COMPOUNDS AS ARGINASE INHIBITORS

Abstract

Claim 1: A compound of formula (1) or a pharmaceutically acceptable salt thereof, wherein R¹ is -NHR¹ᵃ; R¹ᵃ is -H or -C(O)CH(R¹ᵇ)NHR¹ᶜ; and R¹ᵇ is selected from -H, C₁₋₄ -alkyl and CH₂OR¹ᵈ and R¹ᶜ is -H; or R¹ᵇ and R¹ᶜ, together with the atom to which they are attached, form a 5-membered heterocyclic ring; and R¹ᵈ is H or -CH₃.

Description

-03'00' arginase inhibitors and THEIR METHODS of use Background Arginase is a manganese metalloenzyme that catalyzes the conversion of L-arginine to urea and L-ornithine. There are two isoforms: Arginase 1 is a cytosolic enzyme found predominantly in hepatocytes, where it plays a crucial role in the elimination of ammonia through the synthesis of urea, and Arginase 2, a mitochondrial enzyme highly expressed in The kidney involved in the production of ornithine, a precursor of polyamines and prolines important for cell proliferation and collagen production, respectively. Although L-arginine is not an essential amino acid as it can be produced by protein turnover in healthy adults, increased expression and secretion of arginases results in reduced L-arginine levels in various physiological and pathological conditions (e.g., pregnancy, autoimmune diseases, cancer). Immune cells, in particular, are sensitive to reduced L-arginine levels. T cells, when exposed to a low L-arginine microenvironment, reduce their proliferation rate and decrease the expression of Οϋ3ζ chain, IFNy, and lytic enzymes resulting in altered T cell responsiveness. Dendritic cells respond to low L-arginine conditions by reducing their ability to present antigens, and cytolytic lymphocytes reduce both proliferation and expression of lytic enzymes. Tumors use multiple immunosuppressive mechanisms to evade the immune system. One of these IF-2019-3 6421651 -APN-ANP#INPI Page 1 of 170 is the reduction of L-arginine through elevated levels of circulating arginase, increased expression and secretion of arginase by tumor cells, and the recruitment of suppressor cells of myeloid origin that express and secrete arginase. Together, these lead to a reduction of Larginine in the tumor microenvironment and an immunosuppressive phenotype. Pharmacological inhibition of arginase activity has been shown to reverse the immunosuppression induced by a low concentration of L-arginine in animal models. Therefore, there is a need for potent and selective arginase inhibitors to reverse immunosuppression and reactivate anticancer immunity in patients, either as a single agent or in combination with therapies that reverse additional immunosuppressive mechanisms. Compendium In one embodiment, a compound of formula (I), or a pharmaceutically acceptable salt thereof, is disclosed: where R1es -NHRla; Rlaes -H or -C(O)CH(Rlb)NH2; and Rlbes -CH3o -CH(CH3)2. In one embodiment, a compound of formula (la), or a pharmaceutically acceptable salt thereof, is disclosed: IF-2019-3 6421651 -APN-ANP#INPI Page 2 of 170 where R1es -NHRla; Ria is -H or -C(0)CH(Rlb)NHR1C; and Rlb is selected from -H, -(C1-C4)alkyl and CH2ORl and Rlces -H; either Rlband Rlc, together with the atom to which they are attached, form a 5-membered heterocyclic ring; and Rides-η or -CH3. In one embodiment, a compound of formula (Ib), or a pharmaceutically acceptable salt thereof, is disclosed: HO (Ib), where R1 is -NHRla; Rlaes -H or -C(O)CH(Rlb)NHR1C; and Rlb is selected from -H, -(C1-C4)alkyl and CH2ORldy Ríe is -H; either Rlband Rlc, together with the atom to which they are attached, form a 5-membered heterocyclic ring; and Rldes -H or -CH3; In one embodiment, a compound of formula (II), or a pharmaceutically acceptable salt thereof, is disclosed: IF-2019-3 6421651 -APN-ANP#INPI Page 3 of 170 where R2 is -OH or -NHR2a; R2a is -H or -C(O)CH(R2b)NH2; and R2bes -CH3o -CH(CH3)2. In one embodiment, a compound of formula (lia), or a pharmaceutically acceptable salt thereof, is disclosed: where R2 is -OH or -NHR2a; R2a is -H or -C(O)CH(R2b)NHR2c; R2b is selected from -H, -(C1-C4)alkyl and CH2OR2d and R2ces -H; either R2b and R2c, together with the atom to which they are attached, form a 5-membered heterocyclic ring; and R2des -H or -CH3. In one embodiment, a compound of formula (Ilb), or a pharmaceutically acceptable salt thereof, is disclosed: IF-2019-3 6421651 -APN-ANP#INPI Page 4 of 170 HO (lib), where R2 is -OH or -NHR2a; R2aes -H or -C(0)CH(R2b)NHR2c; R2b is selected from -H, -alkyl (C1-C4) and CH2OR2dy R2ces -H; either R2b and r2c, together with the atom to which they are attached, form a 5-membered heterocyclic ring; and R2des -H or -CH3. In some embodiments, a compound of formula (III), or a pharmaceutically acceptable salt thereof, is disclosed: (III), where R3 is -CH3 or -CH(CH3)z. In some embodiments, a compound of formula (Illa), or a pharmaceutically acceptable salt thereof, is disclosed: (Illa), IF-2019-3 6421651 -APN-ANP#INPI Page 5 of 170 or where R3 is selected from -H, -(C1-C4)alkyl and CH2OR3a; and R3a is -Η or -CH3. In one embodiment, a compound of formula 5 (Illb), or a pharmaceutically acceptable salt thereof, is disclosed: ?' THERE IS" HÓ (Illb), where R3 is selected from -H, -(C1-C4)alkyl and CH2OR3a; and R3aes -H or —CH3. In some embodiments, a compound of formula (IV), or a pharmaceutically acceptable salt thereof, is disclosed: (IV), where R4 is -OH or -NH2. In one embodiment, a compound of formula (IVb), or a pharmaceutically acceptable salt thereof, is disclosed: (IVb), where R4 is -OH or -NH2. IF-2019-3 6421651 -APN-ANP#INPI Page 6 of 170 In some embodiments, a compound of formula (V), or a pharmaceutically acceptable salt thereof, is disclosed: In one embodiment, a compound of formula (Vb), or a pharmaceutically acceptable salt thereof, is disclosed: In one embodiment, a compound of formula (VI), or a pharmaceutically acceptable salt thereof, is disclosed: H A <nvC?0H R6b Λ, —hT\ ^OH \ « R6a' OH (VI) where R6a is -H or -CH3; R6bes -C(O)C(R6cR6d)ΝΗ2; o -(C1-C3)alkyl which is substituted with 0 or 1 amino or -OR6e; and R6ces -(C1-C3)alkyl which is substituted with 0 or 1 amino or -OR6f; R6des-η or -CH3; and R6e and r6 are independently -H or -CH3. In one embodiment, a compound of formula (VIb), or a pharmaceutically acceptable salt thereof, is disclosed: IF-2019-3 6421651 -APN-ANP#INPI Page 7 of 170 R6bI N. R6a I NH θχ ) HO (VIb), where R6a is -Η or -CH3; R6bes ~C (O) C (R$cR6d) NH2; o -(C1-C3)alkyl which is substituted with 0 or 1 amino or -0R6e; and R6ces-alkyl (C1-C3) which is substituted with 0 or 1 amino or -OR6f; R6des -H or -CH3; and R6e and R6f are independently -H or -CH3. In some embodiments, the compounds of Table 1, or a pharmaceutically acceptable salt thereof, are disclosed: In some embodiments, pharmaceutical compositions are disclosed comprising a compound of formula (I), (la), (Ib), (II), (Ila), (lib), (III), (Illa), (Illb), (IV), (IVb), (V), (Vb), (VI), (VIb), including any subgenera or species thereof, or Table 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier acceptable. In some embodiments, methods of treating cancer are disclosed comprising a compound of formula (I), (la), (Ib), (II), (Ila), (lib), (III), (Illa), ( Illb), (IV), (IVb)t (V), (Vb), (VI), (VIb), including any subgenera or species thereof, or Table 1, or a pharmaceutically acceptable salt thereof. In some embodiments, compounds of formula (I), (la), (Ib), (II), (Ha), (Hb), (III), (Illa), IF-2019-3 6421651 -APN-ANP#INPI Page 8 of 170 or (Illb), (IV), (IVb), (V), (Vb), (VI), (VIb), including any subgenera or species thereof, or Table 1, or a pharmaceutically acceptable salt thereof, to treat cancer. In some embodiments, the use of a compound of formula (I), (la), (Ib), (II), (Ha), (Ilb), (III), (Illa), (Illb), (Illb) is disclosed. IV), (IVb), (V), (Vb), (VI), (VIb), including any subgenera or species thereof, or Table 1, or a pharmaceutically acceptable salt thereof in the manufacture of a medicine for use in the treatment of cancer. In some embodiments, pharmaceutical compositions are disclosed comprising a compound of formula (I) f (la), (Ib), (II), (Ha), (lib), (III), (IHa), (Illb), (IV), 15 (IVb), (V), (Vb), (VI), (VIb), including any subgenera or species thereof, or Table 1, or a pharmaceutically acceptable salt thereof, for use in cancer treatment. In some . Embodiments, methods are disclosed for treating an inflammatory respiratory disease comprising a compound of formula (I), (la), (Ib), (II), (Ila), (lib), (III), (Illa), (Illb), (IV), (IVb), (V), (Vb), (VI), (VIb), including any subgenera or species thereof, or Table 1, or a pharmaceutically acceptable salt thereof . In some embodiments, compounds of formula (I), (la), (Ib), (II), (Ha), (lib), (III), (IHa), (Illb), (IV), ( IVb), (V), (Vb), (VI), (VIb), which include any subgenera or species thereof, or Table 1, IF-2019-3 6421651 -APN-ANP#INPI Page 9 of 170 Or or a pharmaceutically acceptable salt thereof, to treat an inflammatory respiratory disease. In some embodiments, the use of a compound of formula (I), (la), (Ib), (II), (Ha), (Ilb), (III), (Illa), (Illb), (Illb) is disclosed. IV), (IVb), (V), (Vb), (VI), (VIb), including any subgenera or species thereof, or Table 1, or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in the treatment of an inflammatory respiratory disease. In some embodiments, pharmaceutical compositions are disclosed comprising a compound of formula (I), (la), (Ib), (II), (Ila), (lib), (III), (Illa), (Illb), (IV), (IVb), (V), (Vb), (VI), (VIb), including any subgenera or species thereof, or Table 1, or a pharmaceutically acceptable salt thereof, for use in the treatment of an inflammatory respiratory disease. In some embodiments, the aforementioned inflammatory respiratory disease is chronic obstructive pulmonary disease (COPD) or asthma. Brief description of the drawings Figure 1 shows NMR spectra showing the conversion of compound B to compound A, where compound B is prepared in 100% d6-DMSO (labeled A), 75% D2O in d6-DMSO (labeled B) , 50% D2O in d6-DMSO (labeled C), 25% D2O in d6-DMSO (labeled E) and 100% D2O (labeled F). Figure 2 shows the NMR spectrum (at 0.1 M DC1 in D2O) of compound B showing how acidification provides virtually complete conversion to compound A. IF-2019-3 6421651 -APN-ANP#INPI Page 10 of 170 Figure 3 compares the NMR spectra of amorphous material in d6-DMSO (Labeled B) with crystalline compound B in d6-DMSO (Labeled A) showing that both materials have the same cyclic structure as crystalline compound B. Detailed description Compounds In one embodiment, a compound of formula (I), or a pharmaceutically acceptable salt thereof, is disclosed: where R1es -NHRla; Riaes_H o-c(O)CH(Rlb)NH2; and Rlbes -CH3o -CH(CH3)2. In one embodiment, a compound of formula (I) is disclosed: In another embodiment, a pharmaceutically acceptable salt of the compound of formula (I) is disclosed. In some embodiments of formula (I), R1 is -NHR and Rla is -H. In some embodiments of formula (I), R1 is -NHRla, Rla is -C(O)CH(Rlb)NH2 and Rlbes -CH3. In some embodiments of formula (I), R1 is -NHRla, Rla is -C (O) CH (Rlb) NH2 and Rlb is -CH(CH3)2. In one embodiment, a compound of formula (la), or a pharmaceutically acceptable salt thereof, is disclosed: IF-2019-3 6421651 -APN-ANP#INPI Page 11 of 170 EITHER where R1es -NHRla; Ria is -H or -C(O)CH(Rlb)NHR1C; and Rlb is selected from -H, -(C1-C4)alkyl and CH2ORld; and Rlces -H; either Rlby Ric, together with the atom to which they are attached, form a 5-membered ring; and Rldes -H or -CH3; In one embodiment, a compound of formula (la) is disclosed: In another embodiment, a pharmaceutically acceptable salt of the compound of formula (la) is disclosed. In some embodiments, a compound of formula (la) is represented by formula (lal) or (Ia2): where R1 is equal to as defined above; In some embodiments of formula (la), Rlaes -H. In some embodiments of formula (la), Rlais C(O)CH(Rlb)NHR1C; Rlbes -H and Rlces -H. In some embodiments of formula (la), Rlais C(O)CH(Rlb)NHR1C; Rlbes CH2ORld; Rlces -H and Rldes -H. IF-2019-3 6421651 -APN-ANP#INPI Page 12 of 170 EITHER In some embodiments of formula (la), Rlais C(0)CH(Rlb)NHR1C; Rlbes CH20Rld; Rlces -H and Rldes -CH3. In some embodiments of formula (la), Rlais C(0)CH(Rlb)NHR1C; Rlbes -alkyl (C1-C4) and Rlces -H. In some embodiments, the C1-C4 alkyl is selected from methyl, ethyl, isopropyl, sec-butyl, tert-butyl and isobutyl. In some embodiments of formula (la), Rlais C(0)CH(Rlb)NHR1C; Rlbes methyl and Rlces -H. In some embodiments of formula (la), Rlais C(0)CH(Rlb)NHR1C; Rlbes ethyl and Rlces -H. In some embodiments of formula (la), Rla is C (0) CH (Rlb)NHRlc; Isopropyl Rlbes and Rlces -H. In some embodiments of formula (la), Rla is C (0) CH (Rlb)NHRlc; Rlbes sec-butyl and Rlces -H. In some embodiments of formula (la), Rlais C(0)CH(Rlb)NHR1C; Rlbes isobutyl and Rlces -H. In some embodiments of formula (la), Rla is C (0) CH (Rlb)NHRlc; Rlbes tert-butyl and Rlces -H. In some embodiments of formula (la), Rlaes C (0) CH (Rlb) NHR1Cy Rlby Rlc, together with the atom to which they are attached, form a 5-membered ring. In one embodiment, a compound of formula (Ib), or a pharmaceutically acceptable salt thereof, is disclosed: HO (Ib) where IF-2019-3 6421651 -APN-ANP#INPI Page 13 of 170 • R1es -NHRla; Riaes_H o-C (0) CH (Rlb) NHRlc; and Rlb is selected from -H, -(C1-C4)alkyl and CH2ORld; and Ríe is -H; either Rlband Rlc, together with the atom to which they are attached, form a 5-membered heterocyclic ring; and Rldes -H or -CH3; In one embodiment, a compound of formula (Ib) is disclosed: In another embodiment, a pharmaceutically acceptable salt of the compound of formula (Ib) is disclosed. In some embodiments, a compound of formula (Ib) is represented by the formula (Ibl) or (Ib2): where R1 is equal to as defined above; In some embodiments of formula (Ib), Rlaes -H. In some embodiments of formula (Ib), Rlais C(O)CH(Rlb)NHRlc; Ribes -H and Rlc is -H. In some embodiments of formula (Ib), Riaes C(O)CH(Rlb)NHR1C; Ribes CH2ORid; Laughs is -H and Rides is -H. In some embodiments of formula (Ib), Riais C(O)CH(Rib)NHR1C; Ribes CfoORi*1; Rlces -H and Rides -CH3. In some embodiments of formula (Ib), Ria is C(O)CH(Rib)NHRic; Rlbes -alkyl (C1-C4) and Rlces -H. In some embodiments, the C1-C4 alkyl is selected from methyl, ethyl, isopropyl, sec-butyl, tert-butyl and isobutyl. IF-2019-3 6421651 -APN-ANP#INPI Page 14 of 170 In some embodiments of formula (Ib), Rlais C(O)CH(Rlb)NHR1C; Rlbes methyl and Rlces -H. In some embodiments of formula (Ib), RlaesC(O)CH(Rlb)NHRlc; Rlbes ethyl and Rlces -H. In some embodiments of formula (Ib), RlaesC(O)CH(Rlb)NHR1C; Isopropyl Rlbes and Rlces -H. In some embodiments of formula (Ib), RlaesC(O)CH(Rlb)NHR1C; Rlbes sec-butyl and Rlces -H. In some embodiments of formula (Ib), RlaesC(O)CH(Rlb)NHR1C; Rlbes isobutyl and Rlces -H. In some embodiments of formula (Ib), Rlais C(O)CH(Rlb)NHR1C; Rlbes tert-butyl and Rlces -H. In some embodiments of formula (Ib), Rlaes C (O) CH (Rlb) NHRlcy Rlby Ríe, together with the atom to which they are attached, form a 5-membered ring. In one embodiment, a compound of formula (II), or a pharmaceutically acceptable salt thereof, is disclosed: OH (II) where R2 is -OH or -NHR2a; R2a is -H or -C(O)CH(R2b)NH2; and R2bes -CH3o -CH(CH3)2. In one embodiment, a compound of formula (II) is disclosed: In another embodiment, a pharmaceutically acceptable salt of the compound of formula (II) is disclosed. In some embodiments of formula (II), R2 is -OH. IF-2019-3 6421651 -APN-ANP#INPI Page 15 of 170 EITHER In some embodiments of formula (II) / R2 is NHR2a and R2a is -H. In some embodiments of formula (II), r2es_ NHR2a, R2aes-c (o) CH (R2b) nh2y R2bes -CH3. In some embodiments of formula (II), R2esNHR2a, R2aes-c(O)CH(R2b)nh2yR2bes CH(CH3)2. In one embodiment, a compound of formula (lia), or a pharmaceutically acceptable salt thereof, is disclosed: where R2 is -OH or -NHR2a; R2a is -H or -C(O)CH(R2b)NHR2c; R2b is selected from -H, -(C1-C4)alkyl and CH2OR2d; and R2ces -H; either R2b and R2Cf, together with the atom to which they are attached, form a 5-membered heterocyclic ring; and R2des -H or -CH3; In one embodiment, a compound of formula (Ha) is disclosed: In another embodiment, a pharmaceutically acceptable salt of the compound of formula (Ha) is disclosed. In one embodiment of the formula (Ila), R2 is -OH. In one embodiment of the formula (Ha), R2 is -NHR2a and R2a is -H. IF-2019-3 6421651 -APN-ANP#INPI Page 16 of 170 EITHER In one embodiment of formula (Ila), R2is -NHR2a;y R2aes-c(0)CH(R2b)NHR2c; R2bes H and R2ces H. In one embodiment of formula (Ila), R2 is -NHR2a;y R2aes -C(0)CH(R2b)NHR2c; R2bes -CH2OR2d; R2c is H and R2des is H. In one embodiment of formula (Ila), R2is -NHR2a;y R2aes -C(0)CH(R2b)NHR2c; R2bes -CH2OR2d; R2= is H and R2 is CH3. In some embodiments of formula (Ila), R2 is NHR2a; R2aes -C(0)CH(R2b)NHR2c; R2bes -alkyl (Ci-C4) and R2= is -H. In some embodiments, the C1-C4 alkyl is selected from methyl, ethyl, isopropyl, sec-butyl, tert-butyl and isobutyl. In some embodiments of formula (Ila), R2 is NHR2a; R2aes -C(0)CH(R2b)NHR2c; R2bes methyl and R2= is -H. In some embodiments of formula (Ila), R2 is -NHR2a; R2aes -C(0)CH(R2b)NHR2c; R2bes H and R2c is H. In some embodiments of formula (Ila), R2 is -NHR2a; R2aes -C(0)CH(R2b)NHR2c; R2bes isopropyl and R2ces -H. In some embodiments of formula (Ila), R2 is -NHR2a; R2aes -C(0)CH(R2b)NHR2c; R2bes sec-butyl and R2ces -H. In some embodiments of formula (Ila), R2 is NHR2a; R2aes -C(0)CH(R2b)NHR2c; R2bes isobutyl and R2= is -H. In some embodiments of formula (Ila), R2 is -NHR2a; R2aes -C(0)CH(R2b)NHR2c; R2bes tert-butyl and R2ces -H. In some embodiments of formula (Ila), R2 is -NHR2a; R2. es -C (0) CH (R2b) NHR2cy R2b and r2", together with the atom to which they are attached, they form a 5-membered ring. In one embodiment, a compound of formula (Ilb), or a pharmaceutically acceptable salt thereof, is disclosed: IF-2019-3 6421651 -APN-ANP#INPI Page 17 of 170 where R2 is -OH or -NHR2a; R2a is -H or -C(O)CH(R2b)NHR2c; R2b is selected from -H, -(C1-C4)alkyl and CH2OR2d; and R2ces -H; either R2b and R2c, together with the atom to which they are attached, form a 5-membered heterocyclic ring; and R2d is -H or -CH3. In one embodiment, a compound of formula (Ilb) is disclosed. In another embodiment, a pharmaceutically acceptable salt of the compound of formula (Ilb) is disclosed. In one embodiment of the formula (Ilb), R2 is -OH. In one embodiment of the formula (Ilb), R2es -NHR2a and R2aes -H. In one embodiment of the formula (Ilb), R2 is -NHR2a; and R2aes -C(O)CH(R2b)NHR2c; R2bes H and R2ces H. In one embodiment of the formula (Ilb), R2 is -NHR2a; and R2aes -C(O)CH(R2b)NHR2c; R2bes -CH2OR2d; R2ces H and R2des H. In one embodiment of the formula (Ilb), R2 is -NHR2a; and R2aes -C(O)CH(R2b)NHR2c; R2bes -CH2OR2d; R2<= is H and R2is CH3. In some embodiments of the formula (Ilb), R2 is NHR2a; R2aes -C(O)CH(R2b)NHR2c; R2bes -alkyl (C1-C4) and R2ces -H. IF-2019-3 6421651 -APN-ANP#INPI Page 18 of 170 In some embodiments, the C1-C4 alkyl is selected from methyl, ethyl, isopropyl, sec-butyl, tert-butyl and isobutyl. In some embodiments of the formula (Hb), R2 isNHR2a; R2aes -C(O)CH(R2b)NHR2c; R2bes methyl and R2ces-H. In some embodiments of the formula (Hb), R2 isNHR2a; R2aes -C(O)CH(R2b)NHR2c; R2bes ethyl and R2ces -H. In some embodiments of the formula (Hb), R2 isNHR2a; R2aes -C(O)CH(R2b)NHR2c; R2bes isopropyl and R2ces -H. In some embodiments of formula (Hb), R2 is NHR2a; R2aes -C(O)CH(R2b)NHR2c; R2bes sec-butyl and R2= is -H. In some embodiments of the formula (Hb), R2 isNHR2a; R2aes -C(O)CH(R2b)NHR2c; R2bes isobutyl and R2ces-H. In some embodiments of the formula (Hb), R2 isNHR2a; R2aes -C(O)CH(R2b)NHR2c; R2bes tert-butyl and R2cesH. In some embodiments of formula (Hb), R2 is NHR2a; R2aes -C(O)CH(R2b)NHR2cy R2b and R2c, together with the atom to which they are attached, form a 5-membered ring. In some embodiments, a compound of Formula (III), or a pharmaceutically acceptable salt thereof, is disclosed: B OH where R3 is -CH3 or -CH(CH3)2 IF-2019-3 6421651 -APN-ANP#INPI Page 19 of 170 EITHER In one embodiment, a compound of formula (III) is disclosed. In another embodiment, a pharmaceutically acceptable salt of the compound of formula (III) is disclosed. In some embodiments of formula (III), R3 is CH3. In some embodiments of formula (III), R3 is CH(CH3)2. In some embodiments, a compound of formula (Illa), or a pharmaceutically acceptable salt thereof, is disclosed: B OH (Illa) where R3 is selected from -H, -alkyl (Ci-C4) and CH2OR3a; and R3a is -H or -CH3. In one embodiment, a compound of formula (Illa) is disclosed. In another embodiment, a pharmaceutically acceptable salt of the compound of formula (Illa) is disclosed. In one embodiment of the formula (Illa), R3 is -H. In one embodiment of the formula (Illa), R3es -CH2OR3a and R3aes -H. In one embodiment of the formula (Illa), R3es -CH2OR3a and R3aes -CH3. In one embodiment of the formula (Illa), R3 is (C1-C4) alkyl. In some embodiments, the -(C1-C4)alkyl is IF-2019-3 6421651 -APN-ANP#INPI Page 20 of 170 Or select from methyl, ethyl, isopropyl, sec-butyl and isobutyl. In one embodiment of the formula (Illa), R3 is methyl. In one embodiment of the formula (Illa), R3 is ethyl. In one embodiment of the formula (Illa), R3 is isopropyl. In one embodiment of the formula (Illa), R3 is secbutyl. In one embodiment of the formula (Illa), R3 is isobutyl. In one embodiment of the formula (Illa), R3 is tert-butyl. In some embodiments, a compound of formula (Illb), or a pharmaceutically acceptable salt thereof, is disclosed: (Illb) where R3 is selected from -H, -(C1-C4)alkyl and CH2OR3a; and R3a is -H or -CH3. In one embodiment, a compound of formula (Illb) is disclosed. In another embodiment, a pharmaceutically acceptable salt of the compound of formula (Illb) is disclosed. In one embodiment of formula (Illb), R3 is -H. In one embodiment of formula (Illb), R3es -CH2OR3a and R3aes -H. IF-2019-3 6421651 -APN-ANP#INPI Page 21 of 170 In one embodiment of the formula (IHb), R3es -CH2OR3a and R3aes -CH3. In one embodiment of the formula (IHb), R3 is -(C1-C4)alkyl. In some embodiments, -(C1-C4)alkyl is selected from methyl, ethyl, isopropyl, sec-butyl and isobutyl. In one embodiment of the formula (IHb), R3 is methyl. In one embodiment of formula (Illb), R3 is ethyl. In one embodiment of formula (Illb), R3 is isopropyl. In one embodiment of formula (Illb), R3 is secbutyl. In one embodiment of formula (Illb), R3 is isobutyl. In one embodiment of formula (Illb), R3 is tert-butyl. In some embodiments, a compound of formula (IV), or a pharmaceutically acceptable salt thereof, is disclosed: where R4 is -OH or -NH2. In one embodiment, a compound of formula (IV) is disclosed: In another embodiment, a pharmaceutically acceptable salt of the compound of formula (IV) is disclosed. In some embodiments of formula (IV), R4 is -OH. In some embodiments of formula (IV), R4 is NH2. IF-2019-3 6421651 -APN-ANP#INPI Page 22 of 170 In some embodiments, a compound of formula (IVb), or a pharmaceutically acceptable salt thereof, is disclosed: (IVb) where R4 is -OH or -NH2. In one embodiment, a compound of formula (IVb) is disclosed. In another embodiment, a pharmaceutically acceptable salt of the compound of formula (IVb) is disclosed. In some embodiments of formula (IVb), R4 is OH. In some embodiments of formula (IVb), R4 is NH2. In some embodiments, a compound of formula (V), or a pharmaceutically acceptable salt thereof, is disclosed: H ° u NH \ OH 'B °H(V) . In one embodiment, a compound of formula (V) is disclosed. In another embodiment, a pharmaceutically acceptable salt of the compound of formula (V) is disclosed. In some embodiments, a compound of formula (Vb), or a pharmaceutically acceptable salt thereof, is disclosed: IF-2019-3 6421651 -APN-ANP#INPI Page 23 of 170 EITHER In one embodiment, a compound of formula (Vb) is disclosed. In another embodiment, a pharmaceutically acceptable salt of the compound of formula (Vb) is disclosed. In some embodiments, a compound of Formula (VI), or a pharmaceutically acceptable salt thereof, is disclosed: where R6a is -H or -CH3; R6faes-C(O)C(R6cR6d)NH2; o -(C1-C3)alkyl which is substituted with 0 or 1 amino or -OR6e; and R6ces -alkyl (C1-C3) which is substituted with 0 or 1 amino or -OR6f; R6des_H o_CH3.y R6e and R6f are independently -H or -CH3. In one embodiment, a compound of formula (VI) is disclosed. In another embodiment, a pharmaceutically acceptable salt of the compound of formula (VI) is disclosed. In some embodiments of formula (VI), R6a is -H or -CH3; and R6bes -(C1-C3)alkyl which is substituted with 0 or 1 amino. IF-2019-3 6421651 -APN-ANP#INPI Page 24 of 170 or In some embodiments of formula (VI), R6a is -H or -CH3; R6b is -C(0)C(R6cR6d)NH2; R6c is -aikyl (C1_C3) which is substituted with 0 or 1 amino or -OH; and R6des H or -CH3. In some embodiments, a compound of formula (VI) is represented by the formula (Vial) or (VIa2): where R6a and R6b are same as defined above; In one embodiment, a compound of formula (Vial) is disclosed. In another embodiment, a pharmaceutically acceptable salt of the compound of formula (Vial) is disclosed. In one embodiment, a compound of formula (VIa2) is disclosed. In another embodiment, a pharmaceutically acceptable salt of the compound of formula (VIa2) is disclosed. In one embodiment of Formula (VI), R6b is -CH3o CH2CH2NH2. In some embodiments, a compound of formula (VIb), or a pharmaceutically acceptable salt thereof, is disclosed: where R6a is -H or -CH3; IF-2019-3 6421651 -APN-ANP#INPI Page 25 of 170 EITHER R6bes-C(0)C(R6cR6d)NH2; o -(C1-C3)alkyl which is substituted with 0 or 1 amino or -0R6e; and. R6ces-aiqUiio(C1-C3) which is substituted with 0 or 1 amino or -OR6f; R6des -H or -CH3; and R6e and R6f are independently -H or -CH3. In one embodiment, a compound of formula (VIb) is disclosed. In another embodiment, a pharmaceutically acceptable salt of the compound of formula (VIb) is disclosed. In one embodiment of formula (VIb), R6b is -CH3o CH2CH2NH2. In some embodiments of formula (VIb), R6a is -H or -CH3; and R6bes-alkyl (C1-C3) which is substituted with 0 or 1 amino. In some embodiments of formula (VIb), R6a is -H or -CH3; R^bes -C(O)C(RecR6d)NH2;R6ces-(C1-C3)alkyl which is substituted with 0 or 1 amino or —OH; and R®des r q In some embodiments, a compound of formula (VIb) is represented by the formula (VIbl) or (VIb2): (vid±j or river (VIb2), where R6a and R6b are equal to as defined above; In some embodiments, compounds of formula (I), (la), (II), (Ila), (III), (Illa), (IV), (V) and (VI), including species thereof, are converted into the compounds of formula (Ib), (Ilb), (Illb), (ivb), (Vb) and (VIb), 26 IF-2019-3 6421651 -APN-ANP#INPI Page 26 of 170 or including species of these through intramolecular delation, and vice versa. That is, it is an interconversion process. The compounds of formula (I), (la), (II), (Ila), (III), (Illa), (IV), (V) and (VI), including species thereof and the compounds of formula ( Ib), (Ilb), (Illb), (IVb), (Vb) and (VIb), including species of these are converted each into the other partially or completely depending on conditions such as temperature, pressure, humidity, the pH and / or the composition of the medium (e.g. solvents) and etc. It is illustrated in the diagram below: where R1 is equal to as defined in formula (la) and (Ib) above. In some embodiments, the compounds of Table 1, or a pharmaceutically acceptable salt thereof, are disclosed: Table 1 Example Compound Name 2 H fl f ΥΓ0Η HO''’ L^b,OH OH (2R, 4S) -2-(4boronobutyl)-4hydroxypyrrolidine-2carboxylic acid IF-2019-3 6421651 -APN-ANP#INPI Page 27 of 170 or Example Ce tax Name 3 H O Acid (22?, 4Ή)-2-(4boronobutyl)-4- HOZ L^oh Óh hydroxypyrrolidine-2carboxylic 4 H Ns υ JL Acid (2S, 4S)-4—amino-2-(4 - < OH boronobutyl)pyrrolidin-2- h2n' Vx^OH OH carboxylic 5 H ~O “ <^OH Acid (27?, 4S)-4-amino-2-(4- boronobutyl)pyrrolidin-2- h2n' U ^OH Óh carboxylic 6 H N ~O “ Λη Acid (2S,4R)-4-amino-2-(4boronobutyl)pyrrolidine-2- H2N ¿h carboxylic 7 H N ü Acid (27?, 42?)