Pyrrolidine compounds

Abstract

The present disclosure provides compounds of formula (III) and pharma- ceutically acceptable salts thereof, and compounds of formula (IV) and pharma- ceutically acceptable salts thereof, and pharmaceutical compositions comprising these compounds, as well as intermediates for preparing the compounds.

Description

[Technical Field]

[0001] The present invention relates to pyrrolidine compounds, pharmaceutically acceptable salts thereof, pharmaceutical compositions, and therapeutic uses of these compounds, particularly their use in lowering plasma levels of lipoprotein(a) (Lp(a)). The present invention also relates to intermediates for use in the preparation of therapeutic pyrrolidine compounds. [Background technology]

[0002] Significant advances have been made in the treatment of cardiovascular disease (CVD). Despite these advances, patients continue to experience cardiovascular events, such as angina, myocardial infarction, and stroke, which, if untreated, can lead to death. Lipid disorders, or dyslipidemia, remain a major risk factor for CVD. Lipid disorders can be divided into four general risk factors: elevated low-density lipoprotein cholesterol (LDL-c), low high-density lipoprotein cholesterol (HDL-c), elevated triglycerides (TG), and elevated Lp(a). Various treatment regimens target high LDL-c, low HDL-c, and elevated triglycerides. Few approved treatment options exist for patients with elevated Lp(a). In some cases, apheresis can be used to filter blood to remove LDL and Lp(a); however, the effect is temporary and typically needs to be repeated every two weeks. There are no approved pharmacological treatments to reduce Lp(a) levels. Although the physiological function of Lp(a) is complex, elevated Lp(a) plasma levels have been reported to be an independent risk factor for CVD.

[0003] Lp(a) can exhibit both prothrombotic and antithrombotic properties, as well as both atherogenic and atherothrombotic properties. Lp(a) inhibits fibrinolysis and can accumulate in the vascular wall, inducing thrombus formation and atherosclerotic lesions. Plasma levels of Lp(a) vary substantially between individuals. Unlike other risk factors, Lp(a) plasma levels do not change significantly with diet and exercise. Lp(a) plasma levels may be associated with genetic predisposition.

[0004] Lp(a) is similar to LDL-c in that it contains an LDL lipid core with associated apolipoprotein B (apoB); however, unlike LDL-c, Lp(a) contains a unique apolipoprotein(a) (apo(a)) linked to apoB via a disulfide bond. Apo(a) is synthesized in the liver. Assembly of apo(a) and Lp(a) from LDL particles can occur within liver cells, on the cell wall, or in plasma. Inhibition of LDL particle assembly with apo(a) can reduce Lp(a) levels. Additional treatment options are desirable for patients suffering from cardiovascular disease, particularly those suffering from lipid disorders or dyslipidemia. Additional treatment options are needed for patients whose cardiovascular risk is not adequately controlled using current standard therapies, such as diet, exercise, and / or the use of one or more medications, such as statins, fibrates, or niacin. The present invention provides an alternative treatment option for patients suffering from CVD. Pharmaceutically acceptable compounds and treatment options are needed to reduce plasma Lp(a) levels. Summary of the Invention [Means for solving the problem]

[0005] In a first aspect, there is provided a compound of formula (III):

[0006] [ka] During the ceremony, L 1 But, A1 , A 2 Or A 3 Bonded with, and bonded with, -(CH2) p NHC(O)NH(CH2) p -, -(CH2) p C(O)NH(CH2) p -, -(CH2) p S(O)2NH(CH2) p -, -(CH2) q -, -(CH2) p NH(CH2) p -,

[0007] [ka] Selected from or or L 1 A on one ring 2 Rank and A 3 together with the carbon at position 1 to form the following fused ring:

[0008] [ka] R 1 , R 1’ , R 2- and R 2’ However, at each occurrence, independently, H, C 1-4 alkyl and F; R 3 , R 3’ , R 4 and R 4’ is, in each occurrence, independently either H or F; R 5 and R 5’ However, at each occurrence, independently, H, C 1-4 alkyl, or cyclopropyl; Z and Z', in each occurrence, independently represent H, C 1-4 alkyl, OH, cyclopropyl, CHOH, CHNH, or CHOCHphenyl; Y and Y′, in each occurrence, are independently CH, CH(CH), O, or S; A1 , A 1’ , A 2 , A 2’ , A 3 , A 3’ , A 4 , A 4’ , A 5 , A 5’ and A 6 is independently, in each occurrence, C or N, and A on each ring 1 , A 2 , A 3 , A 4 and A 5 At most two of the 1’ , A 2’ , A 3’ , A 4’ , A 5’ and A 6 At most two of are N, Q 3 and Q 3’ may, at each occurrence independently, be H;-(CH2) n O(CH2) n R 10 ;-(CH2) n NR 15 (CH2) n R 10 ;-CN;-(CH2) n CO2R 10 ;C 1-6 Alkyl;-C 2-6 Alkenyl;-C 2-6 Alkynyl;Halo;-C(O)-R 10 ;-C(O)NR 15 R 10 ;-S(O) m (CH2) n R 10 ;-(CH2) n NR 15 S(O) m (CH2) n R 10 ;-(CH2) n S(O) m NR 15 (CH2) n R 10 ;-(CH2) n NHCONR 15 R 10;-NHCO(CH2) n R 10 ;-NHCOOR 10 ;NO2;CF3;C 3-6 Cycloalkyl; -NH(C=NH)CHCN; 5- or 6-membered heterocyclyl optionally substituted with 1 to 4 halo or phenyl; indoline optionally substituted with 1 or 2 CH; (CH)CF, CH, or (CH) n imidazolidinone, pyrrolidinone, imidazolidine-2,5-dione, pyrrolidine-2,5-dione, or oxazolidin-2-one optionally substituted with phenyl, the phenyl being optionally substituted with OH or OCH; indolin-2-one, isoindolin-1-one, or benzimidazol-2-one optionally substituted with one or two substituents independently selected from OCH, CH, and halo; phenyl, 5- or 6-membered heteroaryl, or 9- or 10-membered bicyclic heteroaryl, the phenyl and heteroaryl being independently selected from halo, OC, 1-4 Haloalkyl, C 3-6 Cycloalkyl, -OC 3-6 Cycloalkyl, OH, C 1-4 C optionally substituted with alkoxy, OH, or 1 to 4 halo 1-6 Alkyl, NH2, C 1-6 Alkyl COOC 1-2 alkyl, phenyl, or benzyl, wherein the phenyl or benzyl is optionally substituted with one to three substituents independently selected from —OCH, CF, CH, CN, and halo, or pyridine optionally substituted with CHOH; or

[0009] [ka] and Q 4 But R 11 , CF3, OR 11 , OCF3, halo, or CN; m in each occurrence is independently 0, 1, or 2; n in each occurrence is independently 0, 1, 2, or 3; R 10 is independently selected at each occurrence from H; halo; OH; carboxyl; —S(O)OH; C optionally substituted with 1 to 4 OH or OCH 1-4 alkyl; C optionally substituted with 1 or 2 halo 3-6 Cycloalkyl; C 1-4 Haloalkyl;-C 2-6 Alkynyl; 1-benzyl-4-piperidyl; 2-tert-butoxy-2-oxo-ethyl; benzyloxyphenyl optionally substituted with one or two halo; O(C 1-2 alkyl) r OCH3;NH2;2,3-Dihydro-1H-indene;2,3-Dihydrobenzo[b][1,4]dioxine;Benzo[d][1,3]dioxole optionally substituted with one or two halo;Indoline optionally substituted with C(O)CH3;C 1-4 Alkyl, C 1-4 5- or 6-membered heteroaryl or 9- or 10-membered bicyclic heteroaryl optionally substituted with alkoxy, halo, or phenyl; independently, halo, C 1-4 Alkoxy, hydroxy, C 1-4 Alkyl, CF3, CN, -(CH2)2C(O)OH, -C(O)NHNH2, -OCF3, -N(CH3)2, C 3-6 Cycloalkyl, -OC 3-6 Cycloalkyl, -OCH2C 3-6 Cycloalkyl, 5- or 6-membered heteroaryl, -(CH2) n (5- or 6-membered heterocyclyl), or -(CH2) n phenyl optionally substituted with 1 to 3 substituents selected from phenyl, said phenyl optionally substituted with 1 or 2 halo; R 11 But H, C 1-4 alkyl, or cyclopropyl; L 2 But, A 1’ , A2’ or A 3’ and C 1-3 is an alkylene or a bond; p, in each occurrence, is independently 0 to 3; q is 1 to 5; r is 1, 2, or 3; R 15 But H or C 1-3 is alkyl, The compound is not a compound of the formula:

[0010] [ka] During the ceremony, L 1 -CH2NHCH2-, -CH2NH-, -NH-,

[0011] [ka] is selected from the group consisting of R 5 is H or CH3, Compounds, or pharmaceutically acceptable salts thereof, are provided wherein Z is H or CH3.

[0012] In a second aspect, there is provided a compound of formula IV,

[0013] [ka] During the ceremony, R 1 and R 2 However, independently, H, C 1-4 alkyl, and F; R 3 and R 4 is independently either H or F; R 5 But H, C 1-4 alkyl, or cyclopropyl; Z is H, C 1-4alkyl, OH, cyclopropyl, CHOH, CHNH, or CHOCHphenyl; Y is CH2, CH(CH3), O, or S; A 1 , A 2 , A 3 , A 4 , and A 5 are each independently C or N, and A 1 , A 2 , A 3 , A 4 , or A 5 At most two of are N, Q 1 But -(CH2) n O(CH2) n R 10 ;-(CH2) n NR 15 (CH2) n R 10 ;-CN;-(CH2) n CO2R 10 ;-B(OR 10 )2;Boronic acid ethylene glycol ester;Boronic acid pinacol ester;Boronic acid propylene-1,3-diol ester;Boronic acid 2,2-dimethyl-propylene-1,3-diol ester;-N3;C 1-6 Alkyl;-C 2-6 Alkenyl;-C 2-6 Alkynyl;Halo;-C(O)-R 10 ;-C(O)NR 15 R 10 ; -S(O) m (CH2) n R 10 ;-(CH2) n NR 15 S(O) m (CH2) n R 10 ;-(CH2) n S(O) m NR 15 (CH2) n R 10 ;-(CH2) n NHCONR 15 R 10 ;-NHCO(CH2)n R 10 ;-NHCOOR 10 ;NO2;CF3;C 3-6 Cycloalkyl; -NH(C=NH)CHCN; 5- or 6-membered heterocyclyl optionally substituted with 1 to 4 halo or phenyl; indoline optionally substituted with 1 or 2 CH; (CH)CF, CH, or (CH) n imidazolidinone, pyrrolidinone, imidazolidine-2,5-dione, pyrrolidine-2,5-dione, or oxazolidin-2-one optionally substituted with phenyl, the phenyl being optionally substituted with OH or OCH; indolin-2-one, isoindolin-1-one, or benzimidazol-2-one optionally substituted with one or two substituents independently selected from OCH, CH, and halo; phenyl, 5- or 6-membered heteroaryl, or 9- or 10-membered bicyclic heteroaryl, the phenyl and heteroaryl being independently selected from halo, OC, 1-4 Haloalkyl, C 3-6 Cycloalkyl, -OC 3-6 Cycloalkyl, OH, C 1-4 C optionally substituted with alkoxy, OH, or 1 to 4 halo 1-6 Alkyl, NH2, C 1-6 Alkyl COOC 1-2 alkyl, phenyl, or benzyl, wherein the phenyl or benzyl is optionally substituted with one to three substituents independently selected from —OCH, CF, CH, CN, and halo, or pyridine optionally substituted with CHOH; or

[0014] [ka] and Q 2 But R 11 , CF3, OR 11 , OCF3, halo, or CN; m is 0, 1, or 2; n is 0, 1, 2, or 3; R 10 is optionally substituted with H; halo; OH; carboxyl; -S(O)2OH; C optionally substituted with 1 to 4 OH or OCH3 1-4 alkyl; C optionally substituted with 1 or 2 halo 3-6 Cycloalkyl; C 1-4 Haloalkyl;-C 2-6 Alkynyl; 1-benzyl-4-piperidyl; 2-tert-butoxy-2-oxo-ethyl; benzyloxyphenyl optionally substituted with one or two halo; O(C 1-2 alkyl) r OCH3;NH2;2,3-Dihydro-1H-indene;2,3-Dihydrobenzo[b][1,4]dioxine;Benzo[d][1,3]dioxole optionally substituted with one or two halo;Indoline optionally substituted with C(O)CH3;C 1-4 Alkyl, C 1-4 5- or 6-membered heteroaryl or 9- or 10-membered bicyclic heteroaryl optionally substituted with alkoxy, halo, or phenyl; independently, halo, C 1-4 Alkoxy, hydroxy, C 1-4 Alkyl, CF3, CN, -(CH2)2C(O)OH, -C(O)NHNH2, -OCF3, -N(CH3)2, C 3-6 Cycloalkyl, -OC 3-6 Cycloalkyl, -OCH2C 3-6 Cycloalkyl, 5- or 6-membered heteroaryl, -(CH2) n (5- or 6-membered heterocyclyl), or -(CH2) n phenyl optionally substituted with 1 to 3 substituents selected from phenyl, said phenyl optionally substituted with 1 or 2 halo; R 11 But H, C 1-4 alkyl, or cyclopropyl; r is 1, 2, or 3; R 15 But H or C 1-3 a compound, or a pharmaceutically acceptable salt thereof.

[0015] In an alternative embodiment, the compound of formula I is

[0016] [ka] During the ceremony, R 1 and R 2 However, independently, H, C 1-4 alkyl, and F; R 3 and R 4 is independently either H or F; R 5 But H, C 1-4 alkyl, or cyclopropyl; Z is H, C 1-4 alkyl, or cyclopropyl; A 1 , A 2 , A 3 , A 4 , and A 5 may each independently be C or N, and A 1 , A 2 , A 3 , A 4 , or A 5 At most two of are N, Q 1 But -(CH2) n O(CH2) n R 10 , -(CH2) n NH(CH2) n R 10 , -CN, -(CH2) n CO2R 10 , -B(OR 10 )2, ethylene glycol boronic acid ester, pinacol boronic acid ester, propylene-1,3-diol boronic acid ester, 2,2-dimethyl-propylene-1,3-diol boronic acid ester, -N3, C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, halo, -C(O)-R10 , -C(O)NHR 10 , -NH-NH2, -S(O) m (CH2) n R 10 , -(CH2) n NHS(O) m (CH2) n R 10 , -(CH2) n S(O) m NH(CH2) n R 10 , -(CH2) n NHCONHR 10 , -NHCO(CH2) n R 10 , -NHCOOR 10 or an aryl or heteroaryl selected from phenyl, pyrrole, imidazole, pyrazole, triazole, furan, thiophene, oxazole, isoxazole, thiazole, isothiazole, pyridine, pyridazine, pyrimidine and pyrazine, the aryl and heteroaryl optionally substituted with halo or OCF3 substituents; Q 2 But R 11 , CF3, OR 11 , OCF3, halo, or CN; m is 0, 1, or 2; n is 0, 1, or 2; R 10 C optionally substituted with H; hydroxy; carboxyl; OH 1-4 Alkyl; C 3-6 Cycloalkyl;4,4-difluorocyclohexyl;C 1-4 Haloalkyl; 3-(1H)-benzimidazol-2-yl; thiazole optionally substituted with methyl; methyl(phenyl)carbamoyl; 1-benzyl-4-piperidyl; 8-quinolyl; 2-methoxyethyl; 3-methoxypropyl; 3-phenyl-1,2,4-oxadiazol-5-yl; 2-tert-butoxy-2-oxo-ethyl; benzyloxyphenyl; independently, halo, C 1-4 Alkoxy, hydroxy, C 1-4Alkyl, CF3, CN, (CH2)2C(O)OH, C(O)NHNH2, OCF3, N(CH3)2, C 3-6 Cycloalkyl, -OC 3-6 Cycloalkyl and OCH2C 3-6 phenyl optionally substituted with 1 to 3 substituents selected from cycloalkyl; R 11 But H, C 1-4 alkyl, or cyclopropyl, or a pharmaceutically acceptable salt thereof.

[0017] In a third aspect, there is provided a compound of formula V:

[0018] [ka] During the ceremony, R 1 and R 2 However, independently, H, C 1-4 alkyl, and F; R 3 and R 4 is independently either H or F; R 5a But H, C 1-4 alkyl, cyclopropyl, or a protecting group; X is OH, -OR 6 , or

[0019] [ka] and R 6 But C 1-4 is alkyl, D and E are each independently O or S; R 7 But H, C 1-4 alkyl, phenyl or benzyl (wherein the phenyl and benzyl are independently halo, C 1-4optionally substituted with 1 or 2 substituents selected from alkyl, trifluoromethyl, amino, C1-4 alkylamino, and di-C1-4 alkylamino; R 8 and R 9 However, independently, H, C 1-4 alkyl, or phenyl optionally substituted by one or two substituents independently selected from halo, C alkyl, trifluoromethyl, amino, C alkylamino, and di-C alkylamino; Z is H, C 1-4 alkyl, OH, cyclopropyl, CHOH, CHNH, or CHOCHphenyl; Y is CH2, CH(CH3), O or S; A 1 , A 2 , A 3 , A 4 , and A 5 are each independently C or N, and A 1 , A 2 , A 3 , A 4 , or A 5 At most two of are N, Q 1 But -(CH2) n O(CH2) n R 10 ;-(CH2) n NR 15 (CH2) n R 10 ;-CN;-(CH2) n CO2R 10 ;-B(OR 10 )2;Boronic acid ethylene glycol ester;Boronic acid pinacol ester;Boronic acid propylene-1,3-diol ester;Boronic acid 2,2-dimethyl-propylene-1,3-diol ester;-N3;C 1-6 Alkyl;-C 2-6 Alkenyl;-C 2-6 Alkynyl;Halo;-C(O)-R 10 ;-C(O)NR 15 R 10 ; -S(O)m (CH2) n R 10 ;-(CH2) n NR 15 S(O) m (CH2) n R 10 ;-(CH2) n S(O) m NR 15 (CH2) n R 10 ;-(CH2) n NHCONR 15 R 10 ;-NHCO(CH2) n R 10 ;-NHCOOR 10 ;NO2;CF3;C 3-6 Cycloalkyl; -NH(C=NH)CHCN; 5- or 6-membered heterocyclyl optionally substituted with 1 to 4 halo or phenyl; indoline optionally substituted with 1 or 2 CH; (CH)CF, CH, or (CH) n imidazolidinone, pyrrolidinone, imidazolidine-2,5-dione, pyrrolidine-2,5-dione, or oxazolidin-2-one optionally substituted with phenyl, the phenyl being optionally substituted with OH or OCH; indolin-2-one, isoindolin-1-one, or benzimidazol-2-one optionally substituted with one or two substituents independently selected from OCH, CH, and halo; phenyl, 5- or 6-membered heteroaryl, or 9- or 10-membered bicyclic heteroaryl, the phenyl and heteroaryl being independently selected from halo, OC, 1-4 Haloalkyl, C 3- 6 Cycloalkyl, -OC 3-6 Cycloalkyl, OH, C 1-4 C optionally substituted with alkoxy, OH, or 1 to 4 halo 1-6 Alkyl, NH2, C 1-6 Alkyl COOC 1-2alkyl, phenyl, or benzyl, wherein the phenyl or benzyl is optionally substituted with one to three substituents independently selected from —OCH, CF, CH, CN, and halo, or pyridine optionally substituted with CHOH; or

[0020] [ka] and Q 2 But R 11 , CF3, OR 11 , OCF3, halo, or CN; m is 0, 1, or 2; n is 0, 1, 2, or 3; R 10 is optionally substituted with H; halo; OH; carboxyl; -S(O)2OH; C optionally substituted with 1 to 4 OH or OCH3 1-4 alkyl; C optionally substituted with 1 or 2 halo 3-6 Cycloalkyl; C 1-4 Haloalkyl;-C 2-6 Alkynyl; 1-benzyl-4-piperidyl; 2-tert-butoxy-2-oxo-ethyl; benzyloxyphenyl optionally substituted with 1 or 2 halo; O(C 1-2 alkyl) r OCH3;NH2;2,3-Dihydro-1H-indene;2,3-Dihydrobenzo[b][1,4]dioxine;Benzo[d][1,3]dioxole optionally substituted with one or two halo;Indoline optionally substituted with C(O)CH3;C 1-4 Alkyl, C 1-4 5- or 6-membered heteroaryl or 9- or 10-membered bicyclic heteroaryl optionally substituted with alkoxy, halo, or phenyl; independently, halo, C 1-4 Alkoxy, hydroxy, C 1-4 Alkyl, CF3, CN, -(CH2)2C(O)OH, -C(O)NHNH2, -OCF3, -N(CH3)2, C 3-6Cycloalkyl, -OC 3-6 Cycloalkyl, -OCH2C 3-6 cycloalkyl, 5- or 6-membered heteroaryl, -(CH2) n (5- or 6-membered heterocyclyl), or -(CH2) n phenyl optionally substituted with 1 to 3 substituents selected from phenyl, said phenyl optionally substituted with 1 or 2 halo; 11 But H, C 1-4 alkyl, or cyclopropyl; r is 1, 2, or 3; R 15 But H or C 1-3 is alkyl, When X is OH, R 5a must be a protecting group, The compound is: tert-butyl-3-[1-[(3-bromophenyl)methyl]-2-methoxy-2-oxo-ethyl]pyrrolidine-1-carboxylate, 3-(3-bromophenyl)-2-[1-tert-butoxycarbonylpyrrolidin-3-yl]-2-methyl-propanoic acid, tert-butyl-3-[2-[4-benzyl-2-oxo-oxazolidin-3-yl]-1-[(3-bromophenyl)methyl]-2-oxo-ethyl]pyrrolidine-1-carboxylate, tert-butyl-3-[(2-[4-benzyl-2-oxo-oxazolidin-3-yl]-1-[(3-nitrophenyl)methyl]-2-oxo-ethyl]pyrrolidine-1-carboxylate, 3-(3-bromophenyl)-2-[1-tert-butoxycarbonylpyrrolidin-3-yl]propanoic acid, 2-[1-tert-butoxycarbonylpyrrolidin-3-yl]-3-(3-nitrophenyl)propanoic acid, tert-butyl-3-[1-[(3-bromophenyl)methyl]-2-tert-butoxy-2-oxo-ethyl]pyrrolidine-1-carboxylate, tert-butyl-3-[1-[(3-bromophenyl)methyl]-2-tert-butoxy-1-methyl-2-oxo-ethyl]pyrrolidine-1-carboxylate, tert-butyl-3-[(2-tert-butoxy-1-[(3-nitrophenyl)methyl]-2-oxo-ethyl]pyrrolidine-1-carboxylate, tert-butyl-3-[2-tert-butoxy-1-[(3-formylphenyl)methyl]-2-oxo-ethyl]pyrrolidine-1-carboxylate, tert-butyl-3-[2-tert-butoxy-1-[(3-formylphenyl)methyl]-1-methyl-2-oxo-ethyl]pyrrolidine-1-carboxylate, tert-butyl-3-[1-[[3-(aminomethyl)phenyl]methyl]-2-tert-butoxy-2-oxo-ethyl]pyrrolidine-1-carboxylate, tert-butyl-3-[1-[(3-aminophenyl)methyl]-2-tert-butoxy-2-oxo-ethyl]pyrrolidine-1-carboxylate, tert-butyl-3-[2-tert-butoxy-1-[[3-(hydroxymethyl)phenyl]methyl]-2-oxo-ethyl]pyrrolidine-1-carboxylate, [3-[3-tert-butoxy-2-[1-tert-butoxycarbonylpyrrolidin-3-yl]-3-oxo-propyl]phenyl]boronic acid, A compound, or a salt thereof, is provided which is not tert-butyl-3-[2-tert-butoxy-1-[(3-hydroxyphenyl)methyl]-2-oxo-ethyl]pyrrolidine-1-carboxylate.

[0021] In an alternative embodiment, the compound of formula II is

[0022] [ka] During the ceremony, R 1 and R 2 However, independently, H, C1-4 alkyl, and F; R 3 and R 4 is independently either H or F; R 5a But H, C 1-4 alkyl, cyclopropyl, or a protecting group; X is OH, -OR 6 , or

[0023] [ka] and R 6 But C 1-4 is alkyl, D and E are each independently O or S; R 7 But H, C 1-4 alkyl, phenyl, or benzyl, wherein the phenyl and benzyl are optionally substituted with one or two substituents independently selected from halo, C alkyl, trifluoromethyl, amino, C alkylamino, and di-C alkylamino; R 8 and R 9 However, independently, H, C 1-4 alkyl, or phenyl optionally substituted by one or two substituents independently selected from halo, C alkyl, trifluoromethyl, amino, C alkylamino, and di-C alkylamino; Z is H, C 1-4 alkyl, or cyclopropyl; A 1 , A 2 , A 3 , A 4 , and A 5 may each independently be C or N, and A 1 , A 2 , A 3 , A 4 , or A 5 At most two of are N, Q 1 But -(CH2)n O(CH2) n R 10 , -(CH2) n NH(CH2) n R 10 , -CN, -(CH2) n CO2R 10 , -B(OR 10 )2, ethylene glycol boronic acid ester, pinacol boronic acid ester, propylene-1,3-diol boronic acid ester, 2,2-dimethyl-propylene-1,3-diol boronic acid ester, -N3, C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, halo, -C(O)-R 10 , -C(O)NHR 10 , -NH-NH2, -S(O) m (CH2) n R 10 , -(CH2) n NHS(O) m (CH2) n R 10 , -(CH2) n S(O) m NH(CH2) n R 10 , -(CH2) n NHCONHR 10 , -NHCO(CH2) n R 10 , -NHCOOR 10 or an aryl or heteroaryl selected from phenyl, pyrrole, imidazole, pyrazole, triazole, furan, thiophene, oxazole, isoxazole, thiazole, isothiazole, pyridine, pyridazine, pyrimidine and pyrazine, the aryl and heteroaryl optionally substituted with halo or OCF3 substituents; Q 2 But R 11 , CF3, OR 11 , OCF3, halo, or CN; m is 0, 1, or 2; n is 0, 1, or 2; R 10C optionally substituted with H; hydroxy; carboxyl; OH 1-4 Alkyl; C 3-6 Cycloalkyl;4,4-difluorocyclohexyl;C 1-4 Haloalkyl; 3-(1H)-benzimidazol-2-yl; thiazole optionally substituted with methyl; methyl(phenyl)carbamoyl; 1-benzyl-4-piperidyl; 8-quinolyl; 2-methoxyethyl; 3-methoxypropyl; 3-phenyl-1,2,4-oxadiazol-5-yl; 2-tert-butoxy-2-oxo-ethyl; benzyloxyphenyl; independently, halo, C 1-4 Alkoxy, hydroxy, C 1-4 Alkyl, CF3, CN, (CH2)2C(O)OH, C(O)NHNH2, OCF3, N(CH3)2, C 3-6 Cycloalkyl, -OC 3-6 Cycloalkyl and OCH2C 3-6 phenyl optionally substituted with 1 to 3 substituents selected from cycloalkyl; R 11 But H, C 1-4 alkyl, or cyclopropyl; When X is OH, R 5a must be a protecting group, or a salt thereof is provided.

[0024] In a fourth aspect, there is provided a compound of the formula:

[0025] [ka] During the ceremony, R 1 and R 2 However, independently, H, C 1-4 alkyl, and F; R 3 and R 4 is independently either H or F; R 5a But H, C 1-4 alkyl, cyclopropyl, or a protecting group; D and E are each independently O or S; R 7 But H, C 1-4 alkyl, phenyl, or benzyl, wherein the phenyl and benzyl are optionally substituted with one or two substituents independently selected from halo, C alkyl, trifluoromethyl, amino, C alkylamino, and di-C alkylamino; R 8 and R 9 However, independently, H, C 1-4 alkyl, or phenyl optionally substituted by one or two substituents independently selected from halo, C alkyl, trifluoromethyl, amino, C alkylamino, and di-C alkylamino; Z is H, C 1-4 alkyl, OH, cyclopropyl, CHOH, CHNH, or CHOCHphenyl; Provided is a compound, or a salt thereof, wherein the compound is not:

[0026] [ka]

[0027] In a fifth aspect, there is provided the use of a compound of Formula I, II, IV, V or VI in the preparation of an oligomer.

[0028] In a sixth aspect, there is provided an oligomer prepared from a compound of Formula I, II, IV, V or VI.

[0029] In a seventh aspect, there is provided a pharmaceutical composition comprising the aforementioned oligomer.

[0030] In one embodiment of the compound of Formula III, L 1 But, A 1 , A 2 Or A 3 Bonded with, and bonded with, -(CH2) p NHC(O)NH(CH2) p -, -(CH2)p C(O)NH(CH2) p -, -(CH2) p S(O)2NH(CH2) p -, -(CH2) q -, -(CH2) p NH(CH2) p -

[0031] [ka] Selected from or or L 1 A on one ring 2 Rank and A 3 together with the carbon at position 1 to form the following fused ring:

[0032] [ka] R 1 , R 1’ , R 2- and R 2’ However, at each occurrence, independently, H, C 1-4 selected from alkyl and F; R 3 , R 3’ , R 4 and R 4’ is, in each occurrence, independently either H or F; R 5 and R 5’ However, at each occurrence, independently, H, C 1-4 alkyl, or cyclopropyl; Z and Z', in each occurrence, independently represent H, C 1-4 alkyl, OH, or cyclopropyl; Y and Y′ in each occurrence are independently CH, O, or S; A 1 , A 1’ , A 2 , A 2’ , A 3 , A 3’ , A 4 , A 4’ , A 5 , A 5’ and A6 is independently, in each occurrence, C or N, and A on each ring 1 , A 2 , A 3 , A 4 and A 5 At most two of the 1’ , A 2’ , A 3’ , A 4’ , A 5’ and A 6 At most two of are N, Q 3 and Q 3’ may, at each occurrence, independently be H, -(CH2) n O(CH2) n R 10 , -(CH2) n NH(CH2) n R 10 , -CN, -(CH2) n CO2R 10 , C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, halo, -C(O)-R 10 , -C(O)NHR 10 , -S(O) m (CH2) n R 10 , -(CH2) n NHS(O) m (CH2) n R 10 , -(CH2) n S(O) m NH(CH2) n R 10 , -(CH2) n NHCONHR 10 , -NHCO(CH2) n R 10 -NHCOOR 10, NO2, cyclopropyl, -O-cyclopropyl, CF3, OCF3, OH, or an aryl or heteroaryl selected from phenyl, pyrrole, imidazole, pyrazole, triazole, furan, thiophene, oxazole, isoxazole, thiazole, isothiazole, pyridine, pyridazine, pyrimidine, and pyrazine, wherein the aryl or heteroaryl is substituted with halo or OCF3; Q 4 But R 11 , CF3, OR 11 , OCF3, halo, or CN; m in each occurrence is independently 0, 1, or 2; n in each occurrence is independently 0, 1, or 2; R 10 is independently selected at each occurrence from H; halo; hydroxy; carboxyl; C optionally substituted with OH; 1-4 Alkyl; C 3-6 Cycloalkyl;4,4-difluorocyclohexyl;C 1-4 Haloalkyl; 3-(1H)-benzimidazol-2-yl; thiazole optionally substituted with methyl; Methyl(phenyl)carbamoyl; 1-benzyl-4-piperidyl; 8-quinolyl; 2-methoxyethyl; 3-methoxypropyl; 3-phenyl-1,2,4-oxadiazol-5-yl; 2-tert-butoxy-2-oxo-ethyl; benzyloxyphenyl; independently, halo, C 1-4 Alkoxy, hydroxy, C 1-4 Alkyl, CF3, CN, (CH2)2C(O)OH, C(O)NHNH2, OCF3, N(CH3)2, C 3-6 Cycloalkyl, -OC 3-6 Cycloalkyl and OCH2C 3-6 phenyl optionally substituted with 1 to 3 substituents selected from cycloalkyl; R 11 But H, C 1-4 alkyl, or cyclopropyl; L 2 But, A 1’ , A2’ or A 3’ and C 1-3 is an alkylene or a bond; p, in each occurrence, is independently 0 to 3; q is 1 to 5; or a pharmaceutically acceptable salt thereof; The compound is not a compound of the formula:

[0033] [ka] During the ceremony, L 1 -CH2NHCH2-, -CH2NH-, -NH-,

[0034] [ka] is selected from the group consisting of R 5 is H or CH3, Z is H or CH3.

[0035] In compounds of formula III, L 1 may be attached at different points on each ring. In one embodiment of the compound of formula III, L 1 is the A on each ring 2 A on one ring 2 and A on the other ring 3 A on each ring 3 or A on one ring 1 and A on the other ring 2 In a further embodiment, L 1 is the A on each ring 2 A on one ring 2 and A on the other ring 3 or A on each ring 3 In a preferred embodiment, L 1 A on each ring 2 Combine with.

[0036] In one embodiment of the compound of Formula III, L 1 However, the following Bond, -(CH2) p NHC(O)NH(CH2) p -, -(CH2) p C(O)NH(CH2) p -, -(CH2) p S(O)2NH(CH2) p -, -(CH2) q -

[0037] [ka] Selected from or or L 1 A on one ring 2 Rank and A 3 together with the carbon at position 1 to form the following fused ring:

[0038] [ka] Form.

[0039] In one embodiment of the compound of Formula III, L 1 But -(CH2) p NH(CH2) p -,

[0040] [ka] or at least one Q 3 But it is not H.

[0041] In one embodiment of the compound of Formula III, L 1 is the bond, -(CH2) p NHC(O)NH(CH2) p -, -(CH2) p C(O)NH(CH2) p -, -(CH2) p S(O)2NH(CH2) p -, -(CH2) q -, -(CH 2p NH(CH2) p -,

[0042] [ka] or L 1 is at position A on one ring 2 and A 3 together with the carbon atom to form the following fused ring:

[0043] [ka] In a further embodiment, L 1 is a bond, -NHC(O)NH-, -NHC(O)NHCH2-, -C(O)NH-, -S(O)2NH-, -CH2CH2CH2-, -NH-

[0044] [ka] or L 1 A on one ring 2 Rank and A 3 together with the carbon at position 1 to form the following fused ring:

[0045] [ka] In a preferred embodiment, L 1 is a bond, -NHC(O)NH-, -NHC(O)NHCH2-, -NH-

[0046] [ka] or L 1 A on one ring 2 Rank and A 3 together with the carbon at position 1 to form the following fused ring:

[0047] [ka] Form.

[0048] In one embodiment of the compound of Formula III, L 1 However, the following

[0049] [ka] In a further embodiment, L 1 However, the following

[0050] [ka] In still further embodiments, L 1 However, the following

[0051] [ka] In a preferred embodiment, L 1 However, the following

[0052] [ka] is selected from.

[0053] In one embodiment of the compound of Formula III, on each ring, R 1 and R 2 are both H or R 1 and R 2 One of them is H and the other is CH3.

[0054] In one embodiment of the compound of Formula III, on each ring, R 3 and R 4 are both H or R 3 and R 4 Both are F.

[0055] In one embodiment of the compound of Formula III, at each occurrence, R 5 But it's H.

[0056] In one embodiment of the compound of formula III, Z at each occurrence is H, CH 3 or OH.

[0057] In one embodiment of the compound of Formula III, on each ring, A 1 , A 2 , A 3 , A 4 and A 5 are all C or on one ring, A 1 , A 2 , A 3 , A 4 and A 5 Two of them are N and the other A 1 , A 2 , A 3 , A 4 and A 5 are all C or on each ring, A 3 is N and all others are C. In a preferred embodiment, on each ring, A 1 , A 2 , A 3 , A 4 and A 5 are all C.

[0058] In one embodiment of the compound of Formula III, at each occurrence, Q 3 is H, F, CF3 or CN. In a preferred embodiment, at each occurrence, Q 3 is H, F or CF3.

[0059] In one embodiment, the compound of formula III is:

[0060] [ka] Selected from or or a pharmaceutically acceptable salt thereof.

[0061] In one embodiment, the compound of formula IV is R 1 and R 2 However, independently, H, C 1-4 alkyl, and F; R 3and R 4 is independently either H or F; R 5 But H, C 1-4 alkyl, or cyclopropyl; Z is H, C 1-4 alkyl, OH, or cyclopropyl; Y is CH, O, or S; A 1 , A 2 , A 3 , A 4 , and A 5 are each independently C or N, and A 1 , A 2 , A 3 , A 4 , or A 5 At most two of are N, Q 1 But -(CH2) n O(CH2) n R 10 , -(CH2) n NH(CH2) n R 10 , -CN, -(CH2) n CO2R 10 , -B(OR 10 )2, ethylene glycol boronic acid ester, pinacol boronic acid ester, propylene-1,3-diol boronic acid ester, 2,2-dimethyl-propylene-1,3-diol boronic acid ester, -N3, C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, halo, -C(O)-R 10 , -C(O)NHR 10 , -NH-NH2, -S(O)m(CH2) n R 10 , -(CH2) n NHS(O) m (CH2) n R 10 , -(CH2) n S(O) m NH(CH2) n R 10 , -(CH2) n NHCONHR 10, -NHCO(CH2) n R 10 , -NHCOOR 10 , NO2, or aryl or heteroaryl selected from phenyl, pyrrole, imidazole, pyrazole, triazole, furan, thiophene, oxazole, isoxazole, thiazole, isothiazole, pyridine, pyridazine, pyrimidine, and pyrazine, wherein the aryl and heteroaryl are optionally substituted with halo or OCF3 substituents; Q 2 But R 11 , CF3, OR 11 , OCF3, halo, or CN; m is 0, 1, or 2; n is 0, 1, or 2; R 10 C optionally substituted with H; halo; hydroxy; carboxyl; OH 1-4 Alkyl; C 3-6 Cycloalkyl;4,4-difluorocyclohexyl;C 1-4 Haloalkyl; 3-(1H)-benzimidazol-2-yl; thiazole optionally substituted with methyl; methyl(phenyl)carbamoyl; 1-benzyl-4-piperidyl; 8-quinolyl; 2-methoxyethyl; 3-methoxypropyl; 3-phenyl-1,2,4-oxadiazol-5-yl; 2-tert-butoxy-2-oxo-ethyl; benzyloxyphenyl; independently, halo, C 1-4 Alkoxy, hydroxy, C 1-4 Alkyl, CF3, CN, (CH2)2C(O)OH, C(O)NHNH2, OCF3, N(CH3)2, C 3-6 Cycloalkyl, -OC 3-6 Cycloalkyl and OCH2C 3-6 phenyl optionally substituted with 1 to 3 substituents selected from cycloalkyl; R 11 But H, C 1-4 alkyl, or cyclopropyl.

[0062] In a further embodiment, the compound according to formula IV is the following compound of formula IV':

[0063] [ka] or a pharmaceutically acceptable salt thereof.

[0064] In one embodiment, the compound according to formula I is a compound of formula I':

[0065] [ka] or a pharmaceutically acceptable salt thereof.

[0066] In another embodiment, the compound according to Formula I or IV is

[0067] [ka] or a pharmaceutically acceptable salt thereof.

[0068] In yet a further embodiment, the compound of formula I or IV is

[0069] [ka] Selected from or or a pharmaceutically acceptable salt thereof.

[0070] In some embodiments, the compound of Formula I or IV is

[0071] [ka]

[0072] [ka]

[0073] [ka]

[0074] [ka]

[0075] [ka] or a pharmaceutically acceptable salt thereof.

[0076] In still further embodiments, the compound of formula I or IV is

[0077] [ka] Selected from or or a pharmaceutically acceptable salt thereof.

[0078] In a further embodiment, the compound of formula I or IV is

[0079] [ka] or a pharmaceutically acceptable salt thereof.

[0080] In one embodiment of the compound of Formula I, I', IV or IV', Q 1 But -(CH2) n O(CH2) n R 10 ;-(CH2) n NR 15 (CH2) n R 10 ;-CN;-(CH2) n CO2R 10 ;-N3;C 1-6 Alkyl;-C 2-6 Alkenyl;-C 2-6 Alkynyl;Halo;-C(O)-R 10 ;-C(O)NR15 R 10 ;-S(O) m (CH2) n R 10 ; -(CH2) n NR 15 S(O) m (CH2) n R 10 ;-(CH2) n S(O) m NR 15 (CH2) n R 10 ;-(CH2) n NHCONR 15 R 10 ;-NHCO(CH2) n R 10 ;CF3;C 3-6 Cycloalkyl; -NH(C=NH)CHCN; 5- or 6-membered heterocyclyl optionally substituted with 1 to 4 halo or phenyl; indoline optionally substituted with 1 or 2 CH; (CH)CF or (CH) n imidazolidinone or imidazolidine-2,5-dione optionally substituted with phenyl, the phenyl optionally substituted with OH; indolin-2-one or benzimidazol-2-one optionally substituted with CH; phenyl, 5- or 6-membered heteroaryl, or 9-membered bicyclic heteroaryl, where the phenyl and heteroaryl are independently halo, OC 1-4 Haloalkyl, C 3-6 Cycloalkyl, -OC 3-6 Cycloalkyl, C 1-4 C optionally substituted with alkoxy, OH or halo 1-6 optionally substituted with 1 or 2 substituents selected from alkyl, phenyl, or benzyl, wherein the phenyl or benzyl is optionally substituted with 1 to 3 substituents independently selected from —OCH and halo; or

[0081] [ka] is selected from.

[0082] In one embodiment of the compound of Formula I, I', IV or IV', Q 2 is H, CH3, F or Br.

[0083] In one embodiment of the compound of Formula I, I', IV or IV', R 5 is H. In another embodiment of the compound of Formula I, I', IV or IV', R 1 , R 2 , R 3 and R 4 At least one of is F. In still another embodiment of the compound of formula I, I', IV or IV', R 1 , R 2 , R 3 , and R 4 At least two of are F. In a further embodiment of the compound of Formula I, I', IV or IV', R 1 , R 2 , R 3 and R 4 are all H. In a further embodiment of the compound of Formula I, I', IV or IV', R 1 , R 2 is H and R 3 and R 4 is F.

[0084] In one embodiment of a compound of Formula I, I', IV or IV', Z is selected from H, methyl, CHOH, CHNH and CHOCHphenyl. In yet another embodiment of a compound of Formula I, I', IV or IV', Z is selected from H, methyl, ethyl, n-propyl and i-propyl.

[0085] In one embodiment, the compound according to Formula I or IV is

[0086] [ka] is selected from R 13 is selected from OH, OCH3, CH3, and NH2; R 14is selected from Br, OH, C(O)H, CHOH, CHNH, and B(OH), or a pharmaceutically acceptable salt thereof.

