Human plasma kallikrein inhibitor

Abstract

The present invention discloses compounds of formula I and pharmaceutically acceptable salts thereof. The compounds are inhibitors of plasma kallikrein. The present invention also provides pharmaceutical compositions comprising at least one compound of the present invention, and methods of using the compounds and compositions of the present invention to treat and prevent diseases and conditions characterized by undesirable plasma kallikrein activity.

Description

[0001] This application is a divisional application of the Chinese patent application with application number 201680069679.7 (international application number PCT / US2016 / 054619), application date September 30, 2016, and invention name “Human Plasma Kallikrein Inhibitors”.

[0002] This application claims the benefit of priority to U.S. Provisional Patent Application No. 62 / 235,754, filed October 1, 2015, the contents of which are incorporated herein by reference. Field of the Invention

[0003] The present invention relates to a compound as a plasma kallikrein inhibitor, a pharmaceutical composition containing the compound, and the use of the compound. Background Art

[0004] Serine proteases constitute the largest and most extensively studied group of proteolytic enzymes. Their key roles in physiological processes are spread over different areas such as coagulation, fibrinolysis, complement activation, reproduction, digestion and the release of physiologically active peptides. Many of these important processes begin with the cleavage of a single peptide bond or several peptide bonds in a precursor protein or peptide. Continuous limited proteolytic reactions or cascades involve blood coagulation, fibrinolysis and complement activation. The biological signals that start these cascades can also be controlled and amplified. Similarly, controlled proteolysis can shut down or inactivate proteins or peptides by single bond cleavage.

[0005] Kallikreins are a subgroup of serine proteases. In humans, plasma kallikreins (KLKB1) have no known homologs, while tissue kallikrein-related peptidases (KLKs) encode a family of fifteen closely related serine proteases. Plasma kallikreins participate in many pathways related to the intrinsic coagulation pathway, inflammation, and the complement system.

[0006] Coagulation is the process of blood clotting, for example, for the purpose of stopping bleeding. The physiological mechanism of coagulation is somewhat complex, as it involves two separate initial pathways that converge into a final common pathway leading to clot formation. In the final common pathway, prothrombin is converted to thrombin, which in turn converts fibrinogen to fibrin, the major building block of the cross-linked fibrin polymer that forms the hemostatic plug. Of the two initial pathways upstream of the final common pathway, one is called the contact-activated or intrinsic pathway, and the other is called the tissue factor or extrinsic pathway.

[0007] The intrinsic pathway begins with high molecular weight kininogen (HMWK), prekallikrein and FXII (factor XII; Hageman factor) forming a primary complex on collagen. Prekallikrein is converted into kallikrein, and FXII is activated to become FXIIa. FXIIa then converts factor XI (FXI) into FXIa, and FXIa in turn activates factor IX (FIX), which forms an "X enzyme" complex with its cofactor FVIIIa, which activates factor X (FX) to FXa. FXa is responsible for converting prothrombin into thrombin in the final common pathway.

[0008] Prekallikrein is an inactive precursor of plasma kallikrein, synthesized in the liver and circulated in plasma bound to HMWK or as a free zymogen. Prekallikrein is split by activated factor XII (FXIIa) to release activated plasma kallikrein (PK). Activated plasma kallikrein shows endopeptidase activity on peptide bonds after arginine (preferred) and lysine. PK then produces additional FXIIa in a feedback loop, which in turn activates factor XI (FXI) to FXIa to connect to the common pathway. Although the initial activation of the intrinsic pathway is by activating a small amount of PK through a small amount of FXIIa, it is the subsequent feedback activation of FXII by PK that controls the degree of activation of the intrinsic pathway and thus controls downstream coagulation. Hathaway, WE, et al. (1965) Blood 26: 521-32.

[0009] Activated plasma kallikrein also splits HMWK to release the potent vasodilator peptide bradykinin. It is also able to split many inactive precursor proteins to produce active products, such as plasmin (from plasminogen) and urokinase (from urokinaseogen). Plasmin is a coagulation regulator that can proteolytically split fibrin into fibrin degradation products that inhibit excessive fibrin formation.

[0010] Patients with acute myocardial infarction (MI) show clinical evidence of being in a hypercoagulable (clot-promoting) state. This hypercoagulable state is further exacerbated in patients receiving fibrinolytic therapy. Increased thrombin generation, measured as thrombin-antithrombin III (TAT) levels, has been observed in patients receiving such therapy compared to the already high levels observed in patients receiving heparin alone. Hoffmeister, HM et al. (1998) Circulation 98:2527-33. It has been proposed that the increase in thrombin is caused by activation of the intrinsic pathway mediated by plasmin, resulting from direct activation of FXII by plasmin.

[0011] Fibrinolysis-induced hypercoagulability not only leads to an increase in reocclusion rates, but may also be at least partially responsible for the failure to achieve complete fibrinolysis of blood clots (thrombi), a major drawback of fibrinolytic therapy (Keeley, EC et al. (2003) Lancet 361: 13-20). Another problem with fibrinolytic therapy is the increased risk of intracranial hemorrhage. Menon, V. et al. (2004) American Journal of Chest 126: 549S-575S; Fibrinolytic Therapy Trial Collaboration Group (1994) Lancet 343: 311-22. Therefore, adjunctive anticoagulant therapy that does not increase the risk of bleeding but inhibits new thrombin formation would be very beneficial.

[0012] Therefore, there is a need to develop additional PK inhibitors that can tip the balance of fibrinolysis / thrombosis at occlusive thrombi toward lysis, thereby promoting reperfusion and attenuating the hypercoagulable state, thereby preventing thrombi from reforming and reoccluding the vessel. Summary of the invention

[0013] In certain aspects, the present invention provides compounds of formula (I) and pharmaceutically acceptable salts thereof:

[0014]

[0015] where each occurrence is independently:

[0016] R 1 Indicates -OH, -OR c 、-NH 2 、-NHR c 、-NR c R d , alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, halo, haloalkyl, cycloalkyl, (cycloalkyl)alkyl, -C(O)R c 、-C(O)OH、-C(O)OR c 、-OC(O)R c 、-C(O)NH 2 、-C(O)NHR c 、-C(O)NR c R d 、-NHC(O)R c or -NR c C(O)R d ; or two Rs in pairs 1 Together with the carbon to which they are attached, they represent -C(O)-; or two ortho or paired R 1 together form an optionally substituted fused or spirocyclic carbocyclic or heterocyclic ring;

[0017] W is a chemical bond, -C(O)NH-, -C(O)N(R c )-、-C(O)O-、-CH 2 -or-C(O)-;

[0018] R 2 represents optionally substituted aryl, heteroaryl, aralkyl, heteroaralkyl, cycloalkyl, heterocycloalkyl, (cycloalkyl)alkyl or (heterocycloalkyl)alkyl;

[0019] V represents an optionally substituted aryl or heteroaryl group;

[0020] Z is absent or represents one or more substituents independently selected from the group consisting of halogen, haloalkyl, -NO 2 、-CN、-C(O)R c 、-C(O)OH、-C(O)OR c 、-OC(O)R c 、-C(O)NH 2 、-C(O)NHR c 、-C(O)NR c R d 、-NHC(O)R c 、-N(R c )C(O)R d 、-OS(O) p (R c )、-NHS(O) p (R c ) and -NR c S(O) p (R c );

[0021] X represents -C(NH 2 )-、-C(NH(R c ))-、-C(NR c R d )-、-C(NHS(O) p R c )-、-C(NHC(O)R c )-、-C(NHC(O)NH 2 )-、-C(NHC(O)NHR c )-、-C(NHC(O)NR c R d )-、-C(OH)-、-C(O(alkyl))-、-C(N 3 )-、-C(CN)-、-C(NO 2 )-、-C(S(O) n Ra )-、-C[-C(=O)R c ]-、-C[-C(=O)NR c R d ]-、-C[-C(=O)SR c ]-、-C[-S(O)R c ]-、-C[-S(O)2R c ]-、-C[S(O)(OR c )]-、-C[-S(O) 2 (OR c )]-、-C[-SO 2 NR c R d ]-, -C(halogen)-, -C(alkyl), -C((cycloalkyl)alkyl), -C(alkenyl)-, -C(alkynyl)-, or -C(aralkyl)-;

[0022] R 3 represents optionally substituted aryl, heteroaryl, cycloalkyl or heterocycloalkyl;

[0023] R 3a is absent or represents one or more substituents independently selected from the group consisting of: halo, hydroxy, alkyl, -CF 3 、-OCF 3 , alkoxy, aryl, heteroaryl, aryloxy, amino, aminoalkyl, -C(O)NH 2 , cyano, -NHC(O)alkyl, -SO 2 Alkyl, -SO 2 NH 2 , cycloalkyl, -(CH 2 ) r OR a 、-NO 2 、-(CH 2 ) r NR a R b 、-(CH 2 ) r C(O)R a 、-NR a C(O)R b 、-C(O)NR c R d 、-NR a C(O)NR c R d 、-C(=NR a )NR c R d 、-NHC(=NR a )NRc R d 、-NR a R b 、-SO 2 NR c R d 、-NR a SO 2 NR c R d 、-NR a SO 2 Alkyl, -NR a SO 2 R a 、-S(O) p R a ,-(CF 2 ) r CF 3 、-NHCH 2 R a 、-OCH 2 R a 、-SCH 2 R a 、-NH(CH 2 ) 2 (CH 2 ) r R a 、-O(CH 2 ) 2 (CH 2 ) r R a or -S(CH 2 ) 2 (CH 2 ) r R a ;

[0024] Y represents a chemical bond; or -YR 4 represents an optionally substituted -alkylene-R 4 、-CH 2 C(O)-R 4 、-CH 2 NH-R 4 、-CH 2 N(alkyl)-R 4 , -CR a R b -R 4 、-NH-R 4 、-NHCH 2 -R 4 、-NHC(O)-R 4 、-N(alkyl)-R 4 、-N(alkyl)CH 2-R 4 、-N((CH 2 ) 2 OH)-R 4 , -N((cycloalkyl)alkyl)R 4 , -heterocyclyl-R 4 、-OR 4 、-OCH 2 -R 4 、-OC(O)-R 4 、-OC(O)NR a R b 、-SCH 2 R 4 or -SR 4 ;

[0025] R 4 represents hydrogen, hydroxy, optionally substituted alkyl, cycloalkyl, (heterocycloalkyl)alkyl, (cycloalkyl)alkyl, -CH 2 OH, -CH(alkyl)OH, -CH(NH 2 )CH(alkyl) 2 , aryl, aralkyl, heteroaryl, heteroaralkyl, -CH 2 S(alkyl), amino or cyano; or -(CR a R b ) r (CR a R b ) p - fused to the 4-position of the ring bearing Z to form a 5- to 7-membered heterocyclic ring with optional substituents; or,

[0026] When R 3 When it is phenyl, R 4 It can represent -NR fused to the ortho position of X on the phenyl group. a -;

[0027] R a and R b are each independently H, alkyl, alkenyl, alkynyl, aralkyl, (cycloalkyl)alkyl, -C(=O)R c 、-C(=O)OR c 、-C(=O)NR c R d 、-C(=O)SR c 、-S(O)R c 、-S(O) 2 R c 、-S(O)(OR c ) or -SO 2 NR c R d ;

[0028] R c and R d Each occurrence independently represents optionally substituted alkyl, alkenyl, alkynyl, haloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl, (cycloalkyl)alkyl, heterocycloalkyl, (heterocycloalkyl)alkyl, -C(O)alkyl, or -S(O) p (alkyl); or R c and R d may together form an optionally substituted heterocyclic ring;

[0029] Can be expressed

[0030] r is 0, 1, 2, or 3;

[0031] n is an integer from 0 to 6; and

[0032] p is 0, 1 or 2.

[0033] In certain aspects, the present invention provides a pharmaceutical composition comprising a compound of the present invention or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.

[0034] In certain aspects, the present invention provides a method for treating or preventing a disease or condition characterized by undesirable plasma kallikrein activity. The method comprises the following steps: administering a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof to a subject in need thereof, thereby treating or preventing a disease or condition characterized by undesirable plasma kallikrein activity. In one embodiment, the disease or condition characterized by undesirable plasma kallikrein activity is selected from the group consisting of: stroke, inflammation, reperfusion injury, acute myocardial infarction, deep vein thrombosis, post-fibrinolytic therapy condition, angina pectoris, edema, angioedema, hereditary angioedema, sepsis, arthritis, hemorrhage, blood loss during cardiopulmonary bypass, inflammatory bowel disease, diabetes, retinopathy, diabetic retinopathy, diabetic macular edema, diabetic macular degeneration, age-related macular edema, age-related macular degeneration, proliferative retinopathy, neuropathy, hypertension, cerebral edema, increased albumin excretion, macroalbuminuria and nephropathy. DETAILED DESCRIPTION

[0035] Inhibitors of plasma kallikrein have been reported and can be used in treatment methods and compositions suitable for eliminating or reducing various forms of ischemia, including but not limited to perioperative blood loss, cerebral ischemia, onset of systemic inflammatory response and / or reperfusion injury, such as reperfusion injury associated with cerebral ischemia or focal cerebral ischemia. Perioperative blood loss is caused by invasive surgical procedures that result in contact activation of complement components and coagulation / fibrinolysis systems. Kallikrein inhibitors can be used to reduce or prevent perioperative blood loss and systemic inflammatory response in patients undergoing invasive surgical procedures, particularly cardiothoracic surgery. Kallikrein inhibitors can also be used to reduce or prevent cerebral ischemia and stroke, and / or reperfusion injury associated with cerebral ischemia. They can also prevent neurological and cognitive deficits associated with stroke, blood loss and cerebral ischemia, such as events unrelated to surgical intervention. Other examples of kallikrein inhibitor applications include pediatric cardiac surgery, lung transplantation, total hip replacement, and orthotopic liver transplantation to reduce or prevent stroke during these procedures, as well as to reduce or prevent stroke during coronary artery bypass grafting (CABG) and extracorporeal membrane oxygenation (ECMO).

[0036] definition

[0037] The articles "a" and "an" are used herein to refer to one or to more than one (ie, to at least one) of the grammatical object of an article. For example, "an element" means one element or more than one element.

[0038] The term "heteroatom" is art-recognized and refers to an atom of any element other than carbon or hydrogen. Illustrative heteroatoms include boron, nitrogen, oxygen, phosphorus, sulfur, and selenium, or oxygen, nitrogen, or sulfur.

[0039] As used herein, the term "alkyl" is a technical term and refers to a saturated aliphatic group, including a straight chain alkyl group, a branched chain alkyl group, a cycloalkyl (alicyclic) group, an alkyl substituted cycloalkyl group, and a cycloalkyl substituted alkyl group. In certain embodiments, a straight chain or branched chain alkyl group has about 30 or fewer carbon atoms in its backbone (e.g., a straight chain C 1 -C 30 , branched chain C 3 -C 30 ), or about 20 or fewer carbon atoms, or 10 or fewer carbon atoms. In certain embodiments, the term "alkyl" refers to a C 1 -C 10 In certain embodiments, the term "alkyl" refers to a C 1 -C 6 In certain embodiments, the term "alkyl" refers to a C 3 -C 12In certain embodiments, the term "alkyl" refers to a C 3 -C 8 Branched chain alkyl groups. Representative examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, and n-hexyl.

[0040] The term "cycloalkyl" refers to a monocyclic or bicyclic or bridged saturated carbocyclic ring, each cycloalkyl having 3 to 12 carbon atoms. Certain cycloalkyls have 5 to 12 carbon atoms in their ring structure, and may have 6 to 10 carbons in the ring structure. Preferably, the cycloalkyl is (C 3 -C 7 )cycloalkyl, which represents a monocyclic saturated carbocyclic ring with 3 to 7 carbon atoms. Examples of monocyclic cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl and cyclooctyl. Bicyclic cycloalkyl ring systems include bridged monocyclic and fused bicyclic rings. The bridged monocyclic ring contains a monocyclic cycloalkyl ring in which two non-adjacent carbon atoms of the monocyclic ring are connected by an alkylene bridge (i.e., in the form of -(CH 2 ) w -bridged groups, wherein w is 1, 2 or 3) connected. Representative examples of bicyclic systems include but are not limited to bicyclo [3.1.1] heptane, bicyclo [2.2.1] heptane, bicyclo [2.2.2] octane, bicyclo [3.2.2] nonane, bicyclo [3.3.1] nonane and bicyclo [4.2.1] nonane. Fused bicyclic cycloalkyl ring system contains a monocyclic cycloalkyl ring fused to phenyl, monocyclic cycloalkyl, monocyclic cycloalkenyl, monocyclic heterocyclic radical or monocyclic heteroaryl. The bicyclic cycloalkyl of bridged or fused is connected to the parent molecular moiety by any carbon atom contained in the monocyclic cycloalkyl ring. Cycloalkyl groups are optionally substituted. In certain embodiments, the fused bicyclic cycloalkyl is a 5 or 6 membered monocyclic cycloalkyl ring fused to a benzene ring, a 5 or 6 membered monocyclic cycloalkyl, a 5 or 6 membered monocyclic cycloalkenyl, a 5 or 6 membered monocyclic heterocyclyl, or a 5 or 6 membered monocyclic heteroaryl, wherein the fused bicyclic cycloalkyl is optionally substituted.

[0041] The term "cycloalkylalkyl" as used herein refers to an alkyl group substituted by one or more cycloalkyl groups. An example of a cycloalkylalkyl group is a cyclohexylmethyl group.

[0042] As used herein, the term "heterocyclyl" refers to a radical of a non-aromatic ring system, including but not limited to monocyclic, bicyclic and tricyclic rings, which may be fully saturated or which may contain one or more units of unsaturation, provided, for the avoidance of doubt, that the unsaturation does not result in an aromatic ring system, and having from 3 to 12 atoms, including at least one heteroatom, such as nitrogen, oxygen or sulfur. For the purpose of illustration, which should not be construed as limiting the scope of the invention, the following are examples of heterocycles: aziridine, aziridine, oxirane, thiirane, thiirane, dioxirane, diazirane, diazepanyl, 1,3-dioxanyl, 1,3-dioxolanyl, 1,3-dithiolanyl, 1,3-dithiolanyl, imidazolidinyl, isothiazolinyl, isothiazolidinyl, isoxazolinyl, isoxazolidinyl, azetidinyl, oxetanyl, oxetanyl, thietanyl, thietanyl, diazetidinyl, dioxetanyl, dioxetanyl , dithietanyl, dithietanyl, dioxolanyl, oxazolyl, thiazolyl, triazine, isothiazolyl, isoxazolyl, azepine, azetidinyl, morpholinyl, oxadiazolinyl, oxadiazolidinyl, oxazolinyl, oxazolidinyl, oxopiperidinyl, oxopyrrolidyl, piperazinyl, piperidinyl, pyranyl, pyrazolinyl, pyrazolidinyl, pyrrolinyl, pyrrolidinyl, quinuclidine, thiomorpholinyl, tetrahydropyranyl, tetrahydrofuranyl, tetrahydrothienyl, thiadiazolinyl, thiadiazolidinyl, thiazolinyl, thiazolidinyl, thiomorpholinyl, 1,1-dioxothiomorpholinyl (thiomorpholine sulfone), thiopyranyl and trithiolanyl. The heterocyclic radical group is optionally substituted by one or more substituents as described below.

[0043] As used herein, the term "heterocycloalkylalkyl" refers to an alkyl group substituted with one or more heterocycloalkyl (ie, heterocyclyl) groups.

[0044] As used herein, the term "alkenyl" refers to a straight or branched hydrocarbon group containing 2 to 10 carbons and containing at least one carbon-carbon double bond formed by removing two hydrogens. Representative examples of alkenyl include but are not limited to vinyl, 2-propenyl, 2-methyl-2-propenyl, 3-butenyl, 4-pentenyl, 5-hexenyl, 2-heptenyl, 2-methyl-1-heptenyl and 3-decenyl. The unsaturated bonds of the alkenyl group can be located at any position in the moiety and can have (Z) or (E) configuration around the double bond.

[0045] As used herein, the term "alkynyl" refers to a straight or branched hydrocarbon group containing 2 to 10 carbon atoms and containing at least one carbon-carbon triple bond. Representative examples of alkynyl include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 3-butynyl, 2-pentynyl and 1-butynyl.

[0046] The term "alkylene" is recognized in the art and, as used herein, refers to a diradical obtained by removing two hydrogen atoms of an alkyl group as defined above. In one embodiment, alkylene refers to a disubstituted alkane, i.e., an alkane substituted at two positions by a substituent such as halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxy, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silane, ether, alkylthio, sulfonyl, sulfonamido, ketone, aldehyde, ester, heterocyclic, aromatic or heteroaromatic moiety, fluoroalkyl (e.g., trifluoromethyl), cyano, etc. That is, in one embodiment, "substituted alkyl" is an "alkylene".

[0047] The term "amino" is a term of art and, as used herein, refers to unsubstituted and substituted amines, such as moieties that can be represented by the following general formula:

[0048]

[0049] Among them, R a , R b and R c Each independently represents hydrogen, alkyl, alkenyl, -(CH 2 ) x -R d , or R a and R b Together with the nitrogen atom to which they are attached, they form a heterocyclic ring having 4 to 8 carbon atoms in the ring structure; R d represents an aryl group, a cycloalkyl group, a cycloalkenyl group, a heterocyclic group or a polycyclic group; and x is 0 or an integer in the range of 1 to 8. In certain embodiments, R a or R b Only one of them can be a carbonyl group, for example R a , R b and nitrogen together do not form an imide. In other embodiments, R a and R b (and optional R c ) each independently represents hydrogen, alkyl, alkenyl or -(CH 2 ) x -R d In certain embodiments, the term "amino" refers to -NH 2 .

[0050] As used herein, the term "amido" refers to -NHC(=O)-, wherein the amido group is attached to the parent molecular moiety through the nitrogen. Examples of amido groups include alkylamido groups, such as CH 3 C(=O)N(H)- and CH 3 CH 2 C(=O)N(H)-.

[0051] The term "acyl" is a technical term and, as used herein, refers to any group or radical of the form RCO-, where R is any organic group, such as alkyl, aryl, heteroaryl, aralkyl and heteroaralkyl. Representative acyl groups include acetyl, benzoyl and malonyl.

[0052] As used herein, the term "aminoalkyl" refers to an alkyl group substituted with one or more than one amino group. In one embodiment, the term "aminoalkyl" refers to an aminomethyl group.

[0053] The term "aminoacyl" is a term of art and, as used herein, refers to an acyl group substituted with one or more amino groups.

[0054] As used herein, the term "aminosulfinyl" refers to an analog of an aminoacyl group in which the O of RC(O)- has been replaced with sulfur, thus of the form RC(S)-.

[0055] The term "phosphoryl group" is a technical term, and as used herein, can be generally represented by the following formula:

[0056]

[0057] wherein Q50 represents S or O, and R59 represents hydrogen, lower alkyl or aryl; for example -P(O)(OMe)- or -P(O)(OH) 2 When used to replace, for example, an alkyl group, the phosphoryl group of the phosphorylalkyl group may be represented by the following general formula:

[0058]

[0059] wherein Q50 and R59 are each independently as defined above, and Q51 represents O, S or N; for example -OP(O)(OH)OMe or -NH-P(O)(OH) 2 When Q50 is S, the phosphoryl moiety is a "phosphorothioate".

[0060] The term "aminophosphoryl" as used herein refers to a phosphoryl group substituted with at least one amino group as defined herein; for example -P(O)(OH)NMe 2 .

[0061] As used herein, the term "azide" or "azido" refers to -N 3 Group.

[0062] The term "carbonyl" as used herein refers to -C(=O)-.

[0063] As used herein, the term "thiocarbonyl" refers to -C(=S)-.

[0064] The term "alkylphosphoryl" as used herein refers to a phosphoryl group substituted with at least one alkyl group as defined herein; for example -P(O)(OH)Me.

[0065] The term "alkylthio" as used herein refers to alkyl-S-.

[0066] As used herein, the term "carboxyl" refers to -CO 2 H group.

[0067] The term "aryl" is a technical term, and as used herein, includes monocyclic, bicyclic and polycyclic aromatic hydrocarbon groups, such as benzene, naphthalene, anthracene and pyrene. The aromatic ring can be substituted by one or more substituents at one or more ring positions, such as halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxy, amino, nitro, sulfhydryl, imino, amide, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamido, ketone, aldehyde, ester, heterocyclic, aromatic or heteroaromatic moiety, fluoroalkyl (such as trifluoromethyl), cyano, etc. The term "aryl" also includes a polycyclic system with two or more rings, wherein two or more carbons are shared by two adjacent rings (the ring is a "fused ring"), wherein at least one ring is an aromatic hydrocarbon, such as other rings can be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl and / or heterocyclic. In certain embodiments, the term "aryl" refers to a phenyl group. In certain embodiments, "aryl" has 6 to 10 carbon atoms.

[0068] The term "heteroaryl" is a term of art and, as used herein, refers to monocyclic, bicyclic, and polycyclic aromatic groups having from 3 to 12 total atoms in the ring structure including one or more heteroatoms such as nitrogen, oxygen, or sulfur. Exemplary heteroaryl groups include azaindolyl, benzo(b)thienyl, benzimidazolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl, benzoxadiazolyl, furanyl, imidazolyl, imidazopyridinyl, indolyl, indolinyl, indazolyl, isoindolyl, isoxazolyl, isothiazolyl, isoquinolinyl, oxadiazolyl, oxazolyl, purinyl, pyranyl, pyrazinyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrrolyl, pyrrolo[2,3-d]pyrimidinyl, pyrazolo[3,4-d]pyrimidinyl, quinolyl, quinazolinyl, triazolyl, thiazolyl, thienyl, tetrahydroindolyl, tetrazolyl, thiadiazolyl, thienyl, thiomorpholinyl, triazolyl, or tropanyl, and the like. "Heteroaryl" can be substituted at one or more ring positions with one or more substituents, such as halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxy, alkoxy, amino, nitro, sulfhydryl, imino, amide, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamido, ketone, aldehyde, ester, heterocyclyl, aromatic or heteroaromatic moiety, fluoroalkyl (such as trifluoromethyl), cyano, etc. The term "heteroaryl" also includes polycyclic ring systems having two or more rings in which two or more carbons are common to two adjacent rings (the rings are "fused rings"), in which at least one ring is an aromatic group having one or more heteroatoms in the ring structure, for example, the other rings can be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl and / or heterocyclyl.

[0069] The term "aralkyl" or "arylalkyl" is a term of art and, as used herein, refers to an alkyl group substituted with an aryl group, wherein the moiety is attached to the parent molecule through the alkyl group.

[0070] The term "heteroaralkyl" or "heteroarylalkyl" is a term of art and, as used herein, refers to an alkyl group substituted with a heteroaryl group, which is attached to the parent molecular moiety through the alkyl group.

[0071] As used herein, the term "alkoxy" refers to an alkyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom. Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentoxy and hexoxy.

[0072] The term "alkoxycarbonyl" means an alkoxy group, as defined herein, appended to the parent molecular moiety through a carbonyl group, represented by -C(=O)-, as defined herein. Representative examples of alkoxycarbonyl include, but are not limited to, methoxycarbonyl, ethoxycarbonyl and tert-butoxycarbonyl.

[0073] The term "alkylcarbonyl" as used herein refers to an alkyl group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein. Representative examples of alkylcarbonyl include, but are not limited to, acetyl, 1-oxopropyl, 2,2-dimethyl-1-oxopropyl, 1-oxobutyl and 1-oxopentyl.

[0074] The term "arylcarbonyl" as used herein, means an aryl group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein. Representative examples of arylcarbonyl include, but are not limited to, benzoyl and (2-pyridyl)carbonyl.

[0075] As used herein, the terms "alkylcarbonyloxy" and "arylcarbonyloxy" refer to an alkylcarbonyl or arylcarbonyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom. Representative examples of alkylcarbonyloxy include, but are not limited to, acetoxy, ethylcarbonyloxy, and tert-butylcarbonyloxy. Representative examples of arylcarbonyloxy include, but are not limited to, phenylcarbonyloxy.

[0076] The term "alkenoxy" or "alkenoxyl" refers to an alkenyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom. Representative examples of alkenoxy include, but are not limited to, 2-propylene-1-oxy (i.e., CH 2 =CH-CH 2 -O-) and vinyloxy (i.e. CH 2 =CH-O-).

[0077] The term "aryloxy" as used herein, means an aryl group, as defined herein, appended to the parent molecular moiety through an oxygen atom.

[0078] The term "heteroaryloxy" as used herein, means a heteroaryl group, as defined herein, appended to the parent molecular moiety through an oxygen atom.

[0079] As used herein, the term "carbocyclyl" refers to a monocyclic or polycyclic (e.g., bicyclic, tricyclic, etc.) hydrocarbon group containing 3 to 12 carbon atoms, which is fully saturated or has one or more unsaturated bonds, and for the avoidance of doubt, the unsaturation does not result in an aromatic ring system (e.g., phenyl). Examples of carbocyclyl groups include 1-cyclopropyl, 1-cyclobutyl, 2-cyclopentyl, 1-cyclopentenyl, 3-cyclohexyl, 1-cyclohexenyl, and 2-cyclopentenylmethyl.

[0080] The term "cyano" is a term of art and, as used herein, refers to -CN.

[0081] The term "halo" is a term of art and, as used herein, refers to -F, -Cl, -Br or -I.

[0082] The term "haloalkyl" as used herein refers to an alkyl group as defined herein wherein some or all of the hydrogens are replaced by halogen atoms.

[0083] The term "hydroxy" is a term of art, and as used herein, refers to -OH.

[0084] As used herein, the term "hydroxyalkyl" refers to at least one hydroxyl group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of hydroxyalkyl include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, 2,3-dihydroxypentyl and 2-ethyl-4-hydroxyheptyl.

[0085] As used herein, the term "silyl group" includes silyl groups (H 3 Si-) group hydrocarbon derivatives (ie (hydrocarbon) 3 Si-), wherein the hydrocarbyl group is a monovalent group formed by removing a hydrogen atom from a hydrocarbon, such as ethyl, phenyl. The hydrocarbyl group can be a combination of different groups, which can be changed to provide a variety of silyl groups, such as trimethylsilyl (TMS), tert-butyldiphenylsilyl (TBDPS), tert-butyldimethylsilyl (TBS / TBDMS), triisopropylsilyl (TIPS) and [2-(trimethylsilyl)ethoxy]methyl (SEM).

[0086] The term "siloxy" as used herein, means a silyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom.

[0087] Certain compounds contained in the compositions of the present invention may exist in specific geometric or stereoisomeric forms. In addition, the compounds of the present invention may also be optically active. The present invention is considered to include all of these compounds: cis- and trans-isomers, (R)-enantiomers and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, racemic mixtures thereof and other mixtures, as considered to fall within the scope of the present invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. The present invention is intended to include all of these isomers and mixtures thereof.

[0088] For example, if a specific enantiomer of a compound of the invention is desired, it can be prepared by asymmetric synthesis or by derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide the pure desired enantiomer. Alternatively, in the case where the molecule contains a basic functional group such as an amino group or an acidic functional group such as a carboxyl group, diastereomeric salts are formed with a suitable optically active acid or base, followed by separation of the diastereomers thus formed by fractional crystallization or chromatographic means well known in the art, and subsequent recovery of the pure enantiomer.

[0089] It should be understood that "substituted" or "substituted by" includes the implicit proviso that the substitution is compatible with the allowed valencies of the substituted atom and the substituent and that the substitution results in a stable compound, e.g., one that does not spontaneously undergo transformations such as rearrangement, cleavage, decomposition, cyclization, elimination or other reactions.

[0090] The term "substituted" is also considered to include all permissible substituents of organic compounds. In a broad sense, permissible substituents include acyclic and cyclic substituents, branched and unbranched substituents, carbocyclic and heterocyclic substituents, aromatic and non-aromatic substituents of organic compounds. Illustrative substituents include, for example, those described above. For suitable organic compounds, permissible substituents may be one or more and may be the same or different. For purposes of the present invention, heteroatoms such as nitrogen may have hydrogen substituents and / or any permissible substituents of organic compounds described herein that satisfy the heteroatom valence. The present invention is not intended to be limited in any way to the permissible substituents of organic compounds.

[0091] As used herein, the phrase "protecting group" refers to a temporary substituent that protects a potentially reactive functional group from undesirable chemical transformations. Examples of such protecting groups include esters of carboxylic acids, silyl ethers of alcohols, and acetals and ketals of aldehydes and ketones. The field of protecting group chemistry has been reviewed (Greene, TW; Wuts, PGM Protective Groups in Organic Synthesis, 2nd edition; Wiley: New York, 1991). The protected forms of the compounds of the present invention are included within the scope of the present invention.

[0092] For purposes of this invention, the chemical elements are identified according to the CAS version of the Periodic Table of the Elements, Handbook of Chemistry and Physics, 67th ed., 1986-87, inside cover.

[0093] Other chemical terms herein are used according to conventional usage in the art, for example, according to the McGraw-Hill Dictionary of Chemical Terms (Editor: Parker, S., 1985, McGraw-Hill, San Francisco, which is incorporated herein by reference). Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0094] The term "pharmaceutically acceptable salt" as used herein includes salts derived from inorganic or organic acids, including, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, perchloric acid, phosphoric acid, formic acid, acetic acid, lactic acid, maleic acid, fumaric acid, succinic acid, tartaric acid, glycolic acid, salicylic acid, citric acid, methanesulfonic acid, benzenesulfonic acid, benzoic acid, malonic acid, trifluoroacetic acid, trichloroacetic acid, naphthalene-2-sulfonic acid and other acids. The form of a pharmaceutically acceptable salt may include a form in which the ratio of the molecules comprising the salt is not 1:1. For example, a salt may include more than one inorganic or organic acid molecule relative to each base molecule, such as two hydrochloric acid molecules relative to each molecule of a compound of formula I. As another example, a salt may include less than one inorganic or organic acid molecule relative to each base molecule, such as two molecules of a compound of formula I relative to each tartaric acid molecule.

[0095] As used herein, the terms "carrier" and "pharmaceutically acceptable carrier" refer to a diluent, adjuvant, excipient or vehicle with which a compound is administered or formulated for administration. Non-limiting examples of such pharmaceutically acceptable carriers include liquids such as water, saline and oils; and solids such as gum arabic, gelatin, starch paste, talc, keratin, colloidal silica, urea, and the like. In addition, adjuvants, stabilizers, thickeners, lubricants, flavoring agents and coloring agents may be used. Other examples of suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences, by EW Martin, which is incorporated herein by reference in its entirety.

[0096] As used herein, the term "treat" refers to preventing, arresting, or slowing the progression of a disease or condition in a subject, or eliminating a disease or condition. In one embodiment, "treat" refers to arresting or slowing the progression of a disease or condition in a subject, or eliminating a disease or condition. In one embodiment, "treat" refers to reducing at least one objective manifestation of a disease or condition in a subject.

[0097] As used herein, the term "effective amount" refers to an amount sufficient to produce a desired biological effect.

[0098] As used herein, the term "therapeutically effective amount" refers to an amount sufficient to produce the desired therapeutic effect.

[0099] As used herein, the term "inhibit" refers to a reduction in an objectively measurable amount or degree. In various embodiments, "inhibit" refers to a reduction of at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 95% compared to a relevant control. In one embodiment, "inhibit" refers to a 100% reduction, i.e., prevention or elimination.

[0100] As used herein, the term "subject" refers to a mammal. In various embodiments, the subject is a mouse, rat, rabbit, cat, dog, pig, sheep, horse, cow, or non-human primate. In one embodiment, the subject is a human.

[0101] Compound

[0102] The present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof:

[0103]

[0104] where each occurrence is independently:

[0105] R 1 Indicates -OH, -OR c 、-NH 2 、-NHR c 、-NR c R d , alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, halo, haloalkyl, cycloalkyl, (cycloalkyl)alkyl, -C(O)R c 、-C(O)OH、-C(O)OR c 、-OC(O)R c 、-C(O)NH 2 、-C(O)NHR c 、-C(O)NR c R d 、-NHC(O)R c or -NR c C(O)R d ; or two Rs in pairs 1 Together with the carbon to which they are attached, they represent -C(O)-; or two ortho or paired R 1 together form an optionally substituted fused or spirocyclic carbocyclic or heterocyclic ring;

[0106] W is a chemical bond, -C(O)NH-, -C(O)N(R c )-、-C(O)O-、-CH 2 -or-C(O)-;

[0107] R 2 represents optionally substituted aryl, heteroaryl, aralkyl, heteroaralkyl, cycloalkyl, heterocycloalkyl, (cycloalkyl)alkyl or (heterocycloalkyl)alkyl;

[0108] V represents an optionally substituted aryl or heteroaryl group;

[0109] Z is absent or represents one or more substituents independently selected from the group consisting of halogen, haloalkyl, -NO 2 、-CN、-C(O)R c 、-C(O)OH、-C(O)OR c 、-OC(O)R c 、-C(O)NH 2 、-C(O)NHR c 、-C(O)NR c R d 、-NHC(O)R c 、-N(R c )C(O)R d 、-OS(O) p (R c )、-NHS(O) p (R c ) and -NR c S(O) p (R c );

[0110] X represents -C(NH 2 )-、-C(NH(R c ))-、-C(NR c R d )-、-C(NHS(O) p R c )-、-C(NHC(O)R c )-、-C(NHC(O)NH 2 )-、-C(NHC(O)NHR c )-、-C(NHC(O)NR c R d )-、-C(OH)-、-C(O(alkyl))-、-C(N 3 )-、-C(CN)-、-C(NO 2 )-、-C(S(O) n R a )-、-C[-C(=O)R c ]-、-C[-C(=O)NR c R d]-、-C[-C(=O)SR c ]-、-C[-S(O)R c ]-、-C[-S(O) 2 R c ]-、-C[S(O)(OR c )]-、-C[-S(O) 2 (OR c )]-、-C[-SO 2 NR c R d ]-, -C(halogen)-, -C(alkyl), -C((cycloalkyl)alkyl), -C(alkenyl)-, -C(alkynyl)-, or -C(aralkyl)-;

[0111] R 3 represents optionally substituted aryl, heteroaryl, cycloalkyl or heterocycloalkyl;

[0112] R 3a is absent or represents one or more substituents independently selected from the group consisting of: halo, hydroxy, alkyl, -CF 3 、-OCF 3 , alkoxy, aryl, heteroaryl, aryloxy, amino, aminoalkyl, -C(O)NH 2 , cyano, -NHC(O)alkyl, -SO 2 Alkyl, -SO 2 NH 2 , cycloalkyl, -(CH 2 ) r OR a 、-NO 2 、-(CH 2 ) r NR a R b 、-(CH 2 ) r C(O)R a 、-NR a C(O)R b 、-C(O)NR c R d 、-NR a C(O)NR c R d 、-C(=NR a )NR c R d 、-NHC(=NR a )NR c R d 、-NR a R b 、-SO 2NR c R d 、-NR a SO 2 NR c R d 、-NR a SO 2 Alkyl, -NR a SO 2 R a 、-S(O) p R a ,-(CF 2 ) r CF 3 、-NHCH 2 R a 、-OCH 2 R a 、-SCH 2 R a 、-NH(CH 2 ) 2 (CH 2 ) r R a 、-O(CH 2 ) 2 (CH 2 ) r R a or -S(CH 2 ) 2 (CH 2 ) r R a ;

[0113] Y represents a chemical bond; or -YR 4 represents an optionally substituted -alkylene-R 4 、-CH 2 C(O)-R 4 、-CH 2 NH-R 4 、-CH 2 N(alkyl)-R 4 , -CR a R b -R 4 、-NH-R 4 、-NHCH 2 -R 4 、-NHC(O)-R 4 、-N(alkyl)-R 4 、-N(alkyl)CH 2 -R 4 、-N((CH 2 ) 2 OH)-R 4, -N((cycloalkyl)alkyl)R 4 , -heterocyclyl-R 4 、-OR 4 、-OCH 2 -R 4 、-OC(O)-R 4 、-OC(O)NR a R b 、-SCH 2 R 4 or -SR 4 ;

[0114] R 4 represents hydrogen, hydroxy, optionally substituted alkyl, cycloalkyl, (heterocycloalkyl)alkyl, (cycloalkyl)alkyl, -CH 2 OH, -CH(alkyl)OH, -CH(NH 2 )CH(alkyl) 2 , aryl, aralkyl, heteroaryl, heteroaralkyl, -CH 2 S(alkyl), amino or cyano; or -(CR a R b ) r (CR a R b ) p - fused to the 4-position of the ring bearing Z to form a 5- to 7-membered heterocyclic ring with optional substituents; or,

[0115] When R 3 When it is phenyl, R 4 It can represent -NR fused to the ortho position of X on the phenyl group. a -;

[0116] R a and R b are each independently H, alkyl, alkenyl, alkynyl, aralkyl, (cycloalkyl)alkyl, -C(=O)R c 、-C(=O)OR c 、-C(=O)NR c R d 、-C(=O)SR c 、-S(O)R c 、-S(O) 2 R c 、-S(O)(OR c ) or -SO 2 NR c R d ;

[0117] R c and R dEach occurrence independently represents optionally substituted alkyl, alkenyl, alkynyl, haloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl, (cycloalkyl)alkyl, heterocycloalkyl, (heterocycloalkyl)alkyl, -C(O)alkyl, or -S(O) p (alkyl); or R c and R d may together form an optionally substituted heterocyclic ring;

[0118] Can be expressed

[0119] r is 0, 1, 2, or 3;

[0120] n is an integer from 0 to 6; and

[0121] p is 0, 1 or 2.

[0122] In certain embodiments, R 1 Indicates -OH, -OR c 、-NH 2 、-NHR c 、-NR c R d , alkyl, aryl, heteroaryl, halo, haloalkyl, cycloalkyl, -OC(O)R c 、-NHC(O)R c or -NR c C(O)R d ; or two Rs in pairs 1 Together with the carbon to which they are attached, they represent -C(O)-; or two ortho or paired R 1 Together they form an optionally substituted fused or spirocyclic carbocyclic or heterocyclic ring.

[0123] In certain embodiments, R 1 Indicates -OH, -OR c 、-NH 2 , alkyl, aryl, halo, haloalkyl, cycloalkyl or -OC(O)R c .

[0124] In certain embodiments, n is 1.

[0125] In certain such embodiments, R 1 Indicates -OH or -OR c .

[0126] In certain embodiments, wherein n is 1, R 1 Indicates -OR c , for example R 1 Can represent -O((C 1 -C 6 )alkyl).

[0127] In certain embodiments, wherein n is 1, R 1 Indicates -OC(O)R c , for example R 1 Can represent -OC(O)((C 1 -C 6 )alkyl).

[0128] In certain embodiments, R 1 Indicates -NH 2 .

[0129] In certain embodiments, R 1 Indicates (C 1 -C 6 )alkyl.

[0130] In some embodiments, n is 2.

[0131] In certain such embodiments, two occurrences of R 1 are paired, i.e. two occurrences of R 1 connected to the same carbon atom.

[0132] In certain such embodiments, an occurrence of R 1 Indicates -OH or -OR c ; and another occurrence of R 1 represents an aryl group or a heteroaryl group.

[0133] Alternatively, in certain other such embodiments, an occurrence of R 1 Indicates -OH or -OR c ; and another occurrence of R 1 It represents a haloalkyl group.

[0134] In yet another alternative embodiment, two pairs of R 1 They are all halogen groups.

[0135] In certain embodiments, two pairs of R 1 Together with the carbon to which they are attached they represent -C(O)-.

[0136] In certain embodiments, where n is 2, two occurrences of R 1 are adjacent, that is, two occurrences of R 1 Connected to two adjacent carbon atoms.

[0137] In certain such embodiments, two ortho-occurring R 1 Together they form an optionally substituted fused carbocyclic ring.

[0138] In certain embodiments, n is 0.

[0139] In certain embodiments, W is -C(O)NH- or -C(O)N(R c )-.

[0140] In certain such embodiments, R 2 represents an optionally substituted aryl or heteroaryl group.

[0141] In certain embodiments, R 2 represents an aryl or heteroaryl group substituted by one or more substituents selected from the group consisting of: -OH, halo, -NH 2 、-NH((C 1 -C 6 )alkyl), -N((C 1 -C 6 )alkyl) 2 、-CN、-NO 2 , (C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 )alkoxy, -C(O)OH, -C(O)O(C 1 -C 6 )alkyl, -C(O)NH 2 、-C(O)NH(C 1 -C 6 )alkyl and -C(O)N((C 1 -C 6 )alkyl) 2 .

[0142] In certain embodiments, wherein W is -C(O)NH- or -C(O)N(R c )-, R 2 It represents a (halo)aryl group or a (halo)heteroaryl group.

[0143] In certain embodiments, W is -C(O)-.

[0144] In certain such embodiments, R 2 represents an optionally substituted aralkyl or heteroaralkyl group.

[0145] In certain embodiments, V represents optionally substituted aryl.

[0146] In certain embodiments, Z represents one or more substituents independently selected from the group consisting of halo, haloalkyl, -NO 2 and -CN.

[0147] In certain embodiments, Z represents an example of a halo group.

[0148] In certain embodiments, Z represents an example of a fluoro group.

[0149] In certain embodiments, Z is absent.

[0150] In certain embodiments, X represents -C(NH 2 )-、-C(NH(R c ))-、-C(NR c R d )-、-C(NHS(O) p R c )-、-C(NHC(O)R c )-、-C(NHC(O)NH 2 )-、-C(NHC(O)NHR c )-or-C(NHC(O)NR c R d )-.

[0151] In certain embodiments, X represents -C(NH 2 )-、-C(NH(R c ))-、-C(NR c R d )-、-C(NHS(O) p R c )-、-C(NHC(O)R c )-or-C(NHC(O)NHR c )-.

[0152] In certain embodiments, X represents -C(NH 2 )-.

[0153] In certain embodiments, X represents -C(NH(R c ))-.

[0154] In certain such embodiments, X represents -C(NH(cycloalkyl)alkyl)-. In alternative such embodiments, X represents -C(NH(C 1 -C 6 )alkyl)-.

[0155] In certain embodiments, X represents -C(NHS(O) p R c )-.

[0156] In certain such embodiments, X represents -C(NHS(O) p (C 1 -C 6 )alkyl)-, wherein p is 1 or 2.

[0157] In certain embodiments, X represents -C(NHC(O)NHR c )-.

[0158] In certain such embodiments, X represents optionally substituted -C(NHC(O)NH(aryl))- or C(NHC(O)NH(heteroaryl))-.

[0159] In certain embodiments, X represents -C(NHC(O)R c )-.

[0160] In certain such embodiments, X represents -C(NHC(O)((C 1 -C 6 )alkyl))-.

[0161] In certain embodiments, R 3 represents an optionally substituted aryl or heteroaryl group.

[0162] In certain embodiments, R 3 represents an optionally substituted heteroaryl group.

[0163] In certain such embodiments, R 3 It represents pyridyl.

[0164] In certain embodiments, R 3 represents an optionally substituted aryl group.

[0165] In certain such embodiments, R 3 represents a phenyl group optionally substituted by one or more substituents selected from the group consisting of: -CN, halo, -NO 2 , (C 1 -C 6 ) alkyl and (C 1 -C 6 ) haloalkyl.

[0166] In certain embodiments, R 3a Does not exist or represents halogen, alkyl, -CF 3 、-OCF 3 , aryl, heteroaryl, -C(O)NH 2 , cyano, -NHC(O)alkyl, -SO 2 Alkyl, -SO 2 NH 2 、-NO 2 、-NR a C(O)R b 、-C(O)NR c R d 、-NR aC(O)NR c R d 、-C(=NR a )NR c R d 、-NHC(=NR a )NR c R d 、-SO 2 NR c R d 、-NR a SO 2 NR c R d 、-NR a SO 2 Alkyl, -NR a SO 2 R a 、-S(O) p R a or -(CF 2 ) r CF 3 .

[0167] In certain embodiments, Y represents a chemical bond.

[0168] In certain embodiments, R 4 Indicates H.

[0169] In certain embodiments, R 4 represents a (cycloalkyl)alkyl group. For example, R 4 Can represent (cyclopropyl) (C 1 -C 6 )alkyl.

[0170] In certain embodiments, the compounds of the present invention are selected from the compounds in the following table or pharmaceutically acceptable salts thereof:

[0171]

[0172]

[0173]

[0174]

[0175]

[0176]

[0177]

[0178]

[0179]

[0180]

[0181]

[0182]

[0183] Pharmaceutical composition

[0184] The present invention provides pharmaceutical compositions, each of which comprises one or more compounds of the present invention and a pharmaceutically acceptable carrier. In certain embodiments, the pharmaceutical composition comprises one compound of the present invention and a pharmaceutically acceptable carrier. In certain embodiments, the pharmaceutical composition comprises a plurality of compounds of the present invention and a pharmaceutically acceptable carrier.

[0185] In certain embodiments, the pharmaceutical compositions are formulated for parenteral administration.

[0186] In certain embodiments, the pharmaceutical compositions are formulated for oral administration.

[0187] In certain embodiments, the pharmaceutical composition of the present invention further comprises at least one additional pharmaceutically active agent different from the compound of the present invention. The at least one additional pharmaceutically active agent can be an agent for treating a disease or condition characterized by undesirable plasma kallikrein activity. For example, the at least one additional pharmaceutically active agent can be an anticoagulant, an antiplatelet agent, or a thrombolytic agent.

[0188] Anticoagulants prevent blood components from clotting, thereby preventing blood clot formation, such as in atrial fibrillation. Anticoagulants include, but are not limited to, heparin, warfarin, coumarin, dicoumarol, phenprocoumon, acenocoumarol, ethyl dicoumarate, hirudin, bivalirudin, direct thrombin inhibitors, and indandione derivatives.

[0189] Antiplatelet agents inhibit platelet aggregation and are commonly used to prevent thromboembolic stroke in patients who have experienced a transient ischemic attack, stroke, or atrial fibrillation. Antiplatelet agents include, but are not limited to, aspirin, thienopyridine derivatives such as ticlopidine and clopidogrel, dipyridamole, sulfinpyrazone, and RGD mimetics.

