-yl)formamido]pentanamido]propanoate dihydrochloride (95 mg, 98% yield) as a yellow solid. LCMS m/z: 687.5 [M+H]+, (ESI+), Rt = 1.07 (S2) . Example 407 Step D: (3S)-3-{4,4'-difluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl}-3- [(2S)-4-methyl-2-[(6-{5-methyl-2H,4H,5H,6H,7H-pyrazolo[4,3-c]pyridin-2-yl}pyridin-2- yl)formamido]pentanamido]propanoic acid A pre-stirred solution of ethyl (3S)-3-{4,4'-difluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3- yl}-3-[(2S)-4-methyl-2-[(6-{2H,4H,5H,6H,7H-pyrazolo[4,3-c]pyridin-2-yl}pyridin-2- yl)formamido]pentanamido]propanoate dihydrochloride (95.0 mg, 0.121 mmol) and triethylamine (45.0 uL, 0.323 mmol) in anhydrous DCE (1 mL) was treated with paraformaldehyde (22.0 mg, 0.709 mmol) followed by AcOH (45.0 uL, 0.786 mmol) and stirred at RT for 20 min. STAB (142 mg, 0.670 mmol) was then added and the reaction mixture stirred at RT for 18 h. The reaction mixture was diluted with DCM (5 mL) and washed with sat. NaHCO3 (aq.) (5 mL). The organic layer was separated, dried over Na2SO4 and concentrated. The residue was dissolved in a mixture of THF (2 mL), MeOH (0.2 mL) and 2M LiOH (aq.) (200 uL, 0.400 mmol) and stirred at 40^oC for 2 h. The reaction mixture was concentrated, diluted with water (5 mL), acidified with 10% citric acid (aq.) to ~pH4 and the mixture extracted into EtOAc (2 x 10 mL). The combined organic extracts were dried over Na2SO4, concentrated and purified by HPLC (P4) to afford (3S)-3-{4,4'-difluoro-2',5,6'- trimethyl-[1,1'-biphenyl]-3-yl}-3-[(2S)-4-methyl-2-[(6-{5-methyl-2H,4H,5H,6H,7H- pyrazolo[4,3-c]pyridin-2-yl}pyridin-2-yl)formamido]pentanamido]propanoic acid (15 mg, 18% yield) as a white solid. LCMS m/z: 673.8 [M+H]+, (ESI+), Rt = 2.74 (S3)    ¹H NMR (500 MHz, DMSO-d6) δ [ppm]: 8.75 – 8.67 (m, 3H), 8.09 – 8.04 (m, 1H), 7.98 (dd, J = 8.2, 1.0 Hz, 1H), 7.82 (dd, J = 7.4, 1.0 Hz, 1H), 6.93 (dd, J = 6.7, 2.3 Hz, 1H), 6.91 – 6.87 (m, 1H), 6.83 (dd, J = 9.8, 2.7 Hz, 1H), 6.75 (dd, J = 9.8, 2.7 Hz, 1H), 5.56 – 5.47 (m, 1H), 4.60 (td, J = 9.3, 5.2 Hz, 1H), 3.52 – 3.46 (m, 2H), 2.85 – 2.68 (m, 6H), 2.41 (s, 3H), 2.28 – 2.21 (m, 3H), 1.89 (s, 3H), 1.78 (s, 3H), 1.68 – 1.58 (m, 1H), 1.58 – 1.47 (m, 2H), 0.88 – 0.77 (m, 6H). Scheme for general route 26 Synthesis of Examples 271 and 272 Step A: 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 tert-butyl 1-{[(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 A stirring 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) under N₂ at 0°C was treated with 4-nitrophenylchloroformate (109.0 mg, 0.54 mmol) and stirred at RT for 1.5 h. Ethyl (3S)-3-[(2S)-2-amino-4-methylpentanamido]-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 stirred at RT for 18 h. The reaction was diluted with water (10 mL) and extracted with EtOAc (3 x 10 mL). The organics were washed sat. NaHCO₃ solution (2 x 5 mL) then with brine (2 x 10 mL), dried over MgSO₄, filtered and concentrated. The residue was purified by FCC (25 g Sfar Duo; 0%-100% EtOAc in heptane) and product fractions were concentrated to give a mixture of the title compounds (382 mg, 76% Yield) as a colourless gum. 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). Step B: 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)pentanamido]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)pentanamido]propanoate To a solution of the product of step A (380.0 mg, 0.37 mmol) in anhydrous DCM (2 mL) was added TFA (0.11 mL, 1.44 mmol) and the reaction mixture stirred at RT for 5.5 h. The reaction mix was concentrated and the residue purified on an SCX cartridge (10 g, eluting with EtOAc, 10% MeOH in EtOAc then 50% NH3 (7M in MeOH) in EtOAc) to afford a mixture of the title compounds (237 mg, 93% Yield) as a yellow oil. LCMS m/z: 610.4 [M+H]+, (ESI+), Rt = 0.93/0.94 (S1) ¹H NMR (500 MHz, DMSO-d6) δ [ppm]: 8.70 (dd, J = 13.9, 8.3 Hz, 1H), 8.15 – 7.39 (m, 2H), 7.05 – 6.84 (m, 4H), 5.57 – 5.43 (m, 1H), 4.45 – 4.29 (m, 1H), 4.06 – 3.99 (m, 2H), 3.99 – 3.66 (m, 2H), 2.87 – 2.72 (m, 4H), 2.46 – 2.39 (m, 2H), 2.27 – 2.22 (m, 3H), 1.96 – 1.92 (m, 3H), 1.91 – 1.85 (m, 3H), 1.61 – 1.31 (m, 3H), 1.10 – 1.05 (m, 3H), 0.82 – 0.73 (m, 6H). Step C: 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}pentanamido]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}pentanamido]propanoate A stirring solution of the product of step B (235.0 mg, 0.35 mmol) and TEA (0.23 mL, 1.75 mmol) in a mixture of acetone (0.27 mL) and DCM (1.5 mL) at RT under N2 was treated in one portion with STAB (221 mg, 1.04 mmol) and stirred at RT for 20 h. The reaction was diluted with water (15 mL) and sat. NaHCO3 solution (15 mL) then extracted with DCM (3 x 10 mL). The combined organics were dried (hydrophobic frit) and concentrated. The residue was purified by FCC (10 g, 0-100% EtOAc heptane, then 0-15% MeOH EtOAc) to afford a mixture of the title compounds (148 mg, 62% Yield) as a colourless gum. LCMS m/z: 652.5 [M+H]+, (ESI+), Rt = 0.98/0.99 (S1). Step D: (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}pentanamido]propanoic acid and (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}pentanamido]propanoic acid To a solution of the product of step C (148.0 mg, 0.23 mmol) in THF (1.5 mL) and MeOH (0.15 mL) was added 2 M LiOH (aq.) (0.23 mL, 0.46 mmol) and the mixture stirred at RT for 2 h. Reaction mixture was concentrated, diluted with water (3 mL) and acidified to pH3 with citric acid (10% aq solution) and the mix extracted with DCM (2 x 20 mL). The organic layers were combined, dried (hydrophobic frit) and concentrated. The residue was purified using a Waters Sunfire C18 column ((100 mm × 30 mm, 5 μM; temperature: RT) and a gradient of 5-40% B (A= 0.1% formic acid in water; B= 0.1% formic acid in MeCN) over 16.00 min then 95% B for 2.00 min followed by 95% A for 2.00 min at flow rate of 40 mL/min) to afford separation of the regioisomers as; Example 271: (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}pentanamido]propanoic acid (12.3 mg, 8.4% yield) as a solid. LCMS m/z: 624.4 [M+H]+, (ESI+), Rt = 2.86 (S3) ¹H NMR (500 MHz, DMSO-d6) δ [ppm]: 8.79 (d, J = 7.9 Hz, 1H), 7.91 – 7.83 (m, 2H), 6.99 – 6.84 (m, 4H), 5.53 – 5.40 (m, 1H), 4.39 – 4.30 (m, 1H), 3.59 – 3.48 (m, 2H), 2.92 (hept, J = 6.2 Hz, 1H), 2.68 – 2.60 (m, 4H), 2.59 – 2.53 (m, 2H), 2.28 – 2.22 (m, 3H), 1.94 (s, 3H), 1.86 (s, 3H), 1.58 – 1.37 (m, 3H), 1.07 – 1.02 (m, 6H), 0.83 – 0.73 (m, 6H) Example 272: (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}pentanamido]propanoic acid (11.1 mg, 7.5% yield) as a solid LCMS m/z: 624.5 [M+H]+, (ESI+), Rt = 2.89 (S3) ¹H NMR (500 MHz, DMSO-d6) δ [ppm]: 8.79 (d, J = 8.0 Hz, 1H), 7.95 (d, J = 8.8 Hz, 1H), 7.49 (s, 1H), 6.97 – 6.85 (m, 4H), 5.46 (q, J = 7.4 Hz, 1H), 4.40 – 4.26 (m, 1H), 3.80 – 3.77 (m, 2H), 2.92 (hept, J = 7.0 Hz, 1H), 2.69 – 2.57 (m, 4H), 2.48 – 2.45 (m, 2H), 2.28 – 2.19 (m, 3H), 1.94 (s, 3H), 1.88 (s, 3H), 1.60 – 1.35 (m, 3H), 1.08 – 0.99 (m, 6H), 0.85 – 0.72 (m, 6H). Scheme for general route 27 Synthesis of intermediate Y1 Step A: 4-bromo-5,7-dimethyl-1H-indazole To a mixture of 3-bromo-2,4,6-trimethylaniline (1.0 mL, 6.13 mmol) and potassium acetate (903 mg, 9.2 mmol) in chloroform (10 mL) was slowly added acetic anhydride (0.87 mL, 9.2 mmol). The reaction mixture was stirred at 60°C for 1 h.3-methylbutyl nitrite (2.0 mL, 14.89 mmol) was added and the reaction mixture was stirred at 60°C for 18 h. The mixture was concentrated then water (50 mL) and EtOAc (100 mL) were added. The organic phase was separated, washed with water (50 mL) and brine (50 mL), dried through a phase separator and concentrated. The residue was purified by FCC (EtOAc in heptane 0 to 100% gradient) to afford 4-bromo-5,7-dimethyl-1H-indazole (400 mg, 29% Yield) as a light orange solid. LCMS m/z: 225.1/227.1 [M+H]+, (ESI+), Rt = 0.90 (S1). Step B: 4-bromo-2,5,7-trimethyl-2H-indazole To a solution of 4-bromo-5,7-dimethyl-1H-indazole (500.0 mg, 2.22 mmol) in EtOAc (20 mL) was added trimethyloxonium tetrafluoroborate (739 mg, 5.0 mmol) at RT, and the mixture stirred for 18 h. The reaction solution was diluted with water and the mixture extracted with EtOAc and the layers separated. The organic layer was filtered through a phase separator and concentrated. The residue was purified by FCC (0 to 100% EtOAc in heptane gradient) to afford 4-bromo-2,5,7-trimethyl-2H-indazole (350 mg, 44% Yield) as a white powder. ¹H 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). Example 225: (3S)-3-[2,3-difluoro-5-(2,5,7-trimethyl-2H-indazol-4-yl)phenyl]-3- [(2S)-4-methyl-2-[(1-methyl-2-oxo-1,2-dihydropyridin-3- yl)formamido]pentanamido]propanoic acid A mixture of Pd(dppf)Cl₂.DCM (13.5 mg, 0.02 mmol), K₂CO₃ (92 mg, 0.66 mmol), 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-dihydropyridin-3-yl)formamido]pentanamido]propanoate (Intermediate H1) (200.0 mg, 0.33 mmol) and 4-bromo-2,5,7-trimethyl-2H-indazole (87 mg, 0.36 mmol) in 1,4-dioxane (1.9 mL) and water (0.5 mL) was degassed with N2 for 5 min. The reaction mixture was stirred at 150^oC by microwave irradiation for 15 mins. The reaction mixture was filtered and the filtrate concentrated. The residue was dissolved in a mixture of THF (2.8 mL) and water (1.1 mL) and LiOH hydrate (28.5 mg, 0.66 mmol) was added and the mixture stirred at RT for 2 h. The reaction mix was diluted with water (5 mL) and extracted with EtOAc (3 x 5mL). The organics were dried over Na2SO4 and concentrated. The residue was purified by HPLC (P1) to afford (3S)-3-[2,3-difluoro-5-(2,5,7-trimethyl-2H- indazol-4-yl)phenyl]-3-[(2S)-4-methyl-2-[(1-methyl-2-oxo-1,2-dihydropyridin-3- yl)formamido]pentanamido]propanoic acid (45 mg, 22% yield) as a solid. LCMS m/z: 608.4 [M+H]+, (ESI+), Rt = 3.17 (S3) ¹H NMR (400 MHz, DMSO-d6) δ [ppm]: 10.05 (d, J = 8.2 Hz, 1H), 8.92 (s, 1H), 8.19 – 8.13 (m, 1H), 8.07 – 8.01 (m, 1H), 7.91 (s, 1H), 7.38 – 7.29 (m, 1H), 7.23 – 7.17 (m, 1H), 6.95 (s, 1H), 6.43 (t, J = 6.9 Hz, 1H), 5.51 – 5.44 (m, 1H), 4.57 – 4.43 (m, 1H), 4.09 (s, 3H), 3.54 (s, 3H), 2.76 – 2.71 (m, 2H), 2.56 – 2.41 (m, 2H), 2.19 (s, 3H), 1.43 – 1.39 (m, 2H), 0.98 (d, J = 6.5 Hz, 1H), 0.76 – 0.68 (m, 6H). Scheme for general route 28 Synthesis of intermediate Y2 Step A: ethyl 8-bromo-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylate To a cooled solution of (E)-(ethyl N-[(2,4,6- trimethylbenzenesulfonyl)oxy]ethanimidate) (2.47 g, 8.67 mmol) in 1,4-Dioxane (20 mL), perchloric acid (9.97 mL, 115.6 mmol) was added dropwise. The temperature was maintained at 0° C. for 10 minutes and then ice-cold water was added. The resulting precipitate was collected by vacuum filtration and washed with water. 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-bromopyridin-2-amine (1.0 g, 5.78 mmol) in DCM (20 mL). The reaction was allowed to warm to RT and stirred for 1 h. The reaction mixture was evaporated and to the residue was added pyridine (0.93 mL, 11.56 mmol) in DMF (5 mL). Then, at 0^oC ethyl 2-chloro-2-oxo-acetate (0.97 mL, 8.67 mmol) was added and the mixture stirred at RT for 0.5 h. The reaction mixture was concentrated, water (150 mL) was added and the solid was filtered, washed with water (20 mL) and sat. NaHCO₃ (20 mL) and dried. The residue was purified by FCC (Sfar DUO 25 g (EtOAc in heptane 0 to 100% gradient) to afford ethyl 8-bromo-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylate (0.62 g, 39% Yield) as a beige powder. LCMS m/z: 270.0/272.0 [M+H]+, (ESI+), Rt = 0.65 (S1) ¹H 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). Step B: {8-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-yl}methanol ethyl 8-bromo-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylate (350.0 mg, 1.3 mmol) was dissolved into THF (5 mL) then NaBH4 (98 mg, 2.59 mmol) and MeOH (1 mL) were added. The reaction mixture was stirred at RT for 5 min. The reaction mixture was quenched with sat. NaHCO3 solution (2 mL) and extracted with EtOAc (10 mL). The organic layer was filtered through a phase separator and the filtrate concentrated to afford {8-bromo- [1,2,4]triazolo[1,5-a]pyridin-2-yl}methanol (200 mg, 68% Yield) as a white solid. LCMS m/z: 228.0/230.0 [M+H]+, (ESI+), Rt = 0.44 (S1) ¹H 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). Step C: 8-bromo-[1,2,4]triazolo[1,5-a]pyridine-2-carbaldehyde MnO₂ (762 mg, 8.77 mmol) was added to a solution of {8-bromo-[1,2,4]triazolo[1,5- a]pyridin-2-yl}methanol (200 mg, 0.877 mmol) in DCM (20 mL) at RT. The reaction mixture was stirred at reflux for 2 h. Additional MnO₂ (762 mg, 8.77 mmol) and MeCN (10 mL) were added and the reaction mixture stirred at 40^oC for 18 h. The reaction mixture was filtered through celite and the filtrate concentrated to afford 8-bromo-[1,2,4]triazolo[1,5-a]pyridine- 2-carbaldehyde (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). Step D: ({8-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-yl}methyl)dimethylamine To 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 [2 M in THF] (2.0 mL, 4.0 mmol) was added STAB (400.0 mg, 1.83 mmol) and the mixture stirred at RT for 18 h. The reaction mixture was quenched with MeOH (2 mL) and concentrated. The residue was purified by FCC (Sfar Amino 11g (EtOAc in heptane 0 to 100% gradient)) to afford ({8-bromo-[1,2,4]triazolo[1,5- a]pyridin-2-yl}methyl)dimethylamine (170 mg, 75% Yield) as a light yellow solid. LCMS m/z: 255.1/257.1 [M+H]+, (ESI+), Rt = 0.35 (S1) ¹H NMR (400 MHz, DMSO-d6) δ [ppm]: 8.94 (dd, J = 6.8, 1.0 Hz, 1H), 7.98 (dd, J = 7.5, 1.0 Hz, 1H), 7.10 (dd, J = 7.6, 6.7 Hz, 1H), 3.67 (s, 2H), 2.25 (s, 6H). Step E: 2-[(dimethylamino)methyl]-[1,2,4]triazolo[1,5-a]pyridine-8-carboxylic acid hydrochloride To a cooled (-78° C) solution of ({8-bromo-[1,2,4]triazolo[1,5-a]pyridin-2- yl}methyl)dimethylamine (170.0 mg, 0.67 mmol) in anhydrous THF (1 mL), 2.5 M butyllithium [in hexanes] (0.4 mL, 1.0 mmol) was added. The reaction mixture was maintained at temp. for 15 mins and then crushed dry ice was added in one portion. The cooling bath was removed and the reaction stirred at RT for 1 h. The reaction mixture was acidified with 1M HCl and then concentrated to afford 2-[(dimethylamino)methyl]-[1,2,4]triazolo[1,5- a]pyridine-8-carboxylic acid hydrochloride (170 mg, 