[0087] In one embodiment of the compound of formula V, R 1 and R 2 However, independently, H, C 1-4 alkyl, and F; R 3 and R 4 is independently either H or F; R 5a But H, C 1-4 alkyl, cyclopropyl, or a protecting group; X is OH, -OR 6 , or

[0088] [ka] and R 6 But C 1-4 is alkyl, D and E are each independently O or S; R 7 But H, C 1-4 alkyl, phenyl, or benzyl, wherein the phenyl and benzyl are optionally substituted with one or two substituents independently selected from halo, C alkyl, trifluoromethyl, amino, C alkylamino, and di-C alkylamino; R 8 and R 9 However, independently, H, C 1-4 alkyl, or phenyl optionally substituted by one or two substituents independently selected from halo, C alkyl, trifluoromethyl, amino, C alkylamino, and di-C alkylamino; Z is H, C 1-4 alkyl, OH, or cyclopropyl; Y is CH, O, or S; A 1, A 2 , A 3 , A 4 , and A 5 are each independently C or N, and A 1 , A 2 , A 3 , A 4 , or A 5 At most two of are N, Q 1 But -(CH2) n O(CH2) n R 10 , -(CH2) n NH(CH2) n R 10 , -CN, -(CH2) n CO2R 10 , -B(OR 10 )2, ethylene glycol boronic acid ester, pinacol boronic acid ester, propylene-1,3-diol boronic acid ester, 2,2-dimethyl-propylene-1,3-diol boronic acid ester, -N3, C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, halo, -C(O)-R 10 , -C(O)NHR 10 , -NH-NH2, -S(O)m(CH2) n R 10 , -(CH2) n NHS(O) m (CH2) n R 10 , -(CH2) n S(O) m NH(CH2) n R 10 , -(CH2) n NHCONHR 10 , -NHCO(CH2) n R 10 , -NHCOOR 10, NO2, or aryl or heteroaryl selected from phenyl, pyrrole, imidazole, pyrazole, triazole, furan, thiophene, oxazole, isoxazole, thiazole, isothiazole, pyridine, pyridazine, pyrimidine, and pyrazine, wherein the aryl and heteroaryl are optionally substituted with halo or OCF3 substituents; Q 2 But R 11 , CF3, OR 11 , OCF3, halo, or CN; m is 0, 1, or 2; n is 0, 1, or 2; R 10 C optionally substituted with H; halo; hydroxy; carboxyl; OH 1-4 Alkyl; C 3-6 Cycloalkyl;4,4-difluorocyclohexyl;C 1-4 Haloalkyl; 3-(1H)-benzimidazol-2-yl; thiazole optionally substituted with methyl; methyl(phenyl)carbamoyl; 1-benzyl-4-piperidyl; 8-quinolyl; 2-methoxyethyl; 3-methoxypropyl; 3-phenyl-1,2,4-oxadiazol-5-yl; 2-tert-butoxy-2-oxo-ethyl; benzyloxyphenyl; independently, halo, C 1-4 Alkoxy, hydroxy, C 1-4 Alkyl, CF3, CN, (CH2)2C(O)OH, C(O)NHNH2, OCF3, N(CH3)2, C 3-6 Cycloalkyl, -OC 3-6 Cycloalkyl and OCH2C 3-6 phenyl optionally substituted with 1 to 3 substituents selected from cycloalkyl; R 11 But H, C 1-4 alkyl, or cyclopropyl; When X is OH, R 5a must be a protecting group, The compound is: tert-butyl-3-[1-[(3-bromophenyl)methyl]-2-methoxy-2-oxo-ethyl]pyrrolidine-1-carboxylate, 3-(3-bromophenyl)-2-[1-tert-butoxycarbonylpyrrolidin-3-yl]-2-methyl-propanoic acid, tert-butyl-3-[2-[4-benzyl-2-oxo-oxazolidin-3-yl]-1-[(3-bromophenyl)methyl]-2-oxo-ethyl]pyrrolidine-1-carboxylate, tert-butyl-3-[(2-[4-benzyl-2-oxo-oxazolidin-3-yl]-1-[(3-nitrophenyl)methyl]-2-oxo-ethyl]pyrrolidine-1-carboxylate, 3-(3-bromophenyl)-2-[1-tert-butoxycarbonylpyrrolidin-3-yl]propanoic acid, 2-[1-tert-butoxycarbonylpyrrolidin-3-yl]-3-(3-nitrophenyl)propanoic acid, tert-butyl-3-[1-[(3-bromophenyl)methyl]-2-tert-butoxy-2-oxo-ethyl]pyrrolidine-1-carboxylate, tert-butyl-3-[1-[(3-bromophenyl)methyl]-2-tert-butoxy-1-methyl-2-oxo-ethyl]pyrrolidine-1-carboxylate, tert-butyl-3-[(2-tert-butoxy-1-[(3-nitrophenyl)methyl]-2-oxo-ethyl]pyrrolidine-1-carboxylate, tert-butyl-3-[2-tert-butoxy-1-[(3-formylphenyl)methyl]-2-oxo-ethyl]pyrrolidine-1-carboxylate, tert-butyl-3-[2-tert-butoxy-1-[(3-formylphenyl)methyl]-1-methyl-2-oxo-ethyl]pyrrolidine-1-carboxylate, tert-butyl-3-[1-[[3-(aminomethyl)phenyl]methyl]-2-tert-butoxy-2-oxo-ethyl]pyrrolidine-1-carboxylate, tert-butyl-3-[1-[(3-aminophenyl)methyl]-2-tert-butoxy-2-oxo-ethyl]pyrrolidine-1-carboxylate, tert-butyl-3-[2-tert-butoxy-1-[[3-(hydroxymethyl)phenyl]methyl]-2-oxo-ethyl]pyrrolidine-1-carboxylate, [3-[3-tert-butoxy-2-[1-tert-butoxycarbonylpyrrolidin-3-yl]-3-oxo-propyl]phenyl]boronic acid, tert-butyl-3-[2-tert-butoxy-1-[(3-hydroxyphenyl)methyl]-2-oxo-ethyl]pyrrolidine-1-carboxylate, not

[0089] In one embodiment of the compound of formula V, Q 1 But -CN;-(CH2) n CO2R 10 ;Boronic acid ethylene glycol ester;Boronic acid pinacol ester;Boronic acid propylene-1,3-diol ester;Boronic acid 2,2-dimethyl-propylene-1,3-diol ester;-N3;C 1-6 Alkyl;-C 2-6 Alkenyl;-C 2-6 Alkynyl; -C(O)NR 15 R 10 ;-S(O) m (CH2) n R 10 ;-(CH2) n NR 15 S(O) m (CH2) n R 10 ;-(CH2) n S(O) m NR 15 (CH2) n R 10 ;-(CH2) n NHCONR 15 R 10 ;-NHCO(CH2) n R 10 ;-NHCOOR 10 ;CF3;C 3-6Cycloalkyl; -NH(C=NH)CHCN; 5- or 6-membered heterocyclyl optionally substituted with 1 to 4 halo or phenyl; indoline optionally substituted with 1 or 2 CH; (CH)CF, CH, or (CH) n imidazolidinone, pyrrolidinone, imidazolidine-2,5-dione, pyrrolidine-2,5-dione, or oxazolidin-2-one optionally substituted with phenyl, the phenyl being optionally substituted with OH or OCH; indolin-2-one, isoindolin-1-one, or benzimidazol-2-one optionally substituted with one or two substituents independently selected from OCH, CH, and halo; phenyl, 5- or 6-membered heteroaryl, or 9- or 10-membered bicyclic heteroaryl, the phenyl and heteroaryl being independently selected from halo, OC, 1-4 Haloalkyl, C 3-6 Cycloalkyl, -OC 3-6 Cycloalkyl, OH, C 1-4 C optionally substituted with alkoxy, OH, or 1 to 4 halo 1-6 Alkyl, NH2, C 1-6 Alkyl COOC 1-2 alkyl, phenyl, or benzyl, wherein the phenyl or benzyl is optionally substituted with one to three substituents independently selected from —OCH, CF, CH, CN, and halo, or pyridine optionally substituted with CHOH; or

[0090] [ka] is.

[0091] In one embodiment of the compound of Formula II, V or VI, R 5amay represent a protecting group ("PG") for the pyrrolidine nitrogen. The following protecting groups may be considered (the abbreviation for PG is given in parentheses): carbamates such as tert-butyloxycarbonyl (Boc), carboxybenzyl (Cbz), 9-fluorenylmethoxycarbonyl (Fmoc), allyloxycarbonyl (Alloc), trimethylsilylethoxycarbonyl (Teoc), and trichloroethoxycarbonyl (Troc); amides such as trifluoroacetamide (Tfa) and benzamide (Bz); amines such as benzylamine (Bn) and triphenylmethylamine (Tphm); and sulfonamides such as p-toluenesulfonamide. In particular, PG may be selected from Boc, Cbz, Fmoc, Alloc, Teoc, Troc, Tfa, Bz, Bn, Tphm, and p-toluenesulfonamide. 5a is Boc.

[0092] In another embodiment of the compound of Formula II or V, X is:

[0093] [ka] is selected from the group consisting of In the formula, R 12 However, at each occurrence, H or C 1-4 It is alkyl.

[0094] The compound of formula VI is an alternative intermediate that can be used in the preparation of compounds of formula I, I', III, IV, or IV', and other oligomeric compounds. The chirality of the compound of formula VI can be selected to direct the stereoselectivity of the alkylation step (Scheme 2). In embodiments of the compound of formula VI, R7 is benzyl, R 1 , R 2 , R 3 , R 4 , R 5 , R 8 and R 9 is other than H. In alternative embodiments, either D or E is other than O.

[0095] Preferred aryl and heteroaryl groups: phenyl, pyrrole, imidazole, pyrazole, triazole, furan, thiophene, oxazole, isoxazole, thiazole, isothiazole, pyridine, pyridazine, pyrimidine, pyrazine, benzothiophene, indazole, indole, imidazopyridine, benzothiazole and benzimidazole. DETAILED DESCRIPTION OF THE INVENTION

[0096] As noted above, one aspect of the disclosure includes the use of a compound according to Formula I, I', II, IV, IV', V, or VI in the preparation of an oligomer. In a further aspect, the disclosure includes an oligomer prepared from a compound according to Formula I, I', II, IV, IV', V, or VI. In one embodiment, the oligomer comprises two pyrrolidine moieties. In yet another embodiment, the oligomer comprises three pyrrolidine moieties. Accordingly, a further aspect of the disclosure includes a pharmaceutical composition comprising such an oligomer.

[0097] In another embodiment, there is provided a pharmaceutically acceptable composition comprising a compound of Formula I, I', III, IV or IV', or a pharmaceutically acceptable salt thereof, and at least one of a pharmaceutically acceptable carrier, diluent, or excipient.

[0098] In one embodiment, there is provided a method of treating a patient in need of treatment for cardiovascular disease, comprising administering an effective amount of a compound of Formula I, I', III, IV or IV', or a pharmaceutically acceptable salt thereof. In one embodiment, there is provided a method of treating a patient in need of treatment for elevated plasma levels of Lp(a), comprising administering an effective amount of a compound of Formula I, I', III, IV or IV', or a pharmaceutically acceptable salt thereof.

[0099] In one embodiment, there is provided a compound of Formula I, I', III, IV, or IV', or a pharmaceutically acceptable salt thereof, for use in therapy.

[0100] In one embodiment, there is provided a compound of Formula I, I', III, IV, or IV', or a pharmaceutically acceptable salt thereof, for use in the treatment of cardiovascular disease. In one embodiment, there is provided a compound of Formula I, I', III, IV, or IV', or a pharmaceutically acceptable salt thereof, for use in the treatment of elevated plasma levels of Lp(a).

[0101] In one embodiment, there is provided the use of a compound of Formula I, I', III, IV, or IV', or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of cardiovascular disease. In one embodiment, there is provided the use of a compound of Formula I, I', III, IV, or IV', or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of Lp(a) plasma levels.

[0102] The term "halogen" or "halo" refers to fluorine, chlorine, bromine, or iodine.

[0103] "C 1-n The term "alkyl" refers to a straight or branched chain saturated hydrocarbon containing 1 to n carbon atoms. Examples of C1-4 alkyl groups include, but are not limited to, methyl, ethyl, propyl, butyl, and tert-butyl. Examples of C1-3 alkyl groups include, but are not limited to, methyl, ethyl, and propyl. A C1-2 alkyl group is methyl or ethyl.

[0104] "C 1-3 The term "alkylene" refers to a divalent C 1-3 Refers to an alkyl group.

[0105] "C 1-4 The term "haloalkyl" refers to a C, as defined herein, substituted with one or more halogens. 1-4 Refers to alkyl groups. 1-4 Examples of haloalkyl groups include, but are not limited to, trifluoromethyl, difluoromethyl, and pentafluoroethyl.

[0106] "C 1-4 The term "alkoxy" refers to a straight or branched chain saturated hydrocarbon containing 1 to 4 carbon atoms containing a terminal "O" in the chain, i.e., -O(alkyl). 1-4 Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, and butoxy.

[0107] "C 2-6 The term "alkenyl" refers to a straight or branched chain hydrocarbon containing 2 to 6 carbon atoms and at least one double bond.

[0108] "C 2-6 The term "alkynyl" refers to a straight or branched chain hydrocarbon group containing 2 to 6 carbon atoms and at least one triple bond.

[0109] The term "C3-6 cycloalkyl" refers to a monocyclic saturated carbocyclic ring containing from 3 to 6 carbon atoms, specifically cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0110] The term "heteroaryl" preferably refers to a monocyclic aromatic ring containing one or more heteroatoms selected from N, S, and O. Examples of 5-membered heteroaryls include, but are not limited to, pyrazole, triazole, and thiazole. Examples of 6-membered heteroaryls include, but are not limited to, pyridine and pyridazine.

[0111] The term "bicyclic heteroaryl" preferably refers to a bicyclic aromatic ring containing one or more heteroatoms selected from N, S, and O. Examples of 9-membered bicyclic heteroaryls include, but are not limited to, indole, isoindole, indazole, and pyrazolopyridine. Examples of 10-membered bicyclic heteroaryls include, but are not limited to, quinoline and chromene.

[0112] The term "5- or 6-membered heterocyclyl" refers to a 5- or 6-membered monocyclic saturated ring containing one or more heteroatoms, for example, pyrrolidine and piperidine.

[0113] As used herein, the term "oligomer" refers to a compound having at least two pyrrolidine moieties of Formula I, I', II, IV, IV', or V. As used herein, "pyrrolidine moiety" refers to an optionally substituted pyrrolidine. The pyrrolidine moieties in an oligomer may be the same or different.

[0114] As used herein, the term "elevated Lp(a) plasma levels" refers to plasma levels of Lp(a) that are greater than or equal to about 50 mg / dL. The compounds or oligomers provided herein can be used therapeutically to reduce Lp(a) plasma levels.

[0115] The term "pharmaceutically acceptable salt" as used herein refers to a salt of a compound that is acceptable for clinical and / or veterinary use. Examples of pharmaceutically acceptable salts and general methodologies for their preparation can be found in "Handbook of Pharmaceutical Salts: Properties, Selection and Use" P. Stahl, et al., 2nd Revised Edition, Wiley-VCH, 2011 and S. M. Berge, et al., "Pharmaceutical Salts", Journal of Pharmaceutical Sciences, 1977, 66(1), 1-19. In particular, the compounds of Formulas I, I', IV, and IV' can be zwitterions, monoacid, diacid, or triacid addition salts.

[0116] The pharmaceutical composition of the present invention can be prepared using pharmaceutically acceptable additives. The term "pharmaceutically acceptable" refers to one or more carriers, diluents, and / or excipients that are compatible with other components of the composition and are not pharmacologic harmful to patients. Examples of pharmaceutical compositions and processes for their preparation are well known to those skilled in the art and can be found, for example, in "Remington: The Science and Practice of Pharmacy", Loyd, V., et al. Eds., 22nd Ed., Mack Publishing Co., 2012.

[0117] As used herein, the term "effective amount" refers to a dosage that is effective to treat a disorder. The effective amount for a particular patient can be determined by a skilled medical practitioner.

[0118] As used herein, the terms "treating," "treat," or "treatment" include slowing, alleviating, preventing, or reversing the progression or severity of an existing symptom, disorder, condition, or disease. As used herein, "treating cardiovascular disease" means slowing, alleviating, preventing, or reversing the progression of a disease of the heart or blood vessels.

[0119] As used herein, the term "patient" refers to a mammal. Preferably, the patient is a human.

[0120] The pharmaceutical composition may be formulated as a tablet or capsule for oral administration, as a solution for oral administration, or as a solution for injection, hi one embodiment, the composition is suitable for oral administration.

[0121] Certain abbreviations are defined as follows: "ACN" refers to acetonitrile, "Apo" refers to apolipoprotein, "BOC" refers to tert-butoxycarbonyl, "Bn" refers to benzyl, "BSA" refers to bovine serum albumin, "CDI" refers to carbonyldiimidazole, "DAD" refers to diode array detector, "DCM" refers to dichloromethane or methylene chloride, and "de" refers to diastereomeric excess. "DMA" refers to N,N-dimethylacetamide, "DMAP" refers to 4-dimethylaminopyridine, "DMEA" refers to dimethylethylamine, "DMEM" refers to Dulbecco's Modified Eagle's Medium, "DMF" refers to N,N-dimethylformamide, "DMSO" refers to dimethyl sulfoxide, and "ee" refers to enantiomeric excess."EACA" refers to epsilon-aminocaproic acid or 6-aminocaproic acid, "ELISA" refers to enzyme-linked immunosorbent assay, "equiv" refers to equivalent, "EtO" refers to diethyl ether, "EtOAc" refers to ethyl acetate, "EtOH" refers to ethanol or ethyl alcohol, "Ex" refers to an example, and "FBS" refers to fetal bovine serum. "h" refers to hours, "HATU" refers to 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate, "HEC" refers to hydroxy ethyl cellulose, "HEK" refers to human embryonic kidney, "HepG2" refers to human hepatocellular carcinoma cell line, "HEPES" refers to 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid, "HLB" refers to hydrophilic lipophilic balance, "HPLC" refers to high-performance liquid chromatography, "HRP" refers to horseradish peroxidase, and "IC." 50" refers to the concentration of a drug that produces 50% of the maximum inhibitory response possible for that drug, "IPA" refers to isopropanol, "min" refers to minutes, "MeOH" refers to methanol or methyl alcohol, "MTBE" refers to methyl tert-butyl ether, "RP-HPLC / MS" refers to reverse-phase high performance liquid chromatography with mass spectrometry, "RT" refers to room temperature, "SFC" refers to supercritical fluid chromatography, "SPA" refers to scintillation proximity assay, and "t (R) " refers to retention time, "TEA" refers to triethylamine, "THF" refers to tetrahydrofuran, "TMB" refers to 3,3',5,5'-teramethylbenzidine, and "Tris" refers to tris(hydroxymethyl)aminomethane.

[0122] The individual isomers, enantiomers, and diastereomers may be separated or resolved by those skilled in the art at any convenient point in the synthesis of the compounds listed below by methods known to those skilled in the art, such as selective crystallization techniques or chiral chromatography.

[0123] Compounds of Formula I, I', II, III, IV, IV', or V, or any of the depicted formulae, can be readily converted and isolated as pharmaceutically acceptable salts. Salt formation can be achieved by adding a pharmaceutically acceptable acid to form an acid addition salt, or by adding a pharmaceutically acceptable base to form a base addition salt. Salts can also be formed simultaneously during deprotection of nitrogen or oxygen, i.e., removal of a protecting group. Examples, reactions, and conditions for salt formation are known to those skilled in the art.

[0124] Compounds of Formula I, I', II, III, IV, IV', or V, or any of the depicted formulae, or salts thereof, may be prepared by a variety of procedures, some of which are illustrated in the preparations and examples below. Specific synthetic steps of each of the routes described may be combined in different ways or combined with steps of different routes to prepare compounds or salts of the invention. The products of each step in the preparations below can be recovered by conventional methods, including extraction, evaporation, precipitation, chromatography, filtration, trituration, and crystallization.

[0125] In the following schemes, all substituents are as previously defined unless otherwise indicated. The reagents and starting materials are readily available to those skilled in the art. The following schemes, preparations and examples are provided to further illustrate the present invention without limiting its scope. The compounds of the formulas shown above, or salts thereof, can be prepared by using starting materials or intermediates with the corresponding desired stereochemical configuration.

[0126] Scheme 1

[0127] [ka] Scheme 1 illustrates the preparation of compounds of the present invention starting from ester intermediate 1, which is treated with a strong organic base such as lithium diisopropylamide or potassium bis(trimethylsilyl)amide at −78° C., followed by addition of halide 18 to give 2 in step 1. In step 2, the ester can be hydrolyzed using a strong inorganic base such as lithium hydroxide or sodium hydroxide to give 3, with R 5a If R is a protecting group, it can be removed in step 3 to give acid 4 (e.g., R 5a =Boc, it can be removed under acidic conditions).

[0128] Scheme 2

[0129] [ka] Scheme 2 illustrates the preparation of compounds of the present invention using a chiral auxiliary to direct the stereoselectivity of the alkylation of intermediate 5, which is prepared in step 1 at 0 °C from acid 24 via acid chloride and heterocycle 25. In step 2, intermediate 5 is treated with a strong organic base such as lithium bis(trimethylsilyl)amide at low temperature (-78 to 0 °C), followed by addition of halide 18 to give 6. In step 3, the chiral auxiliary is hydrolyzed using aqueous H2O2 and LiOH at 0 °C, after which the reaction is quenched with NaHSO3 to give acid 3. Optionally, 3 is esterified to give 2 in step 4a, or R 5a If is a protecting group, it can be removed to give 4 (step 4b).

[0130] Scheme 3

[0131] [ka] Scheme 3 shows functional groups that can be prepared from amino compound 8, which can be prepared by reducing nitro compound 7 with hydrogen gas using palladium on carbon, or by coupling 13 with ammonium hydroxide using a copper catalyst, e.g., copper(II) acetylacetonate, 2,2,6,6-tetramethyl-3,5-heptanedione, and a carbonate base at elevated temperature. Amino compound 8 can then be reacted with an alkyl halide and a carbonate base to give 9. Furthermore, 9 is accessible by reductive amination with compound 8 (e.g., using an aldehyde and a reducing agent such as sodium triacetoxyborohydride or sodium cyanoborohydride). Urea compound 10 can be prepared by treating 8 with potassium cyanate (R 10 =H to give 10), or 8 to 1,1'-carbonyldiimidazole, followed by the amine HNR 10 The amide compound 11 can be prepared by treating 8 with an acid chloride (R 10 C(O)Cl) and an organic base such as triethylamine, or by reacting 8 with a carboxylic acid (R 10 Compound 8 can be prepared by reacting it with a sulfonyl chloride (R COH) under amide coupling conditions (e.g., using HATU and an organic base). 10 Reaction with HCl (SO2Cl) and an organic base gives sulfonamide 12. Oxidation of aniline 8 with sodium nitrite and HCl followed by reduction with stannous chloride gives hydrazine compound 54. Reaction of 8 with tert-butyl nitrite and azidotrimethylsilane gives azide 55.

[0132] Scheme 4

[0133] [ka] Q 1When Q is a group capable of undergoing metal-halogen exchange (e.g., Cl, Br, I, or -OSO2CF3-), compound 13, numerous derivatives are accessible via various functional group transformations. Sonogashira coupling at elevated temperatures using an alkyne, a palladium catalyst, and an organic base provides aryl alkynes, such as 14 (the product of coupling with ethynyl(trimethyl)silane followed by removal of the trimethylsilyl group under basic conditions). Q of 13 1 When is bromine, urea and amino heterocycles can be coupled onto the aryl ring using a palladium catalyst and sodium tert-butoxide to give 15 and 16, respectively. Negishi coupling of 13 with, for example, (2-tert-butoxy-2-oxoethyl)(chloro)zinc at elevated temperatures using an organozinc compound and a palladium catalyst gives 17. Aldehyde 22 can be prepared from 13 via catalytic carbonylation, and boronate 27 can be prepared by coupling 13 with, for example, bis(pinacolao)diboron, potassium acetate, and a palladium catalyst at elevated temperatures.

[0134] Scheme 5

[0135] [ka] Compound 13 can also be used to prepare sulfonamides 21, as shown in Scheme 5. In step 1, compound 13 is coupled with benzyl mercaptan using a palladium catalyst and an organic base at elevated temperature to give thioether 19, which is converted in step 2 to sulfonyl chloride 20 using 1,3-dichloro-5,5-dimethylhydantoin at 0° C. in a mixture of ACN, water, and acetic acid. The amine (HNR 10 ) and an organic base to prepare sulfonamide 21.

[0136] Scheme 6

[0137] [ka] Scheme 6 shows the synthesis of amines (HNR 10 2 shows the preparation of amine 23 from aldehyde 22, which is achieved by reductive amination using 24 and a reducing agent such as sodium triacetoxyborohydride. Amine 29 can be prepared from nitrile 28 by hydrogenation in the presence of a palladium-on-carbon catalyst.

[0138] Scheme 7

[0139] [ka] Scheme 7 illustrates the preparation of compound 32, which can be either an ether or a thioether. In step 1, intermediate 30 is brominated via a silyl enol ether (prepared by treating intermediate 30 with lithium diisopropylamide at −78° C. and adding chlorotrimethylsilane) and N-bromosuccinimide to give bromide 31. In step 2, bromide 31 is reacted with 33 and a base (a carbonate base if 33 is a phenol, or sodium methoxide if 33 is a thiophenol).

[0140] Scheme 8

[0141] [ka] Scheme 8 illustrates the hydroxylation of intermediate 34. Intermediate 34 is first treated with lithium diisopropylamide at −78° C. and then with 3-phenyl-2-(phenylsulfonyl)-1,2-oxaziridine to give hydroxy compound 35.

[0142] Scheme 9

[0143] [ka] Scheme 9 illustrates the preparation of multimeric urea compounds 37, 39, and 40. Compound 37 can be prepared by reacting amino compound 36 with CDI. Disubstituted amino compound 38 [prepared by reductive amination of 36 with aldehyde 22 (Scheme 4) or, when p = 0, by Buchwald coupling of intermediate 13 (Scheme 4) with aniline intermediate 8 (Scheme 3)] is reacted with amino compound 36 and CDI to give trisubstituted urea 39. Alternatively, amine 38 can be reacted with sodium cyanate followed by 1-2 equivalents of TFA to give urea 40.

[0144] Scheme 10

[0145] [ka] Scheme 10 shows the preparation of tetrameric compound 41 in which amine 38 undergoes reductive amination using an oxyaldehyde and a reducing agent such as sodium triacetoxyborohydride.

[0146] Scheme 11

[0147] [ka] Scheme 11 shows the preparation of dimeric compound 42 in which intermediate 13 is coupled with boronate 27 using a palladium catalyst and a carbonate base at elevated temperature. Intermediate 13 can also be coupled with a protected pyrazole boronic acid (56) using a palladium catalyst and a carbonate base at elevated temperature to give intermediate 57, which can be deprotected and coupled with another equivalent of intermediate 13 using copper(II) acetate and pyridine as the solvent at elevated temperature to give 58.

[0148] Scheme 12

[0149] [ka] Scheme 12 illustrates the preparation of cyclic urea compounds 43, 44, and 45. Intermediate 13 is coupled with tetrahydro-2(1H)-pyrimidinone using a palladium catalyst and sodium tert-butoxide at elevated temperature to give 43, or with imidazolidin-2-one to give 44. Intermediate 13 is also coupled with 1,3-dihydrobenzimidazol-2-one using cuprous iodide, N,N'-dimethylethylenediamine, and a carbonate base at elevated temperature to give 45.

[0150] Scheme 13

[0151] [ka] Scheme 13 illustrates the preparation of compound 47. Intermediate 36 is reacted with chloroacetyl chloride and an organic base to give chloroacetyl intermediate 46, which is then dimerized using a carbonate base at elevated temperature to give dioxopiperazine compound 47.

[0152] Scheme 14

[0153] [ka] Scheme 14 illustrates the preparation of compound 50. Alcohol compound 48 first undergoes a Mitsunobu reaction with (3-hydroxyphenyl)acetate, diethyl azodicarboxylate, and triphenylphosphine, and the acetyl group is removed using a carbonate base in MeOH to give intermediate 49. Another Mitsunobu reaction of intermediate 48 with phenol 49 gives intermediate 50.

[0154] Scheme 15

[0155] [ka] Scheme 15 illustrates the preparation of compound 53 from intermediates 51 and 22 via a one-pot procedure. In step 1, fluoro-nitro compound 51 is reacted with 2-phenylethanamine at elevated temperature.N Ar reaction to give intermediate 52. Na2S2O4 is then added to the reaction, followed by the addition of aldehyde intermediate 22 (see Scheme 4), and heating is continued to give cyclic compound 53.

[0156] Scheme 16

[0157] [ka] Scheme 16 shows the preparation of compound 59 (prepared by click chemistry using copper sulfate, sodium ascorbate, and benzoic acid in a mixture of tert-butanol and water to cyclize alkyne 14 and azide 55 to the 1,2,3-triazole), compound 61 (prepared by coupling aniline 8 with acid 60 under amide coupling conditions, e.g., using HATU in the presence of an organic base), and compound 63 (prepared by reacting aniline 8 with sulfonyl chloride 62 in the presence of an organic base).

[0158] Scheme 17

[0159] [ka] Scheme 17 illustrates the preparation of propyl-linked dimeric compound 66. Aryl halide 13 is coupled with boronate 67 using a palladium catalyst and a carbonate base at elevated temperature to give compound 64, which then undergoes a Heck coupling with another equivalent of halide 13 using a palladium catalyst and an organic base at elevated temperature to give alkene 65. The alkene is then reduced under hydrogen gas using a palladium-on-carbon catalyst to give 66.

[0160] Preparation 1 tert-Butyl (3R)-3-[2-methoxy-2-oxo-1-[[3-(2-trimethylsilylethynyl)phenyl]methyl]ethyl]pyrrolidine-1-carboxylate

[0161] [ka] To a mixture of tert-butyl (3R)-3-[1-[(3-bromophenyl)methyl]-2-methoxy-2-oxo-ethyl]pyrrolidine-1-carboxylate (prepared essentially as described in WO 2020 / 247429, 1.95 g, 4.73 mmol), cuprous iodide (0.90 g, 0.47 mmol), 1,3-bis(diphenylphosphino)propane (390 mg, 0.94 mmol), and tris(dibenzylideneacetone)dipalladium(0) (433 mg, 0.47 mmol) in TEA (39 mL) was added ethynyl(trimethyl)silane (2.67 mL, 1.86 g, 18.9 mmol). The resulting mixture was stirred at 120° C. overnight. The mixture was cooled to room temperature, filtered through Celite®, and washed with EtOAc. The solvent was removed in vacuo to give 4.2 g of a brown oil, which was then purified via silica gel chromatography using a gradient of 10-40% MTBE in hexanes to give the title compound (1.80 g, 84%) as a brown oil. ES-MS m / z 374 (M-tBu+H).

[0162] Preparation 2 2-[(3R)-1-tert-butoxycarbonylpyrrolidin-3-yl]-3-(3-ethynylphenyl)propanoic acid - Isomer 1 and Isomer 2

[0163] [ka] Aqueous NaOH (2 M, 21 mL, 42 mmol) was added to a solution of tert-butyl (3R)-3-[2-methoxy-2-oxo-1-[[3-(2-trimethylsilylethynyl)phenyl]methyl]ethyl]pyrrolidine-1-carboxylate (1.8 g, 4.2 mmol) in THF (21 mL) and MeOH (10 mL). The mixture was stirred at room temperature for 3 days, then EtOAc was added, followed by aqueous HCl (1 M) until pH = 3. The aqueous phase was extracted with EtOAc, and the organic layer was dried over Na2SO4. The solvent was removed under reduced pressure, and the residue was loaded onto an HLB column. The column was eluted with water, then ACN, and the ACN fraction was concentrated to give a brown oil containing the title compound as a mixture of diastereomers.

[0164] The diastereomers were separated by SFC [Column: 20 × 250 mm, SFC 2-ethylpyridine stationary phase, 5 μm, Mobile phase: 10% in CO (10 mM NH4HCO3 in MeOH, pH 8)] to give Isomer 1 (610 mg, 42%, first-eluting isomer) as a yellow solid and Isomer 2 (454 mg, 27%, second-eluting isomer) as a light brown solid. Both Isomer 1 and Isomer 2: ES-MS m / z 288 (M-tBu+H).

[0165] Preparation 3 tert-Butyl (3R)-3-[1-[(6-chloro-3-pyridyl)methyl]-2-methoxy-2-oxo-ethyl]pyrrolidine-1-carboxylate

[0166] [ka] Lithium diisopropylamide (2.0 M in THF / heptane / ethylbenzene, 0.49 mL, 0.99 mmol) was added dropwise to a −78° C. solution of tert-butyl (3R)-3-(2-methoxy-2-oxo-ethyl)pyrrolidine-1-carboxylate (prepared essentially as described in WO 2020 / 247429, 200 mg, 0.82 mmol) in THF (4 mL) under N 2 , and the reaction was stirred at −78° C. for 1 hour. A solution of 5-(bromomethyl)-2-chloropyridine (357 mg, 1.64 mmol) in THF (2 mL) was then added, and the reaction was stirred at −78° C. for 30 minutes. The reaction was quenched with saturated aqueous NH 4 Cl and extracted with EtOAc. The organic phase was separated, dried over MgSO 4 , and concentrated in vacuo. The residue was purified by silica gel column chromatography using a gradient of 25-100% EtOAc in hexanes to give the title compound (mixture of diastereomers, 256 mg, 84%) as a colorless oil. ES / MS m / z 313 (M-tBu+H).

[0167] Preparation 4 2-[(3R)-1-tert-butoxycarbonylpyrrolidin-3-yl]-3-(6-chloro-3-pyridyl)propanoic acid - Isomer 1 and Isomer 2

[0168] [ka] To a solution of tert-butyl (3R)-3-[1-[(6-chloro-3-pyridyl)methyl]-2-methoxy-2-oxo-ethyl]pyrrolidine-1-carboxylate (256 mg, 0.69 mmol) in THF (4 mL) was added LiOH (1 M in water, 4 mL, 4 mmol). The reaction was stirred at room temperature overnight and then at 50° C. for 1 hour. The reaction was quenched with 1N HCl and extracted with EtOAc. The organic phase was separated, dried over MgSO4, and concentrated in vacuo. The residue was purified via silica gel chromatography using 10% MeOH in DCM, and the diastereomers were then separated by chiral SFC [Column: Chiralpak AD20 × 250 mm, 5 μm, Mobile phase: 25% (MeOH + 0.2% DMEA) in CO, 65 mL / min] to give Isomer 1 (107 mg, 43%, first-eluting isomer) and Isomer 2 (70 mg, 28%, second-eluting isomer) of the title compound. Both Isomer 1 and Isomer 2: ES-MS m / z 299 (M-tBu+H).

[0169] Preparation 5 (2S)-3-(3-bromo-5-methyl-phenyl)-2-[(3R)-1-tert-butoxycarbonylpyrrolidin-3-yl]propanoic acid

[0170] [ka] Lithium bis(dimethylsilyl)amide (1.0 M in 6.8 mL of THF, 6.8 mmol) was added to a solution of tert-butyl (3R)-3-[2-[(4S)-4-benzyl-2-oxo-oxazolidin-3-yl]-2-oxo-ethyl]pyrrolidine-1-carboxylate (prepared essentially as described in WO 2020 / 247429, 2.2 g, 5.7 mmol) in THF (40 mL) at 0 ° C. The mixture was stirred for 30 minutes, and then a solution of 1-bromo-3-(bromomethyl)-5-methyl-benzene (1.6 g, 6.2 mmol) in THF (6.6 mL) was added dropwise. The resulting mixture was allowed to reach room temperature and stirred overnight. The mixture was quenched with saturated aqueous NH Cl and extracted with EtOAc. The organic phases were combined, washed with saturated aqueous NaCl, dried over Na2SO4, filtered, and concentrated to dryness. To the residue was added THF (39 mL) and water (7.4 mL), and the mixture was cooled to 0°C. Aqueous hydrogen peroxide (3.1 M, 4.8 mL, 57 mmol) was added, followed by a solution of LiOH (0.24 g, 10 mmol) in water (11 mL). The reaction was stirred at 0°C for 50 minutes, and then the reaction was cooled to 0°C with NaHSO4. 3× The mixture was quenched by the addition of HCl and the mixture was allowed to warm to room temperature. The mixture was extracted with EtOAc, and the organics were then washed with saturated aqueous NaCl, dried over Na2SO4, filtered, and evaporated to dryness. The residue was purified via silica gel chromatography using a gradient of 10-40% EtOAc in hexanes + 1% acetic acid to afford the title compound (1.4 g, 45%) as a white solid. ES-MS m / z 355, 357 (M-tBu+H).

[0171] Preparation 6 (2S)-3-(3-amino-5-methyl-phenyl)-2-[(3R)-1-tert-butoxycarbonylpyrrolidin-3-yl]propanoic acid

[0172] [ka] To a mixture of (2S)-3-(3-bromo-5-methyl-phenyl)-2-[(3R)-1-tert-butoxycarbonylpyrrolidin-3-yl]propanoic acid (0.37 g, 0.68 mmol), sodium azide (0.088 g, 1.4 mmol), and L-proline (0.10 g, 0.88 mmol) in DMSO (3.4 mL) was added CuO (97 mg, 0.68 mmol). The mixture was purged with nitrogen and heated at 100 °C overnight. The mixture was cooled to room temperature, saturated aqueous NH4Cl was added, and the mixture was extracted with EtOAc. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified via reverse-phase chromatography using a gradient of 20–50% ACN in water to afford the title compound (0.11 g, 46%) as a pale yellow solid. ES-MS m / z 249 (M-Boc+H)

[0173] Preparation 7 (2S)-2-[(3R)-1-tert-butoxycarbonylpyrrolidin-3-yl]-3-(3-methyl-5-ureido-phenyl)propanoic acid

[0174] [ka] To a solution of (2S)-3-(3-amino-5-methyl-phenyl)-2-[(3R)-1-tert-butoxycarbonylpyrrolidin-3-yl]propanoic acid (90 mg, 0.26 mmol) in acetic acid (2.1 mL) was added potassium cyanide (0.105 g, 1.29 mmol) in water (1.7 mL). The mixture was stirred at room temperature for 30 minutes and then concentrated. The reaction was acidified with HCl (1N aqueous) and extracted with EtOAc. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was passed through a pad of silica gel eluting with EtOH and then purified by reverse-phase HPLC (Column: XBridge® C18, 19 × 100 mm, 5 μm, mobile phase gradient: 20-40% ACN in 20 mM aqueous NH4HCO3, pH 9) to give the title compound (62 mg, 59%) as a white solid. ES-MS m / z 392 (M+H).

[0175] Preparation 8 tert-Butyl (4-(cyanomethyl)-3,3-difluoro-pyrrolidine-1-carboxylate

[0176] [ka] Methanesulfonyl chloride (8.7 mL, 110 mmol) was slowly added to a solution of tert-butyl-3,3-difluoro-4-(hydroxymethyl)pyrrolidine-1-carboxylate (prepared essentially as described in McAlpine, I.; et al. J. Org. Chem. 2015, 80, 7266-7274; 13.6 g, 57.3 mmol) in TEA (16 mL, 115 mmol) at 0 °C under a nitrogen atmosphere, and the mixture was stirred at 0 °C for 1.5 hours. Water was added at 0 °C, and the mixture was extracted with EtOAc. The combined organic layers were dried over Na SO , filtered, and concentrated. The residue was dissolved in DMF (260 mL), and potassium cyanide (14.5 g, 218 mmol) was added. The mixture was heated at 75 °C under nitrogen for 3 days and then cooled to room temperature. The mixture was then quenched with water and extracted with EtOAc. The combined organics were dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography using 10-40% acetone in hexanes to give the title compound (10.2 g, 54%). ES-MS (m / z) 191 (M+H-tert-butyl).

[0177] Preparation 9 2-[1-tert-butoxycarbonyl-4,4-difluoro-pyrrolidin-3-yl]acetic acid

[0178] [ka] Potassium hydroxide (40% mass in water, 63.5 mL, 628 mmol) was added to a solution of tert-butyl 4-(cyanomethyl)-3,3-difluoro-pyrrolidine-1-carboxylate (10.3 g, 31.4 mmol) in MeOH (125 mL), and the resulting mixture was heated to reflux for 17 h. The reaction was cooled to room temperature, and HCl (1 M aqueous) was added to pH 7, followed by citric acid (5% in water) to pH 3. The mixture was extracted with DCM, washed with saturated aqueous NaCl, and the organic layer was then passed through a phase separation cartridge. The eluent was concentrated to give the title compound (8.32 g, 90%). ES-MS (m / z): 264 (MH).

[0179] Preparation 10 tert-Butyl 4-[2-[(4S)-4-benzyl-2-oxo-oxazolidin-3-yl]-2-oxo-ethyl]-3,3-difluoro-pyrrolidine-1-carboxylate

[0180] [ka] To a solution of 2-[1-tert-butoxycarbonyl-4,4-difluoro-pyrrolidin-3-yl]acetic acid (7.51 g, 28.3 mmol) in anhydrous THF (75 mL) at 0 °C, TEA (9.9 mL) was added, followed by the dropwise addition of pivaloyl chloride (4.58 mL, 36.8 mmol). The reaction was stirred at 0 °C for 1 hour, and a solution of lithium chloride (1.52 g, 35.5 mmol) in anhydrous THF (82.6 mL) was added dropwise, followed by the dropwise addition of a solution of (S)-4-benzyl-2-oxazolidinone (5.07 g, 28.3 mmol) in anhydrous THF (82.6 mL). The mixture was stirred at 0 °C for 1.5 hours and then at room temperature for 20 hours. HCl (1 M, 70 mL) was added, and the aqueous layer was extracted with EtOAc. The organic layer was separated and dried over anhydrous Na2SO4, then filtered and concentrated under reduced pressure. The residue was purified via silica gel chromatography using a gradient of 0-100% EtOAc in hexanes to give the title compound (7.27 g, 61%). ES-MS m / z 369 (M+H-tert-butyl).

[0181] Preparation 11 tert-Butyl 4-[(1S)-2-[(4S)-4-benzyl-2-oxo-oxazolidin-3-yl]-1-[(3-bromophenyl)methyl]-2-oxo-ethyl]-3,3-difluoro-pyrrolidine-1-carboxylate

[0182] [ka] To a solution of tert-butyl 4-[2-[(4S)-4-benzyl-2-oxo-oxazolidin-3-yl]-2-oxo-ethyl]-3,3-difluoro-pyrrolidine-1-carboxylate (7.44 g, 17.5 mmol) in anhydrous THF (37 mL) at −78° C. was added lithium bis(trimethylsilyl)amide (1 M) in toluene (21 mL) dropwise. The reaction was stirred at −78° C. for 2 hours, and a solution of 3-bromobenzyl bromide (4.92 g, 19.3 mmol) in anhydrous THF (14.9 mL) was added dropwise. The reaction was stirred overnight at room temperature, then saturated aqueous NH4Cl was added and the aqueous layer was extracted with EtOAc. The organic layer was washed with saturated aqueous NaCl, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified via silica gel chromatography using a gradient of 10-40% EtOAc in hexanes to give the title compound (7.32 g, 70%). ES-MS m / z 537 / 539 (M+H-tert-butyl).

[0183] Preparation 12 (2S)-3-(3-Bromophenyl)-2-(1-tert-butoxycarbonyl-4,4-difluoro-pyrrolidin-3-yl)propanoic acid - Isomer 1 and Isomer 2

[0184] [ka] To a stirred solution of tert-butyl 4-[(1S)-2-[(4S)-4-benzyl-2-oxo-oxazolidin-3-yl]-1-[(3-bromophenyl)methyl]-2-oxo-ethyl]-3,3-difluoro-pyrrolidine-1-carboxylate (7.32 g, 12.3 mmol) in THF (123 mL) at 0 °C, hydrogen peroxide (35.5 wt% in water, 22.5 mL, 263 mmol) was added, followed by lithium hydroxide solution (1 M in water, 18.5 mL, 18.5 mmol). The mixture was stirred at 0 °C for 6.5 hours, then a solution of sodium bisulfite (15% in water) was added, and the reaction was warmed to room temperature. The pH was adjusted to 12 by the addition of NaOH (5N aqueous), and the aqueous mixture was extracted with EtOAc. The organic layer was washed with saturated aqueous NaCl, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified via silica gel chromatography using a gradient of 0-50% EtOAc in hexanes + 1% acetic acid to give the title compound (3.58 g, 65.5%). ES-MS m / z 378 / 380 (M+H-tert-butyl) as a mixture of diastereomers.

[0185] A portion (3.44 g) of the diastereomeric mixture was separated using chiral SFC chromatography (column: Chiralcel OJ (25 × 2 cm, 5 μm) at 40 °C, flow rate: 80 mL / min, mobile phase: isocratic 7% (IPA + 0.2% DMEA) in CO2 to give Isomer 1 (first-eluting isomer, 1.58 g, 46%, >98% de) and Isomer 2 (second-eluting isomer, 1.93 g, 56%, >95% de). Both isomers—ES-MS m / z 378 / 380 (M+H-tert-butyl).