[0190] Thrombolytic agents can dissolve blood clots that lead to thromboembolic phenomena such as stroke, myocardial infarction, and pulmonary thromboembolism. Thrombolytic agents include, but are not limited to, plasminogen, α2-antiplasmin, streptokinase, anistreplase, TNK, tissue plasminogen activator (tPA), and urokinase. Tissue plasminogen activator includes natural tPA and recombinant tPA, as well as modified forms of tPA that retain the enzymatic activity or fibrinolytic activity of natural tPA.

[0191] Pharmaceutical compositions of the present invention can be prepared by combining one or more compounds of the present invention with a pharmaceutically acceptable carrier and, optionally, one or more additional pharmaceutically active agents.

[0192] How to use

[0193] The invention provides compound, described compound inhibits the formation of thrombin via intrinsic pathway, and therefore reduces the risk of new pathogenic thrombosis (vascular occlusion or reocclusion), and also improves the reperfusion of fibrinolysis induction when using fibrinolysis scheme for adjuvant therapy.The disease and illness that can be treated with the compounds of this invention include but are not limited to stroke, inflammation, reperfusion injury, acute myocardial infarction, deep vein thrombosis, fibrinolysis treatment post-illness, angina pectoris, edema, angioedema, hereditary angioedema, sepsis, arthritis, hemorrhage, blood loss during cardiopulmonary bypass, inflammatory bowel disease, diabetes, retinopathy, diabetic retinopathy, diabetic macular edema, diabetic macular degeneration, age-related macular edema, age-related macular degeneration, proliferative retinopathy, neuropathy, hypertension, cerebral edema, albumin excretion increases, large amounts of proteinuria and nephropathy.

[0194] For example, in patients with angioedema, the small polypeptide PK inhibitor DX-88 (ecallantide) reduces edema in patients with hereditary angioedema (HAE). Williams, A. et al. (2003) Transfus. Apher. Sci. 29:255-8; Schneider, L. et al. (2007) J Allergy Clin Immunol. 120:416-22; and Levy, JH et al. (2006) Expert Opin. Invest. Drugs 15:1077-90. The bradykinin B2 receptor antagonist icatibant is also effective in treating HAE. Bork, K. et al. (2007) J. Allergy Clin. Immunol. 119:1497-1503. Since plasma kallikrein produces bradykinin, inhibition of plasma kallikrein would be expected to inhibit bradykinin production.

[0195] For example, in coagulation produced by fibrinolytic therapy (e.g., treatment with tissue plasminogen activator or streptokinase), higher levels of plasma kallikrein are found in patients with fibrinolysis. Hoffmeister, HM et al. (1998) J. Cardiovasc. Pharmacol. 31:764-72. Plasmin-mediated activation of the intrinsic pathway has been shown to occur in plasma and blood and is significantly attenuated in the plasma of individuals lacking any of the intrinsic pathway components. Ewald, GA et al. (1995) Circulation 91:28-36.

[0196] Levels of activated plasma kallikrein and thrombin were found to be elevated in individuals with acute myocardial infarction. Hoffmeister, HM, et al. (1998) Circulation 98:2527-33.

[0197] DX-88 reduces brain edema, infarct volume, and neurological deficits in animal models of ischemic stroke. Storini, C. et al. (2006) J. Pharm. Exp. Ther. 318:849-854. C1 inhibitors reduce infarct size in a mouse model of middle cerebral artery occlusion (MCAO). De Simoni, MG et al. (2004) Am. J. Pathol. 164:1857-1863; and Akita, N. et al. (2003) Neurosurgery 52:395-400). B2 receptor antagonists were found to reduce infarct volume, brain swelling, and neutrophil accumulation, and to be neuroprotective in an animal model of MCAO. Zausinger, S. et al. (2003) Acta Neurochir. Suppl. 86: 205-7; Lumenta, DB et al. (2006) Brain Res. 1069: 227-34; Ding-Zhou, L. et al. (2003) Br. J Pharmacol. 139: 1539-47.

[0198] With regard to blood loss during cardiopulmonary bypass (CPB), it has been found that the kallikrein-kinin (i.e., contact) system is activated during CABG. Wachtfogel, YT (1989) Blood 73:468. Activation of the contact system during CPB results in a 20-fold increase in plasma bradykinin. Cugno, M. et al. (2006) Chest 120:1776-82; and Campbell, DJ et al. (2001) Am. J. Physiol. Reg. Integr. Comp. Physiol. 281:1059-70.

[0199] Plasma kallikrein inhibitors P8720 and PKSI-527 have also been found to reduce joint swelling in rat models of arthritis. De La Cadena, RA et al. (1995) FASEB J. 9:446-52; Fujimori, Y. (1993) Agents Action 39:42-8. Inflammation in animal models of arthritis has also been found to be accompanied by activation of the contact system. Blais, C. Jr. et al. (1997) Arthritis Rheum. 40:1327-33.

[0200] In addition, the plasma kallikrein inhibitor P8720 has been found to reduce inflammation in acute and chronic rat models of inflammatory bowel disease (IBD). Stadnicki, A. et al. (1998) FASEB J. 12:325-33; Stadnicki, A. et al. (1996) Dig. Dis. Sci. 41:912-20; and DeLa Cadena, RA, et al. (1995) FASEB J. 9:446-52. The contact system is activated during acute and chronic intestinal inflammation. Sartor, RB et al. (1996) Gastroenterology 110:1467-81. B2 receptor antagonists (a high molecular weight kininogen antibody) or reduction of kininogen levels have been found to reduce clinical pathological features in animal models of IBD. Ibid.; Arai, Y. et al. (1999) Dig. Dis. Sci. 44:845-51; and Keith, JC et al. (2005) Arthritis Res. Therapy 7:R769-76.

[0201] HD-Pro-Phe-Arg-chloromethylketone (CMK, a PK and FXII inhibitor and a physiological inhibitor (C1 inhibitor)) has been found to reduce vascular permeability in multiple organs and reduce lipopolysaccharide (LPS)-injured or bacterial-induced sepsis in animals. Liu, D. et al. (2005) Blood 105:2350-5; Persson, K. et al. (2000) J. Exp. Med. 192:1415-24. Clinical improvements were observed in sepsis patients treated with C1 inhibitor. Zeerleder, S. et al. (2003) Clin. Diagnost. Lab. Immunol. 10:529-35; Caliezi, C., et al. (2002) Crit. Care Med. 30:1722-8; and Marx, G. et al. (1999) Intensive Care Med. 25:1017-20. Contact activation was found to be higher in fatal cases of sepsis. Martinez-Brotons, F. et al. (1987) Thromb. Haemost. 58:709-713; and Kalter, ES et al. (1985) J. Infect. Dis. 151:1019-27.

[0202] PrePK levels have also been found to be higher in diabetic patients, especially those with proliferative retinopathy, and correlate with fructosamine levels. Gao, B.-B., et al. (2007) Nature Med. 13:181-8; and Kedzierska, K. et al. (2005) Archives Med. Res. 36:539-43. PrePK has also been found to be highest in patients with sensorimotor neuropathy. Christie, M. et al. (1984) Thromb. Haemost. (Stuttgart) 52:221-3. PrePK levels are elevated in diabetic patients and are associated with elevated blood pressure. PrePK levels are independently associated with albumin excretion rate and are elevated in diabetic patients with heavy proteinuria, suggesting that prePK may be a marker for progressive renal disease. Jaffa, AA et al. (2003) Diabetes 52:1215-21. B1 receptor antagonists have been found to reduce plasma leakage in streptozotocin-treated rats. Lawson, SR et al. (2005) Eur. J. Pharmacol. 514:69-78. B1 receptor antagonists also prevented hyperglycemia and renal dysfunction in streptozotocin-treated mice. Zuccollo, A. et al. (1996) Can. J. Physiol. Pharmacol. 74:586-9.

[0203] In certain aspects, the present invention provides a compound of the present invention or a pharmaceutically acceptable salt thereof for use as a medicament.

[0204] In certain aspects, the present invention provides a method for treating or preventing a disease or condition characterized by undesirable plasma kallikrein activity. The method comprises the steps of administering a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof to a subject in need thereof, thereby treating or preventing a disease or condition characterized by undesirable plasma kallikrein activity. By reducing the plasma kallikrein activity in the subject, a disease or condition characterized by undesirable plasma kallikrein activity is treated.

[0205] Alternatively, in certain aspects, the invention provides a compound of the invention or a pharmaceutically acceptable salt thereof for use in treating a disease or condition characterized by undesirable plasma kallikrein activity.

[0206] Alternatively, in certain aspects, the present invention provides the use of a compound of the present invention or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating a disease or condition characterized by undesirable plasma kallikrein activity.

[0207] As used herein, "a disease or condition characterized by undesirable plasma kallikrein activity" refers to any disease or condition in which it is desirable to reduce plasma kallikrein activity. For example, in the case of a hypercoagulable state, it may be desirable to reduce plasma kallikrein activity. As another example, in the case of tissue ischemia associated with the presence or formation of thrombi, reduced plasma kallikrein activity may be desirable.

[0208] In certain embodiments, the disease or condition characterized by undesirable plasma kallikrein activity is selected from the group consisting of: stroke, inflammation, reperfusion injury, acute myocardial infarction, deep vein thrombosis, post-fibrinolytic therapy condition, angina, edema, angioedema, hereditary angioedema, sepsis, arthritis, hemorrhage, blood loss during cardiopulmonary bypass, inflammatory bowel disease, diabetes, retinopathy, diabetic retinopathy, diabetic macular edema, diabetic macular degeneration, age-related macular edema, age-related macular degeneration, proliferative retinopathy, neuropathy, hypertension, cerebral edema, increased albumin excretion, heavy proteinuria, and nephropathy.

[0209] In certain embodiments, the disease or disorder characterized by undesirable plasma kallikrein activity is angioedema.

[0210] In certain embodiments, the disease or disorder characterized by undesirable plasma kallikrein activity is hereditary angioedema (HAE).

[0211] In certain embodiments, the disease or condition characterized by undesirable plasma kallikrein activity is stroke.

[0212] In certain embodiments, the disease or condition characterized by undesirable plasma kallikrein activity is reperfusion injury.

[0213] In certain embodiments, the disease or condition characterized by undesirable plasma kallikrein activity is acute myocardial infarction.

[0214] In certain embodiments, the disease or disorder characterized by undesirable plasma kallikrein activity is bleeding.

[0215] In certain embodiments, the disease or condition characterized by undesirable plasma kallikrein activity is blood loss during cardiopulmonary bypass.

[0216] In certain embodiments, the disease or disorder characterized by undesirable plasma kallikrein activity is selected from the group consisting of retinopathy, diabetic retinopathy, diabetic macular edema, diabetic macular degeneration, age-related macular edema, age-related macular degeneration, and proliferative retinopathy.

[0217] Formulation, route of administration and dosage

[0218] The compounds of the present invention can be formulated into pharmaceutical compositions and administered to mammalian hosts (e.g., human patients) by intravenous routes, intraperitoneal routes, intramuscular routes, local routes, or subcutaneous routes in various forms suitable for the selected route of administration (e.g., oral or parenteral administration). The present invention also contemplates additional routes of administration.

[0219] Therefore, the present compound can be combined with a pharmaceutically acceptable carrier (such as an inert diluent or an absorbable edible carrier) for systemic administration, such as oral administration. They can be encapsulated in hard or soft shell gelatin capsules, can be compressed into tablets, or can be directly incorporated into the food of the patient's diet. For oral therapeutic administration, the active compound can be combined with one or more excipients and used in the form of ingestible tablets, buccal tablets, lozenges, capsules, elixirs, suspensions, syrups, wafers, etc. Such compositions and preparations should contain at least 0.1% of the active compound. Of course, the percentage of the composition and preparation can vary and can be conveniently between about 2% to about 60% of the weight of a given unit dosage form. The amount of active compound in such a therapeutically useful composition is the amount that can achieve an effective dosage level.

[0220] Tablets, lozenges, pills, capsules, etc. may also contain the following diluents and carriers: binders, such as gum tragacanth, gum arabic, corn starch or gelatin; thief-shaped agents, such as dicalcium phosphate; disintegrants, such as corn starch, potato starch, alginic acid, etc.; lubricants, such as magnesium stearate; and sweeteners (such as sucrose, fructose, lactose or aspartame) or flavoring agents (such as mint, wintergreen oil or cherry flavor) may be added. When the unit dosage form is a capsule, in addition to the above-mentioned types of materials, it may also contain a liquid carrier, such as vegetable oil or polyethylene glycol. Various other materials may exist as coatings or otherwise change the physical form of the solid unit dosage form. For example, tablets, pills or capsules may be coated with gelatin, wax, shellac or sugar. Syrups or elixirs may contain the active compound, sucrose or fructose as a sweetener, methylparaben and propylparaben as preservatives, and dyes and flavorings (such as cherry or orange flavor). Of course, any material used to prepare any unit dosage form should be pharmaceutically acceptable and substantially non-toxic in the amount used. In addition, the active compound may be incorporated into a sustained-release preparation and device.

[0221] The active compound may also be administered intravenously or intraperitoneally by infusion or injection. Solutions of the active compound or its salt may be prepared in water or physiologically acceptable aqueous solutions, optionally mixed with a nontoxic surfactant. Dispersions may also be prepared in glycerol, liquid polyethylene glycols, triacetin and mixtures thereof and in oils. Under normal conditions of storage and use, these preparations contain preservatives to prevent the growth of microorganisms.

[0222] The pharmaceutical dosage form suitable for injection or infusion can include a sterile aqueous solution or dispersion or sterile powder containing active ingredients, and the sterile powder is suitable for temporary preparation of sterile injection or infusion solutions or dispersions, optionally encapsulated in liposomes. In all cases, the final dosage form should be sterile, mobile and stable under preparation and storage conditions. The liquid carrier or carrier can be a solvent or liquid dispersion medium, which includes, for example, water, ethanol, polyols (such as glycerol, propylene glycol, liquid polyethylene glycol, etc.), vegetable oils, non-toxic glycerides and suitable mixtures thereof. For example, by forming liposomes, by maintaining the required particle size in the case of dispersions or by using surfactants to maintain appropriate fluidity. The effect of microorganisms can be prevented by various antibacterial and antifungal agents (such as parabens, chlorobutanol, phenol, sorbic acid, thimerosal, etc.). In many cases, it is preferred to include isotonic agents, such as sugar, buffer or sodium chloride. The absorption of injectable compositions can be extended by using agents (such as aluminum monostearate and gelatin) that delay absorption in the composition.

[0223] Sterile injectable solutions are prepared by incorporating the active compound in the required amount in an appropriate solvent along with various of the other ingredients enumerated above, as required, followed by filtered sterilization. In the case of sterile powders for the preparation of sterile injectable solutions, the preparation methods may include vacuum drying and freeze drying techniques which yield a powder of the active ingredient plus any other desired ingredients present in a previously sterile filtered solution.

[0224] For topical administration, the present compounds can be administered in pure form, ie when they are liquids. However, it will generally be desirable to apply them to the skin as compositions or formulations in combination with a dermatologically acceptable carrier, which may be a solid or a liquid.

[0225] Useful solid carriers include finely divided solids such as talc, clay, microcrystalline cellulose, silicon dioxide, aluminum oxide, and the like. Useful liquid carriers include water, alcohols or glycols or water-alcohol / glycol blends, in which the present compound can be dissolved or dispersed in an effective amount, optionally with the aid of a nontoxic surfactant. Adjuvants (such as spices and other antimicrobial agents) can be added to optimize the properties of a particular use. The resulting liquid composition can be applied from an absorbent pad for impregnating bandages and other dressings, or sprayed onto the affected area using a pump-type or aerosol sprayer.

[0226] Thickening agents (such as synthetic polymers, fatty acids, fatty acid salts and esters, fatty alcohols, modified celluloses, or modified mineral materials) can also be employed with the liquid carrier to form spreadable pastes, gels, ointments, soaps, etc., for application directly to the user's skin.

[0227] Examples of useful dermatological compositions that can be used to deliver the compounds of the present invention to the skin are known in the art; for example, see Jacquet et al. (U.S. Pat. No. 4,608,392; incorporated herein by reference), Geria (U.S. Pat. No. 4,992,478; incorporated herein by reference), Smith et al. (U.S. Pat. No. 4,559,157; ​​incorporated herein by reference), and Wortzman (U.S. Pat. No. 4,820,508; incorporated herein by reference).

[0228] The useful dosage of the compounds of the present invention can be determined at least initially by comparing their in vitro activity and in vivo activity in animal models. Methods for analogizing the effective dosage in mice and other animals to humans are known in the art; for example, referring to U.S. Patent No. 4,938,949 (incorporated herein by reference).

[0229] The amount of the compound or its active salt required for use in treatment will vary not only with the particular compound or salt chosen but also with the route of administration, the nature of the condition being treated and the age and condition of the patient and is ultimately at the discretion of the attending physician or clinician.

[0230] In general, however, suitable dosages will be in the range of about 0.5 mg / kg to about 100 mg / kg of the recipient body weight per day, for example, about 3 mg / kg to about 90 mg / kg body weight per day, about 6 mg / kg to about 75 mg / kg body weight per day, about 10 mg / kg to about 60 mg / kg body weight per day or about 15 mg / kg to about 50 mg / kg body weight per day.

[0231] The compounds of the present invention can be conveniently formulated into unit dosage forms; for example, each unit dosage form contains 5 to 1000 mg, 10 to 750 mg or 50 to 500 mg of active ingredient. In one embodiment, the invention provides a composition comprising a compound of the present invention formulated in such a unit dosage form. The desired dose can be conveniently presented as a single dose, or presented as divided doses administered at appropriate time intervals, such as twice, three times, four times or more sub-doses per day. The sub-doses themselves can be further divided, for example, into multiple discontinuous loosely spaced administrations.

[0232] The compounds of the invention may also be administered in combination with other therapeutic agents, such as other agents useful in treating or preventing ischemia, blood loss, or reperfusion injury.

[0233] Other delivery systems can include time release, delayed release or sustained release delivery systems as well known in the art. Such a system can avoid repeated administration of the active compound, thereby increasing convenience for the experimenter and the doctor. Many types of release delivery systems are available and known to those of ordinary skill in the art. The use of long-term sustained release implants may be desirable. Long-term release as used herein refers to that a delivery system or implant is constructed and arranged to deliver the active ingredient of the treatment level for at least 30 days, and preferably 60 days.

[0234] In certain embodiments, the compounds of the invention are formulated for intraocular administration, such as direct injection or insertion into or in conjunction with an intraocular medical device.

[0235] The compounds of the present invention can be formulated for deposition into medical devices, which can include any of a variety of conventional grafts, stents (including stent grafts), catheters, balloons, basket grafts, or other devices that can be deployed or permanently implanted into a body cavity. As a specific example, it is desirable to have devices and methods that can deliver the compounds of the present invention to a body part that has been treated by an interventional technique.

[0236] In an exemplary embodiment, the compounds of the invention may be deposited within a medical device, such as a stent, and delivered to a treatment site to treat a part of the body.

[0237] Stents have been used as delivery vehicles for therapeutic agents (i.e., drugs). Intravascular stents are usually permanently implanted in coronary arteries or peripheral blood vessels. Stent designs include U.S. Patent No. 4,733,655 (Palmaz), U.S. Patent No. 4,800,882 (Gianturco), or U.S. Patent No. 4,886,062 (Wiktor). This design includes metal and polymer stents, as well as self-expanding and balloon-expandable stents. As disclosed, for example, in U.S. Patent No. 5,102,417 (Palmaz), U.S. Patent No. 5,419,760 (Narciso, Jr.), U.S. Patent No. 5,429,634 (Narciso, Jr), and in International Patent Application No. WO91 / 12779 (Medtronic, Inc.) and No. WO 90 / 13332 (Cedars-Sanai Medical Center), stents can also be used to deliver drugs at sites in contact with the vascular system.

[0238] The term "deposition" refers to coating, adsorbing, placing or otherwise incorporating a compound into a device by methods known in the art. For example, the compound can be embedded in ("frame-type") a polymer material and released therefrom, or can be surrounded by and released through a ("reservoir-type") polymer material that wraps around or spans a medical device. In the latter examples, the compound can be embedded in or coupled to a polymer material using one or more techniques known in the art for producing such materials. In other formulations, the compound can be connected to the surface of a medical device, for example, by a detachable chemical bond without the need for a coating and can be released over time, or can be removed by an active mechanical or chemical process. In other formulations, the compound can be in a permanently immobilized form that presents the compound at the implant site.

[0239] In certain embodiments, the compound can be combined with the polymer composition during the formation of a biocompatible coating for a medical device (e.g., a stent). Coatings made from these components are generally uniform and can be used to coat a variety of devices designed for implantation.

[0240] Depending on the desired release rate or the desired degree of polymer stability, the polymer can be a biostable or bioabsorbable polymer, but for this embodiment, a bioabsorbable polymer is generally preferred because, unlike a biostable polymer, it does not persist long after implantation to cause any adverse chronic local reactions. Bioabsorbable polymers that can be used include, but are not limited to, poly(L-lactic acid), polycaprolactone, polyglycolide (PGA), poly(lactide-co-glycolide) (PLLA / PGA), poly(hydroxybutyrate), poly(hydroxybutyrate-co-valerate), polydioxanone, polyorthoesters, polyanhydrides, poly(glycolic acid), poly(D-lactic acid), poly(L-lactic acid), poly(D,L-lactic acid), poly(D,L-lactide) (PLA), poly(L-lactide) (PLLA), poly(glycolic acid-co-trimethylene carbonate) (PGA / PTMC), polyethylene oxide (PE

[0013] Suitable bioresorbable polymers include, but are not limited to, poly(p-butylene oxide), poly(isocyanate), poly(isocyanate), poly(d-butylene oxide ... Furthermore, biostable polymers with relatively low chronic tissue reactions may be used, such as polyurethanes, silicones, and polyesters, and other polymers may be used if they can be dissolved and cured or polymerized on the medical device, such as polyolefins, polyisobutylenes, and ethylene-alpha-olefin copolymers; acrylic polymers and copolymers, vinyl halide polymers and copolymers, such as polyvinyl chloride; polyvinyl pyrrolidone; polyvinyl ethers, such as polyvinyl methyl ether; polyvinylidene halides, such as polyvinylidene fluoride and polyvinylidene chloride; polyacrylonitrile, polyvinyl ketone; polyvinyl aromatics, such as polystyrene, polyvinyl esters, such as polyvinyl acetate; vinyl monomers and each other Copolymers of olefins, such as ethylene-methyl methacrylate copolymers, acrylonitrile-styrene copolymers, ABS resins and ethylene-vinyl acetate copolymers; pyran copolymers; polyhydroxy-propyl-methacrylamide-phenol; polyhydroxyethyl-aspartamide-phenol; polyethylene oxide-polylysine substituted with palmitoyl residues; polyamides, such as nylon 66 and polycaprolactam; alkyd resins, polycarbonates; polyoxymethylene; polyimides; polyethers; epoxy resins, polyurethanes; rayon; rayon-triethyl; cellulose, cellulose acetate, cellulose butyrate; cellulose acetate butyrate; cellophane; cellulose nitrate; cellulose propionate; cellulose ethers; and carboxymethyl cellulose.

[0241] Polymers and semipermeable polymer matrices can be formed into shaped articles such as valves, stents, conduits, prostheses, etc.

[0242] In certain embodiments of the present invention, the compounds of the present invention are coupled to a polymer or semipermeable polymer backbone formed into a stent or stent-graft device.

[0243] Typically, the polymer is applied to the surface of the implantable device by spin coating, dipping or spraying. Other methods known in the art may also be used for this purpose. Spraying methods include conventional methods and micro-deposition techniques using inkjet type dispensers. In addition, the polymer can be deposited on the implantable device using photolithographic patterns to place the polymer only on specific parts of the device. The coating of the device provides a uniform layer around the device, which allows for improved diffusion of various analytes through the device coating.

[0244] In certain embodiments of the invention, the compound is formulated to be released from the polymer coating into the environment in which the medical device is placed. Preferably, at least one of several known techniques involving polymer carriers or layers is used to control elution, releasing the compound in a controlled manner over an extended time frame (e.g., several months). Some of these techniques are described in U.S. Patent Application 2004 / 0243225A1, the entire disclosure of which is incorporated herein in its entirety.

[0245] Moreover, as described in, for example, U.S. Patent No. 6,770,729 (which is incorporated herein in its entirety), the reagents and reaction conditions of the polymer composition can be manipulated so that the release of the compound from the polymer coating can be controlled. For example, the diffusion coefficient of one or more polymer coatings can be adjusted to control the release of the compound from the polymer coating. In a variation on this scheme, the diffusion coefficient of one or more polymer coatings can be controlled to adjust the ability of the analyte (such as the analyte that promotes the decomposition or hydrolysis of a certain part of the polymer) present in the environment where the medical device is placed to utilize one or more components in the polymer composition (and, for example, thereby regulating the release of the compound from the polymer coating). Another embodiment of the present invention includes a device with multiple polymer coatings, each polymer coating having multiple diffusion coefficients. In such embodiments of the present invention, the release of the compound from the polymer coating can be regulated by multiple polymer coatings.

[0246] In another embodiment of the present invention, the release of the compound from the polymer coating is controlled by adjusting one or more properties of the polymer composition (e.g., the presence of one or more endogenous or exogenous compounds) or the pH of the polymer composition. For example, certain polymer compositions can be designed to release the compound in response to a decrease in the pH of the polymer composition.

[0247] Reagent test kit

[0248] The present invention also provides a kit comprising a compound of the present invention or a pharmaceutically acceptable salt thereof, at least one other therapeutic agent, packaging materials, and instructions for administering the compound of the present invention or a pharmaceutically acceptable salt thereof and the other therapeutic agent to a mammal to treat or prevent ischemia, hemorrhage, or reperfusion injury in the mammal. In one embodiment, the mammal is a human.

[0249] Examples

[0250] The present invention is further illustrated by the following examples, which should not be construed as limiting the scope of the invention claimed. The entire contents of all references (including references, granted patents, published patent applications, and co-pending patent applications) listed throughout this application are expressly incorporated herein by reference.

[0251] Solution 1

[0252]

[0253] Preparation of (2R,4R)-N1-(4-chlorophenyl)-N2-(5-(((cyclopropylmethyl)amino)(phenyl)methyl)-2-fluorophenyl)-4-hydroxypyrrolidine-1,2-dicarboxamide (1p)

[0254] Step 1: Preparation of N-(5-bromo-2-fluorophenyl)-1,1,1-trimethyl-N-(trimethylsilyl)silaneamine (1b)

[0255] To a stirred solution of 5-bromo-2-fluoroaniline (1a) (225 g, 1184 mmol) in triethylamine (3301 mL, 20 eq) at room temperature was added trimethylsilyl trifluoromethylsulfonate (481 mL, 2664 mmol) [Note: heat is generated during the addition, but there is no need to cool the flask]. The mixture was heated to reflux for 16 hours and then cooled to room temperature. The two layers were separated. [Note: try not to expose the solution to air or water vapor during the separation]. The dark bottom solution was discarded and the upper solution was concentrated in vacuo to remove excess triethylamine. The oily residue was transferred to a 1000 mL flask for high vacuum distillation. The compound began to distill at 100°C and 0.5 mm / Hg. The first fraction (about 15 mL) was discarded, and the second fraction was collected when the conditions were stable at 100°C and 0.5 mm / Hg to obtain N-(5-bromo-2-fluorophenyl)-1,1,1-trimethyl-N-(trimethylsilyl)silaneamine (1b) (364 g, 1089 mmol, yield 92%). This material was prepared and used before the next step. 1H NMR (300 MHz, CHLOROFORM-d) δ 7.17-7.11 (m, 1H), 7.09 (dd, J=7.5, 2.5 Hz, 1H), 6.89 (d, J=0.9 Hz, 1H), 0.08 (d, J=0.6 Hz, 18H).

[0256] Step 2: Preparation of (3-(bis(trimethylsilyl)amino)-4-fluorophenyl)magnesium bromide (1c)

[0257] To a solution of magnesium turnings (33.1 g, 1361 mmol) in tetrahydrofuran (15 mL) was added iodine (1.381 g, 5.44 mmol), followed by the addition of N-(5-bromo-2-fluorophenyl)-1,1,1-trimethyl-N-(trimethylsilyl)silaneamine (1b) (4 g) and the reaction was allowed to proceed for about 5 minutes (iodine color faded). At this point, the remaining solution of N-(5-bromo-2-fluorophenyl)-1,1,1-trimethyl-N-(trimethylsilyl)silaneamine (1b) (364 g, 1089 mmol) in tetrahydrofuran (1000 mL) was slowly added over 3 hours (reaction temperature was about 60° C. during addition). The resulting dark grey solution was stirred overnight to afford (3-(bis(trimethylsilyl)amino)-4-fluorophenyl)magnesium bromide (1c) (397 g, 1107 mmol, 102% yield, ca. 1 M solution) which was used fresh in the next step.

[0258] Step 3: Preparation of (R)-(-)-N-benzylidene-2-methylpropane-2-sulfenamide (1d)

[0259] To a stirred solution of benzaldehyde (259 mL, 2541 mmol) in tetrahydrofuran (2500 mL) was added (R)-2-methylpropane-2-sulfenamide (280 g, 2310 mmol) and tetraisopropoxytitanium (1382 mL, 4620 mmol), followed by stirring at room temperature for 36 hours. The reaction mixture was diluted with 1 L of brine with vigorous stirring. Ethyl acetate (6 L) was then added and stirred for 4 hours. The reaction mixture was filtered and washed with ethyl acetate (6×2 L). The organic layers were combined, washed with a solution of sodium metabisulfite (329 mL, 1733 mmol) and water (462 mL), and MgSO 4 Dry, filter, and evaporate to dryness. The crude residue was purified by flash column chromatography (1.5 kg silica gel, eluted with 20% ethyl acetate in hexane solution to give a light yellow oil (R)-(-)-N-benzylidene-2-methylpropane-2-sulfenamide (1d) (472.51 g, 2257 mmol, yield 98%); 1 H NMR (300 MHz, DMSO-d 6)δ8.57(s,1H),8.03-7.89(m,2H),7.70-7.48(m,3H),1.19(s,9H);MS(ES+)232.18(M+Na);Optical rotation:[α] D =(-)112.11[4.155, CHCl 3 ].

[0260] Step 4: Preparation of (R)-N-((R)-(3-amino-4-fluorophenyl)(phenyl)methyl)-2-methylpropane-2-sulfenamide (1e) and (R)-N-((S)-(3-amino-4-fluorophenyl)(phenyl)methyl)-2-methylpropane-2-sulfenamide (1f)

[0261] Batch 1 To a solution of (R)-(-)-N-benzylidene-2-methylpropane-2-sulfenamide (1d) (475 g, 2269 mmol) in toluene (4 L) cooled to -11 °C was added freshly prepared Grignard reagent (3-(bis(trimethylsilyl)amino)-4-fluorophenyl)magnesium bromide (1c) (4.75 L, 3563 mmol) dropwise over 70 min, maintaining the internal temperature between -11.1 and -10 °C. The reaction mixture was stirred at the same temperature until the reaction was complete (checked by TLC). At -10 °C, 1 N KHSO 4 The reaction was quenched. The reaction was kept at room temperature for more than 30 minutes and the organic layer was separated. The aqueous layer was extracted with ethyl acetate (2×2 L). The organic layers were combined, washed with water (2×2 L) and brine (3.5 L), dried, filtered, and concentrated in vacuo to give a crude oil containing a mixture of diastereoisomers (R)-N-((R)-(3-amino-4-fluorophenyl)(phenyl)methyl)-2-methylpropane-2-sulfinamide (1e) and (R)-N-((S)-(3-amino-4-fluorophenyl)(phenyl)methyl)-2-methylpropane-2-sulfinamide (1f) [(de=72 / 28) 727 g, 2269 mmol]. IPA (2000 mL) was added to the crude product in a 22 L flask and heated to reflux while stirring (30 minutes until completely dissolved). The reaction mixture was cooled to 27° C. in 5 hours under gentle stirring. The resulting solid was collected by filtration, washed with IPA (5×100 mL), and air-dried for 24 h to give a white crystalline solid (R)-N-((R)-(3-amino-4-fluorophenyl)(phenyl)methyl)-2-methylpropane-2-sulfenamide (1e) (351 g, 48.3% yield, de=94.63%).

[0262] Batch 2The above procedure was repeated using (R)-(-)-N-benzylidene-2-methylpropane-2-sulfenamide (1d) (0.500 kg, 2.389 mol) to give (R)-N-((R)-(3-amino-4-fluorophenyl)(phenyl)methyl)-2-methylpropane-2-sulfenamide (1e) (329 g, 43% yield, de = 93.58%) as a white crystalline solid.

[0263] Batch 3 The above procedure was repeated using (R)-(-)-N-benzylidene-2-methylpropane-2-sulfenamide (1d) (409 g, 1953 mmol) to give (R)-N-((R)-(3-amino-4-fluorophenyl)(phenyl)methyl)-2-methylpropane-2-sulfenamide (1e) (264 g, 42% yield, de = 94.33%) as a white crystalline solid.

[0264] Second crystallization: The above three batches were combined in a 22 L wide mouth rotary evaporator equipped with a mechanical stirrer, IPA (4000 mL) was added and heated to reflux with stirring (50 minutes to completely dissolve), wherein the mechanical stirrer contained a mixture of diastereomers (1e) and (1f) (batch 1, 351 g, yield 48.3%, de = 94.63) (batch 2, 399 g, yield 43%, de = 93.58%) and (batch 3, 264 g, yield 42%, de = 94.33%). The reaction mixture was cooled to room temperature overnight under gentle stirring (13 ° C). After about 1 hour of cooling and stirring, the crystallized solid continued overnight. The obtained solid was collected by filtration, washed with IPA (1×100 mL and 2×200 mL), and dried under high vacuum for 24 h to give a white crystalline solid (R)-N-((R)-(3-amino-4-fluorophenyl)(phenyl)methyl)-2-methylpropane-2-sulfenamide (1e) (872 g, 92% yield, de=99.2852%); 1 H NMR (300 MHz, DMSO-d 6 )δ7.40-7.26 (m, 4H), 7.25-7.15 (m, 1H), 6.90 (dd, J=11.5, 8.3Hz, 1H), 6.75 (dd, J=8.9, 2.2Hz, 1H), 6.5 7 (ddd, J=8.4, 4.4, 2.2Hz, 1H), 5.77 (d, J=5.4Hz, 1H), 5.33 (d, J=5.3Hz, 1H), 5.11 (s, 2H), 1.13 (s, 9H); 19 F NMR (282MHz, DMSO) δ-137.36; 13C NMR (75 MHz, DMSO) δ 151.32, 148.19, 143.13, 139.74, 139.70, 128.22, 127.63, 126.93, 115.04, 114.98, 114.91, 114.82, 114.60, 114.35, 61.88, 55.42, 22.77; Optical rotation: [α] D =(-)70.70 (MeOH, 1.065); Analytical calculation value C 17 H 21 FN 2 OS: C, 63.72; H, 6.61; N, 8.74; Found: C, 63.74; H, 6.74; N, 8.74.

[0265] Data for (R)-N-((S)-(3-amino-4-fluorophenyl)(phenyl)methyl)-2-methylpropane-2-sulfenamide (1f); 1 H NMR (300 MHz, DMSO-d 6 )δ7.41-7.36 (m, 2H), 7.36-7.27 (m, 2H), 7.26-7.18 (m, 1H), 6.89 (dd, J=11.5, 8.3Hz, 1H), 6.71 (dd, J=8.9, 2.2Hz, 1H), 6.51 (ddd, J=8.4, 4.5, 2.2Hz, 1H), 5.82 (d, J=5.5Hz, 1H), 5.32 (d, J=5.5Hz, 1H), 5.09 (s, 2H, 1H D 2 O interchangeable), 1.14 (s, 9H); 19 FNMR (282 MHz, DMSO-d 6 )δ-137.32; MS (ES+) 321.3 (M+1), 343.3 (M+Na), 663.5 (2M+Na); MS (ES-) 319.3 (M-1). Optical rotation: [α] D =(-)73.21 (MeOH, 2.505).

[0266] Step 5: Preparation of (+)-5-(amino(phenyl)methyl)-2-fluoroaniline (1 g)

[0267] To a mechanically stirred slurry of (R)-N-((R)-(3-amino-4-fluorophenyl)(phenyl)methyl)-2-methylpropane-2-sulfenamide (1e) (99.13 g, 309 mmol) in MTBE (600 mL) was added 4 M HCl(dioxane) (162 mL, 650 mmol) and stirred at room temperature for 11 hours. Once the addition of HCl began, solids began to form. TLC analysis showed unreacted starting material was added, additional 4 M HCl(dioxane) (162 mL, 650 mmol) was added and stirred at room temperature for 16 hours. Excess methanol was evaporated, the mixture was basified with 3N NaOH (455 mL) and the compound was extracted with ethyl acetate (2×750 mL). The combined organic layers were dried over anhydrous MgSO 4, filtered and evaporated to dryness. The solid was triturated with hexane, stirred for 1 hour, and the resulting solid was collected by filtration to give a pale yellow solid (+)-5-(amino(phenyl)methyl)-2-fluoroaniline (1 g) (38.0 g, 57% yield); 1 HNMR (300 MHz, DMSO-d 6 ) δ7.39-7.33 (m, 2H), 7.27 (ddd, J=7.6, 6.6, 1.2Hz, 2H), 7.21-7.13 (m, 1H), 6.86 (dd, J=11. 5, 8.3Hz, 1H), 6.77 (dd, J=9.0, 2.2Hz, 1H), 6.54 (ddd, J=8.3, 4.4, 2.2Hz, 1H), 5.03 (s, 2H, D 2 O interchangeable), 4.96 (s, 1H), 2.71 (s, 2H, D 2 O are interchangeable); 19 F NMR (282 MHz, DMSO-d 6 )δ-138.12; MS (ES+) 217.2 (M+1); 215.1 (M-1); Optical rotation: [α] D =(+)1.47(0.545, MeOH).

[0268] Step 6: Preparation of (-)-N-(cyclopropylmethyl)-5-((cyclopropylmethylamino)(phenyl)methyl)-2-fluoroaniline (1h) and (-)-5-((cyclopropylmethylamino)(phenyl)methyl)-2-fluoroaniline (1i)

[0269] To a stirred solution of (+)-5-(amino(phenyl)methyl)-2-fluoroaniline (1 g) (5.312 g, 24.56 mmol) in MeOH (80 mL) at 0°C was added cyclopropanecarboxaldehyde (1.944 mL, 25.8 mmol) over 10 minutes and stirred for 30 minutes. To this sodium borohydride (1.859 g, 49.1 mmol) was added in several portions and stirred at 0°C for 1 hour. The excess solvent was evaporated and the residue was treated with water (100 mL) and extracted with ethyl acetate (2×100 mL). The organic layers were combined and washed with anhydrous MgSO 4 The residue was purified by flash column chromatography (silica gel 80 g, eluted with ethyl acetate in hexane, 0 to 100%) to give

[0270] 1. Yellow oil (-)-N-(cyclopropylmethyl)-5-((cyclopropylmethylamino)(phenyl)methyl)-2-fluoroaniline (1h) (0.663 g, yield 8%); 1 H NMR (300 MHz, DMSO-d 6 )δ7.44-7.35 (m, 2H), 7.30-7.21 (m, 2H), 7.19-7.08 (m, 1H), 6.96-6.75 (m, 2H), 6.55 (ddd, J=8.3, 4.6, 2.0Hz, 1H), 5.26 (td, J=6.0, 2.3Hz, 1H, D 2 O interchangeable), 4.71 (s, 1H), 2.93 (t, J = 6.2 Hz, 2H), 2.27 (d, J = 7.1 Hz, 3H, 1H, D 2 O interchangeable), 1.09-0.84 (m, 2H), 0.39 (m, 4H), 0.25-0.15 (m, 2H), 0.09-0.02 (m, 2H); 19 F NMR (282 MHz, DMSO-d 6 )δ-137.56; MS (ES+) 325.4 (M+1); Optical rotation: [α] D =(-)6.67[0.27, methanol]

[0271] 2. Yellow oil (-)-5-((cyclopropylmethylamino)(phenyl)methyl)-2-fluoroaniline (1i) (4.84 g, yield 73%); 1 H NMR (300 MHz, DMSO-d 6)δ7.42-7.34(m, 2H), 7.32-7.23(m, 2H), 7.22-7.11(m, 1H), 6.92-6.78(m, 2H), 6.55(ddd, J=8.3, 4.5, 2.2Hz, 1H), 5.04(s, 2H, D 2 O interchangeable), 4.67 (s, 1H), 2.25 (td, J = 9.6, 5.3 Hz, 3H; 1H D 2 O interchangeable), 1.04-0.80 (m, 1H), 0.50-0.28 (m, 2H), 0.11-0.02 (m, 2H); 19 F NMR (282 MHz, DMSO-d 6 )δ-137.92; MS (ES-) 269.3 (M-1); optical rotation: [α] D =(-)12.24[1.275,CHCl 3 ]; The chiral purity was checked by chiral HPLC using a chiral AD-H column, 1 mL / min, solvent: 95% hexane, 5% isopropanol, UV=260 nM, 25°C (>99.99 ee).

[0272] Step 7: Preparation of 5-(amino(phenyl)methyl)-2-fluoroaniline (1k)

[0273] Compound (R)-N-((R)-(3-amino-4-fluorophenyl)(phenyl)methyl)-2-methylpropane-2-sulfinamide (1j) was obtained from the mother liquor of the crystallization of the diastereoisomer mixture of (R)-N-((R)-(3-amino-4-fluorophenyl)(phenyl)methyl)-2-methylpropane-2-sulfinamide (1e) and (R)-N-((S)-(3-amino-4-fluorophenyl)(phenyl)methyl)-2-methylpropane-2-sulfinamide (1f). Compound (1k) was prepared from (R)-N-((3-amino-4-fluorophenyl)(phenyl)methyl)-2-methylpropane-2-sulfinamide (1j) (27.8 g, 87 mmol) using the procedure reported in step 5 of scheme 1 to give 5-(amino(phenyl)methyl)-2-fluoroaniline (1k) (14 g, 75%) as a light brown solid; 1 H NMR (300 MHz, DMSO-d 6)δ7.40-7.32 (m, 2H), 7.27 (ddd, J=7.6, 6.7, 1.2Hz, 2H), 7.21-7.11 (m, 1H), 6.86 (dd, J=11.5, 8.3Hz, 1H) , 6.78 (dd, J=9.0, 2.2Hz, 1H), 6.54 (ddd, J=8.3, 4.5, 2.2Hz, 1H), 5.00 (s, 2H), 4.93 (s, 1H), 2.13 (s, 2H); 19 F NMR (282MHz, DMSO) δ-138.30; MS (ES) 215.1 (M-1).

[0274] Step 8: Preparation of N-(cyclopropylmethyl)-5-((cyclopropylmethylamino)(phenyl)methyl)-2-fluoroaniline (11) and 5-((cyclopropylmethylamino)(phenyl)methyl)-2-fluoroaniline (1m)

[0275] Compounds 11 and 1m were prepared from 5-(amino(phenyl)methyl)-2-fluoroaniline (1k) (1.081 g, 5.00 mmol) according to the procedure reported in step 6 of scheme 1

[0276] 1. Colorless oil N-(cyclopropylmethyl)-5-((cyclopropylmethylamino)(phenyl)methyl)-2-fluoroaniline (1]) (0.194 g, 0.598 mmol, yield 11.96%); 1 H NMR (300 MHz, DMSO-d 6 )δ7.44-7.35 (m, 2H), 7.30-7.21 (m, 2H), 7.19-7.11 (m, 1H), 6.94-6.79 (m, 2H), 6.56 (ddd, J=8.2, 4.6, 2.1Hz, 1H), 5.29 (td, J=5.9, 2.3 Hz, 1H), 4.72 (s, 1H), 2.94 (t, J=6.2Hz, 2H), 2.38-2.20 (m, 3H), 1.10-0.97 (m, 1H), 0.91 (m, 1H), 0.40 (m, 4H), 0.21 (m, 2H), 0.03 (m, 2H); 19 F NMR (282MHz, DMSO) δ-137.78; MS (ES+) 325.3 (M+1); (ES-) 323.2 (M-1).

[0277] 2. Colorless oil 5-((cyclopropylmethylamino)(phenyl)methyl)-2-fluoroaniline (1m) (0.795 g, 2.94 mmol, yield 58.8%); 1 H NMR (300 MHz, DMSO-d 6)δ7.40-7.33 (m, 2H), 7.27 (tt, J=6.6, 0.9Hz, 2H), 7.20-7.12 (m, 1H), 6.90-6.78 (m, 2H), 6.54 (ddd, J=8.3, 4.5 , 2.1Hz, 1H), 5.04(s, 2H), 4.67(s, 1H), 2.34-2.22(m, 3H), 0.91(m, 1H), 0.44-0.30(m, 2H), 0.09-0.00(m, 2H); 19 F NMR (282MHz, DMSO) δ-137.95; MS (ES+) 271.2 (M+1).

[0278] Step 9: Preparation of (2R, 4R)-1-(4-chlorophenylcarbamoyl)-4-hydroxypyrrolidine-2-carboxylic acid (1o) To a stirred solution of cis-hydroxy-D-proline (1 g, 7.63 mmol) in aqueous sodium bicarbonate (61.0 mL, 30.5 mmol, 0.5 molar) was added 4-chlorophenyl isocyanate (1n) (1.952 mL, 15.25 mmol) and heated at 80°C for 5 hours. The reaction was cooled to room temperature and the resulting solid was filtered. The filtrate was washed with ethyl acetate, the pH was adjusted to 1 with concentrated HCl, and extracted with ethyl acetate (3×150 mL). The organic layers of the final extraction were combined, washed with brine, dried and concentrated in vacuo to give a colorless solid (2R, 4R)-1-(4-chlorophenylcarbamoyl)-4-hydroxypyrrolidine-2-carboxylic acid (1o) (1.92 g, 6.74 mmol, 88% yield); 1 H NMR (300 MHz, DMSO-d 6 )δ12.33(s,1H),8.41(s,1H),7.61-7.48(m,2H),7.32-7.22(m,2H),5.16(bs,1H),4.32(m,2H),3.65(dd,J=10.2,5.7Hz,1H),3.31(m,1H),2.32(m,1H),1.90(m,1H);MS(ES+)285.2(M+1),307.2(M+Na),(ES-)283.2(M-1);Optical rotation:[α] D =(+)48.89[0.27, MeOH].

[0279] Step 10: Preparation of (2R,4R)-N1-(4-chlorophenyl)-N2-(5-(((cyclopropylmethyl)amino)(phenyl)methyl)-2-fluorophenyl)-4-hydroxypyrrolidine-1,2-dicarboxamide (1p)

[0280] To a tetrahydrofuran solution (5 mL) of (2R,4R)-1-(4-chlorophenylcarbamoyl)-4-hydroxypyrrolidine-2-carboxylic acid (1o) (0.2 g, 0.703 mmol) and 5-((cyclopropylmethylamino)(phenyl)methyl)-2-fluoroaniline (1m) (0.19 g, 0.703 mmol) was added ethyl 2-ethoxy-1(2H)-quinolinecarboxylate (EEDQ, 0.174 g, 0.703 mmol), and stirred at room temperature overnight. The crude reaction mixture was concentrated in vacuo and the residue was purified by flash column chromatography (silica gel 24 g, eluted with CMA80 in chloroform, 0 to 100%) to give a colorless solid (2R,4R)-N1-(4-chlorophenyl)-N2-(5-((cyclopropylmethylamino)(phenyl)methyl)-2-fluorophenyl)-4-hydroxypyrrolidine-1,2-dicarboxamide (1p) (65 mg, 0.121 mmol, 17.23% yield); 1 H NMR (300 MHz, DMSO-d 6 )δ9.65-9.53 (m, 1H), 8.49 (s, 1H), 8.05 (d, J=7.5Hz, 1H), 7.57-7.52 (m, 2H), 7.41-7.35 (m, 2H), 7.27 (dt, J=7.6 , 3.2Hz, 4H), 7.20-7.12 (m, 3H), 5.29 (d, J=4.7Hz, 1H), 4.81 (s, 1H), 4.51 (dd, J=9.0, 4.6Hz, 1H), 4.34 (q, J=4.8 Hz, 1H), 3.69 (dd, J=10.2, 5.6Hz, 1H), 3.48 (dd, J=10.0, 3.9Hz, 1H), 2.38 (ddd, J=18.8, 9.2, 4.7Hz, 2H), 2.27 (d , J=6.6Hz, 2H), 1.96-1.85 (m, 1H), 0.98-0.85 (m, 1H), 0.36 (dt, J=8.4, 2.8Hz, 2H), 0.05 (dd, J=5.6, 4.0Hz, 2H); 19 F NMR (282 MHz, DMSO-d 6 )δ-128.72 (d, J=2.9 Hz); MS (ES-) 535.4, 536.3, 537.4 (M, M-1, M-2); HPLC purity 93.5%.

[0281] Solution 2

[0282]

[0283] Preparation of (2R, 4R)-N1-(4-chlorophenyl)-N2-(2-fluorophenyl)-4-hydroxypyrrolidine-1,2-dicarboxamide (2a)

[0284] To a solution of (2R, 4R)-1-(4-chlorophenylcarbamoyl)-4-hydroxypyrrolidine-2-carboxylic acid (1o) (0.2 g, 0.703 mmol) and 2-fluoroaniline (0.078 g, 0.703 mmol) in tetrahydrofuran (5 mL) was added 2-ethoxy-1(2H)-quinolinecarboxylic acid ethyl ester (0.174 g, 0.703 mmol), and stirred at room temperature overnight. The reaction mixture was concentrated in vacuo and the obtained residue was purified by flash column chromatography (silica gel 24 g, eluted with ethyl acetate hexane solution, 0 to 100%) to obtain a colorless solid (2R, 4R)-N1-(4-chlorophenyl)-N2-(2-fluorophenyl)-4-hydroxypyrrolidine-1,2-dicarboxamide (2a) (140 mg, 0.371 mmol, yield 52.7%); 1 H NMR (300 MHz, DMSO-d 6 )δ10.11 (s, 1H), 8.94 (s, 1H), 8.42 (m, 1H), 8.00 (m, 2H), 7.78-7.65 (m, 3H), 7.59 (m, 2H), 5.76 (d, J = 4.4Hz, 1H), 5.10-4.92(m, 1H), 4.81(m, 1H), 4.20-4.08(m, 1H), 3.98(m, 1H), 2.92-2.77(m, 1H), 2.47-2.24(m, 1H); 19 F NMR (282 MHz, DMSO-d 6 )δ-126.05; MS (ES+) 400.3 (M+Na), 777.4 (2M+Na), (ES-) 376.3 (M-1); HPLC purity 99.51%.