70% yield) as a yellow solid. LCMS m/z: 221.1 [M+H]+, (ESI+), Rt = 0.20 (S1) ¹H 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). Example 293: (3S)-3-[(2S)-2-({2-[(dimethylamino)methyl]-[1,2,4]triazolo[1,5- a]pyridin-8-yl}formamido)-4-methylpentanamido]-3-{4-fluoro-2',4',5,6'-tetramethyl-[1,1'- biphenyl]-3-yl}propanoic acid 2-[(dimethylamino)methyl]-[1,2,4]triazolo[1,5-a]pyridine-8-carboxylic acid hydrochloride (94 mg, 0.365 mmol), intermediate D4 (120 mg, 0.243 mmol) and TEA (67 mg, 0.664 mmol) were dissolved in anhydrous DMF (1 mL). T3P [50% in DMF] (0.20 mL, 0.332 mmol) was added and the solution stirred at RT for 0.5 h.1M HCl (5 mL) was added and the mix extracted with EtOAc (3 x 50 mL) The combined organics were filtered through a phase separator and concentrated. The residue was purified by FCC (Sfar Amino column, 11 g (EtOAc in heptane 0 to 100% gradient)). The product was dissolved in MeOH (1 mL) then 2 M LiOH (aq.) (0.24 mL, 0.49 mmol) was added and the mixture stirred at RT for 0.5 h. The reaction mixture was acidified with 2M HCl (aq.) and concentrated. The aqueous solution was eluted through a Porapak^TM Rxn cart (500 mg) eluting from MeOH. The solution was concentrated and the residue purified by HPLC (P3) followed by further purification by HPLC (P2) to afford (3S)-3-[(2S)-2-({2-[(dimethylamino)methyl]-[1,2,4]triazolo[1,5-a]pyridin- 8-yl}formamido)-4-methylpentanamido]-3-{4-fluoro-2',4',5,6'-tetramethyl-[1,1'-biphenyl]-3- yl}propanoic acid (1.0 mg, 0.7% Yield) as a solid. LCMS m/z: 631.5 [M+H]+, (ESI+), Rt = 2.86 (S3) ¹H NMR (500 MHz, MeOD-d4) δ [ppm]: 8.01 (dd, J = 8.8, 1.4 Hz, 1H), 7.93 (dd, J = 7.3, 1.4 Hz, 1H), 7.86 (dd, J = 8.8, 7.3 Hz, 1H), 6.82 – 6.79 (m, 2H), 6.73 (s, 1H), 6.63 (s, 1H), 5.66 – 5.55 (m, 1H), 4.82 (dd, J = 8.7, 6.1 Hz, 1H), 4.47 (d, J = 13.8 Hz, 1H), 4.21 (d, J = 13.8 Hz, 1H), 2.80 – 2.69 (m, 7H), 2.67 – 2.59 (m, 1H), 2.30 – 2.18 (m, 6H), 1.90 – 1.65 (m, 9H), 1.01 – 0.95 (m, 6H). Example 87 Step A: tert-butyl 3-[(3-{[(1S)-1-{[(1S)-1-{4,5-difluoro-2',4',6'-trimethyl-[1,1'- biphenyl]-3-yl}-3-ethoxy-3-oxopropyl]carbamoyl}-3-methylbutyl]carbamoyl}-2-oxo-1,2- dihydropyridin-1-yl)methyl]azetidine-1-carboxylate Prepared by analogous way to example 85 (HATU, DIPEA, DMF) using intermediate B5 and intermediate K3c. LCMS m/z: 751.5 [M+H]+, (ESI+), Rt = 1.24 (S2) ¹H NMR (400 MHz, DMSO-d6) δ [ppm]: 9.96 (d, J = 8.0 Hz, 1H), 8.83 (d, J = 8.0 Hz, 1H), 8.22 (dd, J = 7.3, 2.2 Hz, 1H), 8.14 (dd, J = 6.6, 2.2 Hz, 1H), 7.16 – 7.10 (m, 1H), 6.95 – 6.91 (m, 3H), 6.50 – 6.45 (m, 1H), 5.56 – 5.49 (m, 1H), 4.53 – 4.46 (m, 1H), 4.29 – 4.16 (m, 2H), 4.03 – 3.95 (m, 2H), 3.86 (br. s, 2H), 3.68 (br. s, 2H), 3.02 – 2.93 (m, 1H), 2.82 (d, J = 7.8 Hz, 2H), 2.26 (s, 3H), 1.92 – 1.90 (m, 6H), 1.40 – 1.35 (m, 12H), 1.05 (t, 3H), 0.79 – 0.74 (m, 6H). Step B: ethyl (3S)-3-[(2S)-2-({1-[(azetidin-3-yl)methyl]-2-oxo-1,2-dihydropyridin-3- yl}formamido)-4-methylpentanamido]-3-{4,5-difluoro-2',4',6'-trimethyl-[1,1'-biphenyl]-3- yl}propanoate To a stirring solution of tert-butyl 3-[[3-[[(1S)-1-[[(1S)-1-[2,3-difluoro-5-(2,4,6- trimethylphenyl)phenyl]-3-ethoxy-3-oxo-propyl]carbamoyl]-3-methyl-butyl]carbamoyl]-2- oxo-1-pyridyl]methyl]azetidine-1-carboxylate (90%, 170 mg, 0.204 mmol) in DCM (1.5 mL) was added TFA (0.13 mL, 1.70 mmol). The reaction mixture was stirred at RT for 18 hours. The reaction mixture was concentrated in vacuo, sonicated with EtOAc and concentrated in vacuo to get a crude residue. Purification by SCX chromatography (0-100% 7M NH3 in MeOH) afforded (85 mg, 80% pure, 51% Yield) as off-white solid. LCMS m/z: 651.4 [M+H]+, (ESI+), Rt = 1.04 (S2) Step C: (3S)-3-[(2S)-2-({1-[(azetidin-3-yl)methyl]-2-oxo-1,2-dihydropyridin-3- yl}formamido)-4-methylpentanamido]-3-{4,5-difluoro-2',4',6'-trimethyl-[1,1'-biphenyl]-3- yl}propanoic acid Prepared by analogous way to example 85 (LiOH, THF, H2O) using step B product. LCMS m/z: 623.5 [M+H]+, (ESI+), Rt = 2.72 (S3) ¹H NMR (500 MHz, DMSO-d6) δ [ppm]: 11.15 – 10.19 (m, 1H), 9.77 – 9.20 (m, 1H), 8.18 – 8.02 (m, 1H), 7.80 – 7.59 (m, 1H), 7.09 – 6.99 (m, 1H), 6.93 – 6.54 (m, 3H), 6.55 – 6.15 (m, 1H), 5.40 – 5.19 (m, 1H), 4.41 – 4.26 (m, 1H), 4.25 – 4.10 (m, 1H), 4.00 – 3.75 (m, 1H), 3.56 – 3.45 (m, 2H), 3.21 – 3.13 (m, 2H), 2.47 – 2.39 (m, 2H), 2.29 – 2.20 (m, 3H), 2.16 – 2.01 (m, 1H), 1.96 – 1.82 (m, 6H), 1.61 – 1.35 (m, 3H), 0.87 – 0.73 (m, 6H). Example 86 (3S)-3-{4,5-difluoro-2',4',6'-trimethyl-[1,1'-biphenyl]-3-yl}-3-[(2S)-4-methyl-2-({1-[(1- methylazetidin-3-yl)methyl]-2-oxo-1,2-dihydropyridin-3-yl}formamido)pentanamido] propanoic acid Step A: ethyl (3S)-3-{4,5-difluoro-2',4',6'-trimethyl-[1,1'-biphenyl]-3-yl}-3-[(2S)-4- methyl-2-({1-[(1-methylazetidin-3-yl)methyl]-2-oxo-1,2-dihydropyridin-3- yl}formamido)pentanamido]propanoate To a stirring solution of ethyl (3S)-3-[[(2S)-2-[[1-(azetidin-3-ylmethyl)-2-oxo-pyridine-3- carbonyl]amino]-4-methyl-pentanoyl]amino]-3-[2,3-difluoro-5-(2,4,6- trimethylphenyl)phenyl]propanoate (94%, 208 mg, 0.300 mmol) in DCE (1.5 mL) was added aqueous formaldehyde (37%, 0.18 mL, 2.42 mmol). The reaction was stirred vigorously under nitrogen for 5 mins at rt before STAB (254 mg, 1.20 mmol) was added. The reaction was stirred at room temperature under nitrogen for 2 hours. The residue was diluted with DCM (20 ml) and saturated aq. NaHCO3 was added until it remained basic. The layers were separated and the aqueous layer was extracted with DCM (2 x 20 ml). The combined organic extracts were dried (hydrophobic frit) and concentrated in vacuo to give a residue. Purification by column chromatography (10 g silica, 0-100% EtOAc in heptane, followed by 0-10% 7M NH3 in EtOAc) afforded (152 mg, 90% pure, 68% Yield) as a yellow oil. LCMS m/z: 665.5 [M+H]+, (ESI+), Rt = 4.53 (S4) ¹H NMR (500 MHz, DMSO) δ 11.96 – 9.93 (m, 1H), 8.76 (dd, J = 67.4, 8.1 Hz, 1H), 8.14 (ddd, J = 76.0, 6.9, 2.2 Hz, 1H), 7.86 – 7.24 (m, 1H), 7.19 – 7.02 (m, 1H), 7.03 – 6.86 (m, 3H), 6.14 (dt, J = 316.3, 6.8 Hz, 1H), 5.56 – 5.46 (m, 1H), 4.56 – 4.35 (m, 1H), 4.26 – 4.11 (m, 1H), 4.02 – 3.88 (m, 2H), 3.70 – 3.58 (m, 1H), 3.51 – 3.45 (m, 1H), 3.19 – 3.08 (m, 2H), 2.91 – 2.87 (m, 1H), 2.94 – 2.77 (m, 2H), 2.79 – 2.67 (m, 1H), 2.29 – 2.23 (m, 3H), 2.20 – 1.72 (m, 3H), 1.92 – 1.87 (m, 6H), 1.45 – 1.30 (m, 3H), 1.11 – 1.01 (m, 3H), 0.81 – 0.69 (m, 6H). Step B: (3S)-3-{4,5-difluoro-2',4',6'-trimethyl-[1,1'-biphenyl]-3-yl}-3-[(2S)-4-methyl- 2-({1-[(1-methylazetidin-3-yl)methyl]-2-oxo-1,2-dihydropyridin-3- yl}formamido)pentanamido] propanoic acid Prepared by analogous way to example 85 (LiOH, THF, H₂O) using step A product. LCMS m/z: 637.4 [M+H]+, (ESI+), Rt = 2.66 (S4) ¹H NMR (500 MHz, DMSO-d6) δ [ppm]: 9.98 (d, J = 8.1 Hz, 1H), 8.97 (d, J = 7.8 Hz, 1H), 8.15 (dd, J = 7.2, 2.1 Hz, 1H), 8.02 (dd, J = 6.6, 2.2 Hz, 1H), 7.13 – 7.03 (m, 1H), 6.94 – 6.91 (m, 2H), 6.89 – 6.85 (m, 1H), 6.41 (t, J = 6.9 Hz, 1H), 5.45 (q, J = 7.3 Hz, 1H), 4.54 – 4.46 (m, 1H), 4.27 – 4.09 (m, 2H), 3.30 – 3.23 (m, 2H), 3.14 – 2.99 (m, 2H), 2.88 – 2.77 (m, 1H), 2.70 – 2.60 (m, 2H), 2.32 – 2.22 (m, 6H), 1.91 (s, 3H), 1.89 (s, 3H), 1.52 – 1.31 (m, 3H), 0.83 – 0.70 (m, 6H).