[0186] Preparation 13 tert-Butyl (3R)-3-[(1S)-2-tert-butoxy-1-[[3-[(3-fluoro-5-methoxy-phenyl)methylamino]phenyl]methyl-2-oxo-ethyl]pyrrolidine-1-carboxylate

[0187] [ka] To a solution of tert-butyl (3R)-3-[(1S)-1-[(3-aminophenyl)methyl]-2-tert-butoxy-2-oxo-ethyl]pyrrolidine-1-carboxylate (prepared essentially as described in WO 2020 / 247429, 153 mg, 0.39 mmol) in DCM (4 mL) was added 3-fluoro-5-methoxy-benzaldehyde (0.091 g, 0.59 mmol) and sodium triacetoxyborohydride (0.17 g, 0.78 mmol). The reaction was stirred at room temperature for 1 hour, then saturated aqueous NaHCO was added, and the aqueous layer was extracted with DCM. The organic layer was washed with water, then saturated aqueous NaCl, dried over MgSO, filtered, and evaporated under reduced pressure. The residue was purified via reverse-phase HPLC [Column: XBridge™ C18 (19 × 100 mm, 5 μm), Mobile phase: Solvent A = 20 mM ammonium bicarbonate in water (pH 9), Solvent B = ACN, Flow rate: 25 mL / min] to give the title compound (155 mg, 75%). ES-MS m / z 529 (M+H).

[0188] The following were prepared essentially as described in Preparation 13 using the appropriate aldehyde:

[0189] [Table 1] A. Sodium cyanoborohydride is used as the reducing agent and MeOH or MeOH / THF is used as the solvent. The reaction is carried out at room temperature or at a temperature of 60-65°C. B. Silica gel chromatography using a gradient of EtOAc in hexanes C. Reversed-phase chromatography using a gradient of ACN in aqueous HClO (pH 9) (column: Claricep C-series)

[0190] Preparation 20 tert-Butyl (3R)-3-[(1S)-2-tert-butoxy-1-[[3-[(3-fluoro-5-methoxy-anilino]methyl]phenyl]methyl]-2-oxo-ethyl]pyrrolidine-1-carboxylate

[0191] [ka] To a solution of tert-butyl (3R)-3-[(1S)-2-tert-butoxy-1-[(3-formylphenyl)methyl]-2-oxo-ethyl]pyrrolidine-1-carboxylate (prepared essentially as described in WO 2020 / 247429, 425 mg, 1.05 mmol) in DCM (10 mL) was added 3-fluoro-5-methoxy-aniline (0.223 g, 1.58 mmol) and one drop of acetic acid. The reaction was stirred at room temperature for 1 hour, then sodium triacetoxyborohydride (0.456 g, 2.11 mmol) was added and stirring continued for 1 hour. Saturated aqueous NaHCO3 was added and the aqueous layer was extracted with DCM. The organic layer was washed with water, then saturated aqueous NaCl, and then dried over MgSO4. The mixture was filtered and evaporated under reduced pressure. The residue was purified via reverse phase chromatography [column: Claricep C-series, mobile phase: gradient of 70-100% ACN in aqueous NH4CO3 (pH 9)] to give the title compound (433 mg, 78%). ES-MS m / z 417 [M+H-(2×tert-butyl)]

[0192] The following were prepared essentially as described in Preparation 20 using the appropriate amine:

[0193] [Table 2] A. The aldehyde, amine, and catalyst toluenesulfonic acid in toluene were heated to reflux for 4 hours using a Dean-Stark trap. The solvent was removed, the residue was redissolved in MeOH, and sodium borohydride was added. B. RP-HPLC / MS; column XBridge™ C18 (10 x 100 mm, 5 μm), mobile phase—solvent A=20 mM ammonium bicarbonate in water (pH 9), solvent B=ACN, flow rate—25 mL / min

[0194] Preparation 23 (2S)-2-[(3R)-1-tert-butoxycarbonylpyrrolidin-3-yl]-3-[3-(2-fluoro-3-methoxy-phenyl)carbamoylamino]phenyl]propanoic acid

[0195] [ka] To a solution of (2S)-3-(3-bromophenyl)-2-[(3R)-1-tert-butoxycarbonylpyrrolidin-3-yl]propanoic acid (prepared essentially as described in WO 2020 / 247429, 200 mg, 0.50 mmol) in 1,4-dioxane (0.1 M, 5.021 mL), (2-fluoro-3-methoxyphenyl)urea (0.277 g, 1.51 mmol), tBuXPhos-Pd-G3 (0.040 g, 0.050 mmol), and sodium tert-butoxide (0.149 g, 1.51 mmol) were added. The mixture was heated at 100 ° C. under a nitrogen atmosphere for 4 hours, then diluted with NaOH (1 N aqueous) and extracted with EtOAc. The organic layer was discarded, and the aqueous layer was then acidified with HCl (1N aqueous) and extracted with EtOAc. The organic layer was dried over Na2SO4, then filtered and concentrated under reduced pressure. The residue was purified via silica gel chromatography using a gradient of 50-100% EtOAc in hexanes to give the title compound (88 mg, 32%). ES-MS m / z 502 (M+H).

[0196] The following were prepared essentially as described in Preparation 23 using the appropriate amine or urea:

[0197] [Table 3-1]

[0198] [Table 3-2]

[0199] [Table 3-3] A. Alternative Reagent: Tris(dibenzylideneacetone)dipalladium(0) (0.1 equiv.), 2-(di-tert-butylphosphino)-2',4',6'-triisopropyl-3,6-dimethoxy-1,1'-biphenyl (0.15 equiv.), tribasic potassium phosphate (1.5 equiv.), and tert-butyl alcohol (0.1 M) were used, and the reaction was heated to 120°C to give (2S)-3-(3-bromophenyl)-2-[ Starting from the ammonium salt of (3R)-1-tert-butoxycarbonylpyrrolidin-3-yl]propanoic acid, this was prepared as follows: (2S)-3-(3-bromophenyl)-2-[(3R)-1-tert-butoxycarbonylpyrrolidin-3-yl]propanoic acid in MTBE was treated with 2 equivalents of ammonia (7M in MeOH), stirred for 1 hour, filtered, washed with MTBE, and then dried in vacuo. B. Silica gel chromatography using a gradient of 5-20% acetone in hexane + 1% acetic acid C. RP-HPLC / MS [Column: XBridge™ C18 (10 × 100 mm, 5 μm), Mobile Phase: Solvent A = 20 mM aqueous NH4HCO3 (pH 9), Solvent B = ACN, Flow Rate: 25 mL / min]

[0200] Preparation 34 tert-Butyl (3R)-3-[(1S)-1-[[3-[[2-(2-bromophenyl)acetyl]amino]phenyl]methyl]-2-tert-butoxy-2-oxo-ethyl]pyrrolidine-1-carboxylate

[0201] [ka] To a solution of tert-butyl (3R)-3-[(1S)-1-[(3-aminophenyl)methyl]-2-tert-butoxy-2-oxo-ethyl]pyrrolidine-1-carboxylate (prepared essentially as described in WO 2020 / 247429, 1 g, 2.56 mmol) and TEA (1.04 g, 1.43 mL, 10.2 mmol) in DCM (12.8 mL) was slowly added 2-bromophenylacetyl chloride (0.671 g, 0.427 mL, 2.82 mmol). The mixture was stirred at room temperature for 3.5 hours, then additional 2-bromophenylacetyl chloride (0.305 g, 0.194 mL, 1.28 mmol) was added and the mixture was stirred at room temperature for 2.5 hours. Saturated aqueous NaHCO3 was added, and the aqueous layer was extracted with DCM. The organic layer was washed with saturated aqueous NaCl, dried over MgSO, filtered, and concentrated under reduced pressure. The residue was purified via silica gel chromatography using a gradient of 0-50% EtOAc in hexanes to give the title compound (860 mg, 57%). ES-MS m / z 587 / 589 (M+H).

[0202] Preparation 35 tert-Butyl (3R)-3-[(1S)-2-tert-butoxy-1-[[3-(3-hydroxypropanoylamino)phenyl]methyl]-2-oxo-ethyl]pyrrolidine-1-carboxylate

[0203] [ka] To a solution of 3-hydroxypropanoic acid (0.127 g, 0.42 mmol) in DMF (4.3 mL) was added HATU (0.298 g, 0.77 mmol) and 2,4,6-trimethylpyridine (0.047 g, 0.051 mL, 0.38 mmol). The mixture was stirred for 30 minutes, and tert-butyl (3R)-3-[(1S)-1-[(3-aminophenyl)methyl]-2-tert-butoxy-2-oxo-ethyl]pyrrolidine-1-carboxylate (prepared essentially as described in WO 2020 / 247429, 150 mg, 0.38 mmol) was added. The reaction was stirred at room temperature for 18 hours, then concentrated, and the residue was purified via reverse-phase chromatography (Claricep C-series column) using a gradient of 20-70% ACN (pH 9) in aqueous NH4CO3. A second purification was performed by RP-HPLC / MS [column: XBridge™ C18 (19 × 100 mm, 5 μm), mobile phase: Solvent A = 20 mM aqueous NH4HCO3 (pH 9), Solvent B = ACN, flow rate: 25 mL / min] to give the title compound (33.6 mg, 19%). ES-MS m / z 463 (M+H).

[0204] The following were prepared essentially as described in Preparation 35 using the appropriate carboxylic acid:

[0205] [Table 4] A. Reversed-phase flash chromatography was performed using a 20-70% gradient of ACN in aqueous NH4CO3 (pH 9). A second purification was performed by basic SFC [stationary phase: ethylpyridine, column dimensions: 30 × 150 mm, 5 μm, mobile phase: 10 mM NH4CO3 in MeOH / CO2 (pH 8)], flow rate: 100 mL / min.

[0206] Preparation 37 tert-Butyl (3R)-3-[(1S)-2-tert-butoxy-1-[[3-(3-hydroxypropylcarbamoylamino)phenyl]methyl]-2-oxo-ethyl]pyrrolidine-1-carboxylate

[0207] [ka] To a solution of tert-butyl (3R)-3-[(1S)-1-[(3-aminophenyl)methyl]-2-tert-butoxy-2-oxo-ethyl]pyrrolidine-1-carboxylate (prepared essentially as described in WO 2020 / 247429, 200 mg, 0.49 mmol) in THF (5 mL) was added 1,1'-carbonyldiimidazole (0.164 g, 0.98 mmol). The mixture was stirred at room temperature for 18 hours, then 3-amino-1-propanol (0.0569 mL, 0.0556 g, 0.74 mmol) was added. The mixture was stirred at 110°C for 1 hour, then diluted with DCM and concentrated to dryness. The residue was purified via silica gel chromatography using a gradient of 10-40% acetone in DCM to give the title compound (176 mg, 73%). ES-MS m / z 492 (M+H).

[0208] Preparation 38 tert-Butyl (3R)-3-[(1S)-2-tert-butoxy-2-oxo-1-[[3-(2,2,2-trifluoroethylsulfonylamino)phenyl]methyl]ethyl]pyrrolidine-1-carboxylate

[0209] [ka] To a solution of tert-butyl (3R)-3-[(1S)-1-[(3-aminophenyl)methyl]-2-tert-butoxy-2-oxo-ethyl]pyrrolidine-1-carboxylate (prepared essentially as described in WO 2020 / 247429, 130 mg, 0.33 mmol) in anhydrous DCM (3 mL) under a nitrogen atmosphere was added TEA (0.101 g, 0.139 mL, 1.00 mmol). The mixture was cooled to -78 °C, and 2,2,2-trifluoroethanesulfonyl chloride (0.0608 g, 0.33 mmol) was added. The mixture was warmed to room temperature and stirred for 18 hours. Saturated aqueous NaHCO3 was added, and the aqueous layer was extracted with DCM. The layers were separated, and the organic layer was concentrated under reduced pressure. The residue was purified via silica gel chromatography using a gradient of 15-60% acetone in hexanes to give the title compound (123 mg, 66%). ES-MS m / z 425 [M+H-(2×tert-butyl)).

[0210] The following were prepared essentially as described in Preparation 38 using the appropriate sulfonyl chloride:

[0211] [Table 5] A. Add 4-dimethylaminopyridine (0.1 equivalents) B. Reversed phase chromatography using a gradient of ACN in aqueous NH4CO3 (pH 9) (column: Claricep C-series).

[0212] Preparation 41 tert-Butyl (3R)-3-[(1S)-1-[(3-benzylsulfanylphenyl)methyl]-2-tert-butoxy-2-oxo-ethyl]pyrrolidine-1-carboxylate

[0213] [ka] Nitrogen was bubbled through a suspension of tert-butyl (3R)-3-[(1S)-1-[(3-bromophenyl)methyl]-2-tert-butoxy-2-oxo-ethyl]pyrrolidine-1-carboxylate (prepared essentially as described in WO 2020 / 247429, 7.8 g, 17.2 mmol) in toluene (10 mL). To the suspension was added tris(dibenzylideneacetone)dipalladium(0) (1.59 g, 1.72 mmol), 1,1'-bis(diphenylphosphino)ferrocene (1.99 g, 3.45 mmol), N,N-diisopropylethylamine (3.31 mL, 2.45 g, 19.0 mmol), and benzyl mercaptan (2.06 mL, 2.18 mL, 17.4 mmol), and the mixture was stirred at 100 °C for 16 hours. EtOAc was added and the mixture was filtered. Water was added, and the filtrate and aqueous layer were extracted with EtOAc. The organic phase was separated, dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography using a gradient of 5-20% EtOAc in hexanes to give the title compound (6.89 g, 80%). ES-MS m / z 398 (M+H-Boc).

[0214] Preparation 42 tert-Butyl (3R)-3-[(1S)-2-tert-butoxy-1-[(3-chlorosulfonylphenyl)methyl]-2-oxo-ethyl]pyrrolidine-1-carboxylate

[0215] [ka] To a 0° C. solution (30 mL) of 40:1.5:1 tert-butyl (3R)-3-[(1S)-1-[(3-benzylsulfanylphenyl)methyl]-2-tert-butoxy-2-oxo-ethyl]pyrrolidine-1-carboxylate (1500 mg, 3.01 mmol):acetic acid:water in ACN was added 1,3-dichloro-5,5-dimethylhydantoin (1.76 g, 6.03 mmol) slowly in portions. The mixture was stirred at 20° C. for 20 minutes and then concentrated in vacuo. The residue was dissolved in DCM, cooled to 0° C., and NaHCO (5% aqueous) was added. The mixture was stirred for 5 minutes and the organic layer was separated. The organics were dried over MgSO and concentrated in vacuo to give the title compound, which was used directly in the next step without purification. ES-MS m / z 364 (M+H-Boc).

[0216] Preparation 43 tert-Butyl (3R)-3-[(1S)-2-tert-butoxy-1-[[3-[[(3-chlorophenyl)methyl]sulfamoyl]phenyl]methyl]-2-oxo-ethyl]pyrrolidine-1-carboxylate

[0217] [ka] To a solution of tert-butyl (3R)-3-[(1S)-2-tert-butoxy-1-[(3-chlorosulfonylphenyl)methyl]-2-oxo-ethyl]pyrrolidine-1-carboxylate (0.446 g, 0.60 mmol, 64 wt%) in DCM (3 mL) was added TEA (0.122 g, 0.168 mL, 1.21 mmol) and 3-chlorobenzylamine (0.102 g, 0.0888 mL, 0.72 mmol). The reaction was stirred at room temperature for 16 h, then HCl (1N aqueous) was added and the aqueous layer was extracted with DCM. The organic layer was separated, dried over MgSO, filtered, and concentrated in vacuo. The residue was purified via RP-HPLC / MS [column: XBridge™ C18 (10 × 100 mm, 5 μm), mobile phase: solvent A = 20 mM aqueous NH4HCO3 (pH 9), solvent B = ACN, flow rate: 25 mL / min] to give the title compound (156 mg, 45%). ES-MS m / z: 479 (M+H-Boc).

[0218] The following were prepared essentially as described in Preparation 43 using the appropriate amine:

[0219] [Table 6]

[0220] Preparation 47 tert-Butyl (3R)-3-[(2-methoxy-1-[(3-nitrophenyl)methyl]-2-oxo-ethyl]pyrrolidine-1-carboxylate

[0221] [ka] To a solution of tert-butyl (3R)-3-(2-methoxy-2-oxo-ethyl)pyrrolidine-1-carboxylate (prepared essentially as described in WO 2020 / 247429, 6 g, 24.7 mmol) in THF (170 mL) was added potassium bis(trimethylsilyl)amide (0.5 M in toluene, 60 mL, 30 mmol) under nitrogen gas at −78° C. The mixture was stirred at −78° C. for 45 minutes, and then a solution of 1-(bromomethyl)-3-nitro-benzene (5.9 g, 27 mmol) in THF (25 mL) was added. The mixture was warmed to room temperature and stirred for 1.75 hours, then quenched with saturated NH4Cl and extracted with MTBE. The combined organic layers were dried over MgSO4 and concentrated under reduced pressure. The residue was purified via silica gel column chromatography using a gradient of 7-30% acetone in hexanes to give the title compound (3.4 g, 36%) as a yellow oil. ES-MS m / z 279 (M-Boc+H).

[0222] Preparation 48 tert-Butyl (3R)-3-[1-[(3-bromophenyl)methyl]-2-methoxy-2-oxo-ethyl]pyrrolidine-1-carboxylate

[0223] [ka] A mixture of tert-butyl (3R)-3-[2-methoxy-1-[(3-nitrophenyl)methyl]-2-oxo-ethyl]pyrrolidine-1-carboxylate (3.4 g, 9.0 mmol) and palladium (10% on activated carbon, 340 mg, 0.32 mmol) in MeOH (45 mL) was stirred at room temperature under a hydrogen balloon for 4 hours. The reaction mixture was filtered through a Celite® pad, and the filtrate was concentrated to dryness to give the title compound (2.9 g, 93%) as a colorless oil. ES-MS m / z 249 (M-Boc+H).

[0224] Preparation 49 tert-Butyl (3R)-3-[2-methoxy-2-oxo-1-[[3-(prop-2-ynylamino)phenyl]methyl]ethyl]pyrrolidine-1-carboxylate

[0225] [ka] tert-Butyl (3R)-3-[1-[(3-aminophenyl)methyl]-2-methoxy-2-oxo-ethyl]pyrrolidine-1-carboxylate (710 mg, 2.04 mmol) was dissolved in DMF (7 mL), followed by the addition of K2CO3 (0.285 g, 2.04 mmol) and 3-bromoprop-1-yne (80% by weight in toluene, 0.242 mL, 0.333 g, 2.24 mmol). The mixture was stirred overnight at room temperature. Water was added, and the aqueous layer was extracted with EtOAc. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified via silica gel chromatography using a gradient of 10–40% EtOAc in hexanes to afford the title compound (0.252 g, 31%) as a colorless oil. ES-MS m / z 287 (M-Boc+H).

[0226] Preparation 50 2-[(3R)-1-tert-butoxycarbonylpyrrolidin-3-yl]-3-[3-(prop-2-ynylamino)phenyl]propanoic acid

[0227] [ka] To a solution of tert-butyl (3R)-3-[2-methoxy-2-oxo-1-[[3-(prop-2-ynylamino)phenyl]methyl]ethyl]pyrrolidine-1-carboxylate (252 mg, 0.65 mmol) in MeOH (4 mL) and THF (8 mL) was added NaOH (2 M in water, 2 mL, 4 mmol). The mixture was stirred at room temperature overnight, and then HCl (1 N aqueous) was added until the solution reached pH = 4. The aqueous layer was extracted three times with EtOAc, and the combined organics were dried over Na2SO4, filtered, and concentrated. The residue was loaded onto an HLB column and eluted first with water, then 1:1 water:ACN, and then ACN. The appropriate fractions were concentrated, and the resulting solid was dried in vacuo at 40 °C to give the title compound (237 mg, 98%) as a brown solid, a mixture of diastereomers. ES-MS m / z 273 (M-Boc+H).

[0228] Preparation 51 tert-Butyl (3R)-3-[(1S)-2-tert-butoxy-1-[[3-(2-tert-butoxy-2-oxo-ethyl]phenyl]methyl]-2-oxo-ethyl]pyrrolidine-1-carboxylate

[0229] [ka] To a two-necked round-bottom flask equipped with a reflux condenser was added bis(dibenzylideneacetone)palladium (15.8 mg, 0.028 mmol) and 1,2,3,4,5-pentaphenyl-1'-(di-tert-butylphosphino)ferrocene (39.5 mg, 0.055 mmol), and the flask was purged with nitrogen. A solution of tert-butyl (3R)-3-[(1S)-1-[(3-bromophenyl)methyl]-2-tert-butoxy-2-oxo-ethyl]pyrrolidine-1-carboxylate (prepared essentially as described in WO 2020 / 247429, 250 mg, 0.55 mmol) in THF (3 mL) was then added, followed by (2-tert-butoxy-2-oxoethyl)(chloro)zinc (0.5 M in EtO, 3 mL, 1.38 mmol). The reaction was heated at gentle reflux for 1.5 hours and, upon cooling, saturated aqueous NH4Cl was added and the mixture was extracted with EtOAc. The organic layer was separated, dried over MgSO4, filtered, and concentrated. The residue was purified via silica gel chromatography using a gradient of 5-20% EtOAc in hexanes to afford the title compound (212 mg, 79%) as a colorless oil. ES-MS m / z 390 (M-Boc+H).

[0230] Preparation 52 tert-Butyl (3S)-3-[2-[(4R)-4-benzyl-2-oxo-oxazolidin-3-yl]-2-oxo-ethyl]pyrrolidine-1-carboxylate

[0231] [ka] Prepare the title compound essentially as described in Preparation 10 using (S)-N-BOC-3-pyrrolidineacetic acid and (R)-4-benzyl-2-oxazolidinone. Purify the crude product by silica gel chromatography using a gradient of 10-50% EtOAc in hexanes to obtain the title compound as a pale yellow oil. ES / MS (m / z): 333 (M+H-tert-butyl).

[0232] Preparation 53 (3R,7aS)-3-phenyl-3,6,7,7a-tetrahydro-1H-pyrrolo[1,2-c]oxazol-5-one

[0233] [ka] A mixture of (5S)-5-(hydroxymethyl)pyrrolidin-2-one (20.0 g, 174 mmol), benzaldehyde (1.3 equiv., 226 mmol), p-toluenesulfonic acid (0.01 equiv., 1.74 mmol), and toluene (200 mL) was heated to reflux for 2 days in a round-bottom flask equipped with a Dean-Stark trap. The reaction was cooled to room temperature and washed with saturated aqueous NaHCO. The saturated aqueous NaCl solution was dried over NaSO, filtered, and concentrated. The residue was purified by silica gel column chromatography using a gradient of 0–70% EtOAc in hexanes to afford the title compound (29.0 g, 82%) as a pale yellow oil. 1 H NMR(399.80MHz,CDCl3)δ7.48-7.45(m,2H),7.40-7.35(m,3H),6.35(s,1H),4.24(dd,J=6.3,8.0Hz,1H),4.19-4.12(m,1 H),3.50(t,J=8.0Hz,1H),2.87-2.78(m,1H),2.56(ddd,J=17.3,10.0,3.8Hz,1H),2.43-2.37(m,1H),2.00-1.93(m,1H).

[0234] Preparation 54 tert-Butyl 2-[(3R,6R,7aS)-5-oxo-3-phenyl-3,6,7,7a-tetrahydro-1H-pyrrolo[1,2-c]oxazol-6-yl]acetate

[0235] [ka] To a solution of n-butyllithium (2.5 M in hexanes, 86 mL, 214 mmol) under nitrogen at 0° C., diisopropylamine (1.7 equiv., 243 mmol) was slowly added. After the addition was complete, the red slurry was stirred for 15 minutes and then slowly diluted with THF (200 mL). The resulting orange solution was cooled to −76° C., and then a solution of (3R,7aS)-3-phenyl-3,6,7,7a-tetrahydro-1H-pyrrolo[1,2-c]oxazol-5-one (29.0 g, 143 mmol) in THF (200 mL) was added dropwise at a rate such that the internal temperature did not rise above −68° C. The resulting brown solution was stirred for 45 minutes. A solution of tert-butyl bromoacetate (64.1 mL, 85.2 g, 428 mmol) in THF (100 mL) was added dropwise, maintaining the internal temperature below −72° C. After the addition was complete, the mixture was stirred at −78° C. for 2 h. Saturated aqueous NaHCO solution was added, and the reaction was diluted with EtO. The mixture was allowed to warm slowly to room temperature overnight. The layers were separated, and the organic layer was then washed with saturated aqueous NaHCO, saturated aqueous NaCl, dried over MgSO, filtered, and concentrated. The residue was purified by silica gel column chromatography using a gradient of 0–70% EtOAc in hexanes to afford the title compound (40.7 g, 90%) as a yellow oil. 1 H NMR(399.80MHz,CDCl3)δ7.48-7.45(m,2H),7.40-7.36(m,3H),6.34(s,1H),4.26(dd,J=6.3,8.1Hz,1H),4.18-4.11(m,1H),3.63-3.59( m,1H),3.33-3.27(m,1H),2.84(dd,J=4.4,16.7Hz,1H),2.73-2.66(m,1H),2.41(dd,J=8.7,16.7Hz,1H),1.74-1.65(m,1H),1.48(s,9H).

[0236] Preparation 55 tert-Butyl (2S,4R)-2-(hydroxymethyl)-4-(2-methoxy-2-oxo-ethyl)pyrrolidine-1-carboxylate

[0237] [ka] A solution of tert-butyl 2-[(3R,6R,7aS)-5-oxo-3-phenyl-3,6,7,7a-tetrahydro-1H-pyrrolo[1,2-c]oxazol-6-yl]acetate (11.30 g, 35.60 mmol) in dry THF (200 mL) was cooled to 0 °C under nitrogen and then added borane-tetrahydrofuran complex (1 M in THF, 71 mL, 71 mmol). The resulting mixture was heated to reflux for 3 h and then concentrated under reduced pressure. The residue was slowly and carefully dissolved in MeOH (50 mL), resulting in gas evolution. After the reaction stopped gas evolution, HCl (4 M solution in 1,4-dioxane, 50 mL, 200 mmol) was added, resulting in further gas evolution. The resulting mixture was heated to reflux for 2 h, then cooled to ambient temperature and concentrated under reduced pressure. The residue was dissolved in EtOAc and washed twice with saturated aqueous NaHCO3, then saturated aqueous NaCl, then dried over MgSO4, filtered, and concentrated to give methyl 2-[(3R,5S)-1-benzyl-5-(hydroxymethyl)pyrrolidin-3-yl]acetate (8.78 g, 36.7 mmol).

[0238] The product was suspended in dry THF (300 mL) under nitrogen, then tert-butoxycarbonyl tert-butyl carbonate (8.01 g, 36.7 mmol) and palladium on carbon (5 wt%, 4.0 g) were added, the reaction vessel was purged with hydrogen (1 ATM), and stirred overnight. The flask was purged with nitrogen and then filtered through a pad of diatomaceous earth, rinsing with THF. The residue was purified by silica gel chromatography using a gradient of 0-80% EtOAc in hexane to give the title compound (5.90 g, 65%) as a colorless oil. 1 H NMR(399.80MHz,CDCl3)δ4.00-3.94(m,1H),3.89-3.81(m,1H),3.71(m,4H),3.59(dd,J=7. 2,11.6Hz,1H),2.88(t,J=10.5Hz,1H),2.48-2.39(m,3H),2.31-2.24(m,1H),1.49(s,9H).

[0239] Preparation 56 tert-Butyl (2R,4R)-4-[2-[(4S)-4-benzyl-2-oxo-oxazolidin-3-yl]-2-oxo-ethyl]-2-methyl-pyrrolidine-1-carboxylate

[0240] [ka] To a mixture of imidazole (2.94 g, 43.2 mmol) and triphenylphosphine (8.49 g, 32.4 mmol) in dry THF (100 mL) at 0° C. under nitrogen, iodine (8.22 g, 32.4 mmol) was added dropwise as a solution in THF (50 mL). The resulting mixture was stirred for 1 hour, and then a solution of tert-butyl (2S,4R)-2-(hydroxymethyl)-4-(2-methoxy-2-oxo-ethyl)pyrrolidine-1-carboxylate (5.90 g, 21.6 mmol) in THF (100 mL) was added dropwise. The cooling bath was allowed to warm slowly, and the reaction was stirred at room temperature overnight. The reaction mixture was diluted with ether, washed with 10% aqueous sodium thiosulfate solution, saturated aqueous NaCl, dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography using a gradient of 0 to 100% MTBE in hexanes to give tert-butyl (2S,4R)-2-(iodomethyl)-4-(2-methoxy-2-oxo-ethyl)pyrrolidine-1-carboxylate (7.30 g, 88%).

[0241] The product was suspended with palladium on carbon (5% by weight, 4.0 g) in a mixture of TEA (3.19 mL, 2.31 g, 22.9 mmol) in dry THF (300 mL) under nitrogen. The reaction vessel was purged with hydrogen (1 ATM) and stirred overnight. The reaction was recharged with additional Pd—C (200 mg) and stirred for 24 h. The reaction vessel was purged with nitrogen, and the reaction mixture was filtered through a pad of diatomaceous earth and washed with THF. The filtrate was concentrated, and the residue was dissolved in ether and washed with water, 10% aqueous citric acid, and saturated aqueous NaCl. The organics were dried over MgSO4, filtered, and concentrated to give tert-butyl (2R,4R)-4-(2-methoxy-2-oxo-ethyl)-2-methyl-pyrrolidine-1-carboxylate (5.36 g, quantitative yield).

[0242] A mixture of the product, water (30 mL), and lithium hydroxide (0.748 g, 31.2 mmol) in THF (30 mL) was stirred for 2 h, then the reaction mixture was acidified with citric acid to pH = 3-4, and the mixture was extracted with ether. The combined organics were dried over MgSO, filtered, and concentrated to give 2-[(3R,5R)-1-tert-butoxycarbonyl-5-methyl-pyrrolidin-3-yl]acetic acid.

[0243] The resulting product in dry THF (150 mL) under nitrogen was cooled to 0° C. TEA (3.16 g, 4.35 mL, 31.2 mmol) was added, and after 5 min, pivaloyl chloride (3.14 g, 3.18 mL, 26.0 mmol) was added dropwise over 30 min. The resulting slurry was warmed to room temperature and stirred for 1 h. The reaction mixture was cooled to 0° C., then a solution of LiCl (5.29 g, 125 mmol) in minimal THF was added dropwise, followed by (S)-4-benzyl-2-oxazolidinone (4.16 g, 26.0 mmol). The reaction was allowed to warm to room temperature overnight and then diluted with ether. The organics were washed with water, saturated aqueous NaHCO3, saturated aqueous NaCl, then dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography using a gradient of 0-100% MTBE to give the title compound (6.80 g, 81%) as a yellow oil. 1H NMR(399.80MHz,CDCl3)δ7.39-7.31(m,3H),7.23-7.21(m,2H),4.70(ddd,J=13.0,7.2,3.4Hz,1H),4.27-4.19(m,2H),4.03-4.01(m,2H),3.3 1(dd,J=3.3,13.4Hz,1H),3.11-2.96(m,3H),2.83-2.77(m,1H),2.60- 2.53 (m, 1H), 2.48-2.37 (m, 1H), 1.49-1.48 (m, 9H), 1.33-1.24 (m, 3H).

[0244] The following were prepared essentially as described in Preparation 11 using the appropriate starting materials:

[0245] [Table 7-1]

[0246] [Table 7-2] A. The product was used without purification. B. The starting material (tert-butyl (3R)-3-[2-[(4S)-4-benzyl-2-oxo-oxazolidin-3-yl]-2-oxo-ethyl]pyrrolidine-1-carboxylate) was prepared essentially as described in WO 2020 / 247429 C. The reaction was stirred at 0° C. for 20 minutes before the bromide was added.

[0247] The following were prepared essentially as described in Preparation 12 using the appropriate starting materials:

[0248] [Table 8-1]

[0249] [Table 8-2] A. Upon completion of the reaction and aqueous workup, the crude product was dissolved in MTBE, ammonia (7M in MeOH, 2 eq.) was added, stirred for 1 hour, and the resulting solid was filtered, washed with MTBE, and then dried in vacuo. B. No chiral separation was performed

[0250] Preparation 69 tert-Butyl (3S)-3-[(1R)-1-[(3-bromophenyl)methyl]-2-tert-butoxy-2-oxo-ethyl]pyrrolidine-1-carboxylate

[0251] [ka] (2R)-3-(3-bromophenyl)-2-[(3S)-1-tert-butoxycarbonylpyrrolidin-3-yl]propanoic acid (ammonium salt, 0.530 g, 1.28 mmol) was converted to its free carboxylic acid by acidification with KHSO4 (1N) and extraction with DCM. The organics were evaporated, and the residue was dissolved in 2-methyltetrahydrofuran (4 mL). 2-tert-Butyl-1,3-diisopropylisourea (1.0 mL, 0.902 g, 3.83 mmol, 85% by weight) was added, and the reaction mixture was heated and stirred at 65 °C for 4 h. The reaction was cooled to room temperature, the solids in suspension were filtered and discarded, and the filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography using a gradient of 10–40% EtOAc in hexanes to give 0.464 g (80%) of the title compound as a colorless oil. ES / MS m / z 476,478 (M+Na+).

[0252] The following were prepared essentially as described in Preparation 69 using the appropriate acid:

[0253] [Table 9] A. The starting material was used as the free acid, and no neutralization step was required. B. Purification by silica gel chromatography eluting with acetone:hexane C. Starting material isomer 2 was used

[0254] Preparation 74 tert-Butyl-4-[(1S)-1-[(3-bromophenyl)methyl]-2-tert-butoxy-2-oxo-ethyl]-3,3-difluoro-pyrrolidine-1-carboxylate (Isomer 1 and Isomer 2)

[0255] [ka] A mixture of (2S)-3-(3-bromophenyl)-2-(1-tert-butoxycarbonyl-4,4-difluoro-pyrrolidin-3-yl)propanoic acid (1.09 g, 2.31 mmol) and 2-tert-butyl-1,3-diisopropylisourea (1.6 mL, 6.9 mmol) in 2-tert-2-methyltetrahydrofuran (24 mL) was heated at 60 °C for 30 min. After 1 h, additional 2-tert-butyl-1,3-diisopropylisourea (0.8 mL, 3 mmol) was added, and the mixture was heated at 60 °C for 1 h. The reaction was cooled to room temperature. The white solid was filtered and washed with MTBE. The filtrate was evaporated to dryness. The residue was purified by silica gel chromatography using a gradient of 0-60% MTBE in hexanes to give Isomer 1 (280 mg, 25%, first-eluting isomer) as a colorless oil and Isomer 2 (367 mg, 32%, second-eluting isomer) as a colorless oil. Both Isomer 1 and Isomer 2: ES / MS m / z 378, 380 (M-2xtBu+H).

[0256] Preparation 75 tert-Butyl (3S)-3-[1-[(3-bromophenyl)methyl]-2-tert-butoxy-1-hydroxy-2-oxo-ethyl]pyrrolidine-1-carboxylate (Isomer 1 and Isomer 2)

[0257] [ka] Diisopropylamine (4.4 mL, 31.5 mmol) was added to the reaction vessel and cooled in an ice bath (0 ° C.) under an inert atmosphere. n-Butyllithium (12 mL, 29 mmol) was then added, forming a white slurry after several minutes. Anhydrous THF (50 mL) was added to the mixture, and the reaction was cooled to −78 ° C. tert-Butyl (3R)-3-[(1S)-1-[(3-bromophenyl)methyl]-2-tert-butoxy-2-oxo-ethyl]pyrrolidine-1-carboxylate (prepared essentially as described in WO 2020 / 247429, 5.50 g, 12.1 mmol) was added as a solution in THF (50 mL), and the mixture was stirred at −78 ° C. for 2 hours. A solution of 3-phenyl-2-(phenylsulfonyl)-1,2-oxaziridine (5.87 g, 21.8 mmol) in THF (50 mL) was added at −78° C., and the reaction mixture was warmed to room temperature and stirred for 18 h. The reaction mixture was poured onto ice with citric acid and extracted with DCM (2×100 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 0-40% EtOAc in hexane to give the title compound (2.92 g) as a mixture of diastereomers. ES / MS (m / z): 358 / 360 (M+H-2×tert-butyl).

[0258] The diastereomeric mixture was separated by chiral HPLC (column: Lux Amylose-15 × 25 cm, mobile phase: 85:15 CO:IPA, mixture dissolved in IPA @ 50 mg / mL, 350 mg injection every 6 min) to give Isomer 1 (1.136 g, 20%) and Isomer 2 (0.956 g, 17%).

[0259] Preparation 76 tert-Butyl (3S)-3-[1-bromo-2-methoxy-2-oxo-ethyl]pyrrolidine-1-carboxylate

[0260] [ka] To a solution of tert-butyl (3R)-3-(2-methoxy-2-oxo-ethyl)pyrrolidine-1-carboxylate (prepared essentially as described in WO 2020 / 247429, 2 g, 8.2 mmol) in THF (16 mL) was added lithium bis(trimethylsilyl)amide (1.0 M in hexanes (9.9 mL, 9.9 mmol) at −78° C. under a N atmosphere. The mixture was stirred at −78° C. for 30 minutes, and then chlorotrimethylsilane (1.57 mL, 1.34 g, 12.3 mmol) was added. The mixture was stirred at −78° C. for 30 minutes, and then chlorotrimethylsilane (1.57 mL, 1.34 g, 12.3 mmol) was added. The mixture was stirred for 30 minutes. A solution of N-bromosuccinimide (1.81 g, 9.86 mmol) in THF (22 mL) was then added at −78° C. The reaction was stirred overnight at room temperature, and then saturated aqueous NH4Cl was added. The mixture was extracted with EtOAc, and the combined organic phases were washed with saturated aqueous NaCl, dried over MgSO4, filtered, and concentrated. The residue was purified by silica gel column chromatography using a gradient of 0-100% EtOAc in hexanes to give the title compound (mixture of diastereomers) as a yellow oil. ES / MS m / z 266, 268 (M-tBu+H).

[0261] Preparation 77 tert-Butyl (3S)-3-[1-[(3-bromophenyl)sulfanyl-2-methoxy-2-oxo-ethyl]pyrrolidine-1-carboxylate

[0262] [ka] To sodium methoxide (0.5 M solution in MeOH, 20 mL, 8.75 mmol) was added a solution of 3-bromothiophenol (0.956 mL, 1.65 g, 8.75 mmol) in THF (3 mL), and the mixture was heated at 80°C for 1 h. A solution of tert-butyl (3S)-3-[1-bromo-2-methoxy-2-oxo-ethyl]pyrrolidine-1-carboxylate (1.88 g, 5.83 mmol) in THF (6 mL) was added, and the mixture was heated at 80°C for 30 min. Water was added to the reaction mixture, and it was extracted with EtOAc. The combined organic phases were washed with saturated aqueous NaCl, dried over MgSO4, filtered, and concentrated. The residue was purified by silica gel column chromatography using a gradient of 50 to 100% MTBE in hexane to give the title compound (2.2 g, 88%, mixture of diastereomers) as a pale yellow oil. ES / MSm / z, 374, 376(M-tBu+H).

[0263] Preparation 78 2-(3-Bromophenyl)sulfanyl-2-[(3S)-1-tert-butoxycarbonylpyrrolidin-3-yl]propanoic acid

[0264] [ka] A mixture of tert-butyl (3S)-3-[1-(3-bromophenyl)sulfanyl-2-methoxy-2-oxo-ethyl]pyrrolidine-1-carboxylate (2.2 g, 5.1 mmol) and NaOH (5 N aqueous solution, 15 mL, 77 mmol) in MeOH (25 mL) and THF (25 mL) was stirred at room temperature for 2.5 h. The organic solvent was evaporated to dryness, and 1 N aqueous HCl was added to the residue to bring the mixture to pH = 2-3. The mixture was extracted with EtOAc, and the combined organic phases were then washed with saturated aqueous NaCl, dried over MgSO4, filtered, and concentrated to give the title compound (1.84 g, 86%) as a white solid (mixture of diastereomers). ES / MS m / z 360, 362 (M-tBu+H).

[0265] Preparation 79 tert-Butyl (3S)-3-[(1-[(3-bromophenyl)sulfanyl-2-tert-butoxy-2-oxo-ethyl]pyrrolidine-1-carboxylate

[0266] [ka] A mixture of 2-(3-bromophenyl)sulfanyl-2-[(3S)-1-tert-butoxycarbonylpyrrolidin-3-yl]acetic acid (1.84 g, 4.42 mmol) and 2-tert-butyl-1,3-diisopropylisourea (4.6 mL, 4.07 g, 19.9 mmol) in 2-methyltetrahydrofuran (44 mL) was heated at 55 °C for 3 h. The white solid was filtered and discarded, and the filtrate was evaporated to dryness. The residue was purified by silica gel column chromatography using a gradient of 0 to 50% MTBE in hexane to give the title compound (2 g, 96%, mixture of diastereomers) as a colorless oil. ES / MS m / z, 494,496 (M+Na).

[0267] Preparation 80 3-(3-Bromophenyl)-2-[(3R)-1-tert-butoxycarbonylpyrrolidin-3-yl]-2-methyl-propanoic acid (Isomer 1 and Isomer 2)

[0268] [ka] To a solution of tert-butyl (3R)-3-[1-[(3-bromophenyl)methyl]-2-methoxy-2-oxo-ethyl)pyrrolidine-1-carboxylate (prepared essentially as described in WO 2020 / 247429, 8.4 g, 20 mmol) in THF (100 mL) under N and at −78° C. was added lithium bis(trimethylsilyl)amide (1 M solution in THF, 41 mmol, 41 mL). The reaction was stirred at −78° C. for 2 hours, then iodomethane (58 g, 25 mL, 410 mmol) was added and the reaction was allowed to warm to room temperature. The mixture was stirred overnight, then saturated aqueous NH4Cl was added and extracted with EtOAc. The organic layer was washed with saturated aqueous NaCl, dried over MgSO, filtered and concentrated to give tert-butyl (3R)-3-[1-[(3-bromophenyl)methyl]-2-methoxy-1-methyl-2-oxo-ethyl]pyrrolidine-1-carboxylate (9.2 g, 98%) as a brown oil.

[0269] tert-Butyl (3R)-3-[1-[(3-bromophenyl)methyl]-2-methoxy-1-methyl-2-oxo-ethyl]pyrrolidine-1-carboxylate (9.2 g, 20 mmol) was dissolved in MeOH (80 mL) and THF (80 mL), then sodium hydroxide (5 M solution in water, 81 mL, 410 mmol) was added, and the resulting mixture was heated at 60 °C for 3 days. The mixture was cooled to room temperature, then HCl (1 N aqueous solution) was added until pH = 2-3. The aqueous layer was extracted with EtOAc, and the organic layer was dried over MgSO, filtered, and concentrated. The residue was purified by chiral SFC [Column: Chiralpak AD 25 × 3 cm, 5 μm, Mobile phase: Solvent A - CO, Solvent B - MeOH + 0.2% DMEA, Gradient: Isocratic 80 / 20 A / B, Flow rate: 120 mL / min] to give Isomer 1 (first eluting isomer, 1.7 g, 27%, >98% de) as a white solid and Isomer 2 (second eluting isomer, 3.4 g, 41%, >98% de) as a white solid. Both isomers: ES / MS (m / z): 356, 358 (M+H-tert-butyl).