[0285] Solution 3

[0286]

[0287] Preparation of (2R, 4R)-N1-(4-chlorophenyl)-N2-(5-((+)-(cyclopropylmethylamino)(phenyl)methyl)-2-fluorophenyl)-4-hydroxypyrrolidine-1,2-dicarboxamide (3a)

[0288] To a mixture of (2R,4R)-1-(4-chlorophenylcarbamoyl)-4-hydroxypyrrolidine-2-carboxylic acid (1o) (0.205 g, 0.721 mmol) and (-)-5-((cyclopropylmethylamino)(phenyl)methyl)-2-fluoroaniline (1i) (0.195 g, 0.721 mmol) in tetrahydrofuran (5 mL) was added ethyl 2-ethoxy-1(2H)-quinolinecarboxylate (0.178 g, 0.721 mmol), and stirred at room temperature overnight. The crude reaction mixture was concentrated in vacuo, and the obtained residue was purified by flash column chromatography (silica gel 24 g, eluted with CMA 80 in chloroform to 0 to 100%) to give (2R,4R)-N1-(4-chlorophenyl)-N2-(5-((+)-(cyclopropylmethylamino)(phenyl)methyl)-2-fluorophenyl)-4-hydroxypyrrolidine-1,2-dicarboxamide (3a) (25 mg, 0.047 mmol, 6.45% yield) as a white solid; 1 H NMR (300 MHz, DMSO-d 6 )δ9.61 (s, 1H), 8.50 (s, 1H), 8.14-7.98 (m, 1H), 7.59-7.51 (m, 2H), 7.38 (m, 2H), 7.32-7.23 (m, 4H), 7.21-7.09 (m, 3H), 5.30 (d, J=4.8Hz, 1H), 4.80 (s, 1H), 4.51 (dd, J=9.0, 4.7Hz, 1H), 4.34 (q, J=4.8Hz, 1H), 3.69 (dd, J=10.0, 5.2Hz, 1H), 3.48 (dd, J=10.0, 4.1Hz, 1H), 2.39 (m, 2H), 2.27(d, J=6.7Hz, 2H), 1.90(m, 1H), 0.90(m, 1H), 0.43-0.30(m, 2H), 0.06-0.02(m, 2H); 19 F NMR (282MHz, DMSO-d6) δ-128.88; mass spectrum (ES+) 537.4, 539.5 (M, M+2), (ES-) 537.3, 535.4 (M, M-2); HPLC purity 96.99%; optical rotation: [α] D =(+)132[0.2, MeOH].

[0289] Solution 4

[0290]

[0291] Preparation of (2R, 4R)-N2-(5-((+)-1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-N1-(4-chlorophenyl)-4-hydroxypyrrolidine-1,2-dicarboxamide (4 g)

[0292] Step 1: Preparation of 3-(3-cyclopropylacryloyl)benzonitrile (4b)

[0293] To a stirred solution of 3-acetylbenzonitrile (4a) (50 g, 344 mmol) in methanol (800 mL) was added cyclopropanecarboxaldehyde (41 mL, 549 mmol) followed by potassium hydroxide (1 M aqueous solution, 67 mL, 67 mmol) at 0°C. The reaction mixture was allowed to reach room temperature and stirred for 14 hours. The reaction product was acidified to pH 6 with HCl (75 mL, 1 N) and concentrated in vacuo, keeping the bath temperature below 35°C. The residue was diluted with ethyl acetate (1200 mL) and washed with water (800 mL). The aqueous layer was extracted with ethyl acetate (800 mL), the organic layers were combined, washed with brine, dried, filtered and concentrated in vacuo to give the crude 3-(3-cyclopropylacryloyl)benzonitrile (4b) (72.42 gm) as a colorless liquid which was used directly in the next step; 1 H NMR (300 MHz, DMSO-d 6 )δ8.19 (dp, J=7.8, 1.6Hz, 1H), 8.11 (dddt, J=6.3, 3.7, 2.6, 1.4Hz, 1H), 7.80-7.65 (m, 2H), 7.32 (dd, J=15 .1, 7.6Hz, 1H), 6.60 (ddd, J=15.0, 11.3, 10.4Hz, 1H), 1.91-1.74 (m, 1H), 1.04 (m, 2H), 0.85-0.75 (m, 2H).

[0294] Step 2: Preparation of 3-(3-cyclopropylpropionyl)benzonitrile (4c)

[0295] To a stirred solution of 3-(3-cyclopropylacryloyl)benzonitrile (4b) (65.7 g, 333 mmol) in benzene (750 mL) was added tri-n-butyltin hydride (185 mL, 666 mmol) and heated to reflux for 14 hours. The reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel, eluted with ethyl acetate in hexane, 0 to 100%) to give 3-(3-cyclopropylpropanoyl)benzonitrile (4c) (23.3, 116.9 mmol, 34% yield) as a colorless oil; 1 H NMR (300 MHz, DMSO-d 6)δ8.41 (td, J=1.8, 0.6Hz, 1H), 8.24 (ddd, J=7.9, 1.8, 1.2Hz, 1H), 8.09 (dt, J=7.7, 1.4Hz, 1H), 7.73 (td, .J=7.8, 0.6Hz, 1H), 3.15 (t, J=7.2Hz, 2H), 1.52 (q, J=7.1Hz, 2H), 0.81-0.64 (m, 1H), 0.46-0.26 (m, 2H), 0.13-0.00 (m, 2H); MS (ES-) 198.2 (M-1).

[0296] Step 3: Preparation of (-)-N-(1-(3-cyanophenyl)-3-cyclopropylpropylene)-2-methylpropane-2-sulfinamide (4d) Using the procedure reported in Scheme 1, Step 3, compound (4d) was prepared from 3-(3-cyclopropylpropionyl)benzonitrile (4c) (22.8 g, 114 mmol) and (R)-2-methylpropane-2-sulfinamide (13.95 g, 114 mmol) to give (-)-N-(1-(3-cyanophenyl)-3-cyclopropylpropylene)-2-methylpropane-2-sulfinamide (4d) (21.8 g, 72.1 mmol, 63% yield) as a light yellow syrup;

[0297] 1 H NMR (300 MHz, DMSO-d 6 )δ8.29(s,1H),8.21-8.12(m,1H),8.01(d,J=7.7Hz,1H),7.70(t,J=7.9Hz,1H),3.54-3.13(m,2H),1.44(q,J=7.5Hz,2H),1.23(s,9H),0.82-0.65(m,1H),0.44-0.29(m,2H),0.11-0.00(m,2H);MS(ES+)303.3(M+1);(ES-)301.3(M-1);;Optical rotation:[α] D (-)66.92 (0.26, MeOH).

[0298] Step 4: Preparation of (R)-N-((-)-1-(3-amino-4-fluorophenyl)-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-methylpropane-2-sulfenamide (4e)

[0299] To a stirred solution of (-)-N-(1-(3-cyanophenyl)-3-cyclopropylpropylene)-2-methylpropane-2-sulfenamide (4d) (17.72 g, 58.6 mmol) in toluene (350 mL) at -20 °C was added a freshly prepared solution of (3-(bis(trimethylsilyl)amino)-4-fluorophenyl)magnesium bromide (1c) (160 mL, 120 mmol, 0.75 N) dropwise over 30 min. The reaction mixture was stirred at -20 °C for 1 h and quenched with 1 N KHSO 4 The aqueous solution (275mL) was quenched. The reaction mixture was stirred at room temperature for 1 hour, diluted with water (100mL), alkalized to pH 8 with 2N NaOH, and extracted with ethyl acetate (600mL, 300mL). The organic layers were combined, washed with water (2×300mL) and brine (300mL), dried and concentrated to dryness in vacuo. The crude residue was ground with ethyl acetate, and the solid obtained was collected by filtration. The white solid (R)-N-((-)-1-(3-amino-4-fluorophenyl)-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-methylpropane-2-sulfinamide (4e) (10.4g, 42.91% yield) was obtained. The filtrate was concentrated in vacuo and purified by flash column chromatography (silica gel, eluted with ethyl acetate in hexanes, 0 to 50%) to give (R)-N-((-)-1-(3-amino-4-fluorophenyl)-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-methylpropane-2-sulfenamide (4e) (4.11 g, 16.95% yield) as a white solid; 1 H NMR (300 MHz, DMSO-d 6 )δ7.78 (t, J=1.6Hz, 1H), 7.70 (dt, J=7.5, 1.4Hz, 1H), 7.62 (dt, J=8.1, 1.5Hz, 1H), 7.50 (t, J=7.8Hz, 1H), 6.90 (dd, J=11.3, 8.5Hz, 1H), 6.72 (dd, J=8.7, 2.4Hz, 1H), 6.47 (ddd, J=8.5, 4.3, 2.4Hz, 1H), 5.27 (s, 1H), 5.10 (s, 2H), 2.66-2.40 (m, 2H), 1.20-1.03 (m, 1H) , 1.12 (s, 9H), 1.01-0.81 (m, 1H), 0.72-0.57 (m, 1H), 0.36 (m, 2H), 0.03-0.15 (m, 2H); 19F NMR (282MHz, DMSO-d 6 )δ-137.34; MS(ES+): 436.4(M+Na); IR(KBr)2235cm -1 ; Optical rotation: [α] D(-) 107.95 (0.78, MeOH); Analytical calculation value C 23 H 28 FN 3 OS: C, 66.80; H, 6.82; N, 10.16; Found: C, 67.06; H, 6.82; N, 10.28.

[0300] Step 5: Preparation of (2R,4R)-N1-(4-chlorophenyl)-N2-(5-((-)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)-4-hydroxypyrrolidine-1,2-dicarboxamide (4f)

[0301] To a mixture of (2R,4R)-1-(4-chlorophenylcarbamoyl)-4-hydroxypyrrolidine-2-carboxylic acid (1o) (0.2 g, 0.703 mmol) and (R)-N-((-)-1-(3-amino-4-fluorophenyl)-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-methylpropane-2-sulfinamide (4e) (0.291 g, 0.703 mmol) in tetrahydrofuran (5 mL) was added ethyl 2-ethoxy-1(2H)-quinolinecarboxylate (0.174 g, 0.703 mmol) and heated under reflux for 16 hours. The reaction mixture was concentrated in vacuo, and the obtained residue was purified by flash column chromatography (silica gel 24 g, eluted with CMA 80 in chloroform to 0 to 100%) to give a white solid (2R,4R)-N1-(4-chlorophenyl)-N2-(5-((-)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)-4-hydroxypyrrolidine-1,2-dicarboxamide (4f) (175 mg, 0.257 mmol, 36.6% yield); 1 H NMR (300 MHz, DMSO-d 6)δ9.66(s, 1H), 8.52(s, 1H), 8.07(m, 1H), 7.79(m, 1H), 7.71(m, 1H), 7.61-7.47(m, 4H), 7.31-7.24(m , 2H), 7.19 (m, 1H), 7.08 (m, 1H), 5.50 (s, 1H), 5.33 (d, J=4.7Hz, 1H), 4.51 (dd, J=9.0, 4.7Hz, 1H), 4.3 4 (d, J=5.4Hz, 1H), 3.68 (dd, J=10.0, 5.2Hz, 1H), 3.49 (dd, J=10.0, 3.9Hz, 1H), 2.78-2.53 (m, 2H), 2. 38(s,1H),1.90(m,1H),1.13(s,10H),0.90(m,1H),0.63(m,1H),0.34(m,2H),-0.03--0.19(m,2H);9F NMR (282MHz, DMSO-d 6 )δ-128.58; MS(ES+)680.5(M+1), 702.5, 704.5(M+Cl), (ES-)714.4, 716.5(M+Cl); IR(KBr)2231cm-1; Optical rotation: [α] D =(-)19.4[0.175, MeOH].

[0302] Step 6: Preparation of (2R,4R)-N2-(5-((+)-1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-N1-(4-chlorophenyl)-4-hydroxypyrrolidine-1,2-dicarboxamide (4 g)

[0303] To a stirred solution of (2R,4R)-N1-(4-chlorophenyl)-N2-(5-((-)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)-4-hydroxypyrrolidine-1,2-dicarboxamide (4f) (160 mg, 0.235 mmol) in ethanol (10 mL) was added concentrated HCl (0.098 mL, 1.176 mmol) and heated at reflux for 1 hour. The reaction product was concentrated in vacuo, and the obtained residue was purified by flash column chromatography (silica gel 12 g, eluted with 0 to 100% CMA80 in chloroform) to give a colorless solid (2R, 4R)-N2-(5-((+)-1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-N1-(4-chlorophenyl)-4-hydroxypyrrolidine-1,2-dicarboxamide (4 g) (42 mg, 0.073 mmol, 31.0% yield); 1 H NMR (300 MHz, DMSO-d6 )δ9.61 (d, J=1.6Hz, 1H), 8.50 (s, 1H), 8.08-7.99 (m, 1H), 7.86 (m, 1H), 7.63 (m, 2H), 7.59-7.51 (m, 2H), 7.46 (m, 1H), 7.32-7.23 (m, 2H), 7.12 (m, 2H), 5.30 (d, J=4.8Hz, 1H), 4.50 (dd, J=9.1, 4.7Hz, 1 H), 4.34 (q, J=4.8Hz, 1H), 3.68 (dd, J=10.1, 5.3Hz, 1H), 3.48 (dd, J=10.1, 4.0Hz, 1H), 2.46-2.28 ( m, 3H), 2.27-2.16 (m, 2H), 1.90 (m, 1H), 1.02 (m, 2H), 0.70-0.56 (m, 1H), 0.34 (m, 2H), -0.08 (m, 2H); 19 F NMR (282 MHz, DMSO-d 6 )δ-129.29; MS (ES-) 575.3 (M-1); HPLC purity 94.3%; analytical calculation value C 31 H 31 CIF 5 O 3 .0.5H 2 0: C, 63.64; H, 5.51; N, 11.97; Found: C, 63.68; H, 5.75; N, 11.77; Optical rotation: [α] D =(+)93.53[0.34, MeOH].

[0304] Solution 5

[0305]

[0306] Preparation of (2S, 4R)-N2-(5-((-)-1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-N1-(4-chlorophenyl)-4-hydroxypyrrolidine-1,2-dicarboxamide (5e)

[0307] Step 1: Preparation of benzyl (2S,4R)-1-(4-chlorophenylcarbamoyl)-4-hydroxypyrrolidine-2-carboxylate (5b)

[0308] Diisopropylethylamine (1.918 mL, 10.98 mmol) was added dropwise to a stirred suspension of (2S, 4R)-4-hydroxypyrrolidine-2-carboxylic acid benzyl 4-methylbenzenesulfonate (5a) (4.32 g, 10.98 mmol) in anhydrous dichloromethane (100 mL) at room temperature over 10 minutes, followed by the addition of 1-chloro-4-isocyanobenzene (1 n) (1.686 g, 10.98 mmol). The reaction mixture was stirred at room temperature for 2 hours and poured into water (50 mL). The separated solid was collected by filtration to give (2S, 4R)-1-(4-chlorophenylcarbamoyl)-4-hydroxypyrrolidine-2-carboxylic acid benzyl ester (5b) as a white solid. The filtrate was extracted with dichloromethane (3×50 mL), the organic layers were combined, washed with brine (50 mL), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was combined with the filtered solid to give white solid benzyl (2S,4R)-1-(4-chlorophenylcarbamoyl)-4-hydroxypyrrolidine-2-carboxylate (5b) (4.7 g, 12.54 mmol); 1 H NMR (300 MHz, DMSO-d 6 )δ8.54(s, 1H), 7.61-7.45(m, 2H), 7.37-7.31(m, 5H), 7.31-7.25(m, 2H), 5.21(d, J =4.0Hz, 1H), 5.19-5.06 (m, 2H), 4.47 (t, J = 7.8Hz, 1H), 4.37 (m, 1H), 3.63 (dd, J = 10. 5, 4.6 Hz, 1H), 3.49-3.39 (m, 1H), 2.15 (m, 1H), 1.94 (m, 1H); MS (ES+) 375.4 (M+1), 397.4 (M+Na), 749.6 (2M+1), 771.6 (2M+Na), (ES-) 373.3 (M-1), 419.3 (M+Cl); Optical rotation: [α] D =(-)70.08[0.625, MeOH].

[0309] Step 2: Preparation of (4R)-1-(4-chlorophenylcarbamoyl)-4-hydroxypyrrolidine-2-carboxylic acid (5c)

[0310] To a stirred solution of (2S,4R)-1-(4-chlorophenylcarbamoyl)-4-hydroxypyrrolidine-2-carboxylic acid benzyl ester (5b) (3 g, 8.00 mmol) in methanol (30 mL) was added sodium hydroxide (1.601 g, 40.0 mmol) at room temperature and stirred for 2 hours. The reaction was concentrated in vacuo to remove methanol. The residue was dissolved in water (10 mL) and washed with ethyl acetate (2×20 mL). The aqueous layer was acidified to pH 2 with concentrated HCl and extracted with ethyl acetate (3×75 mL). The organic layers were combined, washed with water (2×50 mL), brine (50 mL), dried, filtered and concentrated in vacuo to give (4R)-1-(4-chlorophenylcarbamoyl)-4-hydroxypyrrolidine-2-carboxylic acid (5c) as a white solid; 1 H NMR (300 MHz, DMSO-d 6 )δ12.21(s, 1H), 8.45(2s, 1H), 7.61-7.42(m, 2H), 7.37-7.21(m, 2H), 5.17(d, J=3.9Hz, 1H), 4.32(m, 2H), 3.63(m , 1H), 3.34-3.21(m, 1H), 2.31(m, 1H), 2.22-2.00(m, 1H); MS(ES+)285.2(M+1), 307.1(M+Na), (ES-)283.1(M-1).

[0311] Step 3: Preparation of (2S,4R)-N1-(4-chlorophenyl)-N2-(5-((-)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)-4-hydroxypyrrolidine-1,2-dicarboxamide (5d) and (2R,4R)-N1-(4-chlorophenyl)-N2-(5-((-)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)-4-hydroxypyrrolidine-1,2-dicarboxamide (4f)

[0312] As reported in Scheme 4, Step 5, (4R)-1-(4-chlorophenylcarbamoyl)-4-hydroxypyrrolidine-2-carboxylic acid (5c) (550 mg, 1.932 mmol) was reacted with (R)-N-((-)-1-(3-amino-4-fluorophenyl)-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-methylpropane-2-sulfenamide (4e) (799 mg, 1.932 mmol) in tetrahydrofuran (5 mL) using ethyl 2-ethoxy-1(2H)-quinolinecarboxylate (478 mg, 1.932 mmol) and purified by flash column chromatography (silica gel 24 g, eluted with CMA 80 in chloroform from 0 to 100%) to give

[0313] 1. White solid (2R, 4R)-N1-(4-chlorophenyl)-N2-(5-((-)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)-4-hydroxypyrrolidine-1,2-dicarboxamide (4f) (267 mg, 0.393 mmol, yield 20.32%), then obtained

[0314] 2. Light orange solid (2S,4R)-N1-(4-chlorophenyl)-N2-(5-((-)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)-4-hydroxypyrrolidine-1,2-dicarboxamide (5d) (203 mg, 0.298 mmol, yield 15.45%); 1 H NMR (300 MHz, DMSO-d 6 )δ9.84 (s, 1H), 8.48 (s, 1H), 7.94 (d, J = 7.4Hz, 1H), 7.77 (d, J = 1.9Hz, 1H), 7.70 (dt, J = 7.3, 1.5Hz, 1H ), 7.52 (m, 4H), 7.31-7.23 (m, 2H), 7.19 (m, 1H), 7.09 (m, 1H), 5.49 (s, 1H), 5.18 (d, J=3.7Hz, 1H), 4.66 (t, J=7.5Hz, 1H), 4.39 (s, 1H), 3.67 (m, 1H), 3.47-3.37 (m, 1H), 2.68-2.54 (m, 2H), 2.17-2.05 (m, 1H) , 2.06-1.87(m, 1H), 1.11(s, 10H), 0.89(m, 1H), 0.72-0.49(m, 1H), 0.33(m, 2H), -0.02--0.20(m, 2H); 19 F NMR (282 MHz, DMSO-d 6 )δ-127.00; MS (ES-) 678.4, 679.5 (M-1); optical rotation [α] D =(-)190[0.08, MeOH].

[0315] Step 4: Preparation of (2S,4R)-N2-(5-((-)-1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-N1-(4-chlorophenyl)-4-hydroxypyrrolidine-1,2-dicarboxamide (5e)

[0316] A solution of (2S,4R)-N1-(4-chlorophenyl)-N2-(5-((-)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)-4-hydroxypyrrolidine-1,2-dicarboxamide (5d) (183 mg, 0.269 mmol) in ethanol (5 mL) was reacted with concentrated HCl (0.224 mL, 2.69 mmol) as reported in Scheme 4, Step 6, and purified by flash column chromatography (silica gel 12 g, 0 to 30% CMA 80% chloroform solution) to obtain a colorless solid (2S, 4R)-N2-(5-((-)-1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-N1-(4-chlorophenyl)-4-hydroxypyrrolidine-1,2-dicarboxamide (5e) (100 mg, 0.174 mmol, yield 64.5%); 1 H NMR (300 MHz, DMSO-d 6 )δ9.77 (s, 1H), 8.47 (s, 1H), 7.94 (d, J = 7.5Hz, 1H), 7.86 (t, J = 1.7Hz, 1H), 7.66-7.58 (m, 2H), 7.57- 7.51 (m, 2H), 7.45 (t, J=7.8Hz, 1H), 7.31-7.24 (m, 2H), 7.15-7.08 (m, 2H), 5.17 (d, J=3.8Hz, 1H), 4.6 5(t, J=7.5Hz, 1H), 4.40 (s, 1H), 3.67 (dd, J=10.3, 4.6Hz, 1H), 3.43 (m, 1H), 2.30 (m, 2H), 2.25-2.07 (m, 3H), 2.03-1.89 (m, 1H), 1.09-0.93 (m, 2H), 0.62 (m, 1H), 0.38-0.28 (m, 2H), -0.04--0.14 (m, 2H); 19 F NMR (282 MHz, DMSO-d 6 )δ-127.76; MS (ES+) 598.4, 600).4 (M+Na); HPLC: 5.12 minutes (93.86%); optical rotation [α] D =(-)96.05[0.86, MeOH].

[0317] Solution 6

[0318]

[0319] Preparation of (2R,4R)-N1-(4-chlorophenyl)-N2-(5-((-)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)-4-methoxy-N1-methylpyrrolidine-1,2-dicarboxamide (6c) and (2S,4R)-N1-(4-chlorophenyl)-N2-(5-(1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)-4-methoxy-N1-methylpyrrolidine-1,2-dicarboxamide (6d)

[0320] Step 1: Preparation of methyl (4R)-1-((4-chlorophenyl)(methyl)carbamoyl)-4-methoxypyrrolidine-2-carboxylate (6a)

[0321] To a stirred solution of (2R,4R)-1-(4-chlorophenylcarbamoyl)-4-hydroxypyrrolidine-2-carboxylic acid (1o) (0.837 g, 2.94 mmol) in N,N-dimethylformamide (20 mL) was added sodium hydride (60% dispersion in mineral oil, 0.941 g, 23.52 mmol) at 0°C and stirred at 0°C for 1 hour. Methyl iodide (1.471 mL, 23.52 mmol) was added to the reaction mixture at 0°C and stirred for 2 hours. The mixture was purified by adding 1N KHSO 4 The reaction was quenched with aqueous solution (15 mL) and water (100 mL) and extracted with ethyl acetate (3×100 mL). The organic layers were combined, washed with water (2×50 mL) and brine (50 mL), dried, filtered and concentrated in vacuo. The crude residue was purified by flash column chromatography [silica gel 40 g, eluted with (9:1) ethyl acetate / methanol in hexane to 0 to 40%] to give ((4R)-1-((4-chlorophenyl)(methyl)carbamoyl)-4-methoxypyrrolidine-2-carboxylic acid methyl ester (6a) (250 mg, 0.765 mmol, 26.0% yield), which was used for the next step; 1 H NMR (300 MHz, DMSO-d 6 )δ7.49-7.40(m, 2H), 7.37-7.30(m, 2H), 4.54-4.30(m, 1H), 3.90-3.74(m, 1H), 3.67(d, J=4.7Hz, 3H), 3. 29-3.18 (m, 1H), 3.11 (2s, 3H), 3.06 (2s, 3H), 2.70-2.21 (m, 2H), 1.80-1.60 (m, 1H); MS (ES+) 349.3 (M+1).

[0322] Step 2: Preparation of ((4R)-1-((4-chlorophenyl)(methyl)carbamoyl)-4-methoxypyrrolidine-2-carboxylic acid (6b)

[0323] To a stirred solution of (4R)-1-((4-chlorophenyl)(methyl)carbamoyl)-4-methoxypyrrolidine-2-carboxylic acid methyl ester (6a) (250 mg, 0.765 mmol) in methanol (10 mL) was added sodium hydroxide (0.765 mL, 3.06 mmol, 4N aqueous solution) at room temperature, stirred overnight at room temperature and concentrated in vacuo to remove methanol. The residue was dissolved in water (30 mL) and washed with 1N KHSO 4 Acidify and extract with ethyl acetate (3×50 mL). Combine the organic layers and wash with water (20 mL) and brine (20 mL), dry, filter and concentrate in vacuo to give ((4R)-1-((4-chlorophenyl)(methyl)carbamoyl)-4-methoxypyrrolidine-2-carboxylic acid (6b) (230 mg, 0.735 mmol, 96% yield) as a white solid; 1 H NMR (300 MHz, DMSO-d 6 )δ12.64(s, 1H), 7.47-7.31(m, 4H), 4.40-4.24(m, 1H), 3.90-3.73(m, 1H), 3.33-3.16(m, 1H), 3.1 1 (2s, 3H), 3.08 (2s, 3H), 2.50-2.19 (m, 2H), 1.80-1.57 (m, 1H); MS (ES+) 313.3, (ES-) 311.2 (M-1).

[0324] Step 3: Preparation of (2R,4R)-N1-(4-chlorophenyl)-N2-(5-((-)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)-4-methoxy-N1-methylpyrrolidine-1,2-dicarboxamide (6c) and (2S,4R)-N1-(4-chlorophenyl)-N2-(5-(1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)-4-methoxy-N1-methylpyrrolidine-1,2-dicarboxamide (6d)

[0325] To a mixture of ((4R)-1-((4-chlorophenyl)(methyl)carbamoyl)-4-methoxypyrrolidine-2-carboxylic acid (6b) (230 mg, 0.735 mmol) and (R)-N-((-)-1-(3-amino-4-fluorophenyl)-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-methylpropane-2-sulfenamide (4e) (304 mg, 0.735 mmol) in tetrahydrofuran (5 mL) was added ethyl 2-ethoxy-1(2H)-quinolinecarboxylate (EEDQ, 182 mg, 0.735 mmol) and heated under reflux for 16 hours. The reaction mixture was concentrated in vacuo and the resulting residue was purified by flash column chromatography (silica gel 40 g, eluted with CMA 80 in chloroform, 0 to 100%) to obtain:

[0326] 1. White solid (2R, 4R)-N1-(4-chlorophenyl)-N2-(5-((-)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)-4-methoxy-N1-methylpyrrolidine-1,2-dicarboxamide (6c) (279 mg, 0.394 mmol, yield 53.6%); 1 H NMR (300 MHz, DMSO-d 6 )δ9.89 (s, 1H), 8.02 (d, J = 7.1Hz, 1H), 7.80 (d, J = 1.8Hz, 1H), 7.73 (dt, J = 7.4, 1.3Hz, 1H), 7.66-7.58 (m, 1H), 7.54 (d, J =7.7Hz, 1H), 7.40 (s, 4H), 7.21 (dd, J = 10.5, 8.8Hz, 1H), 7.17-7.05 (m, 1H), 5.55 (s, 1H), 4.75-4.56 (m, 1H), 3.80 (s, 1H ), 3.16 (s, 3H), 3.09 (s, 3H), 3.03 (d, J = 11.2Hz, 1H), 2.78-2.67 (m, 2H), 2.66-2.54 (m, 1H), 2.47-2.23 (m, 1H), 1.82-1. 61 (m, 1H), 1.15 (d, J=1.4Hz, 9H), 1.14-1.00 (m, 1H), 1.04-0.76 (m, 1H), 0.66 (m, 1H), 0.36 (m, 2H), 0.08--0.11 (m, 2H); 19 F NMR (282 MHz, DMSO-d 6 )δ-126.84; MS (ES+) 708.6 (M+1), 730.6, 732.6 (M+Cl), (ES-) 706.6, 708.6 (M-1).

[0327] 2. White solid (2S, 4R)-N1-(4-chlorophenyl)-N2-(5-(1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)-4-methoxy-N1-methylpyrrolidine-1,2-dicarboxamide (6d) (200 mg, 0.282 mmol, yield 38.4%): 1 H NMR (300MHz, DMSO-d6) δ9.73 (s, 1H), 7.95 (d, J=7.3Hz, 1H), 7.81 (t, J=1.7Hz, 1H), 7.72 (dt, J=7.4, 1.3Hz, 1H), 7.62 (d, J=8.3Hz, 1H), 7.54 (d, J=7.7Hz, 1H), 7.40 (s, 4H), 7.22 (dd, J=10.4, 8.7Hz, 1H), 7.14 (m, 1H), 5.56 (s, 1H), 4.58 ( 1 .74-1.50(m, 1H), 1.28-1.16(m, 1H), 1.15(2s, 9H), 0.99-0.78(m, 1H), 0.66(m, 1H), 0.37(m, 2H), 0.10--0.11(m, 2H); 19 F NMR (282MHz, DMSO-d6) δ-127.21; MS (ES+) 708.6 (M+1), 730.6, 732.6 (M+Cl), (ES-) 706.6, 708.6 (M-1).

[0328] Preparation of (2R, 4R)-N2-(5-((-)-1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-N1-(4-chlorophenyl)-4-methoxy-N1-methylpyrrolidine-1,2-dicarboxamide (6e)

[0329] Compound 4g was prepared by reacting a solution of (2R,4R)-N1-(4-chlorophenyl)-N2-(5-((-)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)-4-methoxy-N1-methylpyrrolidine-1,2-dicarboxamide (6c) (170 mg, 0.240 mmol) in ethanol (5 mL) with concentrated HCl (0.200 mL, 2.400 mmol). The product was purified by flash column chromatography (silica gel, 12 g, 0 to 30% CMA). 80% chloroform solution) to obtain a white solid (2R, 4R)-N2-(5-((-)-1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-N1-(4-chlorophenyl)-4-methoxy-N1-methylpyrrolidine-1,2-dicarboxamide (6e) (115 mg, 0.190 mmol, yield 79%); 1 H NMR (300 MHz, DMSO-d 6 )δ9.65 (s, 1H), 7.94 (d, J=7.7Hz, 1H), 7.89 (t, J=1.7Hz, 1H), 7.66 (ddt, J=10.3, 7.7, 1.4Hz, 2H), 7 .49 (d, J=7.9Hz, 1H), 7.46-7.34 (m, 4H), 7.19-7.12 (m, 2H), 4.56 (t, J=8.3Hz, 1H), 3.93-3.77 (m, 1H ), 3.10(s, 3H), 3.08(s, 3H), 2.61-2.39(m, 2H), 2.36(s, 2H), 2.31-2.14(m, 2H), 1.72-1.52(m, 1H) , 1.13-0.97(m, 2H), 0.77-0.57(m, 1H), 0.42-0.27(m, 2H), 3.42-3.19(m, 1H), -0.00--0.07(m, 2H); 19 F NMR (282 MHz, DMSO-d 6 )δ-128.01; MS (ES+) 626.4, 628.4 (M+Na); HPLC purity 99.04%; optical rotation [α] D =(-)142.49[1.005, MeOH].

[0330] Preparation of (2S,4R)-N2-(5-((+)-1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-N1-(4-chlorophenyl)-4-methoxy-N1-methylpyrrolidine-1,2-dicarboxamide (6f)

[0331] A solution of (2S,4R)-N1-(4-chlorophenyl)-N2-(5-(1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)-4-methoxy-N1-methylpyrrolidine-1,2-dicarboxamide (6d) (238 mg, 0.336 mmol) in ethanol (5 mL) was reacted as reported in Scheme 4, Step 6, with concentrated HCl (0.280 mL, 3.36 mmol) and purified by flash column chromatography (silica gel, 12 g, 0 to 30% CMA 80% chloroform solution) to obtain a white solid (2S, 4R)-N2-(5-((+)-1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-N1-(4-chlorophenyl)-4-methoxy-N1-methylpyrrolidine-1,2-dicarboxamide (6f) (106 mg, 0.175 mmol, yield 52.2%); 1 HNMR (300 MHz, DMSO-d 6 )δ9.81(s, 1H), 7.98-7.91(m, 1H), 7.89(t, J=1.7Hz, 1H), 7.70-7.62(m, 2H), 7.48(t, J=7.8Hz, 1H), 7.40 (d, J=1.5Hz, 4H), 7.18-7.10 (m, 2H), 4.63 (dd, J=10.3, 7.0Hz, 1H) , 3.80 (t, J=3.5Hz, 1H), 3.15 (s, 3H), 3.09 (s, 3H), 3.02 (m, 1H), 2.73 (m, 1H), 2.35 (s, 3H), 2.24(m, 2H), 1.70(m, 1H), 1.05(m, 2H), 0.66(m, 1H), 0.36(m, 2H), -0.03(s, 2H); 19 F NMR (282 MHz, DMSO-d 6 )δ-127.42; MS (ES+) 626.4, 627.5 (M+Na), (ES-) 602.5, 603.3 (M-1); HPLC purity 91.30%) Optical rotation [α] D =(+)189.77[0.86, MeOH.

[0332] Solution 7

[0333]

[0334] Preparation of (R)-N2-(5-((+)-1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-N1-(4-chlorophenyl)pyrrolidine-1,2-dicarboxamide (7c)

[0335] Step 1: Preparation of (R)-1-(4-chlorophenylcarbamoyl)pyrrolidine-2-carboxylic acid (7a)

[0336] Using the reaction and workup conditions reported in step 9 of scheme 1, D-proline (1.0 g, 8.69 mmol) in aqueous sodium bicarbonate (69.5 mL, 34.7 mmol, 0.5 M) was reacted with 4-chlorophenylisocyanate (1n) (2.223 mL, 17.37 mmol) to give (R)-1-(4-chlorophenylcarbamoyl)pyrrolidine-2-carboxylic acid (7a) (1.6 g, 5.95 mmol, 68.6% yield) as a white solid; 1 H NMR (300 MHz, DMSO-d 6 )δ12.45(s,1H),8.42(s,1H),7.66-7.41(m,2H),7.41-7.09(m,2H),4.44-4.16(m,1H),3.67-3.38(m,2H),2.28-2.05(m,1H),1.92(m,3H);MS(ES+)269.1(M+1),291.2,293.2(M+Na),(ES-)267.2,269.1(M-1);Optical rotation[α] D =(+)59.33[0.3, MeOH].

[0337] Step 2: Preparation of (R)-N1-(4-chlorophenyl)-N2-(5-((+)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)pyrrolidine-1,2-dicarboxamide (7b)

[0338] Using the reaction and workup conditions reported in Scheme 1, Step 10, a solution of (R)-1-(4-chlorophenylcarbamoyl)pyrrolidine-2-carboxylic acid (7a) (0.5 g, 1.861 mmol) and (R)-N-((-)-1-(3-amino-4-fluorophenyl)-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-methylpropane-2-sulfenamide (4e) (0.770 g, 1.861 mmol) in tetrahydrofuran (25 mL) was reacted with ethyl 2-ethoxy-1(2H)-quinolinecarboxylate (0.460 g, 1.861 mmol) and purified by flash column chromatography (silica gel 25 g, purified by CMA 80% chloroform solution, 0 to 100%) was purified to give a colorless solid (R)-N1-(4-chlorophenyl)-N2-(5-((+)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)pyrrolidine-1,2-dicarboxamide (7b) (1.08 g, 1.626 mmol, 87% yield); 1 H NMR (300 MHz, DMSO-d 6 )δ9.84 (s, 1H), 8.45 (s, 1H), 7.92 (d, J = 7.3Hz, 1H), 7.78 (d, J = 1.8Hz, 1H), 7.71 (dt, J = 7.3, 1.4Hz, 1H ), 7.65-7.44(m, 4H), 7.32-7.24(m, 2H), 7.19(dd, J=10.4, 8.7Hz, 1H), 7.16-7.03(m, 1H), 5.53(s, 1H ), 4.68-4.45(m, 1H), 3.71-3.55(m, 2H), 3.56-3.42(m, 1H), 2.77-2.55(m, 1H), 2.22-2.04(m, 1H), 1. 95(m, 4H), 1.12(s, 9H), 1.00-0.75(m, 1H), 0.74-0.50(m, 1H), 0.41-0.26(m, 2H), 0.10--0.25(m, 2H); 19 F NMR (282 MHz, DMSO-d 6 )δ-127.07; MS (ES+) 686.5, 688.5 (M+Na); optical rotation [α] D =(+)142.65[0.415, MeOH].

[0339] Step 3: (R)-N2-(5-((+)-1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-N1-(4-chlorophenyl)pyrrolidine-1,2-dicarboxamide (7c)

[0340] A solution of (R)-N1-(4-chlorophenyl)-N2-(5-((+)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)pyrrolidine-1,2-dicarboxamide (7b) (0.9 g, 1.355 mmol) in ethanol (20 mL) was reacted with concentrated HCl (1.129 mL, 13.55 mmol) as reported in Scheme 4, Step 6. The resulting mixture was purified by flash column chromatography (silica gel 25 g, purified by CMA 80% chloroform solution, 0 to 30%) was purified to give a white solid (R)-N2-(5-((+)-1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-N1-(4-chlorophenyl)pyrrolidine-1,2-dicarboxamide (7c) (200 mg, 0.357 mmol, yield 26.4%); 1 H NMR (300 MHz, DMSO-d 6 )δ9.76 (s, 1H), 8.43 (s, 1H), 7.94 (d, J = 7.7Hz, 1H), 7.86 (t, J = 1.6Hz, 1H), 7.63 (ddt, J = 7.8 , 6.1, 1.3Hz, 2H), 7.59-7.51 (m, 2H), 7.46 (t, J=7.8Hz, 1H), 7.33-7.23 (m, 2H), 7.19-7.05 ( m, 2H), 4.64-4.52 (m, 1H), 3.61 (m, 1H), 3.49 (m, 1H), 2.31 (m, 2H), 2.22 (m, 2H), 2.14 (m, 1H) , 1.96 (m, 3H), 1.04 (m, 2H), 0.63 (m, 1H), 0.33 (m, 2H), -0.07 (m, 2H); 19FNMR (282MHz, DMSO-d 6 )δ-127.97; MS (ES+) 582.4 (M+Na), (ES-) 558.5 (M-1), 594.3, 596.3 (M+Cl); IR (KBr) 3385, 2229, 1657, 1527, 1494, 1406cm -1 ; Optical rotation [α] D =(+)23.57[0.28, MeOH].

[0341] Solution 8

[0342]

[0343] Preparation of (S)-N2-(5-((-)-1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-N1-(4-chlorophenyl)pyrrolidine-1,2-dicarboxamide (8c)

[0344] Step 1: Preparation of (S)-1-(4-chlorophenylcarbamoyl)pyrrolidine-2-carboxylic acid (8a)

[0345] Using the reaction and workup conditions reported in step 9 of scheme 1, a solution of L-proline (1.0 g, 8.69 mmol) in sodium bicarbonate in water was reacted with 4-chlorophenylisocyanate (1n) (2.223 mL, 17.37 mmol) to give (S)-1-(4-chlorophenylcarbamoyl)pyrrolidine-2-carboxylic acid (8a) (1.643 g, 6.11 mmol, 70.4% yield) as a white solid; 1 H NMR (300 MHz, DMSO-d 6 )δ12.45(s,1H),8.42(s,1H),7.60-7.45(m,2H),7.34-7.20(m,2H),4.39-4.19(m,1H),3.63-3.39(m,1H),2.17(m,1H),2.02-1.80(m,4H);MS(ES+)269.3(M+1),291.3,293.3(M+Na);(ES-)267.2(M-1);Optical rotation[α] D =(-)51.85[0.27, MeOH].

[0346] Step 2: Preparation of (S)-N1-(4-chlorophenyl)-N2-(5-((-)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)pyrrolidine-1,2-dicarboxamide (8b)

[0347] Using the reaction and workup conditions reported in Scheme 1, Step 10, a solution of (S)-1-(4-chlorophenylcarbamoyl)pyrrolidine-2-carboxylic acid (8a) (0.5 g, 1.861 mmol) and (R)-N-((-)-1-(3-amino-4-fluorophenyl)-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-methylpropane-2-sulfenamide (4e) (0.770 g, 1.861 mmol) in tetrahydrofuran (25 mL) was reacted with ethyl 2-ethoxy-1(2H)-quinolinecarboxylate (0.46 g, 1.861 mmol) and purified by flash column chromatography (silica gel 25 g, purified by CMA 80 chloroform solution, 0 to 100%) was purified to give a colorless solid (S)-N1-(4-chlorophenyl)-N2-(5-((-)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)pyrrolidine-1,2-dicarboxamide (8b) (1.002 g, 1.509 mmol, 81% yield);1 H NMR (300 MHz, DMSO-d 6 )δ9.83 (s, 1H), 8.45 (s, 1H), 8.02-7.91 (m, 1H), 7.78 (d, J = 1.8Hz, 1H), 7.71 (dt, J = 7.3, 1.5Hz, 1H ), 7.61-7.45(m, 4H), 7.32-7.25(m, 2H), 7.20(dd, J=10.4, 8.7Hz, 1H), 7.15-7.04(m, 1H), 5.51(s , 1H), 4.72-4.49(m, 1H), 3.62(m, 1H), 3.58-3.42(m, 1H), 2.62(m, 1H), 2.14(m, 1H), 2.06-1.85(m , 4H), 1.12 (s, 10H), 0.97-0.78 (m, 1H), 0.70-0.54 (m, 1H), 0.45-0.26 (m, 2H), 0.02--0.17 (m, 2H); 19 F NMR (282 MHz, DMSO-d 6 )δ-127.28; MS (ES+) 686.5, 688.5 (M+Na); optical rotation [α] D =(-)208.15[0.27, MeOH].

[0348] Step 3: (S)-N2-(5-((-)-1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-N1-(4-chlorophenyl)pyrrolidine-1,2-dicarboxamide (8c)

[0349] (S)-N1-(4-chlorophenyl)-N2-(5-((-)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)pyrrolidine-1,2-dicarboxamide (8b) (0.9 g, 1.355 mmol) in ethanol (20 mL) was reacted with concentrated HCl (1.129 mL, 13.55 mmol) as reported in Scheme 4, Step 6. mL) solution was reacted, and purified by flash column chromatography (silica gel 25 g, eluted with CMA80 chloroform solution, 0 to 30%) to obtain a white solid (S)-N2-(5-((-)-1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-N1-(4-chlorophenyl)pyrrolidine-1,2-dicarboxamide (8c) (300 mg, 0.536 mmol, yield 39.5%); 1 H NMR (300 MHz, DMSO-d 6)δ9.76 (s, 1H), 8.43 (s, 1H), 7.96 (d, J = 7.3Hz, 1H), 7.86 (t, J = 1.7Hz, 1H), 7.63 (ddt, J = 7.8, 4.7 , 1.3Hz, 2H), 7.59-7.51 (m, 2H), 7.46 (t, J=7.8Hz, 1H), 7.31-7.24 (m, 2H), 7.12 (d, J=9.0Hz, 2H), 4.66-4.45(m, 1H), 3.69-3.54(m, 1H), 3.56-3.42(m, 1H), 2.37-2.28(m, 2H), 2.27-2.06(m, 2H), 2 .04-1.86(m, 4H), 1.11-0.89(m, 2H), 0.73-0.54(m, 1H), 0.40-0.25(m, 2H), -0.02--0.15(m, 2H); 19 F NMR (282 MHz, DMSO-d 6 )δ-128.04; MS (ES+) 582.4; 584.5 (M+Na), (ES-) 558.4 (M-1); IR (KBr) 3386, 2229, 1655, 1594, 1526, 1494, 1405cm-1; Optical rotation [α] D =(-)102.42[1.035, MeOH]; Analytical calculation value C 31 H 31 CIF 5 O 2 ; C, 66.48; H, 5.58; N, 12.50; Found: C, 66.23; H, 5.71; N, 12.24.

[0350] Solution 9

[0351]

[0352] Preparation of (2R, 4S)-N2-(5-((+)-1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-N1-(4-chlorophenyl)-4-hydroxypyrrolidine-1,2-dicarboxamide (9c)

[0353] Step 1: Preparation of (2R,4S)-1-(4-chlorophenylcarbamoyl)-4-hydroxypyrrolidine-2-carboxylic acid (9a)

[0354] Using the reaction and workup conditions reported in step 9 of scheme 1, (2S,4S)-4-hydroxypyrrolidine-2-carboxylic acid (trans-D-4-hydroxyproline, 1.0 g, 7.63 mmol) in aqueous sodium bicarbonate (61.0 mL, 30.5 mmol, 0.5 M) was reacted with 4-chlorophenylisocyanate (1n) (1.952 mL, 15.25 mmol) to give (2R,4S)-1-(4-chlorophenylcarbamoyl)-4-hydroxypyrrolidine-2-carboxylic acid (9a) (1.643 g, 5.77 mmol, 76% yield) as a white solid; 1 H NMR (300 MHz, DMSO-d 6 )δ12.43(s,1H),8.47(s,1H),7.57-7.48(m,2H),7.31-7.22(m,2H),5.16(d,J=3.9Hz,1H),4.34(m,2H),3.60(dd,J=10.4,4.6Hz,1H),3.45-3.35(m,1H),2.12(m,1H),1.92(m,1H);MS(ES+)285.3(M+1),307.2,309.3(M+Na),(ES-)283.2,285.3(M-1);Optical rotation[α] n =(+)54.375[0.32, MeOH].

[0355] Step 2: Preparation of (2R,4S)-N1-(4-chlorophenyl)-N2-(5-((+)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)-4-hydroxypyrrolidine-1,2-dicarboxamide (9b)

[0356] Using the reaction and workup conditions reported in Scheme 1, Step 10, a solution of (2R,4S)-1-(4-chlorophenylcarbamoyl)-4-hydroxypyrrolidine-2-carboxylic acid (9a) (0.7 g, 2.459 mmol) and (R)-N-((-)-1-(3-amino-4-fluorophenyl)-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-methylpropane-2-sulfenamide (4e) (1.017 g, 2.459 mmol) in tetrahydrofuran (25 mL) was reacted with ethyl 2-ethoxy-1(2H)-quinolinecarboxylate (0.608 g, 2.459 mmol) and purified by flash column chromatography (silica gel 25 g, purified by CMA 80% chloroform solution, 0 to 100%) was purified to give a white solid (2R, 4S)-N1-(4-chlorophenyl)-N2-(5-((+)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)-4-hydroxypyrrolidine-1,2-dicarboxamide (9b) (1.37 g, 2.014 mmol, yield 82%); 1 HNMR (300 MHz, DMSO-d 6 )δ9.86 (s, 1H), 8.49 (s, 1H), 7.91 (dd, J=7.5, 2.4Hz, 1H), 7.78 (t, J=1.7Hz, 1H), 7.71 (dt, J=7.4, 1.4Hz, 1H), 7.63-7 .45 (m, 4H), 7.31-7.23 (m, 2H), 7.19 (dd, J=10.3, 8.7Hz, 1H), 7.14-7.03 (m, 1H), 5.53 (s, 1H), 5.19 (d, J=3.7Hz, 1H), 4 .66 (t, J=7.5Hz, 1H), 4.39 (m, 1H), 3.67 (dd, J=10.4, 4.6Hz, 1H), 3.44 (d, J=10.0Hz, 1H), 2.80-2.53 (m, 1H), 2.10 (m, 1 H), 2.04-1.84(m, 1H), 1.12(s, 10H), 1.05(s, 1H), 0.90(s, 1H), 0.63(s, 1H), 0.39-0.27(m, 2H), -0.03--0.16(m, 2H); 19 F NMR (282 MHz, DMSO-d 6 )δ-126.81; MS (ES+) 702.5, 704.5 (M+Na); optical rotation [α] D =(+)20.71[0.28, MeOH].