Examples – Integrins cell adhesion assays a4b7 Cell Adhesion assay: A transparent non-binding v bottom plate is used for dispensing the compounds from a stock solution of 10 mM. The compounds are dispensed in a half log dilution series and normalised to 0.1% DMSO. This plate is referred to as Plate 1. Recombinant human MAdCAM (stock: 50 mg protein) is reconstituted in 250 mL PBS to give 200 mg/mL solution. This is then further diluted to give 6 mg/mL in 5 mL of carbonate buffer (150 mL stock + 4850 mL carbonate buffer). On the black high binding maxisorp plate 50 mL of this protein solution is added to the compound wells and 50 mL of carbonate buffer is added to control wells and left to incubate overnight at 4°C. This plate is referred to as Plate 2. RPMI8866 cells are reconstituted in plating media (50 mM HEPES, 3 mM MgCl₂, 1 mM CaCl₂, 1% BSA in PBS) with 1:1000 of calcein AM at the density of 75000 cells/well. The cells are added to the above prepared compound plate (Plate1) and incubated for an hour at 37⁰ C and 5% CO2. The protein coated plate (Plate2) is washed with PBS and is blocked for two hours with 4% BSA prior to the addition of 100 mL of cell suspension using Via Flo (96well format). It is left to incubate for an hour at 37⁰ C and 5% CO₂. The supernatant from this plate is aspirated and is spun at 450g for 30 sec to remove unbound cells. The plate with the remaining adherent cells is then read in a fluorescent read out mode with an excitation wavelength of 485 nm and emission wavelength of 385 nm. a4b1 Cell Adhesion assay: A transparent non-binding v bottom plate is used for dispensing the compounds from a stock solution of 10 mM. The compounds are dispensed in a half log dilution series and normalised to 0.1% DMSO. Recombinant human VCAM (stock: 100 mg protein) is reconstituted in 1000 mL PBS to give 100 mg/mL solution. This is then further diluted to give 3 mg/mL in 5 mL of carbonate buffer (150 mL stock + 4850 mL carbonate buffer). On the black high binding maxisorp plate 50 mL of this protein solution is added to the compound wells and 50 mL of carbonate buffer is added to control wells and left to incubate overnight at 4°C. Jurkat cells are reconstituted in plating media (50 mM HEPES, 3 mM MgCl2, 1 mM CaCl2, 1% BSA in PBS) with 1:1000 of calcein AM at the density of 50000 cells/well. The cells are added to the above prepared compound plate and incubated for an hour at 37⁰ C and 5% CO2. The protein coated plate is washed with PBS prior to the addition of 100 mL of cell suspension using Via Flo (96well format) and is left to incubate for an hour at 37⁰ C and 5% CO2. The supernatant from this plate is aspirated and is spun at 450g for 30 sec to remove unbound cells. The plate with the remaining adherent cells is then read in a fluorescent read out mode with an excitation wavelength of 485 nm and emission wavelength of 385 nm. Activities for the compounds of the present invention are reported in Table 13 and described as follow: C: IC₅₀ > 1 µM; B: 1 µM ≥ IC₅₀ ≥0.01 µM; A: IC₅₀ < 0.01 µM. Table 13 Cell adhesion assays Activities –ranges A: IC50 < 0.01 µM, B: 0.01 µM ≤ IC50 ≤ 1 µM, C: IC50 >1 µM