[0270] Preparation 81 tert-Butyl (2R,4R)-4-[(1S)-1-[(3-aminophenyl)methyl]-2-tert-butoxy-2-oxo-ethyl]-2-methyl-pyrrolidine-1-carboxylate

[0271] [ka] To a solution of (2S)-2-[(3R,5R)-1-tert-butoxycarbonyl-5-methyl-pyrrolidin-3-yl]-3-(3-nitrophenyl)propanoic acid (3.78 g, 9.99 mmol) in toluene (100 mL) at 80° C. was added N,N-dimethylformamide di-tert-butyl acetal (90% by weight, 26.7 mL, 22.6 g, 99.9 mmol), and the reaction was heated overnight at 80° C. The reaction mixture was concentrated in vacuo, and the residue was purified by silica gel chromatography using 40% EtOAc in hexanes to afford tert-butyl (2R,4R)-4-[(1S)-2-tert-butoxy-1-[(3-nitrophenyl)methyl]-2-oxo-ethyl]-2-methyl-pyrrolidine-1-carboxylate (2.8 g, 60%) as a yellow oil.

[0272] The oil was dissolved in THF (70 mL) and palladium on carbon (5% by weight, 2.9 g) was added under nitrogen. The reaction vessel was purged with hydrogen and stirred under 1 atmosphere of hydrogen for 6 hours. The resulting slurry was filtered through a pad of Celite® and washed with THF. The filtrate was concentrated to give a yellow oil, which was again dissolved in THF (70 mL), slurried with palladium on carbon (5% by weight, 2.9 g), and stirred under 1 atmosphere of hydrogen for 24 hours. The reaction mixture was filtered through a pad of Celite and washed with THF. The filtrate was concentrated to give the title compound (2.2 g, 84%) as a dark yellow oil containing a small amount of diastereomeric impurity. ES / MS m / z 403 (M−H).

[0273] A portion of the product (1 g) was further purified by chiral SFC [column: Chiralpak AD-H 21 × 150 mm, mobile phase: 20% IPA in CO, flow rate: 80 mL / min, column temperature: 40 °C] to give the title compound (691 mg, third-eluting isomer, 96.7% de).

[0274] Preparation 82 tert-Butyl (3S)-3-[(1R)-1-[(3-aminophenyl)methyl]-2-tert-butoxy-2-oxo-ethyl]pyrrolidine

[0275] [ka] A mixture of tert-butyl (3S)-3-[(1R)-1-[(3-bromophenyl)methyl]-2-tert-butoxy-2-oxo-ethyl]pyrrolidine-1-carboxylate (0.464 g, 1.02 mmol), copper(II) acetylacetonate (0.027 g, 0.102 mmol), 2,2,6,6-tetramethyl-3,5-heptanedione (0.087 mL, 0.408 mmol), CsCO (0.665 g, 2.04 mmol), DMA (2 mL), and ammonium hydroxide (28% by weight in water, 0.816 mL, 6 mmol) was heated to 110 °C overnight and then cooled to room temperature. MTBE was added, and the mixture was washed with water. The organics were dried over MgSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 20-80% EtOAc in hexanes to give the title compound (0.271 g, 68%). ES / MS (m / z): 291 (M+H-BOC).

[0276] The following were prepared essentially as described in Preparation 82 using the appropriate aryl bromide:

[0277] [Table 10] A. Reagents used: copper(I) oxide (1 equivalent), sodium azide (2 equivalents), L-proline (1.3 equivalents) in DMSO (0.2 M, 9.6 mL); reaction temperature: 100°C. B. Upon completion, the reaction mixture was absorbed onto silica gel and carried forward for purification without aqueous workup. C. Purification by silica gel chromatography eluting with a mixture of MTBE and hexane D. Diastereomers were separated by chiral SFC [Column: Chiralcel OD25 x 2 cm, 5 μm, Mobile phase: CO2-solvent A), MeOH + 0.5% DMEA-solvent B, isocratic 85:15 solvent A:solvent B, Flow rate: 80 mL / min, Column temperature: 40 °C], Isomer 1 is the first eluting isomer and Isomer 2 is the second eluting isomer. E. Prepared from starting aryl bromide isomer 1

[0278] Preparation 88 tert-Butyl-4-[1-[(3-aminophenyl)methyl]-2-tert-butoxy-2-oxo-ethyl]-3,3-difluoro-pyrrolidine-1-carboxylate (isomers 1, 2, 3 and 4).

[0279] [ka] tert-Butyl-4-[(1S)-1-[(3-bromophenyl)methyl]-2-tert-butoxy-2-oxo-ethyl]-3,3-difluoro-pyrrolidine-1-carboxylate (isomer 1, 280 mg, 0.5710 mmol), copper(II) bis(2,4-pentanedionato) (15 mg, 0.057 mmol), 2,2,6,6-tetramethyl-3,5-heptanedione (50 μL, 0.24 mmol), CsCO (372 mg, 1.14 mmol), and DMA (1.2 mL, 13 mmol) were added. NHOH (28% by weight in water, 1.12 mL, 6 mmol) was added, and immediate gas evolution was observed. The reaction was sealed and heated at 110 °C overnight. The mixture was quenched with water and extracted with EtOAc. The combined organic phase was washed with saturated aqueous NaCl, dried over anhydrous MgSO4, filtered, and concentrated. The residue was purified by silica gel chromatography using a gradient of 70-90% MTBE in hexanes to give two diastereomeric products, likely resulting from epimerization during the reaction: the first-eluting isomer—Isomer 1 (100 mg, 41%), a colorless oil; the second-eluting isomer—Isomer 2 (34 mg, 11%), a colorless oil. Both Isomer 1 and Isomer 2: ES / MS m / z 449 (M+Na).

[0280] This procedure was repeated on essentially the same scale as above for tert-butyl-4-[(1S)-1-[(3-bromophenyl)methyl]-2-tert-butoxy-2-oxo-ethyl]-3,3-difluoro-pyrrolidine-1-carboxylate (isomer 2), and the diastereomeric products were purified by silica gel chromatography using 80% MTBE in hexane to give the first-eluting isomer, isomer 3 (77 mg, 28%), a colorless oil, and the second-eluting isomer, isomer 4 (93 mg, 36%), a colorless oil. Both isomer 3 and isomer 4: ES / MS m / z 449 (M+Na).

[0281] Preparation 89 (2S)-2-[(3R)-1-tert-butoxycarbonylpyrrolidin-3-yl]-3-(3-cyanophenyl)propanoic acid

[0282] [ka] A mixture of (2S)-3-(3-bromophenyl)-2-[(3R)-1-tert-butoxycarbonylpyrrolidin-3-yl]propanoic acid (600 mg, 1.506 mmol, prepared essentially as described in WO 2020 / 247429), potassium ferrocyanide trihydrate (277 mg, 0.753 mmol, 0.5 equiv.), [(2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (tBuXPhos Pd G3 (24 mg, 0.030 mmol) and 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl were added to a sealed reaction vessel, which was evacuated and refilled with nitrogen; this process was repeated three times. A solution of potassium acetate (20 mg, 0.188 mmol) in 1,4-dioxane (2.5 mL) and degassed water (2.5 mL) was then added to the vessel via syringe. The mixture was heated to 100 °C in a microwave oven for 1 h. The reaction was filtered and concentrated in vacuo, and the residue was subjected to silica gel flash chromatography using a gradient of 50 to 100% EtOAc in hexanes to afford the title compound (235 mg, 45%) as a colorless oil. ES / MS (m / z): 343 (M+H).

[0283] Preparation 90 (2S)-3-(3-aminomethyl)phenyl]-2-[(3R)-1-tert-butoxycarbonylpyrrolidin-3-yl]propanoic acid

[0284] [ka] Palladium (10% on carbon, 680 mg, 0.638 mmol) was added to a solution of (2S)-2-[(3R)-1-tert-butoxycarbonylpyrrolidin-3-yl]-3-(3-cyanophenyl)propanoic acid (220 mg, 0.638 mmol) in acetic acid (10 mL) in a pressure vessel. The mixture was purged with hydrogen and stirred at room temperature under 551.7 Kpa of hydrogen for 2 days. The mixture was filtered through diatomaceous earth and rinsed with MeOH. The filtrate was collected and the solvent was evaporated under reduced pressure. The residue was purified by strong cation exchange (SCX) purification eluting with ammonia (2M in MeOH) to give the title compound (123 mg, 39%) in 70% purity, which was used without further purification. ES / MS (m / z): 349 (M+H).

[0285] Preparation 91 tert-Butyl (3S)-3-[2-methoxy-1-(3-nitrophenoxy)-2-oxo-ethyl]pyrrolidine-1-carboxylate

[0286] [ka] Diisopropylamine (1.4 mL, 9.9 mmol, 1.2 equiv.) was added to the reaction vessel, which was cooled on an ice bath (0° C.) under an inert atmosphere, and n-butyllithium (2.5 M solution in hexane, 3.9 mL, 9.9 mmol) was slowly added. After several minutes, a white slurry formed. The slurry was diluted with THF (20 mL). The solution was cooled to −78° C., and tert-butyl (3R)-3-(2-methoxy-2-oxo-ethyl)pyrrolidine-1-carboxylate (prepared essentially as described in WO 2020 / 247429, 2.0 g, 8.2 mmol, 1 equiv.) in a THF solution (20 mL) was added, and the mixture was stirred at −78° C. for 40 minutes. Chlorotrimethylsilane (1.1 mL, 8.6 mmol) was added at −78° C., and the reaction was stirred for 20 minutes. N-Bromosuccinimide (1.60 g, 8.6 mmol) was then added as a solid. The cooling bath was allowed to warm to room temperature over 18 hours, and the reaction was then diluted with EtOAc and washed with sodium thiosulfate (10% aqueous solution). The organic phase was dried over MgSO, filtered, and concentrated to dryness under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 0 to 50% EtOAc in hexanes to give the bromide intermediate [tert-butyl (3S)-3-(1-bromo-2-methoxy-2-oxo-ethyl)pyrrolidine-1-carboxylate] as a yellow oil. The bromide intermediate (1.84 g, 5.71 mmol) was dissolved in acetone (50 mL), and potassium carbonate (4.74 g, 34.3 mmol) and 3-nitrophenol (3.76 mL, 34.0 mmol) were added. The reaction mixture was stirred under an inert atmosphere for 18 hours, then diluted with EtOAc and washed with water and saturated aqueous NaCl. The organic layer was dried over MgSO, filtered, and concentrated to dryness under reduced pressure. The residue was purified by silica gel chromatography eluting with a gradient of 0-50% EtOAc in hexanes to give the title compound (300 mg, 14%) as a mixture of diastereomers. ES / MS (m / z): 325 (M+H-tert-butyl).

[0287] Preparation 92 tert-Butyl (3S)-3-[2-tert-butoxy-1-(3-nitrophenoxy)-2-oxo-ethyl]pyrrolidine-1-carboxylate (Isomer 1 and Isomer 2)

[0288] [ka] Sodium hydroxide (5N aqueous solution, 8 mL, 40 mmol) was added to a solution of tert-butyl (3S)-3-[2-methoxy-1-(3-nitrophenoxy)-2-oxo-ethyl]pyrrolidine-1-carboxylate (1.24 g, 3.27 g) in MeOH (50 mL) and stirred for 18 hours. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with DCM (100 mL) and citric acid (10% aqueous solution, 50 mL). The organic phase was collected and extracted with DCM (100 mL), and the combined organic extracts were concentrated under reduced pressure. Toluene (20 mL) was added to the residue, and the mixture was heated to 75°C. N,N-Dimethylformamide di-tert-butyl acetal (10 mL, 41 mmol) was added over 30 minutes, and the reaction was stirred at 75°C for 4 hours. The reaction was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 0-100% EtOAc in hexanes to give the title compound (1.05 g) as a mixture of diastereomers. ES / MS (m / z): 311 (M+H-2×t-butyl).

[0289] The mixture of diastereomers was purified by chiral HPLC [column: Lux Cellulose-4 5 × 25 cm, mobile phase: 85:15 CO₂ / IPA, 1.05 g dissolved in IPA to give a 50 mg / mL solution, 50 mg injected every 1.9 min] to give Isomer 1 (first eluting isomer, 376 mg, 27%, >99% de) and Isomer 2 (second eluting isomer, 487 mg, 35%, >99% de).

[0290] Preparation 93 tert-Butyl (3S)-3-[1-[(3-aminophenoxy)-2-tert-butoxy-2-oxo-ethyl]pyrrolidine-1-carboxylate (isomer 2)

[0291] [ka] To a mixture of tert-butyl (3S)-3-[2-tert-butoxy-1-(3-nitrophenoxy)-2-oxo-ethyl]pyrrolidine-1-carboxylate (isomer 2, 486 mg, 1.15 mmol) in EtOH (20 mL) was added Pd (5% by weight on carbon, 250 mg, 0.117 mmol). The slurry was stirred under hydrogen gas for 4 hours, then filtered and concentrated to afford the title compound (410 mg, 91%) as an oil, which was carried forward without characterization.

[0292] Preparation 94 tert-Butyl (3R)-3-[(1S)-2-tert-butoxy-1-[[3-[[3-[(2S)-3-tert-butoxy-2-[(3R)-1-tert-butoxycarbonylpyrrolidin-3-yl]-3-oxo-propyl]phenyl]carbamoylamino]phenyl]methyl]-2-oxo-ethyl]pyrrolidine-1-carboxylate

[0293] [ka] tert-Butyl (3R)-3-[(1S)-1-[(3-aminophenyl)methyl]-2-tert-butoxy-2-oxo-ethyl]pyrrolidine-1-carboxylate (prepared essentially as described in WO 2020 / 247429, 57.80 g, 148.0 mmol) and 1,1′-carbonyldiimidazole (12 g, 74 mmol) in 2-methyltetrahydrofuran (240 mL) were stirred at 70° C. overnight. The mixture was cooled to room temperature, and then water (250 mL) and 2-methyltetrahydrofuran (250 mL) were added. The layers were separated, and the organic layer was dried over MgSO 4 , filtered, and concentrated. The residue was triturated in a 1:1 mixture of IPA / water (600 mL) at 60° C. for 4 hours, then at room temperature overnight. The resulting solid was filtered, washed with 1:1 IPA / water, and dried under reduced pressure at 40°C to give the title compound (58 g, 97%). ES / MS (m / z): 706 (M+H-BOC). Analytical chiral SFC [column: Chiralpak IB 4.6 x 100 mm, 5 µm, mobile phase: solvent A = MeOH + 0.2% isopropylamine, flow rate 4 mL / min, column temperature 40°C] shows a de > 98%.

[0294] The following were prepared essentially as described in Preparation 94 using the appropriate amine:

[0295] [Table 11-1]

[0296] [Table 11-2]

[0297] [Table 11-3]

[0298] [Table 11-4]

[0299] [Table 11-5]

[0300] [Table 11-6] A. Purification by silica gel chromatography eluting with EtOAc:hexane B. Purification by reversed-phase flash chromatography, mobile phase: ACN in aqueous NH4CO3 (pH 9) C. tert-Butyl (3R)-3-[(1S)-1-[(3-aminophenyl)methyl]-2-tert-butoxy-2-oxo-ethyl]pyrrolidine-1-carboxylate (prepared essentially as described in WO 2020 / 247429) D. After the reaction was complete, the mixture was concentrated in vacuo and no aqueous workup was performed.

[0301] E. Purification by silica gel chromatography eluting with acetone:DCM F. Purification by silica gel chromatography eluting with acetone:hexane G. Prepared using isomer 1 of the amine starting material H. Prepared using isomer 2 of the amine starting material I. Prepared using isomer 3 of the amine starting material J. Prepared using isomer 4 of the amine starting material K. Starting Material tert-butyl (3R)-3-[(1S)-2-tert-butoxy-1-[[3-[[[3-[(2S)-3-tert-butoxy-2-[(3R)-1-tert-butoxycarbonylpyrrolidin-3-yl]-3-oxo-propyl]phenyl]methylamino]methyl]phenyl]methyl]-2-oxo-ethyl]pyrrolidine-1-carboxylate (prepared essentially as described in WO 2020 / 247429) L. No MS data available, 1H NMR(400.21MHz,CDCl3)δ7.28(m,12H),4.60-4.56(m,4H),3.72-3.62(m,6H),3.31-3.22(m,3H),3.05-2 .95(m,9H),2.51-2.43(m,6H),1.99-1.91(m,3H),1.74-1.70(m,3H),1.48(s,27H),1.30-1.28(m,27H). M.MS data, 1 H NMR(400.13MHz,DMSO-d6)δ7.55-7.48(m,1H),7.32-7.23(m,2H),7.22-7.14(m,2H),7.14-6. 98(m,6H),6.77(d,J=7.7Hz,1H),5.76(d,J=1.3Hz,1H),4.89-4.76(m,2H),3.56-3.41(m,3H) ,3.39-3.27(m,3H),3.20-3.06(m,3H),2.99-2.88(m,3H),2.80-2.61(m,6H),2.58-2.37(m,3 H),2.35-2.17(m,3H),1.90-1.76(m,3H),1.66-1.49(m,3H),1.39(s,27H),1.24-1.21(m,27H)

[0302] Preparation 107 tert-Butyl (3S)-3-[(1S)-2-tert-butoxy-1-[3-[[3-[(1S)-2-tert-butoxy-1-[(3S)-1-tert-butoxycarbonylpyrrolidin-3-yl]-2-oxo-ethoxy]phenyl]carbamoylamino]phenoxy]-2-oxo-ethyl]pyrrolidine-1-carboxylate, isomer 2

[0303] [ka] tert-Butyl (3S)-3-[1-(3-aminophenoxy)-2-tert-butoxy-2-oxo-ethyl]pyrrolidine-1-carboxylate (isomer 2,410 mg, 1.045 mmol) was dissolved in THF (12 mL), and then CDI (102 mg, 0.63 mmol) and DMAP (26 mg, 0.20 mmol) were added to the mixture. The reaction was stirred at room temperature for 56 h, and then additional CDI (160 mg, 0.987 mmol) was added, and the mixture was stirred at 40 °C for 18 h. The reaction mixture was concentrated to dryness under reduced pressure, and the residue was purified by silica gel chromatography using a gradient of 0 to 50% EtOAc in hexanes to afford the title compound (200 mg, 24%) as a clear, glassy solid, which was carried forward without characterization.

[0304] The following were prepared essentially as described in Preparation 107 using the appropriate amine:

[0305] [Table 12] A: Prepared using isomer 1 of the amine starting material B: Upon completion, the reaction was diluted with EtOAc, washed with saturated aqueous NaHCO3, washed with saturated aqueous NaCl, dried over Na2SO4, filtered, concentrated and then purified.

[0306] Preparation 110 (2S)-2-[(3R)-1-tert-butoxycarbonylpyrrolidin-3-yl]-3-[3-[3-[3-[(2S)-2-[(3R)-1-tert-butoxycarbonylpyrrolidin-3-yl]-2-carboxy-ethyl]phenyl]-2-oxo-hexahydropyrimidin-1-yl]phenyl]propanoic acid

[0307] [ka] A mixture of (2S)-3-(3-bromophenyl)-2-[(3R)-1-tert-butoxycarbonylpyrrolidin-3-yl]propanoic acid (prepared essentially as described in WO 2020 / 247429, 347 mg, 0.872 mmol), tetrahydro-2(1H)-pyrimidinone (45 mg, 0.436 mmol), sodium tert-butoxide (126 mg, 1.31 mmol), tBuXPhos Pd G3 (35 mg, 0.043 mmol), and 1,4-dioxane (4.36 mL) was purged with nitrogen for 10 minutes, and then the reaction vessel was sealed and heated at 100° C. for 16 hours. Additional (2S)-3-(3-bromophenyl)-2-[(3R)-1-tert-butoxycarbonylpyrrolidin-3-yl]propanoic acid (174 mg, 0.436 mmol), sodium tert-butoxide (126 mg, 1.31 mmol), and tBuXPhos Pd G3 (35 mg, 0.043 mmol) were added, and the mixture was then purged with nitrogen for 10 minutes, sealed, and heated at 100° C. for 16 hours. Additional sodium tert-butoxide (126 mg, 1.31 mmol) and tBuXPhos Pd G3 (35 mg, 0.043 mmol) were added, and the mixture was then purged with nitrogen for 10 minutes, sealed, and heated at 100° C. for 2.5 hours. The reaction was filtered through a pad of diatomaceous earth and washed with DCM and MeOH. The filtrate was concentrated under reduced pressure, and the residue was purified by reverse-phase flash chromatography using a gradient of 20-50% ACN in aqueous NH4CO3 (pH 9) to give the title compound (155 mg, 48%). ES / MS (m / z): 735 (M+H).

[0308] The following were prepared essentially as described in Preparation 110 using the appropriate aryl halide and imidazolidin-2-one:

[0309] [Table 13] A. Use isomer 2 of the starting aryl bromide B. The product was precipitated from the reaction mixture using a mixture of MTBE and hexane. C. Purification by silica gel chromatography using a gradient of 10-40% EtOH + 1% in hexane + 1% acetic acid

[0310] Preparation 113 tert-Butyl (3R)-3-[(1S)-2-tert-butoxy-1-[[3-(2-chloroacetyl)amino]phenyl]methyl]-2-oxo-ethyl]pyrrolidine-1-carboxylate

[0311] [ka] TEA (1.5 equivalents, 0.107 mL, 0.7682 mmol) was added to a mixture of tert-butyl (3R)-3-[(1S)-1-[(3-aminophenyl)methyl]-2-tert-butoxy-2-oxo-ethyl]pyrrolidine-1-carboxylate (prepared essentially as described in WO 2020 / 247429, 200 mg, 0.5122 mmol) in DCM (0.16 M, 3.201 mL) at 0°C. This was stirred at this temperature for 10 minutes, and then chloroacetyl chloride (1.1 equivalents, 0.04478 mL, 0.5634 mmol) was added. The mixture was stirred at room temperature overnight. NaHCO3 (saturated) (5 mL) was added, and the aqueous layer was extracted with DCM. The organic layer was washed with saturated aqueous NaCl and filtered through diatomaceous earth. The solution was dried over MgSO4 and the solvent removed under reduced pressure to give the title compound (238 g, 99%). ES / MS (m / z) 368 (M+H-BOC).

[0312] Preparation 114 tert-Butyl (3R)-3-[(1S)-2-tert-butoxy-1-[[3-[4-[3-[(2S)-3-tert-butoxy-2-[(3R)-1-tert-butoxycarbonylpyrrolidin-3-yl]-3-oxo-propyl]phenyl]-2,5-dioxo-piperazin-1-yl]phenyl]methyl]-2-oxo-ethyl]pyrrolidine-1-carboxylate

[0313] [ka] Potassium carbonate (0.1409 g, 1.019 mmol) was added to a solution of tert-butyl (3R)-3-[(1S)-2-tert-butoxy-1-[[3-[(2-chloroacetyl)amino]phenyl]methyl]-2-oxo-ethyl]pyrrolidine-1-carboxylate (238 mg, 0.5096 mmol) in ACN (5 mL), and the mixture was stirred at 80° C. overnight. The mixture was cooled to room temperature, quenched with water, and then extracted with EtOAc. The organic layer was washed with saturated aqueous NaCl and filtered through diatomaceous earth. The solution was dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase HPLC [Column: XBridge® C18 19 × 100 mm, 5 μm, Mobile phase: Solvent A - aqueous NH4HCO3 (20 mM, pH 9), Solvent B - ACN, Flow rate: 25 mL / min] to give the title compound (63 mg, 14%) as a colorless oil. ES / MS (m / z): 762 (M+H-BOC).

[0314] Preparation 115 tert-Butyl (3R)-3-[(1S)-2-tert-butoxy-1-[[3-[[3-[(2S)-3-tert-butoxy-2-[(3R)-1-tert-butoxycarbonylpyrrolidin-3-yl]-3-oxo-propyl]-N-carbamoyl-anilino]methyl]phenyl]methyl]-2-oxo-ethyl]pyrrolidine-1-carboxylate

[0315] [ka] A solution of potassium cyanate (115 mg, 1.420 mmol) in water (1.82 mL) was added to a solution of tert-butyl (3R)-3-[(1S)-2-tert-butoxy-1-[[3-[[3-[(2S)-3-tert-butoxy-2-[(3R)-1-tert-butoxycarbonylpyrrolidin-3-yl]-3-oxo-propyl]anilino]methyl]phenyl]methyl]-2-oxo-ethyl]pyrrolidine-1-carboxylate (prepared essentially as described in WO 2020 / 247429, 260 mg, 0.284 mmol) in acetic acid (2.27 mL) at room temperature, and the mixture was stirred for 30 minutes. Water was added, and the aqueous layer was extracted with EtOAc. The organic phase was washed with saturated aqueous NaHCO3. The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 15-100% MTBE in hexane to give the title compound (212 mg, 87%). ES / MS (m / z): 821 (M+H).

[0316] Preparation 116 (2S)-2-[(3R)-1-tert-butoxycarbonylpyrrolidin-3-yl]-3-[3-[3-[3-[(2S)-2-[(3R)-1-tert-butoxycarbonylpyrrolidin-3-yl]-2-carboxy-ethyl]phenyl]-2-oxo-benzimidazol-1-yl]phenyl]propanoic acid

[0317] [ka] (2S)-3-(3-bromophenyl)-2-[(3R)-1-tert-butoxycarbonylpyrrolidin-3-yl]propanoic acid (prepared essentially as described in WO 2020 / 247429, 400 mg, 1.004 mmol), 1,3-dihydrobenzimidazol-2-one (67 mg, 0.5021 mmol, 0.5 equiv), potassium carbonate (486 mg, 3.515 mmol, 3.5 equiv), cuprous iodide (29 mg, 1.506 mmol, 1.5 equiv), N,N'-dimethylethylenediamine (0.322 mL, 3.013 mmol, 3 equiv) and anhydrous toluene (1.5 mL, 1.5 mL / mmol) were purged with nitrogen for 10 minutes, then the reaction vessel was sealed and heated at 100 °C for 4 hours. The reaction mixture was filtered through a pad of diatomaceous earth, and the pad was then washed with DCM and MeOH. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by reverse-phase chromatography using a gradient of 20-50% ACN in aqueous NH4CO3 (pH 9) to give a blue solid. The solid was dissolved in MeOH (12 mL), and then SiliaMetS® Thiol metal scavenger (1.2 g) was added, and the mixture was stirred at room temperature for 18 hours. The suspension was filtered and washed with MeOH. The filtrate was concentrated under reduced pressure to give the title compound (183 mg, 24%). ES / MS (m / z): 769 (M+H).

[0318] Preparation 117 (2S)-2-[(3R)-1-tert-butoxycarbonylpyrrolidin-3-yl]-3-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl]phenyl]propanoic acid

[0319] [ka] (2S)-3-(3-bromophenyl)-2-[(3R)-1-tert-butoxycarbonylpyrrolidin-3-yl]propanoic acid ammonium salt (see Preparation 24; 2 g, 4.82 mmol), bis(pinacolato)diboron (1.85 g, 7.22 mmol), potassium acetate (0.945 g, 9.63 mmol), 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (0.286 g, 0.337 mmol), and anhydrous 1,4-dioxane (12 mL) were purged with nitrogen gas for 10 minutes and stirred at 90°C overnight. The reaction was cooled to room temperature, then water was added, and the aqueous layer was extracted with EtOAc. The organic layer was washed with saturated aqueous NaCl and filtered through a pad of diatomaceous earth. The filtrate was dried over MgSO, filtered, concentrated under reduced pressure, and then purified by silica gel chromatography using a gradient of 0-100% acetone in hexanes to give the title compound (2.14 g, 100%). ES / MS (m / z): 346 (M+H-BOC).

[0320] Preparation 118 (2R)-2-[(3S)-1-tert-butoxycarbonylpyrrolidin-3-yl]-3-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl]phenyl]propanoic acid

[0321] [ka] The title compound was prepared essentially as described in Preparation 117 using (2R)-3-(3-bromophenyl)-2-[(3S)-1-tert-butoxycarbonylpyrrolidin-3-yl]propanoic acid ammonium salt. ES / MS (m / z): 346 (M+H-BOC).

[0322] Preparation 119 (2S)-2-[(3R)-1-tert-butoxycarbonylpyrrolidin-3-yl]-3-[3-[3-[3-[(2S)-2-[(3R)-1-tert-butoxycarbonylpyrrolidin-3-yl]-2-carboxy-ethyl]phenyl]phenyl]propanoic acid

[0323] [ka] (2S)-3-(3-bromophenyl)-2-[(3R)-1-tert-butoxycarbonylpyrrolidin-3-yl]propanoic acid ammonium salt (see Preparation 24; 500 g, 1.20 mmol), (2S)-2-[(3R)-1-tert-butoxycarbonylpyrrolidin-3-yl]-3-[3-(4,4 A mixture of [5,5-tetramethyl-1,3,2-dioxaborolan-2-yl]phenylpropanoic acid (0.804 g, 1.81 mmol), 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (0.201 g, 0.241 mmol), and K2CO3 (0.499 g, 3.61 mmol) was stirred overnight at 110 °C under nitrogen. The reaction was cooled and filtered through a pad of diatomaceous earth, washing with DCM and MeOH. The filtrate was concentrated under reduced pressure, and the residue was purified by reverse-phase HPLC [Column: XBridge® C18 (19 × 100 mm, 5 μm), Mobile phase: Solvent A - aqueous NH4HCO3 (20 mM, pH 9), Solvent B - ACN, 1:3 B:A, Flow rate: 25 mL / min] to give the title compound (442 mg, 58%). ES / MS (m / z): 537 (M+H-BOC).

[0324] Preparation 120 (2R)-2-[(3S)-1-tert-butoxycarbonylpyrrolidin-3-yl]-3-[3-[3-[(2R)-2-[(3S)-1-tert-butoxycarbonylpyrrolidin-3-yl]-2-carboxy-ethyl]phenyl]propanoic acid

[0325] [ka] The title compound is prepared essentially as described in Preparation 119 using (2R)-3-(3-bromophenyl)-2-[(3S)-1-tert-butoxycarbonylpyrrolidin-3-yl]propanoic acid ammonium salt and (2R)-2-[(3S)-1-tert-butoxycarbonylpyrrolidin-3-yl]-3-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]propanoic acid. Upon completion of the reaction, the reaction mixture is quenched with water and extracted with EtOAc. The organic phase is washed with saturated aqueous NaCl, dried over MgSO4, filtered, and concentrated. The residue is purified by silica gel chromatography using a gradient of 90-100% EtOAc in hexanes to afford the title compound as a colorless oil. ES / MS (m / z): 537 (M+H-BOC).

[0326] Preparation 121 tert-Butyl (3R)-3-[(1S)-2-tert-butoxy-1-[[3-[3-[(2S)-3-tert-butoxy-2-[(3R)-1-tert-butoxycarbonylpyrrolidin-3-yl]-3-oxo-propyl]-5-(trifluoromethyl)anilino]phenyl]methyl]-2-oxo-ethyl]pyrrolidine-1-carboxylate

[0327] [ka] tert-Butyl (3R)-3-[(1S)-1-[[3-bromo-5-(trifluoromethyl)phenyl]methyl]-2-tert-butoxy-2-oxo-ethyl]pyrrolidine-1-carboxylate (250 mg, 0.479 mmol), tert-butyl (3R)-3-[(1S)-1-[(3-aminophenyl)methyl]-2-tert-butoxy-2-oxo-ethyl]pyrrolidine-1-carboxylate (essentially WO 2020 / 24

[0044] Prepared as described in US Pat. No. 7429, 0.224 g, 0.574 mmol), cesium carbonate (468 mg, 1.44 mmol), and methanesulfonato(2-dicyclohexylphosphino-2',6'-di-i-propoxy-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (0.3 equiv., 123 mg, 0.144 mmol) were mixed and heated with stirring at 110°C for 16 hours, then filtered through a pad of diatomaceous earth, washing with DCM and MeOH. The filtrate was concentrated under reduced pressure. This material was purified by RP-HPLC / MS [column: XBridge® C18 (19 × 100 mm, 5 μm), mobile phase: 20 mM aqueous NH4HCO3 in water (pH 9)-solvent A, ACN-solvent B, elution conditions: gradient of 74% to 95% B, flow rate: 25 mL / min, column at room temperature] to give the title compound (173 mg, 43%). ES / MS (m / z): 732 (M+H-BOC).

[0328] The following were prepared essentially as described in Preparation 121 using the appropriate starting materials:

[0329] [Table 14] A. Purification on a hydrophobic-lipophilic balance (HLB) column eluted with a gradient of 0-100% ACN in aqueous NH4HCO3 (pH 9).

[0330] Preparation 124 tert-Butyl (3R)-3-[(1S)-1-[(4-bromophenyl)methyl]-2-tert-butoxy-2-oxo-ethyl]pyrrolidine-1-carboxylate

[0331] [ka] (2S)-3-(4-bromophenyl)-2-[(3R)-1-tert-butoxycarbonylpyrrolidin-3-yl]propanoic acid (2.73 g, 6.85 mmol) was dissolved in toluene (68 mL) and heated at 80° C., and 1,1-di-tert-butoxy-N,N-dimethyl-methanamine (12.8 mL, 48.0 mmol) was added. The mixture was stirred and heated at 80° C. for 3 hours. Additional 1,1-di-tert-butoxy-N,N-dimethyl-methanamine (3.0 mL, 11 mmol) was added, and the reaction was stirred at 80° C. for 16 hours. The reaction was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with a gradient of 0-40% EtOAc in hexanes to give the title compound (3.0 g, 90%). ES / MS (m / z): 342 / 344 (M+H-2×tert-butyl).

[0332] Preparation 125 tert-Butyl (3R)-3-[(1S)-1-[(4-aminophenyl)methyl]-2-tert-butoxy-2-oxo-ethyl]pyrrolidine-1-carboxylate

[0333] [ka] A suspension of tert-butyl (3R)-3-[(1S)-1-[(4-bromophenyl)methyl]-2-tert-butoxy-2-oxo-ethyl]pyrrolidine-1-carboxylate (1.51 g, 3.32 mmol), copper(I) oxide (0.490 g, 3.32 mmol), L-proline (0.586 g, 4.98 mmol), and sodium azide (0.655 g, 9.97 mmol) in DMSO (16 mL) was degassed with a positive stream of argon. The reaction mixture was heated in a microwave reactor at 100 °C for 36 h. The reaction was carefully evacuated, poured into EtOAc (100 mL), and washed with saturated aqueous NaHCO (2 × 50 mL). The organic extract was dried over MgSO4, filtered, and concentrated under reduced pressure to give the title compound (quantitative yield, 3.32 mmol) ES / MS (m / z): 291 (M+H-BOC).

[0334] Preparation 126 tert-Butyl (3R)-3-[(1S)-1-[[3-[(3-acetoxyphenoxy)methyl]phenyl]methyl]-2-tert-butoxy-2-oxo-ethyl]pyrrolidine-1-carboxylate

[0335] [ka] Diethyl azodicarboxylate (0.23 mL, 1.5 mmol) was added to a solution of tert-butyl (3R)-3-[(1S)-2-tert-butoxy-1-[[3-(hydroxymethyl)phenyl]methyl]-2-oxo-ethyl]pyrrolidine-1-carboxylate (200 mg, 0.493 mmol), triphenylphosphine (196 mg, 0.739 mmol), and (3-hydroxyphenyl)acetate (82 mg, 0.54 mmol) in THF (2 mL) under a nitrogen atmosphere. The mixture was stirred at room temperature for 16 hours, and saturated aqueous NaHCO was added. The organic phase was separated from the aqueous phase, washed with saturated aqueous NaCl (3x), dried over MgSO, and concentrated under reduced pressure. The resulting residue was chromatographed on silica gel eluting with EtOAc:hexanes (10-60% gradient) to give the title compound (123 mg, 46% yield). ES / MS (m / z): 538 (M−H).

[0336] Preparation 127 tert-Butyl (3R)-3-[(1S)-2-tert-butoxy-1-[[3-[(3-hydroxyphenoxy)methyl]phenyl]methyl]-2-oxo-ethyl]pyrrolidine-1-carboxylate

[0337] [ka] Potassium carbonate (67 mg, 0.68 mmol) was added to a solution of tert-butyl (3R)-3-[(1S)-1-[[3-[(3-acetoxyphenoxy)methyl]phenyl]methyl]-2-tert-butoxy-2-oxo-ethyl]pyrrolidine-1-carboxylate (123 mg, 0.227 mmol) in MeOH (4 mL). The mixture was stirred at room temperature for 15 minutes, and the solvent was evaporated under reduced pressure. 0.5 N aqueous HCl and DCM were added. The organic phase was separated, washed with saturated aqueous NaCl, dried over MgSO4, and concentrated under reduced pressure to give the title compound (117 mg, 92% yield). ES / MS (m / z): 398 (M+H-Boc).

[0338] Preparation 128 tert-Butyl (3R)-3-[(1S)-2-tert-butoxy-1-[[3-[[3-[[3-[(2S)-3-tert-butoxy-2-[(3R)-1-tert-butoxycarbonylpyrrolidin-3-yl]-3-oxo-propyl]phenyl]methoxy]phenoxy]methyl]phenyl]methyl]-2-oxo-ethyl]pyrrolidine-1-carboxylate

[0339] [ka] Diethyl azodicarboxylate (0.11 mL, 0.71 mmol) was added to a solution of tert-butyl (3R)-3-[(1S)-2-tert-butyl-1-[[3-[(3-hydroxyphenoxy)methyl]phenyl]methyl-2-oxo-ethyl]pyrrolidine-1-carboxylate (117 mg, 0.253 mmol), triphenylphosphine (93 mg, 0.352 mmol, 1.5 equivalents), and tert-butyl (3R)-3-[(1S)-2-tert-butoxy-1-[[3-(hydroxymethyl)phenyl]methyl]-2-oxo-ethyl]pyrrolidine-1-carboxylate (prepared essentially as described in WO 2020 / 247429, 105 mg, 0.259 mmol) in THF (2 mL) under a nitrogen atmosphere. The mixture was stirred at room temperature for 16 hours. Further triphenylphosphine (93 mg, 0.352 mmol) and diethyl azodicarboxylate (0.11 mL, 0.705 mmol) were added. After 3 h, saturated aqueous NaHCO was added. The organic phase was separated, washed with saturated aqueous NaCl, dried over MgSO, and concentrated under reduced pressure. The residue was purified by reverse-phase HPLC [Column: XBridge® C18 5 μm, 19 × 100 mm, Mobile phase: Solvent A - aqueous NH4HCO3 (20 mM, pH 9.0), Solvent B - ACN, Gradient: 75-95% Solvent B in Solvent A, Flow rate: 25 mL / min, Column temperature: 50 °C] to give the title compound (50 mg, 24%). ES / MS (m / z): 785 (M+H-Boc).

[0340] Preparation 129 tert-Butyl (3R)-3-[(1S)-2-tert-butoxy-1-[[3-[5-[(2S)-3-tert-butoxy-2-[(3R)-1-tert-butoxycarbonylpyrrolidin-3-yl]-3-oxo-propyl]-1-(2-phenylethyl)benzimidazol-2-yl]phenyl]methyl]-2-oxo-ethyl]pyrrolidine-1-carboxylate

[0341] [ka] tert-Butyl (3R)-3-[(1S)-2-tert-butoxy-1-[(4-fluoro-3-nitrophenyl)methyl]-2-oxo-ethyl]pyrrolidine-1-carboxylate (50 mg, 0.114 mmol) from a freshly prepared stock solution (0.2 M in DMA) was added to 2-phenylethanamine (0.118 mmol) in a tube. DMA (980 μL) was then added, and the mixture was stirred at 90° C. for 2 hours. NaSO (295 μL, 0.59 mmol, 2 M) was added, followed by tert-butyl (3R)-3-[(1S)-2-tert-butoxy-1-[(3-formylphenyl)methyl]-2-oxo-ethyl]pyrrolidine-1-carboxylate (prepared essentially as described in WO 2020 / 247429, 118 μmol, 0.118 mmol) from a stock solution (0.6 M in DMA). The mixture was stirred at 90° C. for 2 hours and then at room temperature overnight. The mixture was loaded onto an HLB cartridge (6 g) and then eluted with water (2 column volumes) and ACN (2 column volumes). The solvent of the organic fraction was evaporated under nitrogen. The crude material was purified by RP-HPLC / MS [Column: XBridge® C18 (19 × 100 mm, 5 μm), Mobile phase: Solvent A - 20 mM NH4HCO3 in water (pH 9), Solvent B - ACN, Gradient of 74% to 95% Solvent B in Solvent A, Flow rate: 25 mL / min, Column at room temperature] to give the title compound (45 mg, 44% yield).

[0342] Preparation 130 tert-Butyl (3R)-3-[(1S)-2-tert-butoxy-1-[[3-[3-[(2S)-3-tert-butoxy-2-[(3R)-1-tert-butoxycarbonylpyrrolidin-3-yl]-3-oxo-propyl]-N-carbamoyl-anilino]phenyl]methyl]-2-oxo-ethyl]pyrrolidine-1-carboxylate

[0343] [ka] To a solution of tert-butyl (3R)-3-[(1S)-2-tert-butoxy-1-[[3-[3-[(2S)-3-tert-butoxy-2-[(3R)-1-tert-butoxycarbonylpyrrolidin-3-yl]-3-oxo-propyl]anilino]phenyl]methyl]-2-oxo-ethyl]pyrrolidine-1-carboxylate (150 mg, 0.2 mmol) in toluene (12 mL / mmol, 2.4 mL) was added sodium cyanate (30 mg, 0.5 mmol). TFA (0.072 mL, 0.9 mmol) was then added, and the mixture was stirred at room temperature overnight. The residue was purified by silica gel chromatography using a gradient of 0-100% acetone in hexane to give the title compound (76 mg, 42%). ES / MS (m / z): 708 (M+H-BOC).

[0344] Preparation 131 tert-Butyl (3R)-3-[(1S)-1[[3-[[2-bis[[3-[(2S)-3-tert-butoxy-2-[(3R)-1-tert-butoxycarbonylpyrrolidin-3-yl]-3-oxo-propyl]phenyl]methyl]amino]ethyl-[[(3-[(2S)-3-tert-butoxy-2-[(3R)-1-tert-butoxycarbonylpyrrolidin-3-yl]-3-oxo-propyl]phenyl]methyl]amino]methyl]phenyl]methyl]-2-tert-butoxy-2-oxo-ethyl]pyrrolidine-1-carboxylate

[0345] [ka] To a solution of tert-butyl (3R)-3-[(1S)-2-tert-butoxy-1-[[3-[[[3-][(2S)-3-tert-butoxy-2-[(3R)-1-tert-[butoxycarbonylpyrrolidin-3-yl]-3-oxo-propyl]phenyl]methylamino]methyl]phenyl]methyl]-2-oxo-ethyl]pyrrolidine-1-carboxylate (prepared essentially as described in WO 2020 / 247429, 185 mg, 0.334 mmol) in EtOH (5 mL) was added oxyaldehyde (16 mg, 13 μL, 0.1667 mmol) and MgSO. The mixture was stirred at room temperature for 30 minutes, then sodium triacetoxyborohydride (101 mg, 0.467 mmol) was added and the reaction was stirred for 5 hours. Additional oxyaldehyde (6 mg, 5 μL, 0.0467 mmol) was added, followed by sodium triacetoxyborohydride (25 mg, 0.117 mmol), and the reaction was stirred for 1 h. The reaction mixture was filtered and concentrated. The residue was dissolved in DCM and washed with saturated aqueous NaHCO and saturated aqueous NaCl, then dried over MgSO, filtered, and concentrated. The residue was purified by silica gel chromatography using a gradient of 10-90% EtOAc in hexanes to give the title compound (89 mg, 24%). 1 H NMR(400.13MHz,CDCl3)δ7.17(s,8H),7.04(s,8H),3.73-3.64(m,2H),3.59-3.39(m,14H),3.24(d,J=6.1Hz,4H),3.07-2.94(m,4H),2.86-2. 72(m,8H),2.64-2.55(m,4H),2.52-2.45(m,4H),2.38-2.34(m,4H),1. 97-1.90(m,4H),1.72-1.62(m,4H),1.48(s,36H),1.26-1.24(m,36H).