[0357] Step 3: (2R,4S)-N2-(5-((+)-1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-N1-(4-chlorophenyl)-4-hydroxypyrrolidine-1,2-dicarboxamide (9c)

[0358] A solution of (2R,4S)-N1-(4-chlorophenyl)-N2-(5-((+)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)-4-hydroxypyrrolidine-1,2-dicarboxamide (9b) (0.725 g, 1.066 mmol) in ethanol (20 mL) was reacted with concentrated HCl (0.888 mL, 10.66 mmol) as reported in Scheme 4, Step 6. The resulting mixture was purified by flash column chromatography (silica gel 25 g, purified by CMA 80 chloroform solution, 0 to 30%) was purified to give a white solid (2R, 4S)-N2-(5-((+)-1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-N1-(4-chlorophenyl)-4-hydroxypyrrolidine-1,2-dicarboxamide (9c) (210 mg, 0.365 mmol, yield 34.2%); 1 H NMR (300 MHz, DMSO-d 6 )δ9.77 (s, 1H), 8.46 (s, 1H), 7.92 (d, J=7.5Hz, 1H), 7.86 (t, J=1.7Hz, 1H), 7.63 (m, 2H), 7.59-7 .50 (m, 2H), 7.45 (t, J = 7.8Hz, 1H), 7.32-7.22 (m, 2H), 7.18-7.08 (m, 2H), 5.17 (d, J = 3.8Hz, 1H), 4.64 (t, J=7.5Hz, 1H), 4.39 (m, 1H), 3.67 (dd, J=10.3, 4.6Hz, 1H), 3.47-3.36 (m, 2H), 2.31 (m, 2 H), 2.21(m, 2H), 2.11(m, 1H), 1.11-0.91(m, 2H), 0.62(m, 1H), 0.41-0.22(m, 2H), -0.08(m, 2H); 19 F NMR (282 MHz, DMSO-d 6 )δ-127.52; MS(ES+)598.4, 600.4(M+Na), (ES-)610.4, 612.4(M+Cl); Optical rotation [α] D =(+)132.69[0.82, MeOH].

[0359] Solution 10

[0360]

[0361] Preparation of (2S,4S)-N2-(5-((-)-1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-N1-(4-chlorophenyl)-4-hydroxypyrrolidine-1,2-dicarboxamide (10c)

[0362] Step 1: Preparation of (2S,4S)-1-(4-chlorophenylcarbamoyl)-4-hydroxypyrrolidine-2-carboxylic acid (10a)

[0363] Using the reaction and workup conditions reported in step 9 of scheme 1, (2S,4S)-4-hydroxypyrrolidine-2-carboxylic acid (cis-L-4-hydroxyproline, 1.0 g, 7.63 mmol) in aqueous sodium bicarbonate (61.0 mL, 30.5 mmol, 0.5 M) was reacted with 4-chlorophenylisocyanate (1n) (1.952 mL, 15.25 mmol) to give (2S,4S)-1-(4-chlorophenylcarbamoyl)-4-hydroxypyrrolidine-2-carboxylic acid (10a) (1.643 g, 5.77 mmol, 76% yield) as a white solid; 1 H NMR (300 MHz, DMSO-d 6 )δ12.33(s,1H),8.41(s,1H),7.64-7.43(m,2H),7.37-7.14(m,2H),5.09(s,1H),4.51-4.16(m,2H),3.65(dd,J=10.3,5.6Hz,1H),3.32(m,1H),2.32(m,1H),1.97-1.78(m,1H);MS(ES+)307.2,309.2(M+Na),(ES-)283.2,285.2(M-1);Optical rotation[α] D =(-)37.74[0.265, MeOH].

[0364] Step 2: Preparation of (2S,4S)-N1-(4-chlorophenyl)-N2-(5-((-)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)-4-hydroxypyrrolidine-1,2-dicarboxamide (10b)

[0365] Using the reaction and workup conditions reported in Scheme 1, Step 10, a solution of (2S,4S)-1-(4-chlorophenylcarbamoyl)-4-hydroxypyrrolidine-2-carboxylic acid (10a) (0.7 g, 2.459 mmol) and (R)-N-((-)-1-(3-amino-4-fluorophenyl)-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-methylpropane-2-sulfenamide (4e) (1.017 g, 2.459 mmol) in tetrahydrofuran (25 mL) was reacted with ethyl 2-ethoxy-1(2H)-quinolinecarboxylate (0.608 g, 2.459 mmol) and purified by flash column chromatography (silica gel 25 g, purified by CMA 80 chloroform solution, 0 to 100%) was purified to give a white solid (2S, 4S)-N1-(4-chlorophenyl)-N2-(5-((-)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)-4-hydroxypyrrolidine-1,2-dicarboxamide (10b) (0.961 g, 1.413 mmol, yield 57.5%); 1 H NMR (300 MHz, DMSO-d 6 )δ9.66 (s, 1H), 8.52 (s, 1H), 8.06 (dd, J=7.6, 2.4Hz, 1H), 7.79 (m, 1H), 7.71 (m, 1H), 7.62-7.45 (m, 4H), 7.34-7.24 (m, 2H), 7.20 (dd, J=10.5, 8.7Hz, 1H), 7.14-7.03 (m, 1H), 5.49 (s, 1H), 5.32 (d, J=4.5Hz, 1H), 4.51 (dd, J=9.0, 4.7H z, 1H), 4.39-4.25 (m, 1H), 3.68 (dd, J=10.1, 5.2Hz, 1H), 3.49 (dd, J=9.9, 3.9Hz, 1H), 2.75-2.51 (m, 2H), 2.49-2.2 0 (m, 1H), 1.97-1.81 (m, 1H), 1.13 (s, 9H), 1.07 (m, 1H), 0.90 (m, 1H), 0.64 (m, 1H), 0.40-0.26 (m, 2H), -0.06 (m, 2H); 19 F NMR (282 MHz, DMSO-d 6 )δ-128.68; MS (ES+) 702.5, 704.5 (M+Na), (ES-) 678.6, 680.5 (M-1); optical rotation [α] D =(-)153.33[0.27, MeOH].

[0366] Step 3: Preparation of (2S,4S)-N2-(5-((-)-1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-N1-(4-chlorophenyl)-4-hydroxypyrrolidine-1,2-dicarboxamide (10c)

[0367] A solution of (2S,4S)-N1-(4-chlorophenyl)-N2-(5-((-)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)-4-hydroxypyrrolidine-1,2-dicarboxamide (10b) (0.5 g, 0.735 mmol) in ethanol (20 mL) was reacted with concentrated HCl (0.613 mL, 7.35 mmol) as reported in Scheme 4, Step 6. The resulting mixture was purified by flash column chromatography (silica gel 25 g, purified by CMA 80 chloroform solution, 0 to 30%) was purified to give a white solid (2S, 4S)-N2-(5-((-)-1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-N1-(4-chlorophenyl)-4-hydroxypyrrolidine-1,2-dicarboxamide (10c) (50 mg, 0.087 mmol, yield 11.81%); 1 H NMR (300 MHz, DMSO-d 6 )δ9.62 (s, 1H), 8.50 (s, 1H), 8.05 (d, J = 7.3Hz, 1H), 7.86 (t, J = 1.7Hz, 1H), 7.63 (m, 2H), 7.59- 7.50 (m, 2H), 7.46 (t, J=7.8Hz, 1H), 7.34-7.24 (m, 2H), 7.19-7.04 (m, 2H), 5.30 (d, J=4.9Hz, 1H ), 4.51 (dd, J=9.0, 4.7Hz, 1H), 4.34 (d, J=5.2Hz, 1H), 3.69 (dd, J=10.1, 5.3Hz, 1H), 3.54-3.43 (m, 1H), 2.40-2.08 (m, 5H), 1.90 (m, 1H), 1.02 (m, 2H), 0.63 (m, 1H), 0.34 (m, 2H), -0.07 (s, 2H); 19 F NMR (282 MHz, DMSO-d 6 )δ-129.13; MS (ES+) 598.4, 600.4 (M+Na); optical rotation [α] D =(-)51.85[0.7, MeOH]; Analytical calculation value C 31 H 31 CIF 5 O 3 0.75H 2O: C, 63.15; H, 5.56; N, 11.88; Found: C, 63.02; H, 5.89; N, 10.83.

[0368] Solution 11

[0369]

[0370] Preparation of (2S, 4S)-N2-(5-((-)-1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-N1-(4-chlorophenyl)-4-methoxypyrrolidine-1,2-dicarboxamide (11e)

[0371] Step 1: Preparation of (2S,4S)-4-methoxypyrrolidine-2-carboxylic acid hydrochloride (11b)

[0372] To a stirred solution of (2S,4S)-1-(tert-butoxycarbonyl)-4-methoxypyrrolidine-2-carboxylic acid (11a) (prepared according to the procedure reported for benzimidazole-proline derivatives as orexin receptor antagonists and their preparation; Boss, Christoph et al.; from PCT International Application No. 2013182972, December 12, 2013; 0.25 g, 1.019 mmol) in tetrahydrofuran (10 mL) was added 6N HCl aqueous solution (0.680 mL, 4.08 mmol) and stirred at room temperature overnight. The reaction product was concentrated and dried in vacuo to give a white solid (2S,4S)-4-methoxypyrrolidine-2-carboxylic acid hydrochloride (11b) (0.185 g, 1.019 mmol, 100% yield), which was used directly in the next step; 1 H NMR (300 MHz, DMSO-d 6 / D 2 O) δ4.42 (t, J=6.7Hz, 1H), 4.06 (m, 1H), 3.38 (d, J=12.4Hz, 1H), 3.25-3.18 (m, 1H), 3.16 (s, 3H), 2.30 (dd, J=7.3, 3.2Hz, 2H).

[0373] Step 2: Preparation of (2S,4S)-1-(4-chlorophenylcarbamoyl)-4-methoxypyrrolidine-2-carboxylic acid (11c)

[0374] Using the reaction and workup conditions reported in Scheme 1, Step 9, (2S,4S)-4-methoxypyrrolidine-2-carboxylic acid hydrochloride (11b) (182 mg, 1.0 mmol) in aqueous sodium bicarbonate (10 mL, 20 mmol, 0.5 M) was reacted with 4-chlorophenylisocyanate (1n) (10.256 mL, 2.0 mmol) to afford (2S,4S)-1-(4-chlorophenylcarbamoyl)-4-methoxypyrrolidine-2-carboxylic acid (11c) (133 mg, 0.445 mmol, 44.5% yield) MS (ES+) 321.3, 323.3 (M+Na), (ES-) 297.3, 299.3 (M-1).

[0375] Step 3: Preparation of (2S,4S)-N1-(4-chlorophenyl)-N2-(5-(1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)-4-methoxypyrrolidine-1,2-dicarboxamide (11d)

[0376] Using the reaction and workup conditions reported in Scheme 1, Step 10, a solution of (2S,4S)-1-(4-chlorophenylcarbamoyl)-4-methoxypyrrolidine-2-carboxylic acid (11c) (120 mg, 0.402 mmol) and (R)-N-((-)-1-(3-amino-4-fluorophenyl)-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-methylpropane-2-sulfenamide (4e) (166 mg, 0.402 mmol) in tetrahydrofuran (20 mL) was reacted with ethyl 2-ethoxy-1(2H)-quinolinecarboxylate (99 mg, 0.402 mmol) and purified by flash column chromatography (silica gel 25 g, purified by CMA 80 chloroform solution, 0 to 100%) was purified to give a white solid (2S, 4S)-N1-(4-chlorophenyl)-N2-(5-((1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)-4-methoxypyrrolidine-1,2-dicarboxamide (11d) (156 mg, 0.225 mmol, yield 55.9%); 1 H NMR (300 MHz, DMSO-d 6)δ9.51 (s, 1H), 8.53 (s, 1H), 7.92 (d, J = 7.3Hz, 1H), 7.79 (s, 1H), 7.71 (d, J = 7.5Hz, 1H), 7.64-7.46 (m, 4H), 7.35-7.25 (m, 2H), 7.24-7.14 (m, 1H), 7.10 (s, 1H), 5.48 (s, 1H), 4.54 (dd, J=9.2, 3.9Hz, 1H), 4.07 (m, 1H), 3 .72 (dd, J=10.6, 5.0Hz, 1H), 3.61 (dd, J=10.0, 2.4Hz, 1H), 3.22 (s, 3H), 2.69-2.51 (m, 2H), 2.43-2.24 (m, 1H ), 2.23-2.06(m, 1H), 1.12(s, 10H), 0.99-0.79(m, 1H), 0.63(s, 1H), 0.42-0.27(m, 2H), 0.06--0.16(m, 2H); 19 F NMR (282 MHz, DMSO-d 6 )δ-128.19; MS (ES+) 716.6, 718.5 (M+Na).

[0377] Step 4: Preparation of (2S,4S)-N2-(5-((-)-1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-N1-(4-chlorophenyl)-4-methoxypyrrolidine-1,2-dicarboxamide (11e)

[0378] A solution of (2S,4S)-N1-(4-chlorophenyl)-N2-(5-(1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)-4-methoxypyrrolidine-1,2-dicarboxamide (11d) (0.143 g, 0.206 mmol) in ethanol (20 mL) was reacted with concentrated HCl (0.172 mL, 2.060 mmol) as reported in Scheme 4, Step 6. The resulting mixture was purified by flash column chromatography (silica gel 25 g, purified by CMA 80% chloroform solution, 0 to 30%) was purified to give a white solid (2S, 4S)-N2-(5-((-)-1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-N1-(4-chlorophenyl)-4-methoxypyrrolidine-1,2-dicarboxamide (11e) (80 mg, 0.136 mmol, yield 65.8%); 1 H NMR (300 MHz, DMSO-d 6)δ9.45 (d, J=1.3Hz, 1H), 8.51 (s, 1H), 7.90 (d, J=7.7Hz, 1H), 7.86 (m, 1H), 7.63 (m, 2H), 7.58 -7.52 (m, 2H), 7.46 (t, J=7.8Hz, 1H), 7.32-7.25 (m, 2H), 7.14 (s, 1H), 7.11 (s, 1H), 4.53 (dd, J=9.1, 3.9Hz, 1H), 4.07 (m, 1H), 3.73 (dd, J=10.6, 5.1Hz, 1H), 3.61 (dd, J=10.4, 3.3Hz, 1H), 3.22(s, 3H), 2.47-1.98(m, 6H), 1.11-0.92(m, 2H), 0.63(m, 1H), 0.33(m, 2H), -0.07(m, 2H); 19 F NMR (282 MHz, DMSO-d 6 )δ-128.86; MS(ES+)612.4, 614.4(M+Na); IR(KBr)2229cm -1 ; Optical rotation [α] D =(-)56.57[0.495, MeOH].

[0379] Solution 12

[0380]

[0381] Preparation of benzyl (R)-2-(5-((-)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenylcarbamoyl)pyrrolidine-1-carboxylate (12b)

[0382] Step 1: Preparation of (R)-1-(benzyloxycarbonyl)pyrrolidine-2-carboxylic acid (12a)

[0383] To a stirred solution of D-proline (1.2 g, 10.42 mmol) in 2N NaOH aqueous solution (20.85 mL, 41.7 mmol) at 0°C was added benzyl chloroformate (1.488 mL, 10.42 mmol) and allowed to warm to room temperature overnight. The reaction product was washed with MTBE (2×25 mL), acidified with concentrated HCl and extracted with ethyl acetate (2×200 mL). The ethyl acetate layers were combined, washed with water (50 mL) and brine (25 mL), dried and concentrated in vacuo to give (R)-1-(benzyloxycarbonyl)pyrrolidine-2-carboxylic acid (12a) (2.41 g, 9.67 mmol, 93% yield), which was used directly in the next step; 1 H NMR (300 MHz, DMSO-d6 )δ12.66 (s, 1H), 7.42-7.25 (m, 5H), 5.14-4.97 (m, 2H), 4.20 (ddd, J=22.7, 8.8, 3.5Hz, 1H), 3.50-3.25 (m, 2H), 2.32- 2.08 (m, 1H), 1.97-1.75 (m, 3H); MS (ES+) 250.2 (M+1), 272.2 (M+Na), (ES-) 248.2 (M-1), 284.2 (M+Cl), 497.4 (2M-1).

[0384] Step 2: Preparation of benzyl (R)-2-(5-((-)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenylcarbamoyl)pyrrolidine-1-carboxylate (12b)

[0385] Using the reaction and workup conditions reported in step 10 of scheme 1, a solution of (R)-1-(benzyloxycarbonyl)pyrrolidine-2-carboxylic acid (12a) (1 g, 4.01 mmol) and (R)-N-((-)-1-(3-amino-4-fluorophenyl)-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-methylpropane-2-sulfenamide (4e) (1.659 g, 4.01 mmol) in tetrahydrofuran (50 mL) was reacted with ethyl 2-ethoxy-1(2H)-quinolinecarboxylate (0.992 g, 4.01 mmol) and purified by flash column chromatography (silica gel 25 g, purified by CMA 80% chloroform solution, 0 to 100%) was purified to give (R)-2-(5-((-)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenylcarbamoyl)pyrrolidine-1-carboxylic acid benzyl ester (12b) (2.4 g, 3.72 mmol, 93% yield) as a white solid; 1 H NMR (300 MHz, DMSO-d 6)δ9.86 (d, J=11.1Hz, 1H), 7.92 (t, J=9.0Hz, 1H), 7.78 (d, J=1.7Hz, 1H), 7.72 (d, J=7.4Hz, 1H), 7.65 -7.56 (m, 1H), 7.51 (m, 1H), 7.37 (m, 2H), 7.29-7.06 (m, 5H), 5.52 (d, J=10.5Hz, 1H), 5.14-4.93 (m, 2 H), 4.62-4.38 (m, 1H), 3.58-3.33 (m, 2H), 2.72-2.57 (m, 1H), 2.33-2.08 (m, 1H), 1.97-1.73 (m, 4H), 1.12 (2s, 9H rotamer), 1.11-1.00 (m, 1H), 0.86 (m, 1H), 0.62 (m, 1H), 0.34 (m, 2H), 0.01-0.18 (m, 2H); 19 F NMR (282 MHz, DMSO-d 6 )δ-126.74; MS (ES+) 645.6 (M+1), 667.6 (M+Na), (ES-) 643.6 (M-1); Optical rotation [α] D =(-)21.18[0.255, MeOH].

[0386] Solution 13

[0387]

[0388] Preparation of (R)-N2-(5-((+)-1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-N1-(5-chloropyridin-2-yl)pyrrolidine-1,2-dicarboxamide (13e)

[0389] Step 1: Preparation of phenyl 5-chloropyridin-2-ylcarbamate (13b)

[0390] Pyridine (4.72 mL, 58.3 mmol) and phenyl chloroformate (4.88 mL, 38.9 mmol) were added to a solution of 2-amino-5-chloropyridine (13a) (5 g, 38.9 mmol) in dichloromethane (100 mL) cooled in an ice-water bath. The resulting mixture was stirred in an ice-water bath for 2 hours, diluted with water (100 mL) and dichloromethane (50 mL). The obtained solid was collected by filtration and dried in vacuo at 50 ° C to obtain phenyl 5-chloropyridin-2-ylcarbamate (13b) (9.519 g, 38.3 mmol, 98% yield) as a white solid; 1 HNMR (300 MHz, DMSO-d 6) δ10.97 (s, 1H), 8.38 (dd, J=2.6, 0.8Hz, 1H), 7.93 (dd, J=9.0, 2.6Hz, 1H), 7.84 (dd, J=8.9, 0.8Hz, 1H), 7.51-7.37 (m, 2H), 7.36-7.17 (m, 3H).

[0391] Step 2: Preparation of (R)-N-(5-(1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)pyrrolidine-2-carboxamide (13c)

[0392] To a suspension of 10% palladium on carbon (0.165 g, 0.155 mmol) in ethanol (75 mL) was added an ethanol solution of (R)-benzyl 2-(5-((-)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenylcarbamoyl)pyrrolidine-1-carboxylate (12b) (1 g, 1.551 mmol) and hydrogenated in a Parr shaker at 50 psi for 5 h. The reaction product was filtered through a small pad of celite and concentrated to give (R)-N-(5-(1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)pyrrolidine-2-carboxamide (13c) (815 mg, 1.596 mmol, 103% yield), which was used in the next step without further purification; 1 H NMR (300 MHz, DMSO-d 6 )δ10.13 (s, 1H), 8.29 (dd, J=7.6, 2.4Hz, 1H), 7.79 (t, J=1.8Hz, 1H), 7.72 (dt, J=7.4, 1.4Hz, 1H), 7.60 (dt, J=8.3, 1.5Hz, 1H), 7.51 (t, J=7.8Hz, 1H), 7.22 (m, 1H), 7.06 (m, 1H), 5.46 (s, 1H), 3.74 (dd, J=9.1, 5.2Hz, 1H), 3.43 (m, 2H), 2.87 (m, 2H), 2.71-2.53 (m, 2H), 2.05 (m, 1H), 1.79 (dq, J=12.4, 6.5Hz, 1H), 1 .72-1.56(m, 2H), 1.14(s, 9H), 0.99-0.82(m, 1H), 0.74-0.54(m, 1H), 0.35(m, 2H), 0.04--0.15(m, 2H); 19 F NMR (282 MHz, DMSO-d 6)δ-131.82; MS(ES+)511.4(M+1), 533.5(M+Na), (ES-)509.4(M-1).

[0393] Step 3: Preparation of (R)-N1-(5-chloropyridin-2-yl)-N2-(5-(1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)pyrrolidine-1,2-dicarboxamide (13d)

[0394] To a solution of (R)-N-(5-(1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)pyrrolidine-2-carboxamide (13c) (0.763 g, 1.494 mmol) in tetrahydrofuran (50 mL) was added phenyl 5-chloropyridin-2-ylcarbamate (13b) (0.446 g, 1.793 mmol) and N-ethyl-N-isopropylpropane-2-amine (1.041 mL, 5.98 mmol). The reaction mixture was heated at reflux for 16 hours. The reaction product was cooled to room temperature, diluted with ethyl acetate (100 mL), washed with water (2×50 mL) and brine (50 mL), dried and concentrated in vacuo. The crude residue was purified by flash column chromatography to give (R)-N1-(5-chloropyridin-2-yl)-N2-(5-(1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)pyrrolidine-1,2-dicarboxamide (13d) (773 mg, 1.162 mmol, 78% yield) as a white solid; 1 H NMR (300 MHz, DMSO-d 6 )δ9.82 (s, 1H), 9.07 (s, 1H), 8.28 (dd, J=2.7, 0.8Hz, 1H), 7.96-7.86 (m, 2H), 7.83-7.76 (m, 2H), 7.71 (dt, J=7.4, 1.5Hz, 1H), 7.58 (d, J=8.0Hz, 1H), 7.50 (m, 1H), 7.27-7.05 (m, 2H), 5.52 (s, 1H), 4.62(d, J=7.7Hz, 1H), 3.78-3.62(m, 1H), 3.62-3.46(m, 1H), 2.73-2.40(m, 2H), 2.26-2.10(m, 1 H), 1.93 (m, 3H), 1.12 (s, 10H), 0.85 (m, 1H), 0.72-0.54 (m, 1H), 0.33 (m, 2H), 0.00--0.16 (m, 2H); 19 F NMR (282 MHz, DMSO-d6 )δ-126.74.

[0395] Step 4: Preparation of (R)-N2-(5-((+)-1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-N1-(5-chloropyridin-2-yl)pyrrolidine-1,2-dicarboxamide (13e)

[0396] A solution of (R)-N1-(5-chloropyridin-2-yl)-N2-(5-(1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)pyrrolidine-1,2-dicarboxamide (13d) (554 mg, 0.833 mmol) in ethanol (100 mL) was prepared using concentrated HCl (0.694 mL, 8.33 mmol) as reported in Scheme 4, Step 6. The reaction was purified by flash column chromatography (silica gel 25 g, eluted with a 9:1 ethyl acetate / methanol mixture in hexane, 0 to 60%) to give a colorless solid (R)-N2-(5-((+)-1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-N1-(5-chloropyridin-2-yl)pyrrolidine-1,2-dicarboxamide (13e) (219 mg, 0.390 mmol, 46.9% yield); 1 H NMR (300 MHz, DMSO-d 6 )δ9.76 (s, 1H), 9.05 (s, 1H), 8.28 (d, J=2.6Hz, 1H), 7.96-7.88 (m, 2H), 7.86 (m, 1H), 7.79 (dd, J=9 .0, 2.6Hz, 1H), 7.63 (ddt, J=7.6, 5.9, 1.3Hz, 2H), 7.46 (t, J=7.8Hz, 1H), 7.14 (d, J=2.0Hz, 1H), 7 .12 (d, J=1.3Hz, 1H), 4.61 (d, J=7.7Hz, 1H), 3.66 (m, 1H), 3.56 (m, 1H), 3.33-3.27 (m, 1H), 2.40-2 .06(m, 4H), 1.94(m, 3H), 1.13-0.85(m, 2H), 0.62(m, 1H), 0.41-0.26(m, 2H), -0.03--0.17(m, 2H); 19 F NMR (282 MHz, DMSO-d 6 )δ-127.82; MS(ES+)561.4, 562.4(M+1), 583.4, 585.5(M+Na); IR(KBr)2229cm -1 ; Optical rotation [α] D=(+)160.49[0.82, MeOH].

[0397] Solution 14

[0398]

[0399] Preparation of (2R, 4R)-N2-(5-(1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-N1-(5-chloropyridin-2-yl)-4-hydroxypyrrolidine-1,2-dicarboxamide (14h)

[0400] Step 1: Preparation of (2R, 4R)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid (14b)

[0401] To (2R,4R)-4-hydroxypyrrolidine-2-carboxylic acid (14a) (10 g, 76 mmol) in THF:H 2 To a solution of 4-nitropropene (125 mL, 2:1) was added 2-5 M aqueous sodium hydroxide solution (42.1 mL, 105 mmol), followed by di-tert-butyl dicarbonate (22.80 g, 104 mmol) in THF:H 2 O (125 mL, 2: 1) solution and stirred at room temperature for 32 hours. The mixture was concentrated in vacuo to remove THF, and the aqueous layer was acidified with 10% aqueous potassium hydrogen sulfate (150 mL). The resulting mixture was extracted with ethyl acetate, washed with water and brine, dried, filtered and evaporated to dryness. The resulting semi-solid was crystallized from hot ethyl acetate to give a white solid (2R, 4R)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid (14b) (13.58 g, 58.7 mmol, 77% yield); 1 H NMR (300 MHz, DMSO-d 6 )δ12.41(s,1H,D 2 O interchangeable), 4.95(s, 1H, D 2 O interchangeable), 4.20 (q, J = 5.1 Hz, 1H), 4.14-4.02 (m, 1H), 3.48 (dt, J = 10.8, 5.4 Hz, 1H), 3.09 (ddd, J = 10.6, 6.2, 4.2 Hz, 1H), 2.41-2.20 (m, 1H), 1.81 (dt, J = 12.8, 5.0 Hz, 1H), 1.37 (d, J = 15.9 Hz, 9H); 1 H NMR (300 MHz, MeOH-d 4)δ4.34 (ddd, J=5.8, 4.0, 1.5 Hz, 1H), 4.30-4.22 (m, 1H), 3.61 (dd, J=11.1, 5.6 Hz, 1H), 3.38-3.33 (m, 1H), 2.54-2.32 (m, 1H), 2.15-1.97 (m, 1H), 1.45 (d, J=12.0 Hz, 9H); MS (ES+) 254.3 (M+Na); MS (ES-) 230.2 (M-1), 461.5 (2M-1); Optical rotation [α] D =(+)52.96[1.065, MeOH].

[0402] Step 2: Preparation of tert-butyl (2R,4R)-2-(5-(1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenylcarbamoyl)-4-hydroxypyrrolidine-1-carboxylate (14c)

[0403] Using the reaction and workup conditions reported in step 10 of scheme 1, a solution of (2R,4R)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid (14b) (0.752 g, 3.25 mmol) and (R)-N-((-)-1-(3-amino-4-fluorophenyl)-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-methylpropane-2-sulfenamide (4e) (1.345 g, 3.25 mmol) in tetrahydrofuran (20 mL) was reacted with ethyl 2-ethoxy-1(2H)-quinolinecarboxylate (0.804 g, 3.25 mmol) and purified by flash column chromatography (silica gel 25 g, purified by CMA 80% chloroform solution, 0 to 100%) was purified to give a white solid (2R,4R)-2-(5-(1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenylcarbamoyl)-4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester (14c) (0.84 g, 1.340 mmol, yield 41.2%); 1 H NMR (300 MHz, DMSO-d 6)δ9.79 (s, 1H), 7.78 (d, J=1.9Hz, 1H), 7.75-7.67 (m, 1H), 7.62 (m, 1H), 7.51 (m, 1H) , 7.20(m, 1H), 6.90(m, 1H), 6.72(m, 1H), 6.48(m, 1H), 5.28(s, 1H), 5.11(s, 1H), 4.3 8-4.14(m, 1H), 3.47(m, 1H), 3.31-3.19(m, 1H), 2.76-2.23(m, 3H), 1.99(m, 1H), 1.1 2(s, 18H), 1.00-0.79(m, 2H), 0.76-0.56(m, 1H), 0.35(m, 2H), -0.00--0.16(m, 2H); 19 F NMR (282 MHz, DMSO-d 6 )δ-137.33; MS (ES+) 649.5 (M+Na), (ES-) 625.5 (M-1).

[0404] Step 3: Preparation of tert-butyl (2R,4R)-4-acetoxy-2-(5-((-)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenylcarbamoyl)pyrrolidine-1-carboxylate (14d)

[0405] To a solution of tert-butyl (2R,4R)-2-(5-(1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenylcarbamoyl)-4-hydroxypyrrolidine-1-carboxylate (14c) (0.8 g, 1.276 mmol) in dichloromethane (30 mL) was added DIPEA (0.669 mL, 3.83 mmol), acetic anhydride (0.145 mL, 1.532 mmol) and DMAP (7.80 mg, 0.064 mmol) and stirred at room temperature overnight. The reaction product was diluted with dichloromethane (100 mL), washed with water (2×25 mL) and brine (25 mL), dried and concentrated. The obtained crude residue was purified by flash column chromatography (silica gel 12 g, eluted with ethyl acetate in hexane, 0 to 50%) to give white semi-solid (2R,4R)-4-acetoxy-2-(5-((-)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenylcarbamoyl)pyrrolidine-1-carboxylic acid tert-butyl ester (14d) (324 mg, 0.484 mmol, 38.0% yield); 1 H NMR (300 MHz, DMSO-d 6)δ9.63 (s, 1H), 7.78 (m, 1H), 7.76-7.55 (m, 3H), 7.51 (m, 1H), 7.21 (m, 2H), 5.49 (s, 1H), 5.09 (t, J=7.2 Hz, 1H), 4.42 (2 sets of dd, J=32.7, 7.2 Hz, 1H rotamer), 3.76-3.59 (m, 1H), 3.49-3.35 (m, 1H) , 2.75-2.38 (m, 2H), 2.09-1.95 (m, 1H), 1.87 (2S, 3H rotamer), 1.36 (2s, 9H rotamer), 1.12 (s, 10H), 1.08-1.00 (m, 1H), 1.00-0.80 (m, 1H), 0.72-0.51 (m, 1H), 0.44-0.24 (m, 2H), -0.06 (m, 2H); 19 F NMR (282 MHz, DMSO-d 6 )δ-125.32; MS (ES+) 691.6 (M+Na), (ES-) 667.6 (M-1); optical rotation [α] D =(-)48.0[0.125, MeOH].

[0406] Step 4: Preparation of (3R,5R)-5-(5-(1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenylcarbamoyl)pyrrolidin-3-yl acetate (14e) and (2R,4R)-N-(5-(1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-4-hydroxypyrrolidine-2-carboxamide (14f)

[0407] As reported in Scheme 4, Step 6, a solution of tert-butyl (2R,4R)-4-acetoxy-2-(5-((-)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenylcarbamoyl)pyrrolidine-1-carboxylate (14d) (0.32 g, 0.478 mmol) in ethanol (10 mL) was reacted with concentrated HCl (0.399 mL, 4.78 mmol) and purified by flash column chromatography (silica gel 12 g, eluted with CMA-80 in chloroform, 0 to 60%) to give

[0408] 1. (3R, 5R)-5-(5-(1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenylcarbamoyl)pyrrolidin-3-yl acetate (14e) (90 mg, 0.194 mmol, yield 40.5%); 1H NMR (300 MHz, DMSO-d6) δ 10.04 (d, J = 2.0 Hz, 1H), 8.24-8.11 (m, 1H), 7.84 (t, J = 1.6 Hz, 1H), 7.64 (tt, J = 7.6, 1.3 Hz, 2H), 7.47 (t, J = 7.8 Hz, 1H), 7.27-7.06 (m, 2H), 5.07 (m, 1H), 3.81 (d, J=9.4Hz, 1H), 3.46 (m, 1H), 3.18 (m, 1H), 2.91 (m, 1H), 2.26 (m, 5H), 2.06 (m, 1H), 1.75 (s, 3H), 1.03 (m, 2H), 0.64 (m, 1H), 0.42-0.28 (m, 2H), -0.07 (m, 2H); 19F NMR (282MHz, DMSO-d6) δ-132.66. MS (ES+) 465.4 (M+1), 487.4 (M+Na), (ES-) 463.4 (M-1), 499.5 (M+Cl).

[0409] 2. (2R, 4R)-N-(5-(1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-4-hydroxypyrrolidine-2-carboxamide (14f) (100 mg, 0.237 mmol, yield 49.5%); 1 H NMR (300 MHz, DMSO-d 6 )δ10.19(s, 1H), 8.42-8.22(m, 1H), 7.86(t, J=1.7Hz, 1H), 7.74-7.59(m, 2H), 7.47( m, 1H), 7.25-6.94 (m, 2H), 4.67 (d, J=3.3Hz, 1H), 4.16 (m, 1H), 3.84-3.60 (m, 1H), 3. 00 (m, 1H), 2.72 (dd, J=10.6, 3.0Hz, 1H), 2.43-2.03 (m, 6H), 1.83 (dt, J=13.0, 3.9Hz , 1H), 1.14-0.88(m, 2H), 0.76-0.51(m, 1H), 0.46-0.25(m, 2H), -0.03--0.10(m, 2H); 19 F NMR (282 MHz, DMSO-d 6)δ-133.44; MS (ES+) 423.4 (M+1), 445.4 (M+Na), (ES-) 457.4 (M+Cl).

[0410] Step 5: Preparation of (2R,4R)-N2-(5-(1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-N1-(5-chloropyridin-2-yl)-4-hydroxypyrrolidine-1,2-dicarboxamide (14h)

[0411] As reported in step 3 of scheme 13, a solution of (2R,4R)-N-(5-(1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-4-hydroxypyrrolidine-2-carboxamide (14f) (92 mg, 0.218 mmol) in tetrahydrofuran (10 mL) was reacted and purified by flash column chromatography (silica gel 12 g, eluted with CMA-80 in chloroform, 0 to 100%) to give (2R,4R)-N2-(5-(1-amino-1-(3-fluorophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-N1-(5-chloropyridin-2-yl)-4-hydroxypyrrolidine-1,2-dicarboxamide (14h) (34 mg, 0.059 mmol, 27.1% yield) as a white solid; 1 H NMR (300 MHz, DMSO-d 6 )δ9.67 (s, 1H), 9.16 (s, 1H), 8.31-8.26 (m, 1H), 8.01 (d, J=7.5Hz, 1H), 7.94-7.83 (m, 2H), 7.79 (dd, J=9.0, 2.7Hz, 1H), 7.63 (m, 2H), 7.46 (t, J=7.8Hz, 1H), 7.13 (dd, J=7.4, 2.0Hz, 2H), 5.31 (d, J=4.7H z, 1H), 4.54 (m, 1H), 4.31 (q, J=4.9Hz, 1H), 3.73 (m, 1H), 3.51 (dd, J=10.5, 4.2Hz, 1H), 2.47-2.28 (m , 3H), 2.28-2.10(m, 2H), 1.89(m, 1H), 1.01(m, 2H), 0.63(m, 1H), 0.34(m, 2H), -0.03--0.17(m, 2H); 19 F NMR (282 MHz, DMSO-d 6 )δ-128.70; MS(ES+)577.5, 579.5(M+1); IR(KBr)2229cm -1 .

[0412] Preparation of (3R,5R)-5-(5-((+)-1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenylcarbamoyl)-1-(5-chloropyridin-2-ylcarbamoyl)pyrrolidin-3-yl acetate (14 g)

[0413] As reported in Scheme 13, Step 3, a solution of (3R,5R)-5-(5-(1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenylcarbamoyl)pyrrolidin-3-yl acetate (14e) (81 mg, 0.174 mmol) in tetrahydrofuran (10 mL) was reacted with phenyl 5-chloropyridin-2-ylcarbamate (43.4 mg, 0.174 mmol) and purified by flash column chromatography ( Silica gel 12 g, eluted with CMA-80 chloroform solution, 0 to 100%), to obtain a white solid (3R, 5R)-5-(5-((+)-1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenylcarbamoyl)-1-(5-chloropyridin-2-ylcarbamoyl)pyrrolidin-3-yl acetate (14 g) (24 mg, 0.039 mmol, yield 22.23%); 1 H NMR (300 MHz, DMSO-d 6 )δ9.64 (s, 1H), 9.18 (s, 1H), 8.30 (d, J=2.6Hz, 1H), 7.91 (dd, J=9.0, 0.8Hz, 1H), 7.86-7.79 (m, 2H), 7.7 5 (dd, J=7.6, 2.2Hz, 1H), 7.63 (m, 2H), 7.46 (m, 1H), 7.23-7.10 (m, 2H), 5.19 (q, J=4.6, 3.7Hz, 1H), 4.72 ( d, J=8.7Hz, 1H), 3.88 (dd, J=11.7, 5.2Hz, 1H), 3.75 (d, J=11.7Hz, 1H), 2.48-2.40 (m, 1H), 2.32 (m, 2H), 2 .22(m, 3H), 1.87(s, 3H), 1.12-0.91(m, 2H), 0.72-0.50(m, 1H), 0.42-0.28(m, 2H), -0.03--0.14(m, 2H); 19 F NMR (282 MHz, DMSO-d 6 )δ-126.76; MS (ES-) 617.4 (M-1), 653.3, 655.3 (M+Cl); optical rotation [α] D =(+)109.1[0.165, MeOH].

[0414] Solution 15

[0415]

[0416] Preparation of (2R, 4R)-N2-(5-((+)-1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-N1-(4-cyanophenyl)-4-methoxypyrrolidine-1,2-dicarboxamide (15f)

[0417] Step 1: Preparation of (2R,4R)-1-(benzyloxycarbonyl)-4-methoxypyrrolidine-2-carboxylic acid (15b)

[0418] To a slurry of sodium hydride (60% oil dispersion, 2.262 g, 56.5 mmol) in tetrahydrofuran (30 mL) was added a solution of (2R, 4R)-1-(benzyloxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid (15a) (2.5 g, 9.42 mmol) in THF (60 mL) at -10°C. The reaction product was stirred for 30 minutes, then dimethyl sulfate (0.901 mL, 9.42 mmol) was added and stirred at room temperature for 16 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride and concentrated in vacuo to remove THF. The reaction mixture was basified, washed with ether, acidified and extracted with ethyl acetate (2×100 mL). The combined ethyl acetate layers were washed with water (50 mL) and brine (50 mL), dried, filtered and evaporated in vacuo to give (2R,4R)-1-(benzyloxycarbonyl)-4-methoxypyrrolidine-2-carboxylic acid (15b) (2.138 g, 7.66 mmol, 81% yield) as a white solid; 1 H NMR (300 MHz, DMSO-d 6 )δ12.56 (s, 1H), 7.55-7.12 (m, 5H), 5.23-4.88 (m, 2H), 4.29 (ddd, J=21.9, 9.4, 3.0 Hz, 1H), 3.95 (qt, J=5.3, 2.7 Hz, 1H), 3.61 (ddd, J=15.6, 11.5, 5.4 Hz, 1H), 3.31 (m, 1H), 3.17 (2s, 3H, rotamer), 2.42-2.24 (m, 1H), 2.17-2.01 (m, 1H); MS (ES-) 278.2 (M-1); optical rotation [α] D =(+)33.81[0.775, MeOH].

[0419] Step 2: Preparation of benzyl (2R,4R)-2-(5-((-)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenylcarbamoyl)-4-methoxypyrrolidine-1-carboxylate (15c)

[0420] Using the reaction and workup conditions reported in step 10 of scheme 1, a solution of (2R,4R)-1-(benzyloxycarbonyl)-4-methoxypyrrolidine-2-carboxylic acid (15b) (1.52 g, 5.44 mmol) and (R)-N-((-)-1-(3-amino-4-fluorophenyl)-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-methylpropane-2-sulfenamide (4e) (2.251 g, 5.44 mmol) in tetrahydrofuran (75 mL) was reacted with ethyl 2-ethoxy-1(2H)-quinolinecarboxylate (1.346 g, 5.44 mmol) and purified by flash column chromatography (silica gel 25 g, purified by CMA 80% chloroform solution, 0 to 100%) was purified to give white solid (2R,4R)-2-(5-((-)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenylcarbamoyl)-4-methoxypyrrolidine-1-carboxylic acid benzyl ester (15c) (3.15 g, 4.67 mmol, yield 86%); 1 H NMR (300 MHz, DMSO-d 6 )δ9.54 (2s, 1H, rotamer), 7.86 (m, 1H), 7.79 (m, 1H), 7.71 (m, 1H), 7.65-7.56 (m, 1H), 7.52 (m, 1H), 7.38 (m, 2H), 7.19 (m, 5H), 5.50 (2s, 1H, rotamer), 5.18-4.93 (m, 2H), 4.54-4.33 (m, 1H), 4.05-3.93 (m , 2H), 3.75-3.59 (m, 1H), 3.49-3.39 (m, 1H), 3.19 (2s, 3H, rotamer), 2.51 (m, 2H), 2.12-2.00 (m, 1H), 1.17-1.01 (m, 10H), 0.98-0.81 (m, 1H), 0.71-0.55 (m, 1H), 0.42-0.25 (m, 2H), 0.01-0.13 (m, 2H); 19 F NMR (282 MHz, DMSO-d 6 )δ-126.94, -127.36; MS (ES+) 675.5 (M+1), 697.5, 698.5 (M+Na), (ES-) 673.5 (M-1), 709.4, 710.4 (M+Cl); Optical rotation [α] D =(-)58.2[0.165, MeOH].

[0421] Step 3: Preparation of (2R,4R)-N-(5-((-)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)-4-methoxypyrrolidine-2-carboxamide (15d)

[0422] According to the procedure reported in step 2 of scheme 13, palladium on carbon 10% (0.265 g, 0.249 mmol) was used as catalyst by the reaction of (2R,4R)-2-(5-((-)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenylcarbamoyl)-4-methoxypyrrolidine-1-carboxylic acid benzyl ester (15c) (3.05 g, 4.52 mmol) in ethanol (100 mL) by hydrogenation to remove the benzyl group to give a white solid (2R,4R)-N-(5-((-)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)-4-methoxypyrrolidine-2-carboxamide (15d) (2.4 g, 4.44 mmol, yield 98%); 1 H NMR (300 MHz, DMSO-d 6 )δ10.09 (d, J=2.2Hz, 1H), 8.29 (dd, J=7.7, 2.4Hz, 1H), 7.80 (t, J=1.8Hz, 1H), 7.71 (dt, J=7.4, 1.3Hz, 1H), 7.62 (dt, J=8 .3, 1.5Hz, 1H), 7.51 (t, J=7.8Hz, 1H), 7.21 (dd, J=10.8, 8.7Hz, 1H), 7.10-7.01 (m, 1H), 5.47 (s, 1H), 3.95-3.81 (m, 1H), 3.74 (dd, J=8.1, 5.1Hz, 1H), 3.11 (s, 3H), 3.08-2.97 (m, 1H), 2.89 (dd, J=11.1, 2.4Hz, 1H), 2.75-2.56 (m, 2H), 2.13-2.0 1(m, 2H), 1.14(s, 10H), 1.12-1.04(m, 1H), 0.96-0.80(m, 1H), 0.72-0.53(m, 1H), 0.43-0.27(m, 2H), 0.00--0.15(m, 2H); 19 F NMR (282 MHz, DMSO-d 6 )δ-132.45; MS(ES+)541.5(M+1), (ES-)575.4(M+Cl); Optical rotation [α] D =(-)67.1[0.155, MeOH].

[0423] Step 4: Preparation of (2R,4R)-N1-(4-cyanophenyl)-N2-(5-((-)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)-4-methoxypyrrolidine-1,2-dicarboxamide (15e)

[0424] Using the reaction and workup conditions reported in Scheme 1, Step 9, (2R,4R)-N-(5-((-)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)-4-methoxypyrrolidine-2-carboxamide (15d) (0.5 g, 0.925 mmol) in tetrahydrofuran (20 mL) was reacted with DIPEA (0.646 mL, 3.70 mmol) as a base. ) solution and 4-isocyanobenzonitrile (0.267 g, 1.849 mmol) to give a white solid (2R, 4R)-N1-(4-cyanophenyl)-N2-(5-((-)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)-4-methoxypyrrolidine-1,2-dicarboxamide (15e) (514 mg, 0.751 mmol, yield 81%); 1 H NMR (300 MHz, DMSO-d 6 )δ9.51 (d, J=1.3Hz, 1H), 8.85 (s, 1H), 7.90-7.84 (m, 1H), 7.78 (t, J=1.6Hz, 1H), 7.77-7.66 (m, 5H), 7.62-7.57 (m, 1H), 7.50 (t, J=7.8Hz, 1H), 7.19 (dd, J=10.3, 8.7Hz, 1H), 7.14-7.06 (m, 1H), 5.50 (s, 1H), 4.57 (dd, J=9.1, 4.1Hz, 1H), 4.11-4.06 (m, 1H), 3.76 (dd, J=10.6, 5.2Hz, 1H), 3.65 (dd, J=10.2, 2.9Hz, 2H), 3.23 (s, 3H), 2.76-2.53 (m, 1H), 2.48-2.31 (m, 1H), 2.18-2 .05(m, 1H), 1.13(s, 9H), 1.11-1.01(m, 1H), 0.98-0.80(m, 1H), 0.72-0.55(m, 1H), 0.41-0.26(m, 2H), -0.02--0.14(m, 2H); 19 F NMR (282 MHz, DMSO-d 6)δ-127.51; MS: (ES+)685.5(M+1), 707.5, 709.7(M+Na), (ES-)719.5, 721.1(M+Cl); Optical rotation [α] D =(-)4.21[0.19, MeOH].

[0425] Step 5: Preparation of (2R, 4R)-N2-(5-((+)-1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-N1-(4-cyanophenyl)-4-methoxypyrrolidine-1,2-dicarboxamide (15f)

[0426] A solution of (2R,4R)-N1-(4-cyanophenyl)-N2-(5-((R)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)-4-methoxypyrrolidine-1,2-dicarboxamide (15e) (445 mg, 0.650 mmol) in ethanol (2 0 mL) solution was reacted, and purified by flash column chromatography (silica gel 12 g, eluted with CMA-80 chloroform solution, 0 to 60%) to obtain a white solid (2R, 4R)-N2-(5-((+)-1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-N1-(4-cyanophenyl)-4-methoxypyrrolidine-1,2-dicarboxamide (15f) (300 mg, 0.517 mmol, yield 80%); 1 H NMR (300 MHz, DMSO-d 6 )δ9.46 (s, 1H), 8.83 (s, 1H), 7.89-7.81 (m, 2H), 7.78-7.60 (m, 6H), 7.46 (t, J=7.8Hz, 1H ), 7.18-7.07 (m, 2H), 4.56 (dd, J=9.1, 4.1Hz, 1H), 4.17-3.98 (m, 1H), 3.77 (dd, J=10.5, 5.2 Hz, 1H), 3.63 (dd, J=10.4, 3.4 Hz, 1H), 3.22 (s, 3H), 2.41-2.14 (m, 5H), 2.14-2.00 (m, 1H), 1.09-0.92 (m, 2H), 0.76-0.49 (m, 1H), 0.41-0.27 (m, 2H), -0.04--0.19 (m, 2H); 19F NMR (282 MHz, DMSO-d6) δ-128.39; MS (ES+) 603.5, 604.5 (M+Na), (ES-) 615.6, 617.4 (M+Cl); optical rotation [α]D =(+)108.68[0.265, MeOH].

[0427] Scheme 16

[0428]

[0429] Preparation of (2R, 4R)-N2-(5-((+)-1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-4-methoxy-N1-(4-methoxyphenyl)pyrrolidine-1,2-dicarboxamide (16b)

[0430] Step 1: Preparation of (2R,4R)-N2-(5-((-)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)-4-methoxy-N1-(4-methoxyphenyl)pyrrolidine-1,2-dicarboxamide (16a)

[0431] A solution of (2R,4R)-N-(5-((-)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)-4-methoxypyrrolidine-2-carboxamide (15d) (0.5 g, 0.925 mmol) in tetrahydrofuran (20 mL), phenyl 1-isocyano-4-methoxybenzene (0.240 mL, 1.849 mmol) and DIPEA (0.646 mL, 3.70 mmol) were reacted to give a white solid (2R, 4R)-N2-(5-((-)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)-4-methoxy-N1-(4-methoxyphenyl)pyrrolidine-1,2-dicarboxamide (16a) (552 mg, 0.800 mmol, yield 87%); 1 HNMR (300 MHz, DMSO-d 6)δ9.50 (s, 1H), 8.28 (s, 1H), 8.00 (dd, J=7.7, 2.4Hz, 1H), 7.79 (t, J=1.7Hz, 1H), 7.71 (m, 1H), 7.60 (m, 1H), 7 .50 (t, J=7.8Hz, 1H), 7.43-7.34 (m, 2H), 7.19 (m, 1H), 6.87-6.79 (m, 2H), 5.50 (s, 1H), 4.52 (dd, J=9.2, 3.7Hz , 1H), 4.07(m, 1H), 3.70(s, 3H), 3.65(m, 2H), 3.22(s, 3H), 2.75-2.48(m, 2H), 2.32(m, 1H), 2.23-2.11(m, 1H ), 1.13(s, 10H), 1.00-0.79(m, 1H), 0.43-0.25(m, 2H), 0.63(m, 1H), 0.43-0.25(m, 2H), -0.01--0.15(m, 2H); 19 F NMR (282 MHz, DMSO-d 6 )δ-127.51; MS(ES+)690.5(M+1), 712.5, 713.5(M+Na), (ES-)724.4, 726.6(M+Cl); Optical rotation [α] D =(-)17.78[0.36, MeOH].