SELECTED EMBODIMENTS Embodiment 1. A compound of Formula (I), or a pharmaceutically acceptable salt thereof: wherein: R^y is -CH(CH3)2, cyclopropyl or cyclobutyl; R^x is hydrogen or methyl; R¹ is -C(O)-R⁷; wherein R⁷ is -C1-6alkyl, substituted with 0 or 1 pyridine, phenyl or cyclopropyl; or R⁷ is phenyl or a 5-10 membered heterocyclyl each of which is independently substituted with 0, 1, 2 or 3 instances of R⁹; each R⁹ is independently selected from halogen, =O, -C1-6alkyl, -C(O)- R¹⁰, -C_1-6haloalkyl, -SO₂-C_1-6alkyl, -NH-C_1-4alkyl, -N(C_1-4alkyl)₂, -C_3- 6cycloalkyl, -O-R¹¹, phenyl and 4-10 membered heterocycle; and each of R⁹ is independently substituted with 0, 1, 2 or 3 independently selected from R¹⁷; R¹⁷ is selected from halogen, -C1-6alkyl, -O-R¹⁵,-C(O)-N(C1-4alkyl)2, - N(R¹²R¹³), 4 to 10 membered heterocycle, wherein when R¹⁷ is heterocycle, it is further substituted with 0, 1 or 2 groups independently selected from halogen, -C_1-6alkyl, =O, -C(O)-R¹⁴, -C_1-6haloalkyl, -SO₂- C_1-6alkyl, -NH-C_1-4alkyl, -N(C_1-4alkyl)₂, -C_3-6cycloalkyl, -O-R¹⁸; R¹⁰ is independently selected from -C_1-6alkyl, -C_1-6alkyl-C_{3- 6}cycloalkyl and C_3-6cycloalkyl; R¹¹ is a -C_1-6 alkyl, - C_1-6haloalkyl , 4 to 10 membered heterocycle or -C_1-6 alkyl-N(C_1-6 alkyl)₂ wherein the 4 to 10 membered heterocycle is substituted with 0 or 1 -C_1-6 alkyl; R¹² and R¹³ are independently selected from -C_1-6alkyl, -C_{1- 6}haloalkyl and cyclopropyl; R¹⁴ is independently selected from -C_1-6alkyl and C_3-6cycloalkyl; R¹⁵ is a -C_1-6 alkyl, - C_1-6haloalkyl, 4 to 10 membered heterocycle, or -C_1-6 alkyl-N(C_1-6 alkyl)₂ and when R¹⁵ is 4 to 10 membered heterocycle it is substituted with 0 or 1 -C1-6alkyl; R¹⁸ is a -C1-6 alkyl or - C1-6haloalkyl; wherein in each - N(C1-6 alkyl)2 or -N(C1-4alkyl)2 the two alkyl groups attached to N can be the same or different; R² is selected from the group consisting of Br, phenyl, naphthyl, and 5-10 membered heteroaryl, each of which can be independently substituted with 0, 1, 2 or 3 groups independently selected from -CN, -C1-6 alkyl, halogen, -C1-6haloalkyl, - O-C1-6 alkyl, phenyl, 5 to 6 membered heteroaryl, -O-C3-6cycloalkyl, -O-phenyl, and -O-(5 to 6 membered heterocycloalkyl); Y is -N= or -C(R³)=; R³ is halogen, -C1-6haloalkyl , -C 1-4alkyl or -C3-6cycloalkyl; R⁴ is halogen or hydrogen; R⁵ is halogen or hydrogen; R⁶ is -C(O)-O-R⁸, wherein R⁸ is hydrogen, -C 16 1-4alkyl or -C1-4alkyl-O-C(O)-R R¹⁶ is -C1-6alkyl, 3 to 6 cycloalkyl, 4 to 6 membered partially saturated heterocycle, wherein the partially saturated heterocycle is further substituted with one or two groups independently selected from =O or -C1- 4alkyl. Embodiment 2. The compound of embodiment 1, or a pharmaceutically acceptable salt thereof, with Formula Ia wherein R¹ to R⁶, R^x, R^y and Y are as defined in embodiment 1. Embodiment 3. The compound of any one of embodiment 1 or 2, or a pharmaceutically acceptable salt thereof, wherein: R^x is hydrogen. Embodiment 4. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein: R^x is methyl. Embodiment 5. The compound of anyone of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R^y is -CH(CH₃)₂. Embodiment 6. The compound of anyone of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R^y is cyclopropyl. Embodiment 7. The compound of anyone of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R^y is cyclobutyl. Embodiment 8. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein: R² is phenyl or 5-10 membered heteroaryl, each of which group is substituted with 1, 2 or 3 groups independently selected from -CN, -C_1-6 alkyl, halogen, -C_{1- 6}haloalkyl. Embodiment 9. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein: R² is substituted with 1, 2 or 3 groups independently selected from -CN, -C1-6 alkyl, halogen, -C1-6haloalkyl and is selected from , . Embodiment 10. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein: R² is substituted with 1, 2 or 3 groups independently selected from methyl, fluorine or -CF3 and is selected from , . Embodiment 11. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein Y is -C(R³)=. Embodiment 12. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein Y is -N=. Embodiment 13. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R³ is halogen, -CF₃, methyl, ethyl, cyclopropyl. Embodiment 14. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R⁴ is halogen or hydrogen. Embodiment 15. The compound of embodiment 7, wherein R⁴ is halogen. Embodiment 16. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R⁴ is fluorine. Embodiment 17. The compound of any one of embodiments Embodiment 1-7, wherein R⁵ is fluorine or hydrogen. Embodiment 18. The compound of any one of embodiments Embodiment 1-7, wherein R⁵ is hydrogen. Embodiment 19. The compound of any one of the preceding embodiments, wherein R⁶ is -C(O)-O-R⁸, wherein R⁸ is hydrogen, methyl, ethyl or isopropyl, -O-CH2-O- C(O)-R¹⁶ or -O-C(CH₃)-O-C(O)-R¹⁶, wherein R¹⁶ is methyl, ethyl, isopropyl, isobutyl, cyclobutyl, cyclopentyl, cyclohexane, neopentyl or (5-methyl-2-oxo-1,3-dioxol-4- yl)methyl. Embodiment 20. The compound of any one of embodiments Embodiment 1-8, wherein R⁶ is -C(O)-O-R⁸, wherein R⁸ is hydrogen, methyl, ethyl or isopropyl. Embodiment 21. The compound of embodiment 9, wherein R⁸ is hydrogen. Embodiment 22. The compound of anyone of the preceding embodiments, wherein R⁷ is -C_1-6alkyl, substituted with 0 or 1 pyridine or R⁷ is phenyl, substituted with 0, 1, 2 or 3 groups selected from -C1-6alkyl, halogen or -O-C1-6alkyl or R⁷ is 5-10 membered heterocyclyl substituted with 0, 1, 2 or 3 groups independently selected from R⁹ and each R⁹ is independently selected from halogen, =O, -C1-6alkyl, -C(O)-R¹⁰, -C1-6haloalkyl, -SO2-C1-6alkyl, -NH-C1-4alkyl, - N(C1-4alkyl)2, -C3-6cycloalkyl, phenyl, 4 to 7 membered heterocycle, -O-R¹¹; each R⁹ is independently substituted with 0, 1 or 2 independently selected from R¹⁷; R¹⁰ is independently selected from -C1-6alkyl, C3-6cycloalkyl and -C1-6alkyl- C3-6cycloalkyl; R¹¹ is a -C1-6 alkyl, -C1-6 alkyl-N(-C1-6 alkyl)2, - C1-6haloalkyl or 4 to 7 membered heterocycle; R¹⁷ is selected from halogen, -O-R¹⁵, -C(O)N(C1-4alkyl)2, -N(R¹²R¹³), and 4 to 10 membered heterocycle, when R¹⁷ is 4 to 10 membered heterocycle is substituted with 0, 1 or 2 independently selected halogen, -C1-6alkyl or - C1-6haloalkyl; R¹² and R¹³ are independently selected from -C_1-6alkyl, -C_1-6haloalkyl and cyclopropyl; R¹⁵ is -C_1-6alkyl, - C_1-6haloalkyl or 4 to 7 membered heterocycle and when R¹⁵ is 4 to 7 membered heterocycle it is substituted with 0 or 1 -C1-6alkyl; and wherein in each - N(C1-6 alkyl)2 or -N(C1-4alkyl)2 the two alkyl groups attached to N can be the same or different. Embodiment 23. The compound of anyone of the preceding embodiments, wherein R⁷ is -C1-6alkyl, substituted with 0 or 1 pyridine. Embodiment 24. The compound of anyone of the preceding embodiments, wherein R⁷ is phenyl, substituted with 0 or 1 groups selected from -C1-6alkyl, halogen or -O- C1-6alkyl. Embodiment 25. The compound of anyone of the preceding embodiments, wherein R⁷ is 5-10 membered heterocyclyl substituted with 0, 1, 2 or 3 groups independently selected from R⁹ and each R⁹ is independently selected from halogen, =O, -C_1-6alkyl, -C(O)-R¹⁰, -C_1-6haloalkyl, -SO₂-C_1-6alkyl, -NH-C_1-4alkyl, - N(C1-4alkyl)2, -C3-6cycloalkyl, phenyl, 4 to 7 membered heterocycle, -O-R¹¹; each R⁹ is independently substituted with 0, 1 or 2 R¹⁷; R¹⁷ is selected from halogen, -O-R¹⁵, -C(O)N(C_1-4alkyl)₂, -N(R¹²R¹³), and 4 to 10 membered heterocycle, when R¹⁷ is 4 to 10 membered heterocycle is substituted with 0, 1 or 2 halogen, -C_1-6alkyl or - C_1-6haloalkyl; R¹⁰ is independently selected from -C1-6alkyl, C3-6cycloalkyl and-C1-6alkyl-C3- 6cycloalkyl; R¹¹ is a -C1-6 alkyl, and when R¹¹ is -C1-6 alkyl, is substituted with 0 or 1 -N(- C1-6 alkyl)2, or R¹¹ is - C1-6haloalkyl or 4 to 7 membered heterocycle; R¹² and R¹³ are independently selected from -C1-6alkyl, -C1-6haloalkyl and cyclopropyl; R¹⁵ is -C1-6alkyl, - C1-6haloalkyl or 4 to 7 membered heterocycle and when R¹⁵ is 4 to 7 membered heterocycle it is substituted with 0 or 1 -C1-6alkyl. Embodiment 26. The compound of anyone of the preceding embodiments, wherein R⁹ is -C_1-6alkyl, substituted with 0, 1, 2 or 3 groups independently selected from - C(O)-N(C_1-4alkyl)₂, -O-R¹⁵, -N(R¹²R¹³), 4 to 10 membered heterocycloalkyl, which heterocycloalkyl is further substituted with 0, 1 or 2 groups independently selected from halogen or -C_1-6alkyl; R¹² and R¹³ are independently selected from -C_1-6alkyl, - C_1-6haloalkyl and cyclopropyl; R¹⁵ is -C1-6alkyl, - C1-6haloalkyl or 4 to 7 membered heterocycle and when R¹⁵ is 4 to 7 membered heterocycle it is substituted with 0 or 1 -C1-6alkyl and wherein in each - N(C1-6 alkyl)2 or -N(C1-4alkyl)2 the two alkyl groups attached to N can be the same or different. Embodiment 27. The compound of anyone of the preceding embodiments, wherein R⁹ is -C1-6alkyl, substituted with 0, 1, 2 or 3 groups independently selected from - C(O)-N(C1-4alkyl)2, -N(R¹²R¹³), -O-R¹⁵, 4 to 7 membered heterocycloalkyl, which heterocycloalkyl is further substituted with 0, 1 or 2 groups independently selected from halogen or -C1-6alkyl; R¹² and R¹³ are independently selected from -C1-6alkyl, - C_1-6haloalkyl and cyclopropyl; R¹⁵ is -C1-6alkyl, - C1-6haloalkyl or 4 to 7 membered heterocycle and when R¹⁵ is 4 to 7 membered heterocycle it is substituted with 0 or 1 -C1-6alkyl; and wherein in each - N(C_1-6 alkyl)₂ or -N(C_1-4alkyl)₂ the two alkyl groups attached to N can be the same or different. Embodiment 28. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R⁷ is selected from a group consisting of substituted or unsubstituted , . Embodiment 29. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R⁷ is selected from a group consisting of