-4-amino- 2-(4- ΧΌΗ boronobutyl)pyrrolidine-2- H2N U-b.OH oh carboxylic 8 H _N. ~o Acid (22?, 42?)-4-( (S)-2- °v £ / <^0H aminopropanamido)-2-(4- _ / -NH Uxb.OH boronobutyl)pyrrolidine-2- nh2 OH carboxylic 9 H N 0 A 4acid (22?, 42?)-4-( (S)-2- °« 5- Ζη 0H amino-3-methylbutanamido)-2- V / NH C-^OH | (4-boronobutyl)pyrrolidin- nh2 OH; Xcarboxylic IF-2019-3 6421651 -APN-ANP#INPI Page 28 of 170 or Example Composite Name 10 >? IZ, T 21 x fg ° O-tD 1 O ' I (2R,4R)-4-( (R)-2amino-3-methylbutanamido)-2(4-boronobutyl)pyrrolidine2-carboxylic acid 11 2^V° L zx z °-CD l O OH (2R,4R)-2-(4boronobutyl)-4-((S)pyrrolidine-2carboxamido)pyrrolidine-2carboxylic acid 13 I Zxir'zv^\ z o L J O !— i 0.03 x b I Acid·(2R,4R )-4-(2aminoacetamido)-2-(4boronobutyl)pyrrolidine-2carboxylic 14 H °Vnw N / “ 0H0 \— / Ί Z NHj H Lb.OH OH Acid (2J?, 4J?)-4-( (S) -2aminobutanamido)-2-(4boronobutyl)pyrrolidine-2carboxylic IF-2019-3 6421651 -APN-ANP#INPI Page 29 of 170 Example Compound Name 15 X °. 1 m-O X ,__J O IZC--L 2 i ZX^-\ X i z rj )pyrrolidine-2carboxylic 16 H °Vnn N / “0H 0 )—' 1 Ή Y >—ς H Λ OH —< nh2 θ' \ OH Acid (27?, 47?)-4-[ [ (2S)-2amino -4- methylpentanoyl]amino]-2-(4boronobutyl)pyrrolidine-2carboxylic 17 H N λ~0Η θ )—' r-ΓH \ OH HO NH2 Q OH Acid (27?, 47?)-4-[ [ (2S) -2amino-3- hydroxypropanoyl]amino]-2(4-boronobutyl)pyrrolidine2-carboxylic 18 1 o z\>° iz L -21 J o / -- X O CD i b X Acid (27?, 47?)-4-[ [ (2S)-2amino-3- methoxypropanoyl]amino]-2(4-boronobutyl)pyrrolidine2-carboxylic 19· 1 H H2NÍ$Y ^nh 0 °' ) HÓ (S)-2-amino-N- ((3R , 5R)-8hydroxy-6-oxo-7-oxa-l-aza8-boraespiro[4.7]dodecan-3yl)-3-methylbutanamide IF-2019-3 6421651 -APN-ANP#INPI Page 30 of 170 Example Compound Name 20 I o z'V.o X / K) / xz Γ zn?v° ,__ / o / -hydroxy-3methylbutanoyl]amino]-2-(4boronobutyl)pyrrolidine-2carboxylic 21 H R\ Ny-OH 0 ✓ 7 Ί \ / -fZ k '' NH2 <b'oh Óh Acid (2R, 4R) -4-[ [ (2S) -2amino-2,3dimethylbutanoyl]amino]-2(4-boronobutyl)pyrrolidine2-carboxylic 22 4R) -2-(4boronobutyl)-4-[[(2S)-2,3diaminopropanoyl]amino]pyrr olidine-2-carboxylic 23 u R\ N >OH ~~~N k h 1 V0H ¿H Acid (2R, 4R )-2-(4boronobutyl)-4(methylamino)pyrrolidine-2carboxylic acid 24 N V°H N k H 1 ^0H H H Acid (2S, 4 J?)-2-(4boronobutyl)-4(methylamino)pyrrolidine-2carboxylic acid IF-2019-3 6421651 -ΑΡΝ-ΑΝΡ#ΙΝΡΙ Page 31 of 170 or Example Compound Name 25 N >-OH \ | VH OH (2R,4R)-2-(4boronobutyl)-4(dimethylamino)pyrrolidine-2carboxylic acid 26 x θ 4(dimethylamino)pyrrolidine-2carboxylic 27 (2S, 4R)-4-(2aminoaethylamino)-2-(4boronobutyl)pyrrolidine-2carboxylic acid 29 Z*\-O χ r Μ 1 _^z Γ 2:E S<^O O-cu x b 4R)-4-[[(2S)-2amino-3- methylbutanoyl]methylamino]2-(4- boronobutyl)pyrrolidine-2carboxylic IF-2019-3 6421651 -APN-ANP#INPI Page 32 of 170 Example Compound Name EITHER NH2 HN C) VoH B'OH Oh (2S,4R)-4-[[(2S)-2amino-3-methylbutanoyl]methylamino]-2-(4boronobutyl)pyrrolidine-2carboxylic acid cicucos having 1-4 carbon atoms. Examples of C1-C< alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl and tert-butyl. The term "pharmaceutically acceptable salt" includes addition compounds of formula (III), (Illa), (IHb), including subgenres or usually non-acidic or addition of bases that maintain efficacy and biological properties (la), (Ib), (II), (IV), (IVb), (V), (Vb), (Ha), (VI), species of these, and the Table are unwanted from the biological or otherwise. In many of formula (l)((Illa), (IHb), (la), (lb), (II), (IV), (IVb), (V), including any subgenus cases, (Vb), s or point species of the (Hb), (VIb), 1, which view the compounds (Hb), (III), (VI), (VIb), , * —of these, and Table 1 are capable of forming salts of addition of acids and / or bases as a result of the presence of basic and / or carboxyl groups or groups similar to these. Acceptable acid addition salts can be formed pharmaceutically organic, benzoate, with inorganic acids and acids for example, acetate, besylate, aspartate, bromide / hydrobromide, bisulfate / sulfate salts, IF-2019-3 6421651 -APN-ANP#INPI Page 33 of 170 O citrate, ethanedisulfonate, fumarate, gluceptate, gluconate, glucuronate, hippurate, iodide / iodide, isethionate, lactate, lactobionate, laurylsulfate, malate, maleate, malonate, mandelate, mesylate, methylsulfate, naphthoate, napsylate, nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate, palmoate, phosphate / hydrogen phosphate / dihydrogen phosphate, polygalacturonate, propionate, stearate, succinate, subsalicylate, sulfate / hydrogen sulfate, tartrate, tosylate AND trifluoroacetate. Inorganic acids from which salts can be obtained include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like. Organic acids from which salts can be obtained include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, trifluoroacetic acid, sulfosalicylic acid and the like. Pharmaceutically acceptable base addition salts can be formed with organic and inorganic bases. Inorganic bases from which salts can be obtained include, for example, ammonia and ammonium salts and metals from columns I to XII of the periodic table. In certain embodiments, the salts are obtained from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc and copper; particularly, suitable salts include ammonium, potassium, sodium, calcium and magnesium salts. The organic bases from which IF-2019-3 6421651 -APN-ANP#INPI Page 34 of 170 salts can be obtained, including, for example, amines. primary, secondary and tertiary, substituted amines, including naturally occurring substituted amines, cyclic amines, basic ion exchange resins and the like. Some organic amines include isopropylamine, benzathine, choline, diethanolamine, diethylamine, Usine, meglumine, piperazine and tromethamine. The pharmaceutically acceptable salts of the compounds of formula (I), (la), (lb), (II), (IIa), (Ilb)io mi), (nia), (iiibj, (IV), (Ivb) ,(vb (vbb (vib (vibb' that include any subgenera or species thereof, and Table 1, can be synthesized from an acidic or basic moiety, by conventional chemical methods. Generally, such salts can be prepared by reacting free acid forms of these compounds with a stoichiometric amount of the appropriate base (such as hydroxide, carbonate, bicarbonate, or the like, of Na, Ca«, Mg!' or K+), or by reacting free base forms of these compounds with a stoichiometric amount of the appropriate acid 20 These reactions are normally carried out in water or in an organic solvent, or in a mixture of both. In general, when possible, the use of a non-aqueous medium such as ether is desirable. , ethyl acetate, ethanol, isopropanol or acetonitrile. Lists of additional suitable salts can be found, for example, in Remington's Pharmaceutical Sciences, 20th ed.. Mack Publishing Company, Easton, Pa., (1985); Berge et al., j.Pharm.Sci.z 1977;66, 1-19 and in Handbook of Pharmaceutical Salts: Properties Selection, and Use by Stahl and Wermuth (Wiley-VCH, Weinheim,' Germany, 2002). IF-2019-3 6421651 -APN-ANP#INPI Page 35 of 170 EITHER It is also intended that any formula provided herein represents unlabeled forms as well as isotopically labeled forms for the compounds of formula (I), (la), (Ib), (II), (Ila), (lib), (III ), (Illa), (mb), (IV), (IVb), (V), (Vb), (VI), (VIb), which include any subgenera or species of these, and Table 1. The compounds Isotopically labeled elements have structures represented by the formulas provided herein, except that one or more atoms are replaced by an atom of the same element but with a different mass number. Some examples of isotopes that can be incorporated into the compounds of formula (I), (la), (lb), (II), (iIa), (nb), (III), (Illa), (mb), ( IV), (IVb), (V), (Vb), (VI), (VIb), including any subgenera or species thereof, and Table 1 and their pharmaceutically acceptable salts include isotopes of hydrogen, carbon, nitrogen, oxygen , phosphorus, sulfur, fluorine, chlorine and iodine such as 2H, 3H, UC, 13C, 14C, 15N, 35S, 36C1 and 1251. The isotopically labeled compounds of formula (I), (la), (lb), (II) , (na), (Hb), (m), (Illa), (Illb), (IV), (IVb), (V), (Vb), (VI), (VIb), which include any subgenres or species thereof, and Table 1 can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples using appropriate isotopically labeled reagents in place of the unlabeled reagents employed previously. The compounds of formula (I), (la), (ib), (n), (Ha), (lib), (III), (Illa), (Illb), (IV), (IVb), (V ), (Vb), (VI), (VIb), which include any subgenera or species of IF-2019-3 6421651 -APN-ANP#INPI Page 36 of 170 Or these and Table 1 may have different isomeric forms. The expression optical isomer, stereoisomer or diastereoisomer refers to any of the various stereoisomeric configurations that may exist for a given compound of formula (I), (la), (Ib), (II), (Ila), (lib), (III), (Illa), (Illb), (IV), (IVb), (V), (Vb), (VI), (VIb), including any subgenera or species thereof, and Table 1. It is understood that a substituent may be attached to a chiral center of a carbon atom and, therefore, the disclosed compounds include enantiomers, diastereomers and racemates. The term enantiomer includes stereoisomers that are non-superimposable mirror images of each other. A 1:1 mixture of a pair of enantiomers is a racemic mixture. The term is used to designate a racemic mixture when appropriate. The terms diastereomers or diastereoisomers include stereoisomers that have at least two asymmetric atoms, but that are not mirror images of each other. Absolute stereochemistry is specified according to the Cahn—Ingold—Prelog R—S system. When a compound is a pure enantiomer, the stereochemistry at each chiral center can be specified by R or S. Solved compounds whose absolute configuration is unknown can be designated (+) or (-) depending on the direction (dextro- or levorotatory) in which rotate plane polarized light to the wavelength of the sodium D line. Certain of the compounds of formula (I), (la), (Ib), (II), (Ha), (Ilb), (III), (Illa), (Illb), (IV), (IVb), (V), (Vb), (VI), (VIb), including any subgenera or species thereof, and Table 1, contain one or more centers or axes of asymmetry and IF-2019-3 6421651 -APN-ANP#INPI Page 37 of 170 Or they can give rise, therefore, to enantiomers, diastereoisomers or other stereoisomeric forms that can be defined, in terms of absolute stereochemistry, as (R)r or (S)-. The present disclosure is intended to include all possible isomers of this type, including racemic mixtures, optically pure forms and intermediate mixtures. Optically active (R)- and (S)-isomers can be prepared using chiral synthons or chiral reagents, or can be resolved using conventional techniques well known in the art such as chiral HPLC. Also disclosed herein are Intermediates 148 in the Examples, and salts thereof. Pharmaceutical compositions In some embodiments, pharmaceutical compositions are disclosed comprising a compound of formula (I), (la), (Ib), (II), (Ha), (Hb), (III), (Illa), (IHb), (IV), (IVb), (V), (Vb), (VI), (VIb), including any subgenera or species thereof, or Table 1, and a pharmaceutically acceptable carrier. The term "pharmaceutically acceptable carrier" includes compounds, materials, compositions and / or dosage forms that, within the scope of sound medical judgment, are suitable for use in contact with the tissues of humans and animals without excessive toxicity, irritation, allergic response. or other problem or complication, as determined by one skilled in the art. The disclosed compositions may be in a form suitable for oral use (for example, as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups. IF-2019-3 6421651 -APN-ANP#INPI Page 38 of 170, for topical use (for example, as creams, ointments, gels, or solutions or oils), for administration by inhalation (for example, as a finely divided powder or a liquid aerosol), for administration by insufflation (for example, in the form of aqueous suspensions or as a powder or for parenteral administration (by a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular or intramuscular dosage or in rectal dosage form). The amount of active ingredient or more pharmaceutically acceptable carriers a single dosage form is combined with to produce will necessarily vary depending on the host treated and the particular route of administration. For more information on Routes of administration and dosage guidelines, the reader is referred to P ulum 25.3 in Volume 5 of Comprehensive Medicinal Hemxstry (Corwin Hansch; Chairman of the Editorial Board), Pergamon Press 1990. therapeutic uses The present compounds are useful as arginase inhibitors in therapies. In one aspect, methods are disclosed for treating cancer in a subject in need thereof, comprising administering to the subject an effective amount of a compound of formula (I) (Ib), (II), (Ha), (Hb), (mb), (ivb), (V), (vb), (vi), {VIb), including any subgenera or species thereof, or Table 1, or a pharmaceutically acceptable salt thereof. In one aspect, methods are disclosed for treating a IF-2019-3 6421651 -APN-ANP#INPI Page 39 of 170 Or inflammatory respiratory disease requires, that effective in a subject that (Ha), (Ilb), (VI), (VIb), comprises administering to the subject a compound amount of formula (I), (ia), (Ib ) / (II)<(III), (Illa), (IIIb), (iv), (IVb), (V), (Vb), of this, or Table 1, of this. including any subgenera or species or a pharmaceutically acceptable salt In one aspect, a compound of formula (I), (la), (Ib), (II), (IIa), (IIb) / (III)( (IIia)j (iv)' (ivb) is disclosed. (v), (vb), (vi), (va,;, including any subgenera or species thereof, or Table 1, or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer. In one aspect, a compound of formula (I), da), (Ib), (II), (lia), (IIb) / (IIIab (iiib), (iv), (IVb), (V) is disclosed. , (Vb), (VI), (VIb), including any subgenera or species thereof, or Table 1, or a pharmaceutically acceptable salt thereof, for use in the treatment of an inflammatory respiratory disease In formula (IIIb ), ' i»,,lvu / , (VIb), which include any subgenera or species of these, or Table 1 ° a pharmaceutically acceptable salt of these in the manufacture of a medicine to treat cancer. In one aspect, the use of a compound of formula (!), (la), (lb), (1I), (iIa), (IIb), (m) / is disclosed. Ib), (IV), (IVb), (V), (Vb), (VI), (vib), including any subgenera or species thereof, or Table 1, or a pharmaceutically acceptable salt thereof, in the a aspect, the use of a compound of (I), (la), (Ib), (ii), (na), (IIb), (IHb (IIIa), IF-2019-3 6421651 -APN-ANP#INPI Page 40 of 170 manufacture of a medicine to treat an inflammatory respiratory disease. In one aspect, pharmaceutical compositions are disclosed comprising a compound of formula (I), (ja), (ib), (II), (Ha), (Hb), (III), (Illa), (Illb), (IV), (IVb), (V), (Vb), (VI), (VIb), including any subgenera or species thereof, or Table 1, or a pharmaceutically acceptable salt thereof, for use in the cancer treatment. In one aspect, pharmaceutical compositions are disclosed comprising a compound of formula (I), (la), (ib), (II), (Ha), (Hb), (HI), (Illa), (Illb), (IV), (IVb), (V), (Vb), (VI), (VIb), including any subgenera or species thereof, or Table 1, or a pharmaceutically acceptable salt thereof, for use in the treatment of an inflammatory respiratory disease. The term cancer includes, for example, renal cell carcinoma, head and neck squamous cell carcinoma, lung cancer (e.g., small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), mesothelioma), cancer. pancreatic cancer, colorectal cancer, breast cancer, acute myeloid leukemia (AML), prostate cancer, gastric cancer, bladder cancer, melanoma, kidney cancer and ovarian cancer. In some embodiments, the cancer has metastasized. In some embodiments, cancer is associated with modulation of Arginase 1 and / or Arginase 2. In some embodiments, cancer is associated with elevated plasma levels of Arginase 1. In some embodiments, cancer is associated with reduced plasma levels of arginine. In some embodiments, cancer is associated with both plasma levels IF-2019-3 6421651 -APN-ANP#INPI Page 41 of 170 elevated Arginase 1 as with reduced plasma levels of arginine. In some embodiments, cancer associated with elevated plasma levels of Arginase 1 and / or reduced plasma levels of arginine includes renal cell carcinoma, head and neck squamous cell carcinoma, lung cancer (e.g., small cell lung cancer (SCLC). ), non-small cell lung cancer (NSCLC), mesothelioma), pancreatic cancer, colorectal cancer and breast cancer. In some embodiments, the cancer secretes Arginase 2, for example, acute myeloid leukemia and prostate cancer. In some embodiments, the cancer is associated with tumor-infiltrating immune cells, for example, lung cancer (small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC)), gastric cancer, bladder cancer, colorectal cancer, melanoma, head and neck squamous cell carcinoma, breast cancer, prostate cancer, ovarian cancer, pancreatic cancer and kidney cancer. The term "inflammatory respiratory disease" refers to inflammatory conditions or disorders that affect the air spaces, pulmonary vasculature, pulmonary interstitium, or a combination of these. These may be limited to the lung or involve multiple organs. In one embodiment, the inflammatory respiratory disease is an inflammatory lung disease. In another embodiment, the inflammatory lung disease is not infectious. In some embodiments, the inflammatory lung disease is asthma, chronic obstructive pulmonary disease IF-2019-3 6421651 -APN-ANP#INPI Page 42 of 170 OR (COPD), chemically induced pulmonary fibrosis, idiopathic pulmonary fibrosis, cystic fibrosis, or a combination of these. In some embodiments, the inflammatory respiratory disease is chronic obstructive pulmonary disease (COPD) or asthma. In one aspect, methods are disclosed for inhibiting arginase in a subject in need thereof, comprising administering to the subject an effective amount of a compound of formula (I), (la), (Ib), (II), (Ha) , (lib), (III), (Illa), (Illb), (IV), (IVb), (V), (Vb), (VI), (VIb), including any subgenera or species thereof, or Table 1, or a pharmaceutically acceptable salt thereof. In one aspect, a compound of formula (I), (la), (Ib), (II), (Ha), (lib), (III), (Illa), (Illb), (IV) is disclosed. (IVb), (V), (Vb), (VI), (VIb), including any subgenera or species thereof, or Table 1, or a pharmaceutically acceptable salt thereof, for use in the inhibition of arginase . In one aspect, the use of a compound of formula (I), (la), (ib), (II), (Ila), (lib), (III), (Illa), (Illb), ( IV), (IVb), (V), (Vb), (VI), (VIb), including any subgenera or species thereof, or Table 1, or a pharmaceutically acceptable salt thereof, in the manufacture of a medication to inhibit arginase. In one aspect, pharmaceutical compositions are disclosed comprising a compound of formula (I), (la), (Ib), (II), (Ha), (lib), (III), (Illa), (Illb), (IV), (IVb), (V), (Vb), (VI), (VIb), including any subgenera or species thereof, or Table 1, or a pharmaceutically acceptable salt thereof, in the inhibition of arginase. IF-2019-3 6421651 -APN-ANP#INPI Page 43 of 170 The term arginase includes manganese-containing enzymes belonging to the ureohydrolase family that catalyze the fifth and final step in the urea cycle that converts L-arginine to L-ornithine and urea. The term arginase includes the two isozymes of the enzyme, for example, Arginase 1, which acts in the urea cycle, and is located mainly in the cytoplasm of the liver, and Arginase 2, which is located in the mitochondria of various tissues. in the body and is involved in the regulation of arginine / ornithine concentrations in the cell. In some embodiments, the compounds of formula (I), (la), (ib), (ii), (na), (iib), (ni), (uIa), (iIIb)r (IV)< (Ivb ), (V), (Vb), (VI), (VIb), including any subgenera or species thereof, and Table 1, or a pharmaceutically acceptable salt thereof, are selective for arginase 1. In some embodiments, the compounds of formula (I), (la), (Ib), (II), (Ha), (Hb), (ni), (Illa), (Illb), (IV), (ivb), (V ), (Vb), (VI), (VIb), including any subgenera or species thereof, and Table 1, or a pharmaceutically acceptable salt thereof, are selective for Arginase 2. In some embodiments, the compounds of formula (I), (ia), (Ib), (II), (lia), (Ufa), (Hi), (ma), (Illb), (IV), (IVb), (V), (Vb ), (VI), (VIb), including any subgenera or species thereof, and Table 1, or a pharmaceutically acceptable salt thereof, inhibit both Arginase 1 and Arginase The term effective amount includes an amount of a compound of formula (I), (ia), (ib), (n), (lia), (llb), (III), (Illa), (illb), (iv ), (ivb), (V), (Vb), (VI), (VIb), including any subgenera or species thereof, or the IF-2019-3 6421651 -APN-ANP#INPI Page 44 of 170 Table 1, which will cause a biological or medical response in a subject, for example, the reduction or inhibition of the activity of enzymes or proteins related to arginase or cancer, improvement of cancer symptoms; or slowing or delaying the progression of cancer. In some embodiments, the term "effective amount" includes the amount of a compound of formula (I), (la), (Ib), (II), (lia), (Ilb), |ni), (Illa), ( Inb),(IV),(lvb), (V), (Vb), (VI), (VIb), including any subgenera or species thereof, or Table 1, which when administered to a subject, is effective , at least in part, to alleviate, inhibit and / or ameliorate cancer or inhibit arginase, and / or reduce or inhibit the growth of a tumor or proliferation of cancer cells in a subject. The term subject includes warm-blooded animals, for example, primates, dogs, cats, rabbits, rats and mice. In some embodiments, the subject is a primate, for example, a human. In some embodiments, the subject suffers from cancer. In some embodiments, the subject needs treatment (for example, the subject could benefit biologically or medically from the treatment). In some embodiments, the patient suffers from cancer. In some embodiments, the subject has elevated plasma levels of Arginase 1. In certain embodiments, the subject has reduced arginine levels. In some embodiments, the patient has both elevated plasma levels of Arginase 1 and reduced plasma levels of arginine. In some embodiments, the subject has a cancer that secretes Arginase 2 (for example, acute myeloid leukemia or prostate cancer). IF-2019-3 6421651 -APN-ANP#INPI Page 45 of 170 EITHER In some embodiments, the subject has Arginase 1-positive tumor-infiltrating immune cells. The term inhibiting, inhibiting or inhibiting includes a decrease in the initial activity of a biological process or activity. In some embodiments, the compounds of formula (I), (la), (Ib), (II), (Ha), (Ilb), (III), (Illa), (Illb), (IV), (IVb ), (V), (Vb), (VI), (VIb), including any subgenera or species thereof, and Table 1, inhibit arginase. The term treat, treating and treatment includes reducing or inhibiting arginase-related enzyme or protein activity in a subject, improving one or more cancer symptoms in a subject, or slowing or delaying progression. of cancer in a subject. The term treat, treating and treatment also includes reducing or inhibiting the growth of a tumor or the proliferation of cancer cells in a subject. Examples Aspects of the present disclosure may be further defined by reference to the following non-limiting examples, which describe in detail the preparation of certain compounds and intermediates of the present disclosure and methods of using compounds of the present disclosure. It will be apparent to those skilled in the art that many modifications, both of materials and methods, can be implemented without departing from the scope of the present disclosure. Unless otherwise indicated: IF-2019-3 6421651 -APN-ANP#INPI Page 46 of 170 (i) all syntheses were carried out at room temperature, that is, in the range of 17 to 25 °C and in an atmosphere of an inert gas such as nitrogen unless otherwise indicated; (ii) evaporations were carried out by rotary evaporation or using a Genevac equipment or Biotage vlO evaporator under vacuum and treatment procedures were carried out after removal of residual solids by filtration; (nor) flash chromatography purifications were performed on a Teledyne Isco CombiFlash® Rf or Teledyne Isco CombiFlash® Companion® using pre-packed RediSep Rf Gold™ silica columns (20-40 pm, spherical particles), GraceResolv™ Cartridges (Davisil® silica) or Silicycle cartridges (40 - 63 pm). (iv) preparative chromatography was carried out on a Gilson preparative HPLC instrument with UV collection; alternatively, preparative chromatography was carried out on a Waters AutoPurification HPLC-MS instrument with MS and UV induced collection; (v) Chiral preparative chromatography was carried out on a Gilson instrument with UV collection (233 injector / fraction collector, pumps 333 & 334, UV detector 155) or a Varian Prep Star instrument (2 x SD1 pumps, UV detector 325 , fraction collector 701) a pump that works with Gilson 305 injection; alternatively, chiral preparative chromatography was carried out on a Waters Prep 100 SFC-MS instrument with MS and UV-induced collection or a MultiGram III SFC instrument with UV collection. IF-2019-3 6421651 -APN-ANP#INPI Page 47 of 170 Or (vi) the returns, when present, are not necessarily the maximum that can be obtained; (vii) overall, the structures of the final products of Formula I were confirmed by nuclear magnetic resonance (NMR) spectroscopy; NMR chemical shift values ​​were measured on the delta scale [proton magnetic resonance spectra were determined using a Bruker Avance III 600 (600 MHz), Bruker Avance 400 (400 MHz), Bruker Avance 300 (300 MHz) instrument. or Bruker DRX 500 (500 MHz)]; measurements were taken at room temperature unless otherwise specified; The following abbreviations have been used: s, smglete; d, doublet; t, triplet; c, quadruplet; m, multiplet; dd, doublet of doublets; ddd, doublet doublet doublet; dt, doublet of triplets; sa, broad signal; (viii) in general, the final products of formula I were also characterized by liquid chromatography mass spectroscopy (LCMS or UPLC); UPLC was carried out using a Waters UPLC instrument equipped with a Waters SQ mass spectrometer (temp, 40 C column, UV - 220-300 nm or 190-400 nm, mass spec = ESI with positive shift / negative) at a flow rate of 1 ml / min using a solvent system of 97% A + 3% B to 3% A + 97% B over 1.50 min (flow time). full run with equilibration back to starting conditions, etc., 1.70 min), where A = 0.1% formic acid or 0.05% trifluoroacetic acid in water (for acid work) or 0.1% ammonium hydroxide in water ( for basic work) and B = acetonitrile. For acid analysis, the column used was a Waters Acquity HSS IF-2019-3 6421651 -APN-ANP#INPI Page 48 of 170 T3J1.8 pm, 2.1 x 50 mm), for the basic analysis the column used was a Waters Acquity BEH C18 (1.7 pm, 2.1 x 50 mm). Alternatively, UPLC was performed using a Waters UPLC equipped with a Waters SQ mass spectrometer (Column Temp 30°C, UV = 210-400 nm, Mass Spec = ESI with positive / negative exchange) at a flow rate of 1 ml / min using a solvent gradient of 2 to 98% B for 1.5 min (total run time with return to equilibrium to starting conditions 2 min), where A = 0.1% formic acid in water and B = 0.1% formic acid in acetonitrile (for acid treatment) or A = 0.1% ammonium hydroxide in water and B = acetonitrile (for basic treatment). For the analysis of acids, the column used was Waters Acquity HSS T3 (1.8 pm 2.1x30 mm), for the analysis of bases the column used was Waters Acquity BEH C18 (1.7 pm 2.1x30 mm); LCMS was carried out using a Waters Alliance HT instrument (2795) equipped with a Waters mass spectrometer. ZQ ESCi and a Phenomenex Gemini-NX C18 column (5 pm, 110A, 2.1x50 mm with a flow rate of 1.1 mL / min from 95% A to 95% B for 4 min and maintaining these conditions for 0.5 min, where A = 0.1% formic acid and B = 0.1% formic acid in acetonitrile (for work with acids) or A = 0.1% ammonium hydroxide in water and B = acetonitrile (for work with bases). , LCMS was carried out using a Shimadzu UFLC equipped with a Shimadzu LCMS-2020 mass spectrometer and a Waters HSS C18 (1.8 pm, 2.1x50 mm) or Shim-pack XR-ODS (2.2 pm, 3.0x50 mm) column. o Phenomenex GeminiNX C18 (3 pm, 3.0x50 mm) with a flow rate of 0.7mL / min (for Waters HSS C18 column), l.OmL / min (for Shim49 column IF-2019-3 6421651 -APN-ANP#INPI Page 49 of 170 Formic or ammonia work EtOAc: LDA: MeOH: TFA: MeCN: LCMS: masses ta or TA: Ac: THF: KHMDS: pack % trifluoroacetic acid in water (for working with acids) or 0.1% ammonium hydroxide or 6.5 mM carbonate in water (for working with bases) and B = acetonitrile. The molecular ion presented corresponds to tM+H]+ unless otherwise specified; For molecules with multiple isotopic patterns (Br, Cl, etc.), the value indicated is that obtained for the isotope with the lowest isotopic mass unless otherwise specified. (ix) ion exchange purification was generally performed using an SCX-2 cartridge (Biotage); (x) The purity of the intermediates was evaluated by thin layer chromatography, mass spectrometry, LCMS, UPLC / MS, HPLC (high performance liquid chromatography) and / or NMR analysis. ^xi) the following abbreviations have been used: ethanol ethyl acetate lithium diisopropylainide methanol trifluoroacetic acid acetonitrile liquid chromatography-room temperature spectroscopy aqueous tetrahydrofuran potassium bis(trimethylsilyl)amide IF-2019-3 6421651 -APN-ANP#INPI Page 50 of 170 DCM: DMF: HATU: [bis(dimethyl b]pyridinium dichloromethane dimethylformamide hexafluorophosphate of 3-6amino oxide)methylenej-1H-1,2,3-triazolo[4,5de 110 BOC: tert-butoxycarbonyl 5,5'-dithiobis (2-nitrobenzoic acid) 2-nitro-5-thiobenzoic acid 4-(2-hydroxyethyl)-1DTNB· AcidTNB:AcidHEPES:(Piperazinethanesulfonic acid) Intermediate 1 Intermedin 1: Example 1 (3S,7aR)-320 (3H) -onaane io 2,2,2 trichloroethane-1,1-diol (2.155 g 13 03 nunol)a solution of D-proline (1 on p CHCÍ3 (100 ^) in nitrogen. E1 stirred with a reverse Dean-stark pot and the best dθ ^Ρ° “-at reflux and stir du“ IF-2019-3 6421651 -APN-ANP#INPI Page 51 of 170 reaction was cooled to with DCM (100 mL) and washed at room temperature, diluted mL) and saturated brine (2 dried with Na2SO4 crude product. crystallization (Intermediate 1, white, 1R NMR 3.20 (1H, m) 5.18 (1H, s). sequentially with water (2 x 200! x 200 mL). The organic layer was filtered and evaporated to provide The EtOH material for the crude oil was purified by providing the 1-13 g, 53.2% yield) as (300 MHz, CDCI3) δ 1.66 - 2.41 (4H, ' 3.40 - 3.50 (1H, m), 4.10 - 4.20 product a solid m), 3.05 (1H, m), Intermediate 2: 7-, , , ;---—'-LaS>7a~( (E) -4-bromobut-2-enyl) -3A solution of LDA (2.0 M in 2.05 mL, 4.09 mmol) was added drop -1 (3H)-one dropwise to a solution of (3H)-one at -78 °C (Intermediate 1, 1.00 g, in a resulting atmosphere was stirred to 1,4-dibromobut-2-ene reaction dropwise Reaction mixture was aropyrrolo[1,2-c]oxazole (4.09 mmol) in THF (500 mL) of nitrogen. ~78 for 20 minutes. (875 mg, as one shaken The solution (E) 4.09 mmol) was added to the THF solution mixture (2 mL). The -780.Cfor 30 minutes and then heated-ή h =y. slow to room temperature stirring for an additional 2 h. with The dry vapor mixture and the resulting residue were diluted in EtOAc (20 mL) v sp lavA (2 x 20mT>, sequentially with water <2 x 20 mL) and saturated brine (2 x 20 t, r „v uΗ* 11 / · The matte organic phase C°]C°n NS2S°4' was filtered and concentrated to dryness. The siieria^Ud°5Θ PURÍFIED by Hice gel chromatography (hexanes / EtOAc) to provide the product n ermedxo 2, 760 mg, 49% performance). iHRMN (300 MHz, IF-2019-3 6421651 -APN-ANP#INPI Page 52 of 170 CDCW δ 1.55 - i.75 (1H, m), 1.85 -2.25 (3H,m),2.52_ 2.73 (2H, m), 3.14 - 3.32 (2H, m), 3.89 - 4.10 (2H, m), 5.01 H, s), 5.79 5.99 (2H, m) ; m / z (ES+) [M+H]+=378 , ,3'· (^^^-^-(^-4-(4,4,5,5-^^±r.3r2-dioxaborolan-2 -yl)but-2-enyl)-3Jtrichloronetll)tetrahldropyrroloyl^-cloxazo!