[0432] Step 2: Preparation of (2R,4R)-N2-(5-((+)-1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-4-methoxy-N1-(4-methoxyphenyl)pyrrolidine-1,2-dicarboxamide (16b)

[0433] A solution of (2R,4R)-N2-(5-((-)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)-4-methoxy-N1-(4-methoxyphenyl)pyrrolidine-1,2-dicarboxamide (16a) (485 mg, 0.703 mmol) in ethanol (20 mL) was reacted with concentrated HCl (0.586 mL, 7.03 mmol) as reported in Scheme 4, Step 6. The resulting mixture was purified by flash column chromatography (silica gel, eluted with CMA 80% chloroform solution, 0 to 100%) was purified to give a white solid (2R, 4R)-N2-(5-((+)-1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-4-methoxy-N1-(4-methoxyphenyl)pyrrolidine-1,2-dicarboxamide (16b) (19 mg, 0.032 mmol, yield 4.61%); 1HNMR (300 MHz, DMSO-d 6 )δ9.44 (s, 1H), 8.26 (s, 1H), 7.97 (d, J=7.6Hz, 1H), 7.86 (t, J=1.7Hz, 1H), 7.71-7.57 (m, 2H), 7 .46 (t, J=7.8Hz, 1H), 7.41-7.32 (m, 2H), 7.13 (d, J=8.0Hz, 2H), 6.88-6.75 (m, 2H), 4.51 (dd, J=9 .3, 3.7Hz, 1H), 4.11-3.99 (m, 1H), 3.70 (s, 3H), 3.67 (m, 1H), 3.64-3.56 (m, 1H), 3.22 (s, 3H), 2. 38-2.11(m, 6H), 1.11-0.94(m, 2H), 0.73-0.55(m, 1H), 0.40-0.24(m, 2H), -0.01--0.21(m, 2H); 19 F NMR (282 MHz, DMSO-d 6 )δ-129.61; MS(ES+)586.5(M+1), 608.5, 610.6(M+Na), (ES-)620.5, 622.5(M+Cl); IR(KBr)2228cm -1 ; Analytical calculation value C 33 H 36 FN 5 O 4 .0.5H 2 O; C, 66.65; H, 6.27; N, 11.78; Found; C, 66.83; H, 6.19; N, 11.71; Optical rotation [α] D =(+)95.48[0.155, MeOH].

[0434] Solution 17

[0435]

[0436] Preparation of (2R, 4R)-N2-(5-((+)-1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-4-methoxy-N1-(4-chlorophenyl)pyrrolidine-1,2-dicarboxamide (17b)

[0437] Step 1: Preparation of (2R,4R)-N2-(5-((-)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)-4-methoxy-N1-(4-chlorophenyl)pyrrolidine-1,2-dicarboxamide (17a)

[0438] A solution of (2R,4R)-N-(5-((-)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)-4-methoxypyrrolidine-2-carboxamide (15d) (0.5 g, 0.925 mmol) in tetrahydrofuran (20 mL), 4-chlorophenyl isocyanate (1n) (0.237 mL, 1.84 9mmol) and DIPEA (0.646mL, 3.70mmol) were reacted to give a white solid (2R,4R)-N2-(5-((-)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)-4-methoxy-N1-(4-chlorophenyl)pyrrolidine-1,2-dicarboxamide (17a) (555mg, 0.799mmol, yield 86%); 1 H NMR (300 MHz, DMSO-d 6 )δ9.52-9.44 (m, 1H), 8.53 (s, 1H), 7.96-7.88 (m, 1H), 7.79 (t, J=1.7Hz, 1H), 7.71 (dt, J=7.5, 1.3Hz, 1H), 7. 63-7.46 (m, 4H), 7.33-7.25 (m, 2H), 7.19 (dd, J=10.4, 8.8Hz, 1H), 7.11 (m, 1H), 5.50 (s, 1H), 4.54 (m, 1H), 4.1 0-4.05 (m, 1H), 3.72 (m, 1H), 3.68-3.57 (m, 1H), 3.22 (s, 3H), 2.63 (m, 2H), 2.42-2.26 (m, 1H), 2.12 (m, 1H), 1. 13(s, 9H), 1.12-1.01(m, 1H), 0.98-0.76(m, 1H), 0.72-0.56(m, 1H), 0.43-0.22(m, 2H), -0.02--0.16(m, 2H); 19 F NMR (282 MHz, DMSO-d 6 )δ-128.06; MS: (ES+)694.5(M+H), 716.5, 718.5(M+Na), (ES-)728.5, 730.4(M+Cl); Optical rotation [α] D =(-)17.31[0.335, MeOH].

[0439] Step 2: Preparation of (2R,4R)-N2-(5-((+)-1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-4-methoxy-N1-(4-chlorophenyl)pyrrolidine-1,2-dicarboxamide (17b)

[0440] A solution of (2R,4R)-N1-(4-chlorophenyl)-N2-(5-((-)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)-4-methoxypyrrolidine-1,2-dicarboxamide (17a) (478 mg, 0.689 mmol) in ethanol (20 mL) was reacted with concentrated HCl (0.574 mL, 6.89 mmol) as reported in Scheme 4, Step 6 and purified by flash column chromatography (silica gel, purified by CMA 80% chloroform solution, 0 to 100%) was purified to give a white solid (2R, 4R)-N2-(5-((+)-1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-N1-(4-chlorophenyl)-4-methoxypyrrolidine-1,2-dicarboxamide (17b) (52 mg, 8.3%); 1 H NMR (300 MHz, DMSO-d 6 )δ9.67 (s, 1H), 9.21 (s, 3H), 8.56 (s, 1H), 7.89 (m, 2H), 7.84 (m, 1H), 7.70-7.58 (m, 2H), 7.58-7.52 (m, 2H), 7.36 (m, 1H), 7.32-7.26 (m, 2H), 7.09 (m, 1H), 4.56 (dd, J=9.2, 4.0Hz, 1H), 4.13-4.04 (m, 1H ), 3.74 (dd, J=10.5, 5.2Hz, 1H), 3.62 (d, J=10.6Hz, 1H), 3.22 (s, 3H), 2.60-2.53 (m, 1H), 2.47-2.32 (m, 1H), 2.08 (m, 1H), 1.15-0.99 (m, 2H), 0.78-0.57 (m, 1H), 0.45-0.17 (m, 2H), 0.17--0.10 (m, 2H); 19 F NMR (282 MHz, DMSO-d 6 )δ-125.67; MS (ES+) 612.5, 614.4 (M+Na), (ES-) 624.4, (M+Cl); Optical rotation [α] D =(+)71.88[0.32, MeOH]; Analytical calculation value: C 32 H 33 CIF 5 O3 .HCl.2H 2 O; C, 58.01; H, 5.78; N, 10.57; Found: C, 58.21; H, 5.41; N, 10.24; IR (KBr) 2233cm -1 .

[0441] Scheme 18

[0442]

[0443] Preparation of (2R, 4R)-N2-(5-((+)-1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-N1-(5-chloropyridin-2-yl)-4-methoxypyrrolidine-1,2-dicarboxamide (18b)

[0444] Step 1: Preparation of ((2R,4R)-N1-(5-chloropyridin-2-yl)-N2-(5-((-)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)-4-methoxypyrrolidine-1,2-dicarboxamide (18a)

[0445] A solution of (2R,4R)-N-(5-((-)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)-4-methoxypyrrolidine-2-carboxamide (15d) (0.475 g, 0.879 mmol) in tetrahydrofuran (20 mL) and phenyl 5-chloropyridin-2-ylcarbamate (13b) (0.437 g, 1. 757mmol) and DIPEA (0.614mL, 3.51mmol) were reacted to obtain a white powder ((2R,4R)-N1-(5-chloropyridin-2-yl)-N2-(5-((-)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)-4-methoxypyrrolidine-1,2-dicarboxamide (18a) (484mg, 0.696mmol, yield 79%); 1 H NMR (300 MHz, DMSO-d 6)δ9.49 (s, 1H), 9.17 (s, 1H), 8.30 (d, J = 2.7Hz, 1H), 7.93-7.86 (m, 2H), 7.84-7.77 (m, 2H), 7.71 (dt, J = 7.5, 1.3Hz , 1H), 7.59 (dt, J=8.2, 1.6Hz, 1H), 7.50 (t, J=7.8Hz, 1H), 7.19 (dd, J=10.4, 8.7Hz, 1H), 7.14-7.06 (m, 1H), 5.50 ( s, 1H), 4.59 (dd, J=9.1, 3.9Hz, 1H), 4.04 (m, 1H), 3.81-3.63 (m, 2H), 3.21 (s, 3H), 2.75-2.52 (m, 2H), 2.48-2.29 ( m, 1H), 2.11 (m, 1H), 1.13 (s, 10H), 0.97-0.80 (m, 1H), 0.72-0.49 (m, 1H), 0.40-0.27 (m, 2H), -0.01--0.15 (m, 2H); 19 F NMR (282 MHz, DMSO-d 6 )δ-127.91; MS(ES+)695.5(M+1), 717.5, 719.5(M+Na), (ES-)729.5, 731.5(M+Cl); IR(KBr)2230cm -1 ; Optical rotation [α] D =(-)19.10[0.335, MeOH]; CHN calculated value: C 35 H 40 CIF 6 O 4 S.0.5H 2 O; C, 59.69; H, 5.87; N, 11.93; Found: C, 59.74; H, 5.75; N, 11.79.

[0446] Step 2: Preparation of (2R,4R)-N2-(5-((+)-1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-N1-(5-chloropyridin-2-yl)-4-methoxypyrrolidine-1,2-dicarboxamide (18b)

[0447] A solution of ((2R,4R)-N1-(5-chloropyridin-2-yl)-N2-(5-((-)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)-4-methoxypyrrolidine-1,2-dicarboxamide (18a) (406 mg, 0.584 mmol) in ethanol (20 mL) was reacted with concentrated HCl (0.487 mL, 5.84 mmol) as reported in Scheme 4, Step 6. The resulting mixture was purified by flash column chromatography (silica gel, purified by CMA 80 chloroform solution, 0 to 100%) was purified to give a white solid (2R, 4R)-N2-(5-((+)-1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-N1-(5-chloropyridin-2-yl)-4-methoxypyrrolidine-1,2-dicarboxamide (18b) (60 mg, 10%); 1 H NMR (300 MHz, DMSO-d 6 )δ9.45 (s, 1H), 9.15 (s, 1H), 8.30 (dd, J=2.6, 0.8Hz, 1H), 7.93-7.84 (m, 3H), 7.81 (dd, J=9.0, 2.7Hz, 1H), 7 .63 (ddt, J=7.5, 5.7, 1.3Hz, 2H), 7.46 (t, J=7.8Hz, 1H), 7.15 (d, J=1.3Hz, 1H), 7.13 (d, J=2.9Hz, 1H), 4.57 ( dd, J=9.2, 3.9Hz, 1H), 4.10-3.97(m, 1H), 3.82-3.62(m, 2H), 3.21(s, 3H), 2.41-2.18(m, 5H), 2.17-2.00(m, 1H), 1.08-0.94(m, 2H), 0.72-0.53(m, 1H), 0.42-0.25(m, 2H), -0.03--0.16(m, 2H); 19FNMR (282MHz, DMSO-d 6 )δ-128.61; MS (ES+) 591.5, 593.4 (M+1), (ES-) 625.3, 627.6 (M+Cl); Analytical calculation value: C 31 H 32 CIF 6 O 3 .0.25H 2 O: C, 62.52; H, 5.50; N, 14.11; Found: C, 62.53; H, 5.52; N, 13.89; Optical rotation [α] D =(+)95.38[0.26, MeOH].

[0448] Solution 19

[0449]

[0450] Preparation of (2R, 4R)-4-amino-N2-(5-((+)-1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-N1-(4-chlorophenyl)pyrrolidine-1,2-dicarboxamide (19c)

[0451] Step 1: Preparation of (2R,4R)-4-azido-N1-(4-chlorophenyl)-N2-(5-(1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)pyrrolidine-1,2-dicarboxamide (19a)

[0452] To a solution of (2R,4S)-N1-(4-chlorophenyl)-N2-(5-((+)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)-4-hydroxypyrrolidine-1,2-dicarboxamide (9b) (0.502 g, 0.738 mmol) and triphenylphosphine (0.581 g, 2.214 mmol) in tetrahydrofuran (15 mL) was added a mixture of diphenylphosphoryl azide (0.477 mL, 2.214 mmol) and diisopropyl azodicarboxylate (0.430 mL, 2.214 mmol) in tetrahydrofuran (5 mL) at 0°C over 30 minutes. The reaction product was stirred at room temperature for 24 hours, diluted with ethyl acetate (150 mL), washed with water (2×25 mL) and brine (25 mL), dried, filtered and concentrated in vacuo. The crude residue was purified by flash column chromatography (silica gel 40 g, eluted with (9:1) ethyl acetate / methanol in hexanes, 0 to 100%) to give (2R,4R)-4-azido-N1-(4-chlorophenyl)-N2-(5-(1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)pyrrolidine-1,2-dicarboxamide (19a) (88 mg, 0.125 mmol, 16.91% yield) as a white solid; 1 HNMR (300 MHz, DMSO-d 6)δ9.97(s, 1H), 8.78(s, 1H), 8.06(s, 1H), 7.99(m, 1H), 7.91(m, 1H), 7.76(m, 4H), 7 .51(m,2H),7.39(m,1H),7.38-7.26(m,1H),5.71(s,1H),4.79(m,2H),4.35-4.15(m , 1H), 4.03 (m, 1H), 3.76 (d, J=10.2Hz, 1H), 2.37-2.23 (m, 1H), 1.40-1.35 (m, 1H), 1 .33(s, 11H), 1.23-1.01(m, 1H), 0.84(m, 1H), 0.62-0.46(m, 2H), 0.21-0.06(m, 2H); 19 F NMR (282 MHz, DMSO-d 6 )δ-126.67.

[0453] Step 2: Preparation of (2R,4R)-4-amino-N1-(4-chlorophenyl)-N2-(5-(1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)pyrrolidine-1,2-dicarboxamide (19c)

[0454] According to the procedure reported in step 2 of scheme 13, (2R,4R)-4-azido-N1-(4-chlorophenyl)-N2-(5-(1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)pyrrolidine-1,2-dicarboxamide (19a) (0.08 g, 0.1 13mmol) in ethanol (10mL) solution was hydrogenated for 6 hours to obtain a white solid (2R,4R)-4-amino-N1-(4-chlorophenyl)-N2-(5-(1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)pyrrolidine-1,2-dicarboxamide (19c) (60 mg, 0.088 mmol, yield 78%); 1 H NMR (300 MHz, DMSO-d 6)δ8.46(s, 1H), 8.11(d, J=7.3Hz, 1H), 7.79(m, 1H), 7.70(m, 1H), 7.63-7.46(m, 4H) , 7.26 (m, 2H), 7.23-7.13 (m, 1H), 7.05 (m, 1H), 5.48 (s, 1H), 4.44 (dd, J=9.1, 5.1Hz, 1H), 3.74-3.40(m, 3H), 2.76-2.21(m, 4H), 1.78(m, 1H), 1.13(s, 10H), 1.02-0.74( m, 1H), 0.74-0.51 (m, 1H), 0.34 (m, 2H), -0.06 (m, 2H); MS (ES+) 679.6 (M+1); 702.5 (M + Na).

[0455] Step 3: Preparation of (2R,4R)-4-amino-N2-(5-((+)-1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-N1-(4-chlorophenyl)pyrrolidine-1,2-dicarboxamide (19c)

[0456] A solution of (2R,4R)-4-amino-N1-(4-chlorophenyl)-N2-(5-(1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)pyrrolidine-1,2-dicarboxamide (19c) (0.052 g, 0.077 mmol) in ethanol (5 mL) was reacted with concentrated HCl (0.064 mL, 0.766 mmol) as reported in Scheme 4, Step 6 and purified by flash column chromatography (silica gel, purified by CMA 80% chloroform solution, 0 to 100%) was purified to give a white solid (2R, 4R)-4-amino-N2-(5-((+)-1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-N1-(4-chlorophenyl)pyrrolidine-1,2-dicarboxamide (19c) (12 mg, 0.021 mmol, yield 27.3%); 1 H NMR (300 MHz, DMSO-d 6)δ8.45 (s, 1H), 8.15-7.99 (m, 1H), 7.86 (t, J=1.6Hz, 1H), 7.67-7.60 (m, 2H), 7.57-7. 42(m, 3H), 7.32-7.23(m, 2H), 7.15-7.06(m, 2H), 4.43(dd, J=9.0, 5.3Hz, 1H), 3.64(d d, J=9.6, 5.6Hz, 1H), 3.58-3.47(m, 1H), 2.41-2.27(m, 4H), 2.25-2.18(m, 2H), 1.84- 1.63(m, 1H), 1.12-0.93(m, 2H), 0.72-0.55(m, 1H), 0.34(m, 2H), -0.01--0.14(m, 2H); 19 F NMR (282 MHz, DMSO-d 6 )δ-128.51; MS (ES-) 573.5, 575.4 (M-1); optical rotation [α] D =(+)85.0[0.08, MeOH].

[0457] Solution 20

[0458]

[0459] Preparation of (R)-N2-(5-(1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-N1-(4-chlorophenyl)-4-oxopyrrolidine-1,2-dicarboxamide (20b)

[0460] Step 1: Preparation of (R)-N1-(4-chlorophenyl)-N2-(5-(1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)-4-oxopyrrolidine-1,2-dicarboxamide (20a)

[0461] To a solution of (2R,4S)-N1-(4-chlorophenyl)-N2-(5-((+)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)-4-hydroxypyrrolidine-1,2-dicarboxamide (9b) (50 mg, 0.074 mmol) in dichloromethane (10 mL) was added sodium bicarbonate (24.70 mg, 0.294 mmol) and Dess-Martin periodinane (100 mg, 0.235 mmol) at room temperature and stirred for 30 minutes. The reaction product was diluted with dichloromethane (50 mL), washed with water (2×25 mL) and brine (25 mL), dried, filtered and concentrated to dryness in vacuo. The resulting crude residue was purified by flash column chromatography (silica gel, 4 g, eluted with CMA80 in chloroform, 0 to 100%) to give a nearly colorless solid (R)-N1-(4-chlorophenyl)-N2-(5-(1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)-4-oxopyrrolidine-1,2-dicarboxamide (20a) (40 mg, 0.059 mmol, 80% yield); 1 H NMR (300 MHz, DMSO-d 6 )δ10.09(s, 1H), 8.57(s, 1H), 8.08-7.98(m, 1H), 7.94(m, 1H), 7.85-7.66(m, 2H), 7.61- 7.45(m, 3H), 7.31(m, 2H), 7.26-7.16(m, 1H), 7.13(m, 1H), 5.51(s, 1H), 5.10(d, J=9.7H z, 1H), 4.27-4.10 (m, 1H), 3.98 (d, J=17.4Hz, 1H), 3.40 (m, 2H), 2.63-2.38 (m, 2H), 1.11 (s, 10H), 0.98-0.79 (m, 1H), 0.72-0.51 (m, 1H), 0.40-0.25 (m, 2H), -0.00--0.21 (m, 2H); 19 F NMR (282 MHz, DMSO-d 6 )δ-126.75; MS (ES+) 700.4 (M+23), (ES-) 676.4 (M-1); 712.4, 714.4 (M+Cl).

[0462] Step 2: Preparation of (R)-N2-(5-(1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-N1-(4-chlorophenyl)-4-oxopyrrolidine-1,2-dicarboxamide (20b)

[0463] A solution of (R)-N1-(4-chlorophenyl)-N2-(5-(1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)-4-oxopyrrolidine-1,2-dicarboxamide (20a) (35 mg, 0.052 mmol) in ethanol (5 mL) was reacted as reported in Scheme 4, Step 6, with concentrated HCl (0.043 mL, 0.516 mmol) and purified by flash column chromatography (silica gel, purified by CMA 80 chloroform solution, 0 to 100%) was purified to give a white solid (R)-N2-(5-(1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-N1-(4-chlorophenyl)-4-oxopyrrolidine-1,2-dicarboxamide (20b) (20 mg, 0.035 mmol, yield 67.5%); 1 H NMR (300 MHz, DMSO-d 6 )δ10.03 (s, 1H), 8.56 (s, 1H), 8.04-7.96 (m, 1H), 7.86 (t, J=1.8Hz, 1H), 7.63 (ddt, J=7.6, 5.9, 1.4Hz, 2 H), 7.59-7.51 (m, 2H), 7.45 (t, J=7.8Hz, 1H), 7.34-7.27 (m, 2H), 7.18-7.08 (m, 2H), 5.10 (dd, J=10.0, 2. 2Hz, 1H), 4.19 (d, J=17.6Hz, 1H), 3.98 (d, J=17.5Hz, 1H), 3.11 (m, 1H), 2.61-2.51 (m, 1H), 2.36-2.27 (m , 2H), 2.27-2.15(m, 2H), 1.09-0.90(m, 2H), 0.70-0.51(m, 1H), 0.37-0.27(m, 2H), -0.00--0.13(m, 2H); 19 F NMR (282 MHz, DMSO-d 6 )δ-127.99; MS (ES+) 596.5 (M+Na), (ES-) 610.4 (M+Cl).

[0464] Solution 21

[0465]

[0466] Preparation of (2R, 4R)-N2-(5-((+)-1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-4-hydroxy-N1-phenylpyrrolidine-1,2-dicarboxamide (21d)

[0467] Step 1: Preparation of benzyl (2R,4R)-2-(5-((-)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenylcarbamoyl)-4-hydroxypyrrolidine-1-carboxylate (21a)

[0468] Using the reaction and workup conditions reported in step 10 of scheme 1, a solution of (2R,4R)-1-(benzyloxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid (15a) (1.5 g, 5.65 mmol), (R)-N-((-)-1-(3-amino-4-fluorophenyl)-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-methylpropane-2-sulfenamide (4e) (2.339 g, 5.65 mmol) in tetrahydrofuran (50 mL) was reacted with ethyl 2-ethoxy-1(2H)-quinolinecarboxylate (1.398 g, 5.65 mmol) and purified by flash column chromatography (silica gel 25 g, purified by CMA 80% chloroform solution, 0 to 100%) to obtain a white solid (2R, 4R)-2-(5-((-)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenylcarbamoyl)-4-hydroxypyrrolidine-1-carboxylic acid benzyl ester (21a) (2.396 g, 3.63 mmol, yield 64.1%); 1 H NMR (300 MHz, DMSO-d 6 )δ9.79 (2s, 1H, rotamer), 8.04 (d, J=7.3 Hz, 1H), 7.79 (s, 1H), 7.71 (d, J=7.4 Hz, 1H), 7.60 (m, 1H), 7.51 (m, 1H), 7.37 (m, 2H), 7.26-7.04 (m, 5H), 5.50 (d, J=17.5 Hz, 1H), 5.29 (s, 1H), 5.14-4.89 (m, 2H), 4.53- 4.34 (m, 1H), 4.27 (s, 1H), 3.71-3.47 (m, 2H), 3.47-3.24 (m, 1H), 2.77-2.26 (m, 2H), 1.88 (m, 1H), 1.16-1.01 (m, 10H, rotamer), 0.98-0.77 (m, 1H), 0.73-0.53 (m, 1H), 0.41-0.26 (m, 2H), -0.02--0.16 (m, 2H); 19 F NMR (282 MHz, DMSO-d 6 )δ-127.76, -127.94; MS (ES+) 683.6 (M+Na), (ES-) 695.6 (M+Cl); Optical rotation [α] D=(-)75.0[0.16, MeOH].

[0469] Step 2: Preparation of (2R,4R)-N-(5-((-)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)-4-hydroxypyrrolidine-2-carboxamide (21b)

[0470] According to the procedure reported in step 2 of scheme 13, palladium on carbon 10% (0.378 g, 0.356 mmol) was reacted with (2R,4R)-2-(5-((-)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenylcarbamoyl)-4-hydroxypyrrolidine-1-carboxylic acid benzyl ester (21a) (2.35 g) to obtain a 5-hydroxy-1-hydroxy ... , 3.56 mmol) in ethanol (100 mL) by hydrogenation to remove the benzyl group to give a white solid (2R, 4R)-N-(5-((-)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)-4-hydroxypyrrolidine-2-carboxamide (21b) (1.61 g, 3.06 mmol, yield 86%); 1 H NMR (300 MHz, DMSO-d 6 )δ10.24 (s, 1H), 8.36 (dd, J=7.8, 2.4Hz, 1H), 7.79 (t, J=1.7Hz, 1H), 7.72 (m, 1H), 7.60 (m, 1H), 7.51 (m , 1H), 7.21 (dd, J=10.8, 8.7Hz, 1H), 7.09-6.99 (m, 1H), 5.46 (s, 1H), 4.70 (d, J=3.3Hz, 1H), 4.22-4.10 (m, 1H), 3.84-3.64 (m, 1H), 3.00 (m, 1H), 2.79-2.68 (m, 2H), 2.68-2.52 (m, 2H), 2.21-2.07 (m, 1H), 1.8 4(m, 1H), 1.14(s, 10H), 1.01-0.76(m, 1H), 0.75-0.54(m, 1H), 0.44-0.25(m, 2H), -0.02--0.23(m, 2H); 19 F NMR (282 MHz, DMSO-d 6 )δ-132.73; MS(ES+)527.5(M+1), 549.5(M+Na), (ES-)525.5(M-1), 561.5(M+Cl); Optical rotation [α] D =(-)0.44[0.15, MeOH].

[0471] Step 3: Preparation of (2R,4R)-N2-(5-((-)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)-4-hydroxy-N1-phenylpyrrolidine-1,2-dicarboxamide (21c)

[0472] Using the reaction and workup conditions reported in Scheme 1, Step 9, (2R,4R)-N-(5-((-)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)-4-hydroxypyrrolidine-2-carboxamide (21b) (160 mg, 0.304 mmol) and phenyl isocyanate (0.040 mL, 0.365 mmol) in tetrahydrofuran (10 mL) solution to give a white solid (2R, 4R)-N2-(5-((-)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)-4-hydroxy-N1-phenylpyrrolidine-1,2-dicarboxamide (21c) (176 mg, 0.273 mmol, yield 90%); 1 H NMR (300 MHz, DMSO-d 6 )δ9.67 (s, 1H), 8.37 (s, 1H), 8.14-8.02 (m, 1H), 7.79 (t, J=1.7Hz, 1H), 7.70 (dt, J=7.4, 1.3Hz, 1H), 7.59 (dt, J=8.1, 1.6Hz, 1 H), 7.55-7.44 (m, 3H), 7.29-7.10 (m, 3H), 7.12-7.02 (m, 1H), 6.94 (tt, J=7.3, 1.2Hz, 1H), 5.50 (s, 1H), 5.34 (d, J=4.4Hz, 1H), 4.51 (dd, J=9.1, 4.5Hz, 1H), 4.42-4.27 (m, 1H), 3.67 (dd, J=10.1, 5.1Hz, 1H), 3.52 (m, 1H), 2.74-2.52 (m, 2H), 2.44-2.29 (m, 1 H), 1.93 (dd, J=11.0, 6.5Hz, 1H), 1.13 (s, 10H), 1.00-0.79 (m, 1H), 0.71-0.55 (m, 1H), 0.42-0.26 (m, 2H), 0.02--0.15 (m, 2H); 19 F NMR (282 MHz, DMSO-d 6)δ-128.67; MS: (ES+)646.5(M+1), 668.5(M+Na), (ES-)644.5(M-1), 680.5(M+Cl); Optical rotation [α] D =(-)37.42[0.155, MeOH].

[0473] Step 4: Preparation of (2R,4R)-N2-(5-((+)-1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-4-hydroxy-N1-phenylpyrrolidine-1,2-dicarboxamide (21d)

[0474] As reported in Scheme 4, step 6, (2R,4R)-N2-(5-((-)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)-4-hydroxy-N1-phenylpyrrolidine-1,2-dicarboxamide (21c) (160 mg, 0.248 mmol) in ethanol (10 mL) was reacted with concentrated HCl (0.206 mL, 2.478 mmol) to give a colorless solid (2R,4R)-N2-(5-((+)-1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-4-hydroxy-N1-phenylpyrrolidine-1,2-dicarboxamide (21d) (50 mg, 0.092 mmol, 37.3% yield); 1 H NMR (300 MHz, DMSO-d 6 )δ9.61 (s, 1H), 8.36 (s, 1H), 8.07 (d, J = 7.6Hz, 1H), 7.86 (t, J = 1.7Hz, 1H), 7.68-7.58 (m, 2H), 7.55- 7.39 (m, 3H), 7.29-7.17 (m, 1H), 7.12 (d, J = 9.5Hz, 2H), 6.99-6.85 (m, 1H), 5.30 (d, J = 4.5Hz, 1H), 4. 50 (dd, J=9.1, 4.5Hz, 1H), 4.34 (s, 1H), 3.68 (dd, J=10.1, 5.1Hz, 1H), 3.50 (m, 1H), 2.38-2.19 (m, 6H ), 1.98-1.84(m, 1H), 1.10-0.94(m, 2H), 0.70-0.55(m, 1H), 0.39-0.28(m, 2H), -0.02--0.12(m, 2H); 19 F NMR (282 MHz, DMSO-d 6 )δ-129.38; MS (ES+) 564.4 (M+Na); Analytical calculation value C 31 H32 FN 5 O 3 .0.25H 2 O: C, 67.62; H, 6.04; N, 12.72; Found: C, 67.72; H, 6.10; N, 12.60; Optical rotation [α] D =(+)90.3[0.32, MeOH].

[0475] Solution 22

[0476]

[0477] Preparation of (2R, 4R)-N2-(5-((+)-1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-4-hydroxy-N1-p-tolylpyrrolidine-1,2-dicarboxamide (22b)

[0478] Step 1: Preparation of (2R,4R)-N2-(5-((-)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)-4-hydroxy-N1-p-tolylpyrrolidine-1,2-dicarboxamide (22a)

[0479] Using the reaction and workup conditions reported in Scheme 1, Step 9, (2R,4R)-N-(5-((-)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)-4-hydroxypyrrolidine-2-carboxamide (21b) (160 mg, 0.304 mmol) and p-tolyl isocyanate (0.046 mL, 0.365 mmol) in tetrahydrofuran (10 mL) to give a white solid (2R, 4R)-N2-(5-((-)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)-4-hydroxy-N1-p-tolylpyrrolidine-1,2-dicarboxamide (22a) (154 mg, 0.233 mmol, yield 77%); 1 H NMR (300 MHz, DMSO-d 6)δ9.65 (s, 1H), 8.29 (s, 1H), 8.10 (dd, J=7.7, 2.4Hz, 1H), 7.79 (t, J=1.7Hz, 1H), 7.70 (dt, J=7.4, 1.4Hz, 1H), 7.59 (dt, J=8.1, 1.6Hz, 1H ), 7.55-7.45 (m, 1H), 7.42-7.31 (m, 2H), 7.19 (dd, J=10.6, 8.7Hz, 1H), 7.10-6.98 (m, 3H), 5.51 (s, 1H), 5.32 (d, J=3.7Hz, 1H), 4.50 (d, J =4.7 Hz, 1H), 4.41-4.27 (m, 1H), 3.63 (d, J=5.1 Hz, 1H), 3.55-3.46 (m, 1H), 2.64 (m, 1H), 2.61-2.51 (m, 1H), 2.42-2.28 (m, 1H), 2.22 (m, 3H), 1.92 (m, 1H), 1.14 (d, 9H, rotamer), 1.12-1.00 (m, 1H), 0.98-0.81 (m, 1H), 0.72-0.55 (m, 1H), 0.44-0.29 (m, 2H), -0.01--0.13 (m, 2H); 19 F NMR (282 MHz, DMSO-d 6 )δ-128.93; MS: (ES+)682.5(M+Na), (ES-)658.6(M-1), 694.6(M+Cl); Optical rotation [α] D =(-)14.66[0.15, MeOH].

[0480] Step 2: Preparation of (2R, 4R)-N2-(5-((+)-1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-4-hydroxy-N1-p-tolylpyrrolidine-1,2-dicarboxamide (22b)

[0481] As reported in Scheme 4, Step 6, (2R,4R)-N2-(5-((-)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)-4-hydroxy-N1-p-tolylpyrrolidine-1,2-dicarboxamide (22a) (140 mg, 0.212 mmol) was reacted with concentrated HCl (0.177 mL, 2.122 mmol) to give (2R,4R)-N2-(5-((+)-1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-4-hydroxy-N1-p-tolylpyrrolidine-1,2-dicarboxamide (22b) (39 mg, 0.070 mmol, 33.1% yield) as a white solid; 1 HNMR (300 MHz, DMSO-d 6 )δ9.60 (s, 1H), 8.27 (s, 1H), 8.07 (d, J=7.5Hz, 1H), 7.87 (t, J=1.7Hz, 1H), 7.73-7.57 (m, 2H), 7.46 (t, J=7 .8Hz, 1H), 7.40-7.34 (m, 2H), 7.15-7.09 (m, 2H), 7.03 (d, J=8.3Hz, 2H), 5.29 (d, J=4.3Hz, 1H), 4.49 (dd, J= 9.1, 4.5Hz, 1H), 4.33 (m, 1H), 3.66 (dd, J=10.1, 5.1Hz, 1H), 3.48 (dd, J=10.0, 3.9Hz, 1H), 2.44-2.27 (m, 3H ), 2.22(m, 5H), 1.98-1.84(m, 1H), 1.10-0.93(m, 2H), 0.72-0.54(m, 1H), 0.40-0.26(m, 2H), -0.06(m, 2H); 19 F NMR (282 MHz, DMSO-d 6 )δ-129.66; MS(ES+)578.5(M+Na), (ES-)554.6(M-1), 590.5(M+Cl); Optical rotation [α] D =(+)92.5[0.24, MeOH]; Analytical calculation value C 32 H 34 FN 5 O 3 .0.25H 2 O: C, 68.61; H, 6.21; N, 12.50; Found, 68.68; H, 6.26; N, 12.30; Optical rotation [α] D =(+)90.0[0.32, MeOH].

[0482] Solution 23

[0483]

[0484] Preparation of (2R, 4R)-N2-(5-((+)-1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-N1-(4-bromophenyl)-4-hydroxypyrrolidine-1,2-dicarboxamide (23b)

[0485] Step 1: Preparation of (2R,4R)-N1-(4-bromophenyl)-N2-(5-((-)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)-4-hydroxypyrrolidine-1,2-dicarboxamide (23a)

[0486] Using the reaction and workup conditions reported in Scheme 1, Step 9, (2R,4R)-N-(5-((-)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)-4-hydroxypyrrolidine-2-carboxamide (21b) (160 mg, 0.304 mmol) and 4-bromophenyl isocyanate (72.2 mg, 0.365 mmol) were reacted with 4-bromophenyl isocyanate (100 mg, 0.304 mmol). ol) in tetrahydrofuran (10 mL) to give a white solid (2R, 4R)-N1-(4-bromophenyl)-N2-(5-((-)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)-4-hydroxypyrrolidine-1,2-dicarboxamide (23a) (192 mg, 0.265 mmol, yield 87%); 1 H NMR (300 MHz, DMSO-d 6)δ9.66 (s, 1H), 8.52 (s, 1H), 8.06 (dd, J=7.4, 2.3Hz, 1H), 7.79 (t, J=1.6Hz, 1H), 7.71 (dt, J=7.5, 1.3Hz, 1H), 7.59 (dt, J=8.2, 1.6 Hz, 1H), 7.54-7.46 (m, 3H), 7.45-7.37 (m, 2H), 7.23-7.14 (m, 1H), 7.11-7.03 (m, 1H), 5.50 (s, 1H), 5.33 (d, J=4.4Hz, 1H), 4.51 (dd, J=9.0, 4.7Hz, 1H), 4.41-4.27 (m, 1H), 3.68 (dd, J=10.1, 5.2Hz, 1H), 3.49 (dd, J=9.9, 3.8Hz, 1H), 2.77-2.60 (m, 1H), 2.64-2.51 (m, 1H), 2.47-2.24(m, 1H), 1.97-1.78(m, 1H), 1.13(s, 10H), 0.98-0.77(m, 1H), 0.63(m, 1H), 0.41-0.22(m, 2H), -0.02--0.17(m, 2H); 19 F NMR (282 MHz, DMSO-d 6 )δ-128.38; MS: (ES+)746.5, 748.5(M+Na), (ES-)722.5(M-1), 758.5, 760.4(M+Cl); Optical rotation [α] D =(-)12.9[0.155, MeOH].

[0487] Step 2: Preparation of (2R,4R)-N2-(5-((+)-1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-N1-(4-bromophenyl)-4-hydroxypyrrolidine-1,2-dicarboxamide (23b)

[0488] As reported in Scheme 4, Step 6, (2R,4R)-N1-(4-bromophenyl)-N2-(5-((-)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)-4-hydroxypyrrolidine-1,2-dicarboxamide (23a) (180 mg, 0.248 mmol) was reacted with concentrated HCl (0.207 mL, 2.484 mmol) to give (2R,4R)-N2-(5-((+)-1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-N1-(4-bromophenyl)-4-hydroxypyrrolidine-1,2-dicarboxamide (23b) (41 mg, 0.066 mmol, 26.6% yield) as a white solid; 1 H NMR (300 MHz, DMSO-d 6 )δ9.61 (s, 1H), 8.50 (s, 1H), 8.04 (d, J = 7.6Hz, 1H), 7.86 (t, J = 1.7Hz, 1H), 7.67-7.59 (m, 2H), 7.53 -7.45 (m, 3H), 7.44-7.37 (m, 2H), 7.12 (d, J = 8.9Hz, 2H), 5.30 (d, J = 4.7Hz, 1H), 4.50 (dd, J = 9.1, 4.8 Hz, 1H), 4.41-4.28 (m, 1H), 3.68 (dd, J=10.2, 5.4Hz, 1H), 3.47 (dd, J=9.8, 4.0Hz, 1H), 2.40-2.14( m, 5H), 2.01-1.79 (m, 1H), 1.13-0.88 (m, 2H), 0.63 (m, 1H), 0.42-0.27 (m, 2H), -0.02--0.12 (m, 2H); 19 F NMR (282 MHz, DMSO-d 6 )δ-129.26; MS(ES+)642.4, 644.5(M+Na); IR(KBr)2229cm -1 ; Optical rotation [α] D =(+)101.54 [0.325, MeOH]; Analytical calculation value C 31 H 31 BrFN 5 O 3 .0.5H 2 O: C, 59.15; H, 5.12; N, 11.12; Found: C, 59.11; H, 5.18; N, 10.95.

[0489] Solution 24

[0490]

[0491] Preparation of (2R, 4R)-N2-(5-((+)-1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-N1-(4-fluorophenyl)-4-hydroxypyrrolidine-1,2-dicarboxamide (24b)

[0492] Step 1: Preparation of (2R,4R)-N2-(5-((-)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)-N1-(4-fluorophenyl)-4-hydroxypyrrolidine-1,2-dicarboxamide (24a)

[0493] Using the reaction and workup conditions reported in Scheme 1, Step 9, (2R,4R)-N-(5-((-)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)-4-hydroxypyrrolidine-2-carboxamide (21b) (160 mg, 0.304 mmol) and 4-fluorophenyl isocyanate (0.041 mL, 0.365 mmol) were added to the mixture. ol) in tetrahydrofuran (10 mL) to give a white solid (2R, 4R)-N2-(5-((-)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)-N1-(4-fluorophenyl)-4-hydroxypyrrolidine-1,2-dicarboxamide (24a) (138 mg, 0.208 mmol, yield 68.4%); 1 H NMR (300 MHz, DMSO-d 6)δ9.64 (d, J=7.0Hz, 1H), 8.43 (s, 1H), 8.08 (dd, J=7.6, 2.5Hz, 1H), 7.91-7.75 (m, 1H), 7.71 (dt, J=7.4, 1.4Hz, 1H), 7.59 (dt, J=8.2, 1.6Hz, 1H), 7.50 (m, 3H), 7.12-7.01 (m, 3H), 5.50 (m, 1H), 5.32 (d, J=4.5Hz, 1H), 4.50 (dd, J=9.1, 4.5Hz, 1H) , 4.41-4.28 (m, 1H), 3.66 (dd, J=10.0, 5.1Hz, 1H), 3.49 (dd, J=10.2, 3.8Hz, 1H), 2.74-2.51 (m, 2H), 2.49-2.23 (m, 2H), 1 .98-1.81 (m, 1H), 1.13 (d, J=2.2Hz, 10H), 0.98-0.76 (m, 1H), 0.70-0.52 (m, 1H), 0.38-0.27 (m, 2H), 0.01--0.16 (m, 2H); 19 F NMR (282 MHz, DMSO-d 6 )δ-121.20, -128.61; MS: (ES+)664.5(M+1), 686.5(M+Na), (ES-)662.5(M-1), 698.5(M+Cl); Optical rotation [α] D =(-)10.52[0.095, MeOH].

[0494] Step 2: Preparation of (2R,4R)-N2-(5-((+)-1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-N1-(4-fluorophenyl)-4-hydroxypyrrolidine-1,2-dicarboxamide (24b)

[0495] As reported in Scheme 4, Step 6, (2R,4R)-N2-(5-((-)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)-N1-(4-fluorophenyl)-4-hydroxypyrrolidine-1,2-dicarboxamide (24a) (125 mg, 0.188 mmol) was reacted with concentrated HCl (0.157 mL, 1.883 mmol) to give (2R,4R)-N2-(5-((+)-1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-N1-(4-fluorophenyl)-4-hydroxypyrrolidine-1,2-dicarboxamide (24b) (35 mg, 0.063 mmol, 33.2% yield) as a white solid; 1H NMR (300 MHz, DMSO-d 6 )δ9.60 (s, 1H), 8.42 (s, 1H), 8.06 (d, J=7.6Hz, 1H), 7.86 (t, J=1.8Hz, 1H), 7.63 (m, 2H), 7.55-7. 41 (m, 3H), 7.18-7.06 (m, 2H), 7.05 (d, J = 7.0Hz, 1H), 5.30 (d, J = 4.7Hz, 1H), 4.49 (dd, J = 9.1, 4.6H z, 1H), 4.43-4.22 (m, 1H), 3.67 (dd, J=10.1, 5.3Hz, 1H), 3.58-3.31 (m, 1H), 2.37-2.17 (m, 6H), 1 .98-1.77(m, 1H), 1.11-0.94(m, 2H), 0.71-0.54(m, 1H), 0.40-0.26(m, 2H), -0.03--0.12(m, 2H); 19 F NMR (282 MHz, DMSO-d 6 )δ-121.39, -129.49; MS (ES+) 582.5 (M+Na); optical rotation [α] D =(+)85.93[0.27, MeOH]

[0496] Solution 25

[0497]

[0498] Preparation of (2R, 4R)-N2-(5-((+)-1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-4-hydroxy-N1-(4-nitrophenyl)pyrrolidine-1,2-dicarboxamide (25b)

[0499] Step 1: Preparation of (2R,4R)-N2-(5-((+)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)-4-hydroxy-N1-(4-nitrophenyl)pyrrolidine-1,2-dicarboxamide (25a)

[0500] Using the reaction and workup conditions reported in Scheme 1, Step 9, (2R,4R)-N-(5-((-)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)-4-hydroxypyrrolidine-2-carboxamide (21b) (280 mg, 0.532 mmol) and 4-nitrophenyl isocyanate (105 mg, 0.638 mmol) were reacted with 4-nitrophenyl isocyanate (105 mg, 0.638 mmol) to obtain 4-nitrophenyl isocyanate. l) in tetrahydrofuran (10 mL) solution to give a pale yellow solid (2R, 4R)-N2-(5-((+)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)-4-hydroxy-N1-(4-nitrophenyl)pyrrolidine-1,2-dicarboxamide (25a) (353 mg, 0.511 mmol, yield 96%); 1 H NMR (300 MHz, DMSO-d 6 )δ9.72 (s, 1H), 9.07 (s, 1H), 8.19-8.10 (m, 2H), 8.02 (d, J=7.1Hz, 1H), 7.85-7.75 (m, 3H), 7.70 (m, 1H), 7.62-7.55 (m, 1H), 7.50 (t, J=7.8Hz, 1H), 7.19 (dd, J=10.5, 8.7Hz, 1H), 7.15-7.02 (m, 1H), 5.51 (s, 1H), 5.35 (s, 1H), 4.56 (dd, J=8.8, 5.1Hz, 1 H), 4.36 (m, 1H), 3.75 (dd, J=10.1, 5.4Hz, 1H), 3.52 (dd, J=9.9, 4.2Hz, 1H), 3.48-3.38 (m, 1H), 2.75-2.51 (m, 1H), 2.48-2. 30 (m, 1H), 1.89 (m, 1H), 1.13 (s, 9H), 1.11-1.01 (m, 1H), 0.90 (m, 1H), 0.61 (m, 1H), 0.38-0.30 (m, 2H), -0.00--0.14 (m, 2H); 19 F NMR (282 MHz, DMSO-d 6 )δ-127.81; MS(ES+)713.5(M+Na), (ES-)689.5(M-1), 725.5(M+Cl); Optical rotation [α] D =(+)18.66[0.15, MeOH].

[0501] Step 2: Preparation of (2R,4R)-N2-(5-((+)-1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-4-hydroxy-N1-(4-nitrophenyl)pyrrolidine-1,2-dicarboxamide (25b)

[0502] As reported in step 6 of scheme 4, a solution of (2R,4R)-N2-(5-((+)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)-4-hydroxy-N1-(4-nitrophenyl)pyrrolidine-1,2-dicarboxamide (25a) (100 mg, 0.145 mmol) in ethanol (10 mL) was reacted with concentrated HCl (0.121 mL, 1.448 mmol) to give (2R,4R)-N2-(5-((+)-1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-4-hydroxy-N1-(4-nitrophenyl)pyrrolidine-1,2-dicarboxamide (25b) (61 mg, 0.104 mmol, 71.8% yield) as a pale yellow solid; 1 H NMR (300 MHz, DMSO-d 6 )δ9.66 (s, 1H), 9.05 (d, J=2.7Hz, 1H), 8.15 (ddt, J=9.3, 4.3, 2.1Hz, 2H), 7.99 (d, J=7.3Hz, 1H), 7.89-7.75 (m, 3H) , 7.69-7.56 (m, 2H), 7.47 (ddd, J=8.0, 3.9, 2.3Hz, 1H), 7.18-7.07 (m, 2H), 5.32 (td, J=4.9, 4.2, 2.2Hz, 1H), 4.63-4 .45(m, 1H), 4.41-4.25(m, 1H), 3.85-3.65(m, 1H), 3.58-3.43(m, 1H), 2.49-2.37(m, 1H), 2.36-2.26(m, 1H), 2.29-2 .13 (m, 3H), 1.89 (d, J=13.0Hz, 1H), 1.12-0.92 (m, 2H), 0.71-0.53 (m, 1H), 0.40-0.26 (m, 2H), -0.02--0.15 (m, 2H); 19 F NMR (282 MHz, DMSO-d 6 )δ-128.42; MS(ES+)609.5(M+Na), (ES-)585.5(M-1), 621.4(M+Cl); Optical rotation [α] D =(+)124.90[0.27, MeOH]; Analytical calculation value C 31 H31 FN 6 O 5 .0.5H 2 O: C, 62.51; H, 5.42; N, 14.11; Found: C, 62.58; H, 5.43; N, 13.89.

[0503] Scheme 26

[0504]

[0505] Preparation of (2R, 4R)-N2-(5-((+)-1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-4-hydroxy-N1-(naphthalen-1-yl)pyrrolidine-1,2-dicarboxamide (26b)

[0506] Step 1: Preparation of (2R,4R)-N2-(5-((-)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)-4-hydroxy-N1-(naphthalen-1-yl)pyrrolidine-1,2-dicarboxamide (26a)

[0507] Using the reaction and workup conditions reported in Scheme 1, Step 9, (2R,4R)-N-(5-((-)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)-4-hydroxypyrrolidine-2-carboxamide (21b) (160 mg, 0.304 mmol) and 1-naphthalene isocyanate (61.7 mg, 0.365 mmol) were reacted with 1-naphthalene diisocyanate (21.7 mg, 0.365 mmol) to obtain a 5-nitropropane-2-ylpyrrolidine-2-carboxamide (21b). l) in tetrahydrofuran (10 mL) solution to react to obtain a white solid (2R, 4R)-N2-(5-((-)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)-4-hydroxy-N1-(naphthalen-1-yl)pyrrolidine-1,2-dicarboxamide (26a) (196 mg, 0.282 mmol, yield 93%); 1 H NMR (300 MHz, DMSO-d 6)δ9.69 (s, 1H), 8.55 (s, 1H), 8.17 (dd, J=7.7, 2.4Hz, 1H), 8.04-7.95 (m, 1H), 7.91 (dd, J=8.2, 1.4Hz, 1H), 7.79 (t, J=1.7Hz, 1H), 7.77-7.67(m, 2H), 7.58(m, 1H), 7.54-7.39(m, 5H), 7.21(dd, J=10.6, 8.7Hz, 1H), 7.07(m, 1H), 5.47(s, 1H), 5.38(s, 1H) , 4.56 (dd, J=9.3, 3.9Hz, 1H), 4.42 (s, 1H), 3.80 (dd, J=10.3, 4.9Hz, 1H), 3.64 (dd, J=10.0, 3.1Hz, 1H), 2.75-2.51 (m, 2H), 2 .42(m, 1H), 2.09-2.00(m, 1H), 1.12(s, 10H), 0.99-0.79(m, 1H), 0.70-0.54(m, 1H), 0.41-0.26(m, 2H), -0.02--0.14(m, 2H); 19 F NMR (282MHz, DMSO-d6) δ-129.33; MS (ES+) 718.5 (M+Na), (ES-) 694.6 (M-1), 730.5 (M+Cl); Optical rotation [α] D =(-)61.3[0.075, MeOH].