[0346] Preparation 132 (2S)-2-[(3R)-1-tert-butoxycarbonylpyrrolidin-3-yl]-3-(3-diphenylphenyl)propanoic acid

[0347] [ka] A mixture of (2S)-3-(3-bromophenyl)-2-[(3R)-1-tert-butoxycarbonylpyrrolidin-3-yl]propanoic acid (prepared essentially as described in WO 2020 / 247429, 500 mg, 1.26 mmol), phenylboronic acid (138 mg, 1.13 mmol), and K2CO3 (521 mg, 3.77 mmol) in 1,4-dioxane (12.6 mL) and water (1.3 mL) was purged with N2 for 5 minutes. 1,1'-Bis(diphenylphosphino)ferrocene-palladium(II) dichloride DCM complex (107 mg, 0.126 mmol) was added, and the reaction mixture was purged with N2 for 5 minutes and heated at 100 °C overnight. The reaction mixture was shaken between water and DCM, and the layers were separated. The aqueous layer was washed three times with DCM. The combined organic layers were dried over MgSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 10-50% acetone in hexanes to give the title compound (310 mg, 62%). ES / MS m / z 340 (M-tBu).

[0348] Preparation 133 (2S)-2-[(3R)-1-tert-butoxycarbonylpyrrolidin-3-yl]-3-[3-[2-(3-cyclopropylphenyl)ethoxy]phenyl]propanoic acid

[0349] [ka] A reaction vessel containing a mixture of (2S)-3-(3-bromophenyl)-2-[(3R)-1-tert-butoxycarbonylpyrrolidin-3-yl]propanoic acid (ammonium salt, 415 mg, 1.00 mmol), 8-hydroxyquinoline (19 mg, 0.13 mmol), CuI (14 mg, 0.072 mmol), and tribasic potassium phosphate (440 mg, 2.03 mmol) was purged with nitrogen, and then 2-(3-cyclopropylphenyl)ethanol (500 mg, 2.90 mmol) was added, and the reaction mixture was stirred at 110 °C for 24 h. The mixture was shaken with water, EtO, and HCl (1 M aqueous, 5 mL). The organic layer was washed with water, dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 0–17% EtOAc in DCM. Fractions containing the title compound were concentrated, combined with impure product from a similarly scaled reaction, and repurified by reverse-phase HPLC (Column: XBridge® C18 19 × 100 mm, 5 μm, Mobile phase: 45–65% ACN in aqueous NH4HCO3 (20 mM, pH 9), Flow rate: 25 mL / min) to give 71 mg (7%) of the title compound as a pale yellow oil. ES-MS m / z 424 (M-tBu).

[0350] Preparation 134 3-[(2S)-3-tert-butoxy-2-[(3R)-1-tert-butoxycarbonylpyrrolidin-3-yl]-3-oxo-propyl]phenyl]boronic acid

[0351] [ka] tert-Butyl (3R)-3-[(1S)-1-[(3-bromophenyl)methyl]-2-tert-butoxy-2-oxo-ethyl]pyrrolidine-1-carboxylate (prepared essentially as described in WO 2020 / 247429, 1.00 g, 2.20 mmol), tetrahydroxydiboron (0.302 g, 3.30 mmol), chloro(2-dicyclohexylphosphino-2',4') in EtOH (22 mL). A mixture of 2-(2'-amino-1,1'-biphenyl)palladium(II) (8.8 mg, 0.011 mmol), X-PHOS (0.01 equiv., 0.02201 mmol, 98% by weight, 0.01071 g), potassium acetate (0.65 g, 6.6 mmol), and ethylene glycol (0.37 mL, 0.41 g, 6.6 mmol) was stirred for 10 minutes with a nitrogen purge. The mixture was heated to 100°C for 3.5 hours and then stirred at room temperature overnight. The mixture was filtered through a short plug of diatomaceous earth and washed with EtOH. The filtrate was concentrated to dryness and then taken up in a mixture of water and EtOAc. The phases were separated, and the aqueous phase was extracted twice more with EtOAc. The combined organic phases were washed with saturated aqueous NaCl, dried over MgSO4, filtered, and evaporated to dryness. Half of the residue was purified by silica gel chromatography using a gradient of 25-100% EtOAc in hexanes to give the title compound (294 mg, 64% yield based on the purified portion). ES-MS m / z 280 (M+H-2 t Bu).

[0352] Preparation 135 (2S)-2-[(3R)-1-tert-butoxycarbonylpyrrolidin-3-yl]-3-[3-(5-chloro-2-thienyl)phenyl]propanoic acid

[0353] [ka] A mixture of (2S)-2-[(3R)-1-tert-butoxycarbonylpyrrolidin-3-yl]-3-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]propanoic acid (150 mg, 0.32 mmol), 2-bromo-5-chlorothiophene (98 mg, 0.48 mmol) in anhydrous DMF (3.2 mL) was purged with N for 10 minutes, followed by the addition of potassium phosphate dibasic (1 M solution in water, 1.6 mL, 1.6 mmol) and tetrakis(triphenylphosphine)palladium(0) (27 mg, 0.022 mmol). The resulting mixture was stirred at 100° C. for 4 hours and then cooled to room temperature. The mixture was purged with N for 5 minutes, then tetrakis(triphenylphosphine)palladium(0) (27 mg, 0.022 mmol) and dibasic potassium phosphate (1 M solution in water, 1.6 mL, 1.6 mmol) were added. The reaction was heated at 100 °C for 15.5 hours and then cooled to room temperature. The reaction was purged with N for 5 minutes, then 2-bromo-5-chlorothiophene (98 mg, 0.48 mmol), tetrakis(triphenylphosphine)palladium(0) (27 mg, 0.022 mmol) and dibasic potassium phosphate (1 M solution in water, 1.6 mL, 1.6 mmol) were added. ) was added, and the reaction mixture was stirred at 100 °C for 2 hours and at room temperature for 3 days. The reaction mixture was combined with a similar reaction mixture performed with 0.10 mmol of starting boronic acid. The combined mixture was filtered through a pad of diatomaceous earth and rinsed with MeOH. Aqueous citric acid (5%) was added to the filtrate, and the mixture was extracted with EtOAc. The organic layer was washed with saturated aqueous NaCl, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was repurified by silica gel chromatography using a gradient of 10–40% acetone in DCM, and then by reverse-phase HPLC [Column: XBridge® C18 19 × 100 mm, 5 μm; Mobile phase: 35–55% ACN in aqueous NH4HCO3 (20 mM, pH 9); Flow rate: 25 mL / min] to give the title compound (22.3 mg, 16%) as a white solid. ES-MS m / z 434 (M−H).

[0354] Preparation 136 (2S)-2-[(3R)-1-tert-butoxycarbonylpyrrolidin-3-yl]-3-(3-fluoro-5-thiazol-4-yl-phenyl)propanoic acid

[0355] [ka] A mixture of (2S)-3-(3-bromo-5-fluoro-phenyl)-2-[(3R)-1-tert-butoxycarbonylpyrrolidin-3-yl]propanoic acid (0.25 g, 0.60 mmol), bis(pinacolato)diboron (0.18 g, 0.72 mmol), potassium acetate (0.15 g, 1.5 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.027 g, 0.036 mmol) in 1,4-dioxane (4.8 mL) was heated at 100° C. overnight. The mixture was cooled to 80°C, and 4-bromothiazole (0.11 g, 0.061 mL, 0.66 mmol), Na2CO3 2 M (2 M solution in water, 1.8 mL, 1.8 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.013 g, 0.018 mmol) were added. The mixture was heated at 80°C for 5 h and then cooled to room temperature. The mixture was quenched with HCl (1 N aqueous) and extracted with EtOAc. The combined organic phases were filtered (diatomaceous earth), washed with saturated aqueous NaCl, dried over MgSO4, filtered, and evaporated to dryness. The residue was repurified via silica gel chromatography using a gradient of 0-80% EtOAc + 1% acetic acid, followed by purification via reverse-phase HPLC [Column: Bonus RP 21 × 100 mm, 5 μm, Mobile phase: 30-80% ACN in aqueous NH₄HCO₃ (20 mM, pH 8), Flow rate: 25 mL / min] to afford 88 mg (35%) of the title compound as a white solid. ES-MS m / z 421 (M+H).

[0356] Preparation 137 tert-Butyl (3R)-3-[(1S)-2-tert-butoxy-2-oxo-1-[(3-tetrahydropyran-4-ylphenyl)methyl]ethyl]pyrrolidine-1-carboxylate

[0357] [ka] A mixture of (2S)-3-(3-bromophenyl)-2-[(3R)-1-tert-butoxycarbonylpyrrolidin-3-yl]propanoic acid (prepared essentially as described in WO 2020 / 247429, 200 mg, 0.440 mmol), CsCO (0.431 g, 1.32 mmol) in toluene (3 mL) was purged with N, then 3,3-difluoropyrrolidine hydrochloride (75.8 mg, 0.528 mmol) and methanesulfonato(2-dicyclohexylphosphino-2',6'-di-i-propoxy-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (RuPhos Palladacycle Gen. 4, 113 mg, 0.132 mmol) were added, and the mixture was heated to 85 °C for 2 days. The reaction mixture was then filtered through diatomaceous earth and concentrated to dryness under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 5-25% EtOAc in hexanes to give the title compound (139 mg, 64%) as a brown oil. ES / MS m / z: 381 (M+H-BOC).

[0358] Preparation 138 (2S)-2-[(3R)-1-tert-butoxycarbonylpyrrolidin-3-yl]-3-[3-(5-methyl-2-oxo-indolin-1-yl)phenyl]propanoic acid

[0359] [ka] To a mixture of 5-methylindolin-2-one (202 mg, 1.35 mmol), (2S)-3-(3-bromophenyl)-2-[(3R)-1-tert-butoxycarbonylpyrrolidin-3-yl]propanoic acid (ammonium salt, 500 mg, 1.204 mmol), and K2CO3 (545 mg, 3.90 mmol) was added ACN (4 mL). A steady stream of N2 was bubbled through the suspension while heating at 40 °C for 15 min. Cuprous iodide (34.4 mg, 0.181 mmol) and DMF (39 μL) were added. The reaction vessel was sealed, and the mixture was heated at 80 °C for 15.5 h. The reaction mixture was cooled to room temperature, quenched with 1 N HCl, and extracted with EtOAc. The combined organic phase was washed with saturated aqueous NaCl, dried over MgSO4, filtered, and evaporated to dryness. The residue was purified by silica gel column chromatography using a gradient of 12-50% (1% acetic acid in acetone) in hexane. Toluene was added to the purified product, and the mixture was concentrated. A mixture of MTBE and hexane was then added to the residue and concentrated to give the title compound (277 mg, 50%) as a pale yellow solid. ES-MS m / z 521 (M+H).

[0360] Preparation 139 1-(3-benzyloxyphenyl)imidazolidin-2-one

[0361] [ka] Under an argon atmosphere, a mixture of ethylene urea (1.4 g, 16 mmol), 1-benzyloxy-3-iodobenzene (4.9 g, 16 mmol), cuprous iodide (0.61 g, 3.1 mmol), and potassium dihydrogen phosphate (4.2 g, 31 mmol) was suspended in DMF (argon-sparged, 20 mL), and then N,N'-dimethylethylenediamine (0.28 g, 0.33 mL, 3.1 mmol) was added. The suspension was heated to 120 °C for 3 h. The mixture was cooled and filtered through a pad of silica gel, and the pad was flushed with EtOAc. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography using 1:4:15 MeOH, acetone, and EtOAc to give the title compound (1.10 g, 26%). ES-MS m / z 269 (M+H).

[0362] Preparation 140 (2S)-3-[3-[3-(3-benzyloxyphenyl)-2-oxo-imidazolidin-1-yl]phenyl]-2-[(3R)-1-tert-butoxycarbonylpyrrolidin-3-yl]propanoic acid

[0363] [ka] To a mixture of 1-(3-benzyloxyphenyl)imidazolidin-2-one (1.09 g, 4.05 mmol) and (2S)-3-(3-bromophenyl)-2-[(3R)-1-tert-butoxycarbonylpyrrolidin-3-yl]propanoic acid (ammonium salt, 1.40 g, 3.37 mmol) under N was added ACN (16.9 mL) and DMF (3 mL). A steady stream of argon was bubbled through the suspension for 15 min, then KCO (1.52 g, 10.9 mmol), CuI (128 mg, 0.674 mmol), and N,N'-dimethylethylenediamine (120 mg, 0.147 mL, 1.35 mmol) were added, and the mixture was heated to 100 °C in a microwave reactor for 18 h. The mixture was quenched with water and extracted twice with EtOAc. The pH of the aqueous phase was acidified with 0.5 N aqueous HCl and extracted with EtOAc, DCM, and then again with EtOAc. The combined organic phases were dried over MgSO, filtered, and evaporated to dryness. The residue was purified by silica gel chromatography using a gradient of 10-60% (acetone + 1% acetic acid) in hexanes to give 1.10 g (56%) of a yellow oil that slowly crystallized. ES-MS m / z 486 (M+H-BOC).

[0364] Preparation 141 tert-Butyl (3R)-3-[(1S)-2-tert-butoxy-1-[[3-(3,3-dimethylindolin)-1-yl]phenyl]methyl]-2-oxo-ethyl]pyrrolidine-1-carboxylate

[0365] [ka] The title compound was prepared using 3,3-dimethylindoline essentially as described in Preparation 137. ES-MS m / z 521 (M+H).

[0366] Preparation 142 N,N'-bis[(4-methoxyphenyl)methyl]-N,N'-diphenyl-propanediamide

[0367] [ka] To a solution of N-[(4-methoxyphenyl)methyl]aniline (2.05 g, 9.61 mmol) in DCM (48 mL) was added malonic acid (500 mg, 0.308 mL, 4.80 mmol) and N,N'-dicyclohexylcarbodiimide (1.98 g, 9.60 mmol). The resulting mixture was stirred at room temperature overnight. The reaction was filtered through diatomaceous earth, and the filtrate was concentrated to dryness. The residue was purified by silica gel chromatography using a gradient of 0-10% (ammonia in MeOH) in DCM to afford 1 g (42%) of the title compound as a light gray solid. ES-MS m / z 495 (M+H).

[0368] Preparation 143 1,1'-bis[(4-methoxyphenyl)methyl]-3,3'-spirobi[indoline]-2,2'-dione

[0369] [ka] To a solution of N,N'-bis[(4-methoxyphenyl)methyl]-N,N'-diphenyl-propanediamide (1 g, 2.02 mmol) in 2,2,2-trifluoroethanol (55.2 g, 40 mL, 552 mmol), [bis(trifluoroacetoxy)iodo]benzene (1.9 g, 4.4 mmol) was added portionwise. The resulting mixture was stirred at room temperature for 3 days, then diluted with MeOH and concentrated to dryness. The residue was purified by silica gel chromatography using a gradient of 0-10% (ammonia in MeOH) in DCM to afford 746 mg (74%) of the title compound as a pale yellow solid. ES-MS m / z 491 (M+H).

[0370] Preparation 144 3,3'-Spirobi[indoline]-2,2'-dione

[0371] [ka] To a solution of 1,1'-bis[(4-methoxyphenyl)methyl]-3,3'-spirobi[indoline]-2,2'-dione (746 mg, 1.52 mmol) in DCM (15 mL) was added TFA (15 mL, 22.6 g, 198 mmol) and trifluoromethanesulfonic acid (8 mL) dropwise. The resulting mixture was stirred at room temperature for 3 h and then concentrated under a stream of N2. The residue was dissolved in DCM, then water was added, and the phases were separated. The organic phase was washed with saturated aqueous NaHCO3, then dried over Na2SO4, filtered, and concentrated. The residue was purified via silica gel chromatography using a gradient of 0-10% EtOAc in cyclohexane to afford 210 mg (55%) of the title compound as a pale yellow solid. ES-MS m / z 251 (M+H).

[0372] Preparation 145 (2S)-3-[3-(2,2'-dioxo-3,3'-spirobi[indoline]-1'-yl)phenyl]-2-[(3R)-pyrrolidin-3-yl]propanoic acid

[0373] [ka] The title compound was prepared essentially as described in Preparation 140 using 3,3'-spirobi[indoline]-2,2'-dione. Upon completion, the reaction mixture was diluted with MeOH, filtered through diatomaceous earth, and concentrated to dryness. The residue was purified on an HLB column using a gradient of 0-70% ACN in aqueous NH4HCO3 (pH 9). ES-MS m / z 590 (M+H).

[0374] Preparation 147 (2S)-2-[(3R)-1-tert-butoxycarbonylpyrrolidin-3-yl]-3-[3-[3-(2-oxo-3H-benzimidazol-1-yl]phenyl]propanoic acid

[0375] [ka] A suspension of (2S)-3-(3-bromophenyl)-2-[(3R)-1-tert-butoxycarbonylpyrrolidin-3-yl]propanoic acid (ammonium salt, 0.20 g, 0.48 mmol), 1,3-dihydrobenzimidazol-2-one (0.13 g, 0.96 mmol), cuprous iodide (0.14 g, 0.72 mmol), potassium carbonate (0.23 g, 1.69 mmol), and N,N'-dimethylethane-1,2-diamine (0.13 g, 1.45 mmol) in toluene (2.4 mL) in a pressure tube was sonicated for 5 minutes. The tube was sealed, and the mixture was heated at 110 °C for 16 hours. After cooling to room temperature, saturated aqueous NH4Cl was added, and the reaction was extracted with EtOAc. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by reverse-phase chromatography eluting with 20% to 50% ACN in aqueous NH4HCO3 to give the title compound (68.2 mg, 31%) as a white solid. ES / MS m / z 352 [M+H- t Bu].

[0376] Preparation 148 (2S)-2-[(3R)-1-tert-butoxycarbonylpyrrolidin-3-yl]-3-[3-[2-oxo-3-(2,2,2-trifluoroethyl)imidazolidin-1-yl]phenyl]propanoic acid

[0377] [ka] A sealed tube was charged with (2S)-3-(3-bromophenyl)-2-[(3R)-1-tert-butoxycarbonylpyrrolidin-3-yl]propanoic acid (prepared essentially as described in WO 2020 / 247429, 0.15 g, 0.38 mmol), 1-(2,2,2-trifluoroethyl)imidazolidin-2-one (0.19 g, 1.13 mmol), t-BuXPhos Pd G3 (0.03 g, 0.04 mmol), and sodium tert-butoxide (0.22 g, 2.26 mmol) in anhydrous 1,4-dioxane (3.8 mL), purged with nitrogen for 5 minutes, and stirred overnight at 100 °C. After cooling to room temperature, the reaction was filtered through a pad of diatomaceous earth and rinsed with EtOAc. The filtrate was extracted twice with 1 M aqueous NaOH, and the combined aqueous extracts were acidified to pH 3-4 with 1 M aqueous HCl and extracted twice with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with a gradient of 20% to 80% acetone in hexanes to give the title compound (75 mg, 40%) as a white solid. ES / MS m / z 386 (M+H-BOC).

[0378] Preparation 149 (2S)-2-[(3R)-1-tert-butoxycarbonylpyrrolidin-3-yl]-3-[3-fluoro-5-(2-oxoindolin-1-yl)phenyl]propanoic acid

[0379] [ka] A pressure tube was charged with 2-oxindole (0.11 g, 0.81 mmol), (2S)-3-(3-bromo-5-fluoro-phenyl)-2-[(3R)-1-tert-butoxycarbonylpyrrolidin-3-yl]propanoic acid (0.30 g, 0.72 mmol), and ACN (2.4 mL). A stream of N was bubbled through the solution for 15 minutes while heating to 40 °C. The reaction was then treated with KCO (0.33 g, 2.34 mmol), cuprous iodide (0.014 g, 0.072 mmol), and N,N'-dimethylethylenediamine (0.013 g, 0.14 mmol) to give a light blue suspension. The tube was sealed, and the mixture was heated at 80 °C overnight. After 16 h, the reaction was cooled to room temperature, quenched with 1N aqueous HCl, and extracted with EtOAc. The combined organic extracts were washed with saturated aqueous NaCl, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with a gradient of 12% to 50% acetone (with 1% HOAc) in hexanes to give the title compound (0.22 g, 89% wt, 57%) as a yellow solid. ES / MS m / z 369 (M+H-BOC).

[0380] Preparation 150 (2S)-2-[(3R)-1-tert-butoxycarbonylpyrrolidin-3-yl]-3-[4-(2,5-dioxoimidazolidin-1-yl)phenyl]propanoic acid

[0381] [ka] Hydantoin (0.25 g, 2.4 mmol), (2S)-3-(4-bromophenyl)-2-[(3R)-1-tert-butoxycarbonylpyrrolidin-3-yl]propanoic acid (0.32 g, 0.80 mmol), cuprous iodide (0.46 g, 2.4 mmol), K2CO3 (0.33 g, 2.4 mmol), and DMF (5 mL) were combined in a microwave vial under nitrogen. N,N'-Dimethylethylenediamine (0.22 g, 2.4 mmol) was added and the vial was sealed. The suspension was heated at 100 °C for 1 h. The reaction was cooled, diluted with EtOAc, and washed with 10% aqueous citric acid, water (x3), and then saturated aqueous NaCl. The organics were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with a gradient of 0% to 100% acetone (with 2% AcOH) in hexanes. The title compound (23 mg, 7%) was isolated as a clear wax. ES-MS m / z 362 (M+H- t Bu).

[0382] Preparation 151 tert-Butyl (3R)-3-[(1S)-2-tert-butoxy-2-oxo-1-[[3-(4-phenyl-1-piperidyl)phenyl]methyl]ethyl]pyrrolidine-1-carboxylate

[0383] [ka] A tube was charged with (2S)-3-(3-bromophenyl)-2-[(3R)-1-tert-butoxycarbonylpyrrolidin-3-yl]propanoic acid (prepared essentially as described in WO 2020 / 247429, 0.20 g, 0.44 mmol), cesium carbonate (0.57 g, 1.76 mmol), and toluene (3 mL). The reaction was purged with N, and then 4-phenylpiperidine hydrochloride (0.10 g, 0.53 mmol) and methanesulfonato(2-dicyclohexylphosphino-2',6'-di-i-propoxy-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (0.11 g, 0.13 mmol) were added. The tube was capped, and the reaction was stirred at 85 °C for 16 hours. The reaction was cooled, water was added, and the reaction was extracted with EtOAc. The organic layer was collected, dried over MgSO4, and concentrated under reduced pressure. The residue was taken up in EtOAc and filtered through Celite, and the solids were washed with EtOAc. The filtrate was concentrated under reduced pressure to give a yellow oil, which was purified by silica gel chromatography eluting with a gradient of 0% to 35% EtOAc in hexanes to give the title compound (0.19 g, 77%) as a colorless oil, which was used without further analysis.

[0384] Preparation 153 (2S)-2-[(3R)-1-tert-butoxycarbonylpyrrolidin-3-yl]-3-[3-(2-fluoro-3-methoxy-phenyl)phenyl]propanoic acid

[0385] [ka] A pressure tube was charged with (2S)-3-(3-bromophenyl)-2-[(3R)-1-tert-butoxycarbonylpyrrolidin-3-yl]propanoic acid (ammonia salt, 0.25 g, 0.60 mmol), 2-fluoro-3-methoxyphenylboronic acid (0.16 g, 0.90 mmol), potassium carbonate (0.25 g, 1.81 mmol), 1,4-dioxane (4.2 mL), water (0.60 mL), and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloride DCM complex (0.05 g, 0.06 mmol). The tube was sealed, and the mixture was heated at 100° C. for 2 hours. After cooling, the reaction was quenched with 5% aqueous citric acid and extracted with EtOAc. The combined organic phases were filtered through diatomaceous earth, washed with saturated aqueous NaCl, dried over MgSO, filtered, and concentrated under reduced pressure to give the title compound (0.27 g, 100%), which was used in purification. ES-MS m / z 388 (M+H-BOC).

[0386] Preparation 154 (2S)-2-[(3R)-1-tert-butoxycarbonylpyrrolidin-3-yl]-3-[3-(7-methoxybenzothiophen-2-yl)phenyl]propanoic acid

[0387] [ka] A sealed tube was charged with (2S)-2-[(3R)-1-tert-butoxycarbonylpyrrolidin-3-yl]-3-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]propanoic acid (0.20 g, 0.45 mmol), 2-iodo-7-methoxy-benzothiophene (0.20 g, 0.68 mmol), and anhydrous DMF (4.5 mL). The reaction was purged with N for 10 minutes, then treated with aqueous dipotassium phosphate (1 M, 2.25 mL, 2.25 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.01 g, 0.01 mmol) was added. The tube was sealed, and the reaction mixture was stirred at 80 °C for 3 hours. The reaction was cooled to room temperature, purged with nitrogen for 5 minutes, re-treated with tetrakis(triphenylphosphine)palladium(0) (0.01 g, 0.01 mmol), and stirred at 80 °C for 3 days. The reaction was cooled to room temperature. The mixture was quenched with 5% aqueous citric acid and extracted with EtOAc. The organic layer was washed with saturated aqueous NaCl, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with a gradient of 10% to 40% hexanes to give the title compound (0.15 g, 69%) as a beige solid. ES-MS m / z 480 (M−H).

[0388] Preparation 155 (2S)-2-[(3R)-1-tert-butoxycarbonylpyrrolidin-3-yl]-3-[3-[3-(2,2,2-trifluoroethoxy)phenyl]phenyl]propanoic acid

[0389] [ka] To a stirred mixture of (2S)-3-(3-bromophenyl)-2-[(3R)-1-tert-butoxycarbonylpyrrolidin-3-yl]propanoic acid (ammonia salt, 0.25 g, 0.60 mmol), 3-(2,2,2-trifluoroethoxy)phenylboronic acid (0.20 g, 0.90 mmol), potassium carbonate (0.25 g, 1.81 mmol), 1,4-dioxane (4.2 mL), and water (0.60 mL) at 100° C., 1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloride DCM complex (0.05 g, 0.06 mmol) was added. The tube was sealed, and the mixture was heated at 100° C. overnight. The mixture was stirred at room temperature for 24 hours. The reaction was quenched with 5% aqueous citric acid and extracted with EtOAc. The combined organic phases were washed with saturated aqueous NaCl, dried over MgSO4, filtered, and concentrated under reduced pressure to give the title compound (0.30 g, 100%), which was used without purification. ES-MS m / z 516 (M+Na).

[0390] Preparation 156 (2S)-3-[3-(1,3-benzothiazol-2-yl)phenyl]-2-[(3R)-1-tert-butoxycarbonylpyrrolidin-3-yl]propanoic acid

[0391] [ka] A pressure vial was charged with (2S)-2-[(3R)-1-tert-butoxycarbonylpyrrolidin-3-yl]-3-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]propanoic acid (0.25 g, 0.56 mmol), 2-bromo-1,3-benzothiazole (0.19 g, 0.84 mmol), DMF (5.6 mL), and dipotassium phosphate solution (1 M, 2.8 mL). The tube was warmed to 80° C., and tetrakis(triphenylphosphine)palladium(0) (0.013 g, 0.011 mmol) was added. The tube was sealed, and the mixture was heated at 80° C. for 90 minutes. The reaction was quenched with 5% aqueous citric acid and extracted with EtOAc. The combined organic phases were washed with saturated aqueous NaCl, dried over MgSO4, filtered and concentrated under reduced pressure to give the title compound (0.25 g, 100%), which was used in the next synthetic step without purification. ES-MS m / z 453 (M+H).

[0392] Preparation 157 (2S)-2-[(3R)-1-tert-butoxycarbonylpyrrolidin-3-yl]-3-[3-(3-phenylisoxazol-5-yl)phenyl]propanoic acid

[0393] [ka] A tube was charged with (2S)-3-(3-bromophenyl)-2-[(3R)-1-tert-butoxycarbonylpyrrolidin-3-yl]propanoic acid (prepared essentially as described in WO 2020 / 247429, 100 mg, 0.25 mmol), (3-phenylisoxazol-5-yl)boronic acid (61.7 mg, 0.33 mmol), and tetrakis(triphenylphosphine)palladium(0) (23.9 mg, 0.02 mmol). The tube was purged with nitrogen, then 1,4-dioxane (1 mL) was added. After purging with nitrogen, 2 M aqueous KCO (0.25 mL, 0.50 mmol) was added. The tube was purged with nitrogen three times, capped, and the reaction was stirred at 100 °C for 18 hours. An additional 26 mg of (3-phenylisoxazol-5-yl)boronic acid was added, and the reaction was stirred at 100 °C for an additional 2 h. After cooling, the reaction was loaded onto an HLB cartridge conditioned with ACN and aqueous NH4HCO3 and eluted with aqueous NH4HCO3 and ACN. The resulting residue was purified via reverse-phase purification to give the title compound (116.1 mg, 100%). ES-MS m / z 463 (M+H).

[0394] Manufacturing Example 158 (2S)-3-(3-aminophenyl)-2-[(3R)-1-tert-butoxycarbonylpyrrolidin-3-yl]propanoic acid

[0395] [ka] A mixture of (2S)-2-[(3R)-1-tert-butoxycarbonylpyrrolidin-3-yl]-3-(3-nitrophenyl)propanoic acid (prepared essentially as described in WO 2020 / 247429, 1.70 g, 4.67 mmol) and palladium (10% on activated carbon paste type 87L, 0.17 g) in MeOH (25 mL) was stirred under H2 (balloon) at room temperature for 4 h. The catalyst was removed by filtration through diatomaceous earth, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with a gradient of 10% to 40% ACN in water to give the title compound (1.00 g, 64%) as a white solid. ES-MS m / z 235 (M+H-BOC).

[0396] Manufacturing Example 159 (2S)-3-(3-azidophenyl)-2-[(3R)-1-tert-butoxycarbonylpyrrolidin-3-yl]propanoic acid

[0397] [ka] The title compound was prepared by flow reaction by first preparing the following solutions: Solution A—(2S)-3-(3-aminophenyl)-2-[(3R)-1-tert-butoxycarbonylpyrrolidin-3-yl]propanoic acid (0.80 g, 2.39 mmol) and DMF (80 mL) treated with azidotrimethylsilane (0.34 g, 2.87 mmol), and Solution B—tert-butyl nitrite (0.37 g, 3.59 mmol) in DMF (80 mL). Solutions A and B were mixed by passing them through a flow reactor (PTFE tubing, 15 mL capacity) at a temperature of 100 °C at a flow rate of 0.1 mL / min for Solution A and 0.13 mL / min for Solution B to give a solution of the title compound (120 mL, 0.015 M), which was used without purification.

[0398] Manufacturing Example 160 (2S)-3-[3-(4-benzyltriazol-1-yl)phenyl]-2-[(3R)-1-tert-butoxycarbonylpyrrolidin-3-yl]propanoic acid

[0399] [ka] A 0.015 M solution of (2S)-3-(3-azidophenyl)-2-[(3R)-1-tert-butoxycarbonylpyrrolidin-3-yl]propanoic acid in DMF (10 mL, 0.15 mmol) was combined with a solution of prop-2-ynylbenzene (30 mg, 0.26 mmol), aqueous sodium ascorbate (0.2 M, 0.40 mL, 0.08 mmol), tris[(1-benzyl-1H-1,2,3-triazol-4-yl)methyl]amine (8.0 mg, 0.02 mmol), and aqueous copper(II) sulfate pentahydrate (0.05 M, 0.30 mL, 0.02 mmol). The reaction was stirred at 50 °C for 2 h. Analysis showed mainly starting material. Additional tris[(1-benzyl-1H-1,2,3-triazol-4-yl)methyl]amine (8.0 mg, 0.02 mmol), aqueous sodium ascorbate (0.2 M, 0.40 mL, 0.08 mmol), and aqueous copper(II) sulfate pentahydrate (0.05 M, 0.30 mL, 0.02 mmol) were added. The reaction was stirred overnight at 50 °C. Analysis indicated that some starting material was still present. Sodium ascorbate (0.2 M, 0.40 mL, 0.08 mmol) and aqueous copper(II) sulfate pentahydrate (0.05 M, 0.30 mL, 0.02 mmol) were added, and the reaction was stirred at 50 °C for 2 h. After cooling, water was added. The aqueous layer was extracted with EtOAc, and the organic layer was dried over Na SO . The filtrate was concentrated under reduced pressure and the residue was purified by reverse-phase chromatography eluting with a gradient of 20% to 50% ACN in water to give the title compound (60.7 mg, 85%) as a dark yellow solid. ES-MS m / z 477 (M+H).

[0400] The following compounds were prepared essentially as described in Preparation 160, using the appropriate reagents, adjusting the temperature and reaction time to determine reaction completion, and adjusting the purification system accordingly.

[0401] [Table 15]

[0402] Preparation 164 (2S)-2-[(3R)-1-tert-butoxycarbonylpyrrolidin-3-yl]-3-(3-tetrahydropyran-4-ylphenyl)propanoic acid

[0403] [ka] A mixture of (2S)-3-(3-bromophenyl)-2-[(3R)-1-tert-butoxycarbonylpyrrolidin-3-yl]propanoic acid (prepared essentially as described in WO 2020 / 247429, 0.14 g, 0.35 mmol) and dichloro[1,3-bis(2,6-di-3-pentylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II) (0.01 g, 0.014 mmol) in dry 2-methyltetrahydrofuran (1.1 mL) was degassed with nitrogen for 5 minutes. Bromo(tetrahydropyran-4-yl)zinc (3 mL, 0.5 mol / L in THF, 1.40 mmol) was then added, the reaction vessel was sealed, and the reaction was heated to 100 °C under microwave irradiation for 30 minutes. Analysis indicated that starting material was still present. 2-Methyltetrahydrofuran (1.1 mL) and dichloro[1,3-bis(2,6-di-3-pentylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II) (0.01 g, 0.014 mmol) were added, followed by bromo(tetrahydropyran-4-yl)zinc (4 mL, 0.5 mol / L in THF, 2.09 mmol) at room temperature under a nitrogen atmosphere. The reaction was again heated to 100° C. for 30 minutes under microwave irradiation. 50 mg of the crude material from the reaction was added to this reaction. The mixture was filtered through a pad of diatomaceous earth, and the filtrate was evaporated under reduced pressure. The residue was suspended in DMSO (2 mL) and ACN (3 mL). The suspension was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure. The remaining DMSO solution was purified by C18 reverse-phase chromatography eluting with a gradient of 0% to 100% ACN in water. The resulting material was repurified by reverse-phase chromatography (XBridge® C18) eluting with a gradient of 5% to 40% ACN in aqueous 20 mM NH4HCO3 to give the title compound (10.5 mg, 7%) as a white solid. ES-MS m / z 402 (MH).

[0404] Preparation 165 tert-Butyl (3R)-3-[(1S)-2-tert-butoxy-1-[(3-cyclobutylphenyl)methyl]-2-oxo-ethyl]pyrrolidine-1-carboxylate

[0405] [ka] Tert-butyl (3R)-3-[(1S)-1-[(3-bromophenyl)methyl]-2-tert-butoxy-2-oxo-ethyl]pyrrolidine-1-carboxylate (prepared essentially as described in WO 2020 / 247429, 200 mg, 0.44 mmol), dichloro[1,3-bis(2,6-di-3-pentylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II) (7.36 mg, 0.01 mmol) in THF (1.76 mL) was degassed several times. Cyclobutylzinc bromide (0.5 mol / L in THF, 1 mL) was added dropwise, and the reaction was stirred at 70 °C for 1 hour. The reaction was evaporated under reduced pressure, and the residue was dissolved in DCM and filtered to remove inorganics. The filtrate was evaporated under reduced pressure to give the title compound (0.11 g, 56%) as an amber solid, which was purified by silica gel chromatography eluting with a gradient of 0% to 15% EtOAc in hexanes. ES / MS m / z 318 (M+H-2(tBu).

[0406] Preparation 166 (Z)-3-Amino-3-ethoxy-prop-2-enenitrile

[0407] [ka] Malononitrile (0.51 g, 7.57 mmol) and EtOH (0.38 g, 8.32 mmol) were dissolved in 2 M HCl in EtO (60.5 mL) at 0 °C under a nitrogen atmosphere. The reaction was warmed to room temperature and stirred for 4 h. The resulting precipitate was removed by filtration and washed thoroughly with EtO. The solid was treated with saturated aqueous KCO and extracted with EtO. The combined organic layers were collected, dried over NaSO, filtered, and concentrated under reduced pressure to give the title compound (0.51 g, 60%) as a white gel. 1 H NMR (400MHz, DMSO-d6)d ppm 1.21(t,J=6Hz,3H),3.85(d,J=6Hz,2H),6.51(s,1H).

[0408] Preparation 167 tert-Butyl (3R)-3-[(1S)-1-[[3-[[(E)-1-amino-2-cyano-vinyl]amino]phenyl]methyl]-2-tert-butoxy-2-oxo-ethyl]pyrrolidine-1-carboxylate

[0409] [ka] A tube was charged with (Z)-3-amino-3-ethoxy-prop-2-enenitrile (50 mg, 0.45 mmol), tert-butyl (3R)-3-[(1S)-1-[(3-aminophenyl)methyl]-2-tert-butoxy-2-oxo-ethyl]pyrrolidine-1-carboxylate (prepared essentially as described in WO 2020 / 247429, 210 mg, 0.54 mmol), and EtOH (0.45 mL). The mixture was stirred overnight at room temperature under a nitrogen atmosphere. After 20 h, the reaction was concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with a gradient of 5% to 20% acetone in DCM. The resulting material was repurified by reverse-phase chromatography eluting with a gradient of 50% to 80% ACN in aqueous NH4HCO3 to give the title compound (64 mg, 31%) as a beige solid, which was a 60:40 mixture of cis and trans isomers. ES-MS m / z 457 (M+H).

[0410] Preparation 168 tert-Butyl (3R)-3-[(1S)-2-[(4S)-4-benzyl-2-oxo-oxazolidin-3-yl]-1-[(3-benzylsulfanylphenyl)methyl]-2-oxo-ethyl]pyrrolidine-1-carboxylate

[0411] [ka] Nitrogen was bubbled through a suspension of tert-butyl (3R)-3-[(1S)-2-[(4S)-4-benzyl-2-oxo-oxazolidin-3-yl]-1-[(3-bromophenyl)methyl]-2-oxo-ethyl]pyrrolidine-1-carboxylate (prepared essentially as described in WO 2020 / 247429, 1.0 g, 1.79 mmol) in toluene (4 mL), followed by the addition of tris(dibenzylideneacetone)dipalladium(0) (0.17 g, 0.18 mmol), 1,1′-bis(diphenylphosphino)ferrocene (0.21 g, 0.36 mmol), N,N-diisopropylethylamine (0.26 g, 1.97 mmol), and benzyl mercaptan (0.23 g, 1.79 mmol). The reaction was stirred at 100°C. After 16 hours, the reaction was cooled and filtered. The filtrate was treated with water and extracted with EtOAc. The organic layer was collected, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 20% to 50% EtOAc in hexanes. The resulting material was repurified by silica gel chromatography eluting with a gradient of 20% to 50% EtOAc in hexanes to give the title compound (0.97 g, 71% purity, 64%). ES-MS m / z 501 (M+H-BOC).

[0412] Preparation 169 tert-Butyl (3R)-3-[(1S)-2-[(4S)-4-benzyl-2-oxo-oxazolidin-3-yl]-1-[(3-chlorosulfonylphenyl)methyl]-2-oxo-ethyl]pyrrolidine-1-carboxylate

[0413] [ka] tert-Butyl (3R)-3-[(1S)-2-[(4S)-4-benzyl-2-oxo-oxazolidin-3-yl]-1-[(3-benzylsulfanylphenyl)methyl]-2-oxo-ethyl]pyrrolidine-1-carboxylate (1.02 g, 1.21 mmol, 71% by weight), acetic acid:water (15 mL) in 40:1.5:1 ACN was slowly treated in portions with 1,3-dibromo-5,5-dimethylhydantoin (0.70 g, 2.41 mmol) at 0° C. The reaction was stirred at 0° C. for 10 minutes. The reaction was concentrated under reduced pressure. The residue was dissolved in DCM, cooled to 0° C., and treated with 5% aqueous NaHCO3. After stirring for 5 minutes, the organic layer was collected, dried over MgSO, filtered, and concentrated under reduced pressure to give the title compound (1.1 g, 64% by weight, 100%), which was used in the next synthetic reaction without purification. ES-MS m / z 521 (M+H-BOC).

[0414] Preparation 170 tert-Butyl (3R)-3-[(1S)-2-[(4S)-4-benzyl-2-oxo-oxazolidin-3-yl]-1-[[3-(dimethylsulfamoyl)phenyl]methyl]-2-oxo-ethyl]pyrrolidine-1-carboxylate

[0415] [ka] A room temperature solution of tert-butyl (3R)-3-[(1S)-2-[(4S)-4-benzyl-2-oxo-oxazolidin-3-yl]-1-[(3-chlorosulfonylphenyl)methyl]-2-oxo-ethyl]pyrrolidine-1-carboxylate (0.54 g, 64% by weight, 0.60 mmol) in DCM (5 mL) was treated with TEA (0.12 g, 1.21 mmol) and dimethylamine (0.04 g, 40% in water, 0.90 mmol). The reaction was stirred at room temperature for 60 minutes. Water was added, and the reaction was acidified with 1 M aqueous HCl and extracted with DCM. The organic layer was collected, dried over MgSO, collected, and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with a gradient of 25% to 100% EtOAc in hexanes to give the title compound (0.33 g, 93%) as an oil. ES / MS m / z 530 (M+H- t Bu).

[0416] Preparation 171 (2S)-2-[(3R)-1-tert-butoxycarbonylpyrrolidin-3-yl]-3-(3-dimethylsulfamoyl)phenyl]propanoic acid

[0417] [ka] A solution of tert-butyl (3R)-3-[(1S)-2-[(4S)-4-benzyl-2-oxo-oxazolidin-3-yl]-1-[[3-(dimethylsulfamoyl)phenyl]methyl]-2-oxo-ethyl]pyrrolidine-1-carboxylate (0.33 g, 0.56 mmol) in THF (5 mL) was treated with 1 M aqueous lithium hydroxide (0.84 mL, 0.84 mmol) and hydrogen peroxide (0.44 mL, 35% by weight, 4.48 mmol). The reaction was stirred for 16 hours. The reaction was treated with 1 N aqueous NaOH and extracted with MTBE. The aqueous layer was acidified with 1 N aqueous HCl and extracted with EtOAc. The organic layer was collected, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase chromatography eluting with 20% to 40% ACN in 20 mM aqueous NH4HCO3 to give the title compound (73 mg, 30%) as a white solid. ES-MS m / z 371 (M+H- t Bu).

[0418] Preparation 172 tert-Butyl (3R)-3-[2-[(4S)-4-benzyl-2-oxo-oxazolidin-3-yl]-2-oxo-1-[[4-(trifluoromethyl)phenyl]methyl]ethyl]pyrrolidine-1-carboxylate

[0419] [ka] A solution of tert-butyl (3R)-3-[2-[(4S)-4-benzyl-2-oxo-oxazolidin-3-yl]-2-oxo-ethyl]pyrrolidine-1-carboxylate (prepared essentially as described in WO 2020 / 247429, 0.30 g, 0.77 mmol) in THF (7.72 mL) at -78 °C was treated with lithium bis(trimethylsilyl)amide (1.0 mol / L in THF, 0.93 mL, 0.93 mmol) and the mixture was stirred for 90 minutes. The reaction was then treated with a solution of 4-(trifluoromethyl)benzyl bromide (0.20 g, 0.82 mmol) in THF (3.86 mL), and the resulting mixture was allowed to reach room temperature and stirred overnight. The mixture was quenched with saturated aqueous NH4Cl and extracted with EtOAc. The organic phase was washed with saturated aqueous NaCl, collected, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase chromatography eluting with 60% to 90% ACN in 20 mM aqueous NH4HCO3 to give the title compound (0.20 g, 47%) as a colorless oil. ES-MS m / z 491 [M+H- t Bu].