-!<3H)-or¡„ Pd2(dba)3(85.0 mg, 0.0928 mol) was added to a solution of (3S,7aS)-7a-((E)-4-bromobut-2-enyl)-3(trichloromethyl)tetrahydropyrrolo[l,2- c]oxazol-l(3íí)-one (Intermediate 2, 700 ma i ρς . 9 / .85 mmol) and bis(pmacholate)diboron (942mg, 3.71 mol) in THE (30 mL) in a nitrogen atmosphere. The resulting mixture was heated to 60°C and stirred for 5 h. The reaction mixture was cooled to room temperature and concentrated to dryness. The resulting residue was diluted with EtOAc (50 ml) and washed sequentially with water and saturated brine. The organic phase was dried with Na2so4, filtered and concentrated to dryness. The resulting crude material was purified by silica gel chromatography to provide the product Intermediate 3, 510 mg, 65% yield). iji NMR (300 MHz COCI.) δ 1.28 (12H, s), 1.58 - 1.80 (2H, m), 1.83 - 2.12 (3H,' n» 2.42 - 2.65 (1H, m), 3.20 (1H, dd), 3.47 (1H, c), 3.1Í (1H, t), 3.90 (1H, t), 4.98 (1H, s), 5.38 - 5.53 (1H, m), 5.64 5.83 (1H, m) ; ES+) [M+H]+ = 424. Intermediate 4: (?p 7=p i 7Λ,Λ. _ . ,-------(—'7aR)~7a-(4-(4f4r5,5-tetrainethyl1,3,2-dioxaborolan-2-. il)butyl)-3Orichloromethyl)tetrahydropizrolo[l,2-c]oxa¡ol_1 (3H) Pd / C (10% by weight, 125 mg, 0.12 mmol) was added to a solution of (3S, 7aS)-7a-((E)-4-(4,4,5,5-tetramethyl-l,3 ,2dioxaborolan-2-yl)but-2-enyl)-353 IF-2019-3 6421651 -APN-ANP#INPI Page 53 of 170 O (trichloromethyl)tetrahydropyrrolo[1,2-c]oxazol-1(3H)-one (Intermediate 3, 500 mg, 1.18 mmol) in MeOH (5 mL). The reaction flask was fitted with a balloon of H2 and the suspension was stirred at room temperature for 30 min. The reaction mixture was filtered through diatomaceous earth and washed with MeOH. The filtrate was concentrated to dryness to give the crude product (Intermediate 4, 390 mg, 78% yield) which was used without further purification, m / z (ES+) [M+H]+= 426. Example—1:—(R)-2-(4-boronobutyl)pyrrolidine-2carboxylic acid Concentrated aqueous HC1 (1.00 mL, 12.0 mmol) was added to a solution of (3S,7aü)-7a-(4-(4,4,5,5-tetramethyl-l,3,2dioxaborolan-2-yl)but- 2-enyl)-3(trichloromethyl)tetrahydropyrrolo[1,2-c]oxazol-1(327)-one (Intermediate 4, 300 mg, 0.703 mmol) and phenylboronic acid (172 mg, 1.41 mmol) in 1,4- dioxane (20 mL). The resulting mixture was heated to 80 °C for 15 h. The reaction mixture was cooled to room temperature and concentrated to dryness. The crude material was purified by LCMS (XBridge Prep C18 OBD column, 5μ silica, 19 x 150 mm, H2O (with 0.05% TFA / MeCN). The pure fractions were collected and concentrated to dryness to provide CID(2). ?) -2-(4-boronobutyl)pyrrolidine-2-carboxylic acid (Example 1, 85 mg, 37% yield) as a white solid 1H NMR (400 MHz, D2O) δ 0.63 - 0.74 (2H, m), 1.09 - 1.27 (2H, m), 1.27 - 1.37 (2H, m), 1.65 - 1.75 (1H, m), 1.77 - 2.08 (4H, m), 2.25 - 2.37 (1H, m), 3.21 - 3.37 (2H , m); m / z (ES+) [M+H]+= 216. IF-2019-3 6421651 -APN-ANP#INPI Page 54 of 170 or Example----2j----(2R,4S)-2-(4-boronobutyl)-4hydroxypyrrolidine-2-carboxylic acid Boc O •A OH HO' EITHER OBn Intermediate 6 Intermediate 5 Intermediates Example 2 Intermediate-----(2S,4S) 4~ (benzyloxy)pyrrolidin-l ,2-benzyl 1-tert-butyl dicarboxylate (2S,45)-1-(tert-butoxycarbonyl)-4hydroxypyrrolidine-2-carboxylic acid (5.00 g, 21.6 mmol) was dissolved in DMF (73 mL) and the solution was cooled to 0 °C. Sodium hydride (60% dispersion in mineral oil) was added in 10 portions (1.81 g, 45.3 mmol) and the suspension was stirred at 0 °C for h. Benzyl bromide (12.9 mL, 108 mmol) was added and the reaction mixture was stirred overnight while slowly warming to RT. The crude reaction mixture was diluted with ethyl acetate (250 mL) and washed sequentially with citric acid (10% aq.) and water. The organic phases were dried with Na2SO4, filtered and concentrated to dryness. The crude product was purified by silica gel chromatography (hexanes / EtOAc) to IF-2019-3 6421651 -APN-ANP#INPI Page 55 of 170 Provide the product as a rotamer mixture (Intermediate 5, 5.5 g, 62% yield). XH RMN (300 MHz, DMSO -DG) δ 1.28 -1.40 (9h, S X2) Rotámeros, 2 '.20 (1h, DD), 2.36 -2.45 (1h, m), 3.37 (1h, DD), 3.51 - 3.58 (1H, m), 4.14 (1H, s a), 4.33 - 4.50 (3H, m), 4.94 - 5.17 (2H, m), 7.25 - 7.32 (10H, m); m / z (ES+) [M+H]+ = 412. Intermediate______ $·’ (4S) -4- (benzyloxy) - 2-(but-2- 2-benzyl and 1-tert-butyl enyl)pyrrolidine-1,2-dicarboxylate 2-Benzyl 1-tert-butyl (2S,45)-4-(benzyloxy)pyrrolidine-1,2dicarboxylate (Intermediate 5, 2.75 g, 6.68 mmol) and crotyl bromide (1.03 mL, 10.0 mmol) were dissolved in THE (45 mL) and the solution was cooled to − 78 °C in an N2 atmosphere. The solution was treated with the dropwise addition of a KHMDS solution (0.5 M in toluene, 20.1 mL, 10.0 mmol). The reaction mixture was slowly warmed to room temperature and stirred for 3 h. The crude reaction mixture was quenched with water and the volatile components were removed in vacuo. The crude mixture was diluted in DCM and the phases were separated. The organic phase was washed with water, dried with Na2SO4, filtered and concentrated to dryness. The crude material was purified by silica gel chromatography (hexanes / EtOAc) to provide the product as a mixture of rotamers and E / Z olefins (Intermediate 6, 2.54 g, 82% yield). iHRMN (300 MHz, DMSO-de) δ 1.20 - 1.41 (9H, s x2) rotamers, 1.54 - 1.62 (3H, m), 2.10 - 2.59 (3H, m), 2.67 - 2.97 (1H, m), 3.10 - 3.43 (1H, m), 3.50 - 3.78 (1H, m), 3.98 - 4.15 (1H, m), 4.34 - 4.49 (2H, m), 4.94 - 5.13 (2H, m), 5.18 56 IF-2019-3 6421651 -APN-ANP#INPI Page 56 of 170 5-30 (1H, m), 5.38 - 5.63 (1H, m), 7.25 - 7 36 (10H m> / (ES*) [M+HJ* = 466.10' ' / Z Ib tsriRGcli O 8* Ácirín ZOO z o i -r z. ~-------~a° (t^t-butoxycarboniu ^^-2-(4-(4,4,5,5-^^(,-^----->3'2- dioxaborolan—2— Bis(diphenylphosphino)methane (0.419 round bottom dried in purged with N2) were added. slowly added (1.74 mL, 12.0 mmol) -4'yl dichloride (0.366 <3, 9, 1.09 0.550 mmol) to bis (1.5mmol) and a flask an oven. The flask was sealed and the solids were dissolved in DCM (31 mL) and 4,4,5,5-tetramethyl1-1,3,2-dioxaborolane was added to the solution. room temperature during The reaction was stirred at min. (4S)-42 benzyl and 1-tert-butyl were added (Intermediate θ'-1,2-dicarboxylate 2.54 g, 5.46 mmol) as a solution in DCM (21 mL) and the reaction mixture was stirred overnight. The mixture of reXDCM and Se was quenched with water. The phases were stopped and the aqueous phase was extracted with DCM. The combined organic phases were dried with Na2s01, filtered and concentrated to dryness. The crude material was purified by silica gel chromatography (hexanes / EtOAc) to provide (45) -4-(benzyloxy)-2-(4-(4 4 5 5te, f , 1,3,2-dioxaborolan~2 -yl)butyl)pyrrolidine-1,2-dicarboxylate and 1-tert-butyl (Intermediate 7, 2.0 g, 61% of the reaction was diluted with 2-benzyl as a rotamer mixture. The purified material was 21.2 x 250 mm, 5 pm, Temperature = 23 °C f.co ' ,αl, Mobile phase = n-iς -θ220 Λ'detection W at 220 Load-33 m^y·'conc - ng / mL in MeOH, flow rate - 75 mL / min, Outlet pressure subjected to chiral SFC [column (s,S)Whelk -01, IF-2019-3 6421651 -APN-ANP#INPI Page 57 of 170 100 bar] to provide two diastereoisomers. The stereochemistry for the major isomer was assigned as the anti addition product and the minor isomer was assigned as the syn addition product. The minor isomer (368 mg, 0.620 mmol) was dissolved in ethyl acetate (6.2 mL) and treated with Pd / C (10% by weight, 132 mg, 0.124 mmol). The flask was fitted with a balloon of H2 and the suspension was stirred overnight at room temperature. The reaction mixture was filtered through diatomaceous earth and washed with methanol. The filtrate was concentrated under reduced pressure to give (2R,4S)-1-(tert-butoxycarbonyl)-4hydroxy-2-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan) acid. 2yl)butyl)pyrrolidine-2-carboxylic acid (Intermediate 8, 228 mg, 98% yield) as a rotamer mixture was used without further purification. iJi NMR (300MHz, DMSO-d6) δ 0.57 0.74 (2H, m), 1.17 (12 H, s), 1.24 - 1.47 (13H, m),1.59 1.78 (1H, m), 1.78 - 1.96 (1H, m), 2.01 - 2.20 (2H, m), 2.84 - 3.09 (1H, m), 3.58 - 3.73 (1H, m), 4.14 - 4.31(1H, m), 4.98 - 5.09 (1H, m), 12.20 - 12.60 (1H, m); m / z(ES*) [M+H]+ = 414. Z&HP10----¿i----Acid____(2_R, 4S) -2- (4-boronobutyl) -4hydroxypyrrolidine-2-carboxylic acid Trifluoroacetic acid (0.65 mL, 8.4 mmol) was added to a solution of (2R,4S)-1-(tert25 butoxycarbonyl)-4-hydroxy-2-(4-(4,4,5,5-tetramethyl-l) acid. ,3,2dioxaborolan-2-yl)butyl)pyrrolidine-2-carboxylic acid (Intermediate 8, 175 mg, 0.423 mmol) in DCM (4 mL). The resulting solution was stirred at room temperature for 1 h and subsequently concentrated in vacuo. The crude amino acid was dissolved in Et2O (3 mL) and aq. HC1. 1M (3mL) . acid was added IF-2019-3 6421651 -APN-ANP#INPI Page 58 of 170 phenylboronrco(103 mg, 0.847 and transparent laran was stirred at room temperature for 1 h. The reaction mixture was diluted with water and washed with Et2O'. The aqueous phase was lyophilized and purified by ion exchange chromatography. desired product was ammonia. / methanol 2M. (PoraPak Rxn CX 60 cc column) . The eluate from the column using a... The material obtained was further purified by Hp -f „ , , «“ reverse phase chromatography (RediSen Rf Gold® CISñq, from 0 to 10% to 100« of / . annual u00ΐ of acet°nitrile in ) to obtain acid(2S,4S)_2.(4-boronobutyl)-4hidroxrplrroiidin.2.carboxil.co (Bjen(pleorT” (2cHour white sand·1H NMR í400mh2'5υ·ο' U .78 (2H, m) , 1.08 - 1 41n1 (4H' ' 1.81 - 2.12 (3H, ^), 2.51 (1H, dd) 3-22 - 3.37 m / z (ES+) [M+H] = 232. (2H, m), 4.46 - 4 / 56 (1H, m) ; In __3 *____Acid Boc O BnO Intermediate 9 Boc 9 N BnO Intermediate 10 Boc 9 .nJ \ Γ·., OBn OBn H.O. B°c 9nk .A OBn BnO B'°v / Bnd* Minor isomer Major isomer \ 7a0h HÓ* °s Intermediate 12' H 9 JL \ / ^0H H.O. B'0HOH Example 3 IF-2019-3 6421651 -APN-ANP#INPI Page 59 of 170 Intermediate-----(2S,4R) 4-(benzyloxy)pyrrolidin-l,2-benzyl 1-tert-butyl 2dicarboxylate (2S,4R)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid (5.00 g, 21.6 mmol) was dissolved in DMF (73 mL) and the solution was cooled to 0 °C. Sodium hydride (60% dispersion in mineral oil) was added portionwise (1.81 g, 45.4 mmol) and the suspension was stirred at 0 C for 1 h. Benzyl bromide (12.86 mL, 108.1 mmol) was added and the reaction mixture was stirred overnight while slowly warming to RT. The crude reaction mixture was diluted with ethyl acetate (250 mL) and washed sequentially with citric acid (10% aq.) and water. The organic phases were dried with Na2SO4, filtered and concentrated to dryness. The crude material was purified by silica gel chromatography (hexanes / EtOAc) to provide the product (Intermediate 9, 5.9 g, 66% yield) as a rotamer mixture. ifí NMR (300MHz, DMSO d6) δ 1.27 - 1.39 (9H, s x2) rotamers, 1.95 - 2.08 (1H, m), 2.34 - 2.47 (1H, m), 3.41 - 3.53 (2H, m), 4.17 (1H , s a), 4.28 (1H, c), 4.43 - 4.55 (2H, m), 5.06 - 5.22 (2H, m), 7.25 - 7.41 (10H, m) ; m / z (ES+) [M+H]+ = 412. ^e^io------ÍQ:(4R)_4_(benzyloxy)_2_(but_2_ enyl)pyrrolidine-lf2-dicarboxylate of 2-benzyl and 1-tert-butyl 2-Benzyl 1-tert-butyl (2S,4R)-4-(benzyloxy)pyrrolidine1,2-dicarboxylate (Intermediate 9, 2.75 g, 6.68 mmol) and crotyl bromide (1.03 mL, 10.0 mmol) were dissolved in THF (45 mL) and the solution was cooled to − 78 °C in a N2 atmosphere. The solution was treated with dropwise addition of a KHMDS solution (0.5 M in toluene, 20.1 IF-2019-3 6421651 -APN-ANP#INPI Page 60 of 170 or mL, 10.0 mmol). The reaction mixture was slowly heated to room temperature, dryness. And it was stirred for 3 h. The crude mixture was quenched with anua v inc .a9uaAnd the components were removed under vacuum. the phases were separated. HE The chromatography was dried with Na2SO4, The crude mixture was diluted The organic phase was washed crude material θη silica gel filtered and concentrated to was purified by providing the product (Intermediate lo. (hexanes / EtOAc) for NMR (300MHz, 1-45 - 1.63 m), 3.06 as a mixture of rotamers 1.23 g, 40% DMSO-dg) (3H, 3.19 (1H, m), 4.03 (1H, 4.21δ1-25 - 1.34 2-12 - 2.64 (2H, π), 3.31 - 3.45 (1H, m), 4.30 5-16 (2H , m), 5.16 - 5.34 (1H, m) 7.41 (10H, m) . m / z (ES+) [M+H]+(9H, m), (1H, 4.55 and define E / Z. ifí s x2) rotamers, 2.64 m), (2H, - 3.04 (1H, 3.46 - 3.81 m), 4.90 5.38 - 5.68 (1H, m), 7.25 = 466. Intermediate 12: Acid (2R 4r\ 7 / +- , Z ~(^li'4R)~1-(tert-butoXic^rhr.n·; 7> ^droXr-2-(4-(4,4,5,5-tetr^<^o 71 -71 ·---J-f¿,2-dioxaborolan-2yl)butyl) pyrrolidine-2-carboxyJ ian ’ added cyclooctadiene)diiridium (i) bis(diphenylphosphino)methane (203 dichloride (177 mg, of 0.264 bis (1.5mmol)g' 0.527 mmol) to a round bottom flask and dried in an oven. The flask was sealed and 4 / 4'5'5tetramethyl-^3,2-dioxaborolani(0-84 mL , 5.8 mmol) to the solution at room temperature for 10 min. (benzyloxy)-2-(but-2-enyl)pyrrolidine (4^)-4-1,2-dicarboxylate of o (Intermediate 10 1 99 „o J-u, i.¿3 g, 2.64 mmol) a solution in DCM (lo mL) and imixture IF-2019-3 6421651 -APN-ANP#INPI Page 61 of 170 reaction was stirred overnight. The reaction mixture was diluted with DCM and quenched with water. The phases were separated and the aqueous phase was extracted with DCM. The combined organic phases were dried with Na2SO4, filtered and concentrated to dryness. The crude material was purified by silica gel chromatography (hexanes / EtOAc) to provide (42?)-4-(benzyloxy)-2-(4-(4,4,5,5-tetramethyl1,3,2-dioxaborolan 2-benzyl and 1-tert-butyl -2-yl)butyl)pyrrolidine-1,2-dicarboxylate (Intermediate 11, 950 mg, 60% yield). The purified material was subjected to chiral SFC [(S,S)Whelk-Ol column, 21.2 x 250 mm, 5 pm, Temperature = 23 °C, Mobile phase = 0:-15 MeOH with 0.1% TFA:C02, UV detection at 220 nm, load = 33 mg / inj., conc = 220 mg / mL in MeOH / DCM, flow rate =75 mL / min, Outlet pressure = 100 15 bar] to provide two diastereoisomers. The stereochemistry for the major isomer was assigned as the anti addition product and the minor isomer was assigned as the syn addition product. The major isomer (385 mg, 0.649 mmol) was dissolved in ethyl acetate (6.4 mL) and treated with Pd / C (10% by weight, 138 mg, 0.130 mmol). The flask was fitted with a balloon of H2 and the suspension was stirred overnight at room temperature. The reaction mixture was filtered through diatomaceous earth and washed with methanol. The filtrate was concentrated under reduced pressure to provide the product (Intermediate 12, 249 mg, 93% yield) as a rotamer mixture. 1H NMR (300 MHz, DMSO-dg) δ 0.61 - 0.73 (2H, m), 0.97 - 1.11 (1h, m), 1.12 1.23 (12H, m), 1.25 - 1.44 (12H, m), 1.51 - 1.71 (1H, m), 1.84 - 2.04 (2H, m), 2.05 - 2.19 (2H, m), 3.12 - 3.29 (1H, IF-2019-3 6421651 -APN-ANP#INPI Page 62 of 170 m), 3.37 3.59 (1H, m), 4.09 - 4.23 i1!!, m) ; m / z (ES+) [M+H]+= 414. Ex.emP10____3: (2R,4R)-2-(4-boronobutyl)-4hydroxypyrrolidine-2-carboxylic acid Trifluoroacetic acid (0.65 mL, 8.5 mmol) was added to a solution of (2R,4R)-1-(tert-butoxycarbonyl)-4-hydroxy-2-(4-(4,4,5,5-tetramethyl-l, 3,2dioxaborolan-2-yl)butyl)pyrrolidine-2-carboxy1ic acid (Intermediate 12, 197 mg, 0.179 mmol) in DCM (3 mL). The resulting solution was stirred at room temperature for 1 h and subsequently concentrated in vacuo. The crude amino acid was dissolved in Et2O (3 mL) and aq. HC1. 1M (3mL) . Phenylboronic acid (102 mg, 0.837 mmol) was added and the clear biphasic solution was stirred at room temperature for 1 h. The reaction mixture was diluted with water and washed with Et2O. The aqueous phase was lyophilized and purified by ion exchange chromatography (PoraPak Rxn CX 60 cc column). The desired product was eluted from the column using 2M ammonia / methanol. The obtained material was further purified by reverse phase chromatography (RediSep Rf Gold® C18Aq, 0 to 10% to 100% acetonitrile in water) to provide acid (2R, 4J?)-2-(4boronobutyl)- 4-hydroxypyrrolidine-2-carboxylic acid (Example 3, 25 mg, 25-s yield) as a white solid.1H NMR (300MHz, D2O) δ 0.68 - 0.78 (2H, m), 1.13 - 1.43 (4H, m) , 1.64 - 1.79 (1H, m), 1.94 - 2.14 (2H, m), 2.47 (1H, d), 3.39 (2H, m), 4.46 - 4.53 (1H, m). m / z (ES+) [M+H]+= 232. Example------4:_______Acid_______(2S, 4S) -4-amino-2- (4boronobutyl)pyrrolidine-2-carboxylic acid IF-2019-3 6421651 -APN-ANP#INPI Page 63 of 170 Boc O Intermediate 14 Boc P'OBn NEITHER Intermediate 13 OH Example 4 Intermediate____13:_____(2S, 4S)____4-azidopyrrolidine-l,2dicarboxylate of 2-benzyl and 1-tert-butyl Methanesulfonyl chloride (0.71 mL, 9.2 mmol) was added dropwise to a solution of (2S, 4R)-4hydroxypyrrolidine-1,2—dicarboxylate 2-benzyl and 1—(tert-butyl) (2.45 g, 7.26 mmol ) and triethylamine (1.27 mL, 9.15 mmol) in DCM (9.6 mL) at 0 °C. The reaction mixture was stirred at 0 C for 1 h before warming to room temperature with stirring for an additional 1 h. The reaction mixture was diluted with dichloromethane and washed with water. The organic phase was dried with Na2SO4, filtered and concentrated to dryness to give 2—benzyl and 1-(tert-butyl) (2S, 42?)-4((methylsulfonyl)oxy)pyrrolidine-1,2-dicarboxylate. (2.9 g, 95% yield) which was used without further purification, m / z (ES+) [M+H]+= 400. Sodium azide (1.65 g, 25.4 mmol) was added to a solution of (25.4R )-4-((methylsulfonyl)oxy)pyrrolidine—1,2—dicarboxylate IF-2019-3 6421651 -APN-ANP#INPI Page 64 of 170 of 2-benzyl and 1-(tert-butyl) (7.2 mL). The reaction mixture was stirred overnight, room temperature and (2.90 g, 7.26 mmol) in DMF and was diluted with EtOAc and washed dried with Na2SO4. The resulting residue f was filtered and concentrated with water. The crude organic phase was purified by silica (hexanes / EtOAc) to (Intermediate 13, 2.00 g, 80% rotamers.ΤΗ NMR x2) rotamers, 1.96 3-24 - 3.29 (1H, m), to dryness. Gel chromatography provides the performance) as a mixture (300MHz, DMSO-de) δ 1.27 and 1.40 (9H, s - 2-02 (1H, m), 2.53 - 2.63 (1H, m), 3.58 3.66 (1H, m), 4.32 5.06 - 5.22 (2H, m), 7.33-7.39 (5H, m) ; - 4.41 (2H, 347. m / z (ES+) [M+H] 1^-dicarboxylate of 2-benzyl and ;n--------dio k ·,dlsolved (2S,4S)-4-azidopyrrolidin-l,2arboxylate of 2-benzyl and 1-tert-butyl (Intermediate ! 3, 1.00 g, 2.89 µol) and crotyl bromide (0.44 mL, 4.3 mmol) in THF (20 mL) and the solution was cooled in a N2 sphere. The SQluc.on 3θtrawθ 33 Τ'SO1UC16n KHMDS'°'5 MθtOluen°' «·« mL, .33 mmol). The reaction mixture was slowly warmed to room temperature and stirred for 3 reaction volatiles in DCM and with water, dryness. The crude oil was deactivated with water and removed under vacuum. the phases were separated. was dried with Na2SO4, Mix Chromatography raw material on silica gel until h. The crude mixture of components was diluted The organic phase was washed, filtered and concentrated and purified by (hexanes / EtOAc). for IF-2019-3 6421651 -APN-ANP#INPI Page 65 of 170 provide the product (Intermediate 14, 750 mg, 65% yield) as a mixture of rotamers and olefins E / z ·Η RW (300MHz, DMSO-dg) δ 1.25 - 1.34 (9H, s x2) rotamers , 1-55 1.64 (3H, m), 1.99 - 2.15 (1H, m), 2.33 - 2.62 (2H, m), 2.73 - 3.10 (1H, m), 3.26 - 3.39 (1H, m), 3.52 - 3.84 (1H, m), 4.24 - 4.33 (1H, m), 5.03 - 5.21 (2H, m), 5.28 5 -35 (1H, m), 5.49 - 5.65 (1H, m), 7.31 - 7.36 (5H, m); m / z (ES+) [M+H]+= 401. · -------4-azido-2-(4-(4,4,5,5¿-etra^^-l,3,2-dioXaborolan-2-yl)butyl)plrrolidln-l,2dicarboxylate 2-benzyl and 1-tert-butyl and Intermediate 17: J2R,4S)-4-azido-2-(4-(4,4,5,5-tetramethyl-l,3,2—oxab°rolan-2- 2-benzyl and 1-tert-butylyl)butyl)pyrrolidin-l,2-dicarboxylate Bis(1,5cyclooctadiene)diiridium dichloride (I)(126 mg, 0.188'ybis(diphenylphosphino)methane (144 g, 0.375 mmol) was added to an oven-dried round-bottom flask. The flask was sealed and vented. with Nz. The solids were dissolved in DCM (10 mL) and 4,4,5,5-tetramethyl-l,3,2-dioxaborolane (0.60 mL, 4.1 mmol) was slowly added to the solution. The reaction was stirred at. room temperature for 10 min 2-benzyl 1-tert-butyl (4S)-4-azido2-(but-2-enyl)pyrrolidine-1,2-dicarboxylate (Intermediate 14, 750 mg, 1.87 mmol) was added to the reaction as a solution in DCM (8 mL) and the reaction mixture was stirred overnight at room temperature. The reaction mixture was diluted with DCM and quenched with water. The phases were separated and the aqueous phase was extracted with DCM. The combined organic phases were dried with NazSO., filtered and concentrated to dryness. The crude material was purified. IF-2019-3 6421651 -APN-ANP#INPI Page 66 of 170 by silica gel chromatography (hexanes / EtOAc) to provide (4S)-4-azido-2-(4- (4,4,5,5-tetramethyl-l, 3,2dioxaborolan-2-yl 2-benzyl and 1-tert-butyl )butyl)pyrrolidine-1,2-dicarboxylate (Intermediate 15, 678 mg, 68% yield). The purified material was subjected to chiral SFC [(S,S)Whelk-Ol column, 21.2 x 250 mm, 5 pm, Temperature = 23 °C, Mobile phase = 0-15 of Me0H:C02, UV detection at 220 nm, loading = 33 mg / inj., conc = 220 ng / ml in MeOH, flow rate = 75 ml / min, Outlet pressure = 100 bar] to provide two diastereoisomers. The stereochemistry for the major isomer was assigned as the anti-Intermediate 16 addition product and the minor isomer was assigned as the non-Intermediate 17 addition product. Intermediate 16 (Isomer 1, 608 mg): (2S, 4S)-4-azido-2(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2yl)butyl)pyrrolidine-1 2-benzyl and 1-tert-butyl ,2-dicarboxylate. 1H NMR (500MHz, DMSO-d6) δ 0.64 - 0.72 (2H, m), 1.04 1.12 (1H, m), 1.13 - 1.20 (12H, m), 1.22 - 1.39 (12H, m), 1.69 - 1.80 (1H , m), 2.01 - 2.23 (2H, m), 2.36 - 2.48 (1H, m), 3.35 - 3.42 (1H, m), 3.58 - 3.69 (1H, m), 4.33 (1H, quintuplet), 5.05 - 5.17 (2H, m), 7.31 - 7.40 (5H, m); m / z (ES+) [M+H]+= 529. Intermediate 17 (Isomer 2, 220 mg): (2R, 4S)-4azido-2-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2yl)butyl)pyrrolidine-1, 2-benzyl and 1-tert-butyl 2-dicarboxylate. Intermediate----18: (2S,4S)-4-amino-l-(tert-butoxycarbonyl)-2-(4-(4,4,5,5-tetramethyl-l,3,2dioxaborolan-2-yl) acid butyl)pyrrolidine-2-carboxylic IF-2019-3 6421651 -APN-ANP#INPI Page 67 of 170 2-Benzyl (2S, 4S)-4-azido-2-(4-(4,4,5,5tetramethyl-1,3,2-dioxaborolan-2-yl)butyl)pyrrolidine-1,2dicarboxylate was dissolved and 1-tert-butyl (Intermediate 16, 255 mg, 0.483 mmol) in ethyl acetate (5 mL) and methanol (5 mL) and treated with Pd / C (10 wt%, 128 mg, 0.120 mmol). The flask was fitted with a balloon of H2 and the suspension was stirred overnight at room temperature. The reaction mixture was filtered through diatomaceous earth and washed with methanol. The filtrate was concentrated under reduced pressure to provide the product (Intermediate 18, 190 mg, 95% yield) as a rotamer mixture which was used without further purification. iR NMR (300MHz, DMSO-d6) δ 0.66 (2H, t), 0.88-1.03 (1H, m), 1.16 (12H, s), 1.24-1.38 (13H, m), 1.40 - 1.56 (1H, m) , 1.80 - 1.91 (1H, m), 2.00-2.15 (2H, m), 15 3.17-3.28 (1H, m), 3.58 - 3.61 (1H, m), 3.80 (1H, dd), 9.01 (2H, s a ); m / z (ES+) [M+H]+ = 413. Example 4: (2S,4S)-2-(4-boronobutyl)oirrolidine2-carboxylic acid Trifluoroacetic acid (0.71 mL, 9.2 20 mmol) was added to a solution of (2S, 4S)-4-amino-l-(tert-butoxycarbonyl)-(4-(4,4,5,5-tetramethyl-l, 3) acid. , 2-dioxaborolan2-11)butyl)pyrrolidine-2-carboxylic acid (Intermediate 18, 190 mg, 0.461 mmol) in DCM (4 mL). The resulting solution was stirred at room temperature for 1 h and subsequently concentrated in vacuo. The crude amino acid was dissolved in Et2O (3 mL) and aq. HC1. 