[0508] Step 2: Preparation of (2R,4R)-N2-(5-((+)-1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-4-hydroxy-N1-(naphthalen-1-yl)pyrrolidine-1,2-dicarboxamide (26b)

[0509] As reported in Scheme 4, Step 6, (2R,4R)-N2-(5-((-)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)-4-hydroxy-N1-(naphthalen-1-yl)pyrrolidine-1,2-dicarboxamide (26a) (160 mg, 0.230 mmol) was reacted in ethanol (10 mL) with concentrated HCl (0.192 mL, 2.299 mmol) to give (2R,4R)-N2-(5-((+)-1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-4-hydroxy-N1-(naphthalen-1-yl)pyrrolidine-1,2-dicarboxamide (26b) (30 mg, 0.051 mmol, 22.05% yield) as a white solid; 1 H NMR (300 MHz, DMSO-d6 )δ9.63 (s, 1H), 8.53 (s, 1H), 8.13 (d, J = 7.1Hz, 1H), 8.00 (d, J = 8.2Hz, 1H), 7.91 (d, J = 8.1Hz, 1H), 7.87 (t, J = 1.7Hz, 1H), 7.77-7.69 (m, 1H), 7.66-7.62 (m, 1H), 7.51-7.40 (m, 5H), 7.20-7.07 (m, 2H), 5.34 (s, 1H), 4.55 (dd, J=9.3, 4.0 Hz, 1H), 4.46-4.28 (m, 1H), 3.81 (dd, J=10.3, 5.0Hz, 1H), 3.68-3.55 (m, 1H), 2.48-2.35 (m, 2H), 2.30 (s, 2H), 2.22 ( t, J=8.1Hz, 2H), 2.08-1.96 (m, 1H), 1.12-0.94 (m, 2H), 0.71-0.55 (m, 1H), 0.39-0.28 (m, 2H), -0.03--0.15 (m, 2H); 19 F NMR (282 MHz, DMSO-d 6 )δ-129.99; MS(ES+)614.5(M+Na), (ES-)590.6(M-1), 626.5(M+Cl); Optical rotation [α] D =(+)81.2[0.165, MeOH]; Analytical calculation value: C 35 H 34 FN 5 O 3 .0.5H 2 O: C, 69.98; H, 5.87; N, 11.66; Found: C, 70.25; H, 5.99; N, 11.44.

[0510] Solution 27

[0511]

[0512] Preparation of (2R, 4R)-N2-(5-((+)-1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-4-hydroxy-N1-(4-(trifluoromethyl)phenyl)pyrrolidine-1,2-dicarboxamide (27b)

[0513] Step 1: Preparation of (2R,4R)-N2-(5-((+)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)-4-hydroxy-N1-(4-(trifluoromethyl)phenyl)pyrrolidine-1,2-dicarboxamide (27a)

[0514] Using the reaction and workup conditions reported in Scheme 1, Step 9, (2R,4R)-N-(5-((-)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)-4-hydroxypyrrolidine-2-carboxamide (21b) (160 mg, 0.304 mmol) and 1-isocyanato-4-(trifluoromethyl)benzene (0.043 mL, 0.304 mmol) were stirred at 4 °C for 1 h. ol) in tetrahydrofuran (10 mL) to give a colorless solid (2R, 4R)-N2-(5-((+)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)-4-hydroxy-N1-(4-(trifluoromethyl)phenyl)pyrrolidine-1,2-dicarboxamide (27a) (161 mg, 0.226 mmol, yield 74.2%); 1 H NMR (300MHz, DMSO-d6) δ9.69 (s, 1H), 8.76 (s, 1H), 8.04 (d, J=7.3Hz, 1H), 7.89-7.62 (m, 4H), 7.60 (m, 2H), 7.5 0 (m, 1H), 7.25-7.11 (m, 1H), 7.04 (m, 1H), 5.50 (d, J = 5.7Hz, 1H), 5.35 (d, J = 4.1Hz, 1H), 4.54 (dd, J = 9.0, 4.7Hz , 1H), 4.41-4.28(m, 2H), 3.72(m, 1H), 3.52(m, 1H), 2.75-2.54(m, 1H), 2.48-2.24(m, 1H), 1.99-1.80(m, 1H), 1 .13(m, 10H), 1.11-1.00(m, 1H), 0.97-0.76(m, 1H), 0.71-0.56(m, 1H), 0.42-0.26(m, 2H), 0.00--0.18(m, 2H); 19 F NMR (282MHz, DMSO-d6) δ -59.80, -128.17; MS (ES+) 736.5 (M+Na), (ES-) 712.6 (M-1), 748.5 (M+Cl); Optical rotation [α] D =(+)14.19[0.155, MeOH].

[0515] Step 2: Preparation of (2R,4R)-N2-(5-((+)-1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-4-hydroxy-N1-(4-(trifluoromethyl)phenyl)pyrrolidine-1,2-dicarboxamide (27b)

[0516] (2R,4R)-N2-(5-((+)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)-4-hydroxy-N1-(4-(trifluoromethyl)phenyl)pyrrolidine-1,2-dicarboxamide (27a) (1) was prepared as reported in Scheme 4, Step 6 using concentrated HCl (0.175 mL, 2.101 mmol). 50 mg, 0.210 mmol) in ethanol (10 mL) to give a white solid (2R, 4R)-N2-(5-((+)-1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-4-hydroxy-N1-(4-(trifluoromethyl)phenyl)pyrrolidine-1,2-dicarboxamide (27b) (50 mg, 0.082 mmol, yield 39.0%); 1 H NMR (300 MHz, DMSO-d 6 )δ9.63 (s, 1H), 8.74 (s, 1H), 8.02 (d, J = 7.6Hz, 1H), 7.86 (t, J = 1.8Hz, 1H), 7.74 (d, J = 8.5Hz, 2H), 7 .61 (m, 4H), 7.46 (t, J=7.8Hz, 1H), 7.12 (d, J=8.0Hz, 2H), 5.31 (d, J=4.7Hz, 1H), 4.53 (dd, J=9.0, 4 .9Hz, 1H), 4.42-4.27(m, 1H), 3.72(dd, J=10.1, 5.3Hz, 1H), 3.57-3.45(m, 1H), 2.42-2.15(m, 5H), 1.97-1.77(m, 1H), 1.09-0.92(m, 2H), 0.70-0.55(m, 1H), 0.41-0.24(m, 2H), -0.02--0.14(m, 2H); 19 F NMR (282MHz, DMSO-d6) δ -59.77, -128.84; MS (ES+) 632.5 (M+Na), (ES-) 608.4 (M-1), 644.5 (M+Cl); Optical rotation [α] D =(+)94.00[0.3, MeOH]; Analytical calculation value C 32 H 31 F 4 N 5 O 3 .0.5H 2 O: C, 62.13; H, 5.21; N, 11.32; Found: C, 62.54; H, 5.34; N.11.15.

[0517] Scheme 28

[0518]

[0519] Preparation of (2R, 4R)-N2-(5-((+)-1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-N1-(4-aminophenyl)-4-hydroxypyrrolidine-1,2-dicarboxamide (28b)

[0520] Step 1: Preparation of (2R,4R)-N1-(4-aminophenyl)-N2-(5-((-)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)-4-hydroxypyrrolidine-1,2-dicarboxamide (28a)

[0521] According to the procedure reported in step 2 of scheme 13, palladium on carbon 10% (30.8 mg, 0.029 mmol) was used as catalyst by (2R,4R)-N2-(5-((+)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)-4-hydroxy-N1-(4-nitrophenyl)pyrrolidine-1,2-dicarboxamide (25a) (200 mg, The nitro group was reduced to amine by hydrogenation of a solution of 2-(4-aminophenyl)-N-(5-((-)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)-4-hydroxypyrrolidine-1,2-dicarboxamide (28a) (160 mg, 0.242 mmol, yield 84%) in ethanol (20 mL) to give a pale yellow solid; 1 H NMR (300 MHz, DMSO-d 6)δ9.62 (s, 1H), 8.32 (d, J = 2.2Hz, 1H), 8.15 (d, J = 7.4Hz, 1H), 7.98 (s, 1H), 7.79 (t, J = 1.9Hz, 1H), 7.70 (dd, J = 7.2, 1.5Hz, 1H), 7.63-7.55 (m, 1H), 7.50 (td, J=7.8, 2.3Hz, 1H), 7.19 (ddd, J=10.6, 8.6, 2.0Hz, 1H), 7.11-7.01 (m, 3H), 6.46 (dd, J=8.8, 2.2Hz, 2H), 5.48 (d, J=1.8Hz, 1H), 5 .29 (dd, J=4.7, 2.0Hz, 1H), 4.74 (s, 2H), 4.46 (dd, J=9.3, 4.0Hz, 1H), 4.41-4.26 (m, 1H), 3.59 (m, 1H), 3.53-3.41 (m, 1H), 2.75-2.50 (m, 1H), 2 .41-2.22(m, 1H), 1.94(d, J=13.4Hz, 1H), 1.21-1.03(m, 10H), 0.98-0. 79(m, 1H), 0.72-0.53(m, 1H), 0.44-0.28(m, 2H), -0.03--0.11(m, 2H); 19 F NMR (282 MHz, DMSO-d 6 )δ-129.01; MS(ES+)661.5(M+1), 683.5(M+Na), (ES-)659.5(M-1), 695.6(M+Cl); Optical rotation [α] D =(-)21.9[0.155, MeOH].

[0522] Step 2: Preparation of (2R,4R)-N2-(5-((+)-1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-N1-(4-aminophenyl)-4-hydroxypyrrolidine-1,2-dicarboxamide (28b)

[0523] As reported in Scheme 4, Step 6, (2R,4R)-N1-(4-aminophenyl)-N2-(5-((-)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)-4-hydroxypyrrolidine-1,2-dicarboxamide (28a) (0.15 g, 0.227 mmol) was reacted in ethanol (10 mL) with concentrated HCl (0.208 mL, 2.497 mmol) to give (2R,4R)-N2-(5-((+)-1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-N1-(4-aminophenyl)-4-hydroxypyrrolidine-1,2-dicarboxamide (28b) (65 mg, 0.117 mmol, 51.4% yield) as a white solid; 1 H NMR (300 MHz, DMSO-d 6 )δ9.57 (d, J=1.8Hz, 1H), 8.12 (dd, J=7.7, 2.1Hz, 1H), 7.97 (s, 1H), 7.87 (t, J=1.8Hz, 1H), 7.67-7.58 (m, 2H), 7.46 (t , J=7.8Hz, 1H), 7.19-7.08 (m, 2H), 7.08-7.00 (m, 2H), 6.50-6.40 (m, 2H), 5.26 (d, J=4.7Hz, 1H), 4.75 (s, 2H), 4.45 (dd , J=9.2, 4.1Hz, 1H), 4.38-4.23 (m, 1H), 3.59 (dd, J=10.1, 4.9Hz, 1H), 3.45 (dd, J=10.0, 3.3Hz, 1H), 2.41-2.27 (m, 3H ), 2.23(t, J=8.1Hz, 2H), 2.00-1.86(m, 1H), 1.02(m, 2H), 0.72-0.54(m, 1H), 0.39-0.27(m, 2H), -0.02--0.14(m, 2H); 19 F NMR (282 MHz, DMSO-d 6 )δ-130.17; MS(ES+)579.5(M+Na), (ES-)555.5(M-1), 593.6(M+Cl); Optical rotation [α] D =(+)100.8[0.25, MeOH]; Analytical calculation value C 31 H 33 FN 6 O 3 .0.5H 2 O: C, 65.83; H, 6.06; N, 14.86; Found: C, 65.67; H, 5.98; N, 14.58.

[0524] Solution 29

[0525]

[0526] Preparation of (2R, 4S)-N2-(5-((+)-1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-N1-(5-chloropyridin-2-yl)-4-hydroxy-4-phenylpyrrolidine-1,2-dicarboxamide (29e)

[0527] Step 1: Preparation of (R)-1-(tert-butoxycarbonyl)-4-oxopyrrolidine-2-carboxylic acid (29a)

[0528] To a solution of (2R, 4R)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid (14b) (51 g, 221 mmol) in dichloromethane (2023 mL) was added TEMPO (1.723 g, 11.03 mmol) at 0°C, stirred for 30 minutes at 0°C, and allowed to warm to room temperature overnight. The reaction mixture was diluted with water (100 mL), stirred for 30 minutes, and concentrated in vacuo to remove dichloromethane. The reaction mixture was diluted with 200 mL of ethyl acetate and filtered through a plug of diatomaceous earth. The filtrate was acidified with 8 mL of 1M HCl. The ethyl acetate layer was separated, washed with water (4×200 mL) and brine (100 mL), dried, filtered and concentrated in vacuo to give (R)-1-(tert-butoxycarbonyl)-4-oxopyrrolidine-2-carboxylic acid (29a) (38 g, 166 mmol, 75% yield) as a white solid; 1 H NMR (300 MHz, DMSO-d 6 )δ13.00 (s, 1H), 4.53 (m, 1H), 3.82 (dd, J=18.6, 10.6Hz, 1H), 3.66 (dd, J=18.4, 4.4 Hz, 1H), 3.44 (s, 1H), 3.12 (m, 1H), 1.40 (s, 9H); MS (ES-) 228.2 (M-1), 457.3 (2M-1).

[0529] Step 2: Preparation of (2R,4S)-1-(tert-butoxycarbonyl)-4-hydroxy-4-phenylpyrrolidine-2-carboxylic acid (29b)

[0530] A solution of (R)-1-(tert-butoxycarbonyl)-4-oxopyrrolidine-2-carboxylic acid (29a) (1.45 g, 6.33 mmol) in THF (20 mL) was added dropwise to a 1.0 M solution of phenylmagnesium bromide (17.40 mL, 17.40 mmol) at 0°C. The reaction mixture was stirred at 0°C for 20 minutes, quenched with saturated ammonium chloride (15 mL) and concentrated in vacuo to remove the organic solvent. The reaction mixture was divided into ethyl acetate (50 mL) and 1 M HCl (20 mL). The organic layer was separated, washed with brine, dried, filtered and concentrated to a volume of 25 mL, and the solution was diluted under stirring with hexane (70 mL). The resulting solid was collected by filtration, washed with hexane, and dried in vacuo to give a light brown solid (2R,4S)-1-(tert-butoxycarbonyl)-4-hydroxy-4-phenylpyrrolidine-2-carboxylic acid (29b) (900 mg, 2.93 mmol, yield 46.3%); 1 H NMR (300 MHz, DMSO-d 6 )δ12.47 (s, 1H), 7.53 (d, J=7.7 Hz, 2H), 7.41 (t, J=7.5 Hz, 2H), 7.33 (q, J=7.1, 6.5 Hz, 1H), 5.59 (s, 1H), 4.47-4.29 (m, 1H), 3.76-3.55 (m, 2H), 2.74-2.61 (m, 1H), 2.31 (dd, J=12.8, 6.7 Hz, 1H), 1.56-1.40 (m, 9H); MS (ES+) 330.3 (M+Na), (ES-) 306.3 (M-1); Optical rotation [α] D =(+)38.43[0.255, MeOH].

[0531] Step 3: Preparation of tert-butyl (2R,4S)-2-(5-((-)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenylcarbamoyl)-4-hydroxy-4-phenylpyrrolidine-1-carboxylate (29c)

[0532] Using the reaction and workup conditions reported in step 10 of scheme 1, a solution of (2R,4S)-1-(tert-butoxycarbonyl)-4-hydroxy-4-phenylpyrrolidine-2-carboxylic acid (29b) (500 mg, 1.627 mmol) and (R)-N-((-)-1-(3-amino-4-fluorophenyl)-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-methylpropane-2-sulfenamide (4e) (673 mg, 1.627 mmol) in tetrahydrofuran (75 mL) was reacted with ethyl 2-ethoxy-1(2H)-quinolinecarboxylate (402 mg, 1.627 mmol) and purified by flash column chromatography (silica gel 25 g, purified by CMA 80 chloroform solution, 0 to 100%) was purified to give a white solid (2R,4S)-2-(5-((-)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenylcarbamoyl)-4-hydroxy-4-phenylpyrrolidine-1-carboxylic acid tert-butyl ester (29c) (345 mg, 0.491 mmol, 30.2% yield); 1 H NMR (300 MHz, DMSO-d 6 )δ9.78 (2s, 1H, rotamer), 8.40-7.98 (2m, 1H, rotamer), 7.77 (m, 1H), 7.72 (m, 1H), 7.64 (m, 1H), 7.58-7.46 (m, 3H), 7.37 (m, 2H), 7.33-6.99 (m, 4H), 6.00 (2s, 1H, rotamer), 5.48 (2s, 1H, rotamer), 4.66- 4.30 (m, 1H), 3.82-3.53 (m, 2H), 2.80-2.55 (m, 2H), 2.33-2.14 (m, 1H), 1.32 (2s, 9H, rotamer), 1.14 (2s, 10H, rotamer), 1.00-0.75 (m, 1H), 0.71-0.52 (m, 1H), 0.44-0.26 (m, 2H), 0.01-0.17 (m, 2H); 19 FNMR (282 MHz, DMSO-d 6 )δ-128.69, -129.87; MS(ES+)725.5(M+Na), (ES-)701.6(M-1), 737.5(M+Cl); Optical rotation [α] D =(-)71.10[0.09, MeOH].

[0533] Step 4: Preparation of (2R,4S)-N-(5-((-)-1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-4-hydroxy-4-phenylpyrrolidine-2-carboxamide (29d)

[0534] A solution of (2R,4S)-tert-butyl 2-(5-((-)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenylcarbamoyl)-4-hydroxy-4-phenylpyrrolidine-1-carboxylate (29c) (335 mg, 0.477 mmol) in methanolic HCl (2.383 mL, 7.15 mmol) was reacted, followed by the workup and purification reported in step 6 of scheme 4 to give (2R,4S)-N-(5-((-)-1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-4-hydroxy-4-phenylpyrrolidine-2-carboxamide (29d) (260 mg, 0.455 mmol, 95% yield) as a white solid; 1 H NMR (300 MHz, DMSO-d 6 )δ10.56(s, 1H), 10.26(s, 1H), 9.45(s, 3H), 8.78(s, 1H), 7.90(m, 2H), 7.86(m , 1H), 7.72-7.63(m, 2H), 7.57-7.51(m, 2H), 7.49-7.24(m, 5H), 5.88(s, 1H), 4 .72(m, 1H), 3.60-3.41(m, 3H), 2.79(t, J=12.4Hz, 1H), 1.26-1.14(m, 1H), 1.1 4-1.01 (m, 3H), 0.82-0.59 (m, 1H), 0.48-0.32 (m, 2H), 0.11--0.06 (m, 2H); 19F NMR (282MHz, DMSO-d 6 )δ-123.49; MS(ES+)521.5(M+Na), (ES-)533.5(M+Cl); Optical rotation [α] D =(-)56.67[0.18, MeOH].

[0535] Step 5: Preparation of (2R,4S)-N2-(5-((+)-1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-N1-(5-chloropyridin-2-yl)-4-hydroxy-4-phenylpyrrolidine-1,2-dicarboxamide (29e)

[0536] Using the procedure as reported in step 3 of scheme 13, a solution of (2R,4S)-N-(5-((-)-1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-4-hydroxy-4-phenylpyrrolidine-2-carboxamide (29d) (99 mg, 0.173 mmol) in tetrahydrofuran (20 mL) was reacted with phenyl 5-chloropyridin-2-ylcarbamate (43.1 mg, 0.17 3mmol) was reacted and purified by flash column chromatography (silica gel 12g, eluted with 0 to 100% CMA80 in chloroform) to give an off-white solid (2R,4S)-N2-(5-((+)-1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-N1-(5-chloropyridin-2-yl)-4-hydroxy-4-phenylpyrrolidine-1,2-dicarboxamide (29e) (65mg, 0.100mmol, yield 57.5%); 1H NMR (300MHz, DMSO-d 6 )δ9.74 (s, 1H), 9.24 (s, 1H), 8.30 (dd, J=2.7, 0.8Hz, 1H), 8.11 (d, J=7.6Hz, 1H), 7.91 (dd, J=9.1, 0.8Hz, 1H), 7.87 (t, J=1.7Hz, 1H), 7.81 (dd, J=9.0, 2.6Hz, 1H), 7.68-7.61 (m, 2H), 7.54 (dt, J=6.6, 1.3Hz, 2H), 7.47 (t, J=7.8Hz, 1H), 7.42-7.34 (m, 2H), 7.3 3-7.26 (m, 1H), 7.20-7.11 (m, 2H), 5.95 (s, 1H), 4.71 (d, J=8.5Hz, 1H), 4.02-3.96 (m, 1H), 3.90 (d, J=10.5Hz, 1H), 2.68 (dd, J=1 3.2, 9.7Hz, 1H), 2.34(s, 2H), 2.34-2.18(m, 3H), 1.11-0.95(m, 2H), 0.74-0.54(m, 1H), 0.39-0.29(m, 2H), -0.01--0.11(m, 2H); 19 F NMR (282 MHz, DMSO-d 6 )δ-129.26; MS(ES+)653.5(M+1)675.4, 677.5(M+Na), (ES-)651.5, 653.7(M-1), 689.5(M+Cl); IR(KBr)2229cm -1 ; Optical rotation [α] D =(+)80[0.295, MeOH].

[0537] Scheme 30

[0538]

[0539] Preparation of (2R,4S)-N2-(5-((+)-1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-N1-(4-chlorophenyl)-4-hydroxy-4-phenylpyrrolidine-1,2-dicarboxamide (30a) and (2R,4S)-N1-(4-chlorophenyl)-N2-(5-((+)-1-(3-(4-chlorophenyl)ureido)-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-4-hydroxy-4-phenylpyrrolidine-1,2-dicarboxamide (30b)

[0540] Using the procedure reported in step 9 of scheme 1, a solution of (2R,4S)-N-(5-((-)-1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-4-hydroxy-4-phenylpyrrolidine-2-carboxamide (29d) (150 mg, 0.262 mmol) in dichloromethane (10 mL) was reacted with 4-chlorophenylisocyanate (1n) (0.034 mL, 0.262 mmol) and sodium bicarbonate (5.25 mL, 5.25 mmol) and purified to give

[0541] 1. White solid (2R, 4S)-N2-(5-((+)-1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-N1-(4-chlorophenyl)-4-hydroxy-4-phenylpyrrolidine-1,2-dicarboxamide (30a) (65 mg, 0.100 mmol, yield 38.0%); 1 H NMR (300 MHz, DMSO-d 6)δ 9.69 (s, 1H), 8.53 (s, 1H), 8.14 (d, J = 7.5Hz, 1H), 7.88 (t, J = 1.7Hz, 1H), 7.64 (m, 2H), 7.60-7.53 (m , 4H), 7.48 (d, J=7.8Hz, 1H), 7.45-7.35 (m, 2H), 7.33-7.25 (m, 3H), 7.18-7.10 (m, 2H), 5.97 (s, 1H) , 4.76-4.60 (m, 1H), 3.93 (d, J = 10.2Hz, 1H), 3.83 (d, J = 10.1Hz, 1H), 2.72 (dd, J = 13.2, 9.5Hz, 1H), 2.35-2.21(m, 5H), 1.10-0.96(m, 2H), 0.71-0.56(m, 1H), 0.40-0.28(m, 2H), -0.00--0.11(m, 2H); 19 F NMR (282 MHz, DMSO-d 6 )δ-129.82; MS (ES+) 674.5, 677.5 (M+Na), (ES-) 650.5, 652.0 (M-1), 686.5, 688.6 (M+Cl); IR (KBr) 2229cm-1; optical rotation [α] D =(+)87.5[0.32, MeOH]; Analytical calculation value C 37 H 35 CIF 5 O 3. 0.25H 2 O; C, 67.68; H, 5.45; N, 10.67; Found: C, 67.73; H, 5.53; N, 10.51.

[0542] 2. White solid (2R, 4S)-N1-(4-chlorophenyl)-N2-(5-((+)-1-(3-(4-chlorophenyl)ureido)-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-4-hydroxy-4-phenylpyrrolidine-1,2-dicarboxamide (30b) (68 mg, 0.084 mmol, yield 32.2%); 1 H NMR (300 MHz, DMSO-d 6)δ9.73(s, 1H), 8.85(s, 1H), 8.55(s, 1H), 8.20-8.10(m, 1H), 7.80(s, 1H), 7.67(m, 2H), 7. 58-7.49 (m, 5H), 7.43-7.18 (m, 10H), 7.14 (s, 1H), 7.08 (s, 1H), 5.96 (s, 1H), 4.68 (d, J=9. 6Hz, 1H), 3.93 (d, J=10.2Hz, 1H), 3.83 (d, J=10.1Hz, 1H), 2.80-2.61 (m, 3H), 2.30 (d, J=13 .6Hz, 1H), 1.11-0.91(m, 2H), 0.74-0.57(m, 1H), 0.42-0.29(m, 2H), -0.01--0.13(m, 2H); 19 F NMR (282 MHz, DMSO-d 6 )δ-129.16; MS (ES+) 827.5, 828.6 (M+Na), (ES-) 803.5, 805.4 (M-1), 839.5, 840.6 (M+Cl); IR (KBr) 2229cm-1; optical rotation [α] D =(+)52.0[0.25, MeOH]; Analytical calculation value C 44 H 39 Cl 2 FN 6 O 4 .0.75H 2 O: C, 64.51; H, 4.98; N, 10.26; Found: C, 64.49; H, 5.06; N, 9.99.

[0543] Scheme 31

[0544]

[0545] Preparation of (2R, 4S)-N2-(5-((-)-1-amino-3-cyclopropyl-1-(pyridin-2-yl)propyl)-2-fluorophenyl)-N1-(4-chlorophenyl)-4-hydroxy-4-phenylpyrrolidine-1,2-dicarboxamide (31i)

[0546] Step 1: Preparation of (E)-3-cyclopropyl-1-(pyridin-2-yl)-2-propen-1-one (31b)

[0547] Cyclopropanecarboxaldehyde (52.8 mL, 700 mmol) and aqueous potassium hydroxide solution (1N solution, 88 mL, 88 mmol) were added to a stirred solution of 2-acetylpyridine (31a) (53 g, 438 mmol) in methanol (636 mL) cooled to 0°C. The reaction product was allowed to warm to room temperature overnight. The reaction product was concentrated in vacuo to remove methanol. The crude residue was dissolved in ethyl acetate (500 mL), washed with water (500 mL) and brine (200 mL), dried, filtered and concentrated in vacuo to give (E)-3-cyclopropyl-1-(pyridin-2-yl)-2-propene-1-one (31b) (80 g, 462 mmol, 106% yield), which was used directly in the next step. The crude residue was purified by flash column chromatography (silica gel, eluted with ethyl acetate in hexane, 0 to 100%) to prepare an analytical sample; 1 H NMR (300 MHz, DMSO-d 6 )δ8.80-8.68(m, 1H), 8.07-7.98(m, 2H), 7.74-7.63(m, 2H), 6.63(dd, J=15 .5, 10.4Hz, 1H), 1.93-1.76 (m, 1H), 1.08-0.98 (m, 2H), 0.84-0.71 (m, 2H).

[0548] Step 2: Preparation of 3-cyclopropyl-1-(pyridin-2-yl)propan-1-one (31c)

[0549] To a stirred solution of (E)-3-cyclopropyl-1-(pyridin-2-yl)-2-propene-1-one (31b) (80 g, 462 mmol) in acetonitrile (829 mL) was added tributyltinane (256 mL, 924 mmol) and heated under reflux for 9 hours. The reaction product was cooled to room temperature and separated. The acetonitrile layer was concentrated in vacuo and the obtained residue was purified by flash column chromatography (silica gel, eluted with ethyl acetate in hexane, 0 to 100%) to give 3-cyclopropyl-1-(pyridin-2-yl)propane-1-one (31c) (17.2 g, 98 mmol, 21.25% yield) as an oil.

[0550] 1 H NMR (300 MHz, DMSO-d 6 )δ8.94 (dt, J=4.7, 1.5Hz, 1H), 8.19 (m, 2H), 7.87 (m, 1H), 3.46 (td, J=7.2, 2.0Hz, 2 H), 1.74 (qd, J=7.2, 2.1Hz, 2H), 1.03-0.87 (m, 1H), 0.59 (m, 2H), 0.30-0.20 (m, 2H).

[0551] Step 3: Preparation of (+)-N-(3-cyclopropyl-1-(pyridin-2-yl)propylidene)-2-methylpropane-2-sulfenamide (31d)

[0552] According to the procedure and workup reported in Scheme 1, Step 3, a solution of 3-cyclopropyl-1-(pyridin-2-yl)propan-1-one (31c) (15.2 g, 87 mmol) in tetrahydrofuran (220 mL) was reacted with (S)-2-methylpropane-2-sulfenamide (12.62 g, 104 mmol) and tetraisopropoxytitanium (51.2 mL, 173 mmol) to afford (+)-N-(3-cyclopropyl-1-(pyridin-2-yl)propylidene)-2-methylpropane-2-sulfenamide (31d) (11.65 g, 41.8 mmol, 48.2% yield) as a yellow oil; 1 HNMR (300 MHz, DMSO-d 6 )δ8.70 (dt, J=4.7, 1.4 Hz, 1H), 8.02 (d, J=8.0 Hz, 1H), 7.94 (td, J=7.6, 1.7 Hz, 1H), 7.56 (ddd, J=7.5, 4.7, 1.4 Hz, 1H), 3.53 (m, 1H), 3.41-3.35 (m, 1H), 1.49 (q, J=7.5 Hz, 2H), 1.25 (s, 9H), 0.81-0.65 (m, 1H), 0.44-0.28 (m, 2H), 0.03 (m, 2H); MS (ES+) 279.3 (M+1), 301.3 (M+Na); optical rotation [α] D =(+)50.8[2.64, MeOH].

[0553] Step 4: Preparation of (S)-N-((+)-1-(3-amino-4-fluorophenyl)-3-cyclopropyl-1-(pyridin-2-yl)propyl)-2-methylpropane-2-sulfinamide (31e) and (S)-N-((-)-1-(3-amino-4-fluorophenyl)-3-cyclopropyl-1-(pyridin-2-yl)propyl)-2-methylpropane-2-sulfinamide (31f)

[0554] According to the procedure reported in step 4 of scheme 1, a solution of (+)-N-(3-cyclopropyl-1-(pyridin-2-yl)propylene)-2-methylpropane-2-sulfenamide (31d) (12.665 g, 45.5 mmol) in toluene (400 mL) was reacted with a freshly prepared solution of (3-(bis(trimethylsilyl)amino)-4-fluorophenyl)magnesium bromide (1c) (142 mL, 114 mmol) and purified by flash column chromatography (silica gel 120 g, eluted with ethyl acetate in hexanes, 0 to 60 to 100%) to give

[0555] 1. White solid (S)-N-((+)-1-(3-amino-4-fluorophenyl)-3-cyclopropyl-1-(pyridin-2-yl)propyl)-2-methylpropane-2-sulfenamide (31e) (10 g, 25.7 mmol, yield 56.4%); 1 H NMR (300 MHz, DMSO-d 6 )δ8.52 (dt, J=4.6, 1.5Hz, 1H), 7.73 (td, J=7.8, 1.9Hz, 1H), 7.26 (ddd, J=7.5, 4.8, 1.0Hz, 1H ), 7.07 (dt, J=8.0, 1.1Hz, 1H), 6.88 (dd, J=11.3, 8.5Hz, 1H), 6.78 (dd, J=8.8, 2.4Hz, 1H), 6. 43(ddd, J=8.6, 4.3, 2.3Hz, 1H), 6.09(s, 1H), 5.09(s, 2H), 2.56(m, 1H), 2.45(m,, 1H), 1.29- 1.15(m, 1H), 1.10(s, 9H), 0.63-0.42(m, 2H), 0.35-0.23(m, 2H), -0.07(m, 1H), -0.20(m, 1H); 19 F NMR (282 MHz, DMSO-d 6 )δ-137.14; MS: (ES+)412.4(M+Na), (ES-)388.4(M-1), 424.4(M+Cl); Optical rotation [α] D =(+)136.36[0.55, MeOH].

[0556] 2. White solid (S)-N-((-)-1-(3-amino-4-fluorophenyl)-3-cyclopropyl-1-(pyridin-2-yl)propyl)-2-methylpropane-2-sulfenamide (31f) (300 mg, 0.770 mmol, yield 1.693%); 1 H NMR (300 MHz, DMSO-d 6)δ8.53 (ddd, J=4.9, 1.9, 0.9Hz, 1H), 7.71 (td, J=7.7, 1.8Hz, 1H), 7.35-7.09 (m , 2H), 6.85 (dd, J=11.3, 8.5Hz, 1H), 6.71 (dd, J=8.8, 2.4Hz, 1H), 6.41 (ddd, J=8. 5, 4.3, 2.4Hz, 1H), 5.82 (s, 1H), 5.06 (s, 2H), 2.55 (d, J=8.5Hz, 2H), 1.13 (s, 9H) , 1.08-0.96(m, 1H), 0.81(m, 1H), 0.61(m, 1H), 0.38-0.29(m, 2H), -0.10(m, 2H); 19 F NMR (282 MHz, DMSO-d 6 )δ-137.42; MS(ES+)390.4(M+1), 412.4(M+Na), (ES-)388.4(M-1), 424.4(M+Cl); Optical rotation [α] D =(-)3.28[0.305, MeOH].

[0557] Step 5: Preparation of tert-butyl (2R,4S)-2-(5-(3-cyclopropyl-1-((S)-1,1-dimethylethylsulfinamido)-1-(pyridin-2-yl)propyl)-2-fluorophenylcarbamoyl)-4-hydroxy-4-phenylpyrrolidine-1-carboxylate (31 g)

[0558] Using the reaction and workup conditions reported in step 10 of scheme 1, a solution of (2R,4S)-1-(tert-butoxycarbonyl)-4-hydroxy-4-phenylpyrrolidine-2-carboxylic acid (29b) (158 mg, 0.513 mmol) and (S)-N-((+)-1-(3-amino-4-fluorophenyl)-3-cyclopropyl-1-(pyridin-2-yl)propyl)-2-methylpropane-2-sulfenamide (31e) (200 mg, 0.513 mmol) in tetrahydrofuran (20 mL) was reacted with ethyl 2-ethoxy-1(2H)-quinolinecarboxylate (127 mg, 0.513 mmol) and purified by flash column chromatography (silica gel 25 g, purified by CMA 80 chloroform solution, 0 to 100%) was purified to give a white solid (2R, 4S)-2-(5-(3-cyclopropyl-1-((S)-1,1-dimethylethylsulfinamido)-1-(pyridin-2-yl)propyl)-2-fluorophenylcarbamoyl)-4-hydroxy-4-phenylpyrrolidine-1-carboxylic acid tert-butyl ester (31 g) (130 mg, 0.191 mmol, yield 37.3%); 1 H NMR (300 MHz, DMSO-d 6)δ9.71 (2s, 1H, rotamer), 8.54 (2d, J=4.8 Hz, 1H, rotamer), 8.37-8.04 (m, 1H), 7.75 (m, 1H), 7.59-7.44 (m, 2H), 7.37 (m, 2H), 7.33-7.23 (m, 1H), 7.23-6.94 (m, 2H), 6.14 (m, 1H), 5. 95 (2s, 1H, rotamer), 4.44 (m, 1H), 3.67 (s, 2H), 2.79-2.51 (m, 5H), 2.23 (m, 1H), 1.33 (2s, 9H, rotamer), 1.11 (s, 10H), 0.67-0.46 (m, 2H), 0.31 (m, 2H), 0.01 (m, 1H), -0.18 (m, 1H); 19 F NMR (282 MHz, DMSO-d 6 )δ-128.48, -129.79; MS (ES+) 679.6 (M+1), 701.6 (M+Na), (ES-) 677.7 (M-1), 713.6 (M+Cl).

[0559] Step 6: Preparation of (2R,4S)-N-(5-(1-amino-3-cyclopropyl-1-(pyridin-2-yl)propyl)-2-fluorophenyl)-4-hydroxy-4-phenylpyrrolidine-2-carboxamide (31h)

[0560] A solution of (2R,4S)-tert-butyl 2-(5-(3-cyclopropyl-1-((S)-1,1-dimethylethylsulfinamido)-1-(pyridin-2-yl)propyl)-2-fluorophenylcarbamoyl)-4-hydroxy-4-phenylpyrrolidine-1-carboxylate (31 g) (125 mg, 0.184 mmol) in methanolic HCl (0.614 mL, 1.841 mmol) was reacted, followed by workup and purification as reported in Scheme 4, Step 6 to give (2R,4S)-N-(5-(1-amino-3-cyclopropyl-1-(pyridin-2-yl)propyl)-2-fluorophenyl)-4-hydroxy-4-phenylpyrrolidine-2-carboxamide (31h) (106 mg, 0.182 mmol, 99% yield) as a light brown solid; 1 H NMR (300 MHz, DMSO-d 6)δ10.61(s, 1H), 10.29(s, 1H), 9.06(s, 3H), 8.96-8.78(m, 1H), 8.74(m, 1H), 8. 10-8.02 (m, 1H), 7.96 (t, J=7.8Hz, 1H), 7.65-7.56 (m, 2H), 7.56-7.35 (m, 5H), 7. 31(s, 1H), 4.77(m, 1H), 3.94-3.50(m, 5H), 2.97-2.75(m, 1H), 1.39-1.20(m, 1H) , 1.16(m, 2H), 1.14-1.06(m, 2H), 0.75(m, 1H), 0.46(m, 2H), 0.27--0.13(m, 2H); 19 F NMR (282 MHz, DMSO-d 6 )δ-123.51; MS (ES+) 475.5 (M+1), 497.5 (M+Na), (ES-) 473.6 (M-1), 509.5 (M+Cl).

[0561] Step 7: Preparation of (2R,4S)-N2-(5-((-)-1-amino-3-cyclopropyl-1-(pyridin-2-yl)propyl)-2-fluorophenyl)-N1-(4-chlorophenyl)-4-hydroxy-4-phenylpyrrolidine-1,2-dicarboxamide (31i)

[0562] According to the procedure reported in step 9 of scheme 1, a solution of (2R,4S)-N-(5-(1-amino-3-cyclopropyl-1-(pyridin-2-yl)propyl)-2-fluorophenyl)-4-hydroxy-4-phenylpyrrolidine-2-carboxamide (31h) (50 mg, 0.086 mmol) in dichloromethane (10 mL) was reacted with 4-chlorophenylisocyanate (1n) (10.96 μL, 0.086 mmol) and sodium bicarbonate and purified by flash column chromatography (silica gel 12 g, purified by CMA 80% chloroform solution) to give an off-white solid (2R, 4S)-N2-(5-((-)-1-amino-3-cyclopropyl-1-(pyridin-2-yl)propyl)-2-fluorophenyl)-N1-(4-chlorophenyl)-4-hydroxy-4-phenylpyrrolidine-1,2-dicarboxamide (31i) (36 mg, 0.057 mmol, yield 66.9%); 1 H NMR (300 MHz, DMSO-d 6)δ9.64 (s, 1H), 8.53 (s, 1H), 8.48 (dt, J=4.5, 1.5Hz, 1H), 8.18 (dd, J=7.8, 2.2Hz, 1H), 7.70 (td, J=7.7 , 1.9Hz, 1H), 7.60-7.51 (m, 5H), 7.39 (t, J=7.5Hz, 2H), 7.33-7.26 (m, 3H), 7.21-7.06 (m, 3H), 5.98 (s, 1H), 4.68 (dd, J=9.6, 2.8Hz, 1H), 3.93 (d, J=10.1Hz, 1H), 3.82 (d, J=10.1Hz, 1H), 2.72 (dd, J=13.1, 9. 7Hz, 1H), 2.40-2.21(m, 5H), 1.04(m, 2H), 0.70-0.55(m, 1H), 0.40-0.26(m, 2H), -0.01--0.12(m, 2H); 19 F NMR (282 MHz, DMSO-d 6 )δ-130.30; MS(ES+)650.5, 651.4(M+Na), (ES-)626.5(M-1), 662.6, 664.5(M+Cl); Optical rotation [α] D =(-)56.25[0.16, MeOH].

[0563] Scheme 32

[0564]

[0565] Preparation of (2R,4S)-N2-(5-((+)-1-amino-3-cyclopropyl-1-(pyridin-2-yl)propyl)-2-fluorophenyl)-N1-(5-chloropyridin-2-yl)-4-hydroxy-4-phenylpyrrolidine-1,2-dicarboxamide (32a) and (2R,4S)-N1-(5-chloropyridin-2-yl)-N2-(5-(1-(3-(5-chloropyridin-2-yl)ureido)-3-cyclopropyl-1-(pyridin-2-yl)propyl)-2-fluorophenyl)-4-hydroxy-4-phenylpyrrolidine-1,2-dicarboxamide (32b)

[0566] A solution of (2R,4S)-N-(5-((-)-1-amino-3-cyclopropyl-1-(pyridin-2-yl)propyl)-2-fluorophenyl)-4-hydroxy-4-phenylpyrrolidine-2-carboxamide (31h) (50 mg, 0.086 mmol) in tetrahydrofuran (10 mL) was reacted with phenyl 5-chloropyridin-2-ylcarbamate (13b) (21.29 mg, 0.086 mmol) using the procedure reported in step 3 of scheme 13 with sodium bicarbonate as base and purified by flash column chromatography (silica gel 12 g, eluted with 0 to 100% CMA 80 in chloroform) to give

[0567] 1. Off-white solid (2R, 4S)-N2-(5-((+)-1-amino-3-cyclopropyl-1-(pyridin-2-yl)propyl)-2-fluorophenyl)-N1-(5-chloropyridin-2-yl)-4-hydroxy-4-phenylpyrrolidine-1,2-dicarboxamide (32a) (29 mg, 0.046 mmol, yield 53.8%); 1H NMR (300 MHz, DMSO-d 6 )δ9.70 (s, 1H), 9.23 (s, 1H), 8.56-8.41 (m, 1H), 8.30 (d, J = 2.7Hz, 1H), 8.21-8.07 (m, 1H), 7.92 (d, J = 9.1Hz, 1H), 7.8 1 (dd, J=9.0, 2.7Hz, 1H), 7.70 (td, J=7.7, 1.9Hz, 1H), 7.54 (d, J=7.8Hz, 3H), 7.38 (t, J=7.5Hz, 2H), 7.29 (m, 1H), 7.13 (m, 3H), 5.96 (s, 1H), 4.77-4.66 (m, 1H), 4.00 (d, J = 10.5Hz, 1H), 3.90 (d, J = 10.4Hz, 1H), 2.68 (dd, J = 13.2, 9.6Hz, 1H) , 2.38-2.32(m, 3H), 2.34-2.22(m, 2H), 1.12-0.94(m, 2H), 0.70-0.54(m, 1H), 0.40-0.25(m, 2H), 0.00--0.15(m, 2H); 19 F NMR (282 MHz, DMSO-d 6 )δ-129.71; MS (ES+) 629.5 (M+1) 652.5 (M+Na), (ES-) 627.5, 628.5 (M-1); Optical rotation [α] D =(+)14.81[0.27, MeOH].

[0568] 2. Off-white solid (2R, 4S)-N1-(5-chloropyridin-2-yl)-N2-(5-(1-(3-(5-chloropyridin-2-yl)ureido)-3-cyclopropyl-1-(pyridin-2-yl)propyl)-2-fluorophenyl)-4-hydroxy-4-phenylpyrrolidine-1,2-dicarboxamide (32b) (10 mg, 0.013 mmol, yield 14.90%); 1H NMR (300 MHz, DMSO-d 6 )δ9.88 (s, 1H), 9.69 (s, 2H), 9.24 (s, 1H), 8.62 (d, J = 4.9Hz, 1H), 8.34 (d, J = 2.6Hz, 1H), 8.29 (d, J = 2.6Hz, 1H), 8. 25 (d, J=7.4Hz, 1H), 7.92 (d, J=9.0Hz, 1H), 7.85-7.67 (m, 3H), 7.53 (d, J=7.6Hz, 2H), 7.37 (m, 3H), 7.26 (m, 3H), 7 .14 ​​(m, 2H), 5.92 (s, 1H), 4.71 (d, J = 8.5Hz, 1H), 4.00 (d, J = 10.5Hz, 1H), 3.90 (d, J = 10.4Hz, 1H), 2.76-2.64 (m, 1H ), 2.67-2.54(m, 2H), 2.40-2.20(m, 1H), 1.13-0.93(m, 2H), 0.70-0.53(m, 1H), 0.30(m, 2H), -0.07--0.26(m, 2H); 19 F NMR (282 MHz, DMSO-d 6 )δ-129.58; MS (ES+) 783.6 (M+1) 805.5, 807.5 (M+Na).

[0569] Scheme 33

[0570]

[0571] Preparation of (2R,4S)-4-amino-N2-(5-((+)-1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-N1-(4-chlorophenyl)pyrrolidine-1,2-dicarboxamide (33d)

[0572] Step 1: Preparation of (3R,5R)-1-(4-chlorophenylcarbamoyl)-5-(5-(1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenylcarbamoyl)pyrrolidin-3-yl methanesulfonate (33a) To (2R,4R)-N1-(4-chlorophenyl)-N2-(5-((-)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenylcarbamoyl)pyrrolidin-3-yl methanesulfonate (33a) To an ice-cold solution of 1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)-4-hydroxypyrrolidine-1,2-dicarboxamide (4f) (110 mg, 0.162 mmol) in dichloromethane (10 mL) were added triethylamine (0.09 mL, 0.647 mmol) and methanesulfonyl chloride (0.019 mL, 0.243 mmol) and stirred at room temperature overnight. The reaction product was diluted with dichloromethane (100 mL), washed with water (2×20 mL) and brine (2×20 mL), dried, filtered and concentrated in vacuo to give (3R,5R)-1-(4-chlorophenylcarbamoyl)-5-(5-(1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenylcarbamoyl)pyrrolidin-3-yl methanesulfonate (33a) (136 mg, 0.179 mmol, 111% yield), which was used directly in the next step; 1 H NMR (300 MHz, DMSO-d 6 )δ9.74 (s, 1H), 8.61 (s, 1H), 7.87-7.75 (m, 2H), 7.70 (dt, J=7.4, 1.4Hz, 1H), 7.64-7.44 (m, 4H), 7.40- 7.25 (m, 2H), 7.24-7.10 (m, 2H), 5.46 (s, 1H), 5.36 (d, J=6.6Hz, 1H), 4.01-3.91 (m, 1H), 3.86 (m, 1H), 3. 35(m, 2H), 3.18(s, 3H), 2.75-2.55(m, 1H), 2.44-2.24(m, 2H), 1.13(s, 10H), 0.98-0.80(m, 1H), 0.63(s , 1H), 0.39-0.30 (m, 2H), 0.01--0.14 (m, 2H); MS (ES+) 780.5, 782.4 (M+Na), (ES-) 792.5, 793.4 (M+Cl).

[0573] Step 2: Preparation of ((2R,4S)-4-azido-N1-(4-chlorophenyl)-N2-(5-((+)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)pyrrolidine-1,2-dicarboxamide (33b) To a stirred solution of (3R,5R)-1-(4-chlorophenylcarbamoyl)-5-(5-(1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenylcarbamoyl)pyrrolidin-3-yl methanesulfonate (33a) (120 mg, 0.158 mmol) in DMF (10 mL) was added sodium azide (41.1 mL). g, 0.633 mmol) and heated at 70 ° C for 16 hours. The reaction product was diluted with ethyl acetate (100 mL), washed with water (2×25 mL) and brine (25 mL), dried, filtered and concentrated in vacuo. The crude residue was purified by flash column chromatography (silica gel, 12 g, eluted with CMA80 in chloroform, 0 to 100%) to give a colorless solid ((2R, 4S)-4-azido-N1-(4-chlorophenyl)-N2-(5-((+)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)pyrrolidine-1,2-dicarboxamide (33b) (65 mg, 0.092 mmol, 58.2% yield); 1 H NMR (300 MHz, DMSO-d 6 )δ9.92(s, 1H), 8.60(s, 1H), 7.97(d, J=7.1Hz, 1H), 7.77(s, 1H), 7.74-7.67(m, 1H), 7.62-7.44(m, 3 H), 7.31-7.25 (m, 2H), 7.24-7.16 (m, 1H), 7.12 (m, 1H), 5.51 (s, 1H), 4.70 (t, J=7.5Hz, 1H), 4.45 (m, 1 H), 3.77 (dd, J=11.0, 5.0Hz, 1H), 3.62 (d, J=11.1Hz, 1H), 2.44 (m, 2H), 2.41-2.22 (m, 1H), 2.16 (m, 1 19F NMR (282MHz, DMSO-d 6 )δ-127.00; MS(ES+)727.5, 729.5(M+Na), (ES-)739.5(M+Cl); Optical rotation [α] D=(+)62.25[0.71, MeOH].

[0574] Step 3: (2R,4S)-4-amino-N1-(4-chlorophenyl)-N2-(5-((-)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)pyrrolidine-1,2-dicarboxamide (33 c )

[0575] According to the procedure reported in step 2 of scheme 13, ((2R,4S)-4-azido-N1-(4-chlorophenyl)-N2-(5-((+)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)pyrrolidine-1,2-dicarboxamide (33b) (34 mg, 0.05 μmol) was reacted with palladium on carbon 10% (9.05 mg, 8.51 μmol) as catalyst. 0mmol) in ethanol (10mL) solution was hydrogenated for 3 hours to give an off-white solid (2R,4S)-4-amino-N1-(4-chlorophenyl)-N2-(5-((-)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)pyrrolidine-1,2-dicarboxamide (33c) (34 mg, 0.050 mmol, yield 58.8%); 1 H NMR (300 MHz, DMSO-d 6 )δ9.81 (s, 1H), 8.43 (s, 1H), 7.91 (d, J = 7.4Hz, 1H), 7.78 (d, J = 2.1Hz, 1H), 7.75-7.68 (m, 1H) ,7.64-7.44(m,4H),7.35-7.24(m,2H),7.23-7.06(m,1H),5.51(s,1H),4.65(m,1H),3.81-3 .70(m,1H),3.69-3.55(m,1H),3.23-3.10(m,1H),2.80-2.40(m,4H),2.06-1.73(m,3H),1.1 2(s, 10H), 0.99-0.78(m, 1H), 0.71-0.54(m, 1H), 0.43-0.25(m, 2H), -0.00--0.14(m, 2H); 19F NMR (282MHz, DMSO-d 6 )δ-126.77; MS(ES+)701.6, 703.5(M+Na), (ES-)713.5, 715.6(M+Cl); Optical rotation [α] D =(-)5.07[0.355, MeOH].