[0420] Preparation 173 (2S)-2-[(3R)-1-tert-butoxycarbonylpyrrolidin-3-yl]-3-[4-(trifluoromethyl)phenyl]propanoic acid

[0421] [ka] A solution of tert-butyl (3R)-3-[2-[(4S)-4-benzyl-2-oxo-oxazolidin-3-yl]-2-oxo-1-[[4-(trifluoromethyl)phenyl]methyl]ethyl]pyrrolidine-1-carboxylate (0.20 g, 0.37 mmol) in THF (2.5 mL) and water (0.48 mL) at 0° C. was treated with hydrogen peroxide (0.30 mL, 30% by weight in water, 2.93 mmol) followed by lithium hydroxide (0.02 g, 0.64 mmol) in water (0.73 mL). The reaction mixture was stirred at 0° C. After 30 minutes, the reaction was quenched with sodium thiosulfate (0.24 g, 1.46 mmol) in water (0.73 mL) at 0° C. and allowed to reach room temperature. The solution was extracted with EtOAc. The organic phase was concentrated under reduced pressure. The pH of the residue was adjusted to approximately 3 with 5% aqueous citric acid and extracted with EtOAc. The combined organic phases were washed with saturated aqueous NaCl, dried over MgSO, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase chromatography eluting with 20% to 50% ACN in aqueous NHHCO to give the title compound (60 mg, 40%) as a white solid. ES-MS m / z 288 (M+H-BOC).

[0422] Preparation 174 (2S)-2-[(3R)-1-tert-butoxycarbonylpyrrolidin-3-yl]-3-[3-(1,1-dioxo-1,2-thiazolidin-2-yl]phenyl]propanoic acid

[0423] [ka] The title compound was prepared essentially as described in Preparation 23 using isothiazolidine 1,1-dioxide. Upon completion, the reaction was filtered through a pad of diatomaceous earth and the filtrate was concentrated to dryness. The residue was purified using an HLB cartridge eluting with 0-100% ACN in aqueous NH4HCO3 (pH 9). ES-MS m / z 383 [M+H- t Bu].

[0424] Preparation 175 tert-Butyl (3R)-3-[(1S)-1-[[3-[(3-bromophenoxy)methyl]phenyl]methyl-2-tert-butoxy-2-oxo-ethyl]pyrrolidine-1-carboxylate

[0425] [ka] A stirred solution of tert-butyl (3R)-3-[(1S)-2-tert-butoxy-1-[[3-(hydroxymethyl)phenyl]methyl]-2-oxo-ethyl]pyrrolidine-1-carboxylate (prepared essentially as described in WO 2020 / 247429, 100 mg, 0.25 mmol) in anhydrous THF (2.47 mL) was treated with 3-bromophenol (0.06 g, 0.37 mmol) and triphenylphosphine (0.10 g, 0.37 mmol). After purging the reaction with N, diisopropyl azodicarboxylate (0.07 g, 0.37 mmol) was added, and the resulting mixture was stirred at room temperature for 16 hours. The reaction was concentrated under reduced pressure, and the residue was loaded onto diatomaceous earth. The residue was purified by silica gel chromatography eluting with a gradient of 10% to 40% MTBE in hexane to give the title compound (107 mg, 75%). ES-MS m / z 558 / 560 (M+H).

[0426] Preparation 176 tert-Butyl (3R)-3-[(1S)-2-tert-butoxy-2-oxo-1-[[3-(3-phenylphenoxy)methyl]phenyl]methyl]ethyl]pyrrolidine-1-carboxylate

[0427] [ka] A stirred suspension of tert-butyl (3R)-3-[(1S)-1-[[3-[(3-bromophenoxy)methyl]phenyl]methyl]-2-tert-butoxy-2-oxo-ethyl]pyrrolidine-1-carboxylate (0.11 g, 0.19 mmol), phenylboronic acid (0.03 g, 0.29 mmol), and KCO (0.08 g, 0.57 mmol) in 1,4-dioxane (1.9 mL) and water (0.19 mL) was treated with 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride DCM complex (0.02 g, 0.02 mmol). The resulting mixture was degassed for 5 minutes and heated at 90 °C for 2 hours. The reaction was cooled, treated with water, and extracted with EtOAc. The organic layer was washed with saturated aqueous NaCl, collected, dried over MgSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with a gradient of 5% to 20% MTBE in hexane to give the title compound (91 mg, 85%) as a colorless oil. ES-MS m / z 458 (M+H-BOC).

[0428] Preparation 177 tert-Butyl (3R)-3-[(1S)-2-[(4S)-4-benzyl-2-oxo-oxazolidin-3-yl]-1-[(3-benzyloxyphenyl)methyl]-2-oxo-ethyl]pyrrolidine-1-carboxylate

[0429] [ka] The title compound was prepared essentially as described in Preparation 11 using 1-benzyloxy-3-(bromomethyl)benzene and the reaction product was purified by silica gel chromatography using a gradient of 10-40% acetone in hexanes. ES-MS m / z 607 (M+Na).

[0430] Preparation 178 (2S)-3-(3-benzyloxyphenyl)-2-[(3R)-1-tert-butoxycarbonylpyrrolidin-3-yl]propanoic acid

[0431] [ka] The title compound was prepared essentially as described in Preparation 12, using tert-butyl (3R)-3-[(1S)-2-[(4S)-4-benzyl-2-oxo-oxazolidin-3-yl]-1-[(3-benzyloxyphenyl)methyl]-2-oxo-ethyl]pyrrolidine-1-carboxylate, stirring the reaction at room temperature for 3 hours, then adding additional portions of hydrogen peroxide and lithium hydroxide and stirring the reaction at 0°C for an additional 2 hours. Purify the reaction product by silica gel chromatography using a gradient of 20-80% EtOAc in hexanes + 1T acetic acid. ES-MS m / z 448 (M+Na).

[0432] Preparation 179 tert-Butyl (3R)-3-[(1S)-1-[(3-benzyloxyphenyl)methyl]-2-tert-butoxy-2-oxo-ethyl]pyrrolidine-1-carboxylate

[0433] [ka] A solution of (2S)-3-(3-benzyloxyphenyl)-2-[(3R)-1-tert-butoxycarbonylpyrrolidin-3-yl]propanoic acid (4.86 g, 11.4 mmol) in toluene (103 mL) at 80° C. was treated with a solution of N,N-dimethylformamide di-tert-butyl acetal (12.9 g, 90% by weight, 57.1 mmol) in toluene (11.4 mL) over 1 h. After 3 h, another aliquot of N,N-dimethylformamide di-tert-butyl acetal (12.9 g, 90% by weight, 57.1 mmol) in toluene (11.4 mL) was added dropwise, and stirring was continued at 80° C. overnight. The reaction was cooled to room temperature, diluted with EtOAc, washed with water and saturated aqueous NaCl, collected, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the title compound (5.7 g, 98%) as a yellow oil, which was used without purification. ES-MS m / z 370 (M+H-2 t Bu).

[0434] Preparation 180 tert-Butyl (3R)-3-[(1S)-2-tert-butoxy-1-[(3-hydroxyphenyl)methyl]-2-oxo-ethyl]pyrrolidine-1-carboxylate

[0435] [ka] A mixture of tert-butyl (3R)-3-[(1S)-1-[(3-benzyloxyphenyl)methyl]-2-tert-butoxy-2-oxo-ethyl]pyrrolidine-1-carboxylate (4.45 g, 7.84 mmol) and palladium (10% on activated carbon paste type 87 L, 0.45 g, 0.42 mmol) in EtOAc (39 mL) was stirred under a hydrogen balloon at room temperature for 4 days. The reaction was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with a gradient of 10% to 40% acetone in hexane to give the title compound (2.85 g, 93%) as a white solid. ES-MS m / z 280 (M+H-2 t Bu).

[0436] Preparation 181 tert-Butyl (3R)-3-[(1S)-2-tert-butoxy-1-[[3-[(2,2-difluoro-1,3-benzodioxol-5-yl)methoxy]phenyl]methyl]-2-oxo-ethyl]pyrrolidine-1-carboxylate

[0437] [ka] A tube was charged with tert-butyl (3R)-3-[(1S)-2-tert-butoxy-1-[(3-hydroxyphenyl)methyl]-2-oxo-ethyl]pyrrolidine-1-carboxylate (100 mg, 0.26 mmol), 5-(bromomethyl)-2,2-difluoro-1,3-benzodioxole (76.9 mg, 0.31 mmol), CsCO (100 mg, 0.31 mmol), and DMF (1.3 mL). The reaction was stirred overnight at room temperature. The reaction temperature was increased to 45 °C, and another approximately 0.32 mg of 5-(bromomethyl)-2,2-difluoro-1,3-benzodioxole was added, and the reaction was stirred for an additional 3 hours. The reaction was concentrated under a stream of nitrogen and filtered through a cartridge of diatomaceous earth. The filtrate was diluted with EtOAc, washed with water, and the organic layer was collected and concentrated under reduced pressure. The residue was purified by reverse phase chromatography to give the title compound (66.7 mg, 47%) as a white solid. ES-MS m / z 584 (M+Na).

[0438] The following compounds were prepared essentially as described in Preparation 181, using the appropriate reagents, adjusting the temperature and reaction time to determine reaction completion, and adjusting the purification system accordingly.

[0439] [Table 16]

[0440] Preparation 183 tert-Butyl (3R)-3-[(1S)-2-tert-butoxy-2-oxo-1-[[3-(2-pyridylmethylcarbamothioylamino)phenyl]methyl]ethyl]pyrrolidine-1-carboxylate

[0441] [ka] A 0°C solution of 1,1'-thiocarbonyldiimidazole (0.11 g, 90% by weight, 0.58 mmol) in ACN (1.4 mL) was treated with a solution of tert-butyl (3R)-3-[(1S)-1-[(3-aminophenyl)methyl]-2-tert-butoxy-2-oxo-ethyl]pyrrolidine-1-carboxylate (prepared essentially as described in WO 2020 / 247429, 0.150 g, 0.38 mmol) in ACN (1.4 mL). The cooling bath was removed, and the reaction was allowed to reach room temperature and stirred for 20 minutes. 2-(aminomethyl)pyridine (0.08 g, 0.77 mmol) in ACN (1.4 mL) was added, and the reaction was stirred at room temperature for 1.5 hours. The solvent was removed under reduced pressure and the residue was purified by silica gel chromatography eluting with a gradient of 15% to 60% acetone in hexanes to give the title compound (0.22 g, 107%) as a yellow solid. ES-MS m / z 541 (M+H).

[0442] Preparation 184 tert-Butyl (3R)-3-[(1S)-2-tert-butoxy-1-[[3-(imidazo[1,5-a]pyridin-3-ylamino)phenyl]methyl]-2-oxo-ethyl]pyrrolidine-1-carboxylate

[0443] [ka] A sealed tube was charged with tert-butyl (3R)-3-[(1S)-2-tert-butoxy-2-oxo-1-[[3-(2-pyridylmethylcarbamothioylamino)phenyl]methyl]ethyl]pyrrolidine-1-carboxylate (0.22 g, 0.41 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.11 g, 0.56 mmol), and toluene (3.7 mL). The tube was sealed and heated at 110 °C for 1 h. The reaction was cooled to room temperature, quenched with saturated aqueous NaHCO and extracted with EtOAc (2x). The organic layers were combined, washed with saturated aqueous NaCl, collected, dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase chromatography eluting with a gradient of 60% to 90% ACN in aqueous NHHCO. The resulting fraction was repurified by reverse-phase chromatography eluting with a gradient of 40% to 60% ACN (with 0.05% TFA) in water (with 0.05% TFA) to give the title compound (41.3 mg, 20%) as a white solid. ES-MS m / z 507 (M+H).

[0444] Preparation 185 tert-Butyl (R)-3-((S)-3-(3-(N-(benzo[d][1,3]dioxol-5-ylmethyl)sulfamoyl)phenyl)-1-(tert-butoxy)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate

[0445] [ka] and tert-butyl (3R)-3-[(1S)-2-tert-butoxy-1-[[3-(2,3-dihydro)-1,4-benzodioxin-6-ylmethylsulfamoyl)phenyl]methyl]-2-oxo-ethyl]pyrrolidine-1-carboxylate

[0446] [ka] A room temperature solution of tert-butyl (3R)-3-[(1S)-2-tert-butoxy-1-[(3-chlorosulfonylphenyl)methyl]-2-oxo-ethyl]pyrrolidine-1-carboxylate (0.45 g, 64% by weight, 0.60 mmol) in DCM (3 mL) was treated with TEA (0.12 g, 1.21 mmol) and 1,3-benzodioxol-5-ylmethanamine hydrate (0.11 g, 0.72 mmol). The reaction was stirred for 3 hours. Analysis of the reaction showed only sulfonyl chloride. 2,3-Dihydro-1,4-benzodioxin-6-ylmethylamine (0.12 g, 0.72 mmol) was added and stirring was continued for 2 hours. The reaction was diluted with 1 N aqueous HCl (3 mL) and extracted with DCM. The organic layer was collected, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with a gradient of 25% to 75% in hexane. The two compounds were purified separately by reverse-phase chromatography eluting with a gradient of 60% to 80% ACN in aqueous 20 mM NH4HCO3 to give tert-butyl (3R)-3-[(1S)-1-[[3-(1,3-benzodioxol-5-ylmethylsulfamoyl)phenyl]methyl]-2-tert-butoxy-2-oxo-ethyl]pyrrolidine-1-carboxylate (20 mg, 6%, ES-MS m / z 489 (M+H-BOC)) and tert-butyl (3R)-3-[(1S)-1-[[3-(1,3-benzodioxol-5-ylmethylsulfamoyl)phenyl]methyl]-2-tert-butoxy-2-oxo-ethyl]pyrrolidine-1-carboxylate (27 mg, 7%, ES-MS m / z 503 (M+H-BOC)).

[0447] The following was prepared essentially as described in Preparation 121 using tert-butyl (3R)-3-[(1S)-1-[(3-bromophenyl)methyl]-2-tert-butoxy-2-oxo-ethyl]pyrrolidine-1-carboxylate and the appropriate amine. Prior to purification, the reaction mixture was concentrated and loaded onto an SCX resin, which was washed with MeOH (discarding the wash), then eluted with 2M NH in MeOH and the eluate concentrated.

[0448] [Table 17]

[0449] Preparation 189 tert-Butyl (3R)-3-[(1S)-2-tert-butoxy-1-[[3-[(4-oxazol-5-ylanilino]methyl]phenyl]methyl]-2-oxo-ethyl]pyrrolidine-1-carboxylate

[0450] [ka] The title compound was prepared essentially as described in Preparation 20 using 4-oxazol-5-ylaniline. Upon completion, the reaction was concentrated and loaded onto an SCX resin, which was washed with MeOH (discarding the wash), then eluted with 2 M NH in MeOH, and the eluate was concentrated. The material was purified by reverse-phase chromatography (XBridge® C18 21 × 100 mm, 5 mm column, mobile phase 70%-90% ACN in aqueous NHHCO (20 mM, pH 9), flow rate 25 mL / min) to give the title compound (98 mg, 40%). ES-MS m / z 548 (M+H).

[0451] Preparation 190 tert-Butyl (3R)-3-[(1S)-2-tert-butoxy-1-[[(3-[(3-methoxy-N-methyl-anilino)methyl]phenyl]methyl]-2-oxo-ethyl]pyrrolidine-1-carboxylate

[0452] [ka] The title compound was prepared essentially as described in Preparation 20 using 3-methoxy-N-methylaniline. Upon completion, the reaction was concentrated and loaded onto an SCX resin, which was washed with MeOH (discarding the wash), then eluted with 2M NH in MeOH, and the eluate was concentrated. The residue was purified by reverse-phase HPLC [Column: XBridge® C18 21 x 100 mm, 5 mm, Mobile phase: 70%-90% ACN in aqueous NHHCO (20 mM, pH 9), flow rate 25 mL / min] to give the title compound (46.5 mg, 20%). ES / MS m / z 525 (M+H)

[0453] Preparation 191 tert-Butyl (3R)-3-[1-[(3-bromophenyl)methyl]-2-methoxy-2-oxo-ethyl]pyrrolidine-1-carboxylate (mixture of diastereomers)

[0454] [ka] A 500 mL round-bottom flask equipped with an N2 inlet was charged with THF (90 mL) and diisopropylamine (4.60 g, 45.2 mmol), and the mixture was cooled to -70 °C. N-butyllithium (11 g, 2.5 mol / L in hexane, 41.10 mmol) was added dropwise and stirred for 10 min. A solution of tert-butyl (3R)-3-(2-methoxy-2-oxo-ethyl)pyrrolidine-1-carboxylate (10 g, 41.1 mmol) in THF (30 mL) was added dropwise, and the mixture was stirred for 30 min. 3-Bromobenzyl bromide (11.3 g, 45.2 mmol) was added, and the mixture was warmed to room temperature. After stirring at room temperature for 1 hour, the reaction was diluted with MeOH, concentrated under reduced pressure, and the residue was purified by silica gel chromatography eluting with 20% EtOAc in hexanes to give the title compound (11.5 g, 68%) as a colorless oil. ES / MS m / z 357 [M+H- t Bu].

[0455] Preparation 192 3-(3-Bromophenyl)-2-[(3R)-1-tert-butoxycarbonylpyrrolidin-3-yl]propanoic acid (Isomer 1 and Isomer 2).

[0456] [ka] A solution of tert-butyl (3R)-3-[1-[(3-bromophenyl)methyl]-2-methoxy-2-oxo-ethyl]pyrrolidine-1-carboxylate (10 g, 24.25 mmol) in MeOH (218 mL) and THF (218 mL) was treated with 1 M aqueous NaOH (243 mL). The resulting mixture was stirred at 50° C. for 2 hours. After cooling to room temperature, the reaction was concentrated under reduced pressure. The residue was dissolved in EtOAc, neutralized to pH 4 with aqueous citric acid, and extracted with EtOAc (3×). The organic layers were combined, washed with saturated aqueous NaCl (2×), collected, dried over MgSO4, filtered, and concentrated under reduced pressure to give the title compound (9.5 g, 98%) as a colorless oil. ES / MS m / z 343 [M+H- t Bu] + .

[0457] Isomer 1 and Isomer 2 of tert-butyl (3R)-3-[rac-1-[(3-benzyloxyphenyl)methyl]-2-methoxy-2-oxo-ethyl]pyrrolidine-1-carboxylate (20.3 g, 51.0 mmol) were obtained by chiral SFC chromatography using a Chiralpak® AD column (5 × 25 cm, 5 mm) eluted with 20% CO in IPA. The resulting isomers were separately dissolved in EtOAc and washed with 0.5 M aqueous HCl. The organic layer was collected, dried over Na2SO4, and concentrated under reduced pressure to give Isomer 1 (first-eluting isomer, 7.2 g, 36%) and Isomer 2 (second-eluting isomer, 8.1 g, 40%) as pale yellow solids. ES-MS m / z 344 (M+H- t Bu).

[0458] Preparation 193 tert-Butyl (3R)-3-[1-[(3-bromophenyl)methyl]-2-methoxy-2-oxo-ethyl]pyrrolidine-1-carboxylate (Isomer 2)

[0459] [ka] A room temperature suspension of 3-(3-bromophenyl)-2-[(3R)-1-tert-butoxycarbonylpyrrolidin-3-yl]propanoic acid (isomer 2, 7.7 g, 19 mmol) in MeOH (19 mL) was slowly treated with (trimethylsilyl)diazomethane (12 g, 2 M in hexanes, 33 mmol), and the reaction was stirred for 10 minutes. Two additional aliquots of (trimethylsilyl)diazomethane (12 g, 2 M in hexanes, 33 mmol) were added, and the reaction was stirred for 10 minutes after each addition. The reaction was concentrated under reduced pressure. The residue was dissolved in DCM and filtered through a small pad of silica gel. The filtrate was concentrated under reduced pressure to give the title compound (8.0 g, 100%) as a light brown oil. ES-MS m / z 356 / 358 (M+H- t Bu).

[0460] Preparation 194 tert-Butyl (3R)-3-[1-(benzyloxymethyl)-1-[(3-bromophenyl)methyl]-2-methoxy-2-oxo-ethyl]pyrrolidine-1-carboxylate (mixture of diastereomers)

[0461] [ka] A solution of tert-butyl (3R)-3-[1-[(3-bromophenyl)methyl]-2-methoxy-2-oxo-ethyl]pyrrolidine-1-carboxylate (1.01 g, 2.45 mmol) in THF (24.5 mL) at −78° C. was treated with potassium bis(trimethylsilyl)amide (5.39 mL, 1 M in THF, 5.39 mmol). After 30 minutes, chloromethoxymethylbenzene (0.77 g, 4.90 mmol) dissolved in 5 mL of THF was added. The mixture was allowed to warm slowly to room temperature and then stirred overnight at room temperature. Saturated aqueous NH4Cl was added, and the aqueous layer was extracted with EtOAc. The organic layer was collected, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with a gradient of 7% to 30% EtOAc in hexanes to give the title compound (1.20 g, 73% by mass, 67%) as a colorless oil. ES-MS m / z 476 / 478 (M+H- t Bu).

[0462] Preparation 195 2-(Benzyloxymethyl)-3-(3-bromophenyl)-2-[(3R)-1-tert-butoxycarbonylpyrrolidin-3-yl]propanoic acid (mixture of diastereomers)

[0463] [ka] tert-Butyl (3R)-3-[1-(benzyloxymethyl)-1-[(3-bromophenyl)methyl]-2-methoxy-2-oxo-ethyl]pyrrolidine-1-carboxylate (1.2 g, 2.3 mmol) was dissolved in THF (9 mL) and MeOH (9 mL) and treated with 1 M aqueous NaOH (23 mL, 23 mmol). The reaction was stirred at 60° C. overnight. The reaction was again treated with 1 M aqueous NaOH (23 mL, 23 mmol) and continued stirring at 60° C. overnight. The reaction was diluted with MeOH (9 mL) and heated at 80° C. for 5 h. Due to slow hydrolysis, the reaction was concentrated under reduced pressure, the residue was dissolved in MeOH (15 mL) and THF (9 mL), and the solution was treated with 5 M aqueous NaOH (9 mL, 370 mmol). The reaction was stirred at 80° C. overnight. The reaction was cooled to room temperature and concentrated under reduced pressure. The residue was taken up in EtOAc and water. The pH of the aqueous layer was acidified with 1N aqueous HCl and extracted with EtOAc. The organic layer was collected, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase chromatography eluting with a gradient of 40% to 70% ACN in water to give the title compound (0.58 g, 50%) as a white solid. ES / MS m / z 462 / 464 (M+H- t Bu).

[0464] Preparation 196 2-(Benzyloxymethyl)-2-[(3R)-1-tert-butoxycarbonylpyrrolidin-3-yl]-3-(3-phenylphenyl)propanoic acid (Isomer 1 and Isomer 2).

[0465] [ka] A stirred mixture of 2-(benzyloxymethyl)-3-(3-bromophenyl)-2-[(3R)-1-tert-butoxycarbonylpyrrolidin-3-yl]propanoic acid (0.58 g, 1.11 mmol), phenylboronic acid (0.209 g, 1.67 mmol), and potassium carbonate (0.46 g, 3.33 mmol, 100% by weight) in 1,4-dioxane (11.1 mL) and water (1.1 mL) was treated with 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride DCM complex (0.09 g, 0.11 mmol) at 100°C. The tube was sealed, and the mixture was heated at 100°C overnight. The reaction was cooled to room temperature, diluted with EtOAc, filtered through diatomaceous earth, and concentrated to dryness under reduced pressure. The residue was purified by silica gel chromatography eluting with a gradient of 40% to 70% ACN in water to give the title compound (700 mg).

[0466] The isomers were separated by SFC chromatography using a Chiralpak AD column (2 x 25 cm, 5 mm) eluting with 25% CO in IPA (with 0.2% DMEA) to give isomer 1 (130.3 mg, 23%) as a white solid. Isomer 2 was repurified by SFC chromatography using a Claricep C-series C18 column (20 x 250 mm, 5 mm) eluting with 25% CO in IPA (with 0.2% DMEA) to give isomer 2 (278.1 mg, 49%) as a white solid. ES-MS m / z 460 (M+H- t Bu) + .

[0467] Preparation 197a 2-[(3R)-1-tert-butoxycarbonylpyrrolidin-3-yl]-2-(hydroxymethyl)-3-(3-phenylphenyl)propanoic acid (isomer 2)

[0468] [ka] A mixture of 2-(benzyloxymethyl)-2-[(3R)-1-tert-butoxycarbonylpyrrolidin-3-yl]-3-(3-phenylphenyl)propanoic acid (isomer 2, 100 mg, 0.19 mmol) and palladium (10% on activated carbon paste Type 87 L, 0.1 g, 0.01 mmol) in EtOAc (1.9 mL) was stirred under hydrogen (balloon) at room temperature overnight. The reaction progressed slowly, so it was filtered through diatomaceous earth and concentrated under reduced pressure. The residue was dissolved in EtOH (2.9 mL), treated with palladium hydroxide on carbon (0.05 g), and stirred under hydrogen at 90-100 psi over the weekend. The reaction was filtered through diatomaceous earth and concentrated under reduced pressure. The residue was purified by reverse phase chromatography eluting with a gradient of 30% to 60% ACN in water to give the title compound (0.12 g, 70% by mass, 24%). ES-MS m / z 326 [M+H-Boc]+.

[0469] Preparation 197b 2-[(3R)-1-tert-butoxycarbonylpyrrolidin-3-yl]-2-(hydroxymethyl)-3-(3-phenylphenyl)propanoic acid (isomer 1'1)

[0470] [ka] The title compound was prepared essentially as described in Preparation 197a using 2-(benzyloxymethyl)-2-[(3R)-1-tert-butoxycarbonylpyrrolidin-3-yl]-3-(3-phenylphenyl)propanoic acid (isomer 1) and stirring the starting material in EtOH with palladium hydroxide on carbon under H2 (100 psi) over the weekend. ES-MS m / z 326 [M+H-Boc] + .

[0471] Preparation 198 tert-Butyl (3R)-3-[1-[(3-bromophenyl)methyl]-1-[(1,3-dioxoisoindolin-2-yl)methyl]-2-methoxy-2-oxo-ethyl]pyrrolidine-1-carboxylate (mixture of diastereomers).

[0472] [ka] A solution of tert-butyl (3R)-3-[1-[(3-bromophenyl)methyl]-2-methoxy-2-oxo-ethyl]pyrrolidine-1-carboxylate (1.22 g, 2.96 mmol) in THF (29.6 mL) at −78° C. was treated with potassium bis(trimethylsilyl)amide (1 M in THF, 6.51 mL, 6.51 mmol). After 30 minutes, 2-(bromomethyl)isoindoline-1,3-dione (1.42 g, 5.92 mmol) dissolved in 10 mL of THF was added. The reaction was allowed to warm slowly to room temperature and then stirred at room temperature overnight. The mixture was quenched with saturated aqueous NH4Cl and extracted with EtOAc. The organic layer was collected, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with a gradient of 15% to 60% acetone in hexanes to give the title compound (0.60 g, 94% by mass, 33%) as a white solid. ES-MS m / z 473 (M+H-BOC).

[0473] Manufacturing Example 199 2-[[3-(3-Bromophenyl)-2-[(3R)-1-tert-butoxycarbonylpyrrolidin-3-yl]-2-carboxy-propyl]carbamoyl]benzoic acid (mixture of diastereomers)

[0474] [ka] A solution of tert-butyl (3R)-3-[1-[(3-bromophenyl)methyl]-1-[(1,3-dioxoisoindolin-2-yl)methyl]-2-methoxy-2-oxo-ethyl]pyrrolidine-1-carboxylate (mixture of diastereomers, 0.60 g, 1 mmol) was dissolved in MeOH (7 mL) and THF (7 mL) was treated with 5 M aqueous NaOH (4 mL, 20 mmol), and the reaction was stirred at 80 °C overnight. The reaction was cooled to room temperature and concentrated under reduced pressure. The residue was suspended in water and washed with EtO. The aqueous layer was cooled to 0 °C and the pH was adjusted to 3 with 1 N aqueous HCl to give a solid that was removed by filtration, washed with water, and dried at 40 °C overnight to give the title compound (0.58 g, 100%) as a white solid. ES-MS m / z 475 / 477 (M+H-BOC).

[0475] Preparation 200 2-[[2-[(3R)-1-tert-Butoxycarbonylpyrrolidin-3-yl]-2-carboxy-3-(3-phenylphenyl)propyl]carbamoyl]benzoic acid (mixture of diastereomers).

[0476] [ka] A pressure tube was charged with 2-[[3-(3-bromophenyl)-2-[(3R)-1-tert-butoxycarbonylpyrrolidin-3-yl]-2-carboxy-propyl]carbamoyl]benzoic acid (mixture of diastereomers, 78 mg, 0.14 mmol), phenylboronic acid (25.6 mg, 0.20 mmol), potassium carbonate (56.2 mg, 0.41 mmol), 1,4-dioxane (1.4 mL), and water (0.14 mL). The reaction was warmed to 100 °C and treated with 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride DCM complex (11.3 mg, 0.01 mmol). The tube was sealed, and the mixture was heated at 100 °C overnight. The reaction was cooled to room temperature and filtered through diatomaceous earth. The filtrate was concentrated under reduced pressure. The residue was purified by reverse phase chromatography eluting with a gradient of 20% to 50% ACN in water to give the title compound (35 mg, 45%). ES-MS m / z 473 (M+H-BOC).

[0477] The following was prepared essentially as described in Preparation 11 using tert-butyl (3R)-3-[2-[(4S)-4-benzyl-2-oxo-oxazolidin-3-yl]-2-oxo-ethyl]pyrrolidine-1-carboxylate (prepared essentially as described in WO 2020 / 247429) and the appropriate alkyl bromide, stirring the reaction at 0° C. for 40-50 minutes before adding the alkyl bromide, and purifying the product by silica gel chromatography using a gradient of EtOAc in petroleum ether (starting with 0% EtOAc and increasing to 50-100% EtOAc).

[0478] [Table 18-1]

[0479] [Table 18-2]

[0480] The following was prepared essentially as described in Preparation 12, using the appropriate starting material, stirring the reaction mixture at room temperature for 16 hours after addition of lithium hydroxide, and omitting the chromatography step after reaction workup.

[0481] [Table 19-1]

[0482] [Table 19-2]

[0483] Preparation 218 tert-Butyl (3R)-3-[(1S)-1-[(5-bromopyrazin-2-yl)methyl]-2-tert-butoxy-2-oxo-ethyl]pyrrolidine-1-carboxylate

[0484] [ka] The title compound was prepared essentially as described in Preparation 79 using (2S)-3-(5-bromopyrazin-2-yl)-2-[(3R)-1-tert-butoxycarbonylpyrrolidin-3-yl]propanoic acid, THF as the solvent, and heating the reaction at 65° C. for 16 hours. The reaction mixture was filtered, and the filtrate was poured into saturated aqueous NaCl and extracted with EtOAc. The organics were dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a gradient of 0-50% EtOAc in petroleum ether. f = 0.6 on silica gel plates eluted with 17% EtOAc in petroleum ether and visualized with iodine. TLC (1:5 EtOAc / petroleum ether) R f =0.6.

[0485] Preparation 219 tert-Butyl (3R)-3-[(1S)-1-[(3-bromo-5-methyl-phenyl)methyl]-2-tert-butoxy-2-oxo-ethyl]pyrrolidine-1-carboxylate

[0486] [ka] The title compound was prepared essentially as described in Preparation 79 using (2S)-3-(3-bromo-5-methyl-phenyl)-2-[(3R)-1-tert-butoxycarbonylpyrrolidin-3-yl]propanoic acid, THF as the solvent, and heating the reaction at 65° C. for 16 hours. The reaction mixture was filtered, and the filtrate was poured into saturated aqueous NaCl and extracted with EtOAc. The organics were dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a gradient of 0-50% EtOAc in petroleum ether. TLC (1:5 EtOAc / petroleum ether) Rf=0.6.

[0487] Manufacturing Example 220 Methyl 5-[(2S)-3-tert-butoxy-2-[(3R)-1-tert-butoxycarbonylpyrrolidin-3-yl]-3-oxo-propyl]pyrazine-2-carboxylate

[0488] [ka] A mixture of tert-butyl (3R)-3-[(1S)-1-[(5-bromopyrazin-2-yl)methyl]-2-tert-butoxy-2-oxo-ethyl]pyrrolidine-1-carboxylate (150 mg, 0.30 mmol, 90% by weight) in MeOH (6 mL) was treated with TEA (0.5 mL, 4 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (26 mg, 0.03 mmol) in one portion at 25 °C. The reaction was stirred at 100 °C under CO (2 MPa) for 16 h. The reaction was cooled to room temperature, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with a gradient of 0% to 30% EtOAc in petroleum ether to afford the title compound (100 mg, 62%) as a yellow oil. ES-MS m / z 436 (M+H).

[0489] Preparation 221 5-[(2S)-3-tert-butoxy-2-[(3R)-1-tert-butoxycarbonylpyrrolidin-3-yl]-3-oxopropyl]pyrazine-2-carboxylic acid

[0490] [ka] A mixture of 5-[(2S)-3-tert-butoxy-2-[(3R)-1-tert-butoxycarbonylpyrrolidin-3-yl]-3-oxopropyl]pyrazine-2-carboxylate (100 mg, 80% by weight, 0.18 mmol) in THF (2 mL), MeOH (1 mL), and water (0.5 mL) was treated with lithium hydroxide (50 mg, 1.98 mmol) in one portion at 25° C. The reaction mixture was stirred at 25° C. for 3 hours. The pH of the reaction was adjusted to 7 with 1N aqueous HCl. The reaction was extracted with EtOAc (3×10 mL). The organic phases were combined, dried over Na2SO4, filtered, and concentrated under reduced pressure to afford the title compound (90 mg, 105%) as a yellow oil, which was used directly in the next step without purification. ES / MS m / z 310 (M+H-2 t Bu).

[0491] Preparation 222 tert-Butyl (3R)-3-[(1S)-1-[2-bromo-4-iodo-phenyl)methyl]-2-tert-butoxy-2-oxo-ethyl]pyrrolidine-1-carboxylate

[0492] [ka] The title compound was prepared essentially as described in Preparation 79 using (2S)-3-(2-bromo-4-iodo-phenyl)-2-[(3R)-1-tert-butoxycarbonylpyrrolidin-3-yl]propanoic acid and heating the reaction to 65° C. for 16 hours. The reaction mixture was filtered, and the filtrate was poured into saturated aqueous NaCl and extracted with EtOAc. The organics were dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a gradient of 0-50% EtOAc in petroleum ether. TLC (1:3 EtOAc / petroleum ether) R f =0.6.

[0493] Preparation 223 tert-Butyl (3R)-3-[(1S)-1-[(2-bromo-4-cyano-phenyl)methyl]-2-tert-butoxy-2-oxo-ethyl]pyrrolidine-1-carboxylate

[0494] [ka] A solution of tert-butyl (3R)-3-[(1S)-1-[(2-bromo-4-iodo-phenyl)methyl]-2-tert-butoxy-2-oxo-ethyl]pyrrolidine-1-carboxylate (320 mg, 80% wt, 0.44 mmol) in DMF (4 mL) was treated with zinc cyanide (165 mg, 1.36 mmol) and tetrakis(triphenylphosphine)palladium(0) (110 mg, 0.09 mmol). The resulting mixture was stirred at 80 °C for 3 h. The reaction was cooled to room temperature, diluted with water (100 mL), and extracted with EtOAc (3 × 40 mL). The organic layers were combined, washed with saturated aqueous NaCl (50 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with a gradient of 0% to 30% EtOAc in petroleum ether to afford the title compound (230 mg, 98%) as a yellow oil. 1 H NMR (400MHz, methanol-d4) δppm7.99(m,1H),7.67-7.65(m,1H),7.46-7.43(m,1H),3.70-3.60(m,1H),3.50-3.40(m,1H),3 .35-3.00(m,4H),2.75-2.65(m,1H),2.50-2.40(m,1H),2.00-1.90(m,1H),1.80-1.65(m,1H),1.47(s,9H),1.30(s,9H).

[0495] Preparation 224 tert-Butyl (3R)-3-[(1S)-1-[(3-azidophenyl)methyl]-2-tert-butoxy-2-oxo-ethyl]pyrrolidine-1-carboxylate

[0496] [ka] A mixture of tert-butyl nitrite (280 mg, 2.58 mmol) and azidotrimethylsilane (160 mg, 1.32 mmol) in THF (10 mL) was added to a solution of tert-butyl (3R)-3-[(1S)-1-[(3-aminophenyl)methyl]-2-tert-butoxy-2-oxo-ethyl]pyrrolidine-1-carboxylate (prepared essentially as described in WO 2020 / 247429, 100 mg, 0.26 mmol) in THF (10 mL) at 0° C. The reaction was stirred at 25° C. for 16 hours. The reaction was poured into saturated aqueous NaCl (15 mL) and extracted with EtOAc (3×15 mL). The organics were combined, dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound (60 mg, 85% by weight, 48%) as a yellow oil which was used in the next synthetic step without purification. 1 H NMR(400MHz,CDCl3)δppm7.10-7.06(m,1H),6.82-6.76(m,1H),6.75-6.70(m,1H),6.69-6.64(m,1H),3.56-3.42(m,2H),3.37 3.30(m,1H),3.15-3.05(m,1H),2.90-2.80(m,1H),2.74-2.64(m,1H),2.63-2.56(m,1 H),2.33-2.27(m,1H),2.25-2.17(m,1H),1.86-1.73(m,1H),1.32(s,9H),1.16(s,9H).

[0497] Preparation 225 tert-(2S)-3-(3-methylsulfanylphenyl)-2-[(3R)-pyrrolidin-3-yl]propanoate

[0498] [ka] A solution of tert-butyl (3R)-3-[(1S)-1-[(3-aminophenyl)methyl]-2-tert-butoxy-2-oxo-ethyl]pyrrolidine-1-carboxylate (prepared essentially as described in WO 2020 / 247429, 200 mg, 0.51 mmol) in methyl disulfide (4 mL) was treated with copper(II) chloride (7 mg, 0.05 mmol) and isoamyl nitrite (60 mg, 0.50 mmol) at 25 °C. The reaction was stirred at 60 °C under N (15 psi). Once the starting material was consumed, the reaction was poured into saturated aqueous NaCl (100 mL) and extracted with DCM (3 × 200 mL). The organics were collected, dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography eluting with a gradient of 0% to 10% MeOH in DCM to give the title compound (120 mg, 39%) as a brown solid. ES-MS m / z 322 [M+H-Boc] + .

[0499] Preparation 226 tert-Butyl (3R)-3-[(1S)-2-tert-butoxy-1-[[3-(1-ethoxyvinyl)phenyl]methyl]-2-oxo-ethyl]pyrrolidine-1-carboxylate

[0500] [ka] A solution of tert-butyl (3R)-3-[(1S)-1-[(3-bromophenyl)methyl]-2-tert-butoxy-2-oxo-ethyl]pyrrolidine-1-carboxylate (prepared essentially as described in WO 2020 / 247429, 501 mg, 1.05 mmol) in DMF (5 mL) was treated with tributyl(1-ethoxyvinyl)tin (1.35 g, 3.63 mmol) and tetrakis(triphenylphosphine)palladium(0) (246 mg, 0.21 mmol). The reaction was stirred at 100° C. for 3 hours. The reaction mixture was quenched with saturated aqueous KF (5 mL), stirred at 20° C. for 16 hours, and filtered. The filtrate was diluted with water (50 mL) and extracted with EtOAc (3×40 mL). The combined organics were washed with saturated aqueous NaCl (50 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with a gradient of 0% to 30% EtOAc in petroleum ether to afford the title compound (200 mg, 90% by weight, 39%) as a yellow oil. 1 H NMR (400 MHz, methanol-d4) δ ppm 7.46-7.45 (m, 2H), 7.30-7.12 (m, 2H), 4.64-4.63 (d, 1H, J = 2.4 Hz), 4.22-4.21 (d, 1H, J = 2.4 Hz), 3.91 (c, 2H, J = 6.8 Hz), 3.70-3.55 (m, 1H), 3.50-3.40 (m, 1H), 3 .30-3.20(m,1H),3.10-3.00(m,1H),2.85-2.80(m,2H),2.60-2.50(m,1H),2.40-2.30(m,1H) ,2.00-1.90(m,1H),1.75-1.60(m,1H),1.47(s,9H),1.41(t,3H,J=6.8Hz),1.28-1.27(m,9H).

[0501] Preparation 227 tert-Butyl (3R)-3-[(1S)-2-tert-butoxy-2-oxo-1-[[3-(2-trimethylsilylethynyl)phenyl]methyl]ethyl]pyrrolidine-1-carboxylate

[0502] [ka] A mixture of tert-butyl (3R)-3-[(1S)-1-[(3-bromophenyl)methyl]-2-tert-butoxy-2-oxo-ethyl]pyrrolidine-1-carboxylate (prepared essentially as described in WO 2020 / 247429, 200 mg, 0.44 mmol) and trimethylsilylacetylene (180 mg, 1.80 mmol) in TEA (6 mL) was treated in one portion with 1,3-bis(diphenylphosphino)propane (40 mg, 0.1 mmol), tris(dibenzylideneacetone)dipalladium(0) (41 mg, 0.04 mmol), and copper(I) iodide (8.5 mg, 0.05 mmol) at 25 °C. The reaction was stirred at 120 °C under N (15 psi) for 16 h. The reaction was poured into saturated aqueous NaCl (20 mL) and extracted with EtOAc (3 × 25 mL). The combined organics were washed with water (2 × 20 mL), dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 0% to 30% EtOAc in petroleum ether. The resulting material was repurified by reverse-phase chromatography eluting with a gradient of 75% to 95% ACN in water (with NH and NHHCO) to afford the title compound (50 mg, 90% by mass, 22%) as a yellow oil. ES-MS m / z 472 (M+H).

[0503] Preparation 228 tert-Butyl (3R)-3-[(1S)-2-tert-butoxy-1-[3-formyl-5-methyl-phenyl)methyl-2-oxo-ethyl]pyrrolidine-1-carboxylate

[0504] [ka] A mixture of tert-butyl (3R)-3-[(1S)-1-[(3-bromo-5-methyl-phenyl)methyl]-2-tert-butoxy-2-oxo-ethyl]pyrrolidine-1-carboxylate (400 mg, 90% by weight, 0.77 mmol) in THF (4 mL) was treated portionwise with N-butyllithium (0.80 mL, 2.0 mmol, 2.5 mol / L in hexanes) at −78° C. The reaction was stirred at −78° C. for 1 h. The reaction was then treated with a solution of DMF (0.30 mL, 3.9 mmol) in THF (1 mL), and the reaction was stirred at 25° C. for 16 h. The reaction was poured into saturated aqueous NaCl (20 mL) and extracted with EtOAc (4×30 mL). The combined organics were collected, dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with a gradient of 0% to 20% EtOAc in petroleum ether to give the title compound (60 mg, 60% by mass, 11%) as a yellow oil. ES / MS m / z 318 (M+H-BOC).

[0505] Preparation 229 tert-Butyl (3R)-3-[(1S)-2-tert-butoxy-1-[(3-methoxycarbonylphenyl)methyl]-2-oxo-ethyl]pyrrolidine-1-carboxylate

[0506] [ka] A mixture of tert-butyl (3R)-3-[(1S)-1-[(3-bromophenyl)methyl]-2-tert-butoxy-2-oxo-ethyl]pyrrolidine-1-carboxylate (prepared essentially as described in WO 2020 / 247429, 400 mg, 0.88 mmol), TEA (1.3 mL, 9.3 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (68 mg, 0.09 mmol) in MeOH (5 mL) was degassed three times with a CO atmosphere and cooled to 200°C. The mixture was stirred overnight at 110° C. under an O atmosphere (2 MPa) for 72 hours. The reaction was cooled, poured into water (50 mL), and extracted with EtOAc (3×30 mL). The combined organics were washed with saturated aqueous NaCl (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with a gradient of 0% to 100% EtOAc in petroleum ether to afford the title compound (270 mg, 90% by mass, 83%) as a yellow oil. ES-MS m / z 334 (M+H).