1M (3mL) . Phenylboronic acid (112 mg, 0.919 mmol) was added and the clear biphasic solution was stirred at room temperature for 1 h. The reaction mixture was diluted with water and washed with Et2O. The aqueous phase was lyophilized and purified by chromatography. IF-2019-3 6421651 -APN-ANP#INPI Page 68 of 170 or ion exchange (PoraPak Rxn CX 60 cc column). The desired product was eluted from the column using 2M ammonia / methanol. The obtained material was further purified by reverse phase chromatography (RediSep Rf Gold® C18Aq, 0 to 10% acetonitrile in water) to obtain (2S, 4S)-4-amino-2- (4boronobutyl)pyrrolidine-acid. 2-carboxylic acid (Example 4, 40 mg, 37% yield) as a white solid. NMR (300MHz, D2O) δ 0.73 (2H, t), 1.10 - 1.42 (4H, m), 1.69 (1H, ddd), 1.86 1.99 (1H, m), 2.10 - 2.30 (2H, m), 3.05 (1H , dd), 3.44 (1H, dd), 3.69 (1H, quintuplet) ; m / z (ES+) [M+H]+= 231. Example______5j_______Acid_______(2R, 4S) -4-amino-2- (4boronobutyl)pyrrolidine-2-carboxylic acid Intermediate 19: (2R,4S)-4-amino-l-(tert-butoxycarbonyl)-2-(4-W^S'S-tetramethyl-lrS^dioxaborolan^-yl)butyl)pyrrolidine-2-carboxylic acid 2-(2R,4S)-4-azido-2-(4-(4,4,5,5tetramethyl-1,3,2—dioxaborolan-2-yl)butyl)pyrrolidine-1,2—dicarboxylate was dissolved benzyl and 1-tert-butyl (Intermediate 17, 220 mg, 0.416 mmol) in ethyl acetate (5 mL) and methanol (5 mL) and treated with Pd / C (10% by weight, 111 mg, 0.104 mmol ). The flask was fitted with a balloon of H2 and the suspension was stirred overnight at room temperature. The reaction mixture was filtered through diatomaceous earth and washed with methanol. The filtrate was concentrated under reduced pressure to provide the product (Intermediate 19, 150 mg, 87% of 69 IF-2019-3 6421651 -APN-ANP#INPI Page 69 of 170 Or yield) as a rotamer mixture that was used without further purification. NMR (300MHz, DMSO-de) δ 0.64-0.71 (2H, m), 1.17 (12H, s), 1.31-1.40 (15H, m), 1.49 - 1.93 (3H, m), 2.02 - 2.26 (3H, m ), 3.38-3.47 (1H, m), 3.72 - 3.81 (1H, m) ; m / z (ES+) [M+H]+= 413. ^Í-emP10-------_______Acid_______(2R, 4S)-4-amino-2- (4boronobutyl)pyrrolidine-2-carboxylic acid Trifluoroacetic acid (0.56 mL, 7.3 mmol) was added to a solution of (2R,4S)-4-amino-l-(tert-butoxycarbonyl)-(4-(4,4,5,5-tetramethyl-l,3, 2-dioxaborolan2-yl)butyl)pyrrolidine-2-carboxylic acid (Intermediate 19, 150 mg, 0.364 mmol) in DCM (3 mL). The resulting solution was stirred at room temperature for 1 h and subsequently concentrated in vacuo. The crude amino acid was dissolved in Et2O (2 mL) and in aq. HC1. 1M (2mL). Phenylboronic acid (99 mg, 0.81 mmol) was added and the clear biphasic solution was stirred at room temperature for 1 h. The reaction mixture was diluted with water and washed with Et2O. The aqueous phase was lyophilized and purified by ion exchange chromatography (PoraPak Rxn CX 60 cc column). The desired product was eluted from the column using 2M ammonia / methanol. The obtained material was further purified by reverse phase chromatography (RediSep Rf Gold® C18Aq, 0 to 10% 0 to 100% acetonitrile in water) to obtain (2R, 4S)-4-amino-2 acid -(4boronobutyl)pyrrolidine-2-carboxylic acid (Example 5, 33 mg, 39% yield) as a white solid. *Η NMR (400MHz, D2O) δ 0.72 (1H, m), 1.11 - 1.39 (3H,m), 1.4g _1<55 (1H,m), 1.63 - 1.79 (2H, m), 1.95 .- 2.05 ( 1H, m), 2.58 - 2.65 (1H, IF-2019-3 6421651 -APN-ANP#INPI Page 70 of 170 or m), 2.87 2.95 (1H, m), 3.48 - 3.58 (3H, m) ; m / z (ES+) [M+H]+= 231. Example-------6j_______Acid_______(2S, 4R)-4-amino-2- (4boronobutyl)pyrrolidine-2-carboxylic acid Intermediate______20:______(2S,4R)-4-azidopyrrolidine-l,2-methyl and 1-tert-butyl dicarboxylate Methanesulfonyl chloride (2.86 mL, 36.7 nunol) was added dropwise to a solution of 2-methyl 1-tert-butyl (2S, 4S)4-hydroxypyrrolidine-1,2-dicarboxylate (7.50 g, 30.6 mmol) and triethylamine (5.11 mL, 36.7 mmol) in DCM (38 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 1 h before warming to room temperature with stirring for an additional 1 h. The reaction mixture was diluted with dichloromethane and washed with water. The organic phase was dried with Na2SC>4, filtered and concentrated to dryness to give 1-(tert-butyl)-2-methyl (2S,4S)-4-((methylsulfonyl)oxy)pyrrolidine-1,2dicarboxylate. (9.9 g, 100% IF-2019-3 6421651 -APN-ANP#INPI Page 71 of 170 O yield) which was used without further purification, m / z (ES+) [M+NH4] + = 341. Sodium azide (5.96 g, 91.7 mmol) was added to a solution of 2-methyl 1-(tert-butyl) (2S,45)-4-((methylsulfonyl)oxy)pyrrolidine-1,2dicarboxylate (9.89 g, 30.6 mmol) in DMF (30 mL). The reaction mixture was warmed to 50 °C and stirred overnight. The reaction mixture was cooled to room temperature and concentrated. The resulting residue was diluted with EtOAc and washed with water. The organic phase was dried with Na2SO4, filtered and concentrated to dryness. The crude material was purified by silica gel chromatography (hexanes / EtOAc) to provide the product (Intermediate 20, 5.95 g, 72% yield) as a mixture of rotamers.ΧΗ NMR (300MHz, DMSO-de) δ 1.33 and 1.40 (9H, s x2) rotamers, 2.08 - 2.22 (1H, m), 2.26- 2.41 (1H, m), 3.41 (1H, dt), 3.48 - 3.61 (1H, m), 3.65 and 3.68 (3H, s x2) rotamers, 4.22 (1H, dd), 4.30-4.43 (1H, m) ; m / z (ES+) [M+H]+= 271. Intermediate----21: (2S,4R) 2-benzyl 1-tert-butyl 4-azidopyrrolidine-l,2dicarboxylate A solution of sodium hydroxide (5.28 g, 132 mmol) in water (22 mL) was added dropwise to a solution of 1-tert-butyl 2methyl (2S, 47?)4-azidopyrrolidin-l,2-dicarboxylate (Intermediate 20, 5.95 g, 22.0 mmol) in THF (44 mL) and MeOH (22 mL) at 0 °C. The reaction mixture was stirred overnight while slowly warming to room temperature. The volatile components were removed in vacuo and the aqueous phase was acidified to pH ~3 with 5 M HC1 and extracted with DCM. The combined organic phases were dried with Na2SO4, filtered and concentrated to dryness to IF-2019-3 6421651 -APN-ANP#INPI Page 72 of 170 Or provide (2S,4R)-4-azido-l-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid (5.64 g, 100% yield) as a rotamer mixture which was used without further purification. NMR (300MHz, DMSO-d6) δ 1.35 and 1.40 (9H, s x2) rotamers, 2.07 - 2.18 (1H, m), 2.26 - 2.38 (1H, m), 3.34 - 3.44 (1H, m), 3.48 - 3.63 (1H, m), 4.09-4.17 (1H, m), 4.30 - 4.37 (1H, m) ; m / z (ES“) [M+HCOO] = 301. Benzyl bromide (2.83 mL, 23.8 mmol) was added dropwise to a solution of (2S,4R)-4-azido-l-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid (5.19 g, 19.9 mmol) and triethylamine ( 3.46 mL, 24.8 mmol) in DMF (60 mL) and the reaction mixture was stirred overnight at room temperature. The volatile components were removed in vacuo and the resulting residue was dissolved in EtOAc and washed with water. The organic phase was dried with Na2SO4, filtered and concentrated to dryness. The crude material was purified by silica gel chromatography (hexanes / EtOAc) to provide the product (Intermediate 21, 5.09 g, 74% yield). NMR (300MHz, DMSO-d6) δ 1.26 and 1.39 (9H, s x2) rotamers, 2.11- 2.23 (1H, m), 2.31-2.43 (1H, m), 3.43 (1H, ddd), 3.50 -3.59 (1H , m), 4.25-4.40 (2H, m), 5.07-5.22 (2H, m), 7.31 -7.40 (5H, m) ; m / z (ES+) [M+H]+= 347. Intermediate 22: (4R)—4—azido—2-(but—2—enyl)pyrrolidine—2-benzyl and 1-tert-butyl 1,2-dicarboxylate 2-Benzyl 1-tert-butyl (2S,4R)-4-azidopyrrolidin-l,2dicarboxylate (Intermediate 21, 5.09 g, 14.7 mmol) and crotyl bromide (2.27 mL, 22.0 mmol) were dissolved in THF (100 mL) and the solution was cooled to -78 °C in an N2 atmosphere. The solution was treated with the dropwise addition of a KHMDS solution (0.5 M in toluene, 44.1 mL, IF-2019-3 6421651 -APN-ANP#INPI Page 73 of 170 EITHER 22.0 mmol). The reaction mixture was slowly warmed to room temperature and stirred for 3 h. The crude reaction mixture was quenched with water and the volatile components were removed in vacuo. The crude mixture was diluted in DCM and the phases were separated. The organic phase was washed with water, dried with Na2SO4, filtered and concentrated to dryness. The crude material was purified by silica gel chromatography (hexanes / EtOAc) to provide the product (Intermediate 22, 4.6 g, 78% yield) as a mixture of rotamers and defined E / Z.1H NMR (300MHz, DMSO- d6) δ 1.26 - 1.43 (9H, m), 1.59 - 1.66 (3H, m), 2.07 - 2.17 (1H, m), 2.32 - 2.48 (2H, m), 2.57 - 3.12 (2H, m), 3.35 - 3.82 (1H, m), 4.20 - 4.38 (1H, m), 5.02 5.22 (2H, m), 5.24 - 5.41 (1H, m), 5.46 - 5.68 (1H, m), 7.28 - 7.42 (5H, m) ; m / z (ES+) [M+H]+= 401. Intermediate_____24:______(2S,4R)-4-azido-2-(4-(4,4,5,5tetrame ti 1—1,3,2—dioxaborolan—2—yl)butyl)pyrrolidine—l,2— dicarboxylate of 2-benzyl and 1-tert-butyl and Intermediate 25: (2R,4R) -4-azido-2- (4-(4,4,5,5-tetramethyl-l,3,2dioxaborolan-2-yl) 2-benzyl and 1-tert-butyl butyl)pyrrolidin-l,2-dicarboxylate Bis(1,5cyclooctadiene)diiridium dichloride (I) (772 mg, 1.15 mmol) and bis(diphenylphosphino)methane (883 g, 2.30 mmol) were added to an oven-dried round-bottom flask. The flask was sealed and purged with N2. The solids were dissolved in DCM (66 mL) and 4,4,5,5-tetramethyl-l,3,2-dioxaborolane (3.67 mL, 25.3 mmol) was slowly added to the solution. The reaction was stirred at room temperature for 10 min. (4R)-4-azido2-(but-2-enyl)pyrrolidine-1, 2-benzyl 2-dicarboxylate and 1 were added IF-2019-3 6421651 -APN-ANP#INPI Page 74 of 170 Or tert-butyl (Intermediate 22, 4.60 g, 11.5 mmol) was added to the reaction as a solution in DCM (44 mL) and the reaction mixture was stirred overnight. The reaction mixture was diluted with DCM and quenched with water. The phases were separated and the aqueous phase was extracted with DCM. The combined organic phases were dried with Na2SO4, filtered and concentrated to dryness. The crude material was purified by silica gel chromatography (hexanes / EtOAc) to provide (4R)-4-azido-2-(4-(4,4,5,5-tetramethyl-l,3,2dioxaborolan-2- 2-benzyl and 1-tert-butyl yl)butyl)pyrrolidine-1,2-dicarboxylate (Intermediate 23, 2.7 g, 44% yield). The purified material was subjected to chiral SFC (Chiralpak IG column, 21.2 x 250 mm, 5 pm, Temperature = 23 °C, Mobile phase = 0-7% MeOH (with 0.2% NH4OH):C02, UV detection at 220 nm, loading = 16.8 mg / inj., conc = 112.5 ng / mL in MeOH, flow rate = 70 mL / min, Outlet pressure = 100 bar] to provide two diastereoisomers. The stereochemistry for the major diastereomer Intermediate 25 was assigned. as the anti addition product and the minor diastereoisomer Intermediate 24 was assigned as the syn addition product. Intermediate 24 (436 mg): (2S,4R)-4-azido-2-(4-(4,4,5,5tetramethyl-1,3,2-dioxaborolan-2-yl)butyl)pyrrolidine-1,2dicarboxylate of 2-benzyl and 1-tert-butyl.2Η NMR (400MHz, DMSO-de) δ 0.58 - 0.70 (2H, m), 1.17 (12H, s), 1.25 -1.40 (13 H, m), 1.74-1.83 (1H, s), 2.00 - 2.11 (2H, m), 2.38-2.47 (1H, m), 3.07 - 3.16 (1H, m), 3.81 (1H, m), 4.29 - 4.34 (1H, m), 5.04 - 5.17 (2H, m), 7.34 - 7.39 (m, 5H); m / z (ES+) [M+H]+= 529. IF-2019-3 6421651 -APN-ANP#INPI Page 75 of 170 Intermediate 25 (1.60g): (2R,4R)-4-azido-2-(4-(4,4,5,5tetramethyl-l,3,2-dioxaborolan-2-yl)butyl)pyrrolidine-l,2dicarboxylate of 2-benzyl and 1-tert-butyl. iHRMN (400MHz, DMSO-de) δ 0.56 - 0.73 (2H, m) , 0.98 - 1.13 (1H,m), !.17(12H, s), 1.26 - 1.37 (13H, m) , 1.66 - 1.79 (1H , m), 2.01 2.22 (2H, m), 2.34 - 2.47 (1H, ni), 3.60 (1H, dd a), 4.29 4.35 (1H, m), 5.04 - 5.18 (2H, m), 7.31 - 7.40 ( 5H, m),· m / z (ES+) [M+H]+= 529. Intermediate 26: mZD1 z acid -------Λίΐαο(2S,4R)-4-amino-l-(tert b>jt°^arbonyl)-2-(4-(4,4,5,5-tetramethyl-l,3, 2^i2xabozolan-2-yl)butll)t>irrolidln-2-carboxy 1 2-Benzyl (2S,4R)-4-azido-2-(4-(4,4,5,5-tetramethyl1,3,2-dioxaborolan-2-yl)butyl)pyrrolidin-l,2-diearboxylate was dissolved and 1-tert-butyl (Intermediate 24, 236 mg, 0.447 mol) in ethyl acetate (4.5 mL) and treated with Pd / C (10% by weight, 119 mg, 0.112 mmol). The flask was fitted with Hz balloon and the suspension was stirred overnight at room temperature. The reaction mixture was filtered a through diatomaceous earth and washed with methanol. The filtrate was concentrated under reduced pressure to provide the product (Intermediate 26, 275 mg, 100% yield) which was used without further purification. H NMR (300MHz, DMSO-d6) δ 0.64 - 0.71 (2H, M), 1.17 (12H, s), 1.27 -1.40 (15H, m), 1.57 1-82 (4H, m), 1.98-2.08 (3H , m), 3.70 - 3.78 (1H, m) ; (ES+) [M+H]+= 413. ^ρ1°------------(2S, 4R)-4-amino-2- (4^oronobutyl)pyrrolidine-2-carboxylic acid Trifluoroacetic acid (0.69 mL, 8.9 mmol) was added to a solution of (2S,4R)-4-amino-l-(tert-butoxycarbonyl)-(4-(4,4,5,5-tetramethyl-l,3, 2-dioxaborolan76 IF-2019-3 6421651 -APN-ANP#INPI Page 76 of 170 EITHER 2-11)butyl)pyrrolidine-2-carboxylic acid (Intermediate 26, 184 mg, 0.446 mmol) in DCM (4 mL). The resulting solution was stirred at room temperature for 1 h and subsequently concentrated in vacuo. The crude amino acid was dissolved in Et2O (2 mL) and in aq. HC1. 1M (2mL). Phenylboronic acid (109 mg, 0.894 mmol) was added and the clear biphasic solution was stirred at room temperature for 1 h. The reaction mixture was diluted with water, and washed with Et2O. The aqueous phase was lyophilized and purified by ion exchange chromatography (PoraPak Rxn CX 60 ce column). The desired product was eluted from the column using 2M ammonia / methanol. The obtained material was further purified by reverse phase chromatography (RediSep Rf Gold® C18Aq, 0 to 100% acetonitrile in water) to obtain (2S,4P)-4-amino-2-(4-boronobutyl) acid. pyrrolidine2-carboxylic acid (Example 6, 38 mg, 37% yield) as a white solid. 1R NMR (400MHz, D2O) δ 0.72 (2H, td), 1.09 1.19 (1H, m), 1.22 - 1.39 (3H, m), 1.65 - 1.76 (2H, m), 1.95 - 2.04 (1H, m), 2.58 - 2.64 (1H, m), 2.87 - 2.94 (1H, m), 3.48 - 3.57 (2H, m) ; m / z (ES+) [M+H]+= 231. gj-^P10------21------______(2R,4R)-4-amino-2-(4boronobutyl)pyrrolidine-2-carboxylic acid Intermediate—27¿----Acid (2R, 4R)-4-amino-l-(tert butoxycarbonyl)-2-(4-(4,4,5,5-tetramethyl-l,3,2dioxaborolan-2- yl)butyl)pyrrolidine-2-carboxylic IF-2019-3 6421651 -APN-ANP#INPI Page 77 of 170 EITHER 2- (2R,4R)-4-azido-2-(4-(4,4,5,5-tetramethyl1,3,2-dioxaborolan-2-yl)butyl)pyrrolidin-l,2-dicarboxylate was dissolved benzyl and 1-tert-butyl (Intermediate 25, 688 mg, 1.30 mmol) in ethyl acetate (13 mL) and methanol (4 mL) and treated with Pd / C (10-6 by weight, 346 mg, 0.325 mmol ). The flask was fitted with a balloon of H2 and the suspension was stirred overnight at room temperature. The reaction mixture was filtered through diatomaceous earth and washed with methanol. The filtrate was concentrated under reduced pressure to provide the product (Intermediate 27, 500 mg, 93% yield) which was used without further purification. 1R NMR (300MHz, DMSOd6) δ 0.67 (2H, t), 0.94-1.00 (1H, m), 1.17 (12H, s), 1.22 1.38 (11H, m), 1.43 - 1.53 (1H, m), 1.85 ( 1H, d), 2.00 2.15 (2H, m), 3.23 (2H, dd), 3.58 - 3.61 (1H, m), 3.80 3.88 (1H, m), 8.96 (2H, m) ; m / z (ES+) [M+H]+= 413. Example_______7_:_______Acid_______(2R, 4R)-4-amino-2- (4boronobutyl)pyrrolidine-2-carboxylic acid Trifluoroacetic acid (1.02 mL, 13.3 mmol) was added to a solution of (2R,4R)-4-amino-l-(tert-butoxycarbonyl)-2-(4-(4,4,5,5-tetramethyl-l, 3,2dioxaborolan—2—yl)butyl)pyrrolidine—2—carboxylic acid (Intermediate 27, 275 mg, 0.667 mmol) in DCM (4 mL). The resulting solution was stirred at room temperature for 1 h and subsequently concentrated in vacuo. The crude amino acid was dissolved in Et2O (2 mL) and in aq. HC1. 1M (2mL). Phenylboronic acid (163 mg, 1.34 mmol) was added and the clear biphasic solution was stirred at room temperature for 1 h. The reaction mixture was diluted with water and washed with Et2O. The aqueous phase was lyophilized and purified by ion exchange chromatography (column IF-2019-3 6421651 -APN-ANP#INPI Page 78 of 170 PoraPak Rxn CX 60 cc) . The desired product was eluted from the column using 2M ammonia / methanol. The obtained material was further purified by Reverse phase chromatography (RediSep RfGold® C18Ag, 0 to 10% to 100% acetonitrile in water) to obtain (21?,4R)-4-amino-2(4) acid. -boronobutyl)pyrrolidine-2-carboxylic (Example 7, 53 mg, 34% yield) as a white solid. iHRMN (400MHz, 020) δ 0.76 (2H, dt), 1.10 - 1.46 (4H, m), 1.62 - 1.71 (1H,' m), 1.84 - 1.96 (1H, m), 2.10 - 2.21 (1H, m) , 2.22 - 2.32 <1H, m), 3.07 (1H, dd) , 3.46 (1H, dd), 3.71 (1H, quintuplet); m / z (ES+) [M+H]+ = 231. Intermediate 28: Acid (2R,4R)-1-(tert-butoxycarbonyl)~((S) -2- (tert-butoxycarbonylamino)propanamido) -2- (4_(±,4,5,5-tetramethyl-l, 3,2-dioxaborolan-2ÁJ-)butyl)pyrrolidine-2-carboxylic Triethllamine (0.18 mL, 1.3 mmol) and HATO (213 mg, 0.560 mmol) were added sequentially to a solution of BocAla-OH (106 mg, 0.560 mmol) in DMF (2.4 ml) and the reaction was stirred at room temperature for 30 minutes. min. (2R,4R)-4-amino-l-(tert-butoxycarbonyl)-2-(4-(4,4,5,5tetramethyl-1,3,2-dioxaborolan-2-yl)butyl)pyrrolidine acid was added -2carboxylic acid (Intermediate 27, 210 mg, 0.509 mmol) to the reaction mixture as a solution in DMF (2.4 mL). The reaction was stirred at room temperature overnight. Mix IF-2019-3 6421651 -APN-ANP#INPI Page 79 of 170 Crude reaction was concentrated and purified directly by silica gel chromatography (hexanes / EtOAc) to provide the product (Intermediate 28, 236 mg, 79% yield) as a rotamer mixture. NMR (300MHz, DMSO-de) δ 0.65-0.72 (2H, m), 1.11 - 1.18 (18H, m), 1.261.37 (20H, m), 1.63 - 1.73 (1H, m), 2.02 - 2.25 (2H , m), 3.09 - 3.20 (1H, m), 3.59 - 3.72 (1H, m), 3.83 - 3.94 (1H, m), 4.18 - 4.29 (1H, m), 6.80 (1H, s a), 7.96 (1H , s), 13.78 (1H, s a); m / z (ES+) [M+H]+= 584. Example 8: (2R, 4R)-4-((S)-2-aminopropanamido)-2(4-boronobutyl)pyrrolidine-2-carboxylic acid Trifluoroacetic acid (0.62 mL, 8.1 mmol) was added to a solution of (2R,4R)-1-(tert-butoxycarbonyl)-4((S)-2-(tert-butoxycarbonylamino)propanamido)-2-(4) acid. (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2yl)butyl)pyrrolidine-2-carboxylic acid (Intermediate 28, 236 mg, 0.404 mmol) in DCM (4 mL). The resulting solution was stirred at room temperature for 1 h and subsequently concentrated in vacuo. The crude amino acid was dissolved in Et2O (2 mL) and aq. HC1. 1M (2 mL) . Phenylboronic acid (99 mg, 0.81 mmol) was added and the clear biphasic solution was stirred at room temperature for 1 h. The reaction mixture was diluted with water and washed with Et2O. The aqueous phase was lyophilized and purified by ion exchange chromatography (PoraPak Rxn CX 60 cc column). The desired product was eluted from the column using 2M ammonia / methanol. The obtained material was further purified by reverse phase chromatography (RediSep Rf Gold® C18Aq, 0 to 10% acetonitrile in water) to obtain (2R,4R)-4-((S)-2-aminopropanamido acid) -2-(4 IF-2019-3 6421651 -APN-ANP#INPI Page 80 of 170 boronobutyl)pyrrolidine-2-carboxylic acid (Example 8, 18 mg, 15% yield) as a white solid and rotamer mixture. 1H NMR (500 MHz, D2O) δ 0.69 (2H, dt), 1.05 - 1.14 (1H, m), 1.21 (3H, d), 1.23-1.35 (3H, m), 1.65 (1H, dt), 1.91- 1.96 (1H, m), 2.17 (1H, dd), 2.35 (1H, dd), 3.26 (1H, dd), 3.46 - 3.57 (2H, m), 4.29 - 4.34 (1H, m) ; m / z (ES+) [M+H]+= 302. Example 9: (2R,4R)-4-((S)-2-amino-3methylbutanamido)-2-(4-boronobutyl)pyrrolidine-2-carboxylic acid Intermediate 27 Intermediate 29 Example 9 Intermediate 29: Acid (2R,4R)-1-(tert-butoxycarbonyl)4-((S)-2-(tert-butoxycarbonylamino)-3-methylbutanamido)-2(4- (4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2yl)butyl)pyrrolidine-2-carboxylic Triethylamine (0.21 mL, 1.5 mmol) and HATU (254 mg, 0.668 mmol) were added sequentially to a solution of BocVal-OH (145 mg, 0.668 mmol) in DMF (2.9 mL) and the reaction was stirred at room temperature for 30 minutes. min. (2R,4R)-4-amino-l-(tert-butoxycarbonyl)-2-(4-(4,4,5,5tetramethyl-1,3,2-dioxaborolan-2-yl)butyl)pyrrolidine acid was added -2carboxylic acid (Intermediate 27, 250 mg, 0.606 mmol) to the reaction mixture as a solution in DMF (2.9 mL). The reaction was stirred at room temperature overnight. The crude reaction mixture was concentrated and purified directly by silica gel chromatography (hexanes / EtOAc) to provide the product (Intermediate 29, 250 mg, 67% yield) as a rotamer mixture. -de) δ 0.64 - 0.73 (2H, m), 0.73 - 0.85 (6H, m), 1.13 81 IF-2019-3 6421651 -APN-ANP#INPI Page 81 of 170 1-14 (1H, m), 1.17 (12H, i·75(1H, m), 1.79 - 1.97 s), 1.22 (1H, m), 3-24 (1H, m), 3.54 - 3.77(2H, 6-58 (1H, t), 7.96 Example g: 8.03 (2H, m); ____Acid;“ 1-42 (22H, m), 1.56 2.00 - 2.26 (2H, m), 3.08 m), 4.12 - 4.36 (1H, m), m / z (ES+) [M+HJ+ = 584. (2R, 4R) -4-( (S) -2-amino-32Árrolidine-2-carboxylic netylbutanamide) -2- (4-boronobutyl) a sodium hydroxide added (0.63 mL, 8.2 mmol) to ((S) 2 (7Tbde aCld° 2-(tert-butoxycarbonylamino)-3-methylbutanami^>^ 5-tetramethyl-l,3,2-dloxaborolan-2fl)butyl)pyrrolidine-2-carboxylic acid (Xntermeaio29, 250 m or 0.409 mmol) in DCM (4 mL) The ςΜ'a4. The resulting solution was allowed to concentrate at room temperature for 1 h. During 1h and subsequently (2 mL)VaC1°‘E1 amino acid cr“do was dissolved in Et2O (2 mL) and in aq. HC1. 1M (2 mn ~- „ ’·Phenylboronic acid was added, · mmol) and the clear biphasic solution was left at room temperature for 1h. The mixture was diluted with water and washed with EtzO. The phase (99 mg stirred to aqueous reaction was lyophilized ion exchange and purified by chromatography (PoraPak RXnex soCc column). The desired product was eluted i o · , Y from the column using amomaco / methanol2M.E1 material "*d° additionally by reverse phase chromatography (J^ “ Gold® CISAq, 0 to 10% acetonitrile in water) to obtain acid (2R, 4R)-4-(tS\ ?a o9 Pu} 4((S)- 2-amino-3-methylbutanamido)-2( - °ronobutyl)pyrrolidine-2-carboxylic acid (Example 9, 28 mg 20. yield) as a white solid and a rotamer mixture 1H NMR (300MHz, DzO) δ 0.66 ( 6H, dd), 1.07 - 1.43 (4H, m), 1.55 _ 1-57 (2H, m), 2.13 - 2.33 (2H, m), 3.07 0.76 (2H, m), 0.85 i·68(1H, m), 1.77 (1H, d), 3.08 - 3.16 IF-2019-3 6421651 -APN-ANP#INPI Page 82 of 170 (1H, m), 3.37 3.48 (1H, m), 4.27 - 4.40 (1H, m); m / z (ES+) [M+H]+= 330. Example-----10j_____(2R, 4R)-4- ((R)-2-amino-3methylbutanamido)-2-(4-boronobutyl)pyrrolidine-2-carboxylic acid 5Intermediate 32 Example 10 Intermediate______30:______(2R,4R)-4-amino-2- (4-(4,4,5,5tetramethyl-1r 3,2-dioxaborolan-2-yl)butyl)pyrrolidine-1,2dicarboxylate and 2-benzyl 1-tert-butyl Lindlar catalyst (5% by weight, 0.275 g, 0 2.58 mmol) was added to a solution of (2R, 4R)-4-azido-2-(4-(4,4,5, S.tetramethyl-l, 3 2-Benzyl and 1-tert-butyl ,2-dioxaborolan-2-yl)butyl)pyrrolidine-1,2dicarboxylate (Intermediate 25, 1.56 g, 2.95 mmol) in THE (25 mL). The suspension was stirred in a hydrogen atmosphere (balloon, flask evacuated and refilled with hydrogen x3) at room temperature for 8.5 h. The reaction mixture was diluted with MeOH, filtered through diatomaceous earth, and the filtrate was concentrated to dryness. The crude material was purified by silica gel chromatography (1 to 15% MeOH in DCM) to provide ) (2R,4R)-4-amino-2-(4-(4,4,5,5 2-benzyl and 1-tert-butyl-tetramethyl-l,3,2dioxaborolan-2-yl)butyl)pyrrolidine-1,2-dicarboxylate (Intermediate 30, 1.01 g, 68% IF-2019-3 6421651 -APN-ANP#INPI Page 83 of 170 performance) as a gum and a mixture of rotamers.1H NMR (500MHz, CD2CI2) δ 0.74 (2H, c), 1.20 - 1.22 (14H, m), 1.23 - 1.29 (2H, m), 1.32 (6H, s) , 1.37 - 1.42 (5H, m) , 1.74 1.83 (1H, m), 1.83 - 1.93 (1H, m) , 2.11 - 2.19 (0.6H, m) , 2.21 - 2.32 (1.4H, m) , 3.19 (0.4 H, dd), 3.28 (0.6H, dd), 3.44 - 3.51 (1H, m), 3.63 (1H, dd), 5.07 - 5.20 (2H, m), 7.28 - 7.34 (1H, m), 7.34 - 7.41 (4H, m); m / z (ES+) [M+H]+= 503. Intermediate 31:(2R, 4R)-4- ((R)-2- (tert-butoxycarbonylamino)-3-methylbutanamido)-2-f4-f4,4,5,5tetramethyl-1,3,2-dioxaborolan-2-yl 2-benzyl and 1-tert-butyl )butyl)pyrrolidine-1,2dicarboxylate W,W-diisopropylethylamine (0.235 mL, Γ.34 mmol) was slowly added to a stirred solution of HATU (245 mg, 0.64 mmol) and Boc-D-Val-OH (117 mg, 0.54 mmol) in DMF (2 mL ) at room temperature. The solution was stirred for 20 min and then a solution of (2R,4R)-4-amino-2(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2yl)butyl was added. 2-benzyl and 1-tert-butyl pyrrolidine-1,2-dicarboxylate (Intermediate 30, 270 mg, 0.54 mmol) in DMF (2 mL). The reaction mixture was stirred for 2.5 h, diluted with DCM (30 mL), and washed sequentially with water (3 x 25 mL) and saturated aqueous sodium chloride (30 mL). The organic phase was dried with MgSO4, filtered and concentrated to dryness. The crude material was purified by silica gel chromatography (5 to 65% EtOAc in hexanes) to provide (2R,4R)-4-((R)-2-(tert-butoxycarbonylamino)-3methylbutanamido)- 2-(4-(4,4,5,5-tetramethyl-l,3,2dioxaborolan-2-yl)butyl)pyrrolidine-1,2-dicarboxylate 2-benzyl and 1-tert-butyl (Intermediate 31, 239 mg, 63% of IF-2019-3 6421651 -APN-ANP#INPI Page 84 of 170 performance) as a colorless foam and as a mixture of rotamers. *H NMR (500MHz, CD2C12) δ 0.74 - 0.81 (2H, m), 0.84 (3H, d), 0.87 - 0.94 (3H, m), 1.24 (12H, s), 1.26 1.34 (2H, m), 1.37 (5H, s), 1.40 - 1.43 (2H, m), 1.45 (4H, s), 1.46 (9H, s), 1.78 - 1.89 (1H, m), 1.95 - 2.07 (2H, m), 2.21 - 2.29 (0.6H, m), 2.31 - 2.46 (1.4H, m), 3.51 - 3.60 (1.5H, m), 3.65 (0.5H, d a), 3.72 (1H, dd a), 4.49 - 4.58 (1H, m ), 5.01 (1H, d a), 5.19 - 5.29 (2H, m), 6.93 - 7.09 (1H, m), 7.36 - 7.40 (1H, m), 7.43 (4H, ap d) ; m / z (ES+) [M+H]+= 702. Intermediate 32: Acid (2R,4R)-1-(tert-butoxycarbonyl)4~(—2— (tert-butoxycarbonylamino)-3-methylbutanamide)—2— (4-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2yl)butyl)pyrrolidine-2-carboxylic Pd / C (10% by weight, 25 mg, 0.23 mmol) was added to a solution of (2R,4R)-4-((R)-2-(tert-butoxycarbonylamino)-3methylbutanamide)-2-(4- 2-Benzyl and 1-tert-butyl (4,4,5,5-tetramethyl-l,3,2dioxaborolan-2-yl)butyl)pyrrolidine-1,2-dicarboxylate (Intermediate 31, 239 mg, 0.34 mmol) in EtOAc (4 mL). The suspension was stirred in a hydrogen atmosphere (balloon, flask evacuated and refilled with hydrogen x3) at room temperature for 2 h. The reaction mixture was diluted with MeOH, filtered through diatomaceous earth, and the filtered θΐ was concentrated to dryness. The crude material was purified by silica gel chromatography (2 to 15% MeOH in DCM) to provide (2R, 4R) -1- (tert-butoxycarbonyl)-4-((R)-2-(tert- 2-benzyl and 1-tert-butyl butoxycarbonylamino)-3methylbutanamido)-2-(-4-(4,4,5,5-tetramethyl-l,3,2dioxaborolan-2-yl)butyl)pyrrolidine—2-dicarboxylate (Intermediate 32, 196 mg, 94% IF-2019-3 6421651 -APN-ANP#INPI Page 85 of 170 Or yield) as a white solid and as a mixture of rotamers. *Η NMR (500MHz, DMSO-d6) δ 0.63 - 0 71 (2H m) 0.75 - 0.82(6H,m), 1.15(12H, s), 1.21 - ¿30(2H,' J 1.32 (6H, s), 1.36 (13H, s a), 1.61 - 1.72 (1H, m), 1.81 1.90 (1H, m), 1.92 - 2.05 (2H, m), 2.05 - 2.13 (0.6H, m), 2.13 - 2.28 ( 1.4H, m), 3.03 - 3.14 (1H, m), 3.62 (0.6H, t), 3.66 (1.4H, t), 4.18 - 4.29 (1H, m), 6.59 (1H, d), 7.99 (1H, d) , s a), 12.48 (0.4H, s a), 12.65 (0.6H, s a); Example-----10;-----(2R, 4R)-4- ((R)-2-amino-3methylbutanamido)-2-(4-boronobutyl)pyrrolidine-2-carboxylic acid Trifluoroacetic acid (0.37 mL, 4.8 mmol) was added dropwise to a stirred solution of (2R,4R)-1-(tert-butoxycarbonyl)-4-((R)-2-(tert-butoxycarbonylamino)-3methylbutanamido)-acid. 2-(4-(4,4,5,5-tetramethyl-l,3,2dioxaborolan-2-yl)butyl)pyrrolidine-2-carboxylic acid (Intermediate 32, 195 mg, 0.32 mmol) in DCM (2 mL). The reaction solution was stirred at room temperature for 22 h and subsequently concentrated under reduced pressure. The crude amino acid was dissolved in aq. HC1. 1M (2 mL) and Et2O (2 mL). Phenylboronic acid (117 mg, 0.96 mmol) was added and the clear biphasic solution was stirred at room temperature for 5 h. The mixture was diluted with Et2O (20 mL) and water (5 mL), and the phases were separated. The aqueous phase was washed with Et2O and the aqueous phase was lyophilized. The resulting solid was dissolved in MeOH (3 mL) and purified by ion exchange chromatography (PoraPak Rxn CX 20 cc column). The desired product was eluted from the column using 5% ammonia in MeOH solution (20 mL). The material obtained was further purified by chromatography of IF-2019-3 6421651 -APN-ANP#INPI Page 86 of 170 reverse phase (RediSep Rf Gold® C18, 0 to 80% acetonitrile in water) to obtain acid (2R, 4R)-4-((r)-2amino-3-methylbutanamido)-2- (4-boronobutyl)pyrrolidine-2carboxylic acid (Example 10, 46 mg, 44% yield) as a white solid. *Η NMR (500MHz, D20) δ 0.73 - 0.80 (2H, m), 0.90 (6H, ap t), 1.13 - 1.25 (1H, m), 1.26 - 1.35 (1H, m), 1.40 (2H, quintuplet), 1.68 - 1.80 (1H, m), 1.85 - 1.96 (1H, m) , 2.00 (1H, td), 2.29 (1H, dd), 2.37 - 2.45 (1H, m), 3.18 (1H, d), 3.28 (1H, dd), 3.59 (1H, dd) , 4.36 - 4.49 (1H , 10 m) ; m / z (ES+) [M+H]+= 330. Example----llj____(2R, 4R)-4- ((S)-2-amino-3,3dimethylbutanamide) —2— (4—boronobu,tyl)pyrrolidine—2 — carboxylic acid Intermediate__________33:__________(2R, 4R)-4-((S)-2-(tertbutoxycarbonylamino)-3,3-dimethylbutanamido)-2-(4-(4,4,5,5tetramethyl-1,3,2-dioxaborolan 2-benzyl and 1-tert-butyl -2-yl)butyl)pyrrolidine-1,2dicarboxylate 17,17-Diisopropylethylamine (0.165 mL, 0.95 mmol) was slowly added to a stirred solution of HATO (158 mg, 0.42 mmol) and Boc-Tle-OH (92 mg, 0.40 mmol) in DMF (1.5 mL) at IF-2019-3 6421651 -APN-ANP#INPI Page 87 of 170 room temperature. The solution was stirred for 15 min and then a solution of (22?, 47?) -4-amino-2(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2yl) was added. 