, , , , , each substituted with 0, 1 or 2 substituents independently selected from –F, –Cl, oxo, –Me, isobutyl, isopropyl, cyclobutyl, –CH₂F, –CHF₂, –CH₂CF₃, –OMe, –OCF₃, –O-azetidin-3-yl, –N(Me)₂, –C(O)Me, –C(O)cyclopropyl, 1-Me- azetidin-3-yl, 3-F-azetidin-1-yl, –-C(O)CH2cyclopropyl, –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), –CH2-CH2-(3,3-diMe-azeditin-1-yl),–CH2-azeditin-1-yl, –CH2-(3-F- azeditin-1-yl), –CH2-(1-Me-azetidin-3-yl), –CH2-azetidin-3-yl, –CH2CH2-(3-F- pyrrolidin-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. Embodiment 30. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R¹ is selected from: -C(O)-CH3,

,

, , , , , Embodiment 31. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein each R² is independently selected from a group consisting of -Br, -CF3, . Embodiment 32. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R³ is independently selected from a group consisting of -F, -CF₃ and -CH₃. Embodiment 33. A compound or a pharmaceutically acceptable salt thereof selected from , , , ,

, , , , , , , , , , , , , , , , , , , , , , 69 70 , , , , , , , , , , , , , , , , , , , , , , , ,

Embodiment 34. A pharmaceutical composition comprising a pharmaceutically effective amount of a compound selected from any of the preceding embodiments, or a pharmaceutically acceptable salt of any of the foregoing, and a pharmaceutically acceptable carrier or excipient. Embodiment 35. The use of a compound selected from any of the preceding embodiments or a pharmaceutically acceptable salt of any of the foregoing, in the preparation of a medicament. Embodiment 36. A compound selected from any of the preceding embodiments or a pharmaceutically acceptable salt thereof, for use as a medicament. Embodiment 37. A method of inhibiting the interaction between a α₄β₇ integrins and MAdCAM-1 protein in a subject, the method comprising administering to the subject in need thereof a pharmaceutically effective amount of a compound selected from any of the preceding embodiments, a compound selected from any of the preceding embodiments, or a pharmaceutically acceptable salt thereof. Embodiment 38. A method of treating inflammatory bowel diseases in a human in need thereof, the method comprising administering to the human a pharmaceutically effective amount of a compound selected from any one of the embodiments 1 to 33, or a pharmaceutically acceptable salt of the foregoing. Embodiment 39. A compound selected from any of the preceding embodiments, a compound selected from any one of embodiments 1 to 33 or a pharmaceutically acceptable salt of the foregoing, for use in the treatment of inflammatory bowel diseases. Embodiment 40. The method of Embodiment 37 or 38, wherein the inflammatory bowel diseases is ulcerative colitis. Embodiment 41. The method of Embodiment 37 or 38, wherein the inflammatory bowel diseases is Crohn’s disease. Embodiment 42. A method of treating ulcerative colon disease in a human, the method comprising administering to the human in need thereof a pharmaceutically effective amount of a compound selected from any of Embodiments 1-33 or a pharmaceutically acceptable salt thereof. Embodiment 43. A compound selected from any of the preceding embodiments, a compound of any one of embodiments 1 to 33, or a pharmaceutically acceptable salt thereof, for use in the treatment of ulcerative colon disease. Embodiment 44. The method of Embodiment 42, wherein the ulcerative colon disease is ulcerative colitis. Embodiment 45. The method of Embodiment 42, wherein the ulcerative colon disease is Crohn’s Disease. Embodiment 46. A kit comprising: a) one or more compositions, each composition comprising a pharmaceutically effective amount of a compound selected from any one of Embodiments 1-33 or a pharmaceutically acceptable salt of any of the foregoing, and a pharmaceutically acceptable carrier or excipient; and b) instructions for administering the one or more compositions to a human in need thereof.

Claims

CLAIMS 1. A compound of Formula (I), or a pharmaceutically acceptable salt thereof: wherein: R^y is -CH(CH₃)₂, -CF₃, -CH₂F, CHF₂, -CH(CF₃)₂ cyclopropyl or cyclobutyl; R^x is hydrogen or methyl; R¹ is -C(O)-R⁷; wherein R⁷ is -C_1-6alkyl, substituted with 0 or 1 pyridine, phenyl and cyclopropyl; or R⁷ is phenyl or a 5-10 membered heterocyclyl each of which is independently substituted with 0, 1, 2, 3 or 4 instances of R⁹; each R⁹ is independently selected from halogen, =O, -C_1-6alkyl, -C(O)- R¹⁰, -C_1-6haloalkyl, -SO₂-C_1-6alkyl, -NH-C_1-4alkyl, -N(C_1-4alkyl)₂, -C_{3- 6}cycloalkyl, -O-R¹¹, phenyl and 4-10 membered heterocycle; and each of R⁹ is independently substituted with 0, 1, 2 or 3 independently selected from R¹⁷; R¹⁷ is selected from halogen, -C_1-6alkyl, -O-R¹⁵,-C(O)-N(C_1-4alkyl)₂, - N(R¹²R¹³), cyclopropyl and 4 to 10 membered heterocycle, when R¹⁷ is heterocycle, it is further substituted with 0, 1, 2 or 4 groups independently selected from halogen, -C_1-6alkyl, =O, -C(O)-R¹⁴, -C_{1- 6}haloalkyl, -SO₂-C_1-6alkyl, -NH-C_1-4alkyl, -N(C_1-4alkyl)₂, -C_3-6cycloalkyl, - O-R¹⁸; R¹⁰ is independently selected from -C1-6alkyl, -C1-6alkyl-C3- 6cycloalkyl and C3-6cycloalkyl; R¹¹ is a -C1-6 alkyl, - C1-6haloalkyl, 4 to 10 membered heterocycle or -C1-6 alkyl-N(C1-6 alkyl)2 wherein the 4 to 10 membered heterocycle is substituted with 0 or 1 -C1-6 alkyl; R¹² and R¹³ are independently selected from -C1-6alkyl, -C1- 6haloalkyl, C1-6alkyl-cyclopropyl, C1-6alkyl-(cyclopropyl)2, cyclobutyl and cyclopropyl, wherein C_1-6alkyl-cyclopropyl, C_1-6alkyl- (cyclopropyl)₂, cyclobutyl and cyclopropyl are substituted with 0, 1, 2 or 3 F; R¹⁴ is independently selected from -C1-6alkyl and C3-6cycloalkyl; R¹⁵ is H, a -C1-6 alkyl, - C1-6haloalkyl, 4 to 10 membered heterocycle, or -C1-6 alkyl-N(C1-6 alkyl)2 and when R¹⁵ is 4 to 10 membered heterocycle it is substituted with 0 or 1 -C1-6alkyl; R¹⁸ is a -C1-6 alkyl or - C1-6haloalkyl; wherein in each - N(C1-6 alkyl)2 or -N(C1-4alkyl)2 the two alkyl groups attached to N can be the same or different; R² is selected from the group consisting of Br, phenyl, naphthyl, and 5-10 membered heteroaryl, each of which can be independently substituted with 0, 1, 2, 3 or 4 groups independently selected from -CN, -C1-6 alkyl, halogen, -C1-6haloalkyl, -O-C1-6 alkyl, phenyl, 5 to 6 membered heteroaryl, -O-C3-6cycloalkyl, -O-phenyl, and -O-(5 to 6 membered heterocycloalkyl); Y is -N= or -C(R³)=; R³ is halogen, -C1-6haloalkyl, -C 1-4alkyl or -C3-6cycloalkyl; R⁴ is halogen or hydrogen; R⁵ is halogen or hydrogen; R⁶ is -C(O)-O-R⁸, wherein R⁸ is hydrogen, -C1-4alkyl, -C1-4alkyl-R¹⁶, -C1-4alkyl-C(O)N(Me)-R¹⁶ - C1-4alkyl-R¹⁶, -C1-4alkyl-C(O)N(R¹⁶,R^16a)- or -C1-4alkyl-O-C(O)-R¹⁶; R¹⁶ and R^16a are independently selected from -C1-6alkyl, 3 to 6 cycloalkyl, 4 to 6 membered heterocycle, 4 to 6 membered partially saturated heterocycle, wherein the partially saturated heterocycle is further substituted with one or two groups independently selected from =O or -C_{1- 4}alkyl.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, with Formula Ia wherein R¹ to R⁶, R^x, R^y and Y are as defined in claim 1.