[0507] Preparation 230 tert-Butyl (3R)-3-[(1S)-2-tert-butoxy-1-[[3-[(tert-butoxycarbonylamino)methyl]-5-methyl-phenyl]methyl]-2-oxo-ethyl]pyrrolidine-1-carboxylate

[0508] [ka] A mixture of tert-butyl (3R)-3-[(1S)-1-[(3-bromo-5-methyl-phenyl)methyl]-2-tert-butoxy-2-oxo-ethyl]pyrrolidine-1-carboxylate (500 mg, 1.07 mmol), potassium (((tert-butoxycarbonyl)amino)methyl)trifluoroborate (400 mg, 1.61 mmol), PdCl (1,1′-bis(di-tert-butylphosphino)ferrocene) (140 mg, 0.213 mmol), and KCO (470 mg, 3.23 mmol) in 1,4-dioxane (4 mL) and water (1 mL) was degassed and purged with N three times. The mixture was stirred at 100° C. under N overnight. The reaction mixture was combined with a reaction carried out essentially as described above using 100 mg (0.214 mmol) of the starting aryl bromide. The reaction mixture was diluted with water (30 mL) and extracted with EtOAc (50 mL × 3). The organics were washed with saturated aqueous NaCl (50 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography using a gradient of 0 to 50% EtOAc in petroleum ether to give the title compound (300 mg, 40%) as a yellow oil. ES-MS m / z 419 (M+H-Boc).

[0509] Preparation 231 tert-Butyl (3R)-3-[(1S)-2-tert-butoxy-1-[[3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]-2-oxo-ethyl]pyrrolidine-1-carboxylate

[0510] [ka] A mixture of tert-butyl (3R)-3-[(1S)-1-[(3-bromo-5-methyl-phenyl)methyl]-2-tert-butoxy-2-oxo-ethyl]pyrrolidine-1-carboxylate (1.0 g, 2.14 mmol) and pinacolborane (0.85 g, 6.44 mmol) in 1,2-dichloroethane (10 mL) was treated with dichlorobis(triphenylphosphine)palladium(II) (80 mg, 0.11 mmol) and TEA (1.5 mL, 11 mmol) at 25 °C. The reaction was stirred at 90 °C under N (15 psi) for 16 hours. The reaction was concentrated under reduced pressure. The residue was purified by reverse-phase HPLC eluting with a gradient of 60% to 100% ACN in water (with NH3 and NH4HCO3) to give the title compound (0.35 g, 90% by mass, 29%) as a yellow oil. ES-MS m / z 516 [M+H] + .

[0511] Preparation 232 tert-Butyl (3R)-3-[(1S)-2-tert-butoxy-1-[(3-hydroxy-5-methyl-phenyl)methyl]-2-oxo-ethyl]pyrrolidine-1-carboxylate

[0512] [ka] A solution of tert-butyl (3R)-3-[(1S)-2-tert-butoxy-1-[[3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]-2-oxo-ethyl]pyrrolidine-1-carboxylate (250 mg, 0.49 mmol) in THF (6 mL) was treated with sodium hydroxide (40 mg, 0.99 mmol) and hydrogen peroxide solution (110 mg, 30% by weight in water, 0.97 mmol) at 0 °C. The reaction was stirred at 25 °C for 3 h. The reaction was combined with 50 mg of the reactant for workup. The reaction was poured into saturated aqueous NaCl (50 mL) and extracted with EtOAc (4 × 100 mL). The organics were collected, dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with a gradient of 0% to 100% EtOAc in petroleum ether to give the title compound (240 mg, 80% by mass, 98%) as a yellow oil. ES-MS m / z 406.4 [M+H] + .

[0513] Preparation 233 (2S)-3-(2-bromo-4-carbamoyl-phenyl)-2-[(3R)-1-tert-butoxycarbonylpyrrolidin-3-yl]propanoic acid

[0514] [ka] A mixture of tert-butyl (3R)-3-[(1S)-2-[(4S)-4-benzyl-2-oxo-oxazolidin-3-yl]-1-[(2-bromo-4-cyano-phenyl)methyl]-2-oxo-ethyl]pyrrolidine-1-carboxylate (430 mg, 80% by weight, 0.59 mmol) in THF (8 mL) was treated with hydrogen peroxide (140 mg, 30% in water, 1.23 mmol) in one portion at 0° C. Then, a solution of lithium hydroxide (30 mg, 1.24 mmol) in water (2 mL) was added portionwise to the mixture at 0° C. The reaction was stirred at 20° C. for 3 hours. Saturated aqueous sodium bisulfite solution (30 mL) was added to the reaction over 5 minutes, and the temperature was allowed to rise to 30° C. The pH was adjusted to >12 with 5 N aqueous NaOH and extracted with EtOAc (3×30 mL). The pH of the aqueous layer was adjusted to 2 with 2N aqueous HCl and extracted with EtOAc (3 x 30 mL). The organics from the acidic extractions were combined, dried over NaSO, filtered, and concentrated under reduced pressure to give the title compound (160 mg, 70% by weight, 43%) as a colorless oil. TLC (1:1 EtOAc / petroleum ether) R f =0.2.

[0515] Preparation 234 tert-Butyl (3R)-3-[(1S)-1-[(3-bromophenyl)methyl]-2-methoxy-2-oxo-ethyl]pyrrolidine-1-carboxylate

[0516] [ka] A mixture of (2S)-3-(3-bromophenyl)-2-[(3R)-1-tert-butoxycarbonylpyrrolidin-3-yl]propanoic acid (400 mg, ammonium salt, 0.96 mmol) in DMF (5 mL) was treated with sodium bicarbonate (250 mg, 2.98 mmol) and iodomethane (420 mg, 2.93 mmol) at 25 °C. The reaction was stirred at 25 °C for 16 h. The reaction was poured into saturated aqueous NaCl (15 mL) and extracted with EtOAc (3 × 20 mL). The organics were collected, dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with a gradient of 0% to 20% EtOAc in petroleum ether to afford the title compound (300 mg, 76%) as a yellow oil, which was used in the next synthetic step without characterization.

[0517] Preparation 235 Methyl (2S)-3-(3-bromophenyl)-2-[(3R)-pyrrolidin-3-yl]propanoate

[0518] [ka] tert-Butyl (3R)-3-[(1S)-1-[(3-bromophenyl)methyl]-2-methoxy-2-oxo-ethyl]pyrrolidine-1-carboxylate (390 mg, 0.95 mmol) was treated with HCl (5 mL, 4 M in 1,4-dioxane, 20 mmol) at 25 °C. The reaction was stirred at 25 °C for 3 h. The pH of the reaction was adjusted to 8 with saturated aqueous NaHCO and extracted with EtOAc (4 × 30 mL). The organics were collected, dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with a gradient of 0% to 80% EtOAc in petroleum ether to afford the title compound (230 mg, 90% by mass, 70%) as a colorless oil. ES-MS m / z 312.1 (M+H).

[0519] Preparation 236 Methyl (2S)-2-[(3R)-pyrrolidin-3-yl]-3-(3-vinylphenyl)propanoate

[0520] [ka] A mixture of methyl (2S)-3-(3-bromophenyl)-2-[(3R)-pyrrolidin-3-yl]propanoate (230 mg, 0.74 mmol) and phenylboronic acid pinacol ester (180 mg, 1.11 mmol) in water (1 mL) and 1,2-dimethoxyethane (10 mL) was dissolved in potassium carbonate (200 mg, 1.45 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium. The reaction mixture was treated with 20 mg of methyltrimethylammonium chloride (II) (58 mg, 0.08 mmol) at 25 °C. The reaction was stirred at 90 °C under N (15 psi) for 16 h. The reaction mixture was combined with 20 mg of the reactant and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography eluting with a gradient of 0% to 20% MeOH in DCM to give the title compound (120 mg, 45%) as a yellow oil. TLC (DCM / MeOH=10:1) R f =0.5, and observed by I2 staining.

[0521] Preparation 237 tert-Butyl (3R)-3-[(1S)-2-tert-butoxy-1-[[3-(hydroxymethyl)-5-methyl-phenyl]methyl]-2-oxo-ethyl]pyrrolidine-1-carboxylate

[0522] [ka] A solution of tert-butyl (3R)-3-[(1S)-1-[(3-bromo-5-methyl-phenyl)methyl]-2-tert-butoxy-2-oxo-ethyl]pyrrolidine-1-carboxylate (500 mg, 1.07 mmol), tributylstannylmethanol (412 mg, 1.28 mmol), and (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (100 mg, 0.12 mmol) in 1,4-dioxane (5 mL, 58.57 mmol) was degassed and purged with N three times. The reaction was stirred overnight at 100 °C under a N atmosphere. The reaction was combined with 100 mg of the reaction mixture for workup. The reaction mixture was diluted with HO (30 mL) and extracted with EtOAc (3 × 50 mL). The combined organics were washed with saturated aqueous NaCl (50 mL), dried over anhydrous NaSO, filtered, and concentrated under a gradient of 0% to 50% EtOAc in petroleum ether to give the title compound (400 mg, 90% by mass, 80%) as a yellow oil. ES-MS m / z 442 (M+Na).

[0523] Preparation 238 tert-Butyl (3R)-3-[(1S)-2-tert-butoxy-2-oxo-1-[[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]ethyl]pyrrolidine-1-carboxylate

[0524] [ka] tert-Butyl (3R)-3-[(1S)-1-[(3-bromophenyl)methyl]-2-tert-butoxy-2-oxo-ethyl]pyrrolidine-1-carboxylate (prepared essentially as described in WO 2020 / 247429, 200 mg, 0.44 mmol), bis(pinacolato)diboron (170 mg, 0.66 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II] (34 mg, 0.04 mmol), and potassium acetate (132 mg, 1 mL) in 1,4-dioxane (3 mL). A mixture of 0.33 mmol) was degassed and purged with N2 three times, then the mixture was stirred at 100 °C overnight. The mixture was diluted with HO (15 mL) and extracted with EtOAc (2 × 20 mL). The organic layer was washed with saturated aqueous NaCl (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with a gradient of 0% to 100% EtOAc in petroleum ether to afford the title compound (190 mg, 80% by mass, 69%) as a yellow oil. ES-MS m / z 502 (M+H).

[0525] Preparation 239 tert-Butyl (3R)-3-[(1S)-2-tert-butoxy-2-oxo-1-[[3-[1-(2-trimethylsilylethoxymethyl)pyrazol-3-yl)phenyl]methyl]ethyl]pyrrolidine-1-carboxylate

[0526] [ka] A mixture of [1-(2-trimethylsilylethoxymethyl)pyrazol-3-yl]boronic acid (150 mg, 0.62 mmol), tert-butyl (3R)-3-[(1S)-1-[(3-bromophenyl)methyl]-2-tert-butoxy-2-oxo-ethyl]pyrrolidine-1-carboxylate (prepared essentially as described in WO 2020 / 247429, 200 mg, 0.44 mmol), NaCO (132 mg, 1.25 mmol), and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (46 mg, 0.06 mmol) in 1,4-dioxane (4 mL) and water (1 mL) was purged with N (3 times) and the reaction was stirred at 100° C. overnight. The mixture was diluted with HO (25 mL) and extracted with EtOAc (2 × 20 mL). The organic layer was washed with saturated aqueous NaCl (20 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with a gradient of 0% to 100% EtOAc in petroleum ether to afford the title compound (180 mg, 80% by mass, 41%) as a yellow oil. ES-MS m / z 572 (M+H).

[0527] Preparation 240 tert-Butyl (3R)-3-[(1S)-2-tert-butoxy-2-oxo-1-[[3-(1H-3-pyrazol-3-yl)phenyl]methyl]ethyl]pyrrolidine-1-carboxylate

[0528] [ka] A solution of tert-butyl (3R)-3-[(1S)-2-tert-butoxy-2-oxo-1-[[3-[1-(2-trimethylsilylethoxymethyl)pyrazol-3-yl]phenyl]methyl]ethyl]pyrrolidine-1-carboxylate (180 mg, 80% by weight, 0.25 mmol) in THF (4 mL) was treated with tetrabutylammonium fluoride (1.3 mL, 1N in THF, 1.3 mmol), and the reaction was stirred at 50° C. for 16 h. The reaction was diluted with water (20 mL) and extracted with EtOAc (3×20 mL). The combined organics were washed with saturated aqueous NaCl (30 mL), dried over anhydrous NaSO, filtered, and the filtrate was concentrated under reduced pressure to give the title compound (150 mg, 80% by weight, 108%), which was used in the next synthetic step without purification. ES-MS m / z 442.3 (M+H).

[0529] Preparation 241 tert-Butyl (3R)-3-[(1S)-2-tert-butoxy-1-[[3-[1-[3-[(2S)-3-tert-butoxy-2-[(3R)-1-tert-butoxycarbonylpyrrolidin-3-yl]-3-oxo-propyl]phenyl]pyrazol-3-yl-]phenyl]methyl]-2-oxo-ethyl]pyrrolidine-1-carboxylate

[0530] [ka] A solution of tert-butyl (3R)-3-[(1S)-2-tert-butoxy-2-oxo-1-[[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]ethyl]pyrrolidine-1-carboxylate (100 mg, 80% by weight, 0.16 mmol) and tert-butyl (3R)-3-[(1S)-2-tert-butoxy-2-oxo-1-[[3-(1H-pyrazol-3-yl)phenyl]methyl]ethyl]pyrrolidine-1-carboxylate (140 mg, 80% by weight, 0.25 mmol) in pyridine (4 mL) was treated with copper(II) acetate (60 mg, 0.33 mmol). The reaction was stirred at 70 °C under O overnight. The mixture was diluted with water (10 mL) and extracted with EtOAc (3 × 30 mL). The organic layers were combined, washed with saturated aqueous NaCl (30 mL), collected, dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 0% to 20% EtOAc in petroleum ether, leaving impure product. A second purification was performed by SFC [Column: Daicel CHIRALPAK IC™ (250 mm × 30 mm, 10 μm), Mobile phase: Solvent A = CO, Solvent B = EtOH + 0.1% NHOH), isocratic 35% Solvent B in Solvent A, Flow rate 80 mL / min] to give the title compound (50 mg, 90% by mass, 35%) as a white solid. ES-MS m / z 815.7 (M+H).

[0531] Preparation 243 3-[(2S)-3-tert-butoxy-2-[(3R)-1-tert-butoxycarbonylpyrrolidin-3-yl]-3-oxo-propyl]phenyl]benzoic acid

[0532] [ka] A solution of tert-butyl (3R)-3-[(1S)-2-tert-butoxy-1-[(3-methoxycarbonylphenyl)methyl]-2-oxo-ethyl]pyrrolidine-1-carboxylate (390 mg, 95% wt, 0.85 mmol) in THF (4 mL) and MeOH (2 mL) was treated with lithium hydroxide (150 mg, 3.50 mmol) in water (1 mL) at 25 °C. The reaction was stirred at 25 °C for 12 h. The reaction was concentrated under reduced pressure. The pH of the mixture was adjusted to 6 with HCl (1 N). The mixture was extracted with EtOAc (3 × 30 mL). The combined organics were dried over NaSO, filtered, and concentrated under reduced pressure to give the title compound (370 mg, 98%) as a white solid. ES-MS m / z 320 (M+H-BOC).

[0533] Preparation 244 tert-Butyl (3R)-3-[(1S)-2-tert-butoxy-1-[[3-[[3-[(2S)-3-tert-butoxy-2-[(3R)-1-tert-butoxycarbonylpyrrolidin-3-yl]-3-oxo-propyl]phenyl]carbamoyl]phenyl]methyl]-2-oxo-ethyl]pyrrolidine-1-carboxylate

[0534] [ka] A mixture of 3-[(2S)-3-tert-butoxy-2-[(3R)-1-tert-butoxycarbonylpyrrolidin-3-yl]-3-oxo-propyl]benzoic acid (320 mg, 0.72 mmol) and tert-butyl (3R)-3-[(1S)-1-[(3-aminophenyl)methyl]-2-tert-butoxy-2-oxo-ethyl]pyrrolidine-1-carboxylate (prepared essentially as described in WO 2020 / 247429, 290 mg, 0.74 mmol) in DMF (15 mL, 194 mmol, 100% by weight) was treated with N,N-diisopropylethylamine (380 mg, 2.94 mmol) and HATU (420 mg, 1.10 mmol) at 25° C. The reaction was stirred at 25° C. for 15 hours. The reaction was poured into saturated aqueous NaCl (30 mL) and extracted with EtOAc (3 x 50 mL). The combined organics were dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with a gradient of 0% to 100% EtOAc in petroleum ether to afford the title compound (460 mg, 85% by mass, 68%) as a yellow oil. ES / MS m / z 692 (M+H-BOC).

[0535] Preparation 245 tert-Butyl (3R)-3-[(1S)-2-tert-butoxy-1-[[3-[[3-[(2S)-3-tert-butoxy-2-[(3R)-1-tert-butoxycarbonylpyrrolidin-3-yl]-3-oxo-propyl]phenyl]sulfonylamino]phenyl]methyl]-2-oxo-ethyl]pyrrolidine-1-carboxylate

[0536] [ka] A mixture of tert-butyl (3R)-3-[(1S)-1-[(3-aminophenyl)methyl]-2-tert-butoxy-2-oxo-ethyl]pyrrolidine-1-carboxylate (prepared essentially as described in WO 2020 / 247429, 270 mg, 0.69 mmol) and pyridine (36 mg, 0.45 mmol) in THF (5 mL) was stirred at room temperature for 0.5 h, treated with tert-butyl (3R)-3-[(1S)-2-tert-butoxy-1-[(3-chlorosulfonylphenyl)methyl]-2-oxo-ethyl]pyrrolidine-1-carboxylate (300 mg, 90% by weight, 0.56 mmol) and stirred at room temperature for 2 h. The reaction was diluted with HO (10 mL) and extracted with EtOAc (2 × 20 mL). The combined organic layers were washed with saturated aqueous NaCl (20 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with a gradient of 0% to 60% EtOAc in petroleum ether to give the title compound (330 mg, 90% by mass, 63%) as a pale yellow oil. ES-MS m / z 829 (M+H).

[0537] Preparation 246 tert-Butyl (3R)-3-[(1S)-2-tert-butoxy-1-[(3-ethynylphenyl)methyl]-2-oxo-ethyl]pyrrolidine-1-carboxylate

[0538] [ka] A mixture of tert-butyl (3R)-3-[(1S)-2-tert-butoxy-2-oxo-1-[[3-(2-trimethylsilylethynyl)phenyl]methyl]ethyl]pyrrolidine-1-carboxylate (300 mg, 80% by weight, 0.51 mmol) in THF (2 mL) was treated with tetrabutylammonium fluoride (940 mg, 3.60 mmol) at 25 °C. Upon completion of the reaction (monitored by TLC (1:5 EtOAc:petroleum ether)), the mixture was poured into NH4Cl (20 mL) and extracted with EtOAc (3 × 25 mL). The combined organic phases were washed with water (2 × 20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the title compound (240 mg, 77% by weight, 91%) as a yellow oil. ES-MS m / z 422 (M+Na).

[0539] Preparation 247 tert-Butyl (3R)-3-[(1S)-2-tert-butoxy-1-[[3-[1-[3-[(2S)-3-tert-butoxy-2-[(3R)-1-tert-butoxycarbonylpyrrolidin-3-yl]-3-oxo-propyl]phenyl]thiazol-4-yl-]phenyl]methyl]-2-oxo-ethyl]pyrrolidine-1-carboxylate

[0540] [ka] To a mixture of tert-butyl (3R)-3-[(1S)-1-[(3-azidophenyl)methyl]-2-tert-butoxy-2-oxo-ethyl]pyrrolidine-1-carboxylate (180 mg, 0.432 mmol) and tert-butyl (3R)-3-[(1S)-2-tert-butoxy-1-[(3-ethynylphenyl)methyl]-2-oxo-ethyl]pyrrolidine-1-carboxylate (180 mg, 0.451 mmol) in tert-butanol (2 mL) and water (4 mL) was added copper sulfate (7 mg, 0.044 mmol), sodium ascorbate (26 mg, 0.13 mmol), and benzoic acid (30 mg, 0.25 mmol) in one portion at 25° C. The reaction mixture was stirred at 25° C. for 16 hours and then concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography using a gradient of 0-30% EtOAc in petroleum ether to give the title compound (200 mg, 51%) as a yellow oil. ES-MS m / z 816.5.

[0541] Preparation 248 (R)-tert-Butyl 3-((S)-1-(tert-butoxy)-3-(3-(5-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)pyrazine-2-carboxamido)phenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate

[0542] [ka] To a mixture of 5-[(2S)-3-tert-butoxy-2-[(3R)-1-tert-butoxycarbonylpyrrolidin-3-yl]-3-oxo-propyl]pyrazine-2-carboxylic acid (130 mg, 0.308 mmol) and tert-butyl (3R)-3-[(1S)-1-[(3-aminophenyl)methyl]-2-tert-butoxy-2-oxo-ethyl]pyrrolidine-1-carboxylate (prepared essentially as described in WO 2020 / 247429, 120 mg, 0.307 mmol) in DMF (4 mL) was added N,N-diisopropylethylamine (160 mg, 1.24 mmol) and HATU (180 mg, 0.473 mmol) in one portion at 25°C. The reaction mixture was stirred at 25°C for 5 hours and then combined with the reaction mixture prepared with 20 mg (0.038 mmol) of the starting carboxylic acid. The mixture was poured into saturated aqueous NaCl (15 mL) and extracted with EtOAc (25 mL x 4). The combined organic phases were dried over NaSO, filtered, and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography using a gradient of 0-10% EtOAc in petroleum ether to give the title compound (200 mg, 69%) as a yellow oil. ES-MS m / z 694.6.

[0543] Preparation 249 (2S)-2-[(3R)-1-tert-butoxycarbonylpyrrolidin-3-yl]-3-[2-[3-[4-[(2S)-2-[(3R)-1-tert-butoxycarbonylpyrrolidin-3-yl]-2-carboxy-ethyl]-2-pyridyl]-2-oxo-imidazolidin-1-yl]-4-pyridyl]propanoic acid.

[0544] [ka] A mixture of (2S)-3-(2-bromo-4-pyridyl)-2-[(3R)-1-tert-butoxycarbonylpyrrolidin-3-yl]propanoic acid (2.1 g, 4.7 mmol), imidazolidin-2-one (330 mg, 3.83 mmol), [(2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (400 mg, 0.493 mmol), sodium tert-butoxide (1.4 g, 14 mmol) in 1,4-dioxane (15 mL) was stirred at 100 °C under N (15 Psi) for 16 h. The reaction mixture was concentrated, and the residue was purified by HPLC [Column: Welch Xtimate® C18 250 × 50 mm, 10 μm, Mobile phase: Solvent A = aqueous formic acid, Solvent B = ACN, gradient of 20-100% solvent B in solvent A] to give the title compound (100 mg, 3%) as a yellow oil. ES-MS m / z 723.5.

[0545] Preparation 250 tert-Butyl (3R)-3-[(1S)-1-[[2-bromo-5-iodo-phenyl)methyl]-2-tert-butoxy-2-oxo-ethyl]pyrrolidine-1-carboxylate

[0546] [ka] To a mixture of (2S)-3-(2-bromo-5-iodo-phenyl)-2-[(3R)-1-tert-butoxycarbonylpyrrolidin-3-yl]propanoic acid (4.9 g, 6.5 mmol) in THF (60 mL) was added 2-tert-butyl-1,3-diisopropylisourea (4 g, 19.6 mmol) in one portion at 25 °C. The reaction mixture was stirred at 70 °C for 16 h, then diluted with water (150 mL) and extracted with EtOAc (200 mL × 3). The combined organic layers were washed with saturated aqueous NaCl (100 mL × 2), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a gradient of 0 to 100% EtOAc in petroleum ether to give the title compound (2 g, 48%) as a yellow oil. TLC (1:3 EtOAc:petroleum ether) R f =0.7.

[0547] Preparation 251 tert-Butyl (3R)-3-[(1S)-1-[[2-bromo-5-cyano-phenyl)methyl]-2-tert-butoxy-2-oxo-ethyl]pyrrolidine-1-carboxylate

[0548] [ka] To a solution of tert-butyl (3R)-3-[(1S)-1-[(2-bromo-5-iodo-phenyl)methyl]-2-tert-butoxy-2-oxo-ethyl]pyrrolidine-1-carboxylate (2 g, 3.1 mmol) in DMF (30 mL) was added zinc cyanide (380 mg, 3.14 mmol) and tetrakis(triphenylphosphine)palladium(0) (730 mg, 0.625 mmol) at 25 °C, and the mixture was stirred at 80 °C under N for 1 h. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (100 mL × 3). The combined organic layers were washed with saturated aqueous NaCl (100 mL × 2), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a gradient of 0-100% EtOAc in petroleum ether to give the title compound (1.38 g, 88%) as a yellow oil. TLC (1:3 EtOAc / petroleum ether) R f =0.6.

[0549] Preparation 252 tert-Butyl (3R)-3-[(1R)-2-tert-butoxy-1-[[3-[2-[(2S)-3-tert-butoxy-2-[(3R)-1-tert-butoxycarbonylpyrrolidin-3-yl]-3-oxo-propyl]-4-cyano-anilino]phenyl]methyl]-2-oxo-ethyl]pyrrolidine-1-carboxylate

[0550] [ka] To a solution of tert-butyl (3R)-3-[(1S)-1-[(2-bromo-5-cyano-phenyl)methyl]-2-tert-butoxy-2-oxo-ethyl]pyrrolidine-1-carboxylate (180 mg, 0.376 mmol) in 1,4-dioxane (15 mL) was added potassium tert-butoxide (130 mg, 1.12 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II] (60 mg, 0.082 mmol) and tert-butyl (3R)-3-[(1S)-1-[(3-aminophenyl)methyl]-2-tert-butoxy-2-oxo-ethyl]pyrrolidine To the reaction mixture was added 180 mg of benzophenone-1-carboxylate (prepared essentially as described in WO 2020 / 247429, 180 mg, 0.461 mmol). The reaction mixture was stirred at 100 °C under N for 4 hours. The reaction mixture was poured into water (100 mL), and the aqueous layer was extracted with EtOAc (100 mL × 3). The organic layer was dried over anhydrous NaSO, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a gradient of 0 to 100% EtOAc in petroleum ether to give the title compound (20 mg, 5%) as a yellow oil. ES / MS m / z 633.3 (M-Boc-tert-butyl).

[0551] Preparation 253 tert-Butyl (3R)-3-[(1S)-2-tert-butoxy-1-[[3-[[[3-[(2S)-3-tert-butoxy-2-[(3R)-1-tert-butoxycarbonylpyrrolidin-3-yl]-3-oxo-propyl]-5-methyl-phenyl]methylamino]methyl]-5-methyl-phenyl]methyl]-2-oxo-ethyl]pyrrolidine-1-carboxylate

[0552] [ka] To a solution of tert-butyl (3R)-3-[(1S)-2-tert-butoxy-1-[(3-formyl-5-methyl-phenyl)methyl]-2-oxo-ethyl]pyrrolidine-1-carboxylate (300 mg, 0.719 mmol) in THF (3 mL) was added ammonium acetate (250 mg, 3.24 mmol), and the mixture was stirred at 20° C. for 30 minutes. Sodium triacetoxyborohydride (460 mg, 2.17 mmol) was then added to the mixture, and the mixture was stirred at 20° C. for 2 hours. Saturated aqueous NaCl (300 mL) was added to the reaction mixture, and the mixture was extracted with EtOAc (200 mL×3). The combined organic phase was washed with water (200 mL×2, then 150 mL×3), then dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a gradient of 0-50% EtOAc in petroleum ether to give the title compound (150 mg, 25%). TLC (3:1 EtOAc:petroleum ether) R f =0.2.

[0553] Preparation 254 tert-Butyl (3R)-3-[(1S)-1-[[3-[[bis[[3-[(2S)-3-tert-butoxy-2-[(3R)-1-tert-butoxycarbonylpyrrolidin-3-yl]-3-oxo-propyl]-5-methyl-phenyl]methyl]amino]methyl]-5-methyl-phenyl]methyl]-2-tert-butoxy-2-oxo-ethyl]pyrrolidine-1-carboxylate

[0554] [ka] tert-Butyl (3R)-3-[(1S)-2-tert-butoxy-1-[(3-formyl-5-methyl-phenyl)methyl]-2-oxo-ethyl]pyrrolidine-1-carboxylate (150 mg, 0.359 mmol) and tert-butyl (3R)-3-[(1S)-2-tert-butoxy-1-[[3-[[3-[(2S)-3-tert-butoxy-2-[(3R)-1-tert-butoxyca To a solution of [carbonylpyrrolidin-3-yl]-3-oxo-propyl]-5-methyl-phenyl]methylamino]methyl]-5-methyl-phenyl]methyl]-2-oxo-ethyl]pyrrolidine-1-carboxylate (150 mg, 0.183 mmol) was added acetic acid (60 mg, 1.00 mmol), and the mixture was stirred at 20 °C for 3 h. Then, sodium triacetoxyborohydride (120 mg, 0.566 mmol) was added. The mixture was stirred at 20 °C for 6 h, then poured into saturated aqueous NaCl (20 mL) and extracted with EtOAc (20 mL × 4). The combined organic phases were dried over Na2SO4, filtered, and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography using a gradient of 0 to 30% EtOAc in petroleum ether to give the title compound (60 mg, 19%). ES-MS m / z (M-Boc+2H) / 2

[0555] Preparation 255 tert-Butyl (3R)-3-[(1S)-2-tert-butoxy-1-[[3-[[[3-[(2S)-3-tert-butoxy-2-[(3R)-1-tert-butoxycarbonylpyrrolidin-3-yl]-3-oxo-propyl]-5-methyl-phenyl]methyl-[(3-fluoro-5-methoxy-phenyl)methyl]amino]methyl]-5-methyl-phenyl]methyl]-2-oxo-ethyl]pyrrolidine-1-carboxylate

[0556] [ka] To a solution of tert-butyl (3R)-3-[(1S)-2-tert-butoxy-1-[[3-[[[3-[(2S)-3-tert-butoxy-2-[(3R)-1-tert-butoxycarbonylpyrrolidin-3-yl]-3-oxo-propyl]-5-methyl-phenyl]methylamino]methyl]-5-methyl-phenyl]methyl]-2-oxo-ethyl]pyrrolidine-1-carboxylate (50 mg, 0.061 mmol) in THF (3 mL) was added acetic acid (20 mg, 0.33 mmol), the mixture was stirred at 20° C. for 30 minutes, and then sodium triacetoxyborohydride (40 mg, 0.19 mmol) was added. The mixture was stirred at 20° C. under N for 1 hour, then diluted with HO (20 mL) and extracted with EtOAc (15 mL×3). The combined organic phases were washed with saturated aqueous NaCl (15 mL), dried over NaSO and concentrated under reduced pressure to give the title compound (100 mg, quantitative yield), which was used without further purification. ES-MS m / z 959.5 (M+H).

[0557] Preparation 256 tert-Butyl (3R)-3-[(1S)-1-[(3-allylphenyl)methyl]-2-tert-butoxy-2-oxo-ethyl]pyrrolidine-1-carboxylate

[0558] [ka] To a mixture of tert-butyl (3R)-3-[(1S)-1-[(3-bromophenyl)methyl]-2-tert-butoxy-2-oxo-ethyl]pyrrolidine-1-carboxylate (prepared essentially as described in WO 2020 / 247429, 500 mg, 1.10 mmol) and 2-allyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (560 mg, 3.33 mmol) in water (1 mL) and 1,2-dimethoxyethane (10 mL), potassium carbonate (460 mg, 3.33 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (90 mg, 0.12 mmol) were added, and the reaction mixture was stirred at 90 °C under N for 16 hours. The reaction mixture was added to saturated aqueous NaCl (20 mL). The mixture was then extracted with EtOAc (30 mL x 3), and the combined organic phases were washed with water (20 mL x 2), dried over Na2SO4, and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography using a gradient of 0-20% EtOAc in petroleum ether to give the title compound (300 mg, 59%) as a yellow oil. TLC (1:5 EtOAc / petroleum ether) R f =0.7(I2 staining).

[0559] Preparation 257 tert-Butyl (3R)-3-[(1S)-2-tert-butoxy-1-[[3-[3-[3-[(2S)-3-tert-butoxy-2-[(3R)-1-tert-butoxycarbonylpyrrolidin-3-yl]-3-oxo-propyl]phenyl]propyl]methyl]phenyl]methyl]-2-oxo-ethyl]pyrrolidine-1-carboxylate

[0560] [ka] To a mixture of tert-butyl (3R)-3-[(1S)-1-[(3-allylphenyl)methyl]-2-tert-butoxy-2-oxo-ethyl]pyrrolidine-1-carboxylate (120 mg, 0.289 mmol) and tert-butyl (3R)-3-[(1S)-1-[(3-bromophenyl)methyl]-2-tert-butoxy-2-oxo-ethyl]pyrrolidine-1-carboxylate (prepared essentially as described in WO 2020 / 247429, 200 mg, 0.440 mmol) in 1,4-dioxane (4 mL) was added [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (25 mg, 0.034 mmol), TEA (80 mg, 0.80 mmol), and the reaction mixture was stirred at 70° C. under N for 16 h. The mixture was combined with a reaction carried out essentially as described above using 200 mg (0.481 mmol) of starting alkene, and the resulting mixture was concentrated to dryness under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 0 to 10% EtOAc in petroleum ether to give tert-butyl (3R)-3-[(1S)-2-tert-butoxy-1-[[3-[(E)-3-[3-[(2S)-3-tert-butoxy-2-[(3R)-1-tert-butoxycarbonylpyrrolidin-3-yl]-3-oxo-propyl]phenyl]allyl]phenyl]methyl]-2-oxo-ethyl]pyrrolidine-1-carboxylate (150 mg, 59%) as a yellow oil.

[0561] To a mixture of tert-butyl (3S)-3-[(1S)-2-tert-butoxy-1-[[3-[(E)-3-[3-[(2S)-3-tert-butoxy-2-[(3R)-1-tert-butoxycarbonylpyrrolidin-3-yl]-3-oxo-propyl]phenyl]allyl]phenyl]methyl]-2-oxo-ethyl]pyrrolidine-1-carboxylate (130 mg, 0.148 mmol) in MeOH (10 mL) was added palladium (10 wt % on carbon 30 mg, 0.0282 mmol) at 25° C. The reaction mixture was stirred under H (45 PSI) at 25° C. for 16 h. The reaction mixture was combined with 20 mg (0.022 mmol) of the starting olefin mixture. The mixture was filtered, and the filtrate was concentrated to dryness under reduced pressure to give the title compound (110 mg, 54%) as a yellow oil. TLC (1:5 EtOAc:petroleum ether) R f =0.6.

[0562] Preparation 258 (2S)-2-[(3R)-1-tert-butoxycarbonylpyrrolidin-3-yl]-3-[3-[2-(cyclohexoxy)-3-pyridyl]phenyl]propanoic acid

[0563] [ka] (2S)-3-(3-bromophenyl)-2-[(3R)-1-tert-butoxycarbonylpyrrolidin-3-yl]propanoic acid (prepared essentially as described in WO 2020 / 247429, 100 mg, 0.25 mmol), 2-(cyclohexoxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (114 mg, 0.38 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (19 mg, 0.03 mmol), 2 M aqueous potassium carbonate (0.38 mL), and 1,4-dioxane (1.7 mL) were transferred to a reaction vessel, purged with N, sealed, and stirred at 100 °C for 2 h. The reaction was concentrated under a stream of nitrogen. The residue was taken up in EtOAc and extracted with water. The aqueous layer was acidified with 5% acetic acid and extracted with EtOAc. The organic layer was concentrated under a stream of nitrogen and purified by reverse phase chromatography to give the title compound (57.4 mg, 46%) as a white solid. ES-MS m / z 495 (M+H).

[0564] Prepare the following essentially as described in Preparation 258 using the appropriate boronic acid or boronic ester:

[0565] [Table 20]

[0566] The following were prepared essentially as described in Preparation 10 using 2-[(3R)-1-tert-butoxycarbonylpyrrolidin-3-yl]acetic acid (prepared essentially as described in WO 2020 / 247429) and the appropriate heterocyclic starting material. The compounds in the table below were purified by HPLC (Column: Phenomenex® C18 75×30 mm, 3 μm, Mobile Phase: Solvent A—aqueous NH4OH+NH4HCO3, Solvent B—ACN, Flow Rate: 25 mL / min).

[0567] [Table 21-1]

[0568] [Table 21-2]

[0569] [Table 21-3]

[0570] Example 1a 3-(3-ethynylphenyl)-2-[(3R)-pyrrolidin-3-yl]propanoic acid, hydrochloride - isomer 1

[0571] [ka] To 2-[(3R)-1-tert-butoxycarbonylpyrrolidin-3-yl]-3-(3-ethynylphenyl)propanoic acid isomer 1 (454 mg, 1.32 mmol), HCl in EtO (2.0 M, 13 mL, 26 mmol) was added, and the mixture was stirred at room temperature for 6 hours. The solvent was removed, and the residue was dried in vacuo at 40 °C overnight to give the title compound (370 mg, 100%) as a white powder. ES-MS m / z 244 (M+H).

[0572] Example 1b 3-(3-ethynylphenyl)-2-[(3R)-pyrrolidin-3-yl]propanoic acid, hydrochloride - isomer 2

[0573] [ka] The title compound was prepared essentially as described in Example 1a using 2-[(3R)-1-tert-butoxycarbonylpyrrolidin-3-yl]-3-(3-ethynylphenyl)propanoic acid isomer 2. ES-MS m / z 244 (M+H).

[0574] Example 2a 3-(6-chloro-3-pyridyl)-2-[(3R)-pyrrolidin-3-yl]propanoic acid, hydrochloride - isomer 1

[0575] [ka] To a solution of 2-[(3R)-1-tert-butoxycarbonylpyrrolidin-3-yl]-3-(6-chloro-3-pyridyl)propanoic acid - Isomer 1 (20 mg, 0.056 mmol) in DCM (2 mL) was added HCl (4 M in 1,4-dioxane, 2 mL), and the reaction was stirred at room temperature for 1 hour. The solvent was removed in vacuo, and the residue was then dissolved in water and loaded onto 5 g of SCX resin. The resin was eluted with ACN, and the eluate was discarded. The resin was then eluted with 2 M NH3 in MeOH, and the eluate was concentrated in vacuo to give the title compound (13 mg, 91%) as a white solid. ES-MS m / z 255 (M+H).

[0576] Example 2b 3-(6-chloro-3-pyridyl)-2-[(3R)-pyrrolidin-3-yl]propanoic acid, hydrochloride - isomer 2

[0577] [ka] The title compound was prepared essentially as described in Example 2a using 2-[(3R)-1-tert-butoxycarbonylpyrrolidin-3-yl]-3-(6-chloro-3-pyridyl)propanoic acid - Isomer 2. ES-MS m / z 255 (M+H).

[0578] Example 3 (2S)-3-(3-methyl-5-ureido-phenyl)-2-[(3R)-pyrrolidin-3-yl]propanoic acid, hydrochloride

[0579] [ka] The title compound was prepared essentially as described in Example 1a using (2S)-2-[(3R)-1-tert-butoxycarbonylpyrrolidin-3-yl]-3-(3-methyl-5-ureido-phenyl)propanoic acid. ES-MS m / z 292 (M+H).

[0580] Example 4 (2S)-3-[3-[(3-fluoro-5-methoxy-anilino)methyl]phenyl]-2-[(3R)-pyrrolidin-3-yl]propanoic acid, dihydrochloride

[0581] [ka] To a solution of tert-butyl (3R)-3-[(1S)-2-tert-butoxy-1-[[3-[(3-fluoro-5-methoxy-anilino)methyl]phenyl]methyl]-2-oxo-ethyl]pyrrolidine-1-carboxylate (433 mg, 0.82 mmol) in DCM (10 mL) was added hydrochloric acid (4 M in 1,4-dioxane, 10 mL, 40 mmol) and the mixture was stirred at room temperature for 4 hours. The solvent was removed in vacuo. The residue was dissolved in water and concentrated to remove residual solvent to give the title compound (350 mg, 99%). ES / MS m / z 373 (M+H).

[0582] The following examples were prepared essentially as described in Example 4 using the appropriate starting material, either Boc-protected 2-(pyrrolidin-3-yl)propanoic acid (Preparations 12, 23-33, and 50) or Boc-protected tert-butyl-2-(pyrrolidin-3-yl)propanoate (Preparations 13-22, 34-40, 43-46, and 51). Examples 5a and 5b were prepared using (2S)-3-(3-bromophenyl)-2-(1-tert-butoxycarbonyl-4,4-difluoro-pyrrolidin-3-yl)propanoic acid - Isomer 1 and Isomer 2, respectively (Preparation 12) as the starting material.

[0583] [Table 22-1]

[0584] [Table 22-2]

[0585] [Table 22-3]

[0586] [Table 22-4]

[0587] [Table 22-5]

[0588] [Table 22-6]

[0589] [Table 22-7]

[0590] [Table 22-8]

[0591] [Table 22-9] A. RP-HPLC / MS [Column: XBridge™ C18, Mobile phase: Solvent A = 20 mM aqueous NH4HCO3 (pH 9), Solvent B = ACN]. After purification, the compound was dissolved in water and 1 N aqueous HCl was added, then evaporated to dryness and further dried in vacuo. B. Instead of HCl (4 M in 1,4-dioxane), HCl (2 M) in EtO was used. C. Hydrochloric acid (4 M in 1,4-dioxane) was used as the solvent D. Water was used as the solvent. E. RP-HPLC / MS [Column: Kinetex EVO 30 × 100 mm, 5 μm, Mobile phase: Solvent A = 10 mM NH4HCO3 aqueous solution (pH 10) + 5% MeOH, Solvent B: ACN, Flow rate: 80 mL / min]. After purification, the compound was dissolved in water and 1 N aqueous HCl was added, followed by evaporation to dryness and further drying in vacuo.

[0592] Example 39 (2S)-3-[3-[[3-[(2S)-2-Carboxy-2-[(3R)-pyrrolidin-3-yl]ethyl]phenyl]carbamoylamino]phenyl]-2-[(3R)-pyrrolidin-3-yl]propanoic acid, dihydrochloride

[0593] [ka] A solution of HCl (4.0 M in 1,4-dioxane, 170 mL, 694 mmol) was added to a mixture of tert-butyl (3R)-3-[(1S)-2-tert-butoxy-1-[[3-[[3-[(2S)-3-tert-butoxy-2-[(3R)-1-tert-butoxycarbonylpyrrolidin-3-yl]-3-oxo-propyl]phenyl]carbamoylamino]phenyl]methyl]-2-oxo-ethyl]pyrrolidine-1-carboxylate (56 g, 69.4 mmol) in 1,4-dioxane (56 mL). The mixture was stirred at room temperature overnight. The resulting solid was filtered, washed with 1,4-dioxane, and dried at 40° C. under reduced pressure. The solid was triturated in tert-amyl alcohol (600 mL) overnight. The solid was collected, washed with tert-amyl alcohol, and then dried under reduced pressure at 40°C. The solid was stirred with tert-amyl alcohol (400 mL) and water (60 mL) to give a solution, which was concentrated in vacuo. The resulting solid was stirred in tert-amyl alcohol (400 mL) at room temperature for 72 hours, then filtered, washed with tert-amyl alcohol, and dried in vacuo at 40°C to give the title compound (39.0 g, 99%). ES / MS (m / z): 494 (M+H). Analytical chiral HPLC [Column: XBridge® C18 2.1 × 50 mm, 3.5 μm, Mobile phase: ACN in aqueous NH4HCO3 (10 mM, pH 9.0), Flow rate: 1.2 mL / min; Column temperature: 50°C] shows a de > 98%.