2-Benzyl and 1-tert5-butyl )butyl)pyrrolidine-1,2-dicarboxylate (Intermediate 30, 190 mg, 0.38 mmol) in DMF (1.5 mL). The reaction was stirred for 3 h, diluted with EtOAc (30 mL), and washed sequentially with water (3 x 25 mL), saturated aqueous NaHCO3 (30 mL), and saturated aqueous sodium chloride (30 mL). The organic phase was dried with MgSO4, filtered and concentrated to dryness. The crude material was purified by silica gel chromatography (5 to 65% EtOAc in hexanes) to provide (27?, 47?) -4-((S) -2- (tert-butoxycarbonylamino)-3,3 2-benzyl and 1-tert-butyl -methylbutanamido)-2-(4-(4,4,5,5tetramethyl-1,3,2-dioxaborolan-2-yl)butyl)pyrrolidine-1,215 dicarboxylate (Intermediate 33, 261 mg, 96% yield) as a white solid and as a mixture of rotamers. ifí NMR (500MHz, DMSO-d6) δ 0.69 (2H, c), 0.87 (9H, s), 1.17 (12H, s), 1.26 (5H, s), 1.29 - 1.32 (1H, m), 1.34 (5H , s), 1.38 (9H, s), 1.72 - 1.85 (1H, m), 1.90 20 2.08 (2H, m), 2.06 - 2.18 (1H, m), 2.22 - 2.35 (2H, m), 3.11 3.22 (1H, m), 3.68 - 3.81 (2H, m), 4.23 - 4.37 (1H, m), 5.06 - 5.19 (2H, m), 6.40 (1H, t), 7.31 - 7.40 (5H, m), 8.11 (1H,d); m / z (ES+) [M+Na]+ = 738. Intermediate 34: Acid (2R,4R)-1-(tert-butoxycarbonyl)25—((S)~2~<tert-buto*icarbonylamino)-3,3-dimethylbutanamide)(4~(4,4,5, 5-tetramethyl-l,3,2-dioxaborolan-211)butyl)pyrrolidine-2-carboxylic Pd / C (10% by weight, 25 mg, 0.23 mmol) was added to a solution of (27?, 47?) -4- ((S) -2-(tert-butoxycarbonylamino) 30 3,3-dimethylbutanamide) -2-(4-(4,4,5,5-tetramethyl-l, 3.288 IF-2019-3 6421651 -APN-ANP#INPI Page 88 of 170 2-benzyl and 1-tert-butyl dioxaborolan-2-yl)butyl)pyrrolidine-1,2-dicarboxylate (Intermediate 33, 260 mg, 0.36 mmol) in EtOAc (4 mL). The suspension was stirred in a hydrogen atmosphere (balloon, flask evacuated and refilled with hydrogen x3) at room temperature for 15 h. The reaction mixture was diluted with MeOH, filtered through diatomaceous earth, and the filtrate was concentrated to dryness. The crude material was purified by silica gel chromatography (2 to 10% MeOH in DCM) to provide (2R,4R)1-(tert-butoxycarbonyl)-4-((S)-2-(tert-butoxycarbonylamino 2-benzyl and 1-tert-3,3-dimethylbutanamido)-2-(-4-(4,4,5,5tetramethyl-1,3,2-dioxaborolan-2-yl)butyl)pyrrolidine-2dicarboxylate butyl (Intermediate 34, 207 mg, 91% yield) as a white solid and as a mixture of rotamers. *H NMR (500MHz, DMSO-d6) δ 0.63 - 0.72 (2H, m), 0.86 (9H, s), 1.09 - 1.20 (14H, m), 1.21 - 1.30 (2H, m), 1.33 (5H, s) ), 1.35 - 1.38 (13H, m), 1.61 - 1.73 (1H, m), 1.89 - 2.11 (2H, m), 2.14 - 2.27 (1H, m), 3.06 3.14 (1H, m), 3.59 - 3.72 ( 1H, m), 3.72 - 3.80 (1H, m), 4.20 4.30 (1H, m), 6.35 (1H, d), 8.08 (1H, s a), 12.47 (0.4H, s a), 12.63 (0.6H, s a ); m / z (ES+) [M+H]+ = 626. Example----111____(2R, 4R)-4-((S)-2-amino-3,3dimethylbutanamido)-2-(4-boronobutyl)pyrrolidine-2carboxylic acid Trifluoroacetic acid (0.38 mL, 4.9 mmol) was added dropwise to a stirred solution of (2R,4R)-1-(tert-butoxycarbonyl)-4-((S)-2-(tert-butoxycarbonylamino)-3,3dimethylbutanamide acid. )-2-(4-(4,4,5,5-tetramethyl-l,3,2dioxaborolan-2-yl)butyl)pyrrolidine-2-carboxylic acid (Intermediate 34, 206 mg, 0.33 mmol) in DCM (2 mL ). The reaction IF-2019-3 6421651 -APN-ANP#INPI Page 89 of 170 O was stirred at room temperature for 15 h and subsequently concentrated under reduced pressure. The crude amino acid was dissolved in aq. HC1. 1M (4 mL) and Et2O (4 mL). Phenylboronic acid (120 mg, 0.99 mmol) was added and the clear biphasic solution was stirred at room temperature for 3 h. The mixture was diluted with Et2O (20 mL) and water (5 mL), and the phases were separated. The aqueous phase was washed with Et2O and the aqueous phase was lyophilized. The resulting solid was dissolved in MeOH (3 mL) and purified by ion exchange chromatography (PoraPak Rxn CX 20 cc column). The desired product was eluted from the column using 5% ammonia in MeOH solution (20 mL). The obtained material was further purified by reverse phase chromatography (RediSep Rf Gold® C18, 2 to 50% acetonitrile in water) to obtain (2R,4R)-4-((S)-2-amino-acid). 3,3dimethylbutanamido)-2-(4-boronobutyl)pyrrolidine-2carboxylic (Example 11, 40 mg, 35% yield) as a white solid.3H NMR (500MHz, D2O) δ 0.72 (2H, td), 0.89 (9H , s), 1.10 - 1.21 (1H, m), 1.22 - 1.30 (1H, m), 1.35 (2H, quintuplet), 1.64 - 1.75 (1H, m), 1.90 - 2.02 (1H, m), 2.22 - 2.34 (2H, m), 3.04 (1H, s), 3.22 (1H, dd), 3.56 (1H, dd), 4.41 (1H, quintuplet); m / z (ES+) [M+H]+ = 344. Example 12: (2R,4R)-2-(4-boronobutyl)-4-((S)pyrrolidine-2-carboxamido)pyrrolidine-2-carboxylic acid IF-2019-3 6421651 -APN-ANP#INPI Page 90 of 170 intermediate__________35:__________(2R,4R)-4-((S)-1-(tertbutoxycarbonyl)pyrrolidine-2-carboxamido)-2-(4-(4,4,5,5tetramethyl-l,3,2-dioxaborolan- 2-benzyl and 1-tert-butyl 2-yl)butyl)pyrrolidin-l,2dicarboxylate 27,M-Diisopropylethylamine (0.182 mL, 1.04 mmol) was slowly added to a stirred solution of HATU (175 mg, 0.46 mmol) and Boc-Pro-OH (94 mg, 0.44 mmol) in DMF (1.5 mL) at temperature atmosphere. The solution was stirred for 20 min and then a solution of (2R,4R)-4-amino-2(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2yl)butyl was added. 2-benzyl and 1-tert-butyl pyrrolidine-1,2-dicarboxylate (Intermediate 30, 210 mg, 0.42 mmol) in DMF (1.5 mL). The reaction was stirred for 2 h, diluted with EtOAc (30 mL), and washed sequentially with water (3 x 25 mL), saturated aqueous NaHCO3, and saturated aqueous sodium chloride (30 mL). The organic phase was dried with MgSO4, filtered and concentrated to dryness. The crude material was purified by silica gel chromatography (5 to 100% EtOAc in hexanes) to provide (2R,4R)-4-((S)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxamido) -2-(4-(4,4,5,591 IF-2019-3 6421651 -APN-ANP#INPI Page 91 of 1702-benzyl and 1-tert-butyl tetramethyl-l,3,2-dioxaborolan-2-yl)butyl)pyrrolidine-1,2dicarboxylate (Intermediate 35, 249 mg, 85% yield) as a colorless film and as a mixture of rotamers. 1R NMR (500MHz, CD2C12) δ 0.68 - 0.79 (2H, m), 1.20 (12H, s), 1.31 (5H, s), 1.36 - 1.48 (16H, m), 1.74 - 1.87 (3H, m), 1.89 - 2.10 (3H, m), 2.132.46 (2H, m), 3.27 - 3.40 (1H, m), 3.44 (2H, s a), 3.503.64 (2H, m), 3.78 - 4.05 (1H, m) , 4.49 (1H, s a), 5.105.27 (2H, m), 7.10 (1H, s a), 7.30 - 7.42 (5H, m); m / z (ES+) [M+H]+ = 700. Intermediate 36: Acid (2R,4R)-1-(tert-butoxycarbonyl)~ ((S)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxamido)-2l±-(4'4f5f5-tetramethyl-lf3f2-dioxaborolan -2yl)butyl)pyrrolidine-2-carboxylic Pd / C (10% by weight, 25 mg, 0.23 mmol) was added to a solution of (2E,4K)-4-((S)-l-(tert-butoxycarbonyl)pyrrolidine-2-carboxamido)-2-(4 -2-benzyl and 1-tert-butyl (4,4,5,5tetramethyl-1,3,2-dioxaborolan-2-yl)butyl)pyrrolidine-l,2dicarboxylate (Intermediate 35, 249 mg, 0.36 mmol) in EtOAc (4 mL). The suspension was stirred in a hydrogen atmosphere (balloon, flask evacuated and refilled with hydrogen x3) at room temperature for 5 h. The reaction mixture was diluted with MeOH, filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to give (2K,4B)-1-(tert-butoxycarbonyl)-4((S)-i-( tert-butoxycarbonyl)pyrrolidin-2-carboxamido)-2-(4(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2rl)butyl)pyrrolidine-2-carboxylic (Intermediate 36, 207 mg, 87% yield) as a colorless film and as a rotamer mixture that was used without purification IF-2019-3 6421651 -APN-ANP#INPI Page 92 of 170 Or additional. NMR (500MHz, CD2C12) δ 0.66 - 0.83 (2H, m), 1.21 (12H, s), 1.34 - 1.51 (21H, m), 1.63 - 1.97 (4H, m), 2.06 (1H, m), 2.11 - 2.29 (2H, m), 2.33 - 2.67 (1H, m), 3.24 3.52 (3H, m), 3.53 - 3.67 (1H, m), 4.15 - 4.34 (1H, m), 4.47 - 4.74 (1H, m) , 6.76 - 7.23 (1H, m), 7.17 - 7.69 (1H, m), 9.74 (1H, s a); m / z (ES+) [M+H]+= 610. Example__12: Acid (2R,4R)-2-(4-boronobutyl)-4-((S)~ PÍrrolidin-2-carboxamido) pyrrolidine—2—carboxylic Trifluoroacetic acid (0.518 mL, 6.73 mmol) was added dropwise to a stirred solution of (2R, 4R)-1-(tert-butoxycarbonyl)-4-((S)-1-(tert-butoxycarbonyl)pyrrolidine-2carboxamido) acid. -2-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2yl)butyl)pyrrolidine-2-carboxylic acid (Intermediate 36, 205 mg, 0.34 mmol) in DCM (2 mL) . The reaction was stirred at room temperature for 2 h and subsequently concentrated under reduced pressure. The crude amino acid was dissolved in aq. HC1. 1M (4 mL) and Et2O (4 mL). Phenylboronic acid (123 mg, 1.01 mmol) was added and the clear biphasic solution was stirred at room temperature for 2 h. The mixture was diluted with Et2O (20 mL) and water (5 mL), and the phases were separated. The aqueous phase was washed with Et2O and the aqueous phase was lyophilized. The resulting solid was dissolved in MeOH (3 mL) and purified by ion exchange chromatography (PoraPak Rxn CX 20 cc column). The desired product was eluted from the column using 5% ammonia in MeOH solution (20 mL). The obtained material was further purified by reverse phase chromatography (RediSep Rf Gold® C18, 0 to 50% acetonitrile in water) to provide (2R,4R)-2-(4-boronobutyl)-4-( (S')-pyrrolidine-2carboxamido)pyrrolidine-2-carboxylic acid (Example 12, 89 mg, 81% IF-2019-3 6421651 -APN-ANP#INPI Page 93 of 170 performance) as a white solid. iR NMR (500MHz, D2O) δ 0.70 - 0.79 (2H, m), 1.11 - 1.23 (1H, m), 1.24 - 1.33(1H, m), 1.34 - 1.42 (2H, m), 1.60 - 1.71 (1H, m), 1.81 -1.91 (3H, m), 1.91 - 1.99 (1H, m), 2.18 (lH,,dd), 2.22 -2.29 (1H, m), 2.40 (1H, dd), 3.08 - 3.16 (1H, m), 3.16 -3.22 (1H, m), 3.25 (1H, dd), 3.48 (1H, dd), 3.99 (1H, dd) ), 4.29 - 4.38 (1H, m) ; m / z (ES+) [M+H]+ = 328. Example 13: (2P,4P)-4-(2-aminoacetamido)-2-(4boronobutyl)pyrrolidine-2-carboxylic acid Intermediate 38 Example „ ^er7ned2°---------321__________(2Rf 4R)-4-( (R)-2-(tertbutoxycarbonylamino)acetamido)-2-(4-(4,4,5,5 -tetramethyl—'^'2-d^ox^borolan~2~yl)butyl)plrrolidln~lf2-dicarboxylate of 2-benzyl and 1-tert-butyl N,2\7-diisopropylethylamine (0.182 mL, 1.04 mmol) was slowly added to a stirred solution of HATU (175 mg, 0.46 mmol) and Boc-Gly-OH (77 mg, 0.44 mmol) in DMF (1.5 mL)' at room temperature. The solution was stirred for 20 min and then a solution of (2R,4R)-4-amino-2(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2yl)butyl was added. )pyrrolidin-l,2-dicarboxylate of 2-benzyl and 1-tert94 IF-2019-3 6421651 -APN-ANP#INPI Page 94 of 170 butyl (Intermediate 30, 210 mg, 0.42 mmol) in DMF (1.5 mL). The reaction solution was stirred for 2 h, diluted with EtOAc (30 mL), and washed sequentially with water (3 χ 25 mL), saturated aqueous NaHCO3, and saturated aqueous sodium chloride (30 mL). The organic phase was dried with MgSO4, filtered and concentrated to dryness. The crude material was purified by silica gel chromatography (10 to 100% EtOAc in hexanes) to provide (27?, 47?) -4-(2-(tert-butoxycarbonylamino)acetamido)-2-(4- 2-Benzyl 1-tert-butyl (4,4,5,5-tetramethyl1,3,2-dioxaborolan-2-yl)butyl)pyrrolidine-l,2-dicarboxylate (Intermediate 37, 235 mg, 85% performance) as a colorless film and as a mixture of rotamers. iHRMN (500MHz, CD2C12) δ 0.70 - 0 78 (2H m) 1.12 - 1.18 (1H, m), 1.2O(12H,s), _130;1H;2 1.33 (5H, s), 1.43 (15H, s), 1.74 - 1.86 (1H, m), 1.95 (0.5H, d a), 2.03 (0.5H, d a), 2.15 - 2.26 (1H, m), 2.26 - 2.37 (1H, m), 2.40 (1H, dd), 3.43 - 3.57 (3H, m), 3.57 -3.64 (1H, m), 4.50 (1H, s a), 5.03 (0.5H, s a), 5.10 (0.5 H, s a), 5.13 - 5.25 (1H, m), 7.01 (1H, dd), 7.32 - 7.37 (1H, m), 7.36 - 7.41 (4H, m) ; m / z (ES+) [M+H]+= 660. Intermediate 38: (2R,4R)-1-(tert-butoxycarbonyl)————(-teri:~butoxycarbonylamino)acetamido acid)-2- (4- (4,4,5,5tetramethyl-l,3,2 -dioxaborolan-2-yl)butyl)pyrrolidine-2carboxylic Pd / C (10% by weight, 25 mg, 0.23 mmol) was added to a solution of (2E,4B)-4-(2-(tertbutoxrcarbonylamino)acetamido-2-(4-(4,4,5, 2-Benzyl 1-tert-butyl 5-tetramethyl1,3,2-dioxaborolan-2-yl)butyl)pyrrolidln-1,2-dicarboxylate (Intermediate 37, 233 mg, 0.35 mol) in EtOAc (4 mL). The suspension was stirred in atmosphere IF-2019-3 6421651 -APN-ANP#INPI Page 95 of 170 or of hydrogen (balloon, flask evacuated and filled with hydrogen x3) at room temperature for 6 h. The reaction mixture was diluted with MeOH, filtered through diatomaceous earth and the filtrate was concentrated to dryness to provide (2R, 4R)-1-(tert-butoxycarbonyl)-4-(2(tert-butoxycarbonyl) acid. acetamido-2-(4-(4,4,5,5-tetramethyl1,3,2-dioxaborolan-2-yl)butyl)pyrrolidine-2-carboxylic acid (Intermediate 38, 176 mg, 87% yield) as a film colorless and as a rotamer mixture that was used without further purification iHRMN (500MHz, CD2C12) δ 0.65 - 0.80 (2H, m), 1.11 - 1.18 (iH, m),1>18_1>23 (12H, _. 1.32 (1H, m), 1.36 - 1.45 (13H, m), 1.47 (7H, s), 1.70 1.83 (0.4H, m), 1.84 - 1.95 (0.6H, m), 2.06 - 2.27 (2H, m) , 2.33 - 2.47 (0.4H, m), 2.63 (0.6H, d a), 3.44 - 3.62 (2H, 15 m), 3.63 - 3.82 (2H, m), 4.28 (0.6H, s a), 4.36 - 4.60 ( 0.4H, m), 5.26 (0.6H, s a), 5.58 - 5.90 (0.3H, m), 6.83 (0.6H, s a), 6.97 - 7.44 (0.4H, m) ; m / z (ES+) [M+H]+= 570. Example—13j—Acid—(2R, 4R)-4-(2-aminoacetamido)-2-(4boronobutyl)pyrrolidine-2-carboxylic Trifluoroacetic acid (0.476 mL, 6.18 mmol) to a stirred solution of acid (2R, 4R)-1-(tert-butoxycarbonyl)-4-(2-(tert-butoxycarbonylamino)acetamido)2-(4-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-211)butyl)pyrrolidine-2-carboxylic acid (Intermediate 38, 176 mg, 0.31 mmol) in DCM (2 mL). The reaction solution was stirred at room temperature for 2 h and subsequently concentrated under reduced pressure. The crude amino acid was dissolved in aq. HC1. 1M (4 mL) and Et2O (4 mL). Phenylboronic acid (113 mg, 0.93 mmol) was added and the clear biphasic solution was stirred at room temperature for 2 h. The IF-2019-3 6421651 -APN-ANP#INPI Page 96 of 170 mixture was diluted with EtzO (20 ml) and water (5 mL), and the phases were separated. The aqueous phase was washed with EtzO and the aqueous phase was lyophilized. The resulting solid was dissolved in MeOH (3 mL) and purified by ion exchange chromatography (PoraPak Rxn CX 20 ce column). The desired product was eluted from the column using 5% ammonia in MeOH solution (20 mL). The obtained material was further purified by reverse phase chromatography (RediSep Rf Gold® C18, 0 to 40% acetonitrile in water) to obtain acid (2R,4R)-4-amino-(2-aminoacetamido)2 -(4-boronobutyl)pyrrolidine-2-carboxylic acid (Example 13, 62 mg, 70% yield) as a white solid. iH' NMR (500MHz, DzO) δ 0.76 (2H, td), 1.15 - 1.25 (1H, m), 1.26 1-34 (1H, m), 1.36 - 1.46 (2H, m), 1.69 - 1.79 (1H, m), 2.00 (1H, ddd), 2.27 (1H, dd), 2.44 (1H, dd), 3.33 (1H, dd), 3.42 (2H, s), 3.59 (1H, dd), 4.36 - 4.45 (1H , m); m / z (ES*) (M+H1* = 288. Example 14: Acid (2R,4R) -4- ((S) -2-aminobutanamido) -2l£-boronobutyl)pyrrolidine-2-carboxylif!» Intermediate 40 Example 14 IF-2019-3 6421651 -APN-ANP#INPI Page 97 of 170 Intermedin If 3,2-di oxaborn 1 39: ^-^nciio_y· l-tert-butiin ----(2R¿4R)^4- ( (S) -2- (tert2.(4-(4,4,5,5-tetrameti 7ato Added HATU (804 ma 2 n Boc-Abu-OH (430 ma 2 113“SOluclon1 Umg, 2.11 mmol) in DMF (4 mL)v1 = stirred at room temperature for w (2í, 4í)-4-amino-2-(4-(4 455tflt .min'qzó,5-tetramethyl-i 3 2dioxaborolan-2-yl)butyl)pyrrolidln, , ¿benzyl and l-tert h„r ·, 2y tert butyl 2-carboxylate (Intermediate 30 ρρς to the mixture reaction rate 'm<3'1.76mmol) ... eaction as a solution in DMF (3 mi) ς added N.N-HHo_____, ... mL). N,N-diisopropylethylamine (0.75 mL, 4.3 mmol) was added and room was added overnight. mL). The phases ..(15 ml) Et*° Et2O (2 x 10 mL) Las^^Y 5θeXtra^°concon Utio chloride aT Ovaron MgSO4, 31'δθdried with ' were filtered and concentrated to seauedsH crude se nuri-Fi^A _> $ age. The material was purified by chromatography on »1 „ (hexanes / EtOAc) side nn561 of Sllice «) to provide (2Λ, 4J?)-4-((S)utoxycarbonylamlno)butanamido)-2-(4-(4 4 5 5tt l,3,2-dioxaborolan-2-yl)butin · ' '4'S' 5'tetraraethylreaction was stirred at temperature The reaction was then diluted yield) 0.70 1.36 0.84 as a white solid. (Intermediate 39, 766 mg, 63% of (5H, m), 1-46 (18H, m),m), 3.45 - 3.60 (1H, m)> 4.42 - 4.64 (1H, 1.09 1.46ΧΗ NMR (500MHz, CDC13) δ1.19(1H, m), 1.21 (12H, · 97 (7H, m), m), 3.68 m), 4.73 (2H, m), 7.09 (1H, d a), 7.28 = 688. (1H,d - 5.03 a) z (1H,7·40 (5H, m). 2.12 3.78 m), m / z s), - 2.45 (2H, ~ 3.94 (1H, 5.07 - 5.33 (ES+) [M+HJ + IF-2019-3 6421651 -APN-ANP#INPI Page 98 of 170 EITHER Intermediate 40: (2R,4R) -1- (tert-butoxycarbonyl) acid — ~ ( (S) -2- (tert-butoxycarbonylamino)butanamido) -2- (4_(4,4,5,5-tetramethyl-l , 3,2-dioxaborolan-2yl)butyl)pyrrolidine-2-carboxylicDissolved (2R,4R)-4-((S)-2-(tert-butoxycarbonylamino)butanamido)-2-(4-(4,4,5,5 2-benzyl and 1-tert-butyl-tetramethyl1,3,2-dioxaborolan-2-yl)butyl)pyrrolidine-1,2-dicarboxylate (Intermediate 39, 766 mg, 1.11 mmol) in EtOAc (11 mL) and treated with Pd / C (10% by weight, 119 mg, 0.11 mmol). The flask was fitted with a balloon of H2 and the suspension was stirred overnight at room temperature. The reaction mixture was filtered through diatomaceous earth and washed with EtOAc and methanol. The filtrate was concentrated to dryness. The crude material was purified by silica gel chromatography (hexanes / EtOAc) to provide (2R, 4R)-1-(tert-butoxycarbonylamino)-4-((S)-2(tert-butoxycarbonylamino)butanamido)-2- 2-Benzyl 1-tert-butyl (4-(4,4,5,5tetramethyl-1,3,2-dioxaborolan-2-yl)butyl)pyrrolidine-2dicarboxylate (Intermediate 40, 470 mg, 70% yield ) like a white foam. 1R NMR (500MHz, CDC13) δ 0.67 - 0.82 (2H, m), 0.89 (3H, t a), 1.11 1.28 (14H, m), 1.37 - 1.51 (20H, m), 1.53 - 1.65 (1H, m), 1.65 - 1.94 (2H, m), 2.02 - 2.12 (1H, m), 2.13 - 2.31 (1H, m), 2.70 (1H, d a), 3.40 - 3.62 (2H, m), 3.88 - 4.04 (1H, m ), 4.26 (1H, s a), 5.01 (1H, s a), 6.73 (1H, d a); m / z (ES+) [M+H]+= 598. Example 14: (2R,4R)-4-((S)-2-aminobutanamide)-2(4-boronobutyl)pyrrolidine-2-carboxylic acid Phenylboronic acid (192 mg, 1.57 mmol) was added to a solution of (2R,4R)-1-(tert-butoxycarbonyl)-4-((S)-299 acid IF-2019-3 6421651 -APN-ANP#INPI Page 99 of 170 or ,carboxylic (Intermediate 40, M (5 mL) >utanamido)-2- (4- (4,4,5,5an-2-yl)butyl)pyrrolidin-2470 mg, And the reaction was stirred for 16 h. The reaction was (10 mL) and the phases were separated. Et2o (3 X 5 mL) and subsequently 0-79 mmol) in aq. HC1. 2 at room temperature with water (10 mL) and Et2O aqueous phase was washed with lyophilized to obtain a foam. The organic phase was concentrated to the resulting residue was diluted in HC1 4 „ Í mol) and soleo,·· °Xan°(4 16and the resulting solution was stirred at +« stirred at temperature The reaction was diluted with water (10 room for 20 h. mL) and Et2O (10 mL) and washed with Et2O (3x5 to obtain a foam. P The foams from operations were combined and the amino was purified by chromatography of Zh° Silicycle SiliaSep SPE-R51230B-20X 5,ΓEf was eluted from the eni '1 desired product solution of Z T additionally by íromatogZiZe C18Ag, from 0 to 25% aceten! ZZ (2R,4R)-4-((S) 2-aminobutanamido)-2-(4 layers were separated. The aqueous phase of these two obtained boronobutyl)pyrrolidine-2carboxylic acid (Example 14, δ 0.55 1.56 θ·82 (2H, m), as a white solid. mg, 39%XH NMR (500MHz, D2O) °'88 (3H' V· 1-12 - 1-48 (4H, m). m), 3.15 - 1-81 (3H, m), 1.86 _2.10 (1H,m), '3.37 (1H, m), 3.41-3.53 (1H, m), 3.62 (1H,dd), m / z (ES+) [M-HsO+H]* = 298. 4-35 - 4.52 (1H, m); Example go - 2.53 (2H, ----<-2«, 4R) -4- ((23, as) -2-amino-3LboroaobutiDp) rrolidin-2-ea^, , 100 IF-2019-3 6421651 -APN-ANP#INPI Page 100 of 170 Intermediate 41 Intermediate 42 Intermediate Example 15 41: , 4. . -------(-R'4R)~4~ ( (2S,3S)-2tetramethyl-l,3,2-dioxafcor^^.2n. ' ' ^^ylate^bencloyi-tert-butl m HATU (804 m or 2 11, r—_,Τ1 Λg' -11 mnol) was added to a solution of se agX t θ' ^11”O1)“DMF <4 mL) and the—ion was stirred at room temperature for 10 min. Se (2R,4E)-4-amino-2-(4-(4,4,5,5-tetramethyl-l 3 2dioxaborolan-.-ÍDbutiDpyrrolidin-l^-dicar^Uaro enci o and 1-tert-butyl (Intermediate 30, 885 mg, 1 76 to the reaction mixture as a solution in DMF (3 mL) N,N-dlysopropylethylamine was added (075 reaction was stirred at room temperature overnight. . Z7dÍ1UÓ 6nt0nCeS“n 39ϋ3 (1S ml)* -10 (10 Et2O (2 ΓThey were separated and the aqueous phase was extracted with mL) 'The combined organic phases were washed; 10-- - dried with '1 raronS' and concentrated to dryness. The crude material was purified by silica gel chromatography (hexanes / EtOAc) to provide (2ñ, 4.)-4-((2S,3S)_2. added 2mmol) 101 IF-2019-3 6421651 -APN-ANP#INPI Page 101 of 170 2-Benzyl 1-(tert-butoxycarbonylamino)-3-methylpentanamido)-2-(4(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2yl)butyl)pyrrolidin-l,2-dicarboxylate -tert-butyl (Intermediate 41, 707 mg, 56% yield) as a white solid, , 1.24 (12H, s), 1.32 1.61 (20H, m), 1.62 - 2.02 (4H, m), 2.18 - 2.55 (2H,m), 3.49 - 3.65 (IR, m), 3.65 - 3.78 (IR, m), 3.90 (IR, sa), 4.53 - 4.72 (IR, m), 4.95 (IR, s a), 5.07 - 5.43 (2H,m), 7.16 (IR, d a), 7.30 - 7.44 (5H, m) . m / z (ES+) [M+H]+ = 716. Intermediate 42: Acid (2R,4R) -1- (tert-butoxycarbonyl) 4_- ( (2S,3S) -2- (tert-butoxycarbonylamino) -3methylpentanamido) -2- (4-(4,4,5,5 -tetramethyl-l,3,2^l°xaborolan-2-yl)butyl)pyrrolidine-2-carboxylic (2R, 47?)-4-((2S,3S)-2-(tertbutoxycarbonylamino)-3-methylpentanamido)-2-(4-(4,4,5,5tetramethyl-1,3,2-dioxaborolan) was dissolved 2-Benzyl and 1-tert-butyl -2-yl)butyl)pyrrolidine-1,2dicarboxylate (Intermediate 41, 707 mg, 0.99 mmol) in EtOAc (10 mL) and treated with Pd / C (10 wt %) , 105 mg, 0.10 mmol). The flask was fitted with a balloon of H2 and the suspension was stirred overnight at room temperature. The reaction mixture was filtered through diatomaceous earth and washed with EtOAc and methanol. The filtrate was concentrated to dryness to give acid (2R,4R)-1(tert-butoxycarbonyl)-4-((2S,3S)-2-(tert-butoxycarbonylamino)-3-methylpentanamido)-2-(4-(4, 4,5,5tetramethyl-1,3,2-dioxaborolan-2-yl)butyl)pyrrolidine-2carboxylic acid (Intermediate 42, 603 mg, 98% yield) which was used without further purification.XR NMR (500MHz, CDCI3) δ 0.68 - 0.80 (2H, m), 0.83 - 0.93 (6H, m), 1.05 - 1.14 (IR, 102 IF-2019-3 6421651 -APN-ANP#INPI Page 102 of 170 m), 1.21 (12H, s), 1.28 - 1.36 (1H, m), 1.37 °' 1.71 - 1.96 (2H, m), 2.18 - 2.31 (1H,m), a)z 3.42 - 3.51 (2H, m), 3.52 - 3.63 (1H,m), (1H, m), 4.16 - 4.34 (1H, m), 4.98 (1H, da), to); m / z (ES+) [M+H]+ = 626. - 1-55 (22H, 2.72 (1H, d 3.86 - 4.04 6.69 (1H, s ^emPla------isido----(2R, 4R) -4- ( (2S.3S) -2- amino-3S^lpentanamido) -2- <4-boronobutyl)Plrrolidin-2-carboXíllc„ Trifluoroacetic acid (1.10 mL, 14.3 mmol) was added to a solution of (2R,4R)-1-(tert-butoxycarbonyl)-4((2S,3S)-2-(tert-butoxycarbonylamino)-3-methylpentanamido) acid. 2 (4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2yl)butyl)pyrrolidine-2-carboxylic acid (Intermediate 42, 603 mg 0.96 mmol) in DCM (6 mL). The resulting solution was stirred at 1 room temperature for 16 h and subsequently concentrated in vacuo. The crude amino acid was dissolved in EtzO (10 mL) and re-concentrated in vacuo. This process of redissolution and reconcentration was repeated two more times. The crude amino acid was then dissolved in Et2O (6 mL) and aq. HC1. 1M (6mL). Phenylboronic acid (235 mg, 1.93 mmol) was added and the clear biphasic solution was stirred at room temperature for 3 h. The reaction mixture was diluted with water and washed with EtzO. The aqueous phase was lyophilized and purified by ion exchange chromatography (Silicycle SiliaSep SPE-R51230B20X 5g column). The desired product was eluted from the column using a 5S ammonia in MeOH solution. The obtained material was further purified by reverse phase chromatography (RediSep Rf Gold® CISñg, 0 to 25% acetonitrile in water) to obtain acid (2R,4R)-4-((S)-2amino-3- methylpentanamido)-2-(4-boronobutyl)pyrrolidin-2103 IF-2019-3 6421651 -APN-ANP#INPI Page 103 of 170 or carboxylic (Example 15, 136 mg, 41% white solid. 0.89 (6H, dd),1HRMN (500MHz, D20) δ 0.55 1.07 - 1.52 (6H, m), 1-86 2.09 (1H, m), 2.13 - 2.51 (2H, m), 3.45 = 344. ~ 3.67 (1H, m), θ·81 (2H, m), 1.63 - 1.83 (2H, m), m), 3.11 - 3.40 (2H, 4.39 4.54 (1H, m) ; m / z (ES+) [M+H] Intermediate 44 h^^12-------43:______ (2R,4R)-4-((3,-2-(^ -^oxlcarbonylamino)-4-methyl1pentananiido)-2-(4-(4 ¿ς~ djcarbo^late of 2-benzyl and Ι-terr-^,- -----HATO was added (247 m or 0 κς x _Tg , °·65^1°1) to a solution of Boc-Leu-OH (125 mg, 0.54 mmol) in DCM (2 mL) was stirred at room temperature for min Se (2í,4«)-4-amino-2-(4-(4,4,5, 5-tetramethyl-l 3 2dlozaborolan-2-yl)butyl)Pyrrolidin-l,2-dicar^ozylate ency o and 1 tert butyl (Intermediate 30, 272 mg, 0.54 to the reaction mixture as a solution in DCM (2 mL) ^-dilsopropylethylamine (0.19 mL, l.imol) was added and the reaction added 2mmol) 104 IF-2019-3 6421651 -APN-ANP#INPI Page 104 of 170 .™::: — -- --sequentially with water (25 ZY Se washed saturated (30 mL). The aqueous C1MUr°Sodi“ phase was filtered and purified. It was concentrated to dryness. through The chromatography (hexanes / EtOAc) dried with MgSO4, crude material was To provide .no) -4-methylnAr>+-=r,silica gel tetramethyl-i,3,2-dioxaborolan 2-benzyl dicarboxylate 210 mg, 54% yield) a mixture of rotamers. iH t)z 0.91 (6H, d), 1.06 1.31 m), (2R, 4R)-4-((S) _2_(tertido)-2-(4-(4,4,5,5Y l-tezt-butyl (Xntexmedi. as a colorless foam v 1-51 (20H, m), 1.502.17~2·55 (2H, (1H,m), 4.35_4>757·22(1H, m), 7.28 or 43, ’ as NMR (500MHz, CDCI3) δ 0.77 (2H “1·19(1H, m), 1.19 1-63 (2H, !·24 (12H, m), m), (2H, 7.42 Intermediate 44; / 3.35 m), (5H, - 3.75 5.00 m), (2H, 5.46 1.73 m), (2H,m);m / z (ES+) [M+H] “ 2.02 (2H,3·θ4 - 4.06 m), 7.08 C4-(4,4,5,5-tetramethyl-i mo ) -4-i 3,2-dioxaborolan-?Se Zparboxíiinn = 716. carbonyl)dissolved .A(2jR'4j?)“^-( (S)-2-(terttet ·n°4-metÍlpentanamido)-2-(4-M 4 η etramethyl-l,3,2-dioxaboroian_2.il )but.'í4'4'5'5diearboxylate of 2-benzyl and !-te^ 2 θ·2θ mmol)in Et0Sc 201 mg θη wt, 100 mg, 0.094 mmol) h2 balloon and the suspension was And it was treated with Pd / C (lo for 2 h. diatomaceous earth The mixture of The flask was equipped with a shaker at room temperature And washed with EtOAc, reaction was filtered through and methanol. The filtering 105 IF-2019-3 6421651 -APN-ANP#INPI Page 105 of 170 or butoxycarbonyljXTfsTl 7 / 34R)-j-(tert-Lipendi, r:T:u:Ticarboniiaraino)-4dioxaborolan-2-yl)butl,>5-tetramethyl-i,3,2benzyl and l-tert' “t,Ρ“ ™η-2-ό1„Λοχ11^οtert butyl (Intermediate 44Ί7ηyield) with a solidQ° mg, rotamers. iHRMN (500MHz, d), 1.15 1-25 (12H, m), from 97% and as a mixtureCDC13) δ 0.78 (2H, t), 1.25 (19H, m), 1.55 - 1 72Í?H,Ί o(2H' m), 1,732·11 (1H, m), 2,181.31(2H, m), 1,393·74 (2H, m), 3.96 4.82 626. 5·31 (1H, m),6.62 2nd of 0-93 (6H, 1.51 _9__ „ ~1.89 (1H' m), 2,012.36(1H, m), 2.47 - 2 83 (iw i , (1H, m), 3,374.10(1H, m), 4.17 - 4.32 7.12 (1H, m); (1H, m), m / z (ES+) [M+H] Example ΊΚ- < . , ---- ----—_____(2R, 4R)-4-((5} 9 Pentanamido} ,* 777 --(-(S)~2~3ΐηιηο-^a solution of acid (21? «)7713'°mol> ^-2-^t-b.toxí^ 77'5'5-tet«methyl-1,3,2.dloxaboroian¿lpent--^o)-2-(4’ tH)pyrrO1idin-2-carboxU.co 0-27 mmol) in DCM (2 mL) The , 170 mg, room temperature for 77 was concentrated in vacuo ri ·And subsequently seaC1°-E1 crude amino acid was given <,m ·' (5 mL) and water ( 4 ~ isolvium then < tL) · Phenylboronic acid was added to a transparent biphasic solution and ambiented for 2 h t=> It was diluted with water (5 mL) P*separated The phasesY <2°mL)'and lasn· The aqueous phase was lyOfin, Achromatography HaY It was Purified PorarakRx„cx7(CO1™a9) PaM°obtain“«o (2R,4R)-4-((s)_2. in Et2O (66 mg, stirred reaction phases by θ·54 mmol) and temperature 106 IF-2019-3 6421651 -APN-ANP#INPI Page 106 of 170 amino-4-methylpentanamido)-2-(4-boronobutyl)pyrrolidine-2carboxylic acid (Example 16, 88 mg, 94% yield) as a white solid. 