3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R^x is hydrogen.

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

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

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

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

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

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

10. The compound of any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein R¹² and R¹³ are independently selected from -C1-6alkyl, -C1- 6haloalkyl, C1-6alkyl-cyclopropyl, C1-6alkyl-(cyclopropyl)2, cyclobutyl and cyclopropyl, wherein C1-6alkyl-cyclopropyl, C1-6alkyl-(cyclopropyl)2, cyclobutyl and cyclopropyl are substituted with 0, 1, 2 or 3 F.

11. The compound of any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein R¹⁷ is selected from halogen, -C1-6alkyl, -O-R¹⁵,-C(O)-N(C1-4alkyl)2, -N(R¹²R¹³) and 4 to 10 membered heterocycle, when R¹⁷ is heterocycle, it is further substituted with 0, 1 or 2 groups independently selected from halogen, -C1-6alkyl, =O, -C(O)-R¹⁴, -C_1-6haloalkyl, -SO₂-C_1-6alkyl, -NH-C_1-4alkyl, -N(C_1-4alkyl)₂, -C_{3- 6}cycloalkyl and -O-R¹⁸.

12. The compound of any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, wherein R¹² and R¹³ are independently selected from -C_1-6alkyl, -C_{1- 6}haloalkyl and cyclopropyl.

13. The compound of any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, wherein R¹⁵ is a -C_1-6 alkyl, - C_1-6haloalkyl, 4 to 10 membered heterocycle, or -C_1-6 alkyl-N(C_1-6 alkyl)₂ and when R¹⁵ is 4 to 10 membered heterocycle it is substituted with 0 or 1 -C_1-6alkyl.

14. The compound of any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, wherein R² is independently substituted with 0, 1, 2 or 3 groups.

15. The compound of any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, wherein R⁸ is hydrogen, -C_1-4alkyl or -C_1-4alkyl-O-C(O)-R¹⁶.

16. The compound of any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, wherein R⁸ is hydrogen, -C_1-4alkyl -C_1-4alkyl-R¹⁶, -C_1-4alkyl-C(O)N(Me)-R¹⁶ - or -C_1-4alkyl-O-C(O)-R¹⁶ and R¹⁶ is independently selected from -C_1-6alkyl, 3 to 6 cycloalkyl, 4 to 6 membered partially saturated heterocycle, wherein the partially saturated heterocycle is further substituted with one or two groups independently selected from =O or -C1-4alkyl.

17. The compound of any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, wherein: R² is phenyl or 5-10 membered heteroaryl, each of which group is substituted with 1, 2, 3 or 4 groups independently selected from -CN, -C1-6 alkyl, halogen, -C1- 6haloalkyl.

18. The compound of any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, wherein: R² is substituted with 1, 2, 3 or 4 groups independently selected from -CN, -C1-6 alkyl, halogen and -C1-6haloalkyl and is selected from .

19. The compound of any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, wherein: R² is substituted with 1, 2, 3 or 4 groups independently selected from -CN, methyl, F, Cl and CF₃ and is selected from .

20. The compound of any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof, wherein: R² is substituted with 1, 2, 3 or 4 groups independently selected from -CN, -C_1-6 alkyl, halogen, -C_1-6haloalkyl and is selected from

21. The compound of any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, wherein Y is -C(R³)=.

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

23. The compound of any one of claims 1 to 22, or a pharmaceutically acceptable salt thereof, wherein Y is -C(R³)= and R³ is halogen, -CF3, methyl, ethyl, cyclopropyl.

24. The compound of any one of claims 1 to 23, or a pharmaceutically acceptable salt thereof, wherein R⁴ is halogen or hydrogen.

25. The compound of claim 24, or a pharmaceutically acceptable salt thereof, wherein R⁴ is halogen.

26. The compound of claim 25, or a pharmaceutically acceptable salt thereof, wherein R⁴ is F.

27. The compound of any one of claims Embodiment 1 to 26, or a pharmaceutically acceptable salt thereof, wherein R⁵ is fluorine or hydrogen.

28. The compound of any one of claim 27, or a pharmaceutically acceptable salt thereof, wherein R⁵ is hydrogen.

29. The compound of any one of claims Embodiment 1 to 28, or a pharmaceutically acceptable salt thereof, wherein R⁶ is -C(O)-O-R⁸, wherein R⁸ is hydrogen, methyl, CF₃, ethyl, isopropyl, –CH₂-(5-methyl-2-oxo-1,3-dioxol-4-yl) or –CH₂-C(O)N(Me)₂.

30. The compound of any one of claims Embodiment 1 to 29, or a pharmaceutically acceptable salt thereof, wherein R⁶ is -C(O)-O-R⁸, wherein R⁸ is hydrogen, methyl, ethyl or isopropyl.

31. The compound of any one of claims Embodiment 1 to 30, or a pharmaceutically acceptable salt thereof, wherein R⁶ is -C(O)-O-R⁸, wherein R⁸ is hydrogen.

32. The compound of any one of claims 1 to 31, or a pharmaceutically acceptable salt thereof, wherein R⁷ is -C1-6alkyl, substituted with 0 or 1 pyridine.

33. The compound of anyone of claims 1 to 31, or a pharmaceutically acceptable salt thereof, wherein R⁷ is phenyl, substituted with 0, 1, 2, 3 or 4 groups selected from - C1-6alkyl, halogen or -O-C1-6alkyl.

34. The compound of any one of claims 1 to 31, or a pharmaceutically acceptable salt thereof, wherein R⁷ is phenyl, substituted with 0, 1, 2 or 3 groups selected from -C_{1- 6}alkyl, halogen or -O-C_1-6alkyl.

35. The compound of any one of claims 1 to 31, or a pharmaceutically acceptable salt thereof, wherein R⁷ is 5-10 membered heterocyclyl substituted with 0, 1, 2, 3 or 4 groups independently selected from R⁹ and each R⁹ is independently selected from halogen, =O, -C1-6alkyl, -C(O)-R¹⁰, -C1-6haloalkyl, -SO2-C1-6alkyl, -NH-C1-4alkyl, - N(C1-4alkyl)2, -C3-6cycloalkyl, phenyl, 4 to 7 membered heterocycle, -O-R¹¹; each R⁹ is independently substituted with 0, 1 or 2 independently selected from R¹⁷; R¹⁰ is independently selected from -C1-6alkyl, C3-6cycloalkyl and -C1-6alkyl- C3-6cycloalkyl; R¹¹ is a -C1-6 alkyl, -C1-6 alkyl-N(-C1-6 alkyl)2, - C1-6haloalkyl or 4 to 7 membered heterocycle; R¹⁷ is selected from halogen, -O-R¹⁵, -C(O)N(C1-4alkyl)2, -N(R¹²R¹³), and 4 to 10 membered heterocycle, when R¹⁷ is 4 to 10 membered heterocycle is substituted with 0, 1, 2 or 4 independently selected halogen, -C1-6alkyl or - C1-6haloalkyl; R¹² and R¹³ are independently selected from -C1-6alkyl, -C1-6haloalkyl and cyclopropyl; R¹⁵ is -C1-6alkyl, - C1-6haloalkyl or 4 to 7 membered heterocycle and when R¹⁵ is 4 to 7 membered heterocycle it is substituted with 0 or 1 -C1-6alkyl; and wherein in each - N(C1-6 alkyl)2 or -N(C1-4alkyl)2 the two alkyl groups attached to N can be the same or different.

36. The compound of claim 35, or a pharmaceutically acceptable salt thereof, wherein R⁷ is 5-10 membered heterocyclyl substituted with 0, 1, 2 or 3 groups and R¹⁷ is 4 to 10 membered heterocycle, wherein R¹⁷ is substituted with 0, 1 or 2 groups.

37. The compound of any one of claims 1 to 36, or a pharmaceutically acceptable salt thereof, wherein R⁹ is –C_1-6alkyl, substituted with 0, 1, 2 or 3 groups independently selected from -C(O)-N(C_1-4alkyl)₂, -O-R¹⁵, -N(R¹²R¹³), 4 to 10 membered heterocycloalkyl, which heterocycloalkyl is further substituted with 0, 1 or 2 groups independently selected from halogen or –C_1-6alkyl; R¹² and R¹³ are independently selected from –C_1-6alkyl, -C_1-6haloalkyl and cyclopropyl; R¹⁵ is –C_1-6alkyl, - C_1-6haloalkyl or 4 to 7 membered heterocycle and when R¹⁵ is 4 to 7 membered heterocycle it is substituted with 0 or 1 –C_1-6alkyl and wherein in each - N(C_1-6alkyl)₂ or -N(C_1-4alkyl)₂ the two alkyl groups attached to N can be the same or different.