[0576] Step 4: Preparation of (2R,4S)-4-amino-N2-(5-((+)-1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-N1-(4-chlorophenyl)pyrrolidine-1,2-dicarboxamide (33d)

[0577] (2R,4S)-4-amino-N1-(4-chlorophenyl)-N2-(5-((-)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)pyrrolidine-1,2-dicarboxamide (33c) (32 mg, 0.047 mmol) in ethanol ( 0.039 mL, 0.471 mmol) was prepared as reported in Scheme 4, Step 6. 5 mL) solution was reacted and purified by flash column chromatography (silica gel, eluted with CMA80 in chloroform, 0 to 100%) to give a white solid (2R, 4S)-4-amino-N2-(5-((+)-1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-N1-(4-chlorophenyl)pyrrolidine-1,2-dicarboxamide (33d) (10 mg, 0.017 mmol, yield 36.9%); 1 H NMR (300 MHz, DMSO-d 6 )δ9.76 (s, 1H), 8.44 (s, 1H), 7.92 (d, J = 7.5Hz, 1H), 7.86 (d, J = 1.8Hz, 1H), 7.69-7.40 (m, 4H), 7. 30-7.25 (m, 2H), 7.13 (d, J=7.8Hz, 2H), 4.64 (dd, J=8.3, 4.4Hz, 1H), 3.74 (dd, J=9.4, 6.3Hz, 1H) , 3.62 (p, J=6.6Hz, 1H), 3.17 (dd, J=9.4, 5.8Hz, 1H), 2.43-2.31 (m, 5H), 2.22 (t, J=8.0Hz, 2H), 2 .10-1.87(m, 2H), 1.11-0.91(m, 2H), 0.71-0.54(m, 1H), 0.40-0.26(m, 2H), -0.00--0.15(m, 2H); 19 F NMR (282 MHz, DMSO-d 6 )δ-127.63; MS(ES+)597.4, 599.8(M+Na), (ES-)609.5, 610.4(M+Cl); Optical rotation [α] D =(+)136.0[0.05, MeOH].

[0578] Scheme 34

[0579]

[0580] Preparation of (2R, 4S)-N2-(5-((+)-1-amino-3-cyclopropyl-1-(pyridin-2-yl)propyl)-2-fluorophenyl)-N1-(4-chlorophenyl)-4-methoxy-4-phenylpyrrolidine-1,2-dicarboxamide (34d)

[0581] Step 1: Preparation of (2R,4S)-1-(tert-butoxycarbonyl)-4-methoxy-4-phenylpyrrolidine-2-carboxylic acid (34a)

[0582] To a suspension of sodium hydride (60% oil dispersion) (0.781 g, 19.52 mmol) in tetrahydrofuran (30 mL) was added (2R, 4S)-1-(tert-butoxycarbonyl)-4-hydroxy-4-phenylpyrrolidine-2-carboxylic acid (29b) (1 g, 3.25 mmol) at -10°C, followed by dimethyl sulfate (1 g, 3.25 mmol) after 30 minutes. The reaction mixture was warmed to room temperature and stirred for 16 hours, then quenched with saturated aqueous ammonium chloride solution. THF was removed in vacuo, and the resulting residue was alkalized and washed with ether. The aqueous layer was acidified and extracted with ethyl acetate (2×100 mL). The combined ethyl acetate layers were washed with water (50 mL) and brine (50 mL), dried, filtered and concentrated in vacuo to give (2R,4S)-1-(tert-butoxycarbonyl)-4-methoxy-4-phenylpyrrolidine-2-carboxylic acid (34a) (673 mg, 2.094 mmol, 64.4% yield) as a light brown solid; 1 H NMR (300 MHz, DMSO-d 6 )δ12.49 (s, 1H), 7.52-7.15 (m, 5H), 4.26 (m, 1H), 3.82-3.65 (m, 1H), 3.53 (dd, J=13.4, 11.3 Hz, 1H), 2.82 (2s, 3H, rotamer), 2.67-2.55 (m, 2H), 1.38 (2S, 9H, rotamer); MS (ES+) 344.3 (M+Na), (ES-) 320.3 (M-1); Optical rotation [α] D =(+)44.0[0.25, MeOH].

[0583] Step 2: Preparation of tert-butyl (2R,4S)-2-(5-((+)-3-cyclopropyl-1-((S)-1,1-dimethylethylsulfinamido)-1-(pyridin-2-yl)propyl)-2-fluorophenylcarbamoyl)-4-methoxy-4-phenylpyrrolidine-1-carboxylate (34b)

[0584] Using the reaction and workup conditions reported in Scheme 1, Step 10, a solution of (2R,4S)-1-(tert-butoxycarbonyl)-4-methoxy-4-phenylpyrrolidine-2-carboxylic acid (34a) (111 mg, 0.347 mmol) and (S)-N-((+)-1-(3-amino-4-fluorophenyl)-3-cyclopropyl-1-(pyridin-2-yl)propyl)-2-methylpropane-2-sulfenamide (31e) (86 mg, 0.347 mmol) in tetrahydrofuran (10 mL) was reacted with ethyl 2-ethoxy-1(2H)-quinolinecarboxylate (127 mg, 0.513 mmol) and purified by flash column chromatography (silica gel 25 g, purified by CMA 80% chloroform solution, 0 to 100%) was purified to give solid (2R,4S)--2-(5-((+)-3-cyclopropyl-1-((S)-1,1-dimethylethylsulfinamido)-1-(pyridin-2-yl)propyl)-2-fluorophenylcarbamoyl)-4-methoxy-4-phenylpyrrolidine-1-carboxylic acid tert-butyl ester (34b) (141 mg, 0.203 mmol, yield 58.7%); 1 H NMR (300 MHz, DMSO-d 6 )δ9.66 (2s, 1H, rotamer), 8.73 (d, J=4.8 Hz, 1H), 8.36-8.12 (m, 1H), 7.94 (t, J=7.8 Hz, 1H), 7.60 (m, 4H), 7.52-7.19 (m, 4H), 6.34 (s, 1H), 4.57 (m, 1H), 3.96 (s, 2H), 3.02 ( 2s, 3H, rotamer), 2.95-2.73 (m, 3H), 2.74-2.53 (m, 2H), 1.52 (2s, 9H, rotamer), 1.31 (s, 9H), 1.24-0.94 (m, 1H), 0.88-0.66 (m, 2H), 0.57-0.43 (m, 2H), 0.30-0.06 (m, 2H); 19 F NMR (282 MHz, DMSO-d 6 )δ-128.09, -129.22 (rotamers); MS (ES+) 693.7 (M+1), 715.7 (M+Na), (ES-) 691.7 (M-1), 727.7 (M+Cl); optical rotation [α] D =(+)122.60[0.075, MeOH].

[0585] Step 3: Preparation of (2R,4S)-N-(5-(1-amino-3-cyclopropyl-1-(pyridin-2-yl)propyl)-2-fluorophenyl)-4-methoxy-4-phenylpyrrolidine-2-carboxamide (34c)

[0586] A solution of (2R,4S)-tert-butyl 2-(5-((+)-3-cyclopropyl-1-((S)-1,1-dimethylethylsulfinamido)-1-(pyridin-2-yl)propyl)-2-fluorophenylcarbamoyl)-4-methoxy-4-phenylpyrrolidine-1-carboxylate (34b) (131 mg, 0.189 mmol) in methanolic HCl (1.260 mL, 3.78 mmol) was reacted and then followed by step 4 6 reported workup and purification gave the hydrochloride salt of (2R,4S)-N-(5-(1-amino-3-cyclopropyl-1-(pyridin-2-yl)propyl)-2-fluorophenyl)-4-methoxy-4-phenylpyrrolidine-2-carboxamide (34c) (125 mg, 0.209 mmol, 111% yield), which was used directly in the next step; MS (ES+) 511.5 (M+Na), (ES-) 523.5 (M+Cl).

[0587] Step 4: Preparation of (2R,4S)-N2-(5-((+)-1-amino-3-cyclopropyl-1-(pyridin-2-yl)propyl)-2-fluorophenyl)-N1-(4-chlorophenyl)-4-methoxy-4-phenylpyrrolidine-1,2-dicarboxamide (34d)

[0588] According to the procedure reported in step 9 of scheme 1, a solution of (2R,4S)-N-(5-1-amino-3-cyclopropyl-1-(pyridin-2-yl)propyl)-2-fluorophenyl)-4-methoxy-4-phenylpyrrolidine-2-carboxamide (34c) (44 mg, 0.074 mmol) in dichloromethane (10 mL) was reacted with 4-chlorophenylisocyanate (1n) (9.42 μL, 0.074 mmol) and sodium bicarbonate and purified by flash column chromatography (silica gel 12 g, eluted with CMA 80% chloroform solution) to give a white solid (2R, 4S)-N2-(5-((+)-1-amino-3-cyclopropyl-1-(pyridin-2-yl)propyl)-2-fluorophenyl)-N1-(4-chlorophenyl)-4-methoxy-4-phenylpyrrolidine-1,2-dicarboxamide (34d) (36 mg, 0.056 mmol, yield 76%); 1 H NMR (300 MHz, DMSO-d 6)δ9.41 (s, 1H), 8.55 (s, 1H), 8.47 (m, 1H), 8.00-7.90 (m, 1H), 7.69 (d, J=1.9Hz, 1H), 7.62-7.50 (m, 3H ), 7.45(d, J=5.0Hz, 3H), 7.41-7.35(m, 1H), 7.33-7.25(m, 2H), 7.25-7.18(m, 1H), 7.18-7.05(m, 2H) , 4.62 (t, J=6.0Hz, 1H), 4.11 (d, J=10.4Hz, 1H), 3.79 (d, J=10.5Hz, 1H), 2.85 (s, 3H), 2.74-2.57 (m, 2 H), 2.44-2.19(m, 5H), 1.12-0.89(m, 2H), 0.72-0.51(m, 1H), 0.42-0.24(m, 2H), -0.02--0.14(m, 2H); 19 F NMR (282 MHz, DMSO-d 6 )δ-129.42; MS (ES+) 664.5, 665.6 (M+Na), (ES-) 676.5 (M+Cl); Optical rotation [α] D =(+)89.0[0.155, MeOH].

[0589] Scheme 35

[0590]

[0591] Preparation of (2R, 4S)-N2-(5-((+)-1-amino-3-cyclopropyl-1-(pyridin-2-yl)propyl)-2-fluorophenyl)-N1-(5-chloropyridin-2-yl)-4-methoxy-4-phenylpyrrolidine-1,2-dicarboxamide

[0592] According to the procedure reported in step 3 of scheme 13, (2R,4S)-N-(5-1-amino-3-cyclopropyl-1-(pyridin-2-yl)propyl)-2-fluorophenyl)-4-methoxy-4-phenylpyrrolidine-2-carboxamide (34c) (50 mg, 0.084 mmol) in tetrahydrofuran (10 mL) was reacted with phenyl 5-chloropyridin-2-ylcarbamate (13b) (20.79 mg, 0.084 mmol) using sodium bicarbonate as base and purified by flash column chromatography (silica gel 12 g, 0 to 100% CMA). 80% chloroform solution) to obtain a white solid (2R, 4S)-N2-(5-((+)-1-amino-3-cyclopropyl-1-(pyridin-2-yl)propyl)-2-fluorophenyl)-N1-(5-chloropyridin-2-yl)-4-methoxy-4-phenylpyrrolidine-1,2-dicarboxamide (35a) (36 mg, 0.056 mmol, yield 66.9%); 1 H NMR (300 MHz, DMSO-d 6 )δ9.41 (s, 1H), 9.21 (s, 1H), 8.47 (dd, J=4.8, 1.9Hz, 1H), 8.31 (d, J=2.6Hz, 1H), 7.92 (m, 2H), 7.82 (dd, J=9.0, 2. 7Hz, 1H), 7.69 (td, J=7.7, 1.9Hz, 1H), 7.54 (dt, J=8.1, 1.1Hz, 1H), 7.43 (d, J=4.0Hz, 4H), 7.37 (m, 1H), 7.22 (m, 1H ), 7.19-7.04 (m, 2H), 4.64 (t, J=6.2Hz, 1H), 4.24 (d, J=10.8Hz, 1H), 3.89 (d, J=10.9Hz, 1H), 2.84 (s, 3H), 2.61 (d , J=6.4Hz, 2H), 2.43-2.24(m, 4H), 1.12-0.95(m, 2H), 0.68-0.53(m, 1H), 0.38-0.26(m, 2H), -0.02--0.14(m, 2H); 19 F NMR (282 MHz, DMSO-d 6 )δ-128.95; MS (ES+) 665.5 (M+Na), (ES-) 641.6, 642.3 (M-1); optical rotation [α] D =(+)85.30[0.075, MeOH].

[0593] Scheme 36

[0594]

[0595] Preparation of (2R,4R)-N2-(5-((+)-1-amino-3-cyclopropyl-1-(pyridin-2-yl)propyl)-2-fluorophenyl)-N1-(5-chloropyridin-2-yl)-4-methoxypyrrolidine-1,2-dicarboxamide (36d)

[0596] Step 1: Preparation of (2R,4R)-1-(tert-butoxycarbonyl)-4-methoxypyrrolidine-2-carboxylic acid (36a)

[0597] According to the procedure reported in step 1 of scheme 34, (2R,4R)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid (14b) (6 g, 26 mmol) was reacted with NaH (6.24 g, 156 mmol; 60% suspension in oil) in THF (300 mL) and dimethyl sulfate (3.9 g, 31 mmol) to give (2R,4R)-1-(tert-butoxycarbonyl)-4-methoxypyrrolidine-2-carboxylic acid (36a) (5.82 g, 91%) as a white solid; 1 H NMR (300 MHz, DMSO-d 6 )δ4.14(td, J=8.9, 3.7Hz, 1H), 3.98-3.85(m, 1H), 3.52(m, 1H), 3.27-3.11(m, 4H), 2.33(m, 1H), 2.00(d t, J=13.3, 3.8Hz, 1H), 1.37 (2s, 9H); MS (ES+) 268.4 (M+Na), MS (ES-) 244.3 (M-1), 280.3 (M+Cl); Optical rotation [α] D =(+)45.28[0.265, MeOH].

[0598] Step 2: Preparation of tert-butyl (2R,4R)-2-(5-((+)-3-cyclopropyl-1-((S)-1,1-dimethylethylsulfinamido)-1-(pyridin-2-yl)propyl)-2-fluorophenylcarbamoyl)-4-methoxypyrrolidine-1-carboxylate (36b)

[0599] Using the reaction and workup conditions reported in Scheme 1, Step 10, a solution of (2R,4R)-1-(tert-butoxycarbonyl)-4-methoxypyrrolidine-2-carboxylic acid (36a) (95 mg, 0.388 mmol) and (S)-N-((-)-1-(3-amino-4-fluorophenyl)-3-cyclopropyl-1-(pyridin-2-yl)propyl)-2-methylpropane-2-sulfenamide (31f) (151 mg, 0.388 mmol) in tetrahydrofuran (25 mL) was reacted with ethyl 2-ethoxy-1(2H)-quinolinecarboxylate (96 mg, 0.388 mmol) and purified by flash column chromatography (silica gel, purified by CMA 80 chloroform solution, 0 to 100%) to give a colorless solid (2R,4R)-2-(5-((+)-3-cyclopropyl-1-((S)-1,1-dimethylethylsulfinamido)-1-(pyridin-2-yl)propyl)-2-fluorophenylcarbamoyl)-4-methoxypyrrolidine-1-carboxylic acid tert-butyl ester (36b) (135 mg, 0.219 mmol, yield 56.5%); 1 HNMR (300 MHz, DMSO-d 6 )δ9.43 (2s, 1H, rotamer), 8.61-8.45 (m, 1H), 7.89-7.66 (m, 2H), 7.33-7.23 (m, 2H), 7.15 (t, J=9.6 Hz, 1H), 7.06 (s, 1H), 5.91 (2s, , 1H, rotamer), 4.39-4.17 (m, 1H), 4.01-3.91 (m, 1H), 3.56 (dd, J=11.0, 5.2 Hz, 1H), 3. 21 (2s, 3H, rotamer), 2.70-2.52 (m, 2H), 2.50-2.37 (m, 1H), 2.16-1.86 (m, 1H), 1.34 (2s, 9H, rotamer), 1.14 (s, 10H), 1.11-0.94 (m, 1H), 0.97-0.79 (m, 1H), 0.71-0.54 (m, 1H), 0.42-0.26 (m, 2H), -0.01--0.16 (m, 2H); 19 F NMR (282 MHz, DMSO-d 6 )δ-127.64, -128.92 rotamers; MS (ES+) 639.5 (M+Na), (ES-) 615.6 (M-1); optical rotation [α] D =(+)11.42[0.07, MeOH].

[0600] Step 3: Preparation of (2R,4R)-N-(5-(1-amino-3-cyclopropyl-1-(pyridin-2-yl)propyl)-2-fluorophenyl)-4-methoxypyrrolidine-2-carboxamide (36c)

[0601] A solution of tert-butyl (2R,4R)-2-(5-((+)-3-cyclopropyl-1-((S)-1,1-dimethylethylsulfinamido)-1-(pyridin-2-yl)propyl)-2-fluorophenylcarbamoyl)-4-methoxypyrrolidine-1-carboxylate (36b) (120 mg, 0.195 mmol) in 3N methanolic HCl (0.973 mL, 2.92 mmol) was reacted and then followed by the reaction as reported in Scheme 4, Step 6. Workup and purification gave the hydrochloride salt of (2R,4R)-N-(5-(1-amino-3-cyclopropyl-1-(pyridin-2-yl)propyl)-2-fluorophenyl)-4-methoxypyrrolidine-2-carboxamide (36c) (100 mg, 0.192 mmol, 98% yield), which was used directly in the next step; MS: (ES+) 413.5 (M+1), 435.5 (M+Na), (ES-) 447.5 (M+Cl).

[0602] Step 4: Preparation of (2R,4R)-N2-(5-((+)-1-amino-3-cyclopropyl-1-(pyridin-2-yl)propyl)-2-fluorophenyl)-N1-(5-chloropyridin-2-yl)-4-methoxypyrrolidine-1,2-dicarboxamide (36d)

[0603] According to the procedure reported in step 3 of scheme 13, a solution of (2R,4R)-N-(5-(1-amino-3-cyclopropyl-1-(pyridin-2-yl)propyl)-2-fluorophenyl)-4-methoxypyrrolidine-2-carboxamide (36c) (95 mg, 0.182 mmol) in tetrahydrofuran (25 mL) was reacted with phenyl 5-chloropyridin-2-ylcarbamate (1 3b) (40.7 mg, 0.164 mmol) was reacted and purified by flash column chromatography to give a white solid (2R, 4R)-N2-(5-((+)-1-amino-3-cyclopropyl-1-(pyridin-2-yl)propyl)-2-fluorophenyl)-N1-(5-chloropyridin-2-yl)-4-methoxypyrrolidine-1,2-dicarboxamide (36d) (30 mg, 0.053 mmol, yield 29.1%); 1 H NMR (300 MHz, DMSO-d 6)δ9.42 (s, 1H), 9.14 (s, 1H), 8.53-8.42 (m, 1H), 8.30 (d, J = 2.6Hz, 1H), 7.91 (dd, J = 9.8, 2.5Hz, 2H), 7.81 (dd, J=9.1, 2.6Hz, 1H), 7.69 (td, J=7.7, 1.9Hz, 1H), 7.53 (d, J=8.0Hz, 1H), 7.17 (m, 2H), 7.08 ( m, 1H), 4.57 (dd, J=9.1, 3.9Hz, 1H), 4.12-3.98 (m, 1H), 3.81-3.61 (m, 2H), 3.22 (s, 3H), 2.45-2.23 ( m, 5H), 2.10 (m, 1H), 1.11-0.93 (m, 2H), 0.69-0.53 (m, 1H), 0.39-0.23 (m, 2H), -0.05--0.17 (m, 2H); 19 F NMR (282 MHz, DMSO-d 6 )δ-128.86; MS(ES+)567.4, 569.4(M+1), (ES-)565.4, 567.4(M-1); Optical rotation [α] D =(+)70.7[0.065, MeOH].

[0604] Scheme 37

[0605]

[0606] Preparation of (2R,4R)-N2-(5-((+)-1-amino-3-cyclopropyl-1-(pyridin-2-yl)propyl)-2-fluorophenyl)-N1-(5-chloropyridin-2-yl)-4-methoxypyrrolidine-1,2-dicarboxamide (37d)

[0607] Step 1: Preparation of benzyl (2R,4R)-2-((5-((+)-1-(((S)-tert-butylsulfinyl)amino)-3-cyclopropyl-1-(pyridin-2-yl)propyl)-2-fluorophenyl)carbamoyl)-4-methoxypyrrolidine-1-carboxylate (37a)

[0608] Using the reaction and workup conditions reported in Scheme 1, Step 10, (2R,4R)-1-(benzyloxycarbonyl)-4-methoxypyrrolidine-2-carboxylic acid (15b) (0.17 g, 0.6 mmol), (S)-N-((+)-1-(3-amino-4-fluorophenyl)-3-cyclopropyl-1-(pyridin-2-yl)propyl)-2-methyl A solution of propane-2-sulfenamide (31e) (0.2 g, 0.5 mmol) in tetrahydrofuran (5 mL) was reacted and flash column chromatography was performed to give (2R,4R)-2-((5-((+)-1-(((S)-tert-butylsulfinyl)amino)-3-cyclopropyl-1-(pyridin-2-yl)propyl)-2-fluorophenyl)carbamoyl)-4-methoxypyrrolidine-1-carboxylic acid benzyl ester (37a) (0.29 g, 86%) as a white solid; 1 H NMR (300 MHz, DMSO-d 6 )δ9.54 (2s, 1H, rotamer), 8.58-8.50 (m, 1H), 7.97 (dd, J=7.6, 2.3 Hz, 1H), 7.74 (t, J=7.9 Hz, 1H), 7.37 (s, 2H), 7.31-6.99 (m, 7H), 6.16 (s, 1H), 5.16-4.91 (m, 2H), 4.51-4.34 (m, 1H), 4.05-3.91 (m, 1H), 3.74-3.58 (m, 1H), 3.47-3.37 (m, 1H), 3.19 (d, J = 5.3 Hz, 3H), 2.58 (m, 2H), 1.09 (m, 9H, rotamer), 0.64-0,47 (m, 3H), 0.38-0.24 (m, 2H), -0.10--0.25 (m, 2H); MS (ES+) 651.6 (M+1), 673.5 (M+Na), MS (ES-) 685.6 (M+Cl); optical rotation [α] D =(+)131.3[0.23, MeOH].

[0609] Step 2: Preparation of (2R,4R)-N-(5-(1-(((S)-tert-butylsulfinyl)amino)-3-cyclopropyl-1-(pyridin-2-yl)propyl)-2-fluorophenyl)-4-methoxypyrrolidine-2-carboxamide (37b)

[0610] According to the procedure reported in step 2 of scheme 13, debenzylation by hydrogenation of a solution of (2R,4R)-benzyl 2-((5-((+)-1-(((S)-tert-butylsulfinyl)amino)-3-cyclopropyl-1-(pyridin-2-yl)propyl)-2-fluorophenyl)carbamoyl)-4-methoxypyrrolidine-1-carboxylate (37a) (0.28 g, 0.43 mmol) in ethanol (20 mL) was carried out with palladium on carbon 10% as catalyst to give (2R,4R)-N-(5-(1-(((S)-tert-butylsulfinyl)amino)-3-cyclopropyl-1-(pyridin-2-yl)propyl)-2-fluorophenyl)-4-methoxypyrrolidine-2-carboxamide (37b) (0.21 g, 95% yield) as a sticky solid; 1 HNMR (300 MHz, DMSO-d 6 )δ10.09 (s, 1H), 8.58-8.49 (m, 1H), 8.32 (dd, J=7.8, 2.3Hz, 1H), 7.74 (td, J=7.8, 1.8Hz, 1H), 7.31-7.1 4 (m, 2H), 7.11 (d, J = 8.1Hz, 2H), 7.04-6.96 (m, 1H), 6.14 (s, 1H), 3.91-3.75 (m, 1H), 3.74 (d, J = 7.2Hz, 1H ), 3.04-2.98 (m, 1H), 2.90 (d, J=10.7Hz, 1H), 2.66-2.54 (m, 5H), 2.18-1.95 (m, 2H), 1.08 (s, 9H), 0.68-0 .46 (m, 3H), 0.31 (m, 2H), -0.10--0.25 (m, 2H); MS (ES+) 516.5 (M+1), 539.5 (M+Na), MS (ES-) 515.5 (M-1).

[0611] Step 3: Preparation of (2R,4R)-N2-(5-(1-(((S)-tert-butylsulfinyl)amino)-3-cyclopropyl-1-(pyridin-2-yl)propyl)-2-fluorophenyl)-N1-(5-chloropyridin-2-yl)-4-methoxypyrrolidine-1,2-dicarboxamide (37c)

[0612] According to the procedure reported in step 3 of scheme 13, a solution of (2R,4R)-N-(5-(1-(((S)-tert-butylsulfinyl)amino)-3-cyclopropyl-1-(pyridin-2-yl)propyl)-2-fluorophenyl)-4-methoxypyrrolidine-2-carboxamide (37b) (0.1 g, 0.19 mmol) in THF (5 mL) was reacted with phenyl 5-fluoropyridin-2-ylcarbamate using TEA (50 μL) as base. (13b) (0.06 g, 0.23 mmol) was reacted and purified by flash column chromatography to give a white solid (2R,4R)-N2-(5-(1-(((S)-tert-butylsulfinyl)amino)-3-cyclopropyl-1-(pyridin-2-yl)propyl)-2-fluorophenyl)-N1-(5-chloropyridin-2-yl)-4-methoxypyrrolidine-1,2-dicarboxamide (37c) (0.11 g, 84%); 1 H NMR (300) MHz, DMSO-d 6 )δ9.50 (s, 1H), 9.15 (s, 1H), 8.53 (dd, J=4.9, 1.8, Hz, 1H), 8.29 (d, J=2.6Hz, 1H), 7.96 (dd, J=7.6, 2.3Hz, 1H), 7.89 (d, J=9.0Hz, 1H), 7. 81 (dd, J=9.0, 2.6Hz, 1H), 7.73 (td, J=7.8, 1.8Hz, 1H), 7.26 (m, 1H), 7.22-7.07 (m, 2H), 7.10-6.99 (m, 1H), 6.14 (s, 1H), 4.58 (dd, J=9.1 , 3.9Hz, 1H), 4.03 (d, J=4.3Hz, 1H), 3.72 (m, 2H), 3.21 (s, 3H), 2.63-2.52 (m, 2H), 2.45-2.27 (m, 1H), 2.08 (m, 1H), 1.09 (s, 9H), 0.90-0. 78 (m, 2H), 0.64-0.46 (m, 1H), 0.36-0.23 (m, 2H), -0.19 (m, 2H).; MS (ES+) 671.5 (M+1), 693.5 (M+Na), MS (ES-) 669.5 (M-1), 705.5 (M+Cl).

[0613] Step 4: Preparation of (2R,4R)-N2-(5-((+)-1-amino-3-cyclopropyl-1-(pyridin-2-yl)propyl)-2-fluorophenyl)-N1-(5-chloropyridin-2-yl)-4-methoxypyrrolidine-1,2-dicarboxamide (37d)

[0614] As reported in Scheme 4, step 6, (2R,4R)-N2-(5-(1-(((S)-tert-butylsulfinyl)amino)-3-cyclopropyl-1-(pyridin-2-yl)propyl)-2-fluorophenyl)-N1-(5-chloropyridin-2-yl)-4-methoxypyrrolidine-1,2-dicarboxamide (37c) (0.1 g, 0.15 mmol) in ethanol (5 mL) was reacted with concentrated HCl (0.12 mL) and purified by flash column chromatography to give (2R,4R)-N2-(5-((+)-1-amino-3-cyclopropyl-1-(pyridin-2-yl)propyl)-2-fluorophenyl)-N1-(5-chloropyridin-2-yl)-4-methoxypyrrolidine-1,2-dicarboxamide (37d) (50 mg, 60% yield) as a white solid; 1 H NMR (300 MHz, DMSO-d 6 )δ9.40 (d, J=1.4Hz, 1H), 9.13 (s, 1H), 8.47 (ddd, J=4.9, 1.8, 0.9Hz, 1H), 8.30 (dd, J=2.6, 0.8Hz, 1H), 7 .90 (dd, J=8.2, 1.5Hz, 2H), 7.81 (dd, J=9.0, 2.6Hz, 1H), 7.69 (td, J=7.7, 1.9Hz, 1H), 7.53 (dt, J=8.1, 1. 1Hz, 1H), 7.23-7.03 (m, 3H), 4.56 (dd, J=9.2, 3.9Hz, 1H), 4.11-3.96 (m, 1H), 3.81-3.64 (m, 2H), 3.21 (s , 3H), 2.43-2.20(m, 4H), 2.09(m, 1H), 1.02(m, 2H), 0.71-0.54(m, 1H), 0.40-0.30(m, 2H), -0.08(m, 2H); 19 FNMR (282 MHz, DMSO-d 6 )δ-128.01; MS(ES+)567.5(M+1), (ES-)603.5(M+Cl); Optical rotation [α] D =(+)70.7[0.065, MeOH].

[0615] Scheme 38

[0616]

[0617] Preparation of (2R)-N2-(5-((+)-1-amino-3-cyclopropyl-1-(pyridin-2-yl)propyl)-2-fluorophenyl)-N1-(5-chloropyridin-2-yl)-4-ethyl-4-hydroxypyrrolidine-1,2-dicarboxamide (38d)

[0618] Step 1: Preparation of (2R)-1-(tert-butoxycarbonyl)-4-ethyl-4-hydroxypyrrolidine-2-carboxylic acid (38a)

[0619] Using the reaction and workup conditions reported in Scheme 29, Step 2, a solution of (R)-1-(tert-butoxycarbonyl)-4-oxopyrrolidine-2-carboxylic acid (29a) (0.502 g, 2.19 mmol) in THF (20 mL) was reacted with a 1.0 M solution of ethylmagnesium bromide (6.02 mL, 6.02 mmol) to afford (2R)-1-(tert-butoxycarbonyl)-4-ethyl-4-hydroxypyrrolidine-2-carboxylic acid (38a) (330 mg, 1.273 mmol, 58.1% yield) as an oil which was used directly in the next step; MS (ES+) 282.4 (M+Na), 541.6 (2M+Na), (ES-) 258.3 (M-1), 517.6 (2M-1).

[0620] Step 2: Preparation of tert-butyl (2R)-2-(5-((+)-3-cyclopropyl-1-((S)-1,1-dimethylethylsulfinamido)-1-(pyridin-2-yl)propyl)-2-fluorophenylcarbamoyl)-4-ethyl-4-hydroxypyrrolidine-1-carboxylate (38b)

[0621] Using the reaction and workup conditions reported in Scheme 1, Step 10, (2R)-1-(tert-butoxycarbonyl)-4-ethyl-4-hydroxypyrrolidine-2-carboxylic acid (38a) (300 mg, 1.157 mmol) and (S)-N-((+)-1-(3-amino-4-fluorophenyl)-3-cyclopropyl-1-(pyridin-2-yl)propyl)-2-methylpropane-2-sulfinyl acetate (402 mg, 1.627 mmol) were reacted with ethyl 2-ethoxy-1(2H)-quinolinecarboxylate. A solution of amide (31e) (451 mg, 1.157 mmol) in tetrahydrofuran (25 mL) was reacted, and flash column chromatography was performed to give a white solid (2R)-2-(5-((+)-3-cyclopropyl-1-((S)-1,1-dimethylethylsulfinamido)-1-(pyridin-2-yl)propyl)-2-fluorophenylcarbamoyl)-4-ethyl-4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester (38b) (97 mg, 0.154 mmol, yield 13.29%); 1 H NMR (300 MHz, DMSO-d 6)δ9.68 (2s, 1H, rotamer), 8.69-8.46 (m, 1H), 8.11 (2dd, 1H, rotamer), 7.74 (m, 1H), 7.41-6.95 (m, 3H), 6.14 (d, J=6.5 Hz, 1H), 5.08 (2s, 1H, rotamer), 4.41-4.21 (m, 1H), 3.30-3.17 (m, 1H), 2 .67-2.54 (m, 4H), 2.32-2.11 (m, 1H), 1.98-1.80 (m, 1H), 1.52 (m, 2H), 1.31 (2s, 9H, rotamer), 1.10 (s, 9H), 0.88 (t, J = 7.4 Hz, 3H), 0.57 (m, 3H), 0.38-0.26 (m, 2H), 0.05-0.28 (m, 2H); 19F NMR (282 MHz, DMSO-d 6 )δ-128.40, -129.65 rotamers; MS (ES+) 631.7 (M+1), 653.7 (M+Na), (ES-) 629.7 (M-1), 665.7 (M+Cl); optical rotation [α] D =(+)100.0[0.07, MeOH].

[0622] Step 3: Preparation of (2R)-N-(5-(1-amino-3-cyclopropyl-1-(pyridin-2-yl)propyl)-2-fluorophenyl)-4-ethyl-4-hydroxypyrrolidine-2-carboxamide (38c)

[0623] Using the reaction and workup conditions reported in Scheme 4, Step 6, tert-butyl (2R)-2-(5-((+)-3-cyclopropyl-1-((S)-1,1-dimethylethylsulfinamido)-1-(pyridin-2-yl)propyl)-2-fluorophenylcarbamoyl)-4-ethyl-4-hydroxypyrrolidine-1-carboxylate (38b) (87 mg, 0.138 mmol) was reacted with 3N methanolic HCl (0.919 mL, 2.76 mmol). The product was reacted with methanol (20 mL) to give the hydrochloride salt of (2R)-N-(5-(1-amino-3-cyclopropyl-1-(pyridin-2-yl)propyl)-2-fluorophenyl)-4-ethyl-4-hydroxypyrrolidine-2-carboxamide (38c) (69 mg, 0.138 mmol, 100% yield), which was used directly in the next step without further purification; MS (ES+) 449.4 (M+Na), (ES-) 461.2 (M+Cl).

[0624] Step 4: Preparation of (2R)-N2-(5-((+)-1-amino-3-cyclopropyl-1-(pyridin-2-yl)propyl)-2-fluorophenyl)-N1-(5-chloropyridin-2-yl)-4-ethyl-4-hydroxypyrrolidine-1,2-dicarboxamide (38d)

[0625] According to the procedure reported in step 3 of scheme 13, a solution of (2R)-N-(5-(1-amino-3-cyclopropyl-1-(pyridin-2-yl)propyl)-2-fluorophenyl)-4-ethyl-4-hydroxypyrrolidine-2-carboxamide (38c) (65 mg, 0.130 mmol) in tetrahydrofuran (25 mL) was reacted with phenyl 5-chloropyridin-2-ylcarbamate (29.1 mg, 0.117 mmol) using sodium bicarbonate as base. Purification by flash column chromatography (silica gel 12 g, eluted with 0 to 100% CMA-80 in chloroform) gave a white solid (2R)-N2-(5-((+)-1-amino-3-cyclopropyl-1-(pyridin-2-yl)propyl)-2-fluorophenyl)-N1-(5-chloropyridin-2-yl)-4-ethyl-4-hydroxypyrrolidine-1,2-dicarboxamide (38d) (28 mg, 0.048 mmol, 37.0% yield); 1 H NMR (300 MHz, DMSO-d 6 )δ9.68 (s, 1H), 9.13 (s, 1H), 8.47 (dd, J=4.7, 1.9Hz, 1H), 8.29 (d, J=2.6Hz, 1H), 8.08 (dd, J=7.8, 2.3Hz, 1H), 7.89 ( d, J=9.1Hz, 1H), 7.80 (dd, J=9.0, 2.6Hz, 1H), 7.70 (m, 1H), 7.53 (m, 1H), 7.25-7.03 (m, 3H), 5.77 (s, 1H), 5.11 (s, 1H) , 4.63-4.45 (m, 1H), 3.64 (d, J = 10.3Hz, 1H), 3.48 (d, J = 10.4Hz, 1H), 2.42-2.15 (m, 4H), 2.01-1.89 (m, 1H), 1.56 (q, J=7.4Hz, 2H), 1.12-0.97 (m, 2H), 0.92 (t, J=7.3Hz, 3H), 0.71-0.52 (m, 1H), 0.40-0.26 (m, 2H), -0.02--0.14 (m, 2H); 19 F NMR (282 MHz, DMSO-d6) δ -129.61; MS (ES+) 581.4 (M+1), 604.5, 606.4 (M+Na), (ES-) 579.4, 581.5 (M-1), 615.5, 616.5 (M+Cl); Optical rotation [α]D =(+)67.37[0.19, MeOH].

[0626] Scheme 39

[0627]

[0628] Preparation of (2R,4S)-N2-(5-((+)-1-amino-3-cyclopropyl-1-(pyridin-4-yl)propyl)-2-fluorophenyl)-N1-(5-chloropyridin-2-yl)-4-hydroxy-4-phenylpyrrolidine-1,2-dicarboxamide (39h)

[0629] Step 1: Preparation of (E)-3-cyclopropyl-1-(pyridin-4-yl)-2-propen-1-one (39b)

[0630] Using the reaction and workup procedures reported in Scheme 31, step 1, a solution of 1-(pyridin-4-yl)ethanone (39a) (1.516 mL, 13.27 mmol) in methanol (100 mL) was reacted with cyclopropanecarboxaldehyde (1.5 mL, 19.90 mmol) and potassium hydroxide solution (1 N, 2.65 mL, 2.65 mmol) to give (E)-3-cyclopropyl-1-(pyridin-4-yl)-2-propen-1-one (39b) (479 mg, 20.85%); 1 H NMR (300 MHz, DMSO-d 6 )δ8.89-8.59(m, 2H), 7.91-7.71(m, 2H), 7.19(d, J=15.1Hz, 1H), 6.58(dd, J= 15.1, 10.4Hz, 1H), 1.88-1.71 (m, 1H), 1.10-0.96 (m, 2H), 0.87-0.72 (m, 2H).

[0631] Step 2: Preparation of 3-cyclopropyl-1-(pyridin-2-yl)propan-1-one (39c)

[0632] Using the procedure reported in Scheme 31, Step 2, a solution of (E)-3-cyclopropyl-1-(pyridin-4-yl)-2-propen-1-one (39b) (18.35 g, 106 mmol) in acetonitrile (180 mL) and tributylstannane (60.0 mL, 216 mmol) was reacted and purified by flash column chromatography (silica gel, eluting with 0 to 30% ethyl acetate in hexanes) to give 3-cyclopropyl-1-(pyridin-4-yl)propan-1-one (39c) (3.028 g, 15%) as an oil; 1 H NMR (300 MHz, DMSO-d 6) δ3.14 (t, J=7.2Hz, 2H), 1.52 (q, J=7.1Hz, 2H), 0.75 (dddd, J=12.0, 8.1, 7.0, 2.8Hz, 1H), 0.47-0.28 (m, 2H), 0.14-0.02 (m, 2H).

[0633] Step 3: Preparation of (-)-N-(3-cyclopropyl-1-(pyridin-4-yl)propylidene)-2-methylpropane-2-sulfenamide (39d)

[0634] Compound (39d) was prepared using the procedure reported in Scheme 31, Step 3, from 3-cyclopropyl-1-(pyridin-4-yl)propan-1-one (39c) (1.8 g, 10.27 mmol) and (R)-2-methylpropane-2-sulfenamide (1.566 g, 12.84 mmol) to give (-)-N-(3-cyclopropyl-1-(pyridin-4-yl)propylidene)-2-methylpropane-2-sulfenamide (39d) (1.838 g, 6.57 mmol, 63.9% yield) as a yellow syrup; 1 H NMR (300 MHz, DMSO-d 6 )δ8.76-8.69 (m, 2H), 7.80-7.73 (m, 2H), 3.49-3.15 (m, 2H), 1.45 (q, J=7.4 Hz, 2H), 1.24 (s, 9H), 0.84-0.65 (m, 1H), 0.43-0.30 (m, 2H), 0.10-0.03 (m, 2H); MS (ES+) 301.3, (M+Na); (ES-) 277.3 (M-1); Optical rotation [α] D =(-)27.61[0.355, MeOH].

[0635] Step 4: Preparation of (R)-N-((-)-1-(3-amino-4-fluorophenyl)-3-cyclopropyl-1-(pyridin-4-yl)propyl)-2-methylpropane-2-sulfenamide (39e)

[0636] Compound (39e) was prepared from (-)-N-(3-cyclopropyl-1-(pyridin-4-yl)propylidene)-2-methylpropane-2-sulfenamide (39d) (1.7 g, 6.11 mmol) using the procedure reported in step 4 of scheme 31 to give (R)-N-((-)-1-(3-amino-4-fluorophenyl)-3-cyclopropyl-1-(pyridin-4-yl)propyl)-2-methylpropane-2-sulfenamide (39e) (1.443 g, 3.7 mmol, 60.7% yield) as a white solid; 1 H NMR (300 MHz, DMSO-d 6)δ8.77-8.68(m, 2H), 7.62-7.53(m, 2H), 7.15(dd, J=11.3, 8.5Hz, 1H), 7.00-6.94(m, 1H), 6.77-6.70(m, 1H), 5.50(s, 1H), 5.35(s, 2 H), 2.90-2.60(m, 2H), 1.47-1.27(m, 1H), 1.38(s, 9H), 1.25-1.05(m, 1H), 0.97-0.80(m, 1H), 0.65-0.55(m, 2H), 0.32-0.10(m, 2H); 19 F NMR (282 MHz, DMSO-d 6 )-137.30; MS (ES+): 390.4 (M+1); chiral purity was checked by chiral HPLC using a chiral AD-H column, 1 mL / min, solvent: 90% hexane, 10% EtOH, 0.1% TEA, UV=260 nM, 25°C (>99.99 ee); optical rotation [α] D =(-)78.49[0.265, MeOH].

[0637] Step 5: Preparation of tert-butyl (2R,4S)-2-(5-((-)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)-1-(pyridin-4-yl)propyl)-2-fluorophenylcarbamoyl)-4-hydroxy-4-phenylpyrrolidine-1-carboxylate (39f)

[0638] The reaction and workup conditions were reported using Scheme 1, Step 10, with (2R,4S)-1-(tert-butoxycarbonyl)-4-hydroxy-4-phenylpyrrolidine-2-carboxylic acid (29b) (225 mg, 0.732 mmol), (R)-N-((-)-1-(3-amino-4-fluorophenyl)-3-cyclopropyl-1-(pyridin-4-yl)propyl)-2-methylpropane-2-sulfenamide (39e) and 2-ethoxy-1(2H)-quinoline Carboxylic acid ethyl ester (181 mg, 0.732 mmol) was used to prepare compound 39f to give (2R,4S)-2-(5-((-)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)-1-(pyridin-4-yl)propyl)-2-fluorophenylcarbamoyl)-4-hydroxy-4-phenylpyrrolidine-1-carboxylic acid tert-butyl ester (39f) (235 mg, 0.346 mmol, yield 47.3%) as a white solid; 1 H NMR (300 MHz, DMSO-d 6)δ9.78 (d, J=93.3 Hz, 1H), 8.59-8.47 (m, 2H), 8.32 (s, 1H), 8.29-8.06 (m, 1H), 7.51 (dt, J=6.6, 1.4 Hz, 2H), 7.43-7.07 (m, 6H), 5.99 (2s, 1H, rotamer), 5.51 (m, 1H), 4.44 ( m, 1H), 3.68 (m, 2H), 2.78-2.51 (m, 2H), 2.35-2.15 (m, 1H), 1.33 (2s, 9H, rotamer), 1.15 (s, 10H), 0.92 (m, 2H), 0.73-0.57 (m, 1H), 0.42-0.30 (m, 2H), 0.00-0.13 (m, 2H); 19 F NMR (282 MHz, DMSO-d 6 )δ-128.66, -130.04 (rotamers); MS (ES+) 679.5 (M+1), 701.5 (M+Na), (ES-) 677.5 (M-1), 713.5 (M+Cl); optical rotation [α] D =(-)55.55[0.18, MeOH].

[0639] Step 6: Preparation of (2R,4S)-N-(5-(1-amino-3-cyclopropyl-1-(pyridin-4-yl)propyl)-2-fluorophenyl)-4-hydroxy-4-phenylpyrrolidine-2-carboxamide (39 g)

[0640] A solution of tert-butyl (2R,4S)-2-(5-((-)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)-1-(pyridin-4-yl)propyl)-2-fluorophenylcarbonyl)-4-hydroxy-4-phenylpyrrolidine-1-carboxylate (39f) (200 mg, 0.295 mmol) in methanol (10 mL) was reacted with hydrochloric acid (1.964 mL, 5.89 mmol). ) was reacted and treated and purified as reported in Scheme 4, Step 6 to give the hydrochloride salt of (2R,4S)-N-(5-(1-amino-3-cyclopropyl-1-(pyridin-4-yl)propyl)-2-fluorophenyl)-4-hydroxy-4-phenylpyrrolidine-2-carboxamide (39 g) (169 mg, 0.289 mmol, 98% yield), which was used directly in the next step; MS (ES-) 509.4 (M+Cl).

[0641] Step 7: (2R,4S)-N2-(5-((+)-1-amino-3-cyclopropyl-1-(pyridin-4-yl)propyl)-2-fluorophenyl)-N1-(5-chloropyridin-2-yl)-4-hydroxy-4-phenylpyrrolidine-1,2-dicarboxamide (39h)

[0642] According to the procedure reported in step 3 of scheme 13, a solution of (2R,4S)-N-(5-(1-amino-3-cyclopropyl-1-(pyridin-4-yl)propyl)-2-fluorophenyl)-4-hydroxy-4-phenylpyrrolidine-2-carboxamide (39 g) (160 mg, 0.274 mmol) in tetrahydrofuran (25 mL) was reacted with phenyl 5-chloropyridin-2-ylcarbamate (13b) (6 1.3 mg, 0.247 mmol) was reacted and purified by flash column chromatography to obtain a white solid (2R, 4S)-N2-(5-((+)-1-amino-3-cyclopropyl-1-(pyridin-4-yl)propyl)-2-fluorophenyl)-N1-(5-chloropyridin-2-yl)-4-hydroxy-4-phenylpyrrolidine-1,2-dicarboxamide (98 mg, 0.156 mmol, yield 56.9%); 1 H NMR (300 MHz, DMSO-d 6 )δ9.74 (s, 1H), 9.25 (s, 1H), 8.47-8.41 (m, 2H), 8.30 (d, J = 2.4Hz, 1H), 8.12 (d, J = 7.6Hz, 1H), 7.91 (d, J = 9.0Hz, 1H), 7.81 (dd, J=8.9, 2.6Hz, 1H), 7.54 (dt, J=6.5, 1.3Hz, 2H), 7.41-7.33 (m, 4H), 7.33-7.25 (m, 1H), 7.15 (dd, J=7.3, 1.7 Hz, 2H), 5.95 (s, 1H), 4.80-4.65 (m, 1H), 4.00 (d, J=10, 5Hz, 1H), 3.90 (d, J=10.4Hz, 1H), 2.68 (dd, J=13.1, 9.6Hz, 1H ), 2.31(m, 3H), 2.21(t, J=8.1Hz, 2H), 1.12-0.96(m, 2H), 0.70-0.53(m, 1H), 0.45-0.26(m, 2H), -0.01--0.14(m, 2H); 19 F NMR (282 MHz, DMSO-d 6 )δ-129.43; MS (ES+) 629.4 (M+1), 651.4, 653.4 (M+Na), (ES-) 627.4, 629.4 (M-1); Optical rotation [α] D =(+)7.209 [0.265, MeOH]; Analytical calculation value C 34 H 34 CIF 6 O 3 .0.5H 2O; C, 63.99; H, 5.53; N, 13.17; Found: C, 64.02; H, 5.63; N, 12.86.

[0643] Scheme 40

[0644]

[0645] Preparation of (2R, 4S)-N2-(5-((+)-1-amino-3-cyclopropyl-1-(pyridin-4-yl)propyl)-2-fluorophenyl)-N1-(4-chlorophenyl)-4-hydroxy-4-phenylpyrrolidine-1,2-dicarboxamide (40a)

[0646] According to the procedure reported in step 9 of scheme 1, a solution of (2R,4S)-N-(5-(1-amino-3-cyclopropyl-1-(pyridin-4-yl)propyl)-2-fluorophenyl)-4-hydroxy-4-phenylpyrrolidine-2-carboxamide (39 g) (250 mg, 0.428 mmol) in dichloromethane (20 mL) was reacted with 4-chlorophenylisocyanate (1n) (0.049 mL, 0.385 mmol) and sodium bicarbonate (719 mg, 8.56 mmol) and purified by flash column chromatography (silica gel 12 g, eluted with CMA 80 chloroform solution) to give an off-white solid (2R, 4S)-N2-(5-((+)-1-amino-3-cyclopropyl-1-(pyridin-4-yl)propyl)-2-fluorophenyl)-N1-(4-chlorophenyl)-4-hydroxy-4-phenylpyrrolidine-1,2-dicarboxamide (40a) (134 mg, 0.213 mmol, yield 49.8%); 1 HNMR (300 MHz, DMSO-d 6 )δ9.69 (s, 1H), 8.53 (s, 1H), 8.49-8.37 (m, 2H), 8.16 (d, J=7.8Hz, 1H), 7.61-7.53 (m, 4H), 7.43 -7.34 (m, 4H), 7.33-7.25 (m, 3H), 7.17 (s, 1H), 7.14 (d, J=1.3Hz, 1H), 5.97 (s, 1H), 4.68 (dd, J=9 .7, 2.7Hz, 1H), 3.93 (d, J=10.1Hz, 1H), 3.83 (d, J=10.0Hz, 1H), 2.72 (dd, J=13.1, 9.8Hz, 1H), 2. 39-2.10(m, 5H), 1.12-0.97(m, 2H), 0.73-0.56(m, 1H), 0.43-0.28(m, 2H), -0.00--0.10(m, 2H); 19 F NMR (282 MHz, DMSO-d 6)δ-129.82; MS (ES-), 626.5, 628.5 (M-1); Analytical calculation value C 35 H 35 CIF 5 O 3 .0.5H 2 O: C, 65.98; H, 5.70; N, 10.99; Found: C, 65.94; H, 5.86; N, 10.69; Optical rotation [α] D =(+)65.14[0.175, MeOH].