1HRMN (500MHz, D2O) δ 0.46 - 0.68 (2H, m) θ·73 - 0.82 (6H, m), 1.03 - 1.13 (1H, m), 1.13 - 1.23^1^ 1-23 - 1.42 (4H, m), 1.42 - 1.52 (1H, m), 1.54 - 1.66 (1H, m), 1.76 - 1.93 (1H, m), 2.07 - 2.19 (1H,m),2.29 (1H , dd), 3.13 (1H, c), 3.34 (1H, t), 3.48 (1H, c), 4.23 - 4.40 (1H, m) ; m / z (ES+) [M+H]+= 344. ' ------------(2R, 4R) -4- ( (S) -2- (tertbutoxycarbonylamino) -4-hydroxypropananido) -2- (4- 14,4,5^5^ tra^yl-l,3,2-dioXaboI„la„.2.11)butyl)plri:olldia_'i'2_ 2-benzyl and 1-tert-butyl dicarboxylate W,W-diisopropylethylamine (0.108 mL, 0.62 mol) was added to a stirred solution of COMO (292 mg, 0.68 mmol) (2R,4R)-4-amino-2-(4-(4,4,5,5 2-benzyl and 1-tert-butyl-tetramethyl-l,3,2dioxaborolan-2-yl)butyl)pyrrolidine-l,2-dlcarboxylate (Intermediate 30, 311 mg, 0.62 mmol) 107 IF-2019-3 6421651 -APN-ANP#INPI Page 107 of 170 O and Boc-Ser-OH environment. The water (80 mL) aqueous phase (133 mg, 0.65 mmol) in DMF (5 mL) reaction was stirred for 3 h, and EtOAc (15 mL). The phases were further diluted with saturated aqueous NaHCCb and then extracted with EtOAc (2 combined organic phases were washed with saturated (2 x 10 mL), dried with MgSO4, concentrated to dryness. The crude material by silir gel chromatography provides (2E, 4K) -3-((S) 2 ( t t tMr. . ' ((S)-2-(tert-butoxycarbonylamino)-4hydroxypropanamido)-2- (4-(4,4,5,5-tetramethi)-, , mL) The aqueous NaCl was filtered and o and 1-tert-butyl (Intermediate 45, 358 mg, 84% yield) was purified as a colorless dry film. and as a rotamer mixture iR NMR (500MHz, 1-16 (1H, m), 1.21 (12H, m), 1.43 (11H, s), I.73 2-14 - 2.24 (1H, m), 2.29 m), m), m), 690. 3.52 3.92 3.61 (2H, m), 4.04 (1H, m), 5.36 (1H, s a), 7.30 a CDC13) δ 0.76 (2H,s) ' 1.31 (6H, s), 1.35 - 1.42 1-87 (1H, m), 1.87 - 2.02 (2H, (5H, m), 2.41 (1H, m), 3.43 - 3.52 (0.4H, 3-66 (0.6H, d), 3.79 - 3.92 (1H, 4.51 (1H, s a), 5.06 - 5.26 (2H, 7.40 (5H, m); m / z (ES+) [M+H]+ = 4- < <4^-S.5-tetr^etll-1,3,2-dioXsb0rolan^. ’ illibutiDpyrroiidin^-carboxllir-r, Dissolved (22?, 42?)-4-( (S)-2-(tert^icaroonilamino)-3-hydroxypropanamido)-2-(4-(4 4 55tetrametii-i.a^-dioxaborolan-l-iDbutiDpyrrolidi;- ;;2-benclyl and 1-tert-butyl loarboxylate (Intermediate 45, 108 IF-2019-3 6421651 -APN-ANP#INPI Page 108 of 170 or 358 mg, 0.52 mmol) in EtOAc (4 mL) by weight, 50 mg, 0.047 mmol). of H2 and the suspension was stirred And it was treated with Pd / C (10 The flask was equipped with 3-5 hrs. The reaction mixture was diluted with MeOH, filtered r:::: “*“·'·' —· .tert“butoxycarbonyl) -4(tert-butoxycarbonylamino)-3-hydr · .. .....lc^roxlProPanamido) -2-(4an-2para yl)butyl)Pyrrolidin_2_carlico (Intermediate 46, 303 mg as a white solid and as a CD c.l > Γ?1ΖΟ S1PAdditional verification. 1" CD2C12) or 0.67 - 0 91 . , -91 (2H- 1-25 (14H, (3H, m), 1.48 Í9H iOfi 9' '1.53 (10H' ' 1-82 • θ “ 2.14 (1H, m) , 2.24 - 2 qq z1Lr - 2-W (1H, m), 3.48 - 3.54(1H, , ' <1H, dd), 3.93 (1H, d), 4.03 - 4 ' J('1H' (1H, m);m / r( ES.,[M;H / =6'00m)'4·29 97% yield) of NMR rotamers (500MHz, 1.41 - 1.47 !-90 (2H, m), which are 3.70 -2- (4-boronobut carboxyljnn -.OlloÍTunZ;9Acidic acid ote (0.771n stirred acid δ τ>\ i butoxycarbon-i-n / „ .. ^¿R^R)-1-(terthydroxypropanamido)-2-(4-(4,4 XtoTn'2'11,butyl,pyrrolidin-2-^°--éo ntezmedxo 46, 300 mg, 0.50 mmol) room temperature. Then in no)-3concentrated to dissolved in reduced pressure HC1 aq. 1 m (4 mL, 1.5 h,DCM(4 mL) solution was added phenylboronic acid (183 And the resulting residue 4.00 mmol) yEt2O (4 mL). HE mg, 1.50 mmol) and the solution 109 IF-2019-3 6421651 -APN-ANP#INPI Page 109 of 170 Transparent biphasic O was stirred at t-o for 3 h Τα π room temperature for 3 h. The mixture was diluted with Et2O Í20 π,τ i mL), and the fac?AC!2°(2° AND water (5 Et20 lafseP«-on. The aqueous phase was washed with It is only / 36 3θΡ3Γ3ΓΟη and 13— is freeze-fixed The resulting solid was dissolved in MeOH (3 > internal κ·Y chromatography S°met16 CX 20 cc) The a1OnÍC (“PoraPak Rxn ce column). The desired product was elevated d» ·> using a Uy° of the column raising a 5. deammonia in solution of material obtained (20 mL). Elsepurified by reverse phase acid chromatography (RediSep Rf Gold®cl8, --)4 S)VCetOnltrÍ1° θa'Ua)— ( ,«)-4-( (S)-2-amino-3-hydroxypropanamido)-2-(4oronobutyl)pyrrolidln.2.carboxíi.code yield) as a solid xi9'59° δ 0.77 (2H td) 1 1B' '(500MH2' °20' WH, td), 1.16 -1-26 (1H / m),126_i<Íh dV'L'2”' ^76 2-°2<™), (1H, dd), 2.46 (1H, dd), 3.35 (1H, dd), 3.66 - 3.77 (2H, m), [M+H]+ = 318. Example ip. -é. , r-1·--------lo .______Acid λ m), 2.29 3.62 (ES+) (1H, dd), 3.48 (1H, t), 4.40-4.50 (1H, m); m / z (2R, 4R)-4- ((s)-2-amino-3L) pyrrolidin-9110 IF-2019-3 6421651 -APN-ANP#INPI Page 110 of 170 Boc 9 Λ Jl o ζ-ΛΝΗk^.O, --either " ' NHBoc O-7 Intermediate 48 -Tntermed7r> Boc 9 O J_ / T°Bn'-O » ' NHBoc O—7 Intermediate 47 H 9 ,N^ Jl o J_7T0H_Λ~νη k^ ° nh2 Example 18 'B'°H OH 47: (2Re4R)-4- ((S)-2- (tert~7 ' ~—~e¿ox¿Pr°P^namido;-2-f / ?-4te trame ti 7-7 o -—^-= —— <q'4,5,5--2-dioxaborolan-2-i 1)but i 1 ~------Added W,H-diisopropylethylamine (0 082 (2R \r) 4UM,SO1UC1Ón was added of AS (220 mg, 0.51', (2R,4S)_4_amino.2.(4_(4 / 4;b5_tdioxaborolan-2-yl)butyl)plrrol.d.n?'3'2benzyl and 1-tert-butyl (lnt. „. 'dlCarboxylate uuiio (Intermediate 30 oqc „ And N-Boc-0-methyl-L-serine non9' °'47a t108 mg' °·49mmol)endmp,, at room temperature τ= ·MF(3 mL) eoXr was diluted, ¿' were separated and the phase ' Lasose was extracted with DCM (2 combined organic ml) · The saturated aqueous phases were dried with <30 mL), I was born aqueous MgSO4, filtered under reduced pressure. The crude material silica gel chromatographyProvide (2S,«) -4.((s)_2.(tert_bmethoxypropanamido) -2-(4-(4,4,5,5-tetn ' 0.47 mmol), of 2nunol) phases x 20 were washed with saturated NaHCO3 (2x1O mL), and concentrated and purified by (heXanes / EtOAc)paratoXicarbonylamino)-3111 IF-2019-3 6421651 -APN-ANP#INPI Page 111 of 170 dioxaborolan-2-yl)butyl) ] benzyl and 1-tert-butyl yield) as a mixture of 1·1θ (1H, (5H, s a), Pyrrolidine-l,2-dicarboxyate (Intermediate 47, Dry film rotamers. iHRMN (500MHzddV- 1-22 - 1.26 (13H,'m),1.46 (9H' s), 1.57(1H' m), 1.94 (0.4H, d), MMM), 2.32 3.49 2.47 (1.4H, m), 3.32of 2145mg, 44% colorless and as CDCI3) δ 1.331·74(1H, m)2.01(0.6H, d), 2.18 of a °·7θ (2Hrt), (6H, s), 1.44, 1.74 - 1.85(3H' s), 3.393·55 (0.4H, m), 3.60 (1H, dd) 3654·15UH, d a), 4.51 - 464(1H' 23 - ς oz ,,Í1H'm>' 5.065·34 (1H, m), 7.32 - 7.39 (5H / = 704.' .Ácldo4R>-, / t. ----^^-^^zdroxaborolan^. 2-27 (0.6H, “ 3.46 (IR,3·7θ (1.6H, - 3.22 (2H, (ES+)) [M+HJ + (2R, 4R) -4-( (s) -2- / tert-tetramethyl-1 was dissolved in 2ZTtOXÍPrO“dO!-2-(4-(4'4'5-3- ’ dicarboxylate 145 mg, θη weight, 22 mg -Í,20 21 mmolitert-butyl (Intermediate 47 0-21 mmol) in EtOAc (2mL) and treated with Pd / C (10% Flask B1 was fitted with a balloon f 0-021 mmol). άθ H2y the suspension was stirred at i-o----4h. The ambient reaction mixture during . faction was diluted through diatomaceous earth and COL '“fllled into Provide acid (2RiRi,a drynessfor .1 3ñ'4í)-l-(tert-butoxycarb0n<1>_,_____axDonnamino)-3-metnv-!^ <4-4,5,5-tetramethyl-i 3 2 di κtOxlpr °P—i do) -2-(4I..χ'3'—οχaborolan-2100% yield) carboxylic (Intermediate 48, as a white solid 126 mg, and as a mixture 112 IF-2019-3 6421651 -APN-ANP#INPI Page 112 of 170 of rotamers that are η+-ί i ΐ -?a used Without additional purification ihmN“' —^o-es-o.eo (2H, .),1.14-12 ,Η »), 1-35 - 1.43 (5H, m), ^44(7H< s) 1-77 - 1.95 (1H,2.03 _ 1-46 - 1.60 (8H, m), m), 2.68 (1H, d “3.60 (2H, m), 4-24 (1H, s a), [M+H]+ = 614. Example a)z 3.33 (3H, s), 3-65 - 3.76 (1H, 5.38 (1H, s a), 76;__Acid (1H, 3.38 m), 2.14 - 2.26 (1H, 3.47 (1H, m), 3.47 m), 4.02 - 4.15 (1H, m), 7.06 (1H, s a); m / z (ES+) . · ---~R'4R-—( (s> ~2-amino-3~ίοΧίΡΙΟΡΒη™ίόο)-2-(4-ύοΓθΓΐηύυίίΐ)ρΐΙ1:οΐϊ,ιίηcarboxylic 26 11Γ16 9°ta 3 9°ta ethical acid° (0.25 to a stirred solution of acid (2J?,4H)-1-{tertmethoxypropanamido)-2-(4-(4,4,5,5-tetramethyl dioxaborolan- 2-yl)butyl)pyrrolidin-2 (Intermediate 48, 100 mg, 0.16 concentrated at room temperature. Then reduced pressure dissolved in 1 M aq. HC1 (2 mL, thylammo added) -3-1.3 clear biphasic phenylboronic acid ,2-carboxylic mmol) in DCM (2 mL) άθ 1 h, the solution the resulting residue 2.00 mmol) yEt2O (2 mL). if Se (60 mg, 0.49 mmol) and the solution stirred at room temperature and water (5 for 3 h. The mixture was diluted with Et2O (20 mL) mL), and the phases were separated τ = p P- „ . , they separated. The aqueous phase was washed with the solidSSeParar°n and 13 aCU°Sa Se 1ÍofÍ1-6· to chromaf0θ<3 and« — thio CX 2C ΓdS Interc“bi° ionic (poraPakRxnUtil' 7E1 Pr°dUCt°deSead°seθΐ·^ column add 5% ammonia in MeOH solution (20 mh). material obtained He purified by 113 IF-2019-3 6421651 -APN-ANP#INPI Page 113 of 170 or reversed phase chromatography (RediSep RfGold@ cl3, from ί _ θ to a new product of a seliofil· θ'a9Ua) TheSActions were lifted and the resulting material was subjected to reverse phase flash chromatography (RediSep Rf 2% acetonitrile in water). The resulting θ11OflllzaronV θΐ reverse material was repurifined (RediSepRfGold® C18TXa in water) to obtain 'dacetonutrile Gold® C18, from 0 to 1 product i · 81 (1H, m), dd), 3.31 - 3.38 dd), 4.42 - 4.5i2,02(IR, ddd), 2.30 (4H / m), 3.55 _3 >60 Example 19; (1H, m); m / z (ES+) [M+H] as a 1.14 1-45 (2H, m), 1.72 (1H, dd), 2.41 (3H, m), 3.63 = 332. (1H, (1H, <S) -2-amino-y- f (¾SBio2ga-l-aza-8-boraeSPZor4 -7]^dr, - T^droxx-6-oxo-7Compound n ~—Zí1) -3 -methylbutananH N nh2h OH ^b'Oh Oh N.H. Compound A Compound B delation through (Example 19) a process of interconversions between Compound B were observed IHΗ2Ν*^γΝ' O EITHER O. B HO Compound B was obtained by means of Example 9 interconversion. ' (Compound A) Besides, Compound A (Example 9) under different conditions. the the By 114 IF-2019-3 6421651 -APN-ANP#INPI Page 114 of 170 example, Compound B was converted to Compound A in the presence of water and said conversion was provided at the concentration of water in Figure 1 where the prepared in 100% d6-DMSO (marked B), the solvent. This is demonstrated by NMR spectra of d6-DMSO (labeled A), the compound in B 75% D2Op,n50% D2°end6-DMSO (marked 'η25% 020d6-DMSO (marked E) and a loó» d2O marked F). In d6-DMSO, compound B predominates, while there is a proportional increase in the concentration of compound A with respect to compound B by approximately 90%. Furthermore, the in compound A with the D2O. The proportion of 100% D2O reaches Compound B converted to Compound A under acidic conditions. In Figure 2 the NMR spectrum of compound B in 0.1 M DC1 (in D2O) shows that acidification provides a practically complete conversion to compound A. In addition, it was determined that Compound B crystal inn,, r. . . ristalm and amorphous Compound B have the forraastructural meme. In Figure 3, the spectra (obtained in d6-DMS0) demonstrate that both the Compound B crystalline cyclic structure. as the amorphous Compound B have the same lo 20: amino-3-hydroxy- irrolidine-2carboxylic 115 IF-2019-3 6421651 -APN-ANP#INPI Page 115 of 170 ^-terjnedl°---------__________(2R,4R)-4-((S)2-((tertbutoxycarbonyl)amino)-3-hydroxy-3-methylbutanamido)-2- 2-Benzyl and 1-tert-butyl (-4C4,4,5,5-tetramethyl-l,3,2-dioxaborolan-211)butyl)pyrrolidine-l,2-dicarboxylate N,N-diisopropylethylamine (0.13 mL, 0.76 mmol) was added to. a solution of (S)-N-alpha-t-butyloxycarbonyl-3,3dimethylsenna (106 mg, 0.454 mmol) and RATU (0.173 g, 0.454 mmol) in DMF (2.6 mL) at 0 °C and the reaction was stirred for 15 min. A solution of (2R,4R)-4-amino-2-(4(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2yl)butyl)pyrrolidine-l,2-dicarboxylate was added. 2-benzyl and 1-tert-butyl (Intermediate 30, 190 mg, 0.38 mmol) in DMF (1 mL) and the reaction was stirred for 2 h while slowly warming to room temperature. The reaction mixture was diluted with EtOAc (40 mL) and washed sequentially with aq. NH4C1. saturated (2 x 20 mL), NaHCO3ac. saturated (2 x 20 mL), and brine (20 mi). The organic phase was dried with Na2SO4, filtered and concentrated to dryness. The crude material was purified by silica gel chromatography (0-50% EtOAc in hexanes) to provide (2R, 4R)-4-((S)-2-(tert-butoxycarbonyl)amino)-3-hydroxy-3- 2-benzyl and 1-tert-butyl methylbutanamido)-2-(4(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2yl)butyl)pyrrolidin-l,2-dicarboxylate (Intermediate 52, 223 mg, 82% yield) as a white foam and as a rotamer mixture. iR NMR (500 MHz, MeOH-d4) δ 0.70 - 0.83 (m, 2 H) 1.14 - 1.27 (m, 19 H) 1.31 (s, 6 H) 1.36 - 1.42 (m, 5 H) 1.44 (s, 10 H) 1.81 1.93 (m, 1 H) 2.02 - 2.14 (m, 1 R) 2.14 - 2.30 (m, 1 R) 2.36 2.49 (m, 1 R) 3.39 - 3.48 (m, 1 R) 3.73 - 3.83 (m , 1 R) 116 IF-2019-3 6421651 -APN-ANP#INPI Page 116 of 170 3-87 - 3.97 (m, 1 H) 4 43 _ z no , _ H) 7 28 7 z / z(m'1 H) 5·09-5·252 7.45 (m, 5H); m / z (ES*) [m+H]* = 718. carboxylic acid ----10 Pd / C (10% in ioo or o9h. °e {2R'4R) ((S)~2~ < ^t-butoxycarbonyl)amino)-3hrdroxy-3-methylbutanamido)-2-(4-(4, 4,5,5-tetramethyl-i;3 2^°Xa^>or°lan-2“yl) butyl) pyrrolidine-1, 2-dicarboxylate of ^2en EtOAey(4 ' )rt'bUtÍ1°22° The flask was fitted with a balloon of H2 and the pension was stirred at room temperature for 3 h. The white solid was dissolved in DCM (1 mL). 6.5 mmol) and trifluoroacetic acid (0.50 mL, for 2 h. The solution was dissolved in Et2O (2 mL) phenylboronic acid (100 was stirred at room temperature and the resulting residue was concentrated and HC1 aq. 1 m (2 mL) .Se added biphasic for 2 h washed with transparent Et2O mixture. PoraPak Rxn CX 20cc). column using se 9, 0.82 mmol) and the solution stirred at room temperature reaction was diluted with water and aqueous was lyophilized and purified 1 exchange The desired ionic product (5% ammonia column obtain acid (2R,4R)-4-((s)_2 in MeOH -amino-3-: was eluted from the 1 (20 mL) for (4-boronobutyl)pyrrolidine or κ ι~·«™ιαο)-2R7.H117pyrroyldln-2-carboxylic acid (Example 20.92mg (2H, m), 1.77 - i qo / τυ „ 1-88 (1H, m), 2.04 - 2.14 (1H, m), 2.40 30 117 IF-2019-3 6421651 -APN-ANP#INPI Page 117 of 1702·47 (1H, m), 2.48 - 2.54s)' 3.75 - 3.80 (1H, m) , [M+H]+= 346. (1H, m) , 3.40 (1H, dd), 3.74 (1H, 4*47 - 4.55 (1H, m) ; m / z: (ES+) Intermediate 53 _ --------------—----(_2R,4R)-4-[[ (2S) -2- (tert^'^S,5-tetramethyl-lr3,2 -dioxaborolan-2DUCHO -examine (0.14 mL, 0.82 mmol) to a solution of (S) -9- ( or .... .('2 ((tert-but°xycarbonyl)amino)co acid) solution (0.113 g, 0.489 mmol) in DMF (3 mL) for 15 min. Added a 0.489 mmol) and HATU (0.186 g, 0 C and the reaction was stirred2,,...csolution of (2R, 42?) -4-amino(4-(4,4,5,5-tetramethyl-l, 3,2-dioxaborolan-211)butyl)pyrrolidine-1,2-dicarboxylate of 3_benzylQ ybutyl (Intermediate 30, 205 mg, 0.408 ™ol) in DMF (1 mL)ylentreaC?6nha9ÍW for 3 h The reaction mixture was diluted with EtOAc (50 ml) and washed sequentially with saturated NH Clac (2 χ 25 saturated NaHcOj aq^ mL), and brine (20 ml). 118 IF-2019-3 6421651 -APN-ANP#INPI Page 118 of 170 or Na2SO4 was filtered and concentrated to dryness. The crude material was purified by silica gel chromatography (0.50" EtOAc in hexanes) to provide (2P,4R)-4[[(2S)-2-(tert-butoxycarbonylamino)-2,3-dlmethyl5-butanoyl] 2-benzyl and 1-tert-butyl amino]-2-[4-(4,4,5,5-tetramethyl-l,3,2dioxaborolan-2-yl)butyl)pyrrolidin-l,2-dicarboxylate (Intermediate 53, 211 mg, 72% yield) as a white foam and as a rotamer mixture. >H NMR (500 MHz, MeOH-A) 6 0.72 - 0 79 (2H m> xo o·'»1.36 - 1.47 (16H, m), 1.82 - 1.92 (2H, m), 1.97 - 2.09 (1H, m ), 2.15 - 2.30 (1H, m), 2.34 - 2.51 (1H, m), 3.61 - 3.75 (1H, m), 4.42 - 4.56 (1H, m), 5.08 - 5.31 (2H, m), 7.29 7.46 ( 5H, m) ; m / z: (ES+) [M+H]+ = 716. 15Example 21: <2R,4R)-4-[[(2S)-2-amino-3-hydZoXiÍL^-^ethylbutanoylamine-z-f^boronobutyDpyrrolidine^carboxylic acid Pd / C (10% by weight, 90 mg, 0.08 mmol) was added to a solution of (2R,4R)-4-[[(2S)-2-(tert-butoxycarbonylamino)20 2,3 dimethylbutanoll]amino] 2-benzyl and 1-tert-butyl -2-[4-(4,4,5,5-tetramethyl-l,3,2droxaborolan-2-ll)butyl)pyrrolidine-l,2-dicarboxylate (Intermediate S3, 210 mg , 0.29 mmol) in EtOAc (4 ml). The flask was fitted with a Ha balloon and the suspension was stirred at room temperature for 3 h. The reaction mixture was diluted with MeOH, filtered through diatomaceous earth and concentrated to dryness. The white solid was dissolved in DCM (1 mL) and trifluoroacetic acid (0.50 mL, 6.5 mmol) and the reaction was stirred at room temperature for 2 h. The solution was concentrated and the resulting residue was dissolved in EtzO (2 mL) and aq. HC1. 1 M (2 mL) . was added 119 IF-2019-3 6421651 -APN-ANP#INPI Page 119 of 170 phenylboronic acid (transparent biphasic Arante 2 h. The mixture (100 mg, 0.82 mmol)v the.. ' and the solution was washed with Et2O. The phase by chromatography PoraPak Rxn CX 20cc). ] stirred at room temperature, reaction was diluted with water and lyophilized and purified by ion exchange (desired product was eluted from the column using 5% ammonia in Me0H<20 mL) stopped <2ϋ,4Β) -4-ΓΓί?ς1, drmethylbutanoyljaminol -2- ιλ íI(2s)-2-amino-2,3carboxylic0 ​​(Ε^ρ1ο°21, white solid. °·79 (3H, d), i (1H, m), 2.07 (2H, m), 3.60 344. 1.36 Ex mg, 89% ' Ή NMR (500 MHz, 0.89 (3H, d), 1.17 D2O) δ performance) as a 0.74 °·78 (2H, m), 1-27 (4H, m), 1.28 1.47 (2H, m), 1.70 _1<81¿o 22; TO 2,3-diaminoi C>0 \ A0BnH2N*^ I B-°. I heard Intermediate 30 Interned i 1.35 (1H, m), 1.93 m); m / z; (ES+) [M+H]+ = -4-[ [ (2S) o o^ either. O_____54: °xx-° Jl \ / i OBn B'°' O-J EITHER H2N^l H NH2 H? ,N JL OH .?.OH OH Intermediate 54 Example 22 -2,3-bis(tert) was added N,N-diisopropylethylamine (0.14 mL 0 82 , to a solution of Boc-Oap(Boc)-OH-OCHA (o.238<3r 0.489 mmol) 120 IF-2019-3 6421651 -APN-ANP#INPI Page 120 of 170 and HATO (0.186 g, 0.489mol) in DME (3 mL) at 0Ó c and the reaction was stirred for 15 min. (2R 4R} δ · or added a solution of (2R,4R)-4-amino-2-(4-(4,4,5,5-tetramethyl-l 3 2“-lan-2-yl)butyl) pyrrolidin-1,2-dicar¿oxylatode i6_ in DMF (1 ^^11°(InteCTedi° *>' 205 mg, 0.408 rrnnol) m and the reaction was stirred for 16 h while at room temperature. The reaction mixture was slowly warmed to temperature was diluted with EtOAc (50 ml) sequentially with saturated NH.C1 aq. (2 x saturated (2 x 25 mL), and brine (20 ml). was dried over Na2SO4, The y was washed mL), NaHCO3 was filtered and concentrated The crude material organic phase was purified by silica (0-50% EtOAc (22?,4R)-4-[[(2S) ^-(terta dryness. gel chromatography in hexanes) to provide 2-benzyl butoxycarbonylamino) propanoyl] amino] tetramethyl-l,3,2-dioxaborole dicarboxylate 214 mg, 66% yield a mixture of rotamers. (2H, 1.52 2.50 - 4. 7.26 c), 1.19 -2-(4-(4,4,5,5an-2-yl)butyl)pyrrolidin-1,2y 1-tert-butyl (Intermediate 54, as a NMR (500 MHz, 1-26 (14H, m), 1.27 (24H, m), 1.76 white foam and like 1-93 (1H, m), 2.06 (1H, s), 3.19 - 3.27 (2H, m), 3.66 (1H, m), 4.35 - 4.50 (1H, m) 7.50 (5H, m) ; m / z: (ES+) [M+H] MeOH-d4) δ 0.76 1-34 (6H, m), 1.37 · 31 (2H, m), ' 3.84 (1H, m), 4.00 5.04 - 5.25 (2H, m), = 789. —7 example 22: Acid (2R, 4R) or / δ, 2-(4-boronobutyl) ^^^inopropanoyl]amino]pyrrolid±n9 Pd / C (~4~[[(2S)-carboxylian solution by weight, 57 mg, 0.053 mmol) was added to a (2Rf4R) -4- [ [ (2S) -2,3-( tertiüünuamino) propanoyl]amino]-2-[4-(4,4,5,5_tetramethyl-1,3,2-dioxaborolan-2-yl)butyl)pyrrolidin-1,2121 IF-2019-3 6421651 -APN-ANP#INPI Page 121 of 170 2-benzyl and 1-tert-butyl dicarboxylate (Intermediate 54, 210 mg, 0.27 mmol) in EtOAc (4 mL). The flask was fitted with a balloon of H2 and the suspension was stirred at room temperature for 3 h. The reaction mixture was diluted with MeOH, filtered through diatomaceous earth, and concentrated to dryness. The white solid was dissolved in DCM (1 mL) and trifluoroacetic acid (0.50 mL, 6.5 mmol) and the reaction was stirred at room temperature for 2 h. The solution was concentrated and the resulting residue was dissolved in Et2O (2 mL) and aq. HC1. 1 M (2 mL) . Phenylboronic acid (100 mg, 0.82 mmol) was added and the clear biphasic solution was stirred at room temperature for 3 h. The reaction mixture was diluted with water and washed with Et2O. The aqueous phase was lyophilized and purified by ion exchange chromatography (PoraPak Rxn CX 20cc column). The desired product was eluted from the column using 5% ammonia in MeOH (20 mL) to obtain (2R, 4R)-2-(4-boronobutyl)-4-[[ (2S)-2,3diaminopropanoyl]amino] acid. pyrrolidine-2-carboxylic acid (Example 22, 74 mg, 88% yield) as a white solid. ^-H NMR (500 MHz, D2O) δ 0.71 (2H, t), 1.11 - 1.24 (1H, m), 1.26 1.41 (3H, m), 1.75 - 1.89 (1H, m), 2.00 - 2.13 (1H, m), 2.31 - 2.48 (1H, m), 2.51 - 2.67 (1H, m), 3.39 - 3.53 (3H, m), 3.68 - 3.80 (1H, m), 4.27 (1H, t), 4.41 - 4.52 ( 1H, m); m / z: (ES+) [M+H]+= 317. Example 23: (2R,4R)-2-(4-boronobutyl)-4(methylamino)pyrrolidine-2-carboxylic acid 122 IF-2019-3 6421651 -APN-ANP#INPI Page 122 of 170 Intermediate 55 Intermediate 56 Intermediate , . ~ ---(2S,4R)-4-(tert¿StOXicarbonylaninO)pltro1tdln_12_d.a¡rhnxymethyl and 1-tert-butyl ’ Di-tert-butyl dicarbonate <4.41 g, 20 2 ™ol) was added to a solution of a salt (23,«)-4-aminoPyrroíidin1,2-dicarbozilate of 2-methyl and 1-tert-butyl acid ( 4.50 g, 13.5 mmoi;ytriethylamine (5.63 mL, 40 4 ™ ' in DCM (57 mL) and the reaction was stirred at room temperature overnight in a N2 atmosphere. The mixture 123 IF-2019-3 6421651 -APN-ANP#INPI Page 123 of 170 crude reaction was diluted with DCM (200 mL) and washed sequentially with 0.5 M HCl (aq.), saturated sodium bicarbonate and brine. The organic phase was dried over Na2so„, filtered and concentrated to dryness. The crude material was purified by silica gel chromatography (DCM / MeOH)Para. obtain 2methyl and 1-tert-butyl (2S,4S)-4-(tert-butoxycarbonylamino)pyrrolidine-1,2-dicarboxylate (Intermediate 55, 3.66 g, 7 9% yield) as a white solid. iHRMN (500MHz, DMSO-d6) δ 1.29 - 1.42 (18H, m), 1.96 - 2.17 (2H, m), 3.12 - 3.17 (1H, m), 3.45 - 3.56 (1H, m), 3.62 - 3.69 (3H , m), 3.96 4.06 (1H, m), 4.24 - 4.34 (1H, m), 7.17 - 7.26 (1H, m) ; m / z.· (ES+) [M+H]+= 345. Intermediate 56: (2S, 4R)-4-[tert-butoxycarbonyl(methyl)amino]pyrrolidine-1,2-dicarboxyl.fn 2-methyl and 1-tert-buty1n Sodium hydride (60% dispersion in mineral oil) (0.491 g, 12.3 mmol) was added portionwise to a solution of 2-methyl (2S, 4R)-4-(tert-butoxycarbonylamno)pyrrolidine-1,220 dicarboxylate and 1- tert-butyl (Intermediate 55, 3.66 g, 10.7 mmol) in DMF (35 mL). After addition, the reaction was stirred for 10 min and then methyl iodide (0.715 ml, 11.4 mmol) was added and the reaction was stirred for an additional 3 h. The reaction mixture was cooled to 0°C and quenched with water. The reaction mixture was diluted with EtO±c (200 mL) and the phases were separated. The organic phase was washed sequentially with water and brine, dried with NazSO., filtered and concentrated to dryness. The crude material was purified by silica gel chromatography (hexanes / EtOAc) to provide (2S,4R)-4-[tert124 IF-2019-3 6421651 -APN-ANP#INPI Page 124 of 170 2-methyl and 1-tert-butyl butoxycarbonyl(methyl)amino]pyrrolidine-1,2-dicarboxylate (Intermediate 56, 3.13 g, 82% yield) as a colorless oil. 1R NMR (500MHz, DMSOd6) δ 1.28 - 1.41 (18H, m), 1.87 - 2.02 (IR, m), 2.29 - 2.44 (1H, m), 2.69 (3H, s), 3.13 - 3.25 (IR, m) , 3.44 - 3.57 (IR, m), 3.60 - 3.68 (3H, m), 4.23 - 4.32 (IR, m), 4.62 (IR, s a); m / z: (ES+) [M+H]+ = 359. Intermediate--57;__(2S, 4R)-4-[tert-butoxycarbonyl (methyl)aminoJpyrrolidine-1,2-dicarboxylate 2-benzyl and 1-tert-butyl A solution of sodium hydroxide (2.10 g, 52.4 mmol) in water (11 mL) was added to a solution of (2S, 42?)-4-[tert-butoxycarbonyl(methyl)amino]pyrrolidine-1,2-dicarboxylate of 2- methyl and 1-tert-butyl (Intermediate 56, 3.13 g, 8.73 mmol) in THF (22 mL) and MeOH (11 mL) at 0 °C. The reaction mixture was stirred for 3 h while slowly warming to room temperature. Volatile components were removed under reduced pressure and the aqueous phase was acidified to pH ~3 with 5 M HC1 and extracted with DCM. The combined organic phases were dried with Na2SO4, filtered and evaporated to dryness to obtain the crude carboxylic acid as a white solid which was used without further purification. Benzyl bromide (1.24 mL, 10.5 mmol) was added to a solution of the crude carboxylic acid, sodium iodide (1.7379' 11.59 mmol) and K2CO3 (3.01 g, 21.8 mmol) in DMF (28 mL) and the reaction was stirred at temperature environment for 5 p.m. The reaction mixture was filtered and the solids were washed with EtOAc. The filtrate was concentrated and purified by silica gel chromatography (hexanes / EtOAc) to 125 IF-2019-3 6421651 -APN-ANP#INPI Page 125 of 170 2-Benzyl 1-tert-butyl (2S, 4R)-4-[tert-butoxycarbonyl(methyl)amino]pyrrolidine-1,2-dicarboxylate (Intermediate 57, 3.05 g, 81% yield) as a colorless oil. iHRMN (500MHz, DMSOd6) δ 1.20 - 1.42 (18H, m), 1.91 - 2.07 (1H, m), 2.33 - 2 46 (1H, m), 2.69 (3H, s), 3.12 - 3.26 (1H, m) , 3.44 - 3.57 (1H, m), 4.20 - 4.38 (1H, m), 4.66 (1H, s a), 5.07 - 5.20 (2H, m), 7.25 - 7.41 (5H, m); m / z: (ES+) [M+H]+= 435. Intermediate 58: 2-Benzyl and 1-tert-butyl (4R) 2 (but-2-enyl)-4-[tert?lldin-l,2-dicarboxylateSdissolved (2S, 4R)-4-[tert-butoxycarbonyl(metll)amino]plrrolidine -1,2-benzyl and 1-tert-butyl dicarboxylate (Intermediate 57, 3.05 g, 7.02 mmol) and crotrile bromide (1.08 mL, 10.5 mmol) in THF (25 mL) and the solution was cooled to - 78 »c in an N2 atmosphere. A solution of KHMDS (0.5M in toluene, 21.0 mL, 10.5 mmol) was added dropwise to the reaction mixture and the reaction was stirred for 17 h while slowly warming to room temperature. . The crude reaction mixture was quenched with water and the volatile components were removed under reduced pressure. The crude mixture was diluted in DCM and the phases were separated. The organic phase was washed with water, dried with Na2SO4, filtered and concentrated to dryness. The crude material was purified by silica gel purification (hexanes / EtOAc) to provide (4R)-2-(but-2eml)-4-(tert-butoxycarbonyl (methyl)amino]plrrolidin-l, 2-benclyl 2dicarboxylate and 1-tert-butyl (Intermediate 58, 1.26 g, 37% yield) as a yellow oil and as a mixture of diastereomers, E / 2 olefinic isomers and 126 IF-2019-3 6421651 -APN-ANP#INPI Page 126 of 170 rotamers. Ή NMR (500MHz, DMSO-d6) δ 1.23 - 1.44 (18H, m), 1.51 - 1.70 (3H, m), 2.00 - 2.26 (2H, m), 2.38 - 2.47 (1H, m), 2.57 - 2.68 ( 3H, m), 2.71 - 3.00 (1H, m), 3.00 - 3.25 (1H, m), 3.40 - 3.74 (1H, m), 4.54 - 4.80 (1H, m), 5.01 5.27 (2H, m), 5.28 - 5.47 (1H, m), 5.49 - 5.72 (1H, m), 7.25 - 7.42 (5H, m) ; m / z: (ES+) [M+H]+= 489. Intermediate_______________59:__(4R)-4-[tert^ butoxycarbonyl(methyl)amino]-2-[4-(4,4,5,5-tetramethyl-l,3,2dioxaborolan-2-yl)butyl]pyrrolidin-l 2—benzyl and 1-tert-butyl ,2-dicarboxylate Bis(1,5cyclooctadiene)diiridium (I) dichloride (269 mg, 0.400 mmol) and bis(diphenylphosphino)methane (308 mg, 0.801 mmol) were added to an oven-dried round-bottom flask. The flask was sealed and purged with N2. The solids were dissolved in DCM (11 mL) and 4,4,5,5-tetramethyl-l,3,2-dioxaborolane (1.28 mL, 8.82 mmol) was slowly added to the solution. The reaction was stirred at room temperature for 10 min. 2-Benzyl 1-tert-butyl (4R)-2-(but2-enyl)—4—[tert-butoxycarbonii(methyl)amino]pyrrolidine—1,2dicarboxylate (Intermediate 58, 1.96 g, 4.01 mmol) was added. to the reaction as a solution in DCM (7.5 mL) and the reaction mixture was stirred for 16 h at room temperature. The reaction mixture was cooled to 0 °C and carefully quenched with MeOH and water. The phases were separated and the aqueous phase was extracted with DCM. The combined organic phases were dried with Na2SO4, filtered and concentrated to dryness. The resulting residue was purified by silica gel chromatography (hexanes / EtOAc) to provide (4R)-4-[tert-butoxycarbonyl(methyl)amino]-2-[4(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2127 IF-2019-3 6421651-APN-ANP#INPI Page 127 of 170 2-benzyl and 1-tert-butyl il)butyl)pyrrolidine-l,2-dicarboxylate (Intermediate 59, 2.5 mg, 100% yield) as yellow oil and as a mixture of diastereoisomers and rotamers. The purified material was subjected to chiral SFC 5 [column (S, 3) whelk-01, 30 x 250 mm, 5Pm, Temperature = 20 °C, Mobile phase = 0-30* MeOH:COz, UV detection at 220 nm , loading - 31 mg / inj., conc = 125 mg / ml in MeOH / DCM, flow rate - 75 ml / min. Outlet pressure - 100 bar) to provide two diastereoisomers. The stereochemistry of each diastereoisomer was assigned in retrospect based on the enzymatic potency of Example 23 and Example 24 being consistent with other exemplified compounds. Intermediate 60 (Isomer 2, 637 mg): (2R, 4R)-4-[tert-butoxycarbonyl(methyl)amino]-2-[4-(4,4,5,5-tetramethyl-l,3 215 dioxaborolan-2- 2-benzyl and 1-tert-butyl yl)butyl]pyrrolidine-l,2-dicarboxylate >H NMR (500MHz, DMSO-de) δ 0.58 0-76 (2H, m), 1.15 (12H, d), 1.21 - 1.47 (22H, m), ¿69 1-82 (1H, m), 1.94 - 2.23 (3H, m), 2.56 - 2.62 (3H, m), 3.19 - 3.28 (1H, m), 3.45 - 3.57 (1H, m), m), 4.58 - 4.79 (1H, m), 20 5.01 - 5.26 (2H, m), 7.26 - 7.41 (5H, m). Intermediate 61 (Isomer 1, 860 mg): (2S, 4Λ)-4-[tert-butoxycarbonyl(methyl)amino]-2-[4-(4,4,5,5-tetramethyl-l,3,2dioxaborolan-2- 2benzyl and 1-tert-butylyl)pyrrolidine-l,2-dicarboxylate NMR (500MHz, DMSO-d6) or 0.62 25 0.71 (2H, m), 1.15 (12H, s), 1.20 - 1.42 (22H, m), 1'67 1-84 (1H, m), 1.92 - 2.32 (3H, m), 2.69 (3H, s), 3.04 - 3.15 (1H, m), 3.57 - 3.71 (1H, m), 4.52 - 4.73 (1H, m), 4.98 5.25 (2H, m), 7.24 - 7.40 (5H, m). 