38. The compound of any one of claims 1 to 37, or a pharmaceutically acceptable salt thereof, wherein R⁷ is selected from a group consisting of , , , , , , , each substituted with 0, 1 or 2 substituents independently selected from –F, –Cl, oxo, –Me, isobutyl, isopropyl, cyclobutyl, – CH₂F, –CHF₂, –CH₂CF₃, –CF₃, –OMe, –O-CF₃, –O-azetidin-3-yl, –N(Me)₂, – C(O)Me, –C(O)cyclopropyl, 1-Me-azetidin-3-yl, 3-F-azetidin-1-yl, 3-N(Me)₂-3-Me- azetidin-1-yl, 3-N(Me)2pyrrolidin-1-yl, 4-Me-piperidin-1-yl, 1-Me-piperidin-4-yl, 1- isopropyl-piperidin-4-yl, 4-N(Me)2-piperidin-1-yl, 4-cyclopropyl-piperazin-1-yl, 4- isopropyl-piperazin-1-yl, 4-Me-1,4-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]pyridin-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)-azetidin-1-yl, 2-methyl-2,5- diazabicyclo[2.2.1]heptan-5-yl, –C(O)CH2cyclopropyl, –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-(3-F-3-Me- azeditin-1-yl), –CH2-CH2-CH2-(3-F-3-Me-azeditin-1-yl), –CH2-azeditin-1-yl, –CH2- (3-F-azeditin-1-yl), –CH2-(1-Me-azetidin-3-yl), –CH2-azetidin-3-yl, –CH2CH2-(3-F- pyrrolidin-1-yl), –CH2CH2-(3-CF3-pyrrolidin-1-yl), –CH2CH2-(3,3-diF-pyrrolidin-1-yl), oxetan-3yl, –CH2CH2OCH3, –CH2CH2OH, –CH2C(O)N(Me)2, –CH2N(Me)2, – CH2CH2N(Me)2, –CH2CH2N(Me)CH(cyclopropyl)2, –CH2CH2N(Me)CH2(cyclopropyl), –CH2CH2CH2N(Me)2, –C(Me)2CH2N(Me)2, –CH2C(Me)2N(Me)2, – CH2CH2C(Me)2N(Me)2, –CH2CH2N(Me)CH2CF3, –CH2CH2N(Me)CH(Me)2, – CH2CH2N(Me)C(Me)3, –CH2CH2N(Me)cyclopropyl, 4-F-phenyl, –CH2CH2-(2- azaspiro[3.4]octan-2yl), –CH2CH2CH2-(2-azaspiro[3.4]octan-2yl), – CH2CH2CH2CH2-(2-azaspiro[3.4]octan-2yl), –CH2CH2-(6-azaspiro[3.4]octan-6-yl), – CH2CH2CH2-(6-azaspiro[3.4]octan-6-yl), –CH2CH2-(2,2-diF-6-azaspiro[3.4]octan-6- yl), –CH2CH2-(2-azaspiro[3.3]heptan-2-yl), –CH2CH2-(6-MeO-2- azaspiro[3.3]heptan-2-yl), –CH2CH2-(2-azaspiro[4.5]decan-2-yl), –CH2CH2-(7- azaspiro[3.5]nonan-7-yl), –CH2CH2-(6-azaspiro[3.5]nonan-6-yl), –CH2CH2-(2- azaspiro[3.5]nonan-2-yl), –CH2CH2-(5-oxa-8-azaspiro[3.5]nonan-8-yl), –CH2CH2- (7-oxa-2-azaspiro[3.5]nonan-2-yl), –CH2CH2CH2CH2-(7-oxa-2-azaspiro[3.5]nonan- 2-yl), –CH2CH2-(6,6-diF-2-azaspiro[3.3]heptan-2-yl), –CH2CH2-(8- azabicyclo[3.2.1]octan-8-yl), –CH2CH2-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl), CH₂CH₂CH₂-(2-azabicyclo[2.2.2]octan-2-yl), –CH₂CH₂CH₂-(6-oxa-3- azabicyclo[3.1.1]heptan-3-yl), –CH₂CH₂-(7,7-diF-1,6-diMe-3- azabicyclo[4.1.0]heptan-3-yl), –CH₂CH₂-(3-azabicyclo[3.1.1]heptan-3-yl), – CH₂CH₂CH₂-(2-azabicyclo[2.2.1]heptan-2-yl), CH₂CH₂CH₂-(3- azabicyclo[3.1.1]heptan-3-yl), –CH₂CH₂CH₂CH₂-(3-azabicyclo[3.1.1]heptan-3-yl), – CH₂CH₂-(2-azabicyclo[2.1.1]hexan-2-yl), –CH₂CH₂-(6,6-diMe-3- azabicyclo[3.1.0]hexan-3-yl), –CH₂CH₂N(Me)cyclobutyl), –CH₂CH₂N(Me)(3,3- diF)cyclobutyl-1-yl), –CH₂-CH₂-(4-CF₃-piperidin-1-yl), –CH₂-CH₂-(4,4-diMe- piperidin-1-yl), –CH₂-CH₂-(morpholin-4-yl), –CH₂-CH₂-CH₂-(morpholin-4-yl), –CH₂- CH₂-CH₂-(2,6-diMe-morpholin-4-yl), –CH₂-CH₂-CH₂-(2,2,6,6-tetraMe-morpholin-4- yl), –CH₂-CH₂-CH₂-(2,2-diMe-morpholin-4-yl), –CH₂-CH₂-(2,6-diMe-morpholin-4-yl), –CH₂-CH₂-(1,4-oxazepin-4-yl), –CH₂CH₂-CH₂-(1,4-oxazepin-4-yl), and –S(O)₂Me.

39. The compound of any one of claims 1 to 38, or a pharmaceutically acceptable salt thereof, wherein R⁷ is selected from a group consisting of , , , , , , each substituted with 0, 1 or 2 substituents independently selected from –F, –Cl, oxo, –Me, isobutyl, isopropyl, cyclobutyl, –CH₂F, –CHF₂, –CH₂CF₃, –OMe, –O-CF₃, –O-azetidin-3-yl, –N(Me)₂, –C(O)Me, –C(O)cyclopropyl, 1-Me- azetidin-3-yl, 3-F-azetidin-1-yl, –-C(O)CH₂cyclopropyl, –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), –CH2-CH2-(3,3-diMe-azeditin-1-yl),–CH2-azeditin-1-yl, –CH2-(3-F- azeditin-1-yl), –CH2-(1-Me-azetidin-3-yl), –CH2-azetidin-3-yl, –CH2CH2-(3-F- pyrrolidin-1-yl), –CH2CH2OCH3, –CH2C(O)N(Me)2, –CH2CH2N(Me)2, – CH2CH2CH2N(Me)2 –CH2CH2N(Me)CH2CF3, –CH2CH2N(Me)cyclopropyl, 4-F- phenyl and –S(O)2Me.

40. The compound of any one of the claims 1 to 39, or a pharmaceutically acceptable salt thereof, wherein each R² is independently selected from a group consisting of - Br, -CF₃,

, .

41. The compound of any one of the claims 1 to 40, or a pharmaceutically acceptable salt thereof, wherein each R² is independently selected from a group consisting of

.

42. The compound of any one of the claims 1 to 41, or a pharmaceutically acceptable salt thereof, wherein each R² is independently selected from a group consisting of - Br, -CF₃, , , , .

43. The compound of any one of the claims 1 to 42, or a pharmaceutically acceptable salt thereof, wherein each R² is independently selected from a group consisting of ,

, , , .

44. The compound of any one of claims 1 to 43, or a pharmaceutically acceptable salt thereof, wherein R¹ is selected from: -C(O)-CH3, , , , , , , ,

, ,

45. The compound of any one of claims 1 to 44, or a pharmaceutically acceptable salt thereof, wherein R¹ is selected from:

46. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, selected from

47. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, selected from

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

49. The use of a compound of any one of claims 1 to 47, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament.

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

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

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

53. A compound of any one of claims 1 to 47, or a pharmaceutically acceptable salt thereof, for use in the treatment of inflammatory bowel diseases.

54. The method of claim 52 or 53, wherein the inflammatory bowel diseases is ulcerative colitis.

55. The method of claim 52 or 53, wherein the inflammatory bowel diseases is Crohn’s disease.

56. A method of treating ulcerative colon disease in a human, the method comprising administering to the human in need thereof a pharmaceutically effective amount of a compound of any one of claims 1 to 47, or a pharmaceutically acceptable salt thereof.

57. A compound of 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 of claim 56, wherein the ulcerative colon disease is ulcerative colitis.

59. The method of claim 56, wherein the ulcerative colon disease is Crohn’s Disease.

60. A kit comprising: a) one or more compositions, each composition comprising a pharmaceutically effective amount of a compound of any one of claims 1 to 47, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient; and b) instructions for administering the one or more compositions to a human in need thereof.