[0594] The following examples were prepared essentially as described in Example 39 using the appropriate starting material, which was either Boc-protected 2-(pyrrolidin-3-yl)propanoic acid or Boc-protected tert-butyl-2-(pyrrolidin-3-yl)propanoate.

[0595] [Table 23-1]

[0596] [Table 23-2]

[0597] Table 23-3

[0598] Table 23-4

[0599] Table 23-5

[0600] Table 23-6

[0601] Table 23-7

[0602] Table 23-8

[0603] Table 23-9

[0604] Table 23-10

[0605] Table 23-11

[0606] Table 23-12

[0607] Table 23-13

[0608] Table 23-14

[0609] Table 23-15

[0610] Table 23-16

[0611] Table 23-17

[0612] Table 23-18 (

[0613] Table 23-19

[0614] Table 23-20

[0615] Table 23-21

[0616] Table 23-22

[0617] [Table 23-23]

[0618] [Table 23-24]

[0619] [Table 23-25]

[0620] [Table 23-26]

[0621] [Table 23-27]

[0622] [Table 23-28] A. Reverse-phase HPLC purification [Column: Bonus RP21 x 100 mm, 5 μm, Mobile phase: Solvent A - aqueous TFA (0.05%) pH 2.5, Solvent B - ACN + 0.05% TFA] B. HCl in Et2O (2M) was used instead of HCl (4M in 1,4-dioxane) and DCM was used as the reaction solvent. C. Upon completion of deprotection, the product was isolated by concentrating the reaction mixture to dryness. D. Starting material isomer 1 was used E. Starting material isomer 2 was used F. Starting material isomer 3 was used G. Starting material isomer 4 was used H. The product was triturated with ACN+water I. Upon completion of deprotection, the product was isolated by adding MTBE and collecting the solid by filtration. The product was crushed by grinding with J.MTBE. K. After purification, the HCl salt was prepared by mixing the free base with 2M HCl in water and Et2O, then evaporated to dryness and further dried in vacuo. L. Reversed-phase flash chromatography eluting with a gradient of ACN in aqueous NH4HCO3 M. Reverse-phase HPLC purification [Column: XBridge™ C18, Mobile phase: Solvent A = 20 mM aqueous NH4HCO3 (pH 9), Solvent B = ACN]. N. After purification, the HCl salt was prepared by mixing the free base with water and 1N aqueous HCl, then evaporated to dryness and further dried in vacuo. HCl (5.5 M) in IPA was used instead of HCl (4 M in 1,4-dioxane). P. Starting material used: tert-butyl (3R)-3-[(1S)-1-[[3-[[(E)-1-amino-2-cyano-vinyl]amino]phenyl]methyl]-2-tert-butoxy-2-oxo-ethyl]pyrrolidine-1-carboxylate Q. Strong cation exchange (SCX) purification eluting with NH3 in MeOH R. Reverse-phase HPLC purification [Column: Welch Xtimate® C18 150 x 25 mm, 5 μm, Mobile phase - Solvent A = aqueous HCl, Solvent B = ACN] S. Reverse-phase HPLC purification [Column: Phenomenex® Gemini® NX C18 75 × 30 mm, 3 μm, Mobile phase: Solvent A = 10 mM aqueous NH4HCO3, Solvent B = ACN] T. Reverse-phase HPLC purification [Column: Welch Xtimate® C18 150 × 25 mm, 5 μm, Mobile phase—Solvent A = aqueous NH4HCO3, Solvent B = ACN] U. Starting material used: (2S)-2-[(3R)-1-tert-butoxycarbonylpyrrolidin-3-yl]-3-[3-(1,1-dioxo-1,2-thiazolidin-2-yl)phenyl]propanoic acid, the 1,2-thiazolidine ring was opened under these conditions V. Starting material used: tert-butyl (3R)-3-[(1S)-2-tert-butoxy-1-[[3-(1-ethoxyvinyl)phenyl]methyl]-2-oxo-ethyl]pyrrolidine-1-carboxylate W. Starting material used: tert-butyl (3R)-3-[(1S)-2-tert-butoxy-1-[[3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]-2-oxo-ethyl]pyrrolidine-1-carboxylate

[0623] Example 69 (2S)-3-[3-[[3-[(2S)-2-Carboxy-2-[(3R)-pyrrolidin-3-yl]ethyl]-5-(trifluoromethyl)phenyl]carbamoylamino]-5-(trifluoromethyl)phenyl]-2-[(3R)-pyrrolidin-3-yl]propanoic acid, dihydrochloride

[0624] [ka] A mixture of tert-butyl (3R)-3-[(1S)-1-[[3-amino-5-(trifluoromethyl)phenyl]methyl]-2-tert-butoxy-2-oxo-ethyl]pyrrolidine-1-carboxylate (346 mg, 0.755 mmol) and 1,1'-carbonyldiimidazole (61 mg, 0.38 mmol) in THF (7.5 mL) was stirred for 16 h. The reaction mixture was acidified with 1 M aqueous HCl and extracted with EtOAc. The organic layer was separated, dried over MgSO, filtered, and concentrated. The crude material was dissolved in DCM (2 mL) and 4 M HCl in dioxane (3 mL) was added. The reaction was stirred for 16 h. The solvent was evaporated in vacuo. The residue was purified via reverse-phase flash chromatography using a gradient of 20–60% ACN in aqueous NHCO (pH 9) to give the free base product. This material was treated with 1 M aqueous HCl (1 mL) and the solvent was evaporated to give the title compound (30 mg, 5%): ES / MS (m / z) 631 (M+1).

[0625] Example 70 (2S)-3-[4-[4-[(2S)-2-carboxy-2-[(3R)-pyrrolidin-3-yl]ethyl]anilino]phenyl]-2-[(3R)-pyrrolidin-3-yl]propanoic acid, dihydrochloride

[0626] [ka] tert-Butyl (3R)-3-[(1S)-1-[(4-bromophenyl)methyl]-2-tert-butoxy-2-oxo-ethyl]pyrrolidine-1-carboxylate (620 mg, 1.36 mmol), tert-butyl (3R)-3-[(1S)-1-[(4-aminophenyl)methyl]-2-tert-butoxy-2-oxo-ethyl]pyrrolidine-1-carboxylate (799 mg, 2.05 mmol), [tBuBrettPhos Pd(allyl)]OTf (80 mg, 0.10 mmol), and cesium carbonate (1.33 g, 4.09 mmol) were combined in a microwave vessel, followed by argon-sparged dioxane (14 mL). The reaction mixture was heated under nitrogen at 100 °C in a microwave oven for 12 hours. The reaction mixture was then concentrated to dryness under reduced pressure, and the residue was purified by silica gel chromatography eluting with a 0-50% gradient of EtOAc in hexanes. The residue was dissolved in 4N HCl-dioxane (24 mL), stirred until the desired product was observed, concentrated to a solid, and purified via reverse-phase HPLC [Column: Kinetex Evo 100 x 30 mm 5 μm, Mobile Phase: Solvent A = 10 mM aqueous NH4HCO3 + 5% MeOH, Solvent B = ACN, Gradient: 0-10% Solvent B in Solvent A]. The isolated product was dissolved in HCl (1N aqueous solution) and lyophilized to give the title compound (130 mg, 18%) as a yellow solid. ES / MS (m / z): 452 (M+H).

[0627] Example 146 (2S)-3-[3-(pyrimidin-5-yl)phenyl]-2-[(3R)-pyrrolidin-3-yl]propanoic acid hydrochloride

[0628] [ka] A mixture of pyrimidin-5-ylboronic acid (40 mg, 0.33 mmol), tetrakis(triphenylphosphine)palladium(0) (24 mg, 20 mmol), (2S)-3-(3-bromophenyl)-2-[(3R)-1-tert-butoxycarbonylpyrrolidin-3-yl]propanoic acid (prepared essentially as described in WO 2020 / 247429, 100 mg, 251 mmol), KCO (2 M aqueous, 251 μL, 0.502 mmol), and 1,4-dioxane (1 mL) was purged with N and incubated at 100 °C for 18 h. The reaction mixture was concentrated under N, and the residue was then purified on a hydrophobic-lipophilic balance (HLB) column eluted with a gradient of 0 to 100% ACN in NHHCO (pH 9). To the residue was added HCl (4 M in 1,4-dioxane, 627 μL, 2.51 mmol), and the reaction was stirred at room temperature for 3 hours. The resulting solid was concentrated to give the title compound (71 mg, 85%). ES-MS m / z 298 (M+H).

[0629] Example 147 (2S)-3-(3-{[3-(hydrazinecarbonyl)phenoxy]methyl}phenyl)-2-[(3R)-pyrrolidin-3-yl]propanoic acid hydrochloride

[0630] [ka] To a reaction vessel containing tert-butyl (3R)-3-[(1S)-2-tert-butoxy-1-[[3-(hydroxymethyl)phenyl]methyl]-2-oxo-ethyl]pyrrolidine-1-carboxylate (prepared essentially as described in WO 2020 / 247429, 125 mg, 0.308 mmol), 3-(1,3,4-oxadiazol-2-yl)phenol (75 mg, 0.462 mmol), triphenylphosphine (123 mg, 0.462 mmol), THF (1 mL), and finally diethyl azodicarboxylate (73 μL, 81 mg, 0.462 mmol) were added sequentially. The reaction mixture was stirred at room temperature for 24 hours and then concentrated to dryness. The residue was taken up in DCM and passed through a silica gel plug eluting with 20 / 80 acetone / hexanes. The filtrate was concentrated, and the residue was purified by reverse-phase HPLC [Column: XBridge® C18 19 × 100 mm, 5 μm, Mobile phase: Solvent A = 20 mM NH4HCO3 (pH 9), Solvent B = ACN, Gradient: 62-93% Solvent B in Solvent A, Flow rate 25 mL / min]. The product was treated with HCl (4 M solution in 1,4-dioxane, 77 μL) at 50 °C overnight, and then the solvent was evaporated to give the title compound (12 mg, 7%). ES-MS m / z 384 (M+H).

[0631] Example 148 (2S)-3-{3-[3-(3-hydroxyphenyl)-2-oxoimidazolidin-1yl]phenyl}-2-[(3R)-pyrrolidin-3-yl]propanoic acid hydrochloride

[0632] [ka] To a solution of (2S)-3-[3-[3-(3-benzyloxyphenyl)-2-oxo-imidazolidin-1-yl]phenyl]-2-[(3R)-1-tert-butoxycarbonylpyrrolidin-3-yl]propanoic acid (1.10 g, 1.88 mmol) in toluene (18.8 mL) at 70° C. was added N,N-dimethylformamide di-tert-butyl acetal (3.39 g, 4.02 mL, 15.0 mmol) and the reaction was heated at 70° C. for 3 days. The reaction was concentrated, and the residue was purified on silica gel using a gradient of 0 to 50% EtOAc in hexanes to give tert-butyl (3R)-3-[(1S)-1-[[3-[3-(3-benzyloxyphenyl)-2-oxo-imidazolidin-1-yl]phenyl]methyl]-2-tert-butoxy-2-oxo-ethyl]pyrrolidine-1-carboxylate (345 mg, 27%), a portion of which (120 mg, 0.187 mmol) was diluted with DCM (6 mL) and cooled to 0 °C. Boron tribromide (1 M solution in heptane, 0.56 mL, 0.56 mmol) was added dropwise, and the reaction was stirred at 0 °C for 30 min. MeOH was added, and the reaction was concentrated. The residue was purified by HPLC [Column: Kinetex Evo C18 3 x 100 mm, 5 μm, Mobile phase: Solvent A = 0.1% aqueous formic acid in water, Solvent B = ACN, gradient of 5-38% solvent B in solvent A, Column temperature: 50 °C] to give the title compound (42 mg, 51%). ES-MS m / z 396.2 (M+H).

[0633] Example 149 3-Amino-2-(biphenyl-3-ylmethyl)-2-[(3R)-pyrrolidin-3-yl]propanoic acid dihydrochloride (mixture of diastereomers)

[0634] [ka] A mixture of 2-[[2-[(3R)-1-tert-butoxycarbonylpyrrolidin-3-yl]-2-carboxy-3-(3-phenylphenyl)propyl]carbamoyl]benzoic acid (mixture of diastereomers, 28 mg, 0.049 mmol) and concentrated aqueous HCl (0.489 mL) was heated at 100 °C overnight. The mixture was cooled to room temperature and loaded onto SCX resin (previously washed with 50% CHCN-HO). The column was eluted with 50% CHCN-HO, followed by NH (2 M in MeOH, then 7 M in MeOH). The MeOH-NH fractions were collected and concentrated under reduced pressure. The residue was dried under reduced pressure at 40 °C overnight and then treated with HCl (1 N aqueous solution, 0.462 mL, 0.462 mmol) for 1 h, and then the solvent was removed under a stream of nitrogen. The residue was dried under vacuum at 40° C. overnight to give the title compound (9 mg, 73%) as a light brown solid. ES-MS m / z 325 (M+H).

[0635] Example 150 (2S)-3-(3-ethynylphenyl)-2-[(3R)-pyrrolidin-3-yl]propanoic acid hydrochloride

[0636] [ka] To a mixture of tert-butyl (3R)-3-[(1S)-2-tert-butoxy-2-oxo-1-[[3-(2-trimethylsilylethynyl)phenyl]methyl]ethyl]pyrrolidine-1-carboxylate (40 mg, 0.085 mmol) in DCM (1 mL) was added TFA (2 mL) at 25 °C, and the mixture was stirred at 0 °C for 16 h. The reaction mixture was concentrated to dryness and purified by HPLC [Column: Welch Xtimate® C18 150 × 30 mm, 5 μm, Mobile phase: Solvent A = aqueous HCl, Solvent B = ACN, 0-100% gradient of solvent B in solvent A, Flow rate: 25 mL / min] to give the title compound (5.18 mg, 24%) as a white solid. ES-MS m / z 244.0 (M+H).

[0637] Example 151 (2S)-3-(3-hydrazinylphenyl)-2-[(3R)-pyrrolidin-3-yl]propanoic acid hydrochloride

[0638] [ka] To a solution of tert-butyl (3R)-3-[(1S)-1-[(3-aminophenyl)methyl]-2-tert-butoxy-2-oxo-ethyl]pyrrolidine-1-carboxylate (prepared essentially as described in WO 2020 / 247429, 200 mg, 0.512 mmol) and concentrated HCl (3.2 mL) in water (9.6 mL) was slowly added sodium nitrite (53 mg, 0.77 mmol) in water (2.4 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 0.1 h, then stannous chloride (200 mg, 1.03 mmol) in HCl (1.2 mL) was added at 0 °C, and the mixture was stirred at 0-25 °C for 16 h under N20. The reaction mixture was purified by HPLC (column: Phenomenex® Gemini® NX C18 75 × 30 mm, 3 μm, mobile phase: Solvent A = aqueous HCl, Solvent B = ACN, gradient 0-100% solvent B in solvent A) to give the title compound (22 mg, 16%) as a white oil. ES-MS m / z 250.2 (M+H).

[0639] Example 152 3-{(2S)-2-carboxy-2-[(3R)-pyrrolidin-3-yl]ethyl}benzoic acid hydrochloride

[0640] [ka] To a solution of (2S)-3-[3-(methoxycarbonyl)phenyl]-2-[(3R)-pyrrolidin-3-yl]propanoic acid hydrochloride (120 mg, 0.351 mmol) in THF (1 mL) and water (1 mL) was added LiOH (37 mg, 1.47 mmol) at 25 °C. The resulting mixture was stirred at 40 °C for 2 h, and the reaction mixture was purified by HPLC [Column: Phenomenex® Gemini® NX C18 75 × 30 mm, 3 μm, Mobile phase: Solvent A = aqueous HCl, Solvent B = ACN, Gradient: 0 to 100% solvent B in solvent A] to give the title compound (16 mg, 18%) as a yellow oil. ES-MS m / z 264.1 (M+H).

[0641] Example 153 2S-3-(3-ethenylphenyl)-2-[(3R)-pyrrolidin-3-yl]propanoic acid ammonium salt

[0642] [ka] To a mixture of methyl (2S)-2-[(3R)-pyrrolidin-3-yl]-3-(3-vinylphenyl)propanoate (290 mg, 1.12 mmol) in THF (4 mL), MeOH (2 mL), and water (1 mL) was added LiOH (290 mg, 11.5 mmol) in one portion at 25° C. The reaction mixture was stirred at 25° C. for 3 h, and then the pH was adjusted to 7 by the addition of 1 N aqueous HCl. The mixture was concentrated to dryness under reduced pressure, and the residue was repurified by HPLC [column: Phenomenex® Gemini® NX C18 75 × 30 mm, 3 μm, mobile phase: Solvent A = aqueous HCl, Solvent B = ACN, gradient 0-100% solvent B in solvent A] and repurified by HPLC [column: same, mobile phase: Solvent A = aqueous NH4OH + NH4HCO3, Solvent B = ACN, gradient 0-100% solvent B in solvent A] to give the title compound (18.1 mg, 6%) as a white solid. ES-MS m / z 246.2 (M+H).

[0643] Biological assays In vitro Apo(a) binding assay The in vitro binding affinity of compounds to the intended target, human Apo(a) protein, was tested in a competitive binding assay. Human Apo(a) protein, containing 17 kringle repeats, was affinity purified from the conditioned medium of transiently transfected HEK-293F cells. All reagents were prepared in assay buffer containing 50 mM Tris-HCl pH 7.4, 0.1% BSA. Binding assays were performed by adding 50 μL of each of the following wells to a clear-bottom plate: (1) a dilution series of test compound (final concentrations 0.32–10,000 nM), (2) Apo(a) protein (6 ng / well), (3) resuspended wheat germ agglutinin polyvinyltoluene SPA beads (20 mg / mL), and (4) the radioligand, tritiated (2S)-3-[3-[2-oxo-3-[3-(tritrithiomethoxy)phenyl]imidazolidin-1-yl]phenyl]-2-[(3R)-pyrrolidin-3-yl]propanoic acid, hydrochloride (prepared essentially as described in WO 2020 / 247429, final concentration 0.52 nM). Plates were incubated at room temperature for 60 min and counted on a TRILUX LSC. Specific binding was determined by subtracting nonspecific binding, defined as binding in the presence of 10 μM cold (i.e., non-radiolabeled) ligand: (2S)-3-[3-[2-oxo-3-[3-(methoxy)phenyl]imidazolidin-1-yl]phenyl]-2-[(3R)-pyrrolidin-3-yl]propanoic acid hydrochloride (prepared essentially as described in WO 2020 / 247429). Data were analyzed by fitting to a standard single-site binding model, and IC values ​​for exemplary test compounds were calculated. 50 It was decided that:

[0644] In this assay, the compound of Example 6 had an IC 50 (SEM 2.26 nM, n=2), indicating that it binds to human Apo(a) protein. Inhibition of LDL particle assembly by apo(a) through binding to Apo(a) protein supports the reduction of Lp(a) levels.

[0645] In vitro Lp(a) assembly assay The ability of compounds to inhibit Lp(a) particle formation in vitro was assessed by a cell-free assembly assay. Conditioned medium (DMEM supplemented with 10% FBS, 20 mM HEPES, and 1x penicillin / streptomycin) was collected from confluent wild-type HepG2 cells (a source of endogenously expressed ApoB) after 24 h of culture at 37°C and 5% CO2, and from a HEK293 stable cell line (selected with 1 mg / ml geneticin) expressing human Apo(a) containing 17 kringle repeats. Equal volumes of HepG2 and HEK293 conditioned medium were combined with test compounds added in a dilution series (final concentrations of 0.01–100 nM). Reactions were incubated at 37°C for 2 h and then stopped by the addition of 6-aminocaproic acid (EACA) to a final concentration of 150 mM. Lp(a) was detected using a sandwich ELISA with an anti-Lp(a) capture antibody and an HRP-conjugated anti-ApoB detection antibody. The ELISA was developed using TMB, stopped using 1N sulfuric acid, and the signal was read at 450 nm on a Molecular Devices plate reader. The percent inhibition of Lp(a) formed in each test condition was determined by setting the assembly reaction in the absence of inhibitor (matched DMSO concentration to 1%) as 0% inhibition and the presence of the minimum amount of HepG2 conditioned medium (50-fold dilution) as 100% inhibition. The IC values ​​are summarized in Table 1. 50 The data were fitted to a four-parameter curve to determine values. As summarized in Table 1, addition of exemplary test compounds to conditioned medium containing ApoB and Apo(a) results in concentration-dependent inhibition of Lp(a) formation in vitro. The results indicate that these compounds inhibit the assembly of Apo(a) and Lp(a) from LDL particles.

[0646] [Table 24-1]

[0647] [Table 24-2]

[0648] Table 24-3 The invention as originally claimed in the present application is as follows:[1] A compound of the formula:

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[10] L 1 However, the following

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[11] On each ring, R 1 and R 2 are both H or R 1 and R 2 One of them is H and the other is CH 3 The compound according to any one of [1] to

[10] , or a pharmaceutically acceptable salt thereof, wherein

[12] On each ring, R 3 and R 4 are both H or R 3 and R 4 The compound according to any one of [1] to

[11] , or a pharmaceutically acceptable salt thereof, wherein both are F.

[13] At each occurrence, R 5

[0023] The compound according to any one of [1] to

[12] , or a pharmaceutically acceptable salt thereof, wherein is H.

[14] At each occurrence, Z is 3 or OH, or a pharmaceutically acceptable salt thereof.

[15] On each ring, A 1 、A 2 、A 3 、A 4 , and A 5 are all C, or a pharmaceutically acceptable salt thereof.

[16] At each appearance, Q 3 But H, F, CF 3 The compound according to any one of [1] to

[15] , or a pharmaceutically acceptable salt thereof, wherein:

[17] A compound of the formula:

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[18] The compound according to

[17] , which is a compound of the following formula:

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[19] below:

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[17] or 18, or a pharmaceutically acceptable salt thereof, selected from:

[20] Q 1 However, the following -(CH 2 ) n O(CH 2 ) n R 10 ;-(CH 2 ) n NR 15 (CH 2 ) n R 10 ;-CN;-(CH 2 ) n CO 2 R 10 ;-N 3 ;C 1-6 Alkyl;-C 2-6 Alkenyl;-C 2-6 Alkynyl;Halo;-C(O)-R 10 ;-C(O)NR 15 R 10 ;-S(O) m (CH 2 ) n R 10 ; -(CH 2 ) n NR 15 S(O)m (CH 2 ) n R 10 ;-(CH 2 ) n S(O) m NR 15 (CH 2 ) n R 10 ;-(CH 2 ) n NHCONR 15 R 10 ;-NHCO(CH 2 ) n R 10 ;CF 3 ;C 3-6 Cycloalkyl; -NH(C=NH)CH 2 CN; 5- or 6-membered heterocyclyl optionally substituted with 1 to 4 halo or phenyl; 1 or 2 CH 3 Indoline optionally substituted with (CH 2 )CF 3 or (CH 2 ) n imidazolidinone or imidazolidine-2,5-dione optionally substituted with phenyl, said phenyl optionally substituted with OH; indolin-2-one or benzimidazol-2-one optionally substituted with CH; phenyl, 5- or 6-membered heteroaryl, or 9-membered bicyclic heteroaryl, wherein said phenyl and heteroaryl are independently halo, OC 1-4 Haloalkyl, C 3-6 Cycloalkyl, -OC 3-6 Cycloalkyl, C 1-4 C optionally substituted with alkoxy, OH or halo 1-6 alkyl, phenyl, or benzyl, wherein said phenyl or benzyl is independently —OCH 3 and halo); or

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[17] to

[19] , or a pharmaceutically acceptable salt thereof, selected from:

[21] Q 2 But, H, CH 3 , F, or Br, or a pharmaceutically acceptable salt thereof.

[22] R 5 The compound according to any one of

[17] to

[21] , or a pharmaceutically acceptable salt thereof, wherein is H.

[23] R 1 、R 2 、R 3 , and R 4 are all H, or a pharmaceutically acceptable salt thereof.

[24] R 1 and R 2 is H and R 3 and R 4 or a pharmaceutically acceptable salt thereof.

[25] Z is H, methyl, CH 2 OH, CH 2 NH 2 , and C.H. 2 OCH 2 The compound according to any one of

[17] to

[24] , or a pharmaceutically acceptable salt thereof, wherein phenyl is selected from phenyl.

[26] A compound of the formula:

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Claims

1. A compound of the formula: 【Chemistry 1】 During the ceremony, L １ But, A １ , A ２ Or A ３ and bond, -(CH ２ ) ｐ NHC(O)NH(CH ２ ) ｐ -, -(CH ２ ) ｐ C(O)NH(CH ２ ) ｐ -, -(CH ２ ) ｐ S (O) ２ NH (CH ２ ) ｐ -, -(CH ２ ) ｑ - 【Chemistry 2】 Selected from or or L １ is A on one ring ２ Rank and A ３ together with the carbon at position 1 to form the following fused ring: 【Transformation 3】 R １ , R １’ , R ２ and R ２’ However, at each occurrence, independently, H, C １－４ selected from alkyl and F; R ３ , R ３’ , R ４ and R ４’ is, at each occurrence, independently either H or F; R ５ and R ５’ However, at each occurrence, independently, H, C １－４ alkyl, or cyclopropyl; Z and Z′, in each occurrence, are independently H, C １－４ Alkyl, OH, cyclopropyl, CH ２ OH, CH ２ NH ２ , or CH ２ OCH ２ is phenyl, Y and Y′, in each occurrence, are independently CH ２ , CH(CH ３ ), O, or S; A １ , A １’ , A ２ , A ２’ , A ３ , A ３’ , A ４ , A ４’ , A ５ , A ５’ and A ６ is independently, in each occurrence, C or N, and A on each ring １ , A ２ , A ３ , A ４ and A ５ or less than two of the A on each ring are N １’ , A ２’ , A ３’ , A ４’ , A ５’ and A ６ at most two of are N, Q ３ and Q ３’ may, at each occurrence, independently represent H; -(CH ２ ) ｎ O (CH ２ ) ｎ R １０ ; - (CH ２ ) ｎ NR １５ (CH ２ ) ｎ R １０ ; -CN; -(CH ２ ) ｎ CO ２ R １０ ; C １－６ Alkyl; -C ２－６ Alkenyl; -C ２－６ Alkynyl; Halo; -C(O)-R １０ -C(O)NR １５ R １０ -S(O) ｍ (CH ２ ) ｎ R １０ ; -(CH ２ ) ｎ NR １５ S(O) ｍ (CH ２ ) ｎ R １０ ; -(CH ２ ) ｎ S(O) ｍ NR １５ (CH ２ ) ｎ R １０ ; - (CH ２ ) ｎ NHCONR １５ R １０ ; -NHCO(CH ２ ) ｎ R １０ ;-NHCOOR １０ ;NO ２ ;CF ３ ; C ３－６ Cycloalkyl; -NH(C=NH)CH ２ CN; 5- or 6-membered heterocyclyl optionally substituted with 1 to 4 halo or phenyl; 1 or 2 CH ３ indoline optionally substituted with (CH ２ )CF ３ , C.H. ３ , or (CH ２ ) ｎ Phenyl (wherein the phenyl is OH or OCH ３ optionally substituted with an imidazolidinone, pyrrolidinone, imidazolidine-2,5-dione, pyrrolidine-2,5-dione, or oxazolidin-2-one; ３ , C.H. ３ and halo; phenyl, 5- or 6-membered heteroaryl, or 9- or 10-membered bicyclic heteroaryl, wherein the phenyl and heteroaryl are independently halo, OC １－４ Haloalkyl, C ３－６ Cycloalkyl, —OC ３－６ Cycloalkyl, OH, C １－４ C optionally substituted with alkoxy, OH or 1 to 4 halo １－６ Alkyl, NH ２ , C １－６ Alkyl COOC １－２ alkyl, phenyl or benzyl (wherein the phenyl or benzyl is independently —OCH ３ , C.F. ３ , C.H. ３ , CN and halo), or CH ２ pyridine optionally substituted with OH; 【Chemistry 4】 and m in each occurrence is independently 0, 1, or 2; n in each occurrence is independently 0, 1, 2, or 3; R １０ is independently selected at each occurrence from H; halo; OH; carboxyl; -S(O) ２ OH; 1 to 4 OH or OCH ３ C optionally substituted with １－４ alkyl; C optionally substituted with 1 or 2 halo ３－６ Cycloalkyl; C １－４ Haloalkyl; -C ２－６ Alkynyl; 1-benzyl-4-piperidyl; 2-tert-butoxy-2-oxo-ethyl; benzyloxyphenyl optionally substituted with one or two halo; O(C １－２ alkyl) ｒ OCH ３ ; NH ２ 2,3-Dihydro-1H-indene; 2,3-Dihydrobenzo[b][1,4]dioxine; Benzo[d][1,3]dioxole optionally substituted with one or two halo; C(O)CH ３ indoline optionally substituted with １－４ Alkyl, C １－４ 5- or 6-membered heteroaryl or 9- or 10-membered bicyclic heteroaryl optionally substituted with alkoxy, halo, or phenyl; independently halo, C １－４ Alkoxy, hydroxy, C １－４ Alkyl, CF ３ , CN, -(CH ２ ) ２ C(O)OH, -C(O)NHNH ２ , -OCF ３ , -N(CH ３ ) ２ , C ３－６ Cycloalkyl, —OC ３－６ Cycloalkyl, —OCH ２ C ３－６ cycloalkyl, 5- or 6-membered heteroaryl, —(CH ２ ) ｎ (5- or 6-membered heterocyclyl), or —(CH ２ ) ｎ phenyl optionally substituted with 1 to 3 substituents selected from phenyl, said phenyl optionally substituted with 1 or 2 halo; L ２ But, A １’ , A ２’ or A ３’ and C １ - ３ is an alkylene or a bond; p in each occurrence is independently 0 to 3; q is 1 to 5; r is 1, 2, or 3; R １５ is H or C １－３ a compound, or a pharmaceutically acceptable salt thereof.

2. L １ A on each ring ２ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein

3. L １ is, - (CH ２ ), ｐ NH C(O)NH(CH ２ ), ｐ -, - (CH ２ ), ｐ C(O)NH(CH ２ ), ｐ -, - (CH ２ ), ｐ S(O) ２ NH(CH ２ ), ｐ -, - (CH ２ ), ｑ -, 【Transformation 5】 or L １ is A on one ring ２ Rank and A ３ together with the carbon at position 1 to form the following fused ring: 【Transformation 6】 2. The compound of claim 1, wherein the compound forms:

4. L １ is, bond, -NH C(O)NH-, -NH C(O)NHCH ２ -, -C(O)NH-, -S(O) ２ NH-, -CH ２ CH ２ CH ２ -, 【Transformation 7】 or L １ is A on one ring ２ Rank and A ３ together with the carbon at position 1 to form the following fused ring: 【Transformation 8】 4. The compound of claim 3, wherein the compound forms:

5. On each ring, R １ and R ２ are both H, or R １ and R ２ One of them is H and the other is CH ３ 5. The compound according to any one of claims 1 to 4, wherein:

6. On each ring, R ３ and R ４ are both H, or R ３ and R ４ and R are both F, or a pharmaceutically acceptable salt thereof.

7. At each appearance, R ５ is H, or a pharmaceutically acceptable salt thereof.

8. At each occurrence, Z is H, CH ３ 2. The compound of claim 1, wherein R is 0 or 1; or a pharmaceutically acceptable salt thereof.

9. On each ring, A １ , A ２ , A ３ , A ４ , and A ５ or a pharmaceutically acceptable salt thereof.

10. At each appearance, Q ３ But H, F, CF ３ 2. The compound of claim 1, wherein R is 1 or 2; or CN; or a pharmaceutically acceptable salt thereof.

11. A compound of the formula: 【Chemistry 9】 During the ceremony, R １ and R ２ However, independently, H, C １－４ alkyl, and F; R ３ and R ４ is independently either H or F; R ５ But H, C １－４ alkyl, or cyclopropyl; Z is H, C １－４ Alkyl, OH, cyclopropyl, CH ２ OH, CH ２ NH ２ , or CH ２ OCH ２ is phenyl, Y is CH ２ , CH(CH ３ ), O, or S; A １ , A ２ , A ３ , A ４ , and A ５ are each independently C or N, and A １ , A ２ , A ３ , A ４ , or A ５ at most two of are N, Q １ But -(CH ２ ) ｎ O (CH ２ ) ｎ R １０ ; - (CH ２ ) ｎ NR １５ (CH ２ ) ｎ R １０ ; -CN; -(CH ２ ) ｎ CO ２ R １０ ; -B(OR １０ ) ２ ; Boronic acid ethylene glycol ester; Boronic acid pinacol ester; Boronic acid propylene-1,3-diol ester; Boronic acid 2,2-dimethyl-propylene-1,3-diol ester; -N ３ ; C １－６ Alkyl; -C ２－６ Alkenyl; -C ２－６ Alkynyl; Halo; -C(O)-R １０ -C(O)NR １５ R １０ ; -S(O) ｍ (CH ２ ) ｎ R １０ ; -(CH ２ ) ｎ NR １５ S(O) ｍ (CH ２ ) ｎ R １０ ; -(CH ２ ) ｎ S(O) ｍ NR １５ (CH ２ ) ｎ R １０ ; - (CH ２ ) ｎ NHCONR １５ R １０ ; -NHCO(CH ２ ) ｎ R １０ ;-NHCOOR １０ ;NO ２ ;CF ３ ; C ３－６ Cycloalkyl; -NH(C=NH)CH ２ CN; 5- or 6-membered heterocyclyl optionally substituted with 1 to 4 halo or phenyl; 1 or 2 CH ３ indoline optionally substituted with (CH ２ )CF ３ , C.H. ３ , or (CH ２ ) ｎ Phenyl (wherein the phenyl is OH or OCH ３ optionally substituted with an imidazolidinone, pyrrolidinone, imidazolidine-2,5-dione, pyrrolidine-2,5-dione, or oxazolidin-2-one; ３ , C.H. ３ and halo; phenyl, 5- or 6-membered heteroaryl, or 9- or 10-membered bicyclic heteroaryl, wherein the phenyl and heteroaryl are independently halo, OC １－４ Haloalkyl, C ３－６ Cycloalkyl, —OC ３－６ Cycloalkyl, OH, C １－４ C optionally substituted with alkoxy, OH or 1 to 4 halo １－６ Alkyl, NH ２ , C １－６ Alkyl COOC １－２ alkyl, phenyl or benzyl (wherein the phenyl or benzyl is independently —OCH ３ , C.F. ３ , C.H. ３ , CN and halo), or CH ２ pyridine optionally substituted with OH; 【Chemistry 10】 and Q ２ But, R １１ , C.F. ３ , O-R １１ , OCF ３ , halo, or CN; m is 0, 1, or 2; n is 0, 1, 2, or 3; R １０ H; halo; OH; carboxyl; -S(O) ２ OH; 1 to 4 OH or OCH ３ C optionally substituted with １－４ alkyl; C optionally substituted with 1 or 2 halo ３－６ Cycloalkyl; C １－４ Haloalkyl; -C ２－６ Alkynyl; 1-benzyl-4-piperidyl; 2-tert-butoxy-2-oxo-ethyl; benzyloxyphenyl optionally substituted with one or two halo; O(C １－２ alkyl) ｒ OCH ３ ; NH ２ 2,3-Dihydro-1H-indene; 2,3-Dihydrobenzo[b][1,4]dioxine; Benzo[d][1,3]dioxole optionally substituted with one or two halo; C(O)CH ３ indoline optionally substituted with １－４ Alkyl, C １－４ 5- or 6-membered heteroaryl or 9- or 10-membered bicyclic heteroaryl optionally substituted with alkoxy, halo, or phenyl; independently halo, C １－４ Alkoxy, hydroxy, C １－４ Alkyl, CF ３ , CN, -(CH ２ ) ２ C(O)OH, -C(O)NHNH ２ , -OCF ３ , -N(CH ３ ) ２ , C ３－６ Cycloalkyl, —OC ３－６ Cycloalkyl, —OCH ２ C ３－６ cycloalkyl, 5- or 6-membered heteroaryl, —(CH ２ ) ｎ (5- or 6-membered heterocyclyl), or —(CH ２ ) ｎ phenyl optionally substituted with 1 to 3 substituents selected from phenyl, said phenyl optionally substituted with 1 or 2 halo; R １１ But H, C １－４ alkyl, or cyclopropyl; r is 1, 2, or 3; R １５ is H or C １－３ alkyl, or a pharmaceutically acceptable salt thereof.

12. The compound of claim 11, which is a compound of the following formula: 【Chemistry 11】 or a pharmaceutically acceptable salt thereof.

13. A compound of the formula: 【Chemistry 12】 During the ceremony, R １ and R ２ However, independently, H, C １－４ alkyl, and F; R ３ and R ４ is independently either H or F; R ５ａ But H, C １－４ a protecting group selected from alkyl, cyclopropyl, or tert-butoxycarbonyl, carboxybenzyl, 9-fluorenylmethoxycarbonyl, allyloxycarbonyl, trimethylsilylethoxycarbonyl, trichloroethoxycarbonyl, trifluoroacetamide, benzamide, benzylamine, triphenylmethylamine, and p-toluenesulfonamide, or a salt thereof; X is OH, -OR ６ or 【Chemistry 13】 and R ６ But C １－４ is alkyl, D and E are each independently O or S; R ７ But H, C １ - ４ alkyl, phenyl or benzyl, wherein the phenyl and benzyl are independently halo, C １ - ４ Alkyl, trifluoromethyl, amino, C １ - ４ Alkylamino and di-C １ - ４ optionally substituted with 1 or 2 substituents selected from alkylamino; R ８ and R ９ are each independently H, C １－４ alkyl, or independently halo, C １ - ４ Alkyl, trifluoromethyl, amino, C １ - ４ Alkylamino and di-C １ - ４ phenyl optionally substituted with 1 or 2 substituents selected from alkylamino; Z is H, C １－４ Alkyl, OH, cyclopropyl, CH ２ OH, CH ２ NH ２ , or CH ２ OCH ２ is phenyl, Y is CH ２ , CH(CH ３ ), O, or S; A １ , A ２ , A ３ , A ４ , and A ５ are each independently C or N, and A １ , A ２ , A ３ , A ４ , or A ５ at most two of are N, Q １ -CN; -(CH ２ ) ｎ CO ２ R １０ ; Boronic acid ethylene glycol ester; Boronic acid pinacol ester; Boronic acid propylene-1,3-diol ester; Boronic acid 2,2-dimethyl-propylene-1,3-diol ester; -N ３ ; C １－６ Alkyl; -C ２－６ Alkenyl; -C ２－６ Alkynyl; —C(O)NR １５ R １０ -S(O) ｍ (CH ２ ) ｎ R １０ ; -(CH ２ ) ｎ NR １５ S(O) ｍ (CH ２ ) ｎ R １０ ; -(CH ２ ) ｎ S(O) ｍ NR １５ (CH ２ ) ｎ R １０ ; -(CH ２ ) ｎ NHCONR １５ R １０ ;-NHCO(CH ２ ) ｎ R １０ ;-NHCOOR １０ ; CF ３ ; C ３－６ Cycloalkyl; -NH(C=NH)CH ２ CN; 5- or 6-membered heterocyclyl optionally substituted with 1 to 4 halo or phenyl; 1 or 2 CH ３ indoline optionally substituted with (CH ２ )CF ３ , C.H. ３ , or (CH ２ ) ｎ imidazolidinone, pyrrolidinone, imidazolidine-2,5-dione, pyrrolidine-2,5-dione, or oxazolidin-2-one optionally substituted with phenyl; independently, OCH ３ , C.H. ３ and halo; phenyl, 5- or 6-membered heteroaryl, or 9- or 10-membered bicyclic heteroaryl, wherein the phenyl and heteroaryl are independently halo, OC １－４ Haloalkyl, C ３－６ Cycloalkyl, —OC ３－６ Cycloalkyl, OH, C １－４ C optionally substituted with alkoxy, OH or 1 to 4 halo １－６ Alkyl, NH ２ , C １－６ Alkyl COOC １－２ alkyl, phenyl or benzyl (wherein the phenyl or benzyl is independently —OCH ３ , C.F. ３ , C.H. ３ , CN and halo), or CH ２ pyridine optionally substituted with OH; 【Chemistry 14】 and Q ２ But, R １１ , C.F. ３ , O-R １１ , OCF ３ , halo, or CN; m is 0, 1 or 2; n is 0, 1, 2, or 3; R １０ H; halo; OH; carboxyl; -S(O) ２ OH; 1 to 4 OH or OCH ３ C optionally substituted with １－４ alkyl; C optionally substituted with 1 or 2 halo ３－６ Cycloalkyl; C １－４ Haloalkyl; ２－６ Alkynyl; 1-benzyl-4-piperidyl; 2-tert-butoxy-2-oxo-ethyl; benzyloxyphenyl optionally substituted with one or two halo; O(C １－２ alkyl) ｒ OCH ３ ; NH ２ 2,3-Dihydro-1H-indene; 2,3-Dihydrobenzo[b][1,4]dioxine; Benzo[d][1,3]dioxole optionally substituted with one or two halo; C(O)CH ３ indoline optionally substituted with １－４ Alkyl, C １－４ 5- or 6-membered heteroaryl or 9- or 10-membered bicyclic heteroaryl optionally substituted with alkoxy, halo, or phenyl; independently halo, C １－４ Alkoxy, hydroxy, C １－４ Alkyl, CF ３ , CN, -(CH ２ ) ２ C(O)OH, -C(O)NHNH ２ , -OCF ３ , -N(CH ３ ) ２ , C ３－６ Cycloalkyl, —OC ３－６ Cycloalkyl, —OCH ２ C ３－６ cycloalkyl, 5- or 6-membered heteroaryl, —(CH ２ ) ｎ (5- or 6-membered heterocyclyl), or —(CH ２ ) ｎ phenyl optionally substituted with 1 to 3 substituents selected from phenyl, said phenyl optionally substituted with 1 or 2 halo; １１ But H, C １－４ alkyl, or cyclopropyl; r is 1, 2, or 3; R １５ is H or C １－３ is alkyl, When X is OH, R ５ａ must be a protecting group, or a salt thereof.

14. A compound of the formula: 【Chemistry 15】 During the ceremony, R １ and R ２ However, independently, H, C １－４ alkyl, and F; R ３ and R ４ is independently either H or F; R ５ａ But H, C １－４ a protecting group selected from alkyl, cyclopropyl, or tert-butoxycarbonyl, carboxybenzyl, 9-fluorenylmethoxycarbonyl, allyloxycarbonyl, trimethylsilylethoxycarbonyl, trichloroethoxycarbonyl, trifluoroacetamide, benzamide, benzylamine, triphenylmethylamine, and p-toluenesulfonamide, or a salt thereof; D and E are each independently O or S; R ７ But H, C １－４ alkyl, phenyl or benzyl, wherein the phenyl and benzyl are independently halo, C １ - ４ Alkyl, trifluoromethyl, amino, C １ - ４ Alkylamino and di-C １ - ４ optionally substituted with 1 or 2 substituents selected from alkylamino; R ８ and R ９ are each independently H, C １－４ alkyl, or independently halo, C １ - ４ Alkyl, trifluoromethyl, amino, C １ - ４ Alkylamino and di-C １ - ４ phenyl optionally substituted with 1 or 2 substituents selected from alkylamino; Z is H, C １－４ Alkyl, OH, cyclopropyl, CH ２ OH, CH ２ NH ２ , or CH ２ OCH ２ is phenyl, The compound is selected from the group consisting of: 【Chemistry 16】 is not a compound, or a salt thereof.

15. A method for preparing the compound according to claim 1, which comprises using the compound according to any one of claims 11 to 13, or a salt thereof.

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