128 IF-2019-3 6421651 -APN-ANP#INPI Page 128 of 170 Intermediate 62: Acd η. -410 Suspension Mixture ..u=..2rv™r,T·' “ - °··” 55-tetramethyl-l,3.2-dioxaborolan-2iDbutylJpyrroiidin-i.z-butyl dicarboxylate (Intermediate 60, 637 m or 1 mV Elg'1.03 rnmol) inEtOAc (7 mL) The flask was fitted with a balloon of h2 and stirred overnight at room temperature. diatom. The £iluted”?* ^^3 d®terrafiant chromate^ Z ~ °® — provide acid (2R4R),t' (he-nos / EtOAc) for kutoxdcarb°nyl (methyl) amino]^-[4^(4 ^4 ^tert-dioxaborelan.-il.ut^ (intermediate 62 nm O 62, 350 mg, 64% yield) white.XH NMR (500MHz, 1.19 (12H, m), 1.22 as a solid DMSO-dg) δ 0.63 - 0.73 (2H, m), 1.14 1-42 (21H, m), 1.63 - 1 77 mu < 1-99 - 2.18 (3H, m), 2.63 - 2.67' m), 3.41 - 3 55 '01'3-213.27 (2H, (1H m) / ' ' '* * * 7 * * * *'4-80 (1H'm)'12·32- 12 75(1H ' m); η / z:(ES+) [M+H]+ = 52?. Example 23: L^ethylamino)pjrroijríin~acid----(2Rf 4R) 2~ (4-boronobutyl) z2~carboxyli nn -4Trifluoroacetic acid (0 51 mL β·7 mmol) was added dropwise to a stirred solution of acid (2R iR. butoxycarbonyl-4—rFzar-f- x 4. / )1 tert— (4 4 5 5 °bUt°X1CarbonU<^yl)aminoI-2-[4(4,4,5,5-tetramethyl-i,3, 2-dioxaborolan-2H)butyl]pyrrolidln-2-carboxylic ίτη(-= ... 0.66 mmol) in DCM <4mT>. intermediate 62, 350 mg, (4 mL) at room temperature. After 129 IF-2019-3 6421651 -APN-ANP#INPI Page 129 of 170 h, the solution was concentrated under reduced pressure and the resulting residue was dissolved in aq. HC1. 1 M (5 mL) and Et2O (5 mL). Phenylboronic acid (162 mg, 1.33 mmol) was added and the clear biphasic solution was stirred at room temperature for 1 h. The mixture was diluted with Et2O and water, and the phases were separated. The aqueous phase was washed with EtzO. The aqueous phase was lyophilized and purified by ion exchange chromatography (PoraPak Rxn CX 60cc column). The desired product was eluted from the column using 5% ammonia in MeOH (60 mL) to obtain (2R, 4R)-2-(4boronobutyl)-4-(methylamino)pyrrolidine-2-carboxylic acid (Example 23, 140 mg , 86% yield) as a white solid. 1H NMR (500 MHz, D20) δ 0.72 - 0.82 (2H, m), 1 09 1.43 (4H, m), 1.62 - 1.77 (1H, m), 1.83 - 1.95 (1H, m), 2.23 (2H, d ), 2.46 (3H, s), 3.02 - 3.11 (1H, m), 3.37 - 3.49 (1H, m), 3.49 - 3.61 (1H, m); m / z: (ΕΞ*) [M+H]* = 245. Intermediate 63: Acid (2S,4R)-l-tert-butoXicarbonyl-4^rt~buto!<2carbonyl(methyl)amlnol-2-[4-(4,4,5,5-tetramethyliz3,2-dioXaboranan-2 -yl)butyl]pyrzolldin-2-carboXyl Pd / C (10* by weight, 223 mg, 0.209 mmol) was added to a solution of (23,4R)-4-(tert-butoxycarbonyl(methyl)amino]-2[4-(4,4,5, 5-tetramethyl-l,3,2-dioxaborolan-2130 IF-2019-3 6421651 -APN-ANP#INPI Page 130 of 170 2-benzyl and 1-tert-butyl yl)butyl]pyrrolidine-1,2-dicarboxylate (Intermediate 61, 860 mg, 1.39 mmol) in EtOAc (9.3 mL). The flask was fitted with a balloon of H2 and the suspension was stirred overnight at room temperature. The reaction mixture was diluted with MeOH and filtered through diatomaceous earth. The filtrate was concentrated to dryness and purified by silica gel chromatography (hexanes / EtOAc) to provide (2S,4E)-1-tert-butoxycarbonyl-4-[tert-butoxycarbonyl(methyl)amino]-2-[4- (4,4,5,5-tetramethyl-l,3,2dioxaborolan-2-yl)butyl]pyrrolidine-2-carboxylic acid (Intermediate 63, 520 mg, 71% yield) as a white solid. *H NMR (500MHz, DMSO-d6) δ 0.60 - 0.75 (2H, m), 1.16 (12H, s), 1.28 - 1.45 (22H, m), 1.56 - 1.74 (1H, m), 1.84 1.95 (1H, m), 2.01 - 2.22 (2H, m), 2.69 (3H, s), 3.01 - 3.17 (1H, m), 3.56 - 3.70 (1H, m), 4.52 - 4.73 (1H, m), 12.35 12.77 (1H , m) ; m / z: (ES+) [M+H]+= 527. Example 24: (2S,4R)-2-(4-boronobutyl)-4(methylamino)pyrrolidine-2-carboxylic acid Trifluoroacetic acid (1.23 mL, 16.0 mmol) was added dropwise to a stirred solution of acid (2S,4R}-1-tert-butoxycarbonyl-4-[tert-butoxycarbonyl(methyl)amino]-2-[4(4,4 ,5,5-tetramethyl-l,3,2-dioxaborolan-2yl)butyl]pyrrolidine-2-carboxylic acid (Intermediate 63, 520 mg, 0.80 mmol) in DCM (8.5 mL) at room temperature. solution was concentrated under reduced pressure and the resulting residue was dissolved in 1 M aq. HC1 (5 mL) and Et2O (5 mL) Phenylboronic acid (196 mg, 1.60 mmol) was added and the clear biphasic solution was stirred at room temperature. for 1 h. The mixture was diluted with Et2O and water, and the phases were separated. 131 IF-2019-3 6421651 -APN-ANP#INPI Page 131 of 170 or Aqueous phase was lyophilized and purified by ion exchange chromatography (PoraPak Rxn CX 60cc column). The desired product was eluted from the column using 5% ammonia in MeOH (60 mL) to obtain (2S, 4R)-2-(boronobutyl)-4-(methylamino)pyrrolidine-2-carboxylic acid (Example 24, 163 mg, 83% yield) as a white solid. 1R NMR (500 MHz, D2O) δ 0.70 - 0.90 (2H, m), 1.10 1.46 (4H, m), 1.65 - 1.77 (2H, m), 1.96 - 2.07 (1H, m), 2.43 (3H, s) , 2.68 - 2.77 .(1H, m) , 2.96 - 3.10 (1H, m) , 3.37 10 3.50 (1H, m) , 3.50 - 3.60 (1H, m) ; m / z: (ES+) [M+H]+= 245. Example____25 ;____Acid____(2R, 4R) -2- (4-boronobutyl) -4(dimethylamino)pyrrolidine-2-carboxylic acid 132 IF-2019-3 6421651 -APN-ANP#INPI Page 132 of 170 or Intermediate 70 Example 25 Intermediate 64: (2R.4R) 2-benr.i 1° and 1-tert-bnti1o dicarboxylate Aminopyrrolidin-i,2Triphenylphosphine (7.87 g ml, 30.0 mmol) was added to azidopyrrolidin-l,2-butyl dicarboxylate) environment. during (5.20 g, 15.0 mmol) The reaction is θ h. The mixture at room temperature was sequentially added with water (2 saturated (100 mL). ' 30.0 mmol) and water solution of 2-benzyl in THF (68 mL) heated to 60 temperature and cooled EtOAc, y se x 100 mL) and sodium chloride stirred until washed The organic phase was filtered and concentrated to dryness. dried over Na2SO4, The raw material is 133 IF-2019-3 6421651 -APN-ANP#INPI Page 133 of 170 purified by silica gel chromatography (DCM / MeOH)Ρ3Γ3. Obtain 2-benzyl and 1-tert-butyl(2R, 4R)-4-(tert-butoxycarbonylamino)pyrrolidine-1,2-dicarboxylate (Intermediate 64, 3.2 g, 67% yield) as a colorless oil. iHRMN (500MHz, DMSOd6 > δ 1.20 - 1.49 (9H, m), 1.53 - 1.64 (1H, m), 1.65 - 1.79 (2H, m), 2.26 - 2.40 (1H, m), 2.85 - 3.01 (1H, m ), 3.31 3-42 (1H, m), 3.45 - 3.56 (1H, m), 4.13 - 4.24 (1H, m), 4.99 5.25 (2H, m), 7.36 (5H, s) ; ra / z.· (es*)= 321. Intermediate 65: (2R,4R)-4-rdimethylamino;Pirrolldln-i,,2-benchyl and l-tert-burne dicazboxylate Sodium triacetoxyborohydride (6.35 g, 29.9 mol) was added portionwise to a solution of 2-benzyl 1-tert-butyl (2R,4R)-4aminopyrrolidine-1,2-dicarboxylate (intermediate 64, 3.20 g, 9.99 mmol) and formaldehyde. (37 wt% in HzO, 4.46 mL, 59.9 mmol) in MeOH (79 mL) After addition, the reaction was stirred at room temperature for 17 h. The volatile components were removed under reduced pressure and the resulting residue was diluted with DCM. The solids were removed by filtration and the filtrate was concentrated to dryness. The crude material was purified by silica gel chromatography (hexanes / EtOAc with ΝΗ,ΟΗ) to obtain 2-benzyl and 1-tert-butyl (2R,4R)-4(dimethylamino)pyrrolidin-l,2-dicarboxylate (Intermediate 65 , 3.00 g, 86% yield). >H NMR (500MHz, DMSO-Λ) δ 1.24 (9H, s), 1.53 - 1.67 (1H m) 2-10 (6H, s), 2.40 - 2.48 (1H, m), 2.53 - 2.73 (1H, „ ),'2.83 - 3.06 (1H, m), 3.59 - 3.69 (1H, m), 4.15 - 4.29 (1H, m), 5.02 - 5.21 (2H, m), 7.26 - 7.42 (5H, m), m / z: (ES*) [M+HJ+ 134 IF-2019-3 6421651 -APN-ANP#INPI Page 134 of 170 OM. ---------&_________(±R)-2-(but-2-enll)-4H^tylamino>plrrolldin_lf2_dlcarbox.latotert-butylL--(2R,4R)-4-(dimethylamino)pyrrolidine was dissolved -1 2-benzyl and 1-tert-butyl 2dicarboxylate (Xntezmedium 65, 3-00 g, 8.61 mmol) and crotyl bromide (1.33 mL, 12.9 mol) THF (18 mL) and the solution was cooled to -78 °C in an atmosphere of N2. A solution of KHMDS (0.5M in toluene, 25 8 mL 12.9 mmol) was added dropwise to the reaction mixture and the reaction was stirred for 17 h while slowly warming to room temperature. The crude reaction mixture was quenched with water and removed under reduced pressure. The DCM and phases were separated. The: water, dried with Na2SO4, filtered! Volatile components are mixed raw, diluted in organic phase, washed with The crude material was purified using silica (hexanes / EtOAc) and concentrated to dryness. θ gel purification to provide (4R)-2-(but-2enyl) 4 (dimethylamino)pyrrolidine-1,2-dicarboxylate benzyloy1-tert-butyl (Intermediate 66, 1 55 g yield) as a yellow oil and as a Mixes diastereoisomers, olefin E / z isomers, and rotamers. NMR (500MHz, DMSO-d6) m), 1.79 - 1.96 (1H, 2.31 - 2.43 (1H, m), m), 3.56 - 3.86 (1H, (1H, m), 5.43 [M+H]+= 403. of Four. Five% 2de of δ 1.21 1.44(9H,151_170 (3H, m), 2.05 (6H, s), 2.08 “ 2.24 (1H, m), 2.54 2.74 (1H, m), 2.75 - 3.08 (2H, 5.00 - 5.23 (2H, m), 5.23 - 5.42 (1H, m), 7.23 - 7.41 (5H, m) ; m / z: (ES+) _nintermediate---67_.---(4R)—4 (dimethylamino)-2-[4-(4.4 5 5 ^^yl-l,3,2-dioXaborolan-2-ll) butylO1rra,1dl2 / ó ' ~ dlcarbQXilatOde 2-henzyl and 1-tert-hutil 135 IF-2019-3 6421651 -APN-ANP#INPI Page 135 of 170 or Round bottom cyclooctadiene)diiridium bis(diphenylphosphine)methane dried in dichloride (I) (240 mg, (275 mg, 0.715 mg) were added. 0.36 mmol) to bis (1.5mmol) and one flask purged with N2. an oven. The flask was sealed and .diS°lvler°nθ °™ (lo mL) was added and 4.4 5 * was slowly added. · π -,y(1 14 mL 7fi7^«metxl-1, 3,2-dioxaborolane ' mL, 7.87 mmol) to the solution. The reaction was stirred at room temperature for 10 min. (4R)-2-(butbenzyl and 1-tert-butyl (Intermediate 66) were added to the reaction as a reaction solution and stirred for 16 h. The reaction mixture was cooled to care with MeOH and water. The aqueous phases were extracted with DCM. The phases dried dryness. with He Na2SO4, filtered residue resulting chromatography provide on silica gel DCM (6.7 mL) and the mixture at room temperature. La0C and deactivated with were separated and the combined organic phase was And they were concentrated to purified by (hexanes / EtOAc) para4(dimethylamino)-2-[4-(4.4 5x2-benzyl and 1-tert-butyl carboxylate (Intermediate 67, 1.5 g, 79% mixture of purified u^xenro) as yellow oil and as a lasteorosomers and rotamers. The material -nθSO subjected to SFCchiral [column (S, S) Whelk-Ol mm x 250 mm, 5 pm, Temperature =20 °C, Mobile phase = 015 of Me0H:C02, UV detection at 22Ω nm conc = nn / 7 n uv at 220 nm, loading = 32 mg / iny. mg / ml in MeOH, flow rate = 120 = inn r 7 ml / min, Pressure - or bar) to provide two diastereoisomers. exit Retrospective stereochemistry based on each diastereomer was assigned on which the enzymatic potency of the 136 IF-2019-3 6421651 -APN-ANP#INPI Page 136 of 170 Example 25 and Example 26 were consistent with other exemplified compounds. Intermediate 68 (Isomer 2, 190 mg):(2R,4R)-4(dimethylamino)-2-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan2-yl)butylpyrrolidin-l 2-benzyl 1-tert-butyl 2-dicarboxylate >H NMR (500MHz, DMSO-d6) 6 0.64 - 0 71 (2H m) -3 - - 2 2! (1H,m), 2.55 - 2.74 (1H, m), 3.02 - 3.12 (1H, m), 3-59 - 3.70 (1H, m), 5.00 - 5.20 (2H, m), 7.27 - 7.41(5H Intermediate 69 (Isomer 1, 491 mg): (2S,4R)-4(dimethylamino)-2-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan2-yl)butrl]pyrrolidine 1H NMR (500MHz, DMSO-d6) δ 0.52 - 0 72 (2H m) O- -!.12 (1H, m), 1.12-1.20 (12H) , m), 1.20 - 1.39 (13H, o'ó»1·59'1-74 <1H'm)' ^77' ^93 (1H'm)'2·06<6H- a), 2-08 - 2.15 (1H, m), 2.53 - 2.65 (1H, m), 2.78 - 2.96 (1H, m), 3.67 - 3.82 (1H, m), 5.00 - 5.21 (2H, m), 7.27 - 7.42 Intermediate 70: Acid (2R,4R)-l-tert-butoXicarhanil-4Μ^βη^ίηο)-2-74-(4,4,5,5-ηΡΙ-Γηπβ1ϋ-1,3,2-^ΗηΓη,^ _ LiVbutyl]pyrrolidine-2-carboxylic Pd / C (10% by weight, 57 mg, 0.054 mmol) was added to a tion of (2R,4R)-4-(dimethylamino)-2-[4-(4,4Z5f5tetramethyl-1,3,2-dioxaborolan 2-benzyl and 1-tert-hnt-í 1 / τy x cerc-outyl -2-yl)butylpyrrolidin-1,2dicarboxylate (Intermediate 68, 189 mg, 0.356 mmol) in EtOAc (2.4 mL). The flask was fitted with a balloon of H2 and the suspension was stirred overnight at room temperature. The reaction mixture was diluted with 137 IF-2019-3 6421651 -APN-ANP#INPI Page 137 of 170 MeOH and filtered through diatomaceous earth. The filtrate was concentrated to dryness to give (2R, 4R)-1(tert-butoxycarbonyl)-4-(dimethylamino)-2-[4-(4,4,5,5tetramethyl-l,3,2-dioxaborolan) acid. 2-yl)butyl]pyrrolidine-25 carboxylic acid (Intermediate 70, 150 mg, 96% yield) as a white solid that was used without further purification. 1H NMR (500MHz, DMSO-d6) δ 0.53 - 0.70 (2H, m), 1.11 - 1.20 (12H, m), 1.21 - 1.41 (14H, m), 1.56 - 1.71 (1H, m), 1.92 2.06 (2H , m), 2.20 (7H, s), 2.69 - 2.78 (1H, m), 3.37 - 3.51 10 (1H, m), 3.67 - 4.21 (1H, m) ; m / z: (ES+) [M+H]+= 441. Axis^P10----25^____(2R, 4R)-2- (4-boronobuty 1)-4(dimethilamino)pyrrolidine-2-carboxylic acid Trifluoroacetic acid (0.26 mL, 3.4 mmol) was added dropwise to a stirred solution of (2R,4R)-1-tert15 butoxycarbonyl-4-(dimethylamino)-2-[4-(4,4,5,5) -tetramethyl1'3,2-dioxaborolan-2-yl)butyl]pyrrolidine-2-carboxylic acid (Intermediate 70, 150 mg, 0.34 mmol) in DCM (2 mL) at room temperature. After 1 h, the solution was concentrated under reduced pressure and the resulting residue was dissolved in aq. HC1. 1 M (5 mL) and Et2O (5 mL). Femlboronic acid (83 mg, 0.68 mmol) was added and the clear biphasic solution was stirred at room temperature for 1 h. The mixture was diluted with Et2O and water, and the phases were separated. The aqueous phase was washed with Et2O. The aqueous phase was lyophilized and purified by ion exchange chromatography (PoraPak Rxn CX 20cc column). The desired product was eluted from the column using 5% ammonia in MeOH (20 mL) to obtain (2R,4R)-2-(4-boronobutyl)-4(dimethylamino)pyrrolidine-2-carboxylic acid (Example 25, 73 mg, 30 83-s yield) as a white solid. *Η NMR (500 MHz, 138 IF-2019-3 6421651 -APN-ANP#INPI Page 138 of 170 D2O) δ 0.62 - 0.73 (2H, m), 1.14 (1H, m), 1.992-10 (1H, m), 2.57 1·36 (4H, m), 1.79 - 1.90 2.90 (6H, m), 3.48 - 3.56 (1H, m) -4.20 (1H, m) ; m / z: (ES+) [M+H]+gj.eaplo 26: ÁciHn 2.73 (2H, m), 2.82 3.89 - 3.98 (1H, m), 4.12 = 259. Intermediate 69 Intermediate Intermediate 71 Example 26 .(dimethylamino) -2-(4-(4,4,5,5-tetramet·! Ί ^Vbutylpyrrolidine^-carboxylinn -4_lf3,2-dioxaborol^nPd / C (10% by weight, 148mg,0.139 ^ol) was added to a solution of (2S, 4R)-4-(dimethylamino)-2-(4-(4 4 5 5tetramethyl- 1,3,2-dioxaborolan-2-yl)butyl]pyrrolidine-í 2-benzyln 2dicarboxylate w i <- . oenzyl and 1-tert-butyl (Intermediate 69, 0.93 mmol) in EtOAc (6.7 mL) ri I The flask was equipped 490 mg with a balloon of H2 and the suspension at room temperature. The mixture was stirred overnight MeOH v -F 11- 'άθreaction was diluted with tro through diatomaceous earth. The filtrate was concentrated to dryness to give (2S,4R)-1(tert-butoxycarbonyl)-4-(dimethylamino)-2-[4-(4,4,5s_tetramethyl-1,3,2-dioxaborolan-2) acid. -yl)butyl]pyrroúdiñ-2carboxylico (Intermediate 71, 405 m gas- . ,Ί. , mg, 99« yield) as a white solid that was used without further purification. 1H NMR (500MHz, DMSO-d6) δ 0.52 - 0.71 (2H, m), 0.83 - 1.06 139 IF-2019-3 6421651 -APN-ANP#INPI Page 139 of 170 O ( , m), 1.16 (12H, s), 1.32 (12H, s), 1.53 - 1.67 (1H, m), 1-75 - 1.88 (1H, m), 2.01 - 2.13 (7H, m), 2.54 - 2.69 (1H, 2.79 - 2.95 (1H, m), 3.66 - 3.83 (1H, m), 7.24 - 7.46 (1H, m), 11.86 - 12.88 (1H, m) ; m / z.- (ES') = 441. ^eiaP10-----22·----Acid----(2S, 4R) -2- (4-boronobutyl) -4Xdimethylamino)pyrrolidine-2-carboxylic acid Trifluoroacetic acid (1.0 mL, 13 mmol) was added dropwise to a stirred solution of acid (2S, 4R>-1-tert-butoxycarbonyl-4-(dimethylamino)-2-(4-(4,4,5, 5- tetramethyll,3,2-dloxaborolan-2-yl)butyl)pyrroiidin.2.carboxyl.co(Intermediate 71, 405 mg, 0.919 rrnnol) in DCM (5.1 mL) at room temperature. After 1 h, the solution was concentrated. under reduced pressure and the resulting residue was dissolved in 1 M aq. HCl (5 mL) and Et20 (5 mL). Fenylboronic acid (224 mg, 1.84 mol) was added and the clear solution was stirred at room temperature for 1 h. The mixture was diluted with Et2O and water, and the phases were separated. The aqueous phase was washed with Et2O. The aqueous phase was lyophilized and purified by ion exchange chromatography (PoraPak Rxn CX 60cc column). column using 5% ammonia in MeOH (60 mL) to obtain (2S,4R)-2-(4-boronobutyl)-4(dimethylamino)pyrrolidine-2-carboxylic acid (Example 26, 206 mg, 87% yield) as a white solid. >H NMR (500 MHz 020) 5 0.71 - 0.89 (2H, ,),1.12-1.44 (4H, m), 1.70-1^ m), 1.97 2.11 (IR, m), 2.29 (6H, s), 2.62 - 2.71 (1H, 2.95 - 3.10 (2H, m), 3.61 - 3.68 (1H, m) ; m / z; (ES+) [M+H]+ = 259. Example 27: acid (2R.4R>-4-(2-aminoethylamino)-2-(4boronobutyl)pyrrolidine-2-carboxy n — 140 IF-2019-3 6421651 -APN-ANP#INPI Page 140 of 170 or of 2-methyl and 1-tert-butyl (2S, 4R) -4-[2- (tert-1,2-dicarboxylate Acetic acid (42 pl, 0.73 mmol) was added to a solution of 2-methyl 1-(tert-butyl) (2S,iR)-4-aminopyrrolidin-1,2-dicarboxylate (7.48 g, 30.6 mmol) and (25 141 IF-2019-3 6421651 -APN-ANP#INPI Page 141 of 170 tert-butyl oxoethyl)carbamate (4.64 g, 29.2 mmol) in MeOH (194 mL) and the reaction was stirred at room temperature for 3 h. The solution was cooled to 0 °C and sodium triacetoxyborohydride (9.27 g, 43.7 mmol) was added in portions. The reaction was stirred overnight while slowly warming to room temperature. The reaction mixture was concentrated under reduced pressure and the resulting residue was diluted with DCM, washed sequentially with saturated sodium bicarbonate, water and saturated sodium chloride. The organic phase was dried over Na2SO4, filtered and concentrated to dryness. The crude material was purified by silica gel chromatography (DCM / EtOAc / MeOH) P3”. obtain 2-methyl and 1-tert-butyl (2S,4R)-4-[2-(tert-butoxycarbonylamino)ethylamino]pyrrolidine-l,2-dicarboxylate (Intermediate 72, 4.77 g, 42% yield) as a colorless oil. iHRMN (SOOMh'z, DMSOds) δ 1.25 - 1.48 (20H, m), 1.84 - 2.07 (3H, m), 2.88 - 2.98 (2H, m), 3.02 - 3.17 (1H, m), 3.17 - 3.27 (1H , m), 3.40 3.51 (1H, m), 3.64 (3H, s), 4.14 - 4.24 (1H, m), 6.63 - 6.74 (1H, m); m / z: (ES+) [M+H]+ = 388. Intermediate----73_.----(2S, 4R)-4-[tert-butoxycarbonyl-[2^erb~butolyicarbonylamino)ethyl]amino]pyrrolidine-lf2dicarboxylate 2-methyl and 1-tert-butyl Di-tert-butyl carbonate (4.29 mL, 18.5 ™O1\) was added to a solution of (2S, 4R)-4-[2-(tert-butoxycarbonylamno)ethlamino]pyrrolidine-1,2-dlcarboxylate of 2-methyl and 1-tert -butyl (Intermediate 72, 4.77 g, 12 3 mmol) and W,W-diisoproplletllamlna (4.30 mL, 24.6 mmol) 'in DCM (53 mL) at room temperature and the reaction was stirred for 17 h. The reaction mixture was diluted. 'with DCM and washed 142 IF-2019-3 6421651 -APN-ANP#INPI Page 142 of 170 sequentially with water and saturated aqueous sodium chloride. The organic phase was dried with Na2SO4, filtered and concentrated to dryness. The crude material was purified by silica gel chromatography (hexanes / EtOAc) to provide 2-(2S,4R)-4-[tert-butoxycarbonyl-[2-(tert-butoxycarbonylamino)ethyl]amino]pyrrolidine-1,2-dicarboxylate. -methyl and 1-tert-butyl (Intermediate 73, 4.25 mg, 71% yield), iH NMR (500MHz, DMSO-d6) δ 1.21 - 1.27 (1H, m), 1.27 - 1.42 (27H, m), 1.99 - 2.07 (1H, m), 2.33 - 2.46 (1H, m), 2.93 - 3.14 (3H, m), 3.17 - 3.24 (1H, m), 3.48 - 3.61 (1H, m), 3.61 - 3.69 (3H, m), 4.20 - 4.44 (2H, m), 6.79 6.94 (1H, m) ; m / z: ES+[M+H]+488. Intermediate---74:____(2Sf4R)-4-[tert-butoxycarbonyl-ΐ2^ert-J=>utoxycarbonylamino)ethyl]amino]pyrrolidin-l ,2-benzyl and 1-tert-butyl 2-dicarboxylate A solution of sodium hydroxide (2.09 g, 52.3 mmol) in water (11 mL) was added to a solution of (2S, 4R)-4-[tert-butoxycarbonyl—[2—(tert-butoxycarbonylamino)ethyl]amino]pyrrolidin-1 2-Methyl 1-tert-butyl ,2-dicarboxylate (Intermediate 73, 4.25 g, 8.72 mmol) in THE (22 mL) and MeOH (11 mL) at 0 °C. The reaction mixture was stirred for 6 h while slowly warming to room temperature. Volatile components were removed under reduced pressure and the aqueous phase was acidified to pH ~3 with 5 M HC1 and extracted with DCM. The combined organic phases were dried with Na2SO4, filtered and evaporated to dryness to obtain the crude carboxylic acid as a white solid which was used without further purification. 143 IF-2019-3 6421651 -APN-ANP#INPI Page 143 of 170 Benzyl bromide (1.24 solution of the carboxylic acid) was added 13.1 mmol) and K2CO3 (3.62 reaction stirred mL, 10.5 mmol) to a crude co, sodium iodide (1.96 <3, 26.2 mmol) in DMF (28 mL) at room temperature for 17 reaction mixtures EtOAc. The filtrate was filtered and concentrated and h. <3, Silica gel chromatography provided butoxycarbonyl(methyl)amino]pyrrolidine solids were washed with and purified by (hexanes / EtOAc) to 2-benzyl and 1-tert-butyl (Intermediate 74, yield) as a white solid. 1HRMt / δ 1.20 (1H, m), 3.64 (1H, 1-47 (27H, 2-93 - 3.01 m), 2.00 - 2.13 (1H, (2H, m), 3.02 - 3.26 m), 4.26 - 4.43 (2H, m), 5.05 “ 6-93 (1H, m), 7.25 Intermediate (2S, 4R) -4- [ tertiicarboxylate 3.91 g, 80% of (500MHz, DMSO-d6) m), 2.36 - 2.45 (3H, m), 3.48 5.22 (2H, m) 7.41 (5H, m) ; m / z: (ES+) [m+H] 75; , 6.78 = 564. butoxycarbonyl-[2- (tert-(_4R)-2 (but-2-enyl)-4-[tert·of 2-benzyl and 1-tert-butiΊ„ -1,2-dicarboxylate-n 2-Benzyl (2S,4R)-4-[tert-butoxycarbonyl-[225 'aill-Lnoj pyrrolidine-1,2dicarboxylate and l-tert-hu+H ί ,τ o a-,Y ert butyl (Intermediate) were dissolved 74 3-51 g, 6.94 mmol) and crotyl bromide (0 93 mL 9 or n' θη - (10.6 mL) and the solution was added to a solution of khmds (or sMθηy the area “ θ3 13« action and the reaction was stirred for 17 h while slowly warming to room temperature. The crude reagent mixture was quenched with water and the volatile components were added at reduced pressure. 144 IF-2019-3 6421651 -APN-ANP#INPI Page 144 of 170 DCM and the phases were separated. The organic phase was washed with water, dried with Na2SO4, filtered and concentrated. The crude oil was purified by silica gel purification (hexanes / EtOAc) to provide (47?)-2 -(but-2enyl) 4-[tert-butoxycarbonyl-[2-(tertde 2-benzyl and 1-tert-butyl (Intermediate -1'2-dicarboxylate yield) as a diastereoisomeric oil, NMR (3H, (500MHz, m), 1.91 75, 1.34 g, 31% yellow and as a mixture of E / Z olefin isomers DMSO-d6) δ 1.21 2.32 (2H, m), 2.37 and rotamers. 1-45 (27H, m), 1.53 _ i_71 2-86 (1H, m), 2.86 - 3.11 (4H, m), 3.77 (1H, m), 4.29 - 4.57 (1H, 5.28 - 5.46 (1H, m), 5.46 - ; m), 7.19 - 7.43 (5H, m); m / z: Intermediate 76: 5.71 2.47 (1H, m), 2.69 3.46 - 3.58 (1H, m), 3.58 m), 5.00 - 5.20 (2H,_ m), (1H, m), 6.83 - 7.00 (1H, (ES+) [M+H] + = 618. or. W ~4-tert-butoxycarbonyl-[2- (tert-butoxycarbonylamino)ethyl]amino]-2-[4- (44 of 2-benzyl and 1-tert-butyn Cyclooctadiene)diiridium (i) bis(diphenylphosphino)methane (254 dichloride (222 mg,5r5-tetramethi Ίrl,2-dicarboxylate-r>) were added of 0.331 bis(l.5mmol) <3, 0.661 mmol) to a round bottom flask and dried in an oven. The flask was sealed and purged with N2. The solids were dissolved in DCM (9 mL) and “mL16“te 4*4,5,5~tetramethii-1,3.2-dioxaborolane (1.05 mL, 7.26 mmol) to the solution. The reaction was stirred at 2Τ“ambient for 10”“·2-(but2 enyl) 4-[tert-butoxycarbonyl-(2-(tertse butoxycarbonylaminoJetiDaminoJpyrrolldin) of 2-benzyl and 1-tert-butyl (Intermediate 1,2 dicarboxylate 75, 2.04g, 3.30 145 IF-2019-3 6421651 -APN-ANP#INPI Page 145 of 170 mmol) to the reaction as a solution in DCM (6.1 mL) and the reaction mixture was stirred for 16 h at room temperature. The reaction mixture was cooled to 0 °C and carefully quenched with MeOH and water. The phases were separated and the aqueous phase was extracted with DCM. The combined organic phases were dried with Na2SO4, filtered and concentrated to dryness. The resulting residue was purified by silica gel chromatography (hexanes / EtOAc) to provide (4R)-4-[tert-butoxycarbonyl-[2-(tert-10 butoxycarbonylamino)ethyl]amino]-2-[4-(4.4 2-benzyl and 1-tert-butyl ,5,5-5-tetramethyll,3,2-dioxaborolan-2-yl)butyl]pyrrolidine-l,2-dicarboxylate (Intermediate 76, 1.14 g, 46% yield) as a yellow oil and as a mixture of diastereoisomers and rotamers. The purified material was subjected to chiral SFC [(S,S)Whelk-Ol column, 30 mm x 250 mm, pm, Temperature = 20 °C, Mobile phase = 0-20% IPA with 0.2% NH4OH:CO2 , UV detection at 220 nm, loading = 18 mg / inj., conc = 46 mg / ml in MeOH / DCM, flow rate = 120 ml / min, Outlet pressure = 100 bar] to provide two diastereoisomers. The stereochemistry of each diastereoisomer was assigned in retrospect based on the enzymatic potency of Example 27 and Example 28 being consistent with other exemplified compounds. Intermediate 77 (Isomer 2, 347 mg): (2R,4R)-4-[tert25 . butoxycarbonyl-[2-(tert-butoxycarbonylamino)ethyl]amino]-2[4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2yl)butyl]pyrrolidine-l,2-dicarboxylate 2-benzyl and 1-tert-butyl 1H NMR (500MHz, DMSO-de) δ 0.60 - 0.76 (2H, m), 1.15 (12H, s), 1.21 - 1.52 (31H, m), 1.66 - 1.82 (1H, m) , 1.96 30 2.19 (2H, m), 2.19 - 2.33 (1H, m), 2.83 - 3.10 (4H, m), 3.48 146 IF-2019-3 6421651 -APN-ANP#INPI Page 146 of 170 - 3.66 (1H, m>, 4.34 - 4.53 (1H,m), 5.00 - 5 23 (2Hm)6·83’ θ’”(1«' - 7.43 (5H, m) Intermediate 78 (Isomer 1, 540 mg): - » ZZZZ1' --» - 3.81 (1H, m), 4.33 - 4.49 '(1H ' m)s'n'13c HH, m), 5.00 - 5 2D ton x 6.86 - 6.94 (1H m) 7 oí(2H' ' UH, m), 7.27 - 7.39 (5H, m) . ^^edip__79: Acid (2R . / tert^butov7^^1..7 ---^^utoxycarbonyl-4 {2S, 42?) -4 — [ tertbutoxycarboni 1ajnino)etll}amino].2 4 5,t fbutoXicarbonylamino) et U] amlno]x“ 75a“-t2- <tel,3,2-dxOxaborolan-2-il)butlli . , ' ' ^tramethylde2-benzyl and 1-tert-butyl 2-dicarboxylate ™°1)inEtOAc (2.3 ml). The flask °'* - and -SUSPension became agitated:x \:~:η 91obo atmosphere. Mix . temperature filtered through soil “7closes diatom. npm dryness . mitered concentrated h +- · Provide acid (2R 42?)-i butoxxcarbonyl-4- (tert-butoxycarbonyl-[2.(utoXxcarbonylamino)etll]amino]-2-[4-(4(l^^-dioxaborolan- z-iDbutiijp,^.^4'5l·amet11' (Intermediate 79, 287 mg9« 1 blank to be used) as a solid utxlxzoSln additional puriflcation 147 IF-2019-3 6421651 -APN-ANP#INPI Page 147 of 170 (500MHz, DMSO-d6) δ 0.65 m), 1.31 - 1.43 (31H, m), (3H, m), 2.96 - 3.12 (5H, 3.61 (1H, m), 4.34 - 4.49 (ES+) [M+HJ+ = 656. 