[0647] Scheme 41

[0648]

[0649] Preparation of (2R,4S)-N1-(5-chloropyridin-2-yl)-N2-(5-((+)-3-cyclopropyl-1-(methylamino)-1-(pyridin-4-yl)propyl)-2-fluorophenyl)-4-hydroxy-4-phenylpyrrolidine-1,2-dicarboxamide (41a)

[0650] To a solution of (2R,4S)-N2-(5-((+)-1-amino-3-cyclopropyl-1-(pyridin-4-yl)propyl)-2-fluorophenyl)-N1-(5-chloropyridin-2-yl)-4-hydroxy-4-phenylpyrrolidine-1,2-dicarboxamide (39h) (100 mg, 0.159 mmol) in methanol (10 mL) was added acetic acid (1 drop) paraformaldehyde (23.86 mg, 0.795 mmol) and sodium borohydride (30.1 mg, 0.795 mmol) and stirred at room temperature for 8 hours. Additional paraformaldehyde (23.86 mg, 0.795 mmol) and sodium borohydride (30.1 mg, 0.795 mmol) were added to the reaction product and stirred at room temperature overnight. The reaction product was concentrated in vacuo and the obtained residue was purified by flash column chromatography (silica gel 12 g, eluted with CMA 80 in chloroform) to give a white solid ((2R,4S)-N1-(5-chloropyridin-2-yl)-N2-(5-((+)-3-cyclopropyl-1-(methylamino)-1-(pyridin-4-yl)propyl)-2-fluorophenyl)-4-hydroxy-4-phenylpyrrolidine-1,2-dicarboxamide (41a) (74 mg, 0.115 mmol, 72.4% yield) free base; 1 H NMR (300 MHz, DMSO-d 6)δ9.73 (s, 1H), 9.25 (s, 1H), 8.50-8.41 (m, 2H), 8.34-8.27 (m, 1H), 8.10 (d, J=7.1Hz, 1H), 7.91 (dd, J=9.1, 0.8 Hz, 1H), 7.82 (dd, J=9.0, 2.7Hz, 1H), 7.59-7.48 (m, 2H), 7.43-7.34 (m, 3H), 7.35-7.26 (m, 2H), 7.16 (dd, J=10.5 , 8.8Hz, 1H), 7.11-7.00 (m, 1H), 5.94 (s, 1H), 4.71 (d, J=7.5Hz, 1H), 4.10-3.85 (m, 2H), 2.75-2.63 (m, 1H), 2.2 5 (m, 3H), 1.94 (s, 4H, N-Me and NH), 1.05-0.74 (m, 2H), 0.70-0.56 (m, 1H), 0.40-0.24 (m, 2H), -0.06--0.18 (m, 2H); 19 F NMR (282 MHz, DMSO-d 6 )δ-129.21; MS (ES+) 643.3 (M+1), 665.3, 667.3 (M+Na), (ES-) 641.4, 643.3 (M-1). The free base of compound 41a (100 mg, 0.159 mmol) was converted into a hydrochloride in methanol (10 mL) using concentrated HCl, and freeze-dried to give a white powder (2R, 4S)-N1-(5-chloropyridin-2-yl)-N2-(5-((+)-3-cyclopropyl-1-(methylamino)-1-(pyridin-4-yl)propyl)-2-fluorophenyl)-4-hydroxy-4-phenylpyrrolidine-1,2-dicarboxamide (41a) (64 mg, 0.089 mmol, yield 88%); 1 HNMR (300 MHz, DMSO-d 6)δ10.31 (s, 2H), 9.96 (s, 1H), 9.29 (s, 1H), 8.80 (d, J = 5.3Hz, 2H), 8.31 (d, J = 2.5Hz, 1H), 8.1 7 (d, J=6.7Hz, 1H), 7.95-7.77 (m, 2H), 7.66 (d, J=5.3Hz, 2H), 7.53 (d, J=7.6Hz, 2H), 7.49-7. 17(m, 5H), 4.87-4.58(m, 1H), 4.11-3.84(m, 2H), 2.78-2.54(m, 3H), 2.47-2.13(m, 6H), 1.19 -0.98(m, 1H), 0.96-0.77(m, 1H), 0.76-0.61(m, 1H), 0.45-0.30(m, 2H), -0.00--0.10(m, 2H); 19 F NMR (282 MHz, DMSO-d 6 )δ-124.81; MS (ES+) 665.4, 667.4 (M+Na), (ES-) 641.5, 643.5 (M-1), 677.3, 679.4 (M+Cl); Optical rotation [α] D =(+)6.0[0.19, MeOH].

[0651] Scheme 42

[0652]

[0653] Preparation of (2R,4R)-N1-(5-chloropyridin-2-yl)-N2-(5-(3-cyclopropyl-1-(2-oxopyridin-1(2H)-yl)propyl)-2-fluorophenyl)-4-methoxypyrrolidine-1,2-dicarboxamide (421)

[0654] Step 1: Preparation of (E)-ethyl 3-cyclopropyl acrylate (42b)

[0655] Cyclopropanecarboxaldehyde (200 g, 2853 mmol) was added to a solution of 1-triphenylphosphoranylidenepentane-2-one (42a) (994 g, 2853 mmol) in dichloromethane (3000 mL) and stirred at room temperature for 20 hours. The reaction mixture was concentrated to 1 / 3 volume, diluted with hexane (1000 mL), and concentrated in vacuo to remove dichloromethane. The reaction mixture was diluted with hexane (3000 mL) and stirred for 10 minutes. The resulting triphenylphosphine oxide solid was removed by filtration and washed with hexane (2×400 mL) to obtain a colorless oil (E)-ethyl 3-cyclopropyl acrylate (42b) (410 g, 2925 mmol, 103% yield), which was used directly in the next step without purification; 1H NMR (300 MHz, DMSO-d 6 )δ6.38 (dd, J=15.4, 10.2Hz, 1H), 5.93 (d, J=15.4Hz, 1H), 4.08 (q, J=7.1Hz, 2H), 1.64 (dtt, J=10.2, 8.0, 4.6Hz, 1H), 1.19 (td, J=7.1, 1.0Hz, 3H), 0.98-0.82 (m, 2H), 0.75-0.62 (m, 2H).

[0656] Step 2: Preparation of ethyl 3-cyclopropylpropionate (42c)

[0657] To a solution of (E)-ethyl 3-cyclopropyl acrylate (42b) (290 g, 2069 mmol) in methanol (2000 mL) cooled to 5°C was added cobalt (II) chloride hexahydrate (24.61 g, 103 mmol), followed by dropwise addition of a solution of sodium tetrahydroborate (157 g, 4138 mmol) in DMF (500 mL) at a rate such that the internal temperature did not exceed 10°C. The reaction mixture was stirred at 5°C for 1 hour, poured into water (5000 mL) and stirred for 15 minutes. The resulting black suspension was filtered through a pad of celite and washed with dichloromethane (3×800 mL). The aqueous layer was separated and extracted with dichloromethane (2×600 mL). The dichloromethane layers were combined, washed with water (2×1500 mL) and brine, dried over MgSO 4 , filtered and concentrated in vacuo at a bath temperature below 40° C. to give a colorless liquid ethyl 3-cyclopropylpropionate (42c) (260 g, 88% yield); 1 H NMR (300 MHz, DMSO-d 6 )δ4.03 (q, J=7.1Hz, 2H), 2.33 (t, J=7.3Hz, 2H), 1.41 (q, J=7.2Hz, 2H), 1.16 (t, J=7.1Hz, 3H), 0.75-0.59 (m, 1H), 0.40-0.31 (m, 2H), 0.06--0.06 (m, 2H).

[0658] Step 3: Preparation of 3-cyclopropyl-N-methoxy-N-methylpropionamide (42d)

[0659] To a solution of ethyl 3-cyclopropylpropionate (42c) (260 g, 1828 mmol) in THF (2000 mL) cooled to -10°C was added N,O-dimethylhydroxylamine hydrochloride (268 g, 2743 mmol), followed by dropwise addition of isopropylmagnesium chloride (2743 mL, 5485 mmol, 2M THF solution). The mixture was stirred at -10°C for 2 hours and washed with saturated NH 4The Cl solution was quenched and allowed to warm to room temperature. The THF layer was separated and the aqueous layer was extracted with EtOAc (2×1000 mL). The organic layers were combined, washed with brine, and purified by MgSO 4 Dry, filter and concentrate in vacuo to give an orange liquid 3-cyclopropyl-N-methoxy-N-methylpropionamide (42d) (240 g, 1527 mmol, 83% yield); 1 H NMR (300 MHz, DMSO-d 6 ) δ3.66 (s, 3H), 3.07 (s, 3H), 2.44 (t, J = 7.6Hz, 2H), 1.39 (q, J = 7.3Hz, 2H), 0.76-0.62 (m, 1H), 0.42-0.31 (m, 2H), 0.08--0.09 (m, 2H).

[0660] Step 4: Preparation of 1-(3-amino-4-fluorophenyl)-3-cyclopropylpropan-1-one (42e)

[0661] To a solution of 3-cyclopropyl-N-methoxy-N-methylpropanamide (42d) (240 g, 1527 mmol) in THF (2000 mL) cooled to 5°C was added freshly prepared (3-(bis(trimethylsilyl)amino)-4-fluorophenyl)magnesium bromide (1c) (1908 mL, 1527 mmol in 1M THF) dropwise, maintaining the internal temperature at about 5°C during the addition. The reaction product was stirred at 5°C for 2 hours, quenched with 3N HCl (1000 mL) and stirred for 2 hours. The mixture was washed with solid N a HCO 3 The reaction mixture was basified and extracted with ethyl acetate (2×500 mL). The combined organic layers were washed with brine and MgSO 4 Dry, filter and concentrate in vacuo to give a crude product 42e. The crude product was dissolved in isopropanol (150 mL) and stirred overnight. The solid was collected by filtration, washed with isopropanol and dried to give 1-(3-amino-4-fluorophenyl)-3-cyclopropylpropane-1-one (42e) (90 g, 28.46% of the first batch of products) as a white solid. The filtrate was concentrated and kept at room temperature for 6 hours, and the solid was collected by filtration to give 1-(3-amino-4-fluorophenyl)-3-cyclopropylpropane-1-one (42e) (50 g, 15.81%, the second pyridine product) as a white solid; 1 H NMR (300 MHz, DMSO-d 6)δ7.38 (dd, J=8.9, 2.2Hz, 1H), 7.18 (ddd, J=8.4, 4.7, 2.2Hz, 1H), 7.09 (dd, J=11.1, 8.4Hz, 1H), 5.41 (s, 2H), 2.98 (t, J=7.3Hz, 2H), 1.48(q, J=7.2Hz, 2H), 0.82-0.65(m, 1H), 0.41-0.33(m, 2H), 0.10--0.02(m, 2H); MS(ES+)208.2(M+1), (ES-)206.2(M-1); 19 F NMR (282 MHz, DMSO-d 6 )δ-128.24;

[0662] Step 5: Preparation of 1-(3-amino-4-fluorophenyl)-3-cyclopropylpropan-1-ol (42f)

[0663] To a solution of 1-(3-amino-4-fluorophenyl)-3-cyclopropylpropane-1-one (42e) (13.63 g, 65.8 mmol) in THF (150 mL) and methanol (300 mL) was added sodium borohydride (5.08 g, 132 mmol) at 0°C and stirred at 0°C for 1 hour. The reaction mixture was allowed to warm to room temperature overnight. The reaction mixture was diluted with ethyl acetate (800 mL), neutralized with acetic acid, washed with water (2×300 mL) and brine (300 mL), dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by flash column chromatography [silica gel, eluted with hexane / ethyl acetate (1:0 to 4:1)] to give 1-(3-amino-4-fluorophenyl)-3-cyclopropylpropane-1-ol (42f) (11.47 g, 53.8 mmol, 83% yield) as a white solid; 1 H NMR (300 MHz, DMSO-d 6 )δ6.86 (dd, J=11.5, 8.2Hz, 1H), 6.72 (dd, J=9.1, 2.1Hz, 1H), 6.42 (ddd, J=8.3, 4.5, 2.1Hz, 1H), 5.03 (s, 2H), 4.98 (d, J=4.1 Hz, 1H), 4.40-4.30 (m, 1H), 1.71-1.48 (m, 2H), 1.26-1.01 (m, 2H), 0.73-0.54 (m, 1H), 0.45-0.24 (m, 2H), 0.02--0.14 (m, 2H); 19 F NMR (282MHz, DMSO) δ-138.16; MS (ES+) 210.1 (M+1); (ES-) 208.1 (M-1).

[0664] Step 6: Preparation of tert-butyl (2R, 4R)-2-(5-(3-cyclopropyl-1-hydroxypropyl)-2-fluorophenylcarbamoyl)-4-methoxypyrrolidine-1-carboxylate (42 g)

[0665] Compound 42g was prepared using the reaction and process conditions reported in step 10 of scheme 1 from 1-(3-amino-4-fluorophenyl)-3-cyclopropylpropan-1-ol (42f) (700 mg, 3.35 mmol), (2R,4R)-1-(tert-butoxycarbonyl)-4-methoxypyrrolidine-2-carboxylic acid (36a) (820 mg, 3.35 mmol) and ethyl 2-ethoxy-1(2H)-quinolinecarboxylate (827 mg, 3.35 mmol) to give tert-butyl (2R,4R)-2-(5-(3-cyclopropyl-1-hydroxypropyl)-2-fluorophenylcarbamoyl)-4-methoxypyrrolidine-1-carboxylate (42g) (1.273 g, 2.92 mmol, 87% yield) as a colorless syrup; 1 H NMR (300 MHz, DMSO-d 6 )δ9.42 (2s, 1H, rotamer), 7.87 (dd, J=35.9, 7.7 Hz, 1H, rotamer), 7.17 (dd, J=10.8, 8.4 Hz, 1H), 7.06 (s, 1H), 5.19 (d, J=4.4 Hz, 1H), 4.49 (q, J=5.9 Hz, 1H), 4.29 (m, 1H), 3.99 (m, 1H), 3.59 (dd, J=11.0, 5.5 Hz, 1H ), 3.34-3.30 (m, 1H), 3.22 (2s,, 3H, rotamer), 2.45-2.25 (m, 1H), 2.19-1.89 (m, 1H), 1.77-1.51 (m, 2H), 1.36 (2s, 9H, rotamer), 1.26-1.05 (m, 2H), 0.74-0.53 (m, 1H), 0.46-0.22 (m, 2H), -0.011--0.098 (m, 2H); 19 F NMR (282 MHz, DMSO-d 6 )δ-128.81, -130.11 rotational isomers.

[0666] Step 7: Preparation of tert-butyl (2R,4R)-2-(5-(1-bromo-3-cyclopropylpropyl)-2-fluorophenylcarbamoyl)-4-methoxypyrrolidine-1-carboxylate (42h)

[0667] Bromine (70.8 μL, 1.374 mmol) was added to a solution of triphenylphosphine (451 mg, 1.718 mmol) in dichloromethane (15 mL) at 0° C. and stirred for 15 minutes. A premixed solution of (2R, 4R)-2-(5-(3-cyclopropyl-1-hydroxypropyl)-2-fluorophenylcarbamoyl)-4-methoxypyrrolidine-1-carboxylic acid tert-butyl ester (42 g) (300 mg, 0.687 mmol) and imidazole (117 mg, 1.718 mmol) in dichloromethane (15 mL) was added to the reaction product at 0° C. The reaction product was allowed to warm to room temperature over 1 hour and concentrated in vacuo. The resulting residue was purified by flash column chromatography (silica gel, eluted with ethyl acetate in hexanes, 20 to 30%) to give a light brown semisolid (2R,4R)-tert-butyl 2-(5-(1-bromo-3-cyclopropylpropyl)-2-fluorophenylcarbamoyl)-4-methoxypyrrolidine-1-carboxylate (42h) (279 mg, 0.559 mmol, 81% yield); 1 H NMR (300 MHz, DMSO-d 6 )δ9.56 (2s, 1H, rotamer), 8.05 (2m, 1H, rotamer), 7.37-7.04 (m, 2H), 5.30 (t, J=7.5 Hz, 1H), 4.32 (m, 1H), 4.07-3.90 (m, 1H), 3.59 (dd, J=11.1, 5.4 Hz, 1H), 3.43-3.28 (m, 1H), 3.23 (2s , 3H, rotamer), 2.62-2.23 (m, 2H), 2.20-1.89 (m, 1H), 1.37 (2s, 9H, rotamer), 1.30-1.02 (m, 3H), 0.79-0.63 (m, 1H), 0.48-0.29 (m, 2H), 0.03-0.049 (m, 2H). 19F NMR (282 MHz, DMSO-d 6 )δ-126.1 rotational isomer.

[0668] MS (ES+) 499.46, 501.47 (M+1), 521.45, 523.46 (M+Na), (ES-) 497.41, 499.37 (M-1).

[0669] Step 8: Preparation of tert-butyl (2R,4R)-2-(5-(3-cyclopropyl-1-(2-oxopyridin-1(2H)-yl)propyl)-2-fluorophenylcarbamoyl)-4-methoxypyrrolidine-1-carboxylate (42j)

[0670] To a stirred solution of pyridine-2-ol (42i) (252 mg, 2.65 mmol) in acetonitrile (25 mL) was added potassium carbonate (381 mg, 2.76 mmol), heated at reflux for 1 hour and cooled to room temperature. To the reaction mixture was added a solution of (2R, 4R)-tert-butyl 2-(5-(1-bromo-3-cyclopropylpropyl)-2-fluorophenylcarbamoyl)-4-methoxypyrrolidine-1-carboxylate (42h) (265 mg, 0.531 mmol) in acetonitrile (15 mL) and heated at reflux overnight. The reaction mixture was concentrated in vacuo and the residue was suspended in water (25 mL) and extracted with ethyl acetate (3×50 mL). The ethyl acetate layers were combined, washed with water (2×25 mL) and brine (25 mL), dried and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel 12 g, eluted with a mixture of ethyl acetate / methanol 9:1 in hexane, 0 to 60%) to give an off-white solid (2R,4R)-tert-butyl 2-(5-(3-cyclopropyl-1-(2-oxopyridin-1(2H)-yl)propyl)-2-fluorophenylcarbamoyl)-4-methoxypyrrolidine-1-carboxylate (42j) (120 mg, 0.234 mmol, 44.0% yield); 1 H NMR (300 MHz, DMSO-d 6 )δ9.55 (2s, 1H, rotamer), 7.79 (s, 1H, rotamer), 7.62 (s, 1H), 7.42-7.31 (m, 1H), 7.25 (dd, J=10.5, 8.6 Hz, 1H), 7.18 (bs, 1H), 6.39 (dd, J=9.2, 1.4 Hz, 1H), 6.23 (tt, J=6.7, 1.6 Hz, 1H), 6.06 (t, J=8.2 Hz, 1H), 4.27 (m, 1H), 3.97 (m, 1H), 3.58 (m, 1H), 3.45-3.23 (m, 1H), 3.21 (2s, 3H, rotamer), 2.61-2.23 (m, 1H), 2.23-2.08 (m, 2H), 2.00-1.83 (m, 1H), 1.34 (2s, 9H, rotamer), 1.17-0.96 (m, 2H), 0.79-0.61 (m, 1H), 0.48-0.28 (m, 2H), 0.10-0.10 (m, 2H); 19 F NMR (282 MHz, DMSO-d 6 )δ-126.20, -127.58 rotational isomers; MS (ES+) 514.6 (M+1), 536.6 (M+Na), (ES-) 512.5 (M-1), 548.6 (M+Cl).

[0671] Step 9: Preparation of (2R,4R)-N-(5-(3-cyclopropyl-1-(2-oxopyridin-1(2H)-yl)propyl)-2-fluorophenyl)-4-methoxypyrrolidine-2-carboxamide (42k)

[0672] Compound 42k was prepared from (2R,4R)-tert-butyl 2-(5-(3-cyclopropyl-1-(2-oxopyridin-1(2H)-yl)propyl)-2-fluorophenylcarbamoyl)-4-methoxypyrrolidine-1-carboxylate (42j) (110 mg, 0.214) according to the procedure reported in Scheme 4, Step 6, using 3N HCl in methanol (0.714 mL, 2.142 mmol) to afford (2R,4R)-N-(5-(3-cyclopropyl-1-(2-oxopyridin-1(2H)-yl)propyl)-2-fluorophenyl)-4-methoxypyrrolidine-2-carboxamide (42k) (96 mg, 0.213 mmol, 100% yield) hydrochloride as a light brown solid; 1 H NMR (300 MHz, DMSO-d 6 )δ10.46 (s, 1H), 10.08 (s, 1H), 8.79 (s, 1H), 7.89-7.56 (m, 2H), 7.50-7.11 (m, 2H), 6.40 (d, J=9.3Hz, 1H), 6.25 (d, J=7.2Hz, 1H), 6.07 (s, 1H), 4.49 (d, J=5.6Hz, 1H), 4.09 (s, 1H), 3.39 (s, 1H), 3.35-3.21 (m, 1H), 3.19 (2s, 3H 2 diastereomers), 2.64-2.51 (m, 1H), 2.31-2.15 (m, 4H), 1.25-0.93 (m, 2H), 0.79-0.61 (m, 1H), 0.49-0.28 (m, 2H), 0.07-0.10 (m, 2H); 19 F NMR (282 MHz, DMSO-d 6 )δ-124.71, -124.73 (diastereomers); MS (ES+) 414.5 (M+1), 436.5 (M+Na), (ES-) 4112.5 (M-1), 448.5 (M+Cl).

[0673] Step 10: Preparation of (2R,4R)-N1-(5-chloropyridin-2-yl)-N2-(5-(3-cyclopropyl-1-(2-oxopyridin-1(2H)-yl)propyl)-2-fluorophenyl)-4-methoxypyrrolidine-1,2-dicarboxamide (421)

[0674] According to the procedure reported in step 3 of scheme 13, a solution of (2R,4R)-N-(5-(3-cyclopropyl-1-(2-oxopyridin-1(2H)-yl)propyl)-2-fluorophenyl)-4-methoxypyrrolidine-2-carboxamide (42k) (96 mg, 0.213 mmol) in tetrahydrofuran (10 mL) was reacted with 5-chloropyridin-2-ylamino 5-nitropropane-2-ylcarboxamide using 1 N aqueous sodium bicarbonate (4.27 mL, 4.27 mmol) as a base. Phenyl formate (13b) (80 mg, 0.320 mmol) was reacted and purified by flash column chromatography to give a white solid (2R, 4R)-N1-(5-chloropyridin-2-yl)-N2-(5-(3-cyclopropyl-1-(2-oxopyridin-1(2H)-yl)propyl)-2-fluorophenyl)-4-methoxypyrrolidine-1,2-dicarboxamide (42i) (113 mg, 0.199 mmol, yield 93%); 1 H NMR (300 MHz, DMSO-d 6 )δ9.55 (s, 1H), 9.16 (s, 1H), 8.30 (dd, J=2.6, 0.7Hz, 1H), 7.90 (dd, J=9.1, 0.8Hz, 1H), 7.87-7.77 (m, 2H), 7.65 (d, J =6.9Hz, 1H), 7.35 (ddd, J=8.8, 6.5, 2.0Hz, 1H), 7.29-7.12 (m, 2H), 6.38 (dd, J=9.2, 1.3Hz, 1H), 6.22 (t, J=6.7Hz, 1H ), 6.05 (t, J = 8.0 Hz, 1H), 4.59 (dd, J = 9.2, 3.8 Hz, 1H), 4.08-3.97 (m, 1H), 3.82-3.60 (m, 2H), 3.22 (2s, , 3H, diastereomers), 2.42-2.32 (m, 1H), 2.29-2.04 (m, 3H), 1.18-0.93 (m, 2H), 0.78-0.62 (m, 1H), 0.44-0.29 (m, 2H), 0.04-0.11 (m, 2H); 19 F NMR (282 MHz, DMSO-d 6 )δ-126.35; MS(ES+)568.6, 570.6(M+1), 590.5, 592.5(M+Na), (ES-)566.5, 568.5(M-1); IR(KBr)3420, 3077, 2998, 2932, 1659, 1520cm -1 ; Analytical calculation value C 29 H 31 CIF 5 O 4 .0.5H 2O: C, 60.36; H, 5.59; N, 12.14; Found: C, 60.76; H, 5.66; N, 11.82.

[0675] Scheme 43

[0676]

[0677] Preparation of ((2R,4R)-N1-(5-chloropyridin-2-yl)-N2-(5-((+)-3-cyclopropyl-1-(2-oxopyridin-1(2H)-yl)propyl)-2-fluorophenyl)-4-methoxypyrrolidine-1,2-dicarboxamide (43m)

[0678] Step 1: Preparation of (S)(+)-N-(1-(3-amino-4-fluorophenyl)-3-cyclopropylpropylene)-2-methylpropane-2-sulfenamide (43a)

[0679] Compound (43a) was prepared using the procedure reported in Scheme 31, Step 3, from 1-(3-amino-4-fluorophenyl)-3-cyclopropylpropan-1-one (42e) (100.865 g, 487 mmol), (S)-2-methylpropane-2-sulfenamide (86 g, 681 mmol) and tetraisopropoxytitanium (287 mL, 973 mmol) to afford (S)(+)-N-(1-(3-amino-4-fluorophenyl)-3-cyclopropylpropan-1-one)-2-methylpropane-2-sulfenamide (43a) (64 g, 206 mmol, 42.4% yield) as a light brown solid; 1 H NMR (300 MHz, DMSO-d 6 )δ7.33 (d, J=8.9Hz, 1H), 7.07 (d, J=8.7Hz, 2H), 5.39 (s, 2H), 3.33-3.05 (m, 2H), 1.54 -1.37(m, 2H), 1.21(s, 9H), 0.85-0.63(m, 1H), 0.46-0.32(m, 2H), 0.15-0.02(m, 2H); 19 F NMR (282 MHz, DMSO-d 6 )δ-129.79; MS(ES+)311.4(M+1), 333.4(M+Na), (ES-)309.4(M-1), 345.3(M+Cl); Optical rotation [α] D =(+)20.0[0.18, MeOH].

[0680] Step 2: Preparation of (S)-N-(1-(3-amino-4-fluorophenyl)-3-cyclopropylpropyl)-2-methylpropane-2-sulfenamide (43b)

[0681] To a solution of (S)(+)-N-(1-(3-amino-4-fluorophenyl)-3-cyclopropylpropylene)-2-methylpropane-2-sulfenamide (43a) (64 g, 206 mmol) in tetrahydrofuran (1.5 L) cooled to -78°C was slowly added lithium triethylborohydride (618 mL, 618 mmol) over 2 hours, keeping the reaction temperature below -75°C. The reaction product was stirred at -78°C for 3 hours and allowed to warm to room temperature overnight. The reaction mixture was cooled to 0°C and washed with saturated NH 4 The mixture was quenched with aqueous Cl solution (600 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (2×1000 mL). The combined organic layers were washed with water (2×1000 mL) and brine (500 mL) and MgSO 4 Dry, filter and concentrate in vacuo to give (S)-N-(1-(3-amino-4-fluorophenyl)-3-cyclopropylpropyl)-2-methylpropane-2-sulfenamide (43b) (127 g, 203 mmol, 99% yield), which was used directly in the next step without purification; MS (ES+) 313.4 (M+1), 335.4 (M+Na), (ES-) 311.4 (M-1), 347.3 (M+Cl).

[0682] Step 3: Preparation of methyl 5-((+)-3-cyclopropyl-1-((S)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenylcarbamate (43c)

[0683] To a solution of (S)-N-(1-(3-amino-4-fluorophenyl)-3-cyclopropylpropyl)-2-methylpropane-2-sulfenamide (43b) (127 g, 203 mmol) in ethyl acetate (635 mL) and saturated NaHCO 3 To the biphasic solution of aqueous solution (635 mL) was added methyl chloroformate (23.61 mL, 305 mmol) and stirred vigorously at room temperature overnight. The layers were separated and the aqueous layer was extracted with ethyl acetate (2×1 L). The combined organic layers were washed with brine, dried, filtered, concentrated in vacuo and purified by chromatography to give methyl 5-((+)-3-cyclopropyl-1-((S)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenylcarbamate (43c) (75.344 g, 203 mmol, 100% yield) as a gummy solid; 1 H NMR (300 MHz, DMSO-d 6)δ9.29 (s, 1H), 7.56 (dd, J=7.9, 2.2Hz, 1H), 7.15 (dd, J=10.6, 8.4Hz, 1H), 7.05 (ddd, J=8.5, 4.8, 2.2Hz, 1H), 5.31 (d, J=4.8Hz, 1H), 4.28-4.09 (m, 1H), 3.65 (s , 3H), 2.06-1.88(m, 1H), 1.78-1.61(m, 1H), 1.25-1.11(m, 1H), 1.06(s, 9H), 1. 06-0.88(m, 1H), 0.74-0.55(m, 1H), 0.42-0.29(m, 2H), -0.01--0.09(m, 2H); 19F NMR (282MHz, DMSO-d 6 )δ-126.77; MS(ES+)371.5(M+1), 393.5(M+Na), (ES-)369.4(M-1), 405.4(M+Cl); Optical rotation [α] D =(+)74.4[0.18, MeOH].

[0684] Step 4: Preparation of (-)-methyl 5-(1-amino-3-cyclopropylpropyl)-2-fluorophenylcarbamate (43d)

[0685] To a solution of methyl 5-((+)-3-cyclopropyl-1-((S)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenylcarbamate (43c) (75 g, 202 mmol) in methanol (1000 mL) was added 3M HCl in methanol (337 mL, 1012 mmol), stirred for 30 minutes and concentrated to dryness in vacuo. The residue was dissolved in water (500 mL), basified with saturated sodium bicarbonate and extracted with ethyl acetate (3×1500 mL). The combined organic layers were washed with water (2×300 mL) and brine (500 mL), dried, filtered and concentrated in vacuo to give a thick syrup of (-)-methyl 5-(1-amino-3-cyclopropylpropyl)-2-fluorophenylcarbamate (43d) (63.5 g, 238 mmol, 118% yield); 1 H NMR (300 MHz, DMSO-d 6)δ9.26 (s, 1H), 7.55 (dd, J=8.0, 2.0Hz, 1H), 7.20-7.06 (m, 1H), 3.77 (t, J=6.8Hz, 1H), 3.65 (s, 3H), 3.50-3.14 (m, 2 H), 2.50-2.28(m, 1H), 1.60(m, 2H), 1.24-0.94(m, 2H), 0.72-0.53(m, 1H), 0.41-0.27(m, 2H), -0.02--0.11(m, 2H); 19 F NMR (282 MHz, DMSO-d 6 )δ-127.37; MS(ES+)267.4(M+1), (ES-)265.3(M-1); Optical rotation [α] D =(-)3.0[0.2, MeOH].

[0686] Step 5: Preparation of (+)-methyl 5-(3-cyclopropyl-1-(2,6-dioxopiperidin-1-yl)propyl)-2-fluorophenylcarbamate (43f)

[0687] To a solution of (-)-methyl 5-(1-amino-3-cyclopropylpropyl)-2-fluorophenylcarbamate (43d) (63 g, 237 mmol) in dichloromethane (1000 mL) was added dihydro-2H-pyran-2,6(3H)-dione (43e) (29.7 g, 260 mmol) at room temperature and stirred for 30 minutes. Acetyl chloride (336 mL, 4731 mmol) was added to the reaction product, heated under reflux for 2 hours, and concentrated to dryness in vacuo. The solid separated by crystallization from isopropanol (250 mL) (crude weight 100 g) was obtained as a white solid (+)-methyl 5-(3-cyclopropyl-1-(2,6-dioxopiperidin-1-yl)propyl)-2-fluorophenylcarbamate (43f) (51.5 g, 142 mmol, yield 60.1%); 1 H NMR (300 MHz, DMSO-d 6 )δ9.29 (s, 1H), 7.65-7.41 (m, 1H), 7.19-6.86 (m, 2H), 5.71 (dd, J=9.2, 6.5Hz, 1H), 3.65 (s, 3H), 2.61 (qd, J=7.6, 7.0, 3.2Hz, 4H), 2.42-2.11(m, 2H), 1.81(p, J=6.5Hz, 2H), 1.22-0.99(m, 2H), 0.76-0.56(m, 1H), 0.44-0.28(m, 2H), 0.11--0.12(m, 2H); 19 F NMR (282 MHz, DMSO-d 6)δ-126.82; MS (ES+) 363.5 (M+1), 385.5 (M+Na), (ES-) 361.5; Optical rotation [α] D =(+)101.9[0.21, MeOH].

[0688] Step 6: Preparation of methyl 5-(3-cyclopropyl-1-(2-hydroxy-6-oxopiperidin-1-yl)propyl)-2-fluorophenyl chloroformate (43 g)

[0689] To a solution of (+)-methyl 5-(3-cyclopropyl-1-(2,6-dioxopiperidin-1-yl)propyl)-2-fluorophenylcarbamate (43f) (51 g, 141 mmol) in dichloromethane (1407 mL) was added diisobutylaluminum hydride (422 mL, 422 mmol) at -78°C and stirred for 1 hour at -78°C. The reaction was quenched with methanol (30 mL) and saturated aqueous sodium potassium tartrate solution (1 L) and allowed to reach 0°C. The slurry was stirred for 2 hours, the layers were separated and the aqueous layer was extracted with dichloromethane (2×500 mL). The combined organic layers were washed with water (2×500 mL) and brine (200 mL), dried, filtered and concentrated in vacuo to give methyl 5-(3-cyclopropyl-1-(2-hydroxy-6-oxopiperidin-1-yl)propyl)-2-fluorophenylcarbamate (43 g) (51.3 g, 141 mmol, 100% yield), which was used in the next step without purification; MS (ES-) 363.5 (M-1).

[0690] Step 7: Preparation of (+)-methyl 5-(3-cyclopropyl-1-(2-oxo-3,4-dihydropyridin-1(2H)-yl)propyl)-2-fluorophenylcarbamate (43h)

[0691] To a stirred solution of methyl 5-(3-cyclopropyl-1-(2-hydroxy-6-oxopiperidin-1-yl)propyl)-2-fluorophenylcarbamate (43 g) (52 g, 143 mmol) in dichloromethane (1586 mL) was added triethylamine (119 mL, 856 mmol), cooled to 0°C and added methanesulfonyl chloride (22.24 mL, 285 mmol). The reaction product was stirred at room temperature overnight, diluted with dichloromethane (100 mL) and water (500 mL). The layers were separated and the aqueous layer was extracted with dichloromethane (2×500 mL). The organic layers were combined, washed with water (2×250 mL) and brine (250 mL), dried, filtered and concentrated in vacuo. The crude residue was purified by flash column chromatography (silica gel, eluting with ethyl acetate in hexanes, 0 to 100%) to give (+)-methyl 5-(3-cyclopropyl-1-(2-oxo-3,4-dihydropyridin-1(2H)-yl)propyl)-2-fluorophenylcarbamate (43h) (51.6 g, 149 mmol, 104% yield) as a colorless syrup; 1 H NMR (300 MHz, DMSO-d 6 )δ9.35 (s, 1H), 7.66-7.50 (m, 1H), 7.18 (dd, J=10.7, 8.5Hz, 1H), 7.06 (m, 1H), 6.15 (dt, J=7.9, 1.6Hz, 1H), 5.64 (dd, J=9.8, 6.3Hz, 1H), 5.17 (dt, J=8.2, 4.4Hz, 1H), 3 .66(s, 4H, Me, NH), 2.50-2.36(m, 2H), 2.26-2.14(m, 1H), 2.06-1.87(m, 1H), 1.43( m,1H),1.28-0.99(m,2H),0.72(m,1H),0.44-0.30(m,2H),0.11--0.13(m,2H); 19F NMR (282MHz, DMSO-d 6 )δ-126.08; MS (ES+) 369.5 (M+Na), (ES-) 345.4 (M-1); optical rotation [α] D =(+)123.9[0.255, MeOH].

[0692] Step 8: Preparation of (+)-methyl 5-(3-cyclopropyl-1-(2-oxopyridin-1(2H)-yl)propyl)-2-fluorophenylcarbamate (43i)

[0693] To a stirred solution of (+)-methyl 5-(3-cyclopropyl-1-(2-oxo-3,4-dihydropyridin-1(2H)-yl)propyl)-2-fluorophenylcarbamate (43h) (5.95 g, 17.18 mmol) in dichloromethane (200 mL) was added manganese dioxide (7.47 g, 86 mmol) and heated at reflux for 10 hours. Additional manganese dioxide (7.47 g, 86 mmol) was added in seven portions over 72 hours. The reaction mixture was filtered, washed with dichloromethane and concentrated in vacuo. The resulting crude residue was purified by flash column chromatography (silica gel, eluted with ethyl acetate in hexanes, 0 to 100%) to give (+)-methyl 5-(3-cyclopropyl-1-(2-oxopyridin-1(2H)-yl)propyl)-2-fluorophenylcarbamate (43i) (2.962 g, 8.60 mmol, 50.1% yield) as a light black oil; 1 H NMR (300 MHz, DMSO-d 6 )δ9.40 (s, 1H), 7.75-7.59 (m, 2H), 7.38 (ddd, J=8.8, 6.5, 2.0Hz, 1H), 7.28-7.14 (m, 2H), 6.45-6.37 (m, 1H), 6.25 (td, J=6.7, 1.5Hz, 1H), 6.08 (t, J=8.1Hz, 1H), 3.67 (s, 3H), 2.22 (q, J=7.7Hz, 2H), 1.28-0.93 (m, 2H), 0.84-0.62 (m, 1H), 0.47-0.31 (m, 2H), 0.11--0.13 (m, 2H); 19 F NMR (282 MHz, DMSO-d 6 )δ-125.29; MS(ES+)345.4(M+1), 367.4(M+Na), (ES-)343.4(M-1), 379.3(M+Cl); Optical rotation [α] D =(+)240.0[0.05, MeOH].

[0694] Step 9: Preparation of (+)-1-(1-(3-amino-4-fluorophenyl)-3-cyclopropylpropyl)pyridin-2(1H)-one (43j)

[0695] To a solution of (+)-methyl 5-(3-cyclopropyl-1-(2-oxopyridin-1(2H)-yl)propyl)-2-fluorophenylcarbamate (43i) (2.9 g, 8.42 mmol) in methanol (75 mL) was added aqueous sodium hydroxide solution (14.03 mL, 84 mmol, 6N), heated to reflux for 10 hours and concentrated in vacuo. The residue was diluted with water (200 mL) and extracted with ethyl acetate (3×200 mL). The organic layers were combined, washed with water (2×100 mL) and brine (100 mL), dried, filtered and concentrated in vacuo. The crude residue was purified by flash column chromatography (silica gel, eluted with ethyl acetate in hexanes, 0 to 60 to 100%) to give (+)-1-(1-(3-amino-4-fluorophenyl)-3-cyclopropylpropyl)pyridin-2(1H)-one (43j) (2.173 g, 7.59 mmol, 90% yield) as a syrup; 1 HNMR (300 MHz, DMSO-d 6 )δ7.58 (dd, J=6.9, 2.0Hz, 1H), 7.35 (ddd, J=8.8, 6.5, 2.0Hz, 1H), 6.94 (dd, J=11.5, 8.3Hz , 1H), 6.75 (dd, J=8.7, 2.3Hz, 1H), 6.53 (ddd, J=8.4, 4.3, 2.3Hz, 1H), 6.39 (dd, J=9.1, 1.3H z, 1H), 6.21 (td, J=6.7, 1.5Hz, 1H), 5.99 (dd, J=9.1, 7.0Hz, 1H), 5.19 (s, 2H), 2.23-2.03 (m , 2H), 1.11(m, 1H), 0.99(m, 1H), 0.79-0.62(m, 1H), 0.46-0.28(m, 2H), 0.08--0.12(m, 2H); 19 F NMR (282 MHz, DMSO-d 6 )δ-136.31; MS(ES+)287.4(M+1), 309.4(M+Na), 573.7(2M+1), 595.7(2M+Na), (ES-)285.3(M-1), 321.3(M+Cl); Optical rotation [α] D =(+)296.25[0.16, MeOH].

[0696] Step 10: Preparation of tert-butyl (2R,4R)-2-(5-((+)-3-cyclopropyl-1-(2-oxopyridin-1(2H)-yl)propyl)-2-fluorophenylcarbamoyl)-4-methoxypyrrolidine-1-carboxylate (43k)

[0697] A solution of (2R,4R)-1-(tert-butoxycarbonyl)-4-methoxypyrrolidine-2-carboxylic acid (36a) (158 mg, 0.513 mmol) and (+)-1-(1-(3-amino-4-fluorophenyl)-3-cyclopropylpropyl)pyridin-2(1H)-one (43j) (286 mg, 1.0 mmol) in tetrahydrofuran (20 mL) was reacted with 2-ethoxy-1(2H)-quinolinecarboxylic acid using the reaction and workup conditions reported in step 10 of scheme 1. The ethyl ester (247 mg, 1.0 mmol) was reacted and purified by flash column chromatography (silica gel 25 g, eluted with ethyl acetate in hexane, 0 to 100%) to give a white solid (2R, 4R)-2-(5-((+)-3-cyclopropyl-1-(2-oxopyridin-1(2H)-yl)propyl)-2-fluorophenylcarbamoyl)-4-methoxypyrrolidine-1-carboxylic acid tert-butyl ester (43k) (462 mg, 0.900 mmol, yield 90%); 1 H NMR (300 MHz, DMSO-d 6 )δ9.51 (2s, 1H, rotamer), 7.87 (m, 1H), 7.71-7.56 (m, 1H), 7.36 (ddd, J=8.8, 6.5, 2.0 Hz, 1H), 7.25 (dd, J=10.5, 8.5 Hz, 1H), 7.17 (d, J=8.1 Hz, 1H), 6.39 (dd, J=9.1, 1.4 Hz, 1H), 6.23 (td, J=6.7, 1.4 Hz, 1H), 6.07 (t, J=8.0 Hz, 1H), 4.42-4.21 ( m, 1H), 4.00-3.92 (m, 1H), 3.59 (dd, J=11.1, 5.5 Hz, 1H), 3.35-3.26 (m, 1H), 3.21 (2s, 3H, rotamer), 2.51-2.28 (m, 1H), 2.20 (m, 2H), 2.11-1.85 (m, 1H), 1.34 (2s, 9H, rotamer), 1.26-0.93 (m, 2H), 0.72 (m, 1H), 0.37 (m, 2H), 0.10-0.10 (m, 2H); 19 FNMR (282 MHz, DMSO-d 6 )δ-125.99, -127.39; MS(ES+)514.6(M+1), 536.6(M+Na), (ES-)512.6(M-1)...

Claims

1. A compound represented by formula (I) or a pharmaceutically acceptable salt thereof: in, Independently on each occurrence: R 1 Indicates -OH, -OR c , (C1-C6) alkyl, (C6-C 10 )aryl, halo, halo(C1-C6)alkyl, or (C3-C7)cycloalkyl; W is -C(O)NH-; R 2 represents (C6-C 10 ) aryl or heteroaryl; V represents (C6-C 10 ) aryl; Z is absent or represents a halogen group; X represents -C(NH2)-, -C(NH(R c ))-、-C(NHS(O) p R c )-、-C(NHC(O)R c )-、-C(NHC(O)NHR c )-, or -C(((C3-C7)cycloalkyl)(C1-C6)alkyl); R 3 represents (C6-C 10 )aryl or heteroaryl, wherein the substituent is selected from the group consisting of halogen, (C1-C6)alkyl, (C1-C6)alkoxy, -NH2, nitro, fluoro(C1-C6)alkyl and cyano; R 3a is absent or represents one or more substituents independently selected from the group consisting of: (C1-C6)alkyl and cyano; Y represents a chemical bond; or -YR 4 represents -(C1-C6)alkylene-R 4 or -NH-R 4 ; R 4 represents hydrogen or (C3-C7)cycloalkyl; R c Each occurrence independently represents (C1-C6)alkyl or ((C3-C7)cycloalkyl)(C1-C6)alkyl; n is an integer from 0 to 3; and p is 1 or 2; Further among them: "Heteroaryl" is a monocyclic aromatic group having from 3 to 12 total ring atoms including one heteroatom selected from N and S.

2. The compound according to claim 1, wherein R 1 Indicates -OH, -OR c , (C1-C6) alkyl, (C6-C 10 )aryl, halogenated (C1-C6)alkyl or (C3-C7)cycloalkyl; X represents -C(NH2)-, -C(NH(R c ))-、-C(NHS(O) p R c )-or-C(NHC(O)R c )-;-YR 4 represents -(C1-C6)alkylene-R 4 ;as well as R 4 It represents a (C3-C7) cycloalkyl group.

3. The compound according to claim 1, wherein R 1 represents -OH, -O((C1-C6)alkyl), (C1-C6)alkyl, halogenated (C1-C6)alkyl, (C3-C7)cycloalkyl or (C6-C 10 )aryl.

4. The compound according to claim 3, wherein n is 1; and R 1 It represents -OH, -CH3, -OCH2CH2CH3, -OCH2CH3 or -OCH3.

5. The compound according to claim 3, wherein n is 2; and two occurrences of R 1 connected to the same carbon atom.

6. The compound according to claim 5, wherein R 1 It represents -OH, -OCH3, -CH3, -CF3, cyclopropyl or phenyl.

7. The compound according to claim 5, wherein: (a) An occurrence of R 1 represents -OH or -O((C1-C6)alkyl); and another occurrence of R 1 Indicates (C6-C 10 )aryl or (C3-C7)cycloalkyl; (b) An occurrence of R 1 represents -OH or -O((C1-C6)alkyl); and another occurrence of R 1 represents (C1-C6)alkyl or halogenated (C1-C6)alkyl; or (c) Two occurrences of R 1 They are all halogen groups.

8. The compound according to claim 5, wherein: (a) An occurrence of R 1 represents -OH or -OCH3; and another occurrence of R 1 represents phenyl or cyclopropyl; or (b) An occurrence of R 1 represents -OH or -OCH3; and another occurrence of R 1 It represents -CH2CH3 or -CF3.

9. The compound according to claim 1, wherein R 2 It represents a (C1-C6)aryl or heteroaryl group substituted by -CN.

10. The compound according to claim 1, wherein R 2 Indicates halogenated (C6-C 10 ) aryl or halogenated heteroaryl.

11. The compound according to claim 10, wherein R 2 represents phenyl, pyridyl or thienyl substituted by one occurrence of halo.

12. The compound according to claim 1, wherein Z represents a halogen group.

13. The compound according to claim 1, wherein X represents -C(NH2)-, -C(NH(R c ))-、-C(NHS(O) p R c )-or-C(NHC(O)R c )-.

14. The compound according to claim 13, wherein X represents -C(NH2)-; -C(NH(C1-C6)alkyl)-; -C(NHS(O) p (C1-C6)alkyl)-; or -C(NHC(O)((C1-C6)alkyl))-.

15. The compound according to claim 1, wherein R 3 represents (C6-C 10 )aryl or heteroaryl, the substituents being independently selected from the group consisting of cyano, halogen, -NO2, (C1-C6)alkyl and fluorinated (C1-C6)alkyl.

16. The compound according to claim 15, wherein R 3 represents phenyl or pyridyl optionally substituted by one or more substituents selected from the group consisting of -CN, halogen, -NO2, (C1-C6)alkyl and fluorinated (C1-C6)alkyl.

17. The compound according to claim 1, wherein R 3a It is absent or represents cyano or (C1-C6)alkyl.

18. The compound according to claim 1, wherein R 4 It represents a (C3-C7) cycloalkyl group.

19. The compound according to claim 1, wherein: R 1 represents -OH, -CH3, -OCH3, -OCH2CH3, -OCH2CH2CH3, -F, -CF3, phenyl or cyclopropyl; R 2 represents a phenyl group substituted by a halo group or a cyano group or a pyridyl group substituted by a chloro group; R 3 represents phenyl or pyridyl optionally substituted by one or more substituents selected from the group consisting of halogen, (C1-C6)alkyl, (C1-C6)alkoxy, -NH2, nitro, fluoro(C1-C6)alkyl and cyano; R 3a Absent or representing one or more substituents independently selected from the group consisting of: cyano or -CH3; V represents a phenyl group optionally substituted by a halogen group; Y 4 represents –CH2CH2-cyclopropyl; X represents -C(NH2)-, -C(NH(R c ))-、-C(NHS(O) p R c )-or-C(NHC(O)R c ; Z represents a halogen group; and R c It represents a (C1-C6) alkyl group.

20. The compound of claim 19, wherein Z is F or Z is absent.

21. The compound of claim 19, wherein n is 1; and R 1 It represents -OCH3 or -OCH2CH3.

22. The compound of claim 19, wherein n is 2; and two occurrences of R 1 connected to the same carbon atom.

23. The compound according to claim 22, wherein each R 1 independently represents -OH, -OCH3, -CF3 or phenyl.

24. A pharmaceutical composition comprising a compound according to any one of claims 1-23; and a pharmaceutically acceptable carrier.

25. The pharmaceutical composition of claim 24, wherein the pharmaceutical composition is formulated for parenteral administration.

26. The pharmaceutical composition of claim 24, wherein the pharmaceutical composition is formulated for oral administration.

27. Use of a compound according to any one of claims 1 to 23, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for treating or preventing a disease or condition characterized by undesirable plasma kallikrein activity.

28. Use of a compound according to any one of claims 1 to 23, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for treating angioedema, wherein the angioedema is characterized by undesirable plasma kallikrein activity.

29. The use according to claim 28, wherein the angioedema is hereditary angioedema.

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