0.74 (2H, m), 1.14 - 1.21 (12H, 1.66 - 1.76 (1H, m), 2.00 - 2.27 m), 3.37 - 3.42 (1H, m), 3.49 (1H, m), 6.84 - 6.93 (1H, m), m); m / z: Step 27: Trifluoroacetic acid (0.67 mL, 8.8 mmol) was added dropwise to a stirred solution. acid (2R,4R)-1-tert-butoxycarbonyl-4-[tert-butoxycarbonyl-[2-(tert-butoxycarbonylamino)ethyl]amino)-2-)4-(4,4,5,5-tetramethyl1,3,2- dloxaborolan-2-yl)butyl)pyrrolidine-2-carboxylic acid (Intermediate 79, 287 mg, 0.438 mmol) in DCM (3.7 mL) for 1 h, the solution was reduced pressure and the resulting residue dissolved in HC1 ac. 1 M (5 mL) and Et2o (5 mL). Femlboronic acid (107 mg, 0.878 mmol) was added and the clear asl solution was stirred at room temperature for 1 h. The mixture was diluted with Et2o and water, and the phases were separated. The aqueous phase was washed with EtzO. The aqueous phase was lyophilized and purified by ion exchange chromatography (PoraPak Rxn CX 20cc column). The desired product was eluted from the column using 5% ammonia in MeOH (20 mL) to (2R,4R)-4-(2-aminoethylmethyl)-2-(4boronobutyl)pyrrolidine-2-carboxylic acid (Example 27, 106 mg, yield) as a white solid. iHRMN (500 MHz, δ 0.63 - 0.77 (2H, m), 1.13 - 1.23 (1H, m), 1.37 (3H, d 1-63 - 1.76 (1H, m), 1.92 - 2.02 (1H, m), 2.06 - 2.14 m), 2.24 - 2.33 (1H, m), 2.78 (2H, s), 2.96 (2H, s), 89% D2O) (1H, 148 IF-2019-3 6421651 -APN-ANP#INPI Page 148 of 170 3.08 3.19 (1H, m), 3.28 - 3.43 (1H, m), 3.43 - 3.51 (1H, m) ; m / z: (ES+) [M+H]+= 274. Example 28:_(2S, 4J?)-4-(2-aminoaethylamino)-2-(4boronobutyl)pyrrolidine-2-carboxylic acid Intermediate—80: (2S,4R)-l-tert-butoxycarbonyl-4[tert-butoxycarbonyl-[2-(tert-butoxycarbonylamino)ethyl]amino]-2-[4-(4,4,5,5-tetramethyl) acid 3,2-dioxaborolan-2-yl)butyl]pyrrolidine-2-carboxylic10 Pd / C (10% by weight, 137 mg, 0.129 mmol) was added to a solution of (2S, 47?)-4-[ tert-butoxycarbonyl 2-[2-(tert-butoxycarbonylamino)ethyl]amino]-2-[4-(4,4,5,5-tetramethyl1,3,2-dioxaborolan-2-yl)butyl]pyrrolidine-1,2-dicarboxylate benzyl and 1-tert-butyl (Intermediate 78, 480 mg, 0.64 mmol) in EtOAc (7.2 mL). The flask was fitted with a balloon of H2 and the suspension was stirred overnight at room temperature. The reaction mixture was diluted with MeOH and filtered through diatomaceous earth. The filtrate was concentrated to dryness and purified by silica gel chromatography (hexanes / EtOAc) to provide (2S, 47?)-1te-r't-butoxycarbonyl-4-[ tert-butoxycarbonyl-[2-(tert-butoxycarbonylamino) acid. ) ethyl]amino]-2-[4-(4,4,5,5-tetramethyll,3,2-dioxaborolan-2-yl)butyl]pyrrolidine-2-carboxylic acid (Intermediate 80, 170 mg, 40% yield ) as a white solid.XH NMR (500MHz, DMSO-d6) δ 0.58 - 0.73 (2H, m), 1.15 149 IF-2019-3 6421651 -APN-ANP#INPI Page 149 of 170 or (12H, s), (2H, m), 4.50 (1H, Ahem; 1-37 (31H, d a), 1.58 - i.74(2H,m),2- 3-16 (SH, m), 3.59 - 3.73 (1H,m), 2.92 m), 6.84 c 28: -6·95 (1H, m); m / z. Acid (ES+) [M+H] - 2.33 4.31 = 656. bor°nobutyl) pjrrolidin-9 4R) ~4- (2-aminoethylamino) -2- (4zcarboxíiim ιτ.'τ..: “° “““·-«*» .·»». ,on acidic acid (2S 47?) i +butoxycarbonyl-4-ru. (i>r4R) 1-tertonn 4 [tert-butoxycarbonyl- [2- (tertutoxrcarbonylamino)ethyl]amino)-2-[4-(4 4 5 5 l,3,2-dioxaborolan-2-ii>h„ ri,, · . ' ' '5'tetramatiltemperature concentrated to dissolved in 80, 170 mg, 0.26 room. After reduced pressure and HC1 ac. mmol) of the ^alüOXlllcOenDCM (5 mL) hz the solution was the resulting residue M (5 mL) and Et20 (5 mL). Clear phenylboronic acid (63 mg, 0.52 mmol) was added and stirred at room temperature for 1 h. The mixture was diluted with Et20 and water, and the aqueous phase was washed with Et20. and purified by chromatography of (Coi™. ,c, ' - ri0nico«>. =.>.». · ·*« to obtain acidin(2°mL)Paraboronobutyl)pyrrolidin 2' '^oethylamino) -2- (4de performance) as a ΧζΓ00 9S* d2) δ 0.65 - 1.41(9H, ,anC°·H NMR (50°MHz-DMSOr s x2) rotamers, 0.771·1ί1·24 (1H, m),m) , 1.62 - 1.79 (2H, And the two-phase solution The phases were separated. (1 HOUR, 2.72 - 2.84 3.41 (1H,m)f2.4Ί 1.25 m), (2H, 3.55 1.34 (1H, m), 1.34 1-62 (2H, m), 1. (ES+) 1.97 m), (1H,2.06(1H, m), 2.61 2.93 5.30 (3H, m), (2H, - 2.70 3.30m); m / z(ES*) [M+H]+ = 466> 150 IF-2019-3 6421651 -APN-ANP#INPI Page 150 of 170 or 29: Acid &, 4N) -4- [ [ (2S) -2-^ ^-2 irrolidine-?carboxylicn BnO or h2n' BnO O ΓO .....(' \ / OMe h BnO O BnO, O OMe OBn Intermediate 81 Intermediate 82 Intermediate 83 BnO O BnO O Intermediate 84 Intermediate 85 BnO, OBn OBn BnO, O Οζγ O. B'° EITHER- / EITHER O^H ' o^Z B-o, Intermediate 87 Intermediate 88 Intermediate 86 HN, EITHER \ O^NH' o^z o jí Γόη B-°, 0^7 H 9 .N J XT OHT°H OH Intermediate 90 Example 29 Intermediate 81: pencilo and 2-methyln (2S,4R)-4-(ίtertylate) Di-tert-butyl dicarbonate (6.27 g, 28.8 nimol) was added to a solution of (23 4PI 4 ' . . 42?) -4-aminopyrrolidine -l,2dicarboxlate of 1—benzyln or 4. ·ΊtrjpM1.7 2-metll° <5-00 g, 18.0 ronoi, retrlamine (5.00 mL, 35.9 mmol) in DCM (78 mi) and the reaction was stirred at room temperature for 4 p.m. 151 IF-2019-3 6421651 -APN-ANP#INPI Page 151 of 170 reaction mixture was diluted with DCM and used. sequentially with 0.5 M HC1 (aq) saturated hi κ and sodium chloride- ’ 'blcarb°nate on garlic., °* (DCM / MeOH)n3T.agel of S111ceTo obtain ζρςΛ -toxycarbonylaminopyrrolidin-l, 2-dicarbox^ benzyl and 2-methyl (Intermediate 81, 5.4 g 7«dpa- ~:: — - »- r™9H' m), 1.99 _2.23 (2H, 1^23·65 (4H, m), 3.96 - 4.10 (1Hm) '3'52(1H, m)t4.30 — 4 4fi mp mi λ — 5 1 g / on , _ 1.40 (J.H, m) , 4.92ό·13 ( 2H, m), 7.18 - 7 41 (5H,T.(5H'm); m / z:(ES+) [M+H]+= 379 Intermediate____82. J J / y. butoxy^rh^r,,· 7,. ; ’ ~ -—————(^S'4R)-4-[ter1-15 Izbenzyl and 2-methyl ------------Sodium hydride (60* dispersion in mineral) was added (0 423 n i o o °° in oil (23 4R) 7 ; 1' 'in POrC1OneS a™ solution of (2^, 4R)-4-(tert-butoxycarbonylamino) ni rmi i „ 1-benzyl and 2-methyl dicarboxylate (rnte\ „o«leuixo (Intermediate 81 q s XToVaZa° 'C·la—de— temperature environment withX / - “1βηί3Γ until -gave additional Jti:n- iodide. It was stirred at room temperature for 16 hours, the reaction was cooled to 0 -c and the volatile components were deactivated with water. χ 50 saturated aqueous (2 x 50 mL) Na2SO4, filtered and concentrated to 152 IF-2019-3 6421651 -APN-ANP#INPI Page 152 of 170 dryness for butoxycarbonyl(methyl) 1-benzyl and yield) purification 1-47 (9H, m), (3H, d), 3.22 provide 2-methyl (Intermediate 82, as an additional rotamer mixture. í-89 - 2.08 “ 3-39 (2H,1RRMN (500MHz,4·87- 5.17 (2H, m), [M+H]+ = 393. Butoxycarbonyl (methyl)dibenzyl intermediate 35.62 mmol) was added in (1H, m), m), 3.65 7.18 2.31 (4H, 7.46 s) (2S, 47?) -4- [ tert?-dicarboxylate of 3*33 g, 70% of Which was used without DMSO-cfc) δ 1.252·46 (1H, m), 2.69 ' 4.22 - 4.49 (1H, (5H, m); (ES+) 83: —(2S, 4R) -4 — [tertune solution of sodium hydroxide water. (7.5 mL) to a solution of 1-benzyl dicarboxylate 5' 5.94 mmol) in reaction mixture slowly until 1)amino]pyrrolidin-1,20y 2-methyl (Intermedi THE (15 mL) and MeOH (7.5 mL) were stirred for 6 h while (1.425 g, 2S,4R) -482, 2.33 °C. The extracted aqueous phase components were heated at room temperature. volatuea were removed under reduced pressure and ia8β at “dlfÍC6 h«ta pH -3 with 5M HC1 (ac / °™ (4 The and se And they were evaporated to dryness to co ·· «...... »·..» which added benzyl bromide (Qθ crude carboxylic acid, sodium iodide (111 (1-92 g, 13.9 mmol) in DMf, at temperature environment for 17h was filtered and the And the solids were washed with 7.38 mmol acid solution and K2CO3 reaction mixture was stirred. 9 / the The 153 IF-2019-3 6421651 -APN-ANP#INPI Page 153 of 170 EtOAc. The filtrate was concentrated and purified by silica gel anteromatography / hexanes / EtOAc) to provide (2S, 4R) -4-[ tertb "toxycarbonyl (metll)aminojplrrolidin-1,2-dicarboxylatedibenzyl ((Intermediate 83, 2.45 g, 94 * yield) as a light yellow oil, i,Kq 1500mi!, |ffl, rotamers, 1.55 - 1.28 (3H, m), 2.99 - 1.45 (9H, m), 1.98 2-62 (1H, m), 2.30 - 2.46 (1H, m), 2.64 - 2.7! (3H, m), 3.30 - 3 84 (1H, m), 3.51 - 3.76 (1H, m), 4.48 - 5.21 (1H, m), '4- 53 - 4.75 (1H, m), 4.88 - 5.21 (4H, m), 7.18 - 7.42 (10H, m); m / z (ES+) [M+HJ+ = 401. (ES*) [M+H]+= 469. ^termedi°------2½_______(but-2-enyl)-4-[tertbutoxycarbonyl <^tyl)amino]pyrrolidin-l,2-dicarboxylsto dadibenzyl ’ (2S,4R)-4-(tert-butoxycarbonyl(methyl)aminoJpyrrolidine-1,2-dlcarboxylate dibenzyl (Intermediate 83, 2.45 g, 5.23 mmol) and crotyl bromide (0.81 mL, 7.8 mmol) were dissolved in THF (18 mL ) and the solution was cooled to -78”c in a N2 atmosphere. A KHMDS solution (0.5M in toluene, 15.7 mL, 7.85 mmol) was added dropwise to the reaction mixture and the reaction was stirred for 17 h at the once slowly warmed to room temperature. The crude reaction mixture was quenched with water and the volatile components were removed under reduced pressure. campus The crude mixture was diluted. The organic phase was washed, filtered and concentrated with DCM and water, dryness. purified by purification (hexanes / EtOAc) to provide the phases were separated. was dried with Na2SO4, The raw material is put into silica gel [tert-butoxycarbonyl(methyl)amino]pyrrolidine-1, (4R)-2-(but-2-enyl)-4230 154 IF-2019-3 6421651 -APN-ANP#INPI Page 154 of 170 dibenzyl dicarboxylate (Intermediate 84, 2.10 g, 86% yield) as a yellow oil and as a mixture of diastereomers, E / Z olefinic isomers and rotamers.XH NMR (500MHz, DMSO-d6) δ 1.31 - 1.40 (9H, m), 1.46 - 1.68 (3H, m), 1.99 - 2.31 (2H, m), 2.40 - 2.47 (1H, m), 2.55 -2.68 (3H, m), 2.69 - 3.00 (1H, m), 3.30 (1H, s), 3.51 - 3.77 ( 1 HOUR, m), 4.55 - 4.74 (1H, m), 4.79 - 5.21 (4H, m), 5.26 -5.41 (1H, m), 5.42 - 5.71 (1H, m), 7.16 - 7.42 (10H, m) ; m / z: (ES+) [M+H]+= 523. Intermediate__________85:__________(4R)-2-(but-2-enyl)-4(methylamino)pyrrolidine-1,2-dibenzyl dicarboxylate Trifluoroacetic acid (3.84 mL, 50.2 mmol) was added to a solution of dibenzyl (4R)-2-(but-2-enyl)-4-[tert-butoxycarbonyl (methyl)amino]pyrrolidine-1,2-dicarboxylate (Intermediate 84 , 2.10 g, 4.02 mmol) in DCM (32 mL) and the reaction was stirred at room temperature for 2 h. The reaction mixture was concentrated to dryness to obtain the TEA salt of dibenzyl (4R)-2-(but-2-enyl)-4(methylamino)pyrrolidine-1,2-dicarboxylate (Intermediate 85, 2.55 g, 100 % yield) as a colorless oil which was used without purification. 2.57 - 2.65 (3H, m), 2.66 - 3.07 (1H, m), 3.15 - 3.56 (1H, m), 3.66 - 3.77 (1H, m), 3.81 - 4.13 (1H, m), 4.79 - 5.22 (4H , m), 5.26 - 5.73 (2H, m), 7.20 - 7.41 (10H, m), 8.62 - 8.87 (2H, m) ; m / z: (ES+) [M+H]+= 423. Intermediate 86: Dibenzyl (4R)-2-(but-2-enyl)-4-[ [ (2S)-2-(tert-butoxycarbonylamino)-3-methyl-butanoyl]-methylamino]pyrrolidine-1,2-dicarboxylate 155 IF-2019-3 6421651 -APN-ANP#INPI Page 155 of 170 ^2V-diisopropylethylamine (0.70 mL 4 n) was added to a solution of HATU (1 52 4 02 m τ í ' ’ ^°114.02 mmol) and Boc-Val-OH (873 enDMF (15 mL) and of the 4.02 mmol) room temperature during TEA salt solution. The reaction was stirred at min. A (methylamino)pyrrolidin-1,2-dicarbozyl (4R)-2 (but-2-enyl)-4x, zi-aicarDoxylate (intermediate 85.2.16g, 4.02mol) endxzsopropylethylamine (0.70 mb, 4.0 mmol) and I stir at room temperature for another 17 hours. gives dibenzyl (15 mL) and N,Nreaction was concentrated and purified ’rf·..... chromatography on silica gel, hdlrectamate using °·”’XiJULcinoiiJnietil-amino]pyrrolidin-i 9 . dibenzyl (Intermediate 86, 1.97g 7'1Carboxylate of a mixture of rotamers. iHrmn ',500°ηθyield) c™° H NMR (500MHz, DMSO-d6) δ 1HRMN (500MHz, DMSO-dg) 0.61 (3H, 2.76 (1H, 5.72 m / z: da), 1.79 - °·92 (6H, m), 1-92 (1H, m), 2.03 (2H, m), 2.76 - 3.00 (3H, m), 3.30 1.35 2.331(1H, 5.20 m), 4.04 - 4.16 (1H, m), 4.78(2H'm)'6-72 - 7.03 (IR,m),7.17(ES+) [M+H]+ = 622. (9H, s a), 1.62 (2H, m), 2.57 s), 3.49 - 3.77 (5H, m), 5.267-38 (10H, m); In termed.! η —----------Í-4R) -4-1 ¡ (2S) -2- (tertan-2N2-purged round bottom dibenzyl bis(diphenylphosphino)methane xylate was added. The dichloride solids (213 mg, (244 mg, an oven. of 0.317 0-635 mmol) to bis (1.5mmol) and a flask The flask was sealed and poured into DCM (8.9 mL) and 156 IF-2019-3 6421651 -APN-ANP#INPI Page 156 of 170 4,4,5,5-tetramethyl-l,3,2-dioxaborolane (1.01 mL, 6.97 mmol) was slowly added to the solution. The reaction was stirred at room temperature for 10 min. Dibenzyl (4B)-2-(but2 enyl)-4-[((2S)-2-(tert-butoxyoarbonylamino)-3-methylbutanoyl]-methylamino]pyrrolidin-l,2-dicarboxylate was added (Intermediate 86, 1.97 g, 3.17 mmol) to the reaction as a solution in DCM (5.9 mL) and the mixture was stirred for 16 h at room temperature. reaction The reaction mixture was cooled to 0 MeOH and water. The phases were extracted with DCM. The phases with Na2SO4 were filtered and C and carefully separated and the aqueous phase with combined organic ses were dried and concentrated to dryness. The resulting residue was purified by flash silica chromatography (hexanes / EtOAc) to provide (4R)-4t((23)-2-(tert-butoxycarbonylamino)-3-methylbutanoyl]methylamino]-2[4-(4.4 ,5,5-tetramethyl-l,3,2-dioxaborolan-2yl)butyl]pyrrolidine-1,2-dicarboxylate (Intermediate 87, 1-5 g, 63% yellow and as a mixture of diastereoisomers The purified material was subjected to dibenzyl as oil and rotamers. a Chiral SFC [(S,S)Whelk-Ol column, mobile = 0-30% x 250 mm, 5 pm, Temperature = 20 °C, Phase mg / inj., MeOH:CO2 conc pressure, UV detection = 125 mg / ml in MeOH, at 220 nm, load = 31 flow rate = 75 ml / min, diastereoisomeric output. 100 The diastereoisomer was assigned in bar] to provide two stereochemistries of each retrospective based on the enzymatic potency of Example 29 and Example 30 being consistent with other exemplified compounds. Intermediate (Isomer 2, 2S0 mg): (2R, 4A)-4-[ [ (2S)-2(tert-butoxycarbonylamino)-3-methylbutanoyl]methylamino]-230 157 IF-2019-3 6421651 -APN-ANP#INPI Page 157 of 170 [4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2illbutyljpyrrolidln-l,2-dicarboxylate dibenzyl. NMR (500MHz, DMSO-de) 5 0.51 - 0.70 (2H, m), 0.72 - 0.93 (6H m), 2.54 - 2.90 (3H, m), 3.33 - 3.48 (IH, m), 3.49 - 3.85 07 nú4'01'4'18 (1H'4·71'S·23 (5H'm)'6·717- 07 (1H, m), 7.19 - 7.33 (10H, m). Intermediate 89 (Isomer 1, 590 mg): (2S,4R)-4-[[(2S)-2. Dibenzyl (tert-butoxycarbonylamino)-3-methyl-butanoyl]methylamino]-214-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-211)butiDpyrrolidin-l,2-dicarboxylate. iHRMN (500MHz, DMSO-d6) δ 0.49 - 0.72 (2H, m), 0.73 - 0.90 (6H ZZ5 (12H'S>' - 3 - 2.34 (5H, mi,' 3H, s a), 3.30 (IH, s), 3.63 - 3.76 (IH, m), 3.96 - 4.17 IH, m), 4.75-5.18 (5H, m), 6.71-7.05 (IH, m), 7.17 - 7.41 (10H, m). Siege--90:--Acid___(2^-4-,,(29)-2-(^. buto^cazbonyl^yne) -3-methi Ibutanoyl]-metllamino]¿4'4'5'5-tetramethyl-1,3,2-dioxaborolan-2yl)butyl lpyrrolidine-2-carboxyJ Pd / C (10%) was added by weight, 99 mg, 0.093 ™Ο1)a solution of <2^4R)-4-[[(2S)-2-(tert-butoxycarbonylamino)netylbutanoyl)-methylamino]-2-(4-(4,4, Dibenzyl 5,5-tetramethyl1,3 2~di°xab°rolan-2-yl)butyl]pyrrolidine-1,2-dicarboxylate (Intermediate 88, 280 mg, 0.37 mmol) in EtOñc (4 ni). equipped with a Hz balloon and the suspension was stirred at room temperature for 4 h. reaction was diluted with diatom MeOH. The filtrate was provided with acid and filtered concentrated The soil mixture through dryness for (2R, 4R) -4- [ [ (2S) -2- (tert30 158 IF-2019-3 6421651 -APN-ANP#INPI Page 158 of 170 or ^toxy“tbonylamino)-3-methylbutanoyl]methyl-aminoj.2_[4_ (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2IDbutiDpyrrolidine-i-carboxyUce (Intannedium 92% yield) as an additional purification. *h 0.69 1.30 (1H, 2.91 (2H, m), 0.74 - 0.87 (3H, m), 1.35 (9H, s), m), (3H, 1.82m), - 5.16 (1H, m) [M+H]+ = 526. White solid carboxylic example that was used without NMR (6H, 1.49 1-95 (2H, m), 2.15 (500MHz, DMSO-d6) δ m), 1.16 (12H, s), “1.65 (1H, m), 1.65 2.92 3.21 (3H, m), 4.05 r 6-76 (1H, s), 7.56 2.26 (1H, m), 0.59 1.22 - 1.82 2.63 “4.22 (1H, m), 4.80 “θ.05 (1H, m) ; m / z: (ES+) ---(2Β^±-butyl]pyrrolidi„.2 -oarboxíllco (InteCTedio 0.34 mmol) in DCM (10 mi) h lasol· - room temperature. After 'solution was concentrated under reduced pressure resulting dissolved in aq. HC1. 1 M (5 mL) and (84 mg, 0.69 stirred at Phenylboronic acid was added to ambient clear biphasic solution for 1 h. The mixed mixture was diluted with Et2O and the phases were separated. and the residue Et2O (5 mL). mmol) and temperature and water, and aqueous phase was lyophilized by ion exchange The aqueous phase was washed with Et2O. The y was purified by chromatography (PoraPak Rxn ex 60cc column) The desired product was eluted from Ja -.ia, co ,,Y from the column using ammonia 5, in MeOH (60 mL) to obtain acidQ' ' L L 159 IF-2019-3 6421651 -APN-ANP#INPI Page 159 of 170 or amino 3-metrlbutanoyl]methylamino]-2-(4boronobutyl)pyrroiidln.2.carboxyl.code yield) as a white solid. δ 0.72 - 0.83 (2H, m), 0.85 m), (1H, m), 1-61 1.84 (1H, m), 1.85 - 1.01 (6H, 2.03 m), 2.34 - 2.49 (1H, m), 3.00 (3H, 3.76 - 3.96 (1H, m), [M+H]+= 344. Example 3Q;____Acid4-95 - 5.10 BnO, or o^NH' B-O. < Intermediate 89 IntermediateXH NMR (500 MHz, m), (2H, s), 1.10 - 1.45 m), 2.19 3.16 - 3.51 (1H, m) ; m / z: D2O) (4H, 2.34 (2H, (ES+) (2S, 42?) -4- [ [ (2S) -2-amino-3aoronobutyl)pyrroljdjn_9_ Example 30 —-------(2S'4R)-4-[[(2S) -2-(teri-15 ,TT~--------— -methylamino]-2-[4_ ^'s'S-tetramethyl-1.3,2-dioxaborol'---- ^<^roox2j.j.co Pd / C (10* by weight, 209 mg, o.196 mmol) was added to a solution of (2S, 4R) -4-(((2S) -2-(tert-butoxycarbonylamino). metrlbutanorl]-metllamino]-2-(4-(4,4,5.5-tet _edibenzyl (Intermediate 89, πΛ). with stirred during the night ato 590 mg, 0.79 mmol) in EtOAc (4 a balloon of H2) and the reaction suspension was diluted with MeOH at room temperature. The diatom mixture. The filtrate was provided with acid and filtered through concentrated soil to dryness to (2S,4R)-4-[[(2S)-2-(tert160 IF-2019-3 6421651 -APN-ANP#INPI Page 160 of 170 T4OX5C5TnÍlamlnO,‘3’methylbUtaneO11]metÍ1-amÍn°>2-(^ ' ' '5-tetramethyl-l,3,2-dioxaborolan-21l)butyl]pyrrolidine.2.carboxylco (Intermediate 9i,M7 96% yield) as an additional purification. *η °·67 (2H, m), 0.73 - 0.87 1-31 (3H, m), 1.35 (9H, s), (3H, m), (1H, m), 2.28 - 2.37 (2H, m) white solid that was used without NMR (500MHz, DMSO-d6) δ (θΗ, m), 1.16 (12H, 1.51 1·67 (1H, m)t s), 1.68 0.58 1.22 - 1.95 r 2.95 (4H, S), 4.054\66-4·79 (1H' *·« - 6.90 (1H, m), m); m / z: (ES+) [M+HJ+ = 526. ____isido (2S,4R)-a.rr„^ , . , - 4.20 (1H, 7.85 - 8.15 Trifluoroacetic acid (1 17 mL 5-nmo) was added dropwise to a stirred solution of (2E, 4«)-4-(2^ - ZU5T:TONllamÍnO,-3'methylb—Umethyl-amino) acid,<4 '4'5'5-tetramethyl-l,3,2-dioxaborolan-2„ ^rooxmco (Intermediate 91 0.7 55 mmol) in DCM Μη \' of ! h, ’S ambient temperature. ae4 n, the solution was concentrated =· „ resulting residue was dissolved in HC1 aq^Γμe (5 mL). Phenylboronic acid (186 mg 152) was added to the clear biphasic solution at high ambient temperature for 1 h. h. The mixture was diluted with Et2O and water, and the aqueous phase was washed with Et2O. The phases were separated. aqueous phase was lyophilized 397 mg, After exchange · - · Romeo exchange chromatography (PoraPakRxnex 60cc column) The desired product was eluted Ha i ) · 5% in MeOH (60 mL) to obtain ammonia 2-amlno-3-me^ get <2S-^)-4-([ (2S)_ ion exchange -2-(430 161 IF-2019-3 6421651 -APN-ANP#INPI Page 161 of 170 I' boronobutyl)pyrrolidin_2_ 92% D2O) (4H, δ 0.68 m), 1.66s), 3.22 (1H, m), In carboxylic (Example 30, as a white solid. 0.78 (2H, m), 0.83 - 3.30 4.53 lo 31: 2.13 (1H, 4.66 (4H, m), (1H, 163 mg,XH NMR (500 0.94 (6H, m), 1.lom,z 2,492·68(1H, m), 3.02 MHz, 1.41 (3H, 3.883·43 - 3.60 (1H, m), 3.70 m); m / z:(ES+) [M+H]+ =344biological of the \ inhibitors of Examples 1 to 30 on human Argmasse 1 and the activity of effects The activities of the Human arginase 2 la were quantified by measuring thiol group from dPh ·1 formation ........ . of the The 5,5' thiol acid to provide the d^Z 5-thiobenzoic acid (TNB),aue°Y acid.2-mtroabsorbance of 'quantifies by the rancidity of anwn (TNB2-)at 412 nm. 5~thiobenzoic black (Greiner #deJaV -3 plates d / : 1 Z r1 30- -0 „1de DMS0 ae immediately after aquaatieo Echo centrifuged.Pla“S S*sell-on yse Two premixes were prepared from Angelados immediately before addition to human bulk, with a final concentration of 5 nM and 45 mM HEPES at pH 7.5, brij cLn' of2 100 PM· ~d°* ~n thawed with a concentration of 0.5 test. Arginase 2 mM DTNB 35, 0.045% 162 IF-2019-3 6421651 -APN-ANP#INPI Page 162 of 170 zz ——...... .......*· before adding fifteen microliters of premix. The absorbance test plates 412 were centrifuged before reading the Pherastar for inmate ”” θ ™star multimode plate reader to collect data in the moment The Plates were incubated at temperature b “ ' min before reading * Ambient temperature for 60 temporal 1 (TI)Edata in theP™to measured at T0 (Lo t —V-do the signal A412 temporal 1) The dataT^ ”1 measurement at T1(P^to the equation: using the effect of the Compound = 100*Γ(x-minl / i where esculo) and the max. The concentration activity in 50 representing the % of compound and adjusting from the Examples 1% (that is, the effect against the θ 30 that inhibited the IC50) Genedata SoreUtÍ1Í2 adjustment concentration was calculated using the assay formula shown in page ^1^°3 of these Example 1 Human arginase enzyme 1 IC50 (pM) 13.69 Human arginase enzyme 2 IC50 (μΜ) 26.57 21.44 163 IF-2019-3 6421651 -APN-ANP#INPI Page 163 of 170 Example 3 Human arginase enzyme 1 IC50 (pM) Human arginase enzyme 2 IC50 (pM) 4 5 6 *7 ~41.92 6~.41 3.96 10.40 74.07 ' 16.63 10.41 / 8 IZ * U.01 0.61 O'. 32 0.02 0.56 0.33 10 ΪΪ 1 o 3.77 θ.2Ϊ 4.77 O’. 20 xz 13 ~ 14 15 1 0.70 O’. 43 Γ 0-26 0.31 0.85 O’. 63 Γ 0-31 16 17 18 19 0.31 0.20 0.32 T 0 22 0.26 0.31 0.23 0.38 20 21 0.34 0.48 0.28 0.52 n co 22 23 24 ' 25 ~ ñe 0.93 1714 03 10.80 v. oo 1.32 2.12 0.01 24.55 O 27 28 0.65 K43 0.09 0.15 3?32 O’. 19 164 IF-2019-3 6421651 -APN-ANP#INPI Page 164 of 170 Human arginase enzyme 1 IC50 (μΜ) E 91 ’ Example “ 29 Human arginase enzyme 2 IC50 (μΜ) 30 □ · z / 1.35 9.28 2.42 EJS-flo 32: Studies of -Usponibui „„„ Examples 8, 9v13aof Example 7Sene- ^orr^as of prodrugsbello to pharmacokinetic finish to demonstrate Example 7 from Example 8. a 0.9% w / v saline solution for IV dosing. the He PH The formulation the following bioavailability study of Example 8 was formulated in (adjusted with by femoral catheter to two rst-bc ςο<.atas machoeach (170 Blood samples were taken in series noy n serialBy jugular catheter after Example with HC1alas 0.033, 0-083, 0.167, from the administration. 8 was formulated in 1M water) and administered to 0-5, 1, 2, 4, 8 For dosage HC1 1M) 2 mg / kg 250 g). venous and 24 h PO, the deionized to pH 4 (adjusted mg / kg by oral gavage to two blood in series by cattoned samples of 115234Ven°S°yU9ular wings 0.25, 1Έ, 2, 3, 4, 8, and 24 h after administration. A single set of Example 8 was prepared for Example 107 and the P were prepared by adding blank plasma. The male rat samples each and precipitation standards with two volumes 0.5, tion. It was used as extracted by S of acetonitrile followed by determining the ci ζν °* (mL / mrn / kg), Vdss(L / kg),Cmaxcentrifugation. 165 IF-2019-3 6421651 -APN-ANP#INPI Page 165 of 170 (μΜ h), tmax (h) v %p +-ari4θ- The bioavailability absZ^ZZtZ ’ “”° MC normalized to the h · term comparing administered as an Example Γζ ” ’CUad° ;:r«. when appropriate, sp hhi.· for lime, measured doses were used To calculate bioavailability. He repeated the same as an example. 7. And don't name them Analogously, the procedure narp r, is used. For Examples 9 and 13 a3 are shown in Tables □ results indicate that bioH- ·& 12increase by incorporating prodrugs responsibility. twenty. The results of certain amino acid residues These can as * n ci (mL / min / kg) Vdss (L / kgj Cmax PO (μΜ) AUC PO (pM.h) Tmax (j %F observed value Observed value cu 0 reportable Table 3 Example 8 ÑV # ÑV # ÑV~ # ---- NV # ~ÑV~# NV * do when administered c Example 7 Γ.90 * 0.26 * ”3.60 # 10.40 # 1.00 # 33.00 # -üter a prodrug orno loading NV Value. Table 4 Example 9 Example 7 8.90 * 0.26 * 5^.70 * 16.80 # <-'l (mL / min / kg) J3.30 # Vdss (L / kg) (Γ. 20 # Cmax po (μΜ) Γ AUC Po (pM.h) --- 0.60 # 0.24 # 166 IF-2019-3 6421651 -APN-ANP#INPI Page 166 of 170 or Tmax (h) %F 0.25 3~.2O # observed value 1.00# 59.0Ó # Observed value not reportable / When administered as load.Lv Value Table 5 Example 13 17.90 # Cl (mL / min / kg) Example 7 Vdss (L / kgj 0~. 20 # 0.46 # 0. 62 # 8? 90 í Cmax PO (μΜ) 0.26 * AUC PO (μΜ.Η) ' 3.30 # Tmax (h) θ'. 50 i 13.30 1 %F 3.80 #------- Γ.25 ♦ # observed value Observed value cu not reportable when administered c 40.70 # -stro prodrug orno loading NV Valor Cl (mL / min / kg) Vdss (L / kgj : Cmax PO (μΜ) AUC PO (pM.h) Tmax (h) %F ffobserved value Observed value cu not reportable Table 6 Example 14 ÑV # 1 ÑV # ÑV # NV # NV # NV # do when administered c Example 7 8.90 * / ).26 * Γ. 80 # 8.90 # 1.00 # 29.90 # .stroke an orno loading prodrug. NV Value Page 167 of 170 or Cl (mL / min / kg) 104.0Ó * 0.4 6 # NV » Vdss (L / kg) Cmax PO 7μΜ) 8.90 * 0.26 * AÜC PO (pM.h) Tmax (h) 1 %F # valnr ηλο--- - Γ NV # ÑV # ÑV # ----- ' 5.70 # । 15.60# Ϊ.00# 57.10# * vawobserv c:n°docuand° not reportableΟ°“° ™ Value Table 8 ci (mL / min / kg) Example 16 585.0Ó i 7.41 » ~ÑV # Example 7 Vdss (L / kg) 8.90 * Cmax po (pM) 0.26 * AUC PO (pM.h) ' ÑV # 1.6Ó # Tmax (h) ÑV # Γ 5.80 # %F ÑV # Γ. 00 # 17.00 Γ when administered Value observed when administered with a non-reportable prodrug or loading. NV Value Table 9 C1 (mL / min / kg) Vdss (L / kg) Example 17 40.50 * Example 7 8~. 90 * Cmax po (μΜ) 0.36 # Ñ. 43 # 0.26 * 4.90 n AUu ¿o (pM.h) Tmax (h) %F 0.38 # (Γ.38 # 18.30 # 1.50 # □ . ou * 61.90· 168 IF-2019-3 6421651 -APN-ANP#INPI Page 168 of 170 or » value observed when a prodrug was administered Value observed when it was administered not reportable as a load. NV Value Table 10 C1 (mL / min / kg) Example 18 Example 7 ' 317.00 # 8.90 * Vdss (L / kg) 0.64 # 0.26 * ' Ullox PO (jlM) NV # 4.10 # aug PO (pM.h) Γ NV # 13.10 # Tmax (h) ÑV # ' Ϊ.50 # %F ÑV # 45.70 i ft value observed when admitted was administered as a load. NV Value * Observed value when not reportable Table 11 Example 19 C1 (mL / min / kg) Vdss (L / kg) Cmax PO (μΜ) AUG PO (pM.h) Tmax (h) %F 36.80# 0.20 *~ 0.33# θ.21# 7).25 2.50 Γ # value observed when Example 7 8.90 *~” 0.26 ~ 5.70~ ”16.80Γ 1.00~ 59.00#~ * Value observed when a non-reportable prodrug was administered as loading. NV Value Table 12 Example 20 Example 7 <>·* (mL / mxn / kg) 8.90 » 8.90 * vass (L / kg) 0.29 # 0.26 * 169 IF-2019-3 6421651 -APN-ANP#INPI Page 169 of 170 or Cmax po (μΜ) ' ' Ϊ.80 * 2.20 * AUC PO (pM.h) 6.90 # 12.20 # Lilkox, (a) i.Oó # Γ 3.50 # --- Ί ' Ί-------- -- 25.50 » 59.00 # miui ousel empty when administered Value observed when a prodrug was administered as a load. NV Non-reportable value It is stated that in relation to the method known to the applicant for the aforementioned invention, it is the one that results from the description of the invention. this date, bring to light the present best practice 170 IF-2019-3 6421651 -APN-ANP#INPI Page 170 of 170 Argentine Republic - National Executive Branch 2019 - Year of Export Additional Signature Sheet Graphic report Number: IF-2019-3 6421651 -APN-ANP#INPI BUENOS AIRES CITY Tuesday April 16, 2019 Reference: 20190100382 The document was imported by the GEDO system with a total of 170 page / s. Digitally signed by GESTION DOCUMENTAL ELECTRONICA - GDE DN: cn=ELECTRONIC DOCUMENTARY MANAGEMENT - GDE, c=AR, o=GOVERNMENT SECRETARY OF MODERNIZATION, ou=ADMINISTRATIVE MODERNIZATION SECRETARY, serialNumber=CUIT 30715117564 Date: 2019.04.16 20:22:47 -03'00' Mariela Flavia Gonnet Administrative Advisor National Patent Administration National Institute of Industrial Property Digitally signed by GESTION DOCUMENTAL ELECTRONICA GDE DN: cn=GEST10N ELECTRONIC DOCUMENTARY - GDE, c=AR, o=GOVERNMENT SECRETARY OF MODERNIZATION, ou=ADMINISTRATIVE MODERNIZATION SECRETARY, serialNumber=CUIT 30715117564 Date: 2019.04.16 20:22:48 -03'00'

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof: FORMULA 1, characterized in that R1 is -NHR1a; R1a is -H or -C(O)CH(R1b)NHR1c; and R1b is selected from -H, (C1-4) alkyl and CH2OR1d and R1c is -H; or R1b and R1c, together with the atom to which they are attached, form a 5-membered heterocyclic ring; and R1d is H or -CH